#Oncology and Medicine (OAJOM)

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Lupine Publishers | Immunotherapy in lung cancer in times of the COVID-19 pandemic

Lupine Publishers | Open Access Journal of Oncology and Medicine (OAJOM)

Abstract

The current pandemic due to COVID-19 has become a dilemma in decision-making in clinical oncology. On the one hand, the mortality associated with this viral infection is significantly higher in patients with cancer, especially in lung cancer. On the other hand, it is well-known that immunotherapy (PD-1 blockade) improves survival in advanced lung cancer. In the present view point, we aim to clarify the procedure to follow in the context of this pandemic. We conclude that immunotherapy does not increase the risk of serious events produced by COVID-19 in patients with lung cancer. Then, immunotherapy should not be delayed or stopped in patients with lung cancer in times of viral pandemic.

Keywords: Immunotherapy; PD-1 Blockade; Pandemic; COVID-19; Lung Cancer

Introduction

In the context of the current COVID-19 pandemic, a significant part of the medical community has taken the decision to postpone or suspend oncology therapies with clinical benefit. Here, clinical benefit should be understood as therapies which improve the quality of life and survival in cancer patients. For instance, in a prospective study in patients with lung cancer but negative COVID-19 (n = 211), the corresponding palliative therapy was delayed (interrupted) in the 39.7% (3%) of cases [1]. At the beginning of the pandemic, we may understand this kind of decision due to the insufficient knowledge about the virus behavior in cancer patients. Today, almost one year after the onset of the viral infection, knowledge about this issue has drastically increased.

The Dilemma is the Following

a) The COVID-19 infection significantly increases mortality in cancer patients. Especially in cases of lung cancer. A systemic review (n = 52 studies with 18,650 cases) reveals that patients with cancer and COVID-19 infection have a higher mortality than the COVID-19 infected population without cancer (mortality of 25.6%). Cancer is an independent risk factor for mortality (especially hematologic malignancies and lung cancer). Other risk factors are age, the male gender, the black race, current smoking habit, and comorbidities [2]. b) The immunotherapy (PD-1 blockade) significantly improves survival in advanced lung cancer patients [3, 4]. Taking into account the clinical benefit of PD-1 blockade and the COVID-19 scenario, the question to be faced is the following: Should immunotherapy be postponed or stopped in patients with advanced lung cancer? The answer to this question is of utmost importance because it allows us to make a decision in routine oncological practice. This decision will have a direct impact on the morbidity and mortality of this type of patients. The article “Impact of PD-1 Blockade on Severity of COVID-19 in Patients with Lung Cancers” concludes that in patients with lung cancer and positive COVID-19 (through RT-PCR in nose or throat smears), the use of PD-1 blockade, before the diagnosis of viral infection, does not increase the risk of severe events produced by COVID-19. There was also no significant difference in serious events produced by COVID-19 in patients with lung cancer in relation to those with recent or past exposure to immunotherapy [5].

The Limitations of the Article are the Following

a) Retrospective study b) Single-center study c) Small sample size (n = 69 cases) d) The short follow-up from diagnosis of COVID-19 (14 days).

The Strengths of the Article are

a) The study was approved by an ethics committee b) The primary question of the study was defined (the impact of PD-1 blockade on severity of COVID-19 in patients with lung cancer) c) Diagnosis of COVID-19 infection by laboratory test considered the gold standard d) Exclusion of suspected but unconfirmed cases e) Suitable definition of what is a serious event by COVID-19 f) Appropriate methodological design g) Risk factor adjustment for severe event produced by COVID-19 in lung cancer (smoking status and gender) h) Various data sources were used i) The data record was exhaustive j) Expert human resource in data collection was used k) An independent reviewer was used to give more reliability to the data collection l) Correct statistical analysis m) Updated and relevant bibliographic support n) The primary question of the study was answered According to our analysis, the strengths of this study are greater than its limitations. Therefore, the conclusion of the article is valid. However, a valid conclusion is not necessarily sufficient for decision making.

We Consider that the Mentioned Conclusion is not Sufficient Mainly Because

a) The analyzed article does not have enough statistical weight (the sample size is limited, n = 69) b) And the study is a retrospective one

As a Result, we Should Complement the Discussion

The article “COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study” is a prospective observational study (n = 800 cases), which considers cancer patients who test positive for COVID-19. After adjusting for other risk factors, there was no significant increase in mortality between the group that received immunotherapy within 4 weeks of the diagnosis of COVID-19 versus the group that did not receive this treatment [6]. Thus, based on the best available evidence, we conclude that the immunotherapy (PD-1 blockade) in lung cancer should not be postponed or suspended because it does not increase critical events due to the COVID-19 viral infection. Postponing or suspending immunotherapy would increase morbidity and mortality from lung cancer. However, it should not be forgotten that we must strictly maintain the safeguard measures to reduce the risk of contagion.

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Lupine Publishers | Receptor Status Accuracy in Breast Cancer: Core Biopsy or Excision? A Mini Review

Lupine Publishers | Open Access Journal of Oncology and Medicine (OAJOM)

Abstract

Aim

With the advent of minimally invasive surgical techniques core needle biopsy (CNB) has emerged as an accurate method of obtaining representative tissue providing both prognostic and diagnostic valuable information the management of breast cancer. This review aims to compare the precision and limitations in the reporting of CNB and excisional biopsies. (EB)

Materials and Methods: All patients diagnosed with breast cancer were reviewed. Review of the histological data was the essence of this study. Only patients whose receptors were tested in both core and excisions were included. The hormonal status of estrogen receptors (ER), progesterone receptors (PgR) and Her2 were evaluated immunohistochemically. Equivocal HER2 status was reassessed using Fluorescence in situ hybridization (FISH) test.

Results: The total number of patients diagnosed with breast cancer was 112. In 36 (32.1%) patients complete synchronized immunohistological testing for both CNB and EB was executed and compared. The concordance rate observed in was as follows:ER was matched in 27 (75%), PgR in 22 (61.1%) Her2 in 34(94%).The calculated concordance rate was 86%, 80%, 94% for ER PgR and Her2 respectively.

Conclusion: CNB has proven a valuable and an adequate minimally invasive method for obtaining an accurate representative tissue. The reliability in obtaining HER2 status can be precisely determined however, ER and PgR should be interpreted with caution.

Keywords: Core Needle Biopsy; Excision Biopsy; Concordance; Breast Cancer

Introduction

With the increased prevalence of breast cancer internationally, efficient, cost effective and reliable diagnostic methods are continuously sought. In the emerging era of minimally invasive procedures, coupled by the concordance of both excisional biopsies (EB) with core needle biopsies (CNB), the surgical practice has witnessed a decline in diagnostic surgical excisions [1]. Because of the increased incidence of detected Ductal Carcinoma in Situ (DCIS), fine needle aspiration cytology has become less reliable in obtaining adequate diagnostic samples. On the other hand, the currently widely used CNB in breast lesions has gained popularity over recent years due to the high accuracy in tissue diagnosis obtained from adequate diagnostic samples. Clinicians base their management strategy on the histological diagnosis and hormonal receptors (HR) status in [2]. Chemotherapy treatment, in particular relies on CNB and accurate reporting of HR results [3]. Several studies have demonstrated high concordance rate between CNB and EB in terms of HR status. [2-6] Yet, re-biopsy is strongly indicated in metastatic breast cancer, which may show high discordance between primary and metastatic disease [7].

Materials and Methods

All patients diagnosed with breast cancer between 2016-2017 were reviewed. The review of the histological data was the essence of this study. Both core needle biopsies (CNB) and excisional biopsies (EB) were reviewed. Inclusion criteria included all female patients diagnosed with breast cancer who underwent both diagnostic CNB and EB whose histochemical status was tested in both specimens. The hormonal status of estrogen receptors (ER), progesterone receptors (PgR) and Her2 were evaluated immunohistochemically. Equivocal HER2 status was reassessed using Fluorescence in situ hybridization (FISH) test.

Specimen Handling: The samples were examined by hematoxylin and eosin using 4-microns- thick tissue sections processed from a representative part of the tumor. The tissue was fixed for at least 10 hours in neutral buffered formalin (10% BV). For the ER, PgR and HER2 immunostaining, specimens were immersed in 10% neutral buffered formalin within 1 hour of the biopsy or resection procedure and fixed for 6-72 hours. Her2, ER, PgR assay validation was performed using initial test validation included 20 positive and 20 negative cases (FDA-approved Ventana tests). Validation performed by comparing our laboratory’s results with a specialist hospital assay that has been appropriately validated. Concordance levels were 95%. Equivocal cases were not included in Her2 validation.

Reporting and Interpretation Of ER, PgR, HER2 Was Based According To ASCO/CAP Guidelines

ER and PgR reporting follow that positive test means staining of equal or greater than 1.0 % of tumor cells, whereas a negative test result means staining of less than 1.0 % of tumor cells. Staining is reported as indeterminate if there are problems in sample handling and processing. Scoring was based on the percentage of tumor cells with nuclear staining and staining intensity (weak, moderate or strong); (e.g. ER: 90% strong, PgR: 50% weak). As for HER2 immunostaining, positive result is defined as either a (3+) result by immunohistochemistry or a positive Fluorescence In Situ Hybridization (FISH) analysis result. HER-2 scoring criteria: Her-2 Protein Scoring System: Score 0 (Negative): No staining or faint membrane staining of less than 10% of tumor cells. Score 1+ (Negative): Weak incomplete membrane staining in more than 10% of tumor cells. Score 2+ (Weak Positive): Weak/moderate (thin) complete membrane staining in more than 10% of tumor cells. Score 3+ (Strong Positive): Strong (thick) complete membrane staining in more than 10% of tumor cells. Cases reported as equivocal (2+) were tested by FISH. Statistical Analysis was performed using Kappa values.

Results

112 patients were selected for this study. Seventy-six (67.8%) patients were excluded due to non-fulfillment of the inclusion criteria. 36 (32.1%) of both CNB and EB underwent HR analysis in both specimens, and 34 (30.3%) underwent Her2 testing in CNB and EB.

Types of breast cancer encountered were invasive ductal carcinoma, 67 cases (93%), invasive lobular carcinoma, 2 cases (2.7%), mucinous carcinoma, 1 case (1.3%), mammary carcinoma with mucinous features, 1 case (1.3%), and solid papillary carcinoma, 1 case (1.3%). The diagnosis was initially reported by group of certified pathologists; however, these results were reviewed by a single pathologist for the purpose of this study. ER was positive in 27 (75%). Thirty-one cases (86%) were concordant, while five cases (13.8%) were discordant. Kappa value was 0.67 (Table 1). As for PgR, 22 (61.1%) cases were positive in the CNB. Twenty-nine (80%) were concordant with the EB, while 7 (20%) were discordant. Kappa value was 0.62 (Table 2). HER2 scores were concordant in 32 (94%) cases. Nine (26.5%) were positive, while 27 (79.4%) were reported as negative. Discordance was reported in 2 (6%). Kappa value is 0.84 (Table 3). Twenty-nine patients received neoadjuvant chemotherapy prior to EB. Three of them had discordant ER results; one patient had both discordant ER and PgR results, and 1 with discordant HER2 result. Thus, the inter-rater agreement between the CNB and EB is 0.67 for ER, 0.62 for PgR and 0.84 for HER2.

Discussion

Breast cancer continues to be ranked first among females worldwide, the fast leap of expansion in many developing countries have imposed changes in lifestyle has resulted in many alterations in disease pattern increasing the prevalence of breast cancer [1]. To be able to establish the histological diagnosis that impacts on treatment outcomes, adequate tissue biopsy is mandatory. Excisional biopsy certainly provides larger tissue samples which allow the pathologist to work with ease in reaching a diagnosis, however, it may necessitate general anesthesia, open surgical procedure and delayed further management. Furthermore, a second procedure may lead to architectural distortion of the surgical field leading to a higher incidence of incomplete excisions. The growing demand for prognostic information in determining the receptor status preoperatively is considered a corner stone in modern multidisciplinary treatment. Given the available numerous improved types of with the efficiency, cost effectivity and the adequate tissue yield, promotes the diagnostic accuracy on HR status assessment [2-6]. The importance of assessing the HR status is well demonstrated in evaluating molecular subtypes, ER, PgR, and HER2 status in breast cancer. Estrogen receptor remains a powerful predictive factor for response to endocrine treatment and long-term outcome. Similarly, HER2 overexpression has been associated with worse prognosis in patients with newly diagnosed breast carcinoma [8]. In some cases where the inherent Ki67 heterogeneity in ER+/HER2- diagnosed breast tumors, distinguishing the molecular subtypes maybe difficult in the CNB specimens. In such cases, reliability on excisional biopsy is recommended [9]. The receptor status is significantly associated with treatment and monitoring in advanced disease.[10] The liberal use of chemotherapy as neoadjuvant treatment by many oncologists was reported to change the tumor profile and baseline receptor status [11]. Imaging guided biopsy has also proven its reliability with acceptable concordance of the receptor status between surgery and ultrasound-guided CNB [12]. In this review, ER concordance rate in our study was 86%. Four patients were found to be positive in CNB and negative in the subsequent excisional only one was patient found to be positive on excision, while there was no reactivity in CNB. Similarly, PgR concordance rate was 80%. The discordance was only in 7 patients who were initially reported as positive in CNB and were negative in EB although the concordance rate of ER and PgR is within the acceptable range, it may falsely miss a significant number of patients. [2-6] For this reason, it is recommended to reevaluate the HR status in surgically excised specimens. This discrepancy can partly be explained by the known effect of neoadjuvant chemotherapy as shown in 5 of our patients. We believe it is due to tumor heterogeneity, which has aslo been documented by other authors. It was also noted that Her2 results demonstrated more significant concordance rate of 94% this is probably due to the more robust criteria for identifying HER2 immunostaining in addition to the role of FISH in equivocal cases.

Conclusion

The accuracy of the status in is of paramount importance for both prognosis and treatment. Caution in result interpretation by experienced pathologists may impose significant accuracy and eliminate the false positive results.

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Lupine Publishers|Case Report of Multiple Myeloma Presenting with Unique Skin Manifestation with Literature Review

Abstract

Multiple myeloma (MM), although a rare disease, is the second most common hematologic malignancy. MM is associated with significant morbidity due to its end-organ destruction. It is a disease of the older population and advancements in the diagnosis, monitoring, and treatment of MM are of the utmost importance as the general population lives longer due to other improvements in health care. Herein, we present an interesting case of MM presenting with initially skin manifestation which unfortunately is associated with a poor prognosis due to a relationship indicating higher tumor burden. Despite being on multiple treatment, our patient continued to progress with her disease.

Introduction

Multiple myeloma (MM) accounts for approximately 2% of all malignancies and 13% of hematological malignancies worldwide [1]. MM is the second most common hematologic malignancy [1] and it is a neoplasm of clonal plasma cells which originate from the B-cell lineage and develop after lineage commitment in the bone marrow of progenitor cells [9]. Cutaneous involvement in patients with multiple myeloma is rare and it usually represents of a poor prognosis. Cutaneous involvement indicates an increased tumor burden. The most common cause of cutaneous involvement is due to direct extension from underlying bone lesions of MM or solitary plasmacytoma of bone [2]. It is very rare to have primary cutaneous plasmacytoma [3].

Case Presentation

We present the case of a friendly Caucasian American 70-yearold female with no significant PMH who initially presented to Ruby Memorial Emergency Department in November 2015 with persistent back and left side pain. At that time, she began to notice weakness and some numbness in lower extremities and along with the increasing low back pain decided to seek medical attention and presented to the hospital. On admission, CT thoracic spine (11/16/15) revealed a T5 wedge compression deformity. CT lumbar spine revealed degenerative changes with diffuse osteoporosis. MRI thoracic spine (11/17/15) revealed a T5 burst fracture with retropulsion, focal kyphotic deformity, severe central canal stenosis, possible pathologic fracture deformity, And possible cord contusion at T5. CBC on admission revealed WBC 5.1 with normal differential, Hgb 11.5 with MCV 105.3 and platelet count 170,000. BMP normal, creatinine 0.75, corrected calcium 10.2. Subsequently, she underwent a posterior spinal fusion T3-T8, left costotransversectomy with left pedulectomy and subtotal corpectomy (excision of tumor) via transpedicular approach with placement of anterior cage, T5 laminectomy, and T6-7 partial laminectomy. Pathology revealed a tumor composed of sheets of atypical plasmacytoid cells positive with immunostain for CD138 and negative for pancytokeratin, CD20, and CD3. Insufficient tissue remained for kappa and lambda ISH. The finding was consistent with plasma cell neoplasm. SPEP revealed an M spike seen in the gamma, consistent with monoclonal gammopathy. Random UPEP/ IFE revealed a monoclonal lambda protein without detectable associated IgG, IgA or IgM heavy chain. In December, SPEP/IFE revealed an IgG Lambda monoclonal protein (5.95 g/dL). Free light chain ratio 0.013 (Kappa 0.80 mg/dL, Lambda 60.50 mg/dL). Quantitative IgG 5950 g/dL. Hgb 9.4 with MCV 98.5. Creatinine 0.62. Corrected serum calcium 11.2. Albumin 2.0. Beta 2 microglobulin 4.25. Skeletal survey reveals diffuse osteolytic process with multiple calvarial, vertebral body and rib lesions identified. T3-T8 posterior spinal fusion for pathological T5 compression fracture noted. She had a bone marrow biopsy/aspirate which revealed 47% lambda restricted plasma cells, with marked atypia including a plasmablastic morphology. Preliminary FISH results indicate multiple trisomies, 1q21 gain, del (13q14) and a non-standard IGH rearrangement-t(8;14). Hyperdiploidy detected. She was diagnosed with IgG Lambda Multiple Myeloma. ISS Stage II, DS IIIA. Soon thereafter, she was started on a bortezomib-based triplet regimen - bortezomib, cyclophosphamide, dexamethasone (CyBorD). She completed 4 cycles. In April 2016, SPEP/IFE revealed an IgG Lambda monoclonal protein - not quantified. Quantitative immunoglobulins: IgG 1013 mg/dL. Free light chain assay revealed a ratio of 1.169 (kappa 2.98 mg/dL, Lambda 2.55 mg/ dL). CBC normal. Hgb 13.2. Serum creatinine 0.59. Serum calcium 9.7 (corrected). Serum albumin 3.0 g/dL. Beta 2 microglobulin 2.65 mcg/mL. Skeletal survey demonstrated new evidence of L5 pathological compression fracture. A repeat bone marrow biopsy revealed a variably cellular marrow (10-50%). Maturing trilineage hematopoiesis noted. No atypical plasma cell infiltrate (<5% by CD138 ICH). Cytogenetics normal. Unable to run FISH. At the end of the month, her regimen switched to Lenalidimide/Dexamethasone and she completed 4 cycles. In August, she began maintenance therapy with Lenalidomide at 10 mg daily. She then presented with multiple skin papule skin lesions (Figure 1) mostly on her gluteal region. In January 2017, she had a left gluteal skin biopsy consistent with plasma cell neoplasm with high grade features (plasmablastic differentation) In February 2017, SPEP/IFE revealed a IgG Kappa monoclonal protein (not quantified). IgG level 2303 mg/dL. Free light chain assay reveals a ratio of 1.31 (Kappa 12.63 mg/dL, Lambda 9.62 mg/dL). She completed radiation therapy to left gluteal skin - received 30 Gy/15 fractions. SPEP/IFE revealed a IgG Kappa monoclonal protein (not quantified). IgG level 2357 mg/dL. Free light chain assay reveals a ratio of 1.47 (Kappa 12.20 mg/dL, Lambda 8.32 mg/dL). In March 2017, she was started on Pomalidomide/ Dex. Unfortuatnely she was found to have progression of her disease noted. She was then started on Daratumumab which she could not tolerate and was then started on Carfilzomib/Dex. She has received multiple radiation therapy to her left gluteal region, mid back and left upper lip with significant resolution in all areas. In February 2017, she was admitted to Ruby with worsening pain and lesions located in her lower extremities and edema (Figure 1). Peripheral duplex was obtained and blood cultures to rules out a venous clot and infection respectively. A biopsy was obtained (Figure 2) which showed cutaneous involvement of her multiple myeloma. Radiation Oncology was consulted, and she was started on palliative radiation for 5days which initially improved her pain and swelling. Unfortunately, her lesions continue to arise with intermittent, short lived responses to systemic therapy. Her lesions now too widespread for continued radiation therapy. She noticed lesion in her scalp. She continues to follow up in clinic where she was started on single agent Doxil 40 mg/m2 every 4 weeks. Sadly, she continues have progressive cutaneous disease around the flank, abdomen, and bilateral thighs.

Discussion

We present an interesting case of cutaneous involvement of multiple myeloma where although the patient has been on multiple therapies continues to progress in her disease. Her case is interesting from other presentations in that they don’t usually do not describe the course of regimen used in treatment. The standard of care of cutaneous involvement revolves controlling the origin of the disease. One specific treatment that we tried was localized radiation. There is not much data or past literature discussing the use of radiation or its efficacy. Unfortunately for our case, the treatment only helped briefly. Most common involvement for MM is soft tissue involvement of the upper airway and oral cavity. They usually consist of firm, erythematous, nontender nodules involving the neck, ears, shoulders, axillae, chest, abdomen, and dorsum of the hands [11]. The first reported case of skin involvement in a person with MM was presented by Bruno Block in 1910. He described a patient who had small reddish macules that evolved into brown reddish papules and nodules with scale crusts. Histologically these lesions showed epidermal necrosis. He eventually had disease in pleura, stomach, and heart and passed away two years later [3]. A review of literature reveals that there are over 100 described cases. The age ranges from 36 to 81 with a median of 60 years old. Numeric date was available for 87 cases and 63 of them were male and 24 were female [4]. Cutaneous involvement of MM may appear in area of the skin, but it has been reported most commonly on the trunk and abdomen. Skin lesions is commonly described as papules or nodules that measure 1-5 cm in diameter with firm consistency, smooth surface, and a red or violaceous color [5]. Some authors reported that cutaneous involvement of MM only occurs when the tumor mas burden is over 2-3 kg [6]. Cutaneous involvement in patient with MM and extramedullary plasmacytoma generally appears late during the disease. On average, death occurred within 12 months after the diagnosis. Autopsy of these patients reveal extensive plasmacytic infiltration of multiple organs [7].

A review of the cases of MM involving the skin revealed that 40 cases were IgG, 21 cases were IgA, and 9 cases were IgD. The risk of cutaneous involvement by MM is not associated with a particular class of myeloma immunoglobins. Histopathologically, the lesions of MM involving the skin show 2 patterns: nodular and diffuse interstitial [6]. (Figure 2, 3). The worldwide incidence of myeloma is 86,000 cases annually. Mortality rate in MM is high with a median survival of 50-55 months and 63,000 deaths being reported worldwide each year [8]. Significant advances have been made in understanding multiple myeloma (MM) and its precursor diseases. These advances include the gain in knowledge in the underlying pathophysiology, Food and Drug Administration (FDA) approvals of novel therapies with meaningful efficacy and the science in underlying disparities in patients with MM [9].

Author would like to thank Dr. Mortazavi and Arham Miah for their support.

Parametrium to be excised x—x: as necessary from the caudal edge of the cervix.

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Lupine Publishers | Haematological Studies on Multiple Squamous Cell Carcinoma Patients in Nigeria

Lupine Publishers | Open Access Journal of Oncology and Medicine (OAJOM)

Abstract

Multiple squamous cell carcinomas (MSCCs) in albinos occur mainly due to light melanin and constant exposure to ultraviolet rays of sun light. A study to evaluate changes in haematological parameters was done in albinos with multiple squamous cell carcinomas in a tertiary health institution in Enugu, Nigeria. A total of 40 subjects were recruited for the study comprising 20 subjects each for MSCC and control. About 2ml of venous blood was collected by venepuncture into EDTA anticoagulated containers and Mindray BC-5300 used to measure the haematological parameters. The data were analysed using SPSS version 21 with t-test and significance level set at P<0.05. The results showed increase in ESR (19.80±3.40mm/hr, 6.80±2.33mm/hr, 0.000), WBC (5.91±0.45X109/L,4.65±0.59X109/L,P=0.000), Eosinophils (4.06±1.03%,0.54±0.50%, P=0.000) and Monocytes (5.53±1.18%, 1.53±0.51%, P=0.000), decrease in platelets (182.13±41.31 X109/L, 226.26±25.13 X109/L,P= 0.001) and no significant difference (P>0.05) in RBC (4.60±0. 30 X1012/L, 4.79±0.38 X1012/L, P=0.133), Haemoglobin (13.80±0.89g/dl, 14.40±1.16g/dl, P=0.121) , PCV (41.40±2.66%,43.20±3.50%, P=0.125) and lymphocytes (48.53±6.46%,45.12±5.09%, P=0.120) of MSCC subjects compared to control respectively. The RBC, Haemoglobin and packed cell volume were not affected with this cancer but platelets, WBC, monocytes, eosinophils, neutrophils showed changes that were statistically significant. The clinicians and all the health practitioners involved with the management of albinos with MSCC should monitors these changes and also be careful to avert cardiovascular disease due to shift in neutrophils to lymphocytes ratio.

Keywords: Haematological studies; Multiple squamous cell carcinoma patients; Nigeria

Introduction

Multiple squamous cell carcinomas (MSCCs) involve a lot of varied types of cancer that originate from squamous cells [1]. These cells make up the outer parts of skin and lining of some organs, respiratory and digestive tracts [1]. It has been reported that cancer may be regarded as a very large and exceptionally heterogeneous family of malignant diseases with squamous cell carcinomas comprising one of the largest subsets [2-4].

Cancer has been a public global health challenge with increased morbidity and mortality rates across the world. Cancer demands much attention as many a times are not diagnosed early and managed at the stage it can be controlled. Cancer presents with a lot of challenges including bleeding, pains, loss of weight, fever and so many other features that are excruciating and debilitating. Haematological parameters are good indicators of health and disease status [5,6]. It is important to consider studies in haematological parameters to ascertain the levels of alterations in these aspects of Laboratory Medicine that are crucial in wellbeing of the patients. There is strong evidence between diet and exposure of the skin to sunlight especially ultraviolet rays and MSCC [7,8]. The increased intake of high fat dairy foods increases MSCC tumor risk especially with person with history of skin cancer. Smoking, high beer and liquor consumption increase the risk of MSCC [9]. The study was done to determine haematological parameters of multiple squamous cell carcinoma patients in Nigeria

Materials and methods

Study area

The study was done in National Orthopedic Hospital, Enugu, Nigeria.

Subjects

A total of 40 subjects were recruited for the study comprising 20 subjects each for Multiple squamous cell carcinoma (MSCC) and apparently healthy subjects (Control) blood group who were apparently healthy individuals drawn from the Health institution.

Sample collection

About 2mls of venous blood was collected from the subjects into anticoagulated containers for haematological parameters determination.

Laboratory investigations

The hematological parameters were determined using Mindray BC-5300. The haematological parameters investigated include WBC, Neutrophils, Lymphocytes, Monocytes, Red Blood Cells, Hemoglobin, Packed Cell Volume, Platelets and Erythrocyte Sedimentation Rate (ESR).

Ethical Consideration

The details of the research were explained to the subjects and written consents obtained from them and were assured of joining the study willingly and confidentiality also assured. The subjects who gave their consents were allowed to participate in the study.

Statistical Analysis

The results were expressed as mean± standard deviation. The data were analysed with the statistical package for social science (SPSS) version 20 using t-test, ANOVA and the level of significance was set at P<0.05.

Table 1: Mean± sd values of haematological parameters of MSCC and control subjects.

Significant level - *P < 0.05, ns - Not significant (P > 0.05)

The results showed increase in ESR (19.80±3.40mm/hr, 6.80±2.33mm/hr, 0.000) , WBC (5.91±0.45 X109/L, 4.65±0.59 X109/L, P=0.000) , Eosinophils (4.06±1.03%,0.54±0.50%, P=0.000) and Monocytes (5.53±1.18%, 1.53±0.51%, P=0.000), decrease in platelets (182.13±41.31 X109/L, 226.26±25.13 X109/L,P= 0.001) and no significant difference (P>0.05) in RBC (4.60±0. 30 X1012/L, 4.79±0.38 X1012/L, P=0.133), Haemoglobin (13.80±0.89g/ dl, 14.40±1.16g/dl, P=0.121) , PCV (41.40±2.66%,43.20±3.50%, P=0.125) and lymphocytes (48.53±6.46%,45.12±5.09%, P=0.120 of MSCC subjects compared to control respectively (Table 1).

Discussion

Multiple squamous cell carcinoma (MSCC) of the skin is an extensively rare entity but may be more in albinos because of their melanin level of their skin. It is associated with ultraviolet radiation, immunodeficiency states, local intramuscular metastasis and cell carcinoma [10]. The study of haematological parameters of albino patients with multiple squamous cell carcinomas showed increase in erythrocyte sedimentation rate (ESR). Although, ESR has been reported as nonspecific diagnostic tool but may aid in the diagnosis of MSCC as the increase was statistically significant compared to the levels in apparently healthy age and sex matched subjects. Patients with multiple squamous cell carcinomas have a significantly increased risk of developing a recurrence or spread to their lymph nodes, warranting frequent follow up visits to their dermatologists. Cutaneous squamous cell carcinoma when diagnosed and treated early is highly curable [11]. Albino subjects are easily affected by much exposure to sunlight and MSCC is seen on their skin not always covered against ultraviolet rays of the sun. It shows that MSCC elevates the levels of ESR in the patients which may affect the viscosity of their blood and osmotic fragility of the blood. The study also showed increase in WBC of MSCC patients relative to the control. This could be linked to increased oxidative stress among the patients. There could be increased generation of free radical and reactive oxygen species in the MSCC patients due to increased metabolism and stress and a lot of acute infections that resulted in the increase in the WBC. The study showed increase in eosinophils showing that there could be hypersensitivity reactions. That shows that MSCC is associated to allergens. The eosinophils increased significantly. The study also showed increase in monocytes. This shows that MSCC may have intracellular association with some infections and release of cytokine linked to this increased levels of monocytes. There was a shift in neutrophils to lymphocytes ratio which could point to risk of vadiovascular diseases in patients with MSCC. This shows that the body may utilize more of antibody mediated immunity than cell mediated immunity.

Haematological parameters have been reported as good indicators for health and disease status of patients [5,6]. The study revealed no significant difference in RBC, haemoglobin and packed cell volume together with lymphocytes. This shows that patients with MSCC may not suffer from anemia. The carcinoma may not suppress bone marrow activity. Those involved with the management of MSCC should be mindful of these changes especially in the WBC, eosinophils, neutrophils, erythrocyte sedimentation rate (ESR) and platelets. There may not be bleeding as seen in other cancers as the platelets were not low but decreased when compared to the control.

Conclusion

Cancer is a major global public health issue challenging the whole world with increased morbidity and mortality. Multiple squamous cell carcinomas could be neglected cancer diseases that are more common to albinos due to their melanin levels in the skin and constant exposure to ultraviolet radiation from sun light in the parts of their body not always covered with dress. The RBC, Haemoglobin and packed cell volume were not affected with this cancer but platelets, WBC, monocytes, eosinophils, neutrophils showed changes that were statistically significant. The clinicians and all the health practitioners involved with the management of albinos with MSCC should monitors these changes and also be careful to avert cardiovascular disease due to shift in neutrophils to lymphocytes ratio.

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Lupine Publishers | Beer Consumption: Health Effects

Lupine Publishers | Open Access Journal of Oncology and Medicine (OAJOM)

Abstract

Background: Beer is one of the most seasoned and most broadly expended alcoholic beverages on the planet and is the third most commonly consumed drink after water and tea world over.

Aim: The aim of this review article was to study the health effects of beer consumption and compare the positive effects of consumption of wine, beer and spirits when consumed in moderation.

Methods: Literature was searched in the form of epidemiological studies, prospective studies and clinical trials and the health effects of different alcoholic beverages were studied and compared when consumed in moderation. Moderate consumption of beer was defined as non bingeing utilization of 1 beverage for every day in ladies and upto 2 beverages for each day in men.

Conclusion: Although alcohol consumption is a two-sided coin, moderate alcohol consumption in the form of wine or beer has been shown to have a protective role for the cardiovascular system and in addition to being anti-carcinogenic. Both wine and beer consumption in moderation have been associated with health benefits, but to a lesser degree with beer as compared to that of wine , probably because of beer’s lower phenolic content. Healthy effects of wine and beer are greater in combination with a healthy diet. The main protective effects on the cardiovascular system and cancer resulting from moderate wine and beer intake is mainly due to their common components, alcohol and polyphenols. The general recommendations are one drink (150mL of wine or 10g of alcohol) daily for women and two drinks (300mL of wine or 20g of alcohol) daily for men.

Keywords: Beer; Alcohol; Wine; Spirits; Moderate consumption; Xanthohumol

Introduction

Doctors ought to know about the developing proof supporting the dietary and medical advantages of moderate utilization of alcohol as a component of a sound way of life Beer is one of the most seasoned and most broadly expended alcoholic beverages on the planet and in America it adds to 55.3% of the liquor devoured. It is the third most commonly consumed drink after water and tea world over. Beer is fermented from oat grains-most usually from malted grain, however wheat, maize, and rice may likewise be utilized. Moderate, non-bingeing beer utilization as 1 beverage for every day in ladies and upto 2 beverages for each day in men, diminishes the danger of cardiovascular ailment. This impact is like that of wine, at similar alcohol amounts [1]. The strength of current brew is more often than not around 4% to 6% alcohol by volume (ABV), in spite of the fact that it might differ somewhere in the range of 0.5% and 20%.

A big No!

Consumption of beer, at any measurement isn’t prescribed for youngsters, teenagers, pregnant ladies, people in danger to create liquor abuse, those with cardiomyopathy, cardiovascular arrhythmias, depression, liver and pancreatic illnesses or anybody occupied with activities that require fixation, aptitude or coordination [1].

Wine

The off late affirmed willful mark on wine saying that” The proud people who made this wine encourage you to consult your family doctor about the health effects of wine consumption” suggests that doctors ought to advance wine as the favored wellspring of dietary alcohol. However, studies evaluating the relative benefits of wine versus beer versus spirits suggest that moderate consumption of any alcoholic beverage is associated with lower rates of cardiovascular disease. From a nutritional standpoint, beer contains more protein and vitamin B complex than wine [2]. The antioxidant content of beer is equivalent to that of wine, but the specific antioxidants are different because the barley and hops used in the production of beer contain flavonoids different from those in the grapes used in the production of wine [2]. Wine has a long history of use as a medicine making it the world’s oldest documented human made medicine and is recommended as an antiseptic for treating wounds, a digestive aid, for lethargy, diarrhoea and as an analgesic for pain from childbirth [3]. The risk of colon cancer, prostatic cancer and breast cancer can be reduced by consuming moderate amounts of wine and has been proven to have positive health effects in patients with diabetes mellitus and cardiovascular diseases [3].

Arterial Stiffness

Increased arterial stiffness has been identified as an independent risk factor for future cardiovascular disease [4]. Epidemiological examinations uncover a J‐shaped relationship between liquor utilization and blood vessel stiffness, with blood vessel hardening lower among mild‐to‐moderate consumers than overwhelming consumers or non-drinkers [5]. The changes in arterial stiffness are generally thought to results from structural changes (i.e., elastin and collagen content), functional changes (i.e., sympathetic nervous activity, vasoactive substances), or a combination of both [6]. Consumption of alcoholic beverages in excess of the mild‐tomoderate level is known to elicit a reduction in arterial compliance, which means an increase in arterial stiffness [7].

Pattern of drinking and type of alcoholic beverage

Moderate drinkers have a lower risk of developing coronary heart disease and less mortality compared to both heavy drinkers and abstainers, heavy drinkers being the ones with the highest risk [8]. Mukamal et al. reported that alcohol intake distributed over the week inversely associates with the risk of myocardial infarction independently of the type of beverage or the proportion consumed with meals [9]. Some studies supported the benefits of wine on cardiovascular outcomes and mortality and depicted that a J-shaped relationship was found in wine, but neither in beer nor spirits [10]. A recent study reported by Costanzo et al. provided evidence that the J-shaped association is found in both wine and beer, but not in spirits [11]. Fermented beverages, both wine and beer are rich in antioxidants, mainly polyphenolic compounds [12], that are missing in spirit beverages.

Mechanism of action

A number of studies and clinical trials have suggested that alcoholic beverages may exert different protective effects against atherosclerosis development either by modulating lipid metabolism, platelet activity, inflammation, and thrombogenic factors [13]. Specific interest focuses on fermented alcoholic beverages such as wine or beer wherein epidemiological evidence and results from prospective clinical trials suggests that these beverages with heterogenous content of non-alcoholic components might confer better cardiovascular protection than spirits [1,14].

How much is too much!

Epidemiological and clinical studies have pointed out that moderate consumption of beer viz one glass a day for females and two glasses a day for males, is associated with decreased incidence of cardiovascular disease (CVD), hypertension, diabetes, and certain types of cancer, including colon, basal cell, ovarian, and prostate carcinoma. Excessive intake has been associated with hypertension and atrial fibrillation [15].

Content

Beer is rich in nutrients such as carbohydrates, amino acids, minerals, vitamins and other compounds such as polyphenols. Hop (Humulus lupulus L.) is one of the raw materials of beer which serves as an important source of phenolic compounds. Dried hop cones contain about 14.4% of polyphenols, mainly phenolic acids, prenylated chalcones, flavonoids, catechins and pro- antocianidins [16]. Around 30% of polyphenols from beer comes from hops and 70%–80% originates from malt [17].

Given a choice!

A recent meta-analysis including a parallel and separate evaluation of wine and beer consumption indicated a similar protective effect for beer and wine against cardiovascular risk [18]. On the contrary, no statistically significant association with vascular events was apparent for the intake of spirits- the type of alcoholic drink with the highest alcohol concentration and the lowest polyphenolic concentration- suggesting that the polyphenolic constituents found in wine or beer could be responsible for the beneficial effect of alcoholic beverages on vascular events [19]. Results of another study reveals that moderate consumption of alcoholic drinks with a high alcoholic grade (liquors and distillates) also has a cardio-protector effect [20] explaining the fact that part of the beneficial effects of alcoholic beverages is largely due to ethanol, and not to the other specific components of each type of drink.

Anti- cancer role

Xanthohumol is the best studied anti-carcinogenic present in beer which acts by inhibiting the metabolic activation of procarcinogens, detoxifying enzyme inducers of carcinogens [21]. Other compounds in beer with anti-carcinogenic capacity are 8-prenilnaringenin, isoxanthohumol and other prenilflavonoids, as well as the flavanones, humulones and proantocianidins [22].

Conclusion

Although heavy and excessive beer consumption exerts deleterious effects on the human body, with increased disease risks on many organs and is associated to significant social problems such as addiction, accidents, violence and crime, literature shows no harm with moderate beer consumption for major chronic conditions and some benefit against cardiovascular disease [1]. The main protective effects on the cardiovascular system and cancer resulting from moderate wine and beer intake is mainly due to their common components, alcohol and polyphenols.

It must be emphasized that the benefits associated with wine and beer are dependent upon moderate consumption. The general recommendations are one drink (150mL of wine or 10g of alcohol) daily for women and two drinks (300mL of wine or 20g of alcohol) daily for men. These different recommended daily doses of alcohol between genders are explained by the fact that women are more sensitive to the effects of alcohol on the body.

Healthy effects of wine and beer are greater in combination with a healthy diet. The health benefits associated with the Mediterranean diet, which combines moderate wine and beer consumption with a diet rich in fruits, vegetables and whole grains, suggests that polyphenols have synergistic effects with compounds found in other groups of foods.

There is no evidence to support endorsement of one type of alcoholic beverage over another [2]. However some studies have revealed that although both wine and beer consumption in moderation have been associated with health benefits, but to a lesser degree with beer as compared to that of wine , probably because of beer’s lower phenolic content.

Although alcohol consumption is a two-sided coin, moderate alcohol consumption in the form of wine or beer has been shown to have a protective role for the cardiovascular system and in addition to being anti-carcinogenic. American Heart Association recommends that heavy drinkers or alcohol abstainers should not be encouraged to drink wine for health reasons.

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Lupine Publishers | Recurrent Ischemic Stroke as a First Manifestation of Poorly Differentiated Carcinoma (PDC) of Unknown Etiology

Lupine Publishers | Open Access Journal of Oncology and Medicine (OAJOM)

Introduction

The association between cancer and thrombosis has been known for a long time, and the majority of the thromboembolic events associated with cancer are usually diagnosed after the cancer being identified [1]. However, a thromboembolic event may precede the identification of a cancer and maybe the first manifestation of the underlying malignancy [2]. Malignant cancers promote hypercoagulable state and increases the risk of thromboembolism. Carcinoma is the most common cause of ischemic stroke associated with malignancy [3] with lung cancers being the most common [1,4] while adenocarcinoma confers a higher risk of recurrent venous thromboembolism (VTE) [5]. We report a case of recurrent embolic strokes resistant to anticoagulation as the first manifestation of poorly differentiated carcinoma (PDC) of unknown etiology. It is the first case reported in the literature.

Case Report

A 57 years old male patient presented to our hospital with nonfluent aphasia. There was no significant past medical history and he denied smoking, alcohol or illicit drug use. Clinical examination revealed a right inferior quadrantanopsia, a right upper extremity weakness with strength 4/5 according to Medical Research Council Scale. There were difficulties in word-finding, naming and reading with intact repetition. His admission National Institute of Health Stroke Scale (NIHSS) was 6. He was deemed ineligible for thrombolysis due to unclear onset time and was started on aspirin and high intensity statin. The CT angiography of the head and neck showed no evidence of aneurysm, dissection, significant flow stenosis, or arteriovenous malformations. A Transesophageal Echocardiography (TEE) showed normal left ventricular function with no evidence of a thrombus or a Patent Foramen Ovale (PFO). A Magnetic Resonance Imaging (MRI) of the brain showed acute infarcts within multiple vascular territories, involving the bilateral cerebellum, left frontal, temporal, parietal and occipital lobes, consistent with embolic infarcts (Figure1). A four-vessel digital subtraction cerebral angiogram did not show evidence of vasculitis or vessel malformation. A hypercoagulable panel did not reveal evidence of hematologic hypercoagulability. The patient was treated with warfarin with low molecular weight heparin bridging due to the highly embolic nature of the MRI findings, and was discharged to the acute inpatient rehabilitation facility. While at the rehab, the patient started complaining of back and abdominal pain. A CT abdomen and pelvis identified heterogeneously enhancing lesion within the lower pole of kidney with extensive lymphadenopathy (Figure 2). While waiting for biopsy to be done, the patient had worsening of aphasia and dysarthria prompting readmission. Repeat MRI brain showed new scattered areas of acite infarcts in different vascular territories (Figure 3). Anticoagulation was continued. Two days later, he had worsening mental status and repeat imaging showed more acute infarction. Biopsy of the abdominal lymph node was facilitated, and result showed poorly differentiated carcinoma of unknown origin. The family opted for comfort measures only and the patient expired shortly.

Discussion

Hypercoagulable state is a common finding in patients with malignancy due to the production of substances with procoagulant activity. Different mechanisms have been implicated in the cerebrovascular complications of cancer patients and includes the following: [6]

I. Cerebral infarction from nonbacterial thrombotic endocarditis (NBTE).

II. Thrombosis due to compression or infiltration of cerebral vessels by tumor or coagulopathy induced by chemotherapy.

III. Cerebral venous sinus thrombosis due to hypercoagulable state or chemotherapy.

IV. Cerebral infarction due to tumor emboli or septic thrombi.

V. Intracranial hemorrhage which is more common in patients with hematological malignancies.

Our patient presented with ischemic stokes involving multiple vascular territories. A complete workup for ischemic stroke was performed, including Brain MRI, TEE and cerebral angiogram that ruled out the presence of brain tumors, atherosclerosis, vasculitis, cardiac embolic source as well as sinus thrombosis. The results were in favor of embolic strokes. The physical examination did not reveal any signs of sepsis or infection. The conventional etiologies of stroke could not be identified. Despite appropriate therapeutic anticoagulation the patient had recurrent ischemic strokes. The commonest cause of stroke in cancer patients is embolic due to hypercoagulation [1,4]. Recent study showed that infarction in multiple vascular territories in stroke patients associated with cancer is significantly elevated (34%), compared to 15% of stroke patients not associated with cancer [5], so it is important to consider the existence of a concealed cancer in stroke patients with multiple vascular territories involvement and conventional mechanisms for stroke etiology not identified. A retrospective study showed that in patients with ischemic stroke associated with cancer, the cumulative rates of recurrent ischemic stroke were 7 % at 1 month, 15 % at 3 and 6 months [3]. In our case the patient experienced recurrent events within a two-week period and continued despite adequate anticoagulation. It is unclear whether initiation of aggressive cancer treatment may have improved patient outcome as the family opted for withdrawal of care. Further study on the early initiation of cancer therapy in malignancy-associated ischemic strokes even during the acute phase may be warranted.

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Lupine Publishers | Characteristics of Pure Familial Pancreatic Cancer Families and Those with Additional Breast Cancer

Lupine Publishers | Open Access Journal of Oncology and Medicine (OAJOM)

Abstract

Familial pancreatic cancer (FPC) is a rare hereditary tumor syndrome. The large phenotypic and genotypic heterogeneity is not yet well-established. FPC families without (pure FPC) or with additional occurrence of breast cancer (FPC-breast) were analyzed regarding phenotype, genotype and the diagnostic yield of prospective screening for pancreatic ductal adenocarcinoma (PDAC). The total cohort of 227 FPC families included 85 (38%) pure FPC and 70 (30.7%) FPC-breast families. The proportions of affected family members with PDAC (27.2%, 197/724 vs. 18.3%, 177/962, p<0.0001) and of 2 or more affected generations (84.2% vs. 62.9%, p<0.05) were significantly higher in pure FPC families. In 48 (68.6%) FPC-breast families additional tumor types occurred, most frequently colorectal cancer (n=16, 22.8%). Deleterious germline mutations (2 BRCA2, 1 PALB2) were detected in 3 of 53 (5.6%) analyzed pure FPC and in 17 of 56 (30.4%) analyzed FPC-breast families (3 BRCA1, 6 BRCA2, 3 PALB2, 3 CDKN2A, 2 ATM; p=0.001). Individuals at risk (IAR) from FPC-breast families participated significantly more often in a prospective PDAC screening program (54.4% vs. 33.5%; p=0.0001) resulting in a diagnostic yield of 3.7% and 0% in FPC-breast and pure FPC families, respectively. The phenotypic and genotypic characteristics of pure FPC and FPC-breast families should be considered for the genetic counseling and management of these families.

Keywords: Familial Pancreatic Cancer; Mutations; Phenotype; Genotype

Abbreviations: FPC: Familial Pancreatic Cancer; PDAC: Pancreatic Ductal Adenocarcinoma; HBOC: Hereditary Breast and Ovarian Cancer; PanIN: Pancreatic Intraepithelial Neoplasia; IPMN: Intraductal Papillary Mucinous Neoplasia; AFL: Atypical Flat Lesions; IAR: Individual at Risk

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a challenging tumor entity with an increasing incidence and a dismal prognosis. The overall five-year-survival rate is less than 5%, attributed to late clinical symptoms, low resection rates and poor response to radio- and chemotherapy [1]. One of the greatest risk factors for developing PDAC is a positive family history. A familial aggregation of PDAC is present in 1.9% to 6% of cases depending on the confirmation of the PDAC diagnosis by either only family history or by histopathology and medical reports [2, 3]. An inherited predisposition to PDAC is potentially given in the so-called familial pancreatic cancer (FPC) families, which are characterized by two or more first-degree relatives with PDAC that do not fulfill the criteria for another inherited tumor syndrome [4, 5]. On the other hand several hereditary tumor predisposition syndromes such as Peutz- Jeghers-Syndrome (PJS) and hereditary breast and ovarian cancer (HBOC) might predispose to PDAC, although these syndromes are characterized by another clinical phenotype than PDAC [4, 5]. Tumor registries such as the North American National Familial Pancreatic Tumor Registry (NFPTR), the German National Case Collection of Familial Pancreatic Cancer (FaPaCa) and the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) were established to investigate the phenotype and genotype of FPC families [6-8]. In the last years, studies focused mainly on the discovery of the underlying gene defects and the evaluation of diagnostic yield of prospective PDAC screening programs in individuals at risk (IAR) of such families [9-17]. Current sequencing and WES data suggest that FPC is genetically highly heterogeneous with no major predisposing gene [17]. The phenotypic variance of FPC families, however, is still not well-established. The current analysis was performed to analyze the phenotype and genotype and the diagnostic yield of prospective PDAC screening in pure FPC and FPC-breast cancer families.

Materials and Methods

The FaPaCa registry is a national case collection for familial pancreatic cancer families in Germany funded by the Deutsche Krebshilfe in 1999 [7-18]. Families with two or more first-degree relatives with a confirmed diagnosis of PDAC and without evidence of any other inherited tumor syndrome were collected. The current report analyzed the genotype and phenotype of FPC families with the occurrence of only PDAC (pure FPC families) and FPC families with the additional occurrence of breast cancer (FPC-breast) families. Members from FPC families were recruited between July 1999 and July 2019 by direct referral via their physicians or by personal contact to the FaPaCa study-office based on information about the study, e.g. via the internet (http://www.fapaca.de). All eligible persons and families were initially genetically counseled and a three-generation family pedigree was constructed. All PDAC diagnoses were confirmed by review of medical records, deaths certificates and by examination of the pathology slides when available. All patients with PDAC of FPC families with available blood samples who gave their informed consent were subjected to mutation analysis of the potential predisposing PDAC genes ATM, BRCA1/2, CDKN2A, PALB2, PLLD and CHEK2 as described previously [12-18]. In addition, whole exome sequencing (WES) was performed in 7 of those families (Slater et al., submitted). If a deleterious germline mutation was identified in the index patient, predictive genetic testing of this mutation was offered to all family members after genetic counseling. The result of the predictive testing was explained to the family members during another interdisciplinary counseling, involving a geneticist, a psychologist, a surgeon and gastroenterologist. Individuals at risk (IAR) older than 18 years were encouraged to participate in a prospective screening program that was conducted at our institution. Firstdegree relatives of an affected patient of a FPC family and members of a FPC-family carrying a predisposing mutation such as BRCA2, independent of the degree of relationship, were classified as IAR. The screening started at age 40 years until 2016 and thereafter at age 50 years or 10 years before the earliest age of onset of PDAC in the family, whichever was first [19]. The screening program included an annual physical examination, determination of serum HbA1c, amylase, GOT, GPT, bilirubin and CA19-9, and imaging with magnetic resonance imaging plus MRCP and endosonography as described previously [19]. The screening program was restricted to mutation carriers, if the underlying gene defect was known in the family. Resection specimens were analyzed by experienced pathologists with special regard to the presence of PDAC, pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasia (IPMN) and atypical flat lesions (AFL). Previous screening results of some IAR have been already published [10, 18-20]. The FaPaCa registry, including the genetic analyses and the screening program, was approved by the Ethics Committee of the Philipps- University of Marburg (36/1997, last amendment 9/2010) and all participants provided written informed consent. Descriptive statistics of the relatives who enrolled were compiled. Variables included age, gender, number of relatives with PDAC, earliest age of onset in the family and underlying germline mutations. The age of diagnosis of PDAC was retrieved from the 3-generation pedigrees and early age of onset was defined as the occurrence of PDAC prior to the age of 50 years in a family. Significant lesions were defined as the presence of histologically verified PDAC, PanIN3 or IPMN with high-grade dysplasia. Potentially relevant lesions were defined as histologically verified multifocal PanIN2 lesions with/without BDIPMN with low grade dysplasia and/or atypical flat lesions (AFL). The chi-square, Fisher’s exact test, t test and Wilcoxon rank sum test were performed for categorical and numerical variables, where appropriate, to compare patient characteristics. Two-tailed p values <0.05 were considered to be statistically significant. Analyses were performed using Prism 6 for Mac OS X from GraphPad Software, Inc.

Results

Of 227 verified FPC families, 85 (37.4%) revealed only PDAC and 70 (30.8%) families showed both PDAC and breast cancer. The proportion of affected family members with PDAC was significantly higher in pure FPC families (27.2%, 197/724) compared to all FPCbreast families (18.3%, 177/962, p<0.0001). This also holds true when comparing FPC-breast families with or without detected predisposing germline mutations. In the 17 FPC breast families with a germline mutation the PDAC rate was 18.3% (49 of 267 family members) compared to 16.4% (90 of 550 family members) in the 39 families without mutations. Twenty (24%) pure FPC families had 3 or more affected first-degree relatives with PDAC compared to 26 (37.1%) of the FPC-breast families (p=0.08). The proportion of 2 or more affected generations, however, was significantly higher in pure FPC families than in FPC-breast families (84.2% vs. 62.9%, p<0.05). The rate of females affected with PDAC tended to be lower in pure FPC (48%, 94/197) than in FPCbreast families (56%, 100/177, p=0.08). The median age of PDAC diagnosis (63 vs. 65 years) and the rate of families with early age of PDAC onset <50 years (23.5% vs 21.4%) were not significantly different between family groups (Table 1). In the 70 FPC-breast families a total of 113 (1-6 per family) breast cancers occurred, all but one in female patients. The mean rate of breast cancer cases per family was 1.6 (SD=1.207; SEM=0.1443). At inclusion none of these 70 families fulfilled the criteria for HBOC [21,22], but this was the case for six 6 (8.6%) families due to the additional occurrence of breast/ovarian cancer cases after a median follow-up of 7 years. In 19 families 23 (23%) female patients developed PDAC and breast cancer, synchronous and metachronous. The median age of breast cancer diagnosis was 55 (range 24-93) years, 31 (27.4%) patients had a premenopausal (<50 years) diagnosis. Five (3.6%) female patients developed bilateral breast cancer. In 48 (68.6%) FPCbreast family’s tumor types in addition to PDAC and breast cancer also occurred. The most frequent additional cancers were colon cancer in 16 (22.8%), lung cancer in 10 (14.3%), prostate cancer and malignant melanoma in 8 (11.4%) families each, respectively (Table 1). The characteristics of pure FPC families and FPC-breast families are summarized in (Table 1). Representative pure FPC and FPC-breast families are shown in (Figures 1, 2).

Discussion

Despite several new molecular insights into the pathogenesis of hereditary forms of cancer, its translation into the clinical setting remains still somehow problematic. A comprehensive history of cancer in a family is still one milestone to establish a potentially hereditary cancer syndrome. The family history, however, has been insufficiently recorded in many patients’ medical records, thereby compromising its clinical significance [24]. This is especially true for FPC families, since the phenotype is highly heterogeneous and affected patients die fast due to the aggressive disease. FPC can be mainly divided into two groups, namely pure PC families and those associated with other tumor types [4]. The most frequent other tumor type associated with FPC in the FaPaCa registry is breast cancer, in almost one third (30.7%) of FPC families. Therefore, we undertook a detailed analysis of the phenotype and genotype of pure FPC families and FPC with an additional occurrence of breast cancer. Initially, none of these families fulfilled the criteria for HBOC [21, 22], but after a median follow-up of 7 years this was the case for 6 (8.6%) families due to the new development of additional breast and/or ovarian cancer cases. It has been previously reported that some HBOC families are associated with an increased risk for PDAC. A retrospective analysis of 5143 Italian family trees with breast and/ or ovarian cancer, for example, showed that 392 (7.6%) families also had cases of PDAC [25]. It has also been postulated that the risk of PDAC is especially increased in those 25 to 30% of HBOC families who are associated with BRCA1 or BRCA2 germline mutations [25]. Lynch et al. reported that 213 (3.7%) of 5742 families with a BRCA1 mutation and 138 (6.1%) of 2269 families with a BRCA2 mutation had a case of PDAC [26]. A study by the Breast Cancer Linkage Consortium (BCLC) yielded for female BRCA1 mutation carriers a 2.3-fold risk and for female BRCA2 mutation carriers a 3.5-fold risk for the development of PDAC [27]. From another viewpoint, it has been reported that a familial accumulation of PDAC might be associated with the occurrence of breast and/or ovarian cancer. A mortality analysis of the National Familial Pancreatic Tumor Registry probands, which included over 200,000 person-years of follow-up from 8564 first-degree relatives of PDAC probands, found that relatives of FPC probands had a significantly increased risk of dying from breast (wSMR 1.66, 95% CI 1.15–2.34), ovarian (wSMR 2.05, 95% CI 1.10–3.49), and bile duct cancers (wSMR 2.89, 95% CI 1.04–6.39) [28]. Analysis of the familial aggregation of PDAC with other malignancies using the updated Swedish Family-Cancer Database with more than 11.5 million individuals disclosed that a significantly increased the risk of PDAC was associated with earlyonset breast cancer in siblings [29].

Based on the present analysis one can postulate some phenotypic differences between pure FPC and FPC-breast families. The proportion of affected family members with PDAC (27.2% vs. 18.3%, p<0.0001) and the involvement of 2 or more generations was significantly higher in pure FPC families than in FPC-breast families (84.2% vs. 62.9%, p<0.05). The rate of females affected with PDAC tended to be higher in FPC-breast than in pure FPC families (56% vs. 48%, p=0.0978). A previous analysis of 317 BRCA1/2 mutated HBOC families with 351 cases of PDAC, however, revealed a slightly higher risk in males (58% vs. 46%) [26]. The median age of PDAC diagnosis (63 vs. 65 years) and the rate of families with early age of PDAC onset <50 years (23.5% vs 21.4%) were not significantly different between family groups (Table 1), which is in line with previous reports on pure FPC families and BRCA1/BRCA2 families with the occurrence of PDAC [26, 27]. Comparing the FPC-breast families with the reported characteristics of HBOC families one can also note some phenotypical differences. The PDAC rate in FPC-breast families (18%) appears comparably high to HBOC families with 1.5 to 8% [24, 25]. In the FPC-breast families the rate of breast cancer cases with mean 1.6 cases per family was lower than in German HBOC families [30, 31]. The median age of onset of breast cancer (55 vs. 49 years) was older and the proportion of women with premenopausal onset of breast cancer (27.4% vs. 45%) was also lower than those reported for German HBOC families [30]. It is of note, that 68.5% of analyzed FPC-breast families showed additional cancers, including colorectal cancer (22.8%) and ovarian cancer (8.6%). Recent advances in sequencing technology provided an unbiased way to search for the genes underlying disease susceptibility in FPC. Using this approach BRCA1/2, CDKN2A, PALB2 and ATM were identified as FPC susceptibility genes, together explaining about 8%-15% of FPC cases [17, 18, 32]. A previous whole genome sequencing study of 638 patients from 593 American FPC kindreds demonstrated that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous [17]. This analysis supported the role of the known FPC susceptibility BRCA2, CDKN2A, PALB2 and ATM, and identified a few novel candidate genes such as BUB1B and FANCC harboring rare, deleterious germline variants. Interestingly, many of these candidate genes are involved in processes regulating DNA repair or chromosomal stability. The genetic basis underlying FPC susceptibility, however, remains still unknown in 80% to 90% of patients with FPC. In the present study a predisposing gene defect could be identified in the susceptibility genes BRCA1, BRCA2, CDKN2A, ATM and PALB2 in 17 (15.5%) of 109 analyzed FPC families. As in previous studies BRCA2 was the most frequently mutated gene 8 (7.3%). It is of note, however, that the prevalence of deleterious mutations was significantly higher in FPC-breast (30.4%) than in pure FPCfamilies (5.6%, p=0.001). ATM, BRCA1 and CDKN2A mutations were only detected in FPC-breast families. A previous Italian study postulated a BRCA2 cluster region within c.7180 and c.8248, which might be associated with the occurrence of PDAC [25]. We cannot confirm this observation, since all of the 8 BRCA2 mutations were located outside of this region. Knowledge of the genes responsible for FPC susceptibility is important for a number of reasons. One is that early detection can be targeted to mutation carriers and pancreatic neoplasms can be detected at an earlier stage, when therapeutic interventions with curative intent are still possible. A recent expert consensus conference recommends pancreatic screening under boardapproved protocols for IAR from FPC families [5, 23]. Various screening programs reported a diagnostic yield of PDAC screening between 1.9 and 7%, when defining high grade dysplasia or stage I PDAC as true success of screening [9, 10, 19]. In the present study it was obvious that IAR from FPC-breast families participated significantly more often in the recommended screening than IAR from pure FPC families (33.5% vs. 54.4%, p<0.0001). The reasons for this remain speculative and are probably multifactorial. The diagnostic yield of the screening program itself appears to be more efficient in FPC-breast families compared to pure FPC families (3.7% vs. 0%), although the prospective follow-up of less than 5 years is too short to draw any definitive conclusions. A recent North American study [33] reported that the cumulative incidence of PDAC and high grade dysplasia was significantly higher in the IAR group with predisposing germline mutations compared to those IAR without (RR 2.85, 95% CI 1.0-8.18, p=0.05). We can neither confirm nor reject this observation due to the limited number of mutation carriers (n=21) participating in screening.

Conclusion

In summary, there seems to be a distinct FPC-breast family phenotype, which might be associated with other solid cancers such as colon cancer and has at least a 30% prevalence of predisposing germline mutations in known susceptibility genes BRCA1/2, PALB2, CDKN2A and ATM. IAR of these families have a comparably high motivation to participate in PDAC screening, which in short term appears to be more effective than in pure FPC families. These data should be considered for the counseling and management of these families. For More Open Access Journal of Oncology and Medicine Articles Please Click Here: https://lupinepublishers.com/cancer-journal/index.php

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Lupine Publishers | Johns Hopkins Aramco Healthcare Experience in Management Of Cancer Patient’s Treatment During COVID -19 Pandemic Lockdown Of Qatif Governorate

Lupine Publishers | Open Access Journal of Oncology and Medicine (OAJOM)

Abstract

Background: COVID-19 pandemic is a serious ongoing global public health crisis. It significantly impacted healthcare systems ability to deliver effective and timely cancer treatment. Cancer patients are at increased risk of death from corona virus. It is essential to continue the healthcare of cancer-patients who reside in a lockdown-zone. Therefore, redeployment of healthcare resources and strategies is vital.

Objective: To highlight JHAH efforts in initiating a remote cancer-therapy infusion center in a lockdown-zone located in Qatif governorate, Saudi Arabia, during March to April 2020, to ensure the continuation of quality evidence-based oncology treatment to eligible patients in a timely manner.

Methods: JHAH medical staff residing in Qatif, already under lockdown as precautionary measures, was redeployed to work in a contracted private hospital (Al Zahra General Hospital; ZGH). To provide the required treatment for JHAH cancer patient who were banned from exiting the lockdown-zone and receiving cancer-treatment at the oncology centre in Dhahran. Oncology treatment team reviewed treatment protocols for all scheduled cancer patients. Patients had the required laboratory tests in ZGH, ahead of treatment date. If the results were acceptable, treatment orders were released, and pharmacy prepared the medications for next day appointments. Medications were delivered to ZGH in Qatif governorate, where JHAH medical team administered them and provided the appropriate care.

Results: 116 JHAH cancer patients received various treatments safely as planned in ZGH. Despite an ongoing global pandemic, the care delivery efforts of the oncology team at JHAH resulted in a patient satisfaction rate above 92%.

Conclusions: Our experience showed that delivering quality care for cancer patients under lockdown was feasible and successful. A well-established healthcare system with supportive leadership, multidisciplinary teamwork and a passion to provide quality and effective service to cancer patients are essential for continuity of care during a pandemic event.

Keywords: COVID-19 pandemic; Cancer-treatment; Lockdown; Precautionary measures

Introduction

Corona virus disease 2019 (COVID-19) emerged in China during the last quarter of 2019 and is responsible for the ongoing pandemic affecting people and healthcare systems worldwide. Its rapid spread amongst humans suggests that COVID-19 is a community-acquired respiratory virus (CARV) [1] that causes respiratory illness [2, 3]. Patients with chronic health conditions and immunocompromised patients are at higher risk of complications from COVID [4-6]. Patients with active cancer have an increased risk of death compared to other comorbidities [6]. A preliminary report from Italy indicates that 18-20% of patients with COVID-19 had been diagnosed with cancer in the preceding 5 years [7, 8]. Cancer patients were reported to have a twofold increased risk of contracting COVID-19 compared to the rest of population [9, 10]. Nosocomial infections within the healthcare services were also observed, which stresses the importance of proper infection control [11]. A cohort study in Wuhan, China revealed that the case rate for COVID-19 in hospitalized cancer patients was 10%, compared to 7% in healthcare workers, with higher severity and mortality in cancer patients [12]. A global political commitment to pandemic preparedness is essential. Public health measures including containment and precautionary measures have been implemented worldwide to interrupt viral transmission. Many countries applied lockdown, encouraged social distancing and cancelled mass gatherings [13]. Saudi Arabia has implemented additional restrictive measures, one of which disturbed important religious events that occur annually and affects Muslims worldwide. In 2020, Umrah and Hajj were severely restricted [14, 15]. As COVID-19 cases increase substantially around the world, it will take longer time to control the infection. Therefore, implemented control measures will remain in place for an extended period of time [16]. Lockdown is a major challenge for healthcare systems to overcome while providing safe, timely, effective and efficient healthcare delivery. Restricting visits to hospitals or treatment centers to minimize infection risk might adversely jeopardize cancer patient’s health, [8, 16]. Therefore, a paradigm shift in healthcare services infrastructure, workforce, staffing, and care strategies are rapidly evolving worldwide [17]. The UK National Health Service (NHS) guidelines highlighted that constraint on access to operating theatres might be problematic for cancer patients requiring surgical intervention and a contingency plan is necessary to be discussed by a multidisciplinary cancer treatment team [17-21]. Cancer treatment guidelines during COVID-19 suggest switching to oral and subcutaneous therapies rather than intravenous, whenever possible [22].

Therefore, during the COVID-19 pandemic, the benefit to risk ratio of cancer treatment requires reassessment. Depending on the magnitude of process changes within a certain region, prioritization of cancer therapy is necessary to ensure safe administration. Identification of high-risk endemic areas is important to provide sufficient medical care, since early access to medical care is vital for patient survival chances [23]. Securing access to treatment for cancer patients must be a priority. To ensure that healthcare is delivered despite the constrained resources is a challenge. Methods to be achieved may include; home medication deliveries, use of continuous infusion medication pumps, remote monitoring of patients undergoing oral treatments, and utilizing laboratory testing and healthcare treatment centers closer to home [24-26]. In Saudi Arabia, several restrictive measures have been implemented, one of which involved a lockdown for all cities nationwide, few of which were subjected to whole “quarantine” when defined as an epidemic zone, e.g. Qatif Governorate (QG) in the eastern province that has no medical facility to provide oncology services. Johns Hopkins Aramco Healthcare (JHAH) Oncology Center is located in the same province at Dhahran city. While QG was under lockdown, JHAH cancer patients living there could not access Dhahran to receive their treatment. Herein, we wish to share JHAH experience to continue cancer treatment under lockdown conditions. The main objective is to highlight JHAH efforts in initiating a remote cancer therapy infusion centre in QG during the lockdown period from March to April 2020.

Patients and Methods

An approval to publish this paper was obtained from JHAH institutional review board (IRB). The Cancer Institute at JHAH identified cancer patients with active disease and under lockdown. Patient with active disease included those eligible for curative or palliative, chemotherapy, radiotherapy, surgical intervention, biological therapy, immunotherapy, hormonal therapy, and those patients with bone marrow transplant or under immunosuppressive therapy.

Re-Deployment of JHAH Resources to Continue Access to Oncology Treatment for JHAH QG Cancer Population

There are many JHAH medical staff residing in Qatif, including physicians, nurses, pharmacists, and other allied healthcare providers. Many JHAH’s cancer patients resides in Qatif as well. Because of the lockdown, those patients could not access JHAH oncology services located in Dhahran. JHAH and Cancer Institute leaders re-deployed JHAH resources in QG to initiate a remote cancer-therapy infusion site, as there is no other available oncology service center in the entire QG, to continue treatment for active JHAH cancer patients. Al Zahra General Hospital (ZGH) is a private hospital located in QG. JHAH leadership contracted ZGH to use part of a vacant inpatient ward to serve as an outpatient oncology clinic/ infusion center for JHAH cancer patients. The ward included four beds, an office/clinic and a storage area. JHAH used its medical staff residing in QG to work in ZGH. With one consultant haematologist/ medical oncologist, four certified oncology nurses (one of whom was an oncology nurse educator), a pharmacist, and a phlebotomist. The oncologist and nurses were assigned to care for cancer patients during the entire therapy administration process. An agreement was made with JHAH “shipment and receiving department” to transport any clinical equipment including personal protection equipment, medications and other supplies, daily to ZGH. Medications were delivered and administered at ZGH. A secondary JHAH temporary pharmacy was opened at Al-Muwasat hospital-Qatif (MWT) for all JHAH patients, including narcotic analgesics for cancer patients. Measures were taken to ensure that patients received their controlled medications, whilst complying with the Ministry of Health (MOH) regulations. Two months supply general medications were provided to avoid unnecessary patient visits to hospital during the pandemic and lockdown time.

JHAH Plan for treatment of Cancer Patients in QG

The Oncology Treatment Centre Team (OTCT) in Dhahran is a multidisciplinary team consisting of oncology physicians, nursing manager, nurse practitioners and pharmacists. They are responsible for making collaborative treatment decisions (Figure 1) and overcoming organizational and logistical challenges of providing oncology care at ZGH. Cancer patients were prioritized according to individual therapy protocol, goal of treatment, whether curative/palliative/or control. Treatment was delayed for some patients. Elective surgeries were postponed for others, to ensure patient health and safety by avoiding hospitalization during COVID-19 pandemic. When appropriate, neoadjuvant therapy was given. Patients who were to continue their treatment as planned; a pathway to organize the setting was put in place depending on the therapy type as follows: 1) Patients under chemotherapy protocols The principle of initiating the current remote cancer-therapy infusion centre in a lockdown area is based on visiting the treatment protocols planned for all affected cancer patients, and approve it by OCTC. The medications were prepared by Dhahran pharmacy then sent daily to be administrated at ZGH. A detailed process is illustrated in (Figure 1).

Figure 1: Process map; pathway setting for cancer therapy preparation in JHAH pharmacy in Dhahran and transporting it to ZGH in Qatif Governorate.

2) Patients under immune, biological and hormonal therapy Similar to the pathway setting of chemotherapy preparation, immune, biological and hormonal therapy protocols were prepared by JHAH pharmacy in Dhahran and transported to ZGH daily. 3) Patients under radiotherapy protocol Radiotherapy services were not available in any of QG hospitals. JHAH patients scheduled for radiotherapy were screened for COVID-19. Negative oral/nasopharyngeal swab for SARS-2 CoVi RNA was a prerequisite to obtain a special permission from the MOH and MOI to travel to Dhahran. They stayed in hotels quarantine for 14 days, before they could be resuming or starting radiation. 4) Patients receiving supportive treatments Supportive medication or procedures that were also provided in ZGH including central line (CVAD) flushing, Zoledronic Acid, Factor VII and enzyme therapy administration. 5) Patients under palliative therapy: Patients receiving palliative chemotherapy received their treatment as others with curative intent. They benefited from virtual clinics, all their supportive palliative medications were prescribed by their primary oncologist and they received it from MWT. JHAH palliative care nurse coordinator was one of the registered JHAH nurses working in ZGH; she evaluated patients and coordinated their care with Dhahran oncologists. JHAH patients who were admitted to a medical designated medical facility (MDF) in QG, and deemed to require transfer to JHAH, permission was obtained through MOH.

Plan if any COVID-19 Symptoms Present During Treatment Period

Visual triage was performed in a segregated waiting area, signs and symptoms of cancer patients may experience therapy related side effects similar to COVID-19. In the event that a patient developed or presented with COVID-19 symptoms such as; fever, cough, sore throat or difficulty in breathing, they would be redirected for appropriate viral swabbing and their treatment postponed until a negative result was produced. Physical distancing measures were implemented by spacing out seats and limiting visitors in the treatment areas, and if a high-risk case identified, MOH was notified.

Results

A total of 116 JHAH cancer patients with solid and haematological malignancies on active treatment were served at ZGH during the lockdown period in QG between March to April 2020. This included 30 patients who continued their chemotherapy as planned, 33 patients received biological immunotherapies, 15 patients received hormonal treatment, and 22 patients received supportive treatments. Five patients who were on palliative therapy received care as well. Eleven patients were undergoing radiotherapy, were transferred to JHAH oncology centre in Dhahran and treated. (Figure 2) In addition, a total of 140 blood tests were performed in ZGH laboratory including repeated abnormal tests results. One patient had a Lumbar Puncture for administration of intrathecal chemotherapy.

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Lupine Publishers | Hydrogen Peroxide and Cancer

Lupine Publishers | Open Access Journal of Oncology and Medicine (OAJOM)

Introduction

I was asked to submit a minireview to this journal on oncology. I’ll share an antidotal observation that may prove useful to cancer researchers. I studied hyper-ferritism and Ferric Chloride to see its possible link to schizophrenia. Those results are well published [1,2]. However, I noticed from that research a trend that 12 patients who should have had high hydrogen peroxide (H2O2) also universally had had some form of cancer in their medical history. I wonder if H2O2 is not a carcinogen? Could the H2O2 break down that cell walls leading to cell mutation? I’m not an expert on cancer, nor do I intend to be, but perhaps this clue may lead to further research into to the causes of cancer. I provide here some possible chemical reactions that could take place in a system in balance. The cell walls are fatty acids [3,4].

Lipids =Fatty Acids COOH

COOH-+O2+H2O+ H2

(COOH)2H2+O2+H2 →

(COOH)2H2+O2+H2O→

CH4O2+O2+H2O →

CH4O4+H2O→

CH2O2+H2O→

C+4+H2O2+ H2O

COOH+H2O2+H2→

(COOH)H2 +O2+H2O→

C+4+H2O2+H2O

Carbon Ion + Hydrogen Peroxide + Water

Carboxylic Acid

R- COOH = CH3-COOH +H2+H2O

CH3-COOH +H2+H2O+O2 +Cl→

3CH2-COOH +2H2+2H2O +2O2+Cl2→

CH3+Cl2 →Dichloromethane=Carcinogen

Animal studies have shown increases in liver and lung cancer and benign mammary gland tumors following the inhalation of methylene chloride (Figure 1).

Evidence for Carcinogenicity

Classification: B2; probable human carcinogen. Basis for Classification: Based on inadequate human data and sufficient evidence of carcinogenicity in animals; increased incidence of hepatocellular neoplasms and alveolar/bronchiolar neoplasms in male and female mice, and increased incidence of benign mammary tumors in both sexes of rats, salivary gland sarcomas in male rats and leukemia in female rats. This classification is supported by some positive genotoxicity data, although results in mammalian systems are generally negative. Human Carcinogenicity Data: Inadequate. Animal Carcinogenicity Data: Sufficient.

Conclusion

So we see that dichloride methane, a carcinogen, could be the culprit in allowing cancers (leukemia; Prostate; Breast; and lung cancers) to form. I reiterate; I’m not an expert in the field. I simply provide an observation that I hope is helpful to other researchers.

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Lupine Publishers | Carbon Nanotubes: Exploring Intrinsic Medicinal Activities and Biomedical Applications

Lupine Publishers | Open Access Journal of Oncology and Medicine (OAJOM)

Introduction

Carbon Nano materials the king of nonmaterial’s have fascinating nanofamily including buckyballs or buckminsterfullerenes [1], multiwalled carbon nanotubes [2], the single-walled carbon naotubes(SWCNTs) [3], Carbon Nanohorns(CNHs), Carbon nanocones, Carbon nanofibers (CNFs), carbon nanothread, Buckypaper, carbon dots, nanodimons, nanoonions, nanorods, nanoribbons. Also called as powerful particles, CNTs (carbon nanotubes) has thus bloomed over the past decade [4,5]. Increasing evidence has shown that certain CNT properties such as nano-sized dimension, high surface energy, and large reactive surface area are directly correlated to their biological activities [6,7]. Great property of loading various biomolecules, diagnostic and therapeutic moieties resulting in diversified biomedical applications of CNTs (Figure 1).

Figure 1: Intrinsic Biomedical Applications of Carbon Nanotubes (CNT).

I. Diagonsis and Imaging: CNT act as biosensor or Nanorobots, which helps in diagnosis of disease, their progression level and their pathological condition in quick and better way. CNT biosensor are made up by conjugating different biochemicals with CNTs, like in glucuometer biosensor, glucose peroxidase is conjugated with CNTs that is use for the detection of blood sugar level in diabetic patients. Another example is SWCNTs-DNA biosensor that is use of detection of antigen –antibody comlex, which further helps in molecular diagnosis in pathology [7,8]. Complex of fluorescent agents and CNTs act as radio-opique agent that is use for the detection of cell and biological system in In-vivo organs [9].

II. Cancer Therapy: Carbon nantubes are effective against Pancreatic Cancer, Brain Cancer, Blood Cancer, Breast Cancer, Colon Cancer, Liver Cancer, Lymph Node, Metastasis, Prostate Cancer by using different anticancer drugs like Paclitaxel, Daunorubicin, Amphotericin B, Carboplatin, siRNA, Doxorubicin, Metal halides, Methotrexate etc. Apart from drug delivery route there are another two methods for cancer therapy using CNTs are immunotherapy and anti-tumor hyperthermia therapy [10].

III. Gene Therapy: CNTs and CNHs are used as vector in genetic engineering due to their cylindrical nature, which wrap the desired DNA and deliver it to target site to cure the genetic disorders by correcting misread or missense gene sequence [7].

IV. Infection/HIV Therapy: CNTs itself have antimicrobial activity by oxidising intracellular glutathione and resulted increase the oxidative stress on microbial cell that cause natural death of pathogen. CNTs also used in number of vaccinations to active immune response by triggering MHC-II, which further promote natural antibody production to stop the infection [11]. HIV( human immunodeficiency virus) that attack the immune response and decline the natural immunity, till date we cannot stop it completely but we can suppress or stop virus multiplication and control the disease .In this case conjugation of CNTs with siRNA that further deliver to T-Cell to stop virus proliferation [12].

V. Ocular Delivery: In case of ocular delivery there are number of challenges to deliver the drug to get adequate response with minimizing risk of infection. So therefore, SWCNTs-NH₃+ used as carrier to deliver antigen synthetic vaccination, safely and effectively by avoiding risk of necrosis and tissue degeneration [13].

VI. As Antioxidant: CNTs and CNHs are natural anti-oxidants. They are used in preserving drug molecules in formulation by inhibiting their oxidation. Furthermore, due to this property they are also used in anti-aging cosmetics products that oxidized the skin and stay it healthy and young [7].

VII. Neurodegenerative (ND)/Alzheimer Disease: Graphene sheets, and by extension CNTs, are excellent conductors of electricity, and thus are highly useful in the regeneration of neurons. Neurons can grow successfully on CNT beds, and modifying the surface with 4-hydroxyonoenal, known to be involved with neuron growth, can improve the neuron length and degree of branching over CNTs [11]. CNTs have many small additional sites that provide high surface area for external modification that’s why it is use as carrier to deliver the acetylcholine through blood brain barrier (BBB) and to treat Alzheimer Disease [14-16].

VIII. Tissue/Bone Regenreation: CNTs for the purpose of bone regeneration are being developed, which use negatively charged functional groups with calcium bonded to them. This can provide a scaffold to which hydroxyapatite, the most common inorganic component of bone, can attach. CNTs are very strong, stiff, and flexible which makes them an excellent alternative to the titanium or ceramic bone scaffolds [17,18].

IX. Carbon based nonmaterial by virtue of its therapeutic and diagnostic dual functions have emerged as theranostic nanomedicine. Carbon nanotubes intrinsic medicinal activities along with drug candidates may enhance the effectiveness of drug delivery. Unprecedented growth of patents and publication in last decade has forecasted the future of carbon based drug materials. A precise control for synthesis, purification and tools to increase solubility and further bio-functionality may lead to the development of carbon naotube based formulations. There is a need of clinical investigations for exploring the intrinsic medicinal activities of carbon nanotubes.

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Lupine Publishers | The Prognostic Value of One-Step Nucleic Acid Amplification (OSNA) and Immunohistochemistry (IHC) in Ex Vivo Sentinel Lymph Nodes in Stage I & II Colonic Cancer Patients - A Multicenter Cohort Study

Lupine Publishers | Open Access Journal of Oncology and Medicine (OAJOM)

Abstract

Introduction: Sentinel lymph node (SLN) mapping with multilevel-sectioning and immunohistochemistry (IHC) or One- Step Nucleic Acid Amplification (OSNA) are considered promising techniques to improve LN staging in colon cancer. This study investigates the prognostic significance of OSNA- and IHC-analysis of ex vivo SNLs of stage I&II colon cancer patients.

Methods: 86 stage I&II colon cancer patients were identified from two previously conducted cohort studies. All SLNs were examined with Hematoxylin & Eosin-staining (H&E), multilevel-sectioning with IHC and OSNA analysis. Kaplan-Meier and coxregression analysis were performed to determine the prognostic significance.

Results: Mean disease-free survival (DFS) for OSNA-positive vs OSNA-negative patients was 62.5 vs 62.0 months (p=0.886) and for IHC-positive vs IHC-negative patients 58.1 vs 62.9 months (p=0.519). Cox-regression analysis showed that positive OSNAstatus was not prognostic for DFS (hazard ratio (HR)=0.89, p=0.886). Additionally, also positive IHC-status showed no significant difference for DFS (HR 1.47, p=0.522).

Conclusions: Additional OSNA or IHC-analysis of ex vivo SLNs does not provide a more accurate prognostic value in this small group of stage I&II colon cancer patients compared with conventional H&E. A bigger study is needed to set these results in a broader perspective. Further research is required to identify other clinically relevant upstaging techniques and prognostic factors to tailor the treatment plans of these patients.

Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide with nearly 1,4 million newly diagnosed patients each year, accounting for 8% of all cancer related deaths [1,2]. In CRC, oncologic surgical resection is the primary therapy, followed by adjuvant chemotherapy on indication. Lymph node (LN) metastasis are one of the most important prognostic factors and are associated with worsened 5-year survival [3]. Previous studies demonstrated that 20-30% of node negative (stage I&II) patients suffer from disease recurrence within 5 years after surgery [4,5]. This could suggest that current conventional histopathological staging procedures, consisting of one or two sections of Hematoxylin & Eosin (H&E) through each detected LN, may not be precise enough to accurately describe the metastatic load in the resected LNs, possibly leading to undertreatment [6]. More accurate staging techniques are therefore needed to upstage colorectal patients considered to be node negative with conventional H&E examination. In order to improve the detection of LN metastasis, different techniques have been investigated. Sentinel lymph node (SLN) mapping with multilevel-sectioning and immunohistochemistry (IHC) has been proposed as a promising technique for improved LN staging in patients with colorectal cancer [6,7]. Various studies have demonstrated that the use of either in-vivo or ex-vivo SLN mapping can achieve upstaging rates up to 35% in CRC patients [6, 7]. More recently, the use of One-Step Nucleic Acid Amplification (OSNA) has been trialed in patients with CRC [8-10]. This technique, which is already used in approximately 200 centers as an intra-operative diagnostic tool in breast cancer patients, uses the reversetranscription loop-mediated isothermal amplification (TR-LAMP) method for mRNA amplification [11]. OSNA determines, within 30 minutes, the metastatic status of a whole LN. In recent years, some groups have investigated OSNA in patients with CRC and described it as a reliable method for improved staging of lymphatic metastases in CRC, with reported upstaging rates of 20-25% [8,9].

The long-term prognostic significance of all these new ultrastaging and upstaging techniques in CRC patients has, until now, not yet been fully investigated. Gaining this information could be important as upstaging and ultra-staging could also lead to overtreatment. Therefore, it is of critical importance to study the long-term value of these techniques. The objective of this study is to investigate the prognostic value of OSNA and IHC in ex vivo detected SLNs of stage I&II (H&E node negative) colon cancer patients.

Materials and methods

Patient Selection

For this retrospective follow-up study, patients with stage I&II colon cancer were identified from two previously conducted cohort studies [8]. Patients underwent standard oncological resection between November 2008 and December 2013 at two different centers, Jeroen Bosch hospital (JBH), ‘s Hertogenbosch and Leiden University Medical Center Leiden (LUMC). Stage III patients, T0 patients and high-risk stage I and II patients that had received adjuvant systemic chemotherapy (i.e pT4 tumor, poorly differentiated histology, presence of lymph vascular invasion, localized perforation and bowel obstruction) were excluded from this study. All other exclusion criteria were reported in the previous study [8].

Sentinel Lymph Node Mapping Pathological Examination and OSNA-Procedure

SLN mapping was performed ex-vivo within 15 minutes of resection. In patients operated at the JBH, SLN mapping was performed using Patent blue, whereas SLN mapping in the LUMC was performed using indocyanine green (ICG) and near-infrared light. The patent was injected submucosally and circumferentially around the tumor. In both centers the first three colored lymph nodes were marked as SLNs. The SLNs were processed in the same way in both hospitals as previously described [8]. In brief, the SLNs were cut into 4 pieces and labeled a, b, c and d. Slices a and c were pooled together and analysed using OSNA, and slices b and d were subjected to an intensive multilevel sectioning histologic workup, cut into 4 levels with 250μm between each level, with H&E and immunohistochemistry (anti-Pancytokeratin) [8]. The methods used for OSNA analysis are described in the instrument IFU and reagents package inserts [11,12]. Colon cancer was staged according to the 7th version of the TNM classification system [13]. The SLN’s were examined for the presence of tumor cells. All lymph nodes free from metastasis were judged node negative. Sentinel lymph nodes with at least 1 observed tumor cell detected with immunohistochemistry or >250 mRNA copies/μL in the OSNA analysis were judged as positive. A distinction in macro-metastasis [>2mm], micro-metastasis [ >0.2 and ≥ 2 mm] and isolated tumor cells (ITC) [≤ 0.2mm] was made for H&E and IHC [14]. Importantly, only results of the conventional H&E staging were used in clinical practice for interdisciplinary tumor board decision making.

Follow Up

Follow up data were collected retrospectively from the hospital related clinical charts with a median follow up of 50 months. Disease free survival was defined as absence of local or distant metastatic disease diagnosed with the use of computed tomography, MRI or biopsy. Standard follow up examinations were performed using the Dutch oncological follow-up guidelines for colon cancer after curative colon cancer resection [15].

Statistical Analysis

Statistical analysis was performed using SPSS version 23 (SPSS: An IBM Company, Chicago IL). Continuous variables were compared with the Student’s t, Mann-Whitney, one-way ANOVA and Kruskal- Wallis tests, where appropriate. Differences among proportions derived from categorical data were compared using the Fischer’s or the Pearson chi-square tests, where appropriate. All p values in the univariate analyses were two-sided and considered statistically significant if p ≤ 0.05. Cumulative survival was calculated with the Kaplan-Meier function and comparison were performed with Log Rank test. The COX regression model was used to identify the adjusted hazard ratio of survival for patients with OSNA and IHC workup. Data are presented as mean (SD), median (IQR), and HR (95% CI) where appropriate.

Results

Baseline characteristic

A total of 94 patients were included in the present analysis. Of the conventional H&E negative patients, in four patients there was no tumor present (T0) and to 4 node negative patients featuring high risk factors adjuvant systemic chemotherapy was given who were also excluded. Follow-up was successfully completed in all 86 patients with a median follow up of 50 months (SD:13,31). Baseline characteristics are shown in Table 1.

Oncological Follow Up

During the follow-up period 16 patients died of whom three patients died due to cancer related progressive disease. In 10 patient’s death was not cancer related – in four the cause of death was not further specified, one patient died due to postoperative complications, four dues to another malignancy and one patient due to a cerebro-vascular insult. In three patients the cause of death was unknown. Overall, the mean overall survival (OS) was 61.6 months. During the follow-up period 11 of 86 (12.8%) pN0 patients had tumor recurrence. Overall, mean disease-free survival (DFS) was 62.2 months (95%CI= 58.4-66.1months). Distant recurrences were localized in the liver (N= 6), lung (N= 4), skin (N=1) and brain (N=1). Four patients had distant metastasis at two different places at time of diagnosis. Local regional recurrence was localized in lymph nodes (N=3).

Prognostic Significance of OSNA and IHC in Ex Vivo SLN

A total of 18 patients were node positive by OSNA analysis and 68 OSNA-negative. With the use of multilevel sectioning with immunohistochemistry (IHC) 30 patients were node positive and 54 IHC-negative. Two patients had missing IHC data. In the IHC node positive patients micro-metastases were found in 2 patients and isolated tumor cells in 28 patients. Recurrence occurred in 2 of OSNA-positive patients vs 9 of OSNA-negative patients and in 5 of IHC-positive patients vs 6 of IHC-negative patients (Table 2). No significant difference in mean DFS for OSNA-positive vs OSNAnegative patients was observed (62.5 months vs 62.0 months (p=0.886)). Also mean DFS for IHC-positive vs IHC-negative patients showed no significant difference (58.1 months vs 62.9 months (p=0.519). Survival data is shown in Table 3 and figure 1a,b &2a,b. The prognostic independence of OSNA and IHC was tested with cox regression analysis. A positive-OSNA status was not associated with significant shorter disease-free survival, (Hazard ratio [HR]= 0.89, 95%CI=0.19-4.14, p=0.886). A positive-IHC status was also not associated with significant shorter disease-free survival, (Hazard ratio [HR]= 1.47, 95%CI=0.45-4.83, p=0.522).

Discussion

Our study is one of the first published study investigating the prognostic value for disease free survival of OSNA in the long-term follow-up of ex vivo detected SLNs of a small group of stage I&II colon cancer patients, showing no additional prognostic value. Whilst OSNA analysis and IHC can lead to upstaging of early colon cancer patients as described by Vogelaar et al, positive OSNA or IHC status of the ex vivo detected SNLs were no independent predictors for disease free survival in stage I&II colon cancer patients [8]. Therefore, these new upstaging techniques does not provide a more accurate prognostic value. However, the strength of evidence of these findings might be limited because of the reduced power of this study, since this study consisted of a small group of patients. Therefore, the value of these findings must be proven by a bigger study to set these results in a broader perspective. On the contrary, just recently, Itabashi et al. published a 3-years follow-up study of stage I-III CRC patients with sub-analyses in a small group of 70 stage II patients. Showing a significant worse prognosis for stage II OSNA-positive patients [16]. However, 55% of the OSNA-positive and 22% of the OSNA-negative patients were treated with chemotherapy. Since we corrected for this confounder the results of both studies are not comparable. Furthermore, we believe that our study demonstrates more representative results since chemotherapy influence survival outcome. The above shown discrepancy in OSNA-positive SLNs and SLNs harboring micro metastasis with IHC suggests that the OSNA cut-off value for micro metastasis (> 250-5000 copies of mRNA) is maybe not accurate enough to make a prognostic distinction between positive and negative LN status in stage I&II colon cancer patients [11-17]. New studies in breast cancer patients showed a more accurate cut-off value (> 2500 copies of mRNA) for the detection of micro metastases as a prognostic cut-off value, supporting this suggestion [17,18]. Therefore, it is likely that some LNs harboring ITCs are staged as positive nodes with the OSNA analysis leading to upstaging without clinical prognostic relevance, which is in line with some previous studies showing the prognostic value of micro metastasis but not of ITCs [4-20]. The strength of evidence of this study might be limited because of the combination of datasets from two different hospitals. However, both hospitals used the same protocol for the work up of the LNs and OSNA analysis. Although the type of marker used to detect the SLNs was different between the two hospitals, previous studies have shown that there is a high correlation between these different makers, and therefore it is very likely that this difference did not affect the detection rates [21]. Besides the OSNA cut-off value, the prognostic value of total tumor load (TTL) is recently investigated in breast cancer patients [22]. TTL is defined as the total number of CK19 mRNA in all OSNA positive SLNs [22]. These studies demonstrated that a TTL of > 15.000 mRNA is a new tool to predict the metastatic involvement of non-sentinel axillary nodes [22]. This new intra-operative tool could be of interest in early colon cancer patients when, in the future, more minimally invasive surgery will be performed. However, this data is not yet available in colon cancer patients and therefore further research is needed.

Furthermore, it is noteworthy that almost all disease recurrences seem to be of haematogenic nature. This metastatic pattern, the knowledge that 20-30% of stage I&II patients suffer from disease recurrence within 5 years after surgery and above mentioned results could suggest that LN assessment has less clinical value in stage I&II CRC patients than expected [4,5]. Another alternative that has been investigated in recent years is the prognostic value of tumor specific histopathological characteristics in these patients. Some of these characteristics of interest are tumor budding, poorly differentiated clusters and peri-neural invasion. Literature regarding these tumor specific histopathological characteristics is not unambiguously, but seems to have prognostic value in defining high risk stage I&II CRC patients [23,24]. Besides histopathological characteristics, several molecular biomarkers for stage I&II CRC patients have been studied in recent years, of which microsatellite instability (MSI) and mutations in the KRAS, BRAF and PIK3CA genes are the most wellknown biomarkers [25]. The prognostic value of these biomarkers in stage I&II CRC patients is not yet determined. However, recent studies show that these biomarkers might be valuable in staging I&II CRC patients [25]. Further research is therefore necessary to identify other clinically relevant upstaging techniques or molecular biomarkers and histopathological prognostic factors to improve the treatment of stage I&II CRC patients. In conclusion, this study demonstrated that OSNA-and IHC-analysis of ex vivo detected SLNs does not provide a more accurate prognostic value for disease free survival in a small group of patients with non-metastasized colon cancer compared with the conventional H&E. However, a bigger study is needed to set these results in a broader perspective. Further research is required to identify other clinically relevant ultra-staging and upstaging techniques or molecular biomarkers and histopathological prognostic factors to identify high risk stage I&II CRC patients, to improve the prognostic assessments and tailor the treatment plans.

Acknowledgement

The authors thank Sysmex Corporation for technical support and providing study material. M. Hilbink for statistical advice, J. Damen for technical support and B. Weixler for collecting the LUMC follow-up data.

Statement of Ethics and Funding Sources

The approval of the medical ethics committee of the participating hospitals were described in detail in the previous publication. According to this committees written informed consent was not necessary as this study concerned residual material and there were no treatment consequences. This study was performed according to the code of conduct for responsible use. Sysmex corporation provided the OSNA machine and study material for the OSNA analyses. This source had no role in the preparation of data or the manuscript.

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Lupine Publishers | Carbon Nanotubes: Exploring Intrinsic Medicinal Activities and Biomedical Applications

Lupine Publishers | Open Access Journal of Oncology and Medicine (OAJOM)

Lupine Publishers | Open Access Journal of Oncology and Medicine (OAJOM)

Introduction

Carbon Nano materials the king of nonmaterial’s have fascinating nanofamily including buckyballs or buckminsterfullerenes [1], multiwalled carbon nanotubes [2], the single-walled carbon naotubes(SWCNTs) [3], Carbon Nanohorns(CNHs), Carbon nanocones, Carbon nanofibers (CNFs), carbon nanothread, Buckypaper, carbon dots, nanodimons, nanoonions, nanorods, nanoribbons. Also called as powerful particles, CNTs (carbon nanotubes) has thus bloomed over the past decade [4,5]. Increasing evidence has shown that certain CNT properties such as nano-sized dimension, high surface energy, and large reactive surface area are directly correlated to their biological activities [6,7]. Great property of loading various biomolecules, diagnostic and therapeutic moieties resulting in diversified biomedical applications of CNTs (Figure 1).

I. Diagonsis and Imaging: CNT act as biosensor or Nanorobots, which helps in diagnosis of disease, their progression level and their pathological condition in quick and better way. CNT biosensor are made up by conjugating different biochemicals with CNTs, like in glucuometer biosensor, glucose peroxidase is conjugated with CNTs that is use for the detection of blood sugar level in diabetic patients. Another example is SWCNTs-DNA biosensor that is use of detection of antigen –antibody comlex, which further helps in molecular diagnosis in pathology [7,8]. Complex of fluorescent agents and CNTs act as radio-opique agent that is use for the detection of cell and biological system in In-vivo organs [9].

II. Cancer Therapy: Carbon nantubes are effective against Pancreatic Cancer, Brain Cancer, Blood Cancer, Breast Cancer, Colon Cancer, Liver Cancer, Lymph Node, Metastasis, Prostate Cancer by using different anticancer drugs like Paclitaxel, Daunorubicin, Amphotericin B, Carboplatin, siRNA, Doxorubicin, Metal halides, Methotrexate etc. Apart from drug delivery route there are another two methods for cancer therapy using CNTs are immunotherapy and anti-tumor hyperthermia therapy [10].

III. Gene Therapy: CNTs and CNHs are used as vector in genetic engineering due to their cylindrical nature, which wrap the desired DNA and deliver it to target site to cure the genetic disorders by correcting misread or missense gene sequence [7].

IV. Infection/HIV Therapy: CNTs itself have antimicrobial activity by oxidising intracellular glutathione and resulted increase the oxidative stress on microbial cell that cause natural death of pathogen. CNTs also used in number of vaccinations to active immune response by triggering MHC-II, which further promote natural antibody production to stop the infection [11]. HIV( human immunodeficiency virus) that attack the immune response and decline the natural immunity, till date we cannot stop it completely but we can suppress or stop virus multiplication and control the disease .In this case conjugation of CNTs with siRNA that further deliver to T-Cell to stop virus proliferation [12].

V. Ocular Delivery: In case of ocular delivery there are number of challenges to deliver the drug to get adequate response with minimizing risk of infection. So therefore, SWCNTs-NH₃+ used as carrier to deliver antigen synthetic vaccination, safely and effectively by avoiding risk of necrosis and tissue degeneration [13].

VI. As Antioxidant: CNTs and CNHs are natural anti-oxidants. They are used in preserving drug molecules in formulation by inhibiting their oxidation. Furthermore, due to this property they are also used in anti-aging cosmetics products that oxidized the skin and stay it healthy and young [7].

VII. Neurodegenerative (ND)/Alzheimer Disease: Graphene sheets, and by extension CNTs, are excellent conductors of electricity, and thus are highly useful in the regeneration of neurons. Neurons can grow successfully on CNT beds, and modifying the surface with 4-hydroxyonoenal, known to be involved with neuron growth, can improve the neuron length and degree of branching over CNTs [11]. CNTs have many small additional sites that provide high surface area for external modification that’s why it is use as carrier to deliver the acetylcholine through blood brain barrier (BBB) and to treat Alzheimer Disease [14-16].

VIII. Tissue/Bone Regenreation: CNTs for the purpose of bone regeneration are being developed, which use negatively charged functional groups with calcium bonded to them. This can provide a scaffold to which hydroxyapatite, the most common inorganic component of bone, can attach. CNTs are very strong, stiff, and flexible which makes them an excellent alternative to the titanium or ceramic bone scaffolds [17,18].

IX. Carbon based nonmaterial by virtue of its therapeutic and diagnostic dual functions have emerged as theranostic nanomedicine. Carbon nanotubes intrinsic medicinal activities along with drug candidates may enhance the effectiveness of drug delivery. Unprecedented growth of patents and publication in last decade has forecasted the future of carbon based drug materials. A precise control for synthesis, purification and tools to increase solubility and further bio-functionality may lead to the development of carbon naotube based formulations. There is a need of clinical investigations for exploring the intrinsic medicinal activities of carbon nanotubes.

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Lupine Publishers | Cancer: Our Body’s Global Warming Warning

Lupine Publishers Open Access Journal of Oncology and Medicine (OAJOM)

Opinion

Monday 4 February 2019 was yet another World Cancer Day. We celebrated our efforts to find and eradicate cancer without admitting to ourselves that cancer isn’t a single disease, but rather a group of diseases all caused by our bodies responding to the toxic environment we are exposing ourselves to, just as our planet is responding to the toxic wastes we are dumping into it. The question is WHY do our bodies run amok. The answer lies in the same answer to why Global Warming exists. It is the untold unimaginable continued damage and destruction we cause to the world and to ourselves that accounts for the destruction of the planet and the development of cancer within us. While some individuals may have a genetic predisposition [1] for certain types of cancers, it is nonetheless this constant bombarding of ourselves with toxins, which our bodies try to react to and when overwhelmed the climate change of our bodies occur and call for the eradication of first the damaged cells and then eventually ourselves. Just as the continued bombardment of our Earth with environmental toxins is resulting in violent changes on the planet in an attempt to respond to and eradicate the cause of the toxins to the plant, so too are our bodies reacting to try to eradicate these toxins and their effect within our bodies. This process on a biological basis is reflected in how the cells of our body respond to the cellular environment as shown in Figure1. The process of developing cancer or not developing cancer is not a sudden change but rather a transitional series of events resulting from the interaction between the specific responses and expression of the genome of the cell involved and the specific environment in which the cell is immersed. This environment includes both carcinogenic and non-carcinogenic factors. As the insults occur, the cellular mechanisms to respond to those insults include a variety of responses, including cellular repair and immunologic reactions. The outcome is determined by the interaction between these two opposing sets of factors. Progression or regression is determined by these responses. Clearly no one wants to have cancer or for the planet to be destroyed. Confusion comes from not knowing what is helpful and what is hurting us. Until recently [2], we have been limited by testing (qualitative imaging, biomarkers, etc.), which at best can only provide a yes/no answer to the question of whether a person has cancer or not. Many of these tests do not even provide a yes/no answer, but rather infer there could be a problem. These qualitative approaches are unable to provide us with information warning us that these transitional changes are happening [3]; changes which we could act upon if we only knew they were occurring. Changes which when measured could be used to determine if a given treatment is working [4], harming us or having no effect. Measurable changes which can show us cancer in its early stages [5]. These transitional changes can now be measured using FMTVDM [2]. The only question is whether we use this tool to help find these transitional changes and guide our treatment regimens or whether we will continue to pretend that what we are doing is working?

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Lupine Publishers | Micro-Environmental Systems and Endothelial Cells in Cooperative Tumorigenesis Account for Potential Malignant Transformation in Neurofibromatosis Type 1 Patients

Open Access Journal of Oncology and Medicine (OAJOM)

Lupine Publishers Open Access Journal of Oncology and Medicine (OAJOM)

Abstract

Overall tumorigenesis in neurofibromatosis type 1 patients constitutes a series of specific targeting events with a central role enacted by proliferation of fibroblasts and endothelial cells in overproduction of growth factors and cytokines such as transforming growth factor-beta and CXCL12 cytokine. The plexiform neurofibroma well-illustrates dimensions of such cooperative participation within operative fields of the initial Schwann cell proliferation leading in a significant number of patients to malignant transformation of the peripheral nerve sheath tumors. Inclusive directions in operative targeting of Schwann cells or astrocytes are staged performance in the transformation of hyperproliferative induction and constitute further evolutionarily defined incorporation of such systems as endothelial cells. Hyperproliferative cell subsets are initial and also consequential target formulation of potential malignant states as induced in malignant peripheral nerve sheath tumors.

Introduction

Neurofibromatosis type 1 (NF1) is a neurogenetic disorder and involves both heterozygous and homozygous absence/reduction of neurofibromin that acts normally as a tumor suppressor. There is a need to assess predisposing genetic factors and loss of heterozygosity causing emergence of aggressive neoplasms in patients with NF1 [1]. The two hit hypothesis helps account for the emergence of Schwann cell-based proliferations and for neurofibromas and plexiform neurofibromas. Gherkin may act on tumorigenesis of cutaneous neurofibromas via growth hormone secretagogue receptor [2]. It is important to consider the neurofibroma that is based on micro-environmental potentiation of tumor generation in patients that develop malignant nerve sheath tumors and astrocytomas in patients with NF1 +/- genotype; this occurs in a manner that involves growth factor overactivity and mast cell and endothelial overactivity within a milieu that dysfunctionally stimulates tumorigenesis. Reactive oxygen species overproduction lead to epithelial-mesenchymal transit in patients with neurofibromin deficiency and plays a crucial role in NF1 tumor growth [3]. RAS activation alone is not sufficient for malignant transformation of peripheral nerve sheath tumors; signal transduction may potentially help identify therapies for this neoplasm type [4].

Neurofibromin

The dynamics of neurofibromin as a cytoplasmic protein involve the regulation of K-Ras, and the PI3K/Akt pathways; absence of neurofibromin leads to overactivation of these pathways in various ways in inducing tumorigenesis in such lesions as optic tract pilocytic astrocytomas, brain stem astrocytomas and also other CNS astrocytomas in terms of progression of these lesions. The cell of origin determines the temporal course of neurofibromatosis-1 low-grade glioma formation [5]. The micro-environment of plexiform neurofibromas of peripheral nerves and of nerve plexi include a 10% risk of malignant change with subsequent aggressive clinical behavior in the affected patients. Over expression of cellular retinoid acid binding protein 2 is reported in several cancer types, including malignant peripheral nerve sheath tumors (MPNSTs) [6].

Related Tumor Predispositions

The neurofibromin insufficiency status in Schwann cells and fibroblasts allows for enhanced participation of immune system component cells such as microglia as evidenced in optic pathway low-grade astrocytomas. Telomere erosion is described in many tumor types and may potentially drive genomic instability and clonal progression in NF1-associated MPNSTs [7]. Tumor dimensions include proliferation of astrocytic cells in optic pathways, and of various subtypes of stromal cells such as fibroblasts and mast cells in the peripheral nervous system. It is significant to consider particularly the micro-environmental active participation in the genesis of the most common tumor type in Neurofibromatosis type 1 patient, that is the neurofibroma, which invokes proliferation of fibroblasts and endothelial cells. The congenital plexiform neurofibroma is in fact a hypervascular lesion that transgresses tissue margins and induces a significant risk for malignant transformation. NF1 loss is the primary driver of tumorigenesis in neurofibromatosis type 1-related plexiform neurofibroma [8]. It is further to such considerations that important cooperative intervention in malignant transformation of plexiform neurofibromas invokes multi-type cells in inducing proliferation of an integral Schwann cell-fibroblastic twin population in enhancing potential malignant transformation of the peripheral nerve sheath. A therapeutic window for neuroprotective intervention exists as detected by optical coherence tomography in mice with optic glioma, and particularly as an accurate biomarker of retinal ganglion cell apoptosis [9]. The heterozygous absence of one neurofibromin allele in mice results in plexiform neurofibromas and low-grade optic pathway astrocytomas. Mast cells appear to play a causal role in neurofibroma formation and also in microglia in optic pathway glioma evolution [10]. Such implications of the micro-enviromental factors includes a distinctive cooperative participation that carries implications for significant enhancement of cell proliferation and of such cytokines such as transforming growth factor and CXCL12 in formulating malignant transformation in such tumors. The methylemetetrahydrofolate reductase 1298 and 677 gene polymorphisms are related to optic glioma and hamartoma risk in NF1 patients through effects on DNA synthesis and methylation [11].

Convergent Targeting

The related tuberous sclerosis complex is analogous to neurofibromatosis type 1 as a neurogenetic disorder associated with increased risk for astrocytomas in the form of subependymal giant cell astrocytomas. A convergent targeting of systems of cell proliferation include in particular cyclic AMP and Ras in a manner that includes dimensions of micro-environmental conditioning. Mutations of the NF 1 gene are frequent in many cancer types in patients without NF1 and this is suggestive of a more general role for the NF1 gene in oncogenesis. In melanoma NF1 mutations potentially drive tumorigensis and promote drug resistance [12]. Inclusive dynamics allow for permissive tumorigenesis in a manner that includes the incorporation of malignant transformation within confines of a Schwann cell-fibroblast-endothelial cell system in the case of malignant peripheral nerve sheath tumors. Astrocytes and microglia are analogous counterparts in the induction of CNS astrocytomas. Such considerations are inclusive phenomena of multi-component induction of potential malignancy that recharacterizes conditioning of the micro-environment of proliferative states preceding tumorigenesis. Interaction between neoplastic Schwann cells and their surrounding neural microenvironment has important implications for early cellular events promoting tumorigenesis in neurofibroma development [13].

Performance Dynamics

Performance dynamics of tumors in neurofibromatosis type 1 may potentially modify the biologic significance of a two-hit hypothesis in a manner that implicates micro-environmental conditioning of the resultant cell hyperplasias and proliferations in such lesions as peripheral nerve sheath tumors and astrocytomas. NF1 provides unique vantage points to examine co-contributions of molecular, cellular, and tissue processes in tumor biology [14]. Such proposed dimensions invoke in particular an over-activation in production and action of growth factors that provoke selective malignant transformation of hyper-proliferative lesions composed of Schwann cells and astrocytes in the peripheral and central nervous systems respectively. Plasma soluble levels of transforming growth factor-beta and interleukin-6 are increased in NF1 patients and a shift towards an anti0inflammatory profile has been reported in cells expressing cytokines [15].

Hyperproliferation

The hyperproliferative states affecting Schwann cells and astrocytes invoke also fibroblast and microglial cell proliferations in a manner transforming tumorigenesis. Such facilitation to tumorigenesis invokes dimensions of transformation as well seen in plexiform neurofibromas that may undergo malignant transformation in a significant number of affected individuals. Such considerations are selective targeting of specific cell subpopulations in a manner that allows permissive transformation. Insertional mutagenesis identifies a STAT3/Arid1b/beta-catenin pathway that drives neurofibroma initiation in the context of Nf1 loss [16]. Mast cells and fibroblasts may potentially incorporate endothelial cells that may participate as central dysregulatory dimensions in plexiform neurofibroma tumorigenesis. The provocations for malignant transformation further cooperate in systems of derivative consequence as hypervascular lesions that subsequently lead to potential malignant cells in individual patients. Cross species comparative oncogenomic may identify driver mutations in mouse cancer models and allow validation in human tumors [17].

Concluding Remarks

Propositional implications in tumorigenesis include the multi-component participation of Schwann cells on the one hand and of fibroblasts, mast cells, endothelial cells and also of microglia in an inductive process that includes specific pathways of malignant transformation. Endothelial cell proliferation is related to substantial participation in modes related to key-events of increased proliferation of Schwann cells and astrocytes in initial stages of lesion infliction. Inclusive phenomena have thus become systems of consequence in affecting such specific cell proliferative states. Such events occur within the added dimensions of directed targeting of multiple-agent micro environmental modeling of the initial proliferation of the Schwann cells or astrocytes. A pivotal series of roles played by fibroblasts, endothelial cells, mast cells and of microglia and astrocytes appears a dynamic milieu within added consequences of malignant transformation of both Schwann cells and astrocytes that progress as cooperative systems of tumorigenesis.

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Lupine Publishers | Acupuncture and Reiki as a Prevention Strategy of Burnout and Occupational Stress in Oncology

Lupine Publishers |  Open Access Journal of Oncology and Medicine (OAJOM)

Introduction

Burnout is one of the health problems that occur most prominently among human service professionals. This syndrome was first identified in [1] by Freudenberger and defined as “a physical and emotional fatigue that leads to a loss of motivation for the work, which can evolve until the onset of feelings of failure [2]. In the following years other definitions have been proposed, highlighting the syndrome impact on the personal and professional dimension of the worker’s life as well as the relationship of the health professional with his clients. Schaufeli e Greenglass [3] stated that Burnout is “a state of physical, emotional and mental exhaustion that results from long-term involvement in work situations that are emotionally demanding” [3]. When affected, human service professionals can fail to feel compassion for the suffering of others and stop giving them the care they need, particularly the emotional and communicational needs. In the same extent, professionals suffering from burnout tend to depart completely from their functions, which could result in serious damage to public health as it results in a waste of talent and training resources [4].

A study conducted by the European Young Oncologists from ESMO (2017) has shown that burnout is highly prevalent amongst European oncologists, being the cause for several negative consequences on quality of patient care, professional satisfaction and personal life. Acupuncture is an integral part of Traditional Chinese medicine and defined as a reflex therapy in which the nociceptive stimulus of the point of acupuncture triggers responses in other areas of the body (Schippers, 1993). Reiki is a complementary therapy that uses a healing system characterized by the laying on of hands on human bodies with the intention to re-establish the physical, mental and spiritual balance [5]. As both therapies have demonstrated efficacy in the treatment of anxiety and stress, a study was conducted in order to evaluate the role of these therapies in the Burnout and Stress prevention of healthcare professionals working in a busy Oncology and Hematology Department in a Portuguese hospital – Centro Hospital de Vila Nova de Gaia/Espinho (CHVNG).

Method

Subjects and methods

An experimental, cross-sectional study was conducted between April and June 2017 in accordance with the ethical standards of the IGH-GCP guidelines and the Declaration of Helsinki. Medical doctors, nurses and other healthcare staff of the Oncology and Haematology Department were invited to participate. Each participant underwent three simultaneous sessions of Acupuncture and Reiki during two months and completed the Maslach’s Burnout Inventory – Human Service Surveys (MBI-HSS), previously translated to and validated in Portuguese [6], and the Stress Questionnaire for Health Professionals (SQHP), before and after the acupuncture and Reiki sessions, in order to collect comparative data about the burnout and stress situation of the healthcare professionals submitted to the experience. The data obtained was analysed using SPSS and their internal consistency assessed by the Alfa Cronbach measurement resulted in good consistency values (.70-.90). Statistical analysis was divided in a descriptive analysis and a multiple comparisons in between data collected before and after the attendance on the acupuncture and Reiki sessions.

On the multiple comparisons, all the non-parametric variables resulting from the implementation of the above mentioned instruments were tested by the Wilcoxon signed-rank test. In addition, two qualitative issues were addressed to participants with the aim of registering opinions about the effectiveness of acupuncture and Reiki. The results were submitted to the content analysis method [7].

Results

Sixteen physicians, nurses and other healthcare staff aged 44.3 years (PD= 7.67) answered to MBI-HSS and the data collected revealed that Emotional Exhaustion followed by Personal Achievement are the main factors of burnout in their profession (Table 1). Regarding to the intervention itself, and taking into account the fact that only three acupuncture and Reiki sessions were performed in each participant, data showed a slightly decline of the Burnout in each of the factors. Personal Achievement was the predicting variable that has decreased more significantly with an average decrease of 50%. The non-parametric statistical hypothesis test used to compare the values of the sample after and before the experiment denoted the existence of asymptotic significance for the level of significance μ0=,05. For the items Emotional Exhaustion and Depersonalization the null hypothesis was rejected being only retained when considering the repeated measures for Personal Achievement.

The Wilcoxon signed-rank test for Burnout values of the sample did not show a statistically significant reduction in the burnout levels for the studied population. Similar results were also seen for the values referring to occupational stress, as shown in Table 2. As far as the participants’ opinion regarding acupuncture and Reiki is concerned, the results revealed a positive development of the perception of the participants. In fact, before the beginning of the experiment the participants had very low expectations about these therapies. However, after three sessions the majority affirmed to be satisfied and showed willing to continue.

Discussion

A decrease in burnout and stress levels in our sample after acupuncture and Reiki treatment was determined, although the reduction was not significant. Considering these results it is important not to overlook some aspects and conditions under which the experiment was conducted, namely the difficulty in building a solid sample and to ensure that all participants received the same number of treatments in the same period of time, due to constraints of working hours of the investigators. In fact, it was necessary to conjugate the available time of all participants with the time that the acupuncture and Reiki techniques, only two for the whole sample, had to perform the sessions. These difficulties prevented the completion of the initially desired five treatment sessions, which obviously, impact the results obtained. As stated by the European Young Oncologists from ESMO (2017), burnout is the cause for many negative consequences on the quality of patient care, professional satisfaction and personal life, and it is a health problem that most frequently affects human service professionals [4], a fact that was also verified in the present study sample (Table 3).

The results of our study suggest that acupuncture and Reiki have potential to reduce the prevalence of burnout and occupational stress related to cancer care. Furthermore, we underline the qualitative opinions registered among participants when completing the questionnaire, after acupuncture and Reiki sessions. Initially all felt a mixture of curiosity and scepticism but, in the end, all unanimously express their willingness to continue to have acupuncture and Reiki treatments because this experience make them to restore inner peace and balance. Furthermore, it should be stressed that participants reported, at the end of the treatment, an improvement of debilitating symptoms such as migraines, premenstrual syndrome, breathing difficulties, nausea related to pregnancy and osteoarticular pain. Those findings, although not being part of the main objective of the study, highlight other positive aspects of acupuncture and Reiki with regard to the promotion of physical and emotional well-being amongst Oncology and Hematology professionals [8].

Conclusion

The obtained results are not sufficient to demonstrate the benefits of acupuncture and Reiki as supportive therapies in the burnout and occupational stress prevention of healthcare professionals working with cancer patients. Nevertheless, they pave the way for new studies, with larger samples and therapy sessions, that adequately assess the real impact of these alternative therapies in health and well-being of healthcare professionals in oncology.

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Lupine Publishers | Micro-Environmental Systems and Endothelial Cells in Cooperative Tumorigenesis Account for Potential Malignant Transformation in Neurofibromatosis Type 1 Patients

Lupine Publishers |  Open Access Journal of Oncology and Medicine (OAJOM)

Abstract

Overall tumorigenesis in neurofibromatosis type 1 patients constitutes a series of specific targeting events with a central role enacted by proliferation of fibroblasts and endothelial cells in overproduction of growth factors and cytokines such as transforming growth factor-beta and CXCL12 cytokine. The plexiform neurofibroma well-illustrates dimensions of such cooperative participation within operative fields of the initial Schwann cell proliferation leading in a significant number of patients to malignant transformation of the peripheral nerve sheath tumors. Inclusive directions in operative targeting of Schwann cells or astrocytes are staged performance in the transformation of hyperproliferative induction and constitute further evolutionarily defined incorporation of such systems as endothelial cells. Hyperproliferative cell subsets are initial and also consequential target formulation of potential malignant states as induced in malignant peripheral nerve sheath tumors.

Introduction

Neurofibromatosis type 1 (NF1) is a neurogenetic disorder and involves both heterozygous and homozygous absence/reduction of neurofibromin that acts normally as a tumor suppressor. There is a need to assess predisposing genetic factors and loss of heterozygosity causing emergence of aggressive neoplasms in patients with NF1 [1]. The two hit hypothesis helps account for the emergence of Schwann cell-based proliferations and for neurofibromas and plexiform neurofibromas. Gherkin may act on tumorigenesis of cutaneous neurofibromas via growth hormone secretagogue receptor [2]. It is important to consider the neurofibroma that is based on micro-environmental potentiation of tumor generation in patients that develop malignant nerve sheath tumors and astrocytomas in patients with NF1 +/- genotype; this occurs in a manner that involves growth factor overactivity and mast cell and endothelial overactivity within a milieu that dysfunctionally stimulates tumorigenesis. Reactive oxygen species overproduction lead to epithelial-mesenchymal transit in patients with neurofibromin deficiency and plays a crucial role in NF1 tumor growth [3]. RAS activation alone is not sufficient for malignant transformation of peripheral nerve sheath tumors; signal transduction may potentially help identify therapies for this neoplasm type [4].

Neurofibromin

The dynamics of neurofibromin as a cytoplasmic protein involve the regulation of K-Ras, and the PI3K/Akt pathways; absence of neurofibromin leads to overactivation of these pathways in various ways in inducing tumorigenesis in such lesions as optic tract pilocytic astrocytomas, brain stem astrocytomas and also other CNS astrocytomas in terms of progression of these lesions. The cell of origin determines the temporal course of neurofibromatosis-1 low-grade glioma formation [5]. The micro-environment of plexiform neurofibromas of peripheral nerves and of nerve plexi include a 10% risk of malignant change with subsequent aggressive clinical behavior in the affected patients. Over expression of cellular retinoid acid binding protein 2 is reported in several cancer types, including malignant peripheral nerve sheath tumors (MPNSTs) [6].

Related Tumor Predispositions

The neurofibromin insufficiency status in Schwann cells and fibroblasts allows for enhanced participation of immune system component cells such as microglia as evidenced in optic pathway low-grade astrocytomas. Telomere erosion is described in many tumor types and may potentially drive genomic instability and clonal progression in NF1-associated MPNSTs [7]. Tumor dimensions include proliferation of astrocytic cells in optic pathways, and of various subtypes of stromal cells such as fibroblasts and mast cells in the peripheral nervous system. It is significant to consider particularly the micro-environmental active participation in the genesis of the most common tumor type in Neurofibromatosis type 1 patient, that is the neurofibroma, which invokes proliferation of fibroblasts and endothelial cells. The congenital plexiform neurofibroma is in fact a hypervascular lesion that transgresses tissue margins and induces a significant risk for malignant transformation. NF1 loss is the primary driver of tumorigenesis in neurofibromatosis type 1-related plexiform neurofibroma [8]. It is further to such considerations that important cooperative intervention in malignant transformation of plexiform neurofibromas invokes multi-type cells in inducing proliferation of an integral Schwann cell-fibroblastic twin population in enhancing potential malignant transformation of the peripheral nerve sheath. A therapeutic window for neuroprotective intervention exists as detected by optical coherence tomography in mice with optic glioma, and particularly as an accurate biomarker of retinal ganglion cell apoptosis [9]. The heterozygous absence of one neurofibromin allele in mice results in plexiform neurofibromas and low-grade optic pathway astrocytomas. Mast cells appear to play a causal role in neurofibroma formation and also in microglia in optic pathway glioma evolution [10]. Such implications of the micro-enviromental factors includes a distinctive cooperative participation that carries implications for significant enhancement of cell proliferation and of such cytokines such as transforming growth factor and CXCL12 in formulating malignant transformation in such tumors. The methylemetetrahydrofolate reductase 1298 and 677 gene polymorphisms are related to optic glioma and hamartoma risk in NF1 patients through effects on DNA synthesis and methylation [11].

Convergent Targeting

The related tuberous sclerosis complex is analogous to neurofibromatosis type 1 as a neurogenetic disorder associated with increased risk for astrocytomas in the form of subependymal giant cell astrocytomas. A convergent targeting of systems of cell proliferation include in particular cyclic AMP and Ras in a manner that includes dimensions of micro-environmental conditioning. Mutations of the NF 1 gene are frequent in many cancer types in patients without NF1 and this is suggestive of a more general role for the NF1 gene in oncogenesis. In melanoma NF1 mutations potentially drive tumorigensis and promote drug resistance [12]. Inclusive dynamics allow for permissive tumorigenesis in a manner that includes the incorporation of malignant transformation within confines of a Schwann cell-fibroblast-endothelial cell system in the case of malignant peripheral nerve sheath tumors. Astrocytes and microglia are analogous counterparts in the induction of CNS astrocytomas. Such considerations are inclusive phenomena of multi-component induction of potential malignancy that recharacterizes conditioning of the micro-environment of proliferative states preceding tumorigenesis. Interaction between neoplastic Schwann cells and their surrounding neural microenvironment has important implications for early cellular events promoting tumorigenesis in neurofibroma development [13].

Performance Dynamics

Performance dynamics of tumors in neurofibromatosis type 1 may potentially modify the biologic significance of a two-hit hypothesis in a manner that implicates micro-environmental conditioning of the resultant cell hyperplasias and proliferations in such lesions as peripheral nerve sheath tumors and astrocytomas. NF1 provides unique vantage points to examine co-contributions of molecular, cellular, and tissue processes in tumor biology [14]. Such proposed dimensions invoke in particular an over-activation in production and action of growth factors that provoke selective malignant transformation of hyper-proliferative lesions composed of Schwann cells and astrocytes in the peripheral and central nervous systems respectively. Plasma soluble levels of transforming growth factor-beta and interleukin-6 are increased in NF1 patients and a shift towards an anti0inflammatory profile has been reported in cells expressing cytokines [15].

Hyperproliferation

The hyperproliferative states affecting Schwann cells and astrocytes invoke also fibroblast and microglial cell proliferations in a manner transforming tumorigenesis. Such facilitation to tumorigenesis invokes dimensions of transformation as well seen in plexiform neurofibromas that may undergo malignant transformation in a significant number of affected individuals. Such considerations are selective targeting of specific cell subpopulations in a manner that allows permissive transformation. Insertional mutagenesis identifies a STAT3/Arid1b/beta-catenin pathway that drives neurofibroma initiation in the context of Nf1 loss [16]. Mast cells and fibroblasts may potentially incorporate endothelial cells that may participate as central dysregulatory dimensions in plexiform neurofibroma tumorigenesis. The provocations for malignant transformation further cooperate in systems of derivative consequence as hypervascular lesions that subsequently lead to potential malignant cells in individual patients. Cross species comparative oncogenomic may identify driver mutations in mouse cancer models and allow validation in human tumors [17].

Concluding Remarks

Propositional implications in tumorigenesis include the multi-component participation of Schwann cells on the one hand and of fibroblasts, mast cells, endothelial cells and also of microglia in an inductive process that includes specific pathways of malignant transformation. Endothelial cell proliferation is related to substantial participation in modes related to key-events of increased proliferation of Schwann cells and astrocytes in initial stages of lesion infliction. Inclusive phenomena have thus become systems of consequence in affecting such specific cell proliferative states. Such events occur within the added dimensions of directed targeting of multiple-agent micro environmental modeling of the initial proliferation of the Schwann cells or astrocytes. A pivotal series of roles played by fibroblasts, endothelial cells, mast cells and of microglia and astrocytes appears a dynamic milieu within added consequences of malignant transformation of both Schwann cells and astrocytes that progress as cooperative systems of tumorigenesis.

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