Chewing Doma (Fermented Betel Nut): Culture versus Cancer?

Dr. Amol PatelAreca nut consumption is embedded in many cultures, including that of Bhutan, several parts of India, and other South Eastern countries. Traditional fermenting of areca nut results in the production of what is called doma in Bhutan. The process enhances its carcinogenic potential and is tightly linked to oral and upper gastrointestinal cancers. As many as 45% of Bhutanese people chew doma. It is the number one cause of cancers of the oral cavity, oropharynx, hypopharynx, and larynx. We propose the slogan "Don't chew your way to cancer, say no to doma" would help in reducing oral and esophageal cancers in Bhutan.

Real world study of safety and efficacy of lorlatinib as second line and beyond in ALK-rearranged advanced non-small cell lung cancer patients in India - a multicentre chart review study (ROSELAND).

Background: Lorlatinib, an anaplastic lymphoma kinase (ALK)-inhibitor, is approved as frontline as well as subsequent line of therapy in ALK-rearranged advanced non-small cell lung cancer (NSCLC). There is limited literature about safety and efficacy of lorlatinib in Indian patients. Materials and methods: This was a retrospective multicentre study on patients with ALK-rearranged advanced NSCLC received lorlatinib as second line and beyond between May 2017 and December 2021. ALK was tested either by immunohistochemistry or fluorescent in-situ hybridisation. Clinicopathologic features, treatment details, toxicity and outcomes were analysed. Results: A total of 38 patients were enrolled with a median age of 54 years (range: 30-72) and male: female ratio of 20:18. Fifteen (44%) patients had brain metastases at baseline. Lorlatinib use was - second line in 11 (29%), third line in 21 (55%) and fourth line in 4 (11%) of patients, respectively. The best radiologic response to lorlatinib was - complete response in 9 (24%), partial response in 17 (46%), stable disease in 9 (24%) and progressive disease in 2 (5%) of patients, respectively. After a median follow-up of 76.6 months (95% CI: 68.9-100), the median progression-free survival (PFS) of lorlatinib was not reached (95% CI: 24.3-not reached) and median overall survival (OS) of the whole cohort was 93.1 months (95% CI: 62-not reached). Both median PFS (p = 0.48) and median OS (p = 0.74) was similar between second line and later line use of lorlatinib. Thirty-three (87%) patients experienced treatment-related toxicity and six (16%) patients required dose modification. Conclusion: Lorlatinib was highly efficacious in terms of overall response rate, median PFS and median OS in this small real-world cohort of advanced ALK+ve NSCLC with a manageable safety profile.

Effectiveness of Immune Checkpoint Inhibitors in Various Tumor Types Treated by Low, Per-Weight, and Conventional Doses at a Tertiary Care Center in Mumbai.

PURPOSE: The cost of immune checkpoint inhibitors (ICIs) limits their accessibility to a small number of patients with cancer in low- and middle-income countries. Early-phase clinical trials have shown target inhibition and high activity at doses lower than those registered and evaluated in clinical trials. Here, we report everyday experience of using ICIs in 100 Indian patients, many of whom received lower doses of ICIs. METHODS: Consecutive patients who received at least one dose of an ICI irrespective of tumor type at a tertiary care hospital in Mumbai, India, that was able to access ICIs for its patients were enrolled. The objectives were to study the doses used over a 3-year time period, and the effectiveness of therapy, assessed primarily by the overall response rate (ORR), overall survival (OS), and progression-free survival were secondary end points. RESULTS: Twenty-five patients were treated with conventional doses of ICIs, 29 patients received lower doses per body weight, and 46 patients received low-dose treatment. The median number of cycles received was 5 (range, 1-28). Seventy-eight patients received ICIs in a palliative setting. The median follow-up time was 10.2, 9.8, and 3.9 months for those receiving fixed approved dosing, per body weight dosing, and low-dose treatment, respectively. There was a trend with time to prescribe lower doses. Response evaluation was available for 92 patients. Twenty-one (five-adjuvant and 16-palliative) patients received ICIs only. The ORR did not differ statistically among different dosing groups, but comparisons are confounded by inclusion of different ICIs, different tumor sites, and concurrent treatments. The median OS was 6.8 (range, 4.6-9.0) months. CONCLUSION: Adoption of per-body weight and lower dosing of ICIs appears to give acceptable outcomes. Lower dosing can improve access and timely delivery of ICIs in low- and middle-income countries.

Phase 1/2 Study of the Timing and Efficacy of 3 mg Peg-GCSF in Neo/Adjuvant Dose Dense Breast Cancer Treatment Protocols.

Amol PatelBackground Peg-GCSF has similar efficacy at a dose of 60 µg/kg and 100 µg/kg. The conventional 6 mg SC dose was based on the maximum tolerable dose. In Japan, 3.6 mg dose was approved on the basis of dose finding studies. Peg-GCSF is an integral part of dose-dense chemotherapy protocols. Dose finding and scheduling study of peg-GCSF have not been conducted in Indian patients. Materials and Methods We conducted two-center phase 1/2 clinical study addressing the timing and efficacy of peg-GCSF in Indian breast cancer patients (CTRI no: 2021/07/034751). Three groups of timing administration were studied, namely 1, 6, and 24 hours post chemotherapy. The phase 2 part was the expansion of the best timing group. The primary objective was dose density, which was defined as receiving chemotherapy on < 3 days of scheduled date. Adriamycin/epirubicin cyclophosphamide (AC/EC) was administered q2 weeks. The total leucocyte (TLC) and absolute neutrophil (ANC) kinetics were studied. Other outcomes were incidence of grade 4 neutropenia, febrile neutropenia (FN), and requirement of additional doses of G-CSF. Bone pain, fever, and myalgia were studied for adverse effects. Results From November 20 to December 21, 36 patients were enrolled. Patient characteristics are depicted in Table 1. Initially, three patients received the peg-GCSF in each timing group. One patient in each 1-hour and 6 hours needed G-CSF support for maintaining the dose density. The 24-hour group was carried to phase 2 part. Dose density was maintained in 97% of patients. None of the patient in 24-hour group had FN. Also, 4/30 patients had grade 4 neutropenia and required an additional dose of GCSF. Grade 3 or 4 bone pain was not noticed by any of the patients. During the first cycle, the mean ANC (cells/µL) was 5284, 20704, 3010, 6954 on D0, D + 3, D + 7, and D + 13, respectively (Fig. 1A-TLC and 1B-ANC). The mean ANC (cells/µL) rise on D + 3 in cycles 1, 2, 3, 4 was 23810, 29209, 32428,22455, respectively. Conclusion Dose density of AC/EC breast cancer protocol is maintained with peg-GCSF 3 mg. Post chemotherapy 24-hour timing of peg-GCSF administration remains as the standard. A phase 3 trial of 6 mg versus 3 mg is warranted.

Molecular basis and clinical application of targeted therapy in oncology.

Targeted therapy and precision oncology aim to improve efficacy and minimize side effects by targeting specific molecules involved in cancer growth and spread. With the advancements in genomics, proteomics, and transcriptomics with the accessible modalities such as next-generation sequencing, circulating tumor cells, and tumor Deoxyribonucleic Acid (DNA), more number of patients are being offered the targeted therapy in form of monoclonal antibodies and various intracellular targets, specific for their tumor. The harnessing of host immunity against the cancer cells by utilizing immune-oncology agents and chimeric antigen receptor T-cell therapy has further revolutionized the management of various cancers. These agents, however, have the challenge of managing the adverse effects that are peculiar to the class of drugs and very different from the conventional chemotherapy. This review article discusses the molecular basis, diagnostics, and use of targeted therapy in oncology.

Cancer trends and burden among Armed Forces personnel, veterans and their families: Cancer registry data analysis from tertiary care hospital.

Background: Cancer incidence is rising across the globe. The incidence and patterns of various cancers among Armed Forces Personnel and Veterans is not known. We did the analysis of registry data maintained at our hospital. Methods: A retrospective analysis was performed of all patients registered at our hospital cancer registry between 01st January 2017 and 31st December 2019. Patients were registered with unique identification number. Baseline demographics and cancer subtype data were retrieved. Patients with histopathologically proven diagnosis and age ≥18 years were studied. Armed Forces Personnel (AFP) were defined as those who are in active service, and Veterans as those who had retired from service at the time of registration. Patients with Acute and Chronic Leukemias were excluded. Results: New cases registered were 2023, 2856 and 3057 in year 2017, 2018, 2019 respectively. AFP, Veterans and dependents among them were 9.6%, 17.8%, and 72.6% respectively. Haryana, Uttar Pradesh and Rajasthan represented 55% of all cases with male to female ratio 1.14:1 and median age was 59 years. The median age among AFP was 39 years. Among AFP as well as veterans, Head and Neck cancer was the most common malignancy. Cancer incidence was significantly higher in adults >40 years as compared to <40 years. Conclusion: Seven percent rise per year of new cases in this cohort is alarming. Tobacco-related cancers were the most common. There is an unmet need to establish a prospective centralized Cancer Registry to better understand the risk factors, outcomes of treatment and strengthen the policy matters.

Real-World Breast Cancer Patient Follow-Up Practices by Medical Oncologists in India-A Survey Report.

Amol PatelBackground In India, breast cancer patients' post-treatment follow-up practices are not known. We did this survey to understand how the breast cancer patients are followed-up and tried to explore the challenges associated with it. Methods We conducted a survey-based study among Indian oncologists. Seven questions were framed pertaining to follow-up practices. Answers were provided in the form of multiple options. Google forms platform was used. Survey was circulated through social media apps and through mail. We sought suggestions and opinions to address the challenges from participants. Results A total of 158 medical oncologists responded to this survey. 10% were not aware that only history and clinical examination are the scientific recommendations for follow-up. Ninety percent of the medical oncologists felt clinical breast examination as an uncomfortable practice for patients and physicians and 39% ordered a chest X-ray and an ultrasound abdomen. Annual mammogram was ordered by 83%, and blood investigations were recommended by 14% routinely. The majority (49.6%) felt that the absence of a female attendant, physician and patient factors were responsible for nonadherence to clinical breast examination. The DEXA scan was recommended by 84 (53%) medical oncologists regularly for patients on aromatase inhibitors, while 23 (14%) did not recommend it. Conclusion There is a disparity between scientific recommendations and real-world follow-up practices. A large number of medical oncologists relied on chest X-ray and ultrasound abdomen. There is an unmet need to address this issue.

Cancer in the Adolescent and Young Adults (AYA) and Children: A Comprehensive Analysis of the Epidemiology and Psychosocial Morbidity in the Indian Population.

Bhupesh GuleriaAims Adolescent and young adults (AYAs), children with cancer, and their guardians have unique psychosocial morbidities adversely effecting quality of life (QOL). This is measurable using patented tools. We analyzed epidemiological and clinicopathological patterns of solid organ cancers in this subgroup. We also assessed psychosocial morbidity and changes in QOL faced by them. Methods All patients aged 2 to 39 years, newly diagnosed with cancer from April 2017 to March 2019 were included. Clinical history, diagnosis, staging, treatment, outcomes, and follow-up were recorded. The National Comprehensive Cancer Network (NCCN) distress thermometer and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C-30) were used to assess psychosocial morbidity of AYAs, children ≥ 12 years, and parents of children < 12 years. Pediatric Quality of Life Inventory (Peds QL) version 3.0 was used for children < 12 years. Data was analyzed using descriptive statistics. Results A total of 571 patients (512 AYAs, 59 children) were enrolled. Median age was 30 years with male predominance (58.1%). Most cases (98.6%) were absent from school or work. Carcinoma breast was the most common in females (29.3%) and non-Hodgkin lymphoma in males (12.6%). 91.06% had overall NCCN distress score ≥ 4. Also, 73.81 and 79.49% had "quite a bit" or "very much" responses on functional and symptom scales, respectively, in EORTC QLQ C-30 questionnaire. Peds QL version 3.0 revealed total score ranging from 276 to 523 for each patient. Conclusion AYAs and children with cancer are extremely vulnerable to psychological stress and morbidity. Use of well-established tools help in assessing their mental status and timely psychiatric referral can be initiated.

Gallbladder reporting and data system (GB-RADS) for risk stratification of gallbladder wall thickening on ultrasonography: an international expert consensus.

The Gallbladder Reporting and Data System (GB-RADS) ultrasound (US) risk stratification is proposed to improve consistency in US interpretations, reporting, and assessment of risk of malignancy in gallbladder wall thickening in non-acute setting. It was developed based on a systematic review of the literature and the consensus of an international multidisciplinary committee comprising expert radiologists, gastroenterologists, gastrointestinal surgeons, surgical oncologists, medical oncologists, and pathologists using modified Delphi method. For risk stratification, the GB-RADS system recommends six categories (GB-RADS 0-5) of gallbladder wall thickening with gradually increasing risk of malignancy. GB-RADS is based on gallbladder wall features on US including symmetry and extent (focal vs. circumferential) of involvement, layered appearance, intramural features (including intramural cysts and echogenic foci), and interface with the liver. GB-RADS represents the first collaborative effort at risk stratifying the gallbladder wall thickening. This concept is in line with the other US-based risk stratification systems which have been shown to increase the accuracy of detection of malignant lesions and improve management.

Lipoma Arborescens: A rare cause of knee swelling.

Introduction: Lipoma Arborescens is a chronic, slow growing intra articular lesion of benign nature which is commonly seen in the supra patellar region of the knee joint. It is characterised by villous proliferation of the synovium, with the replacement of the subsynovial connective tissue with fat cells. It is not a neoplasm but non-specific reactive response to chronic synovial irritation, due to mechanical or inflammatory insults. We highlight this condition to raise awareness to be kept as a differential diagnosis in knee joint affected by various slow, progressive chronic inflammatory conditions. Case Report: We present case of 51-year female with severe knee swelling since 3 to 4 years with episodes of remission and regression on and off. She was diagnosed with lipoma arborescens after magnetic resonance imaging and confirmed after post operative histology. Conclusion: We in this case study highlight this rare condition with its imaging characteristics and arthroscopic treatment. Keeping in mind that lipoma arborescens though benign in nature and as one of the rare causes for knee swelling, has to be treated to get an optimal outcome.

Genomic Landscape and Targeted Treatment of Gallbladder Cancer: Results of a First Ongoing Prospective Study.

Background Prognosis of gallbladder cancer (GBC) has not changed in the past 20 years. Comprehensive genomic profiling (CGP) carries potential to determine the actionability for multiple targets, including ERBB2 , ERBB3 , MET , ROSI , FGFR , and PIK3 . This study evaluates the role of CGP and targeted therapies. Methods This is a multicenter, prospective, single-arm study. All consecutive patients of unresectable and/or metastatic GBC of age ≥18 years were enrolled. Hybrid capture-based CGP was performed by Foundation Medicine CDx. All patients received first-line chemotherapy with gemcitabine-cisplatin regimen. Patients with ERBB2/3 amplification received trastuzumab with capecitabine or nab-paclitaxel, and patients with MET amplification were treated with crizotinib. For ERBB2/3 mutations, lapatinib plus capecitabine regimen was used. Results Fifty patients were studied with a median age of 56 years (range 26-83) and a male-to-female ratio of 1:1.6. ERBB2 and ERBB3 amplification was seen in 9 (18%) and 2 (4%) patients, respectively. Four patients with ERBB2 amplification received trastuzumab and/or lapatinib, showed partial response, and maintained response beyond 12 weeks. One patient had mixed response, whereas two patients progressed on trastuzumab and lapatinib. Three patients with ERBB3 mutations showed response to lapatinib-capecitabine. One patient with MET amplification responded to crizotinib for 4 weeks. PIK3 mutations were present in 14% of cases and were independent of ERBB aberrations. Conclusion GBC is enriched in 28% of patients with ERBB2 and ERBB3 amplifications and/or mutations. Responses are seen with lapatinib in concurrent ERBB2 mutation and amplification. ERBB3 mutation showed response to lapatinib. MET and PIK3 are new findings in GBC, which may be targeted.

Discordance between Fluorescence In Situ Hybridization and Immunohistochemistry Analysis of Anaplastic Lymphoma Kinase Rearrangement in Indian Patients with Non-Small Cell Lung Cancer.

Aims This study aims to evaluate the incidence of anaplastic lymphoma kinase (ALK) mutation in nonsmall cell lung cancer (NSCLC) incorporating fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods and to look for any discordance. Methods We evaluated 101 samples obtained from an enriched cohort of NSCLCs patients from the Army Hospital Research and Referral, New Delhi, India, between November 2016 and November 2018. IHC was performed using the highly-sensitive D5F3 rabbit monoclonal primary antibody. FISH was performed with dual-color, break-apart probe (ZytoLight SPEC) on formalin-fixed, and paraffin-embedded tissue. Discordance between IHC and FISH for ALK rearrangements was evaluated. Pearson correlation coefficient ( r ) was performed to identify any association of ALK presence (by IHC and FISH) with smoking brain metastasis, programmed death-ligand (PD-L1) expression, pleural effusion, and histopathological subtype. Results A total of 7.92% (8/101) cases tested by IHC and 9.9% (10/101) cases tested by FISH were positive for ALK rearrangement. Of 93 ALK IHC-negative cases, 4 were ALK FISH-positive, whereas of 91 ALK FISH-negative cases, 4 were ALK IHC-positive cases. The correlation analysis demonstrated no or very weak correlation in ALK mutations by IHC or FISH with smoking, brain metastasis, PD-L1 expression, pleural effusion, and histopathological examination, except a weak positive correlation ( r = 0.33) observed between brain metastasis and ALK rearrangement identified by FISH. Conclusions Our study demonstrated a somewhat similar incidence of ALK FISH-positive cases and ALK IHC-positive cases, though the incidence was numerically higher for ALK-FISH method.

Epidemiology of hepatitis C virus infection in a tertiary care hospital.

BACKGROUND: There are epidemiological lacunae in literature of hepatitis C virus (HCV) infection. We report a prospective observational study of asymptomatic HCV infected patients from a tertiary care Government Hospital. METHODS: All consecutive asymptomatic antibodies to hepatitis C virus (anti-HCV) positive patients were studied from July 2011 to April 2016. Patients were reviewed for demographic factors including symptom profile, risk factors, family screening, and point prevalence in relation to various districts of Punjab and Haryana. RESULTS: One thousand twelve patients were studied with median age of 52 years (range:13-85) with a male to female ratio of 0.87. Eight hundred (79.25%) patients were from Punjab and 110 (10.67%) from Haryana. Forty percent patients were in 40-60 age group. Six hundred seventy patients (66.21%) did not have any apparent risk factor, 274 (27.08%) had one risk factor, and 68 patients (6.72%) had > 2 risk factors. Commonest risk factor was h/o surgery in 243 patients (24.01%), 32 patients had h/o IV drug abuse and 29 among them were < 30 years. Three hundred and sixty-seven families and children were screened, and 27 spouses and 16 children were found to be anti-HCV positive. The risk factor of IV drug abuse was more common in the younger adults with age ≤ 30 years as compared with age > 30 years (p = 0.001). CONCLUSION: HCV infection was common in certain districts of Punjab and common in adults of 40-60 years. This finding needs to be confirmed in larger population-based study. The IV drug abuse is the risk factor of concern among young adults.

Predictors of Outcome in Pediatric Anaplastic Large Cell Lymphoma.

OBJECTIVE: To determine the event-free survival (EFS), overall survival (OS) and predictors of outcome in pediatric anaplastic large cell lymphoma treated with a uniform protocol. METHOD: This hospital record review was done between June, 2016 to March, 2019 and data was extracted from January, 2003 to May, 2016 for anaplastic large cell lymphoma (ALCL) in patients aged 1 to 18 years (n=27). EFS and OS were calculated by the Kaplan Meier method. Cox proportional model and the Cox regression model were used for univariate analysis and multivariate analysis respectively. RESULTS: EFS and OS at three years was 70.4% (CI: 0.49-0.84) and 77.2% (CI: 0.56 -0.89), respectively. On univariate analysis stage III and IV, hemoglobin less than 10 g/dL and presence of pleural effusion predicted lower survival. On multivariate analysis, pleural effusion was a significant predictor of low EFS and OS. CONCLUSION: Pleural effusion is a potential clinical marker of poor outcome among children with anaplastic large cell lymphoma.