Ideal sequencing in Stage IV epidermal growth factor receptor mutant Non-Small-Cell Lung Cancer.

Evidence from several studies has shown improved progression-free survival (PFS) with first- or second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) compared with chemotherapy for advanced NSCLC patients. But resistance to first or second-generation TKI therapies after 9 to 12 months of treatment initiation is a concern. Osimertinib is a third-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFRm (epidermal growth factor receptor mutated) and EGFR T790M and has demonstrated efficacy in NSCLC central nervous system (CNS) metastases. Trials have reported significantly longer PFS and higher median duration of response with osimertinib compared with first-generation EGFR-TKIs (erlotinib, gefitinib) and chemotherapy, respectively. And relatively lower rates of discontinuation due to adverse events (AEs). Significant improvement in overall survival was also observed when used as first-line treatment. Because EGFR-mutated tumors are highly dependent on EGFR signaling, optimal sequence of available TKIs - erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib - is necessary. The sequencing of EGFR-TKIs has changed over the past decade and depends on factors such as expected efficacy, CNS activity, tolerability, and options available after progression. Third-generation TKI may be the preferred first-line treatment because patients may not opt for or die before the start of second-line therapy, and it is difficult to predict which patients will eventually develop T790M mutation. The favorable tolerability profile alongside a longer time to disease progression makes osimertinib a preferred first-line treatment. Though clinical practice guidelines do not provide clear consensus on the most preferred EGFR-TKI, recent updates recommend osimertinib as a first-line treatment for advanced NSCLC patients. Also, improved patient selection incorporating clinical and molecular characteristics will help translate to better survival outcomes and improved quality of life. This review aims to determine the optimal sequence of administration of the EGFR-TKIs considering toxicity, quality of life, and survival outcomes among advanced NSCLC patients.

Genetic Counseling, Testing, and Management of HBOC in India: An Expert Consensus Document from Indian Society of Medical and Pediatric Oncology.

PURPOSE: Hereditary breast and ovarian cancer (HBOC) syndrome is primarily characterized by mutations in the BRCA1/2 genes. There are several barriers to the implementation of genetic testing and counseling in India that may affect clinical decisions. These consensus recommendations were therefore convened as a collaborative effort to improve testing and management of HBOC in India. DESIGN: Recommendations were developed by a multidisciplinary group of experts from the Indian Society of Medical and Pediatric Oncology and some invited experts on the basis of graded evidence from the literature and using a formal Delphi process to help reach consensus. PubMed and Google Scholar databases were searched to source relevant articles. RESULTS: This consensus statement provides practical insight into identifying patients who should undergo genetic counseling and testing on the basis of assessments of family and ancestry and personal history of HBOC. It discusses the need and significance of genetic counselors and medical professionals who have the necessary expertise in genetic counseling and testing. Recommendations elucidate requirements of pretest counseling, including discussions on genetic variants of uncertain significance and risk reduction options. The group of experts recommended single-site mutation testing in families with a known mutation and next-generation sequencing coupled with multiplex ligation probe amplification for the detection of large genomic rearrangements for unknown mutations. Recommendations for surgical and lifestyle-related risk reduction approaches and management using poly (ADP-ribose) polymerase inhibitors are also detailed. CONCLUSION: With rapid strides being made in the field of genetic testing/counseling in India, more oncologists are expected to include genetic testing/counseling as part of their clinical practice. These consensus recommendations are anticipated to help homogenize genetic testing and management of HBOC in India for improved patient care.

Indian clinical practice consensus guidelines for the management of squamous cell carcinoma of head and neck.

Head and neck cancers (HNCs) are malignant tumors of the upper aerodigestive tract and are the sixth most common cancer worldwide. In India, around 30-40% of all cancers are HNCs. Even though there are global guidelines or recommendations for the management of HNCs, these may not be appropriate for Indian scenarios. In an effort to discuss current practices, latest developments and to come to a consensus to recommend management strategies for different anatomical subsites of HNCs for Indian patients, a group of experts (medical, surgical and radiation oncologists and dentists) was formed. A review of literature from medical databases was conducted to provide the best possible evidence base, which was reviewed by experts during a consensus group meeting (January, 2019) to provide recommendations.

The future of lung cancer therapy: Striding beyond conventional EGFR and ALK treatments.

Lung cancer, one of the most frequently diagnosed cancers worldwide has long relied on testing for the molecular biomarkers EGFR/ALK. However, achieving superior clinical outcomes for patients with lung cancer requires developing comprehensive techniques beyond contemporary EGFR/ALK testing. Current technologies are on par with molecular testing for EGFR/ALK in terms of efficacy, most of them failing to offer improvements perhaps primarily due to skepticism among clinicians, despite being recommended in the NCCN guidelines. The present study endeavored to minimize chemotherapy-dependence in EGFR/ALK-negative patient cohorts, and use evidence-based methods to identify ways to improve clinical outcomes. In total, 137 lung cancer cases obtained from 'PositiveSelect NGS data', comprising 91 males and 46 females, were investigated. EGFR- and ALK-positivity was used for data dichotomization to understand the therapeutic utility of rare gene alterations beyond just EGFR/ALK. Statistics obtained from PositiveSelect were collated with data from international studies to construct a meta-analysis intended to achieve better clinical outcomes. Upon dichotomization, 23% of cases harbored EGFR variants indicating that treating with EGFR TKIs would be beneficial; the remaining 77% exhibited no EGFR variants that would indicate favorable results using specific currently available chemotherapy practices. Similarly, 28% of cases had EGFR+ALK variants favoring EGFR/ALK-based targeted therapeutics; the remaining 72% harbored no EGFR/ALK variants with known beneficial chemotherapy routes. The present study aimed to overcome current inadequacies of targeted therapies in patients with a conventional EGFR/ALK-positive diagnosis and those in EGFR+ALK-negative cohorts. Upon analysis of the negative cohorts, significant and clinically relevant single nucleotide variants were identified in KRAS, ERBB2, MET and RET, with frequencies of 7, 1, 2 and 3% in patients who were EGFR-negative and 6, 1, 1, and 3% in patients who were EGFR and ALK-negative, respectively, enabling the use of targeted therapeutics aside from EGFR/ALK TKIs. From the results of the current study only 35% of the two negative arms (EGFR negative and EGFR+ALK negative) would be recommended NCCN or off-label chemotherapy; prior to the current study, the entire cohorts would have been recommended this treatment. The present study emphasizes the potential of comprehensive genomics in identifying hallmarks of lung cancer beyond EGFR/ALK, using broad-spectrum genetic testing and data-sharing among medical professionals to circumvent ineffective chemotherapy.

Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations.

PURPOSE: Breast and/or ovarian cancers are among the most common cancers in women across the world. In the Indian population, the healthcare burden of breast and/or ovarian cancers has been steadily rising, thus stressing the need for early detection, surveillance, and disease management measures. However, the burden attributable to inherited mutations is not well characterized. METHODS: We sequenced 1010 unrelated patients and families from across India with an indication of breast and/or ovarian cancers, using the TruSight Cancer panel which includes 14 genes, strongly associated with risk of hereditary breast and/or ovarian cancers. Genetic variations were identified using the StrandNGS software and interpreted using the StrandOmics platform. RESULTS: We were able to detect mutations in 304 (30.1%) cases, of which, 56 mutations were novel. A majority (84.9%) of the mutations were detected in the BRCA1/2 genes as compared to non-BRCA genes (15.1%). When the cases were stratified on the basis of age at diagnosis and family history of cancer, the high rate of 75% of detection of hereditary variants was observed in patients whose age at diagnosis was below 40 years and had first-degree family member(s) affected by breast and/or ovarian cancers. Our findings indicate that in the Indian population, there is a high prevalence of mutations in the high-risk breast cancer genes: BRCA1, BRCA2, TP53, and PALB2. CONCLUSION: In India, socioeconomic inequality limiting access to treatment is a major factor towards increased cancer burden; therefore, incorporation of a cost-effective and comprehensive multi-gene test will be helpful in ensuring widespread implementation of genetic screening in the clinical practice for hereditary breast and/or ovarian cancers.

Human papillomavirus in head and neck cancer in India: Current status and consensus recommendations.

Human papillomavirus (HPV) associated head and neck squamous cell cancers (HNSCC) have become increasingly common in the West, but the same cannot be said about India. These cancers have a different biology and confer a better prognosis, however, its current role in the management of patients in India is not clearly defined. At the 35th Indian Cooperative Oncology Network conference held in September 2016, a panel of radiation, surgical and medical oncologists, pathologists, and basic scientists from across the country having experience in clinical research with respect to HPV in HNSCC reviewed the available literature from India. All the ideas and facts were thereafter collated in this report. Various topics of controversy in dealing with the diagnosis and management of HPV-associated HNSCC have been highlighted in this report in context to the Indian scenario. Furthermore, the prevalence of the same and its association with tobacco and high-risk sexual behavior has been touched on. Conclusively, a set of recommendations has been proposed by the panel to guide the practicing oncologists of the country while dealing with HPV-associated HNSCC.

Reliability of 18F-FDG PET Metabolic Parameters Derived Using Simultaneous PET/MRI and Correlation With Prognostic Factors of Invasive Ductal Carcinoma: A Feasibility Study.

OBJECTIVE: The objective of our study was to correlate semiquantitative PET parameters-standardized uptake value (SUV) and total lesion glycolysis (TLG)-derived in simultaneous PET/MRI using MRI-based attenuation correction with clinical and histopathologic prognostic factors in patients with breast cancer. MATERIALS AND METHODS: Eighty-two invasive ductal carcinomas in 69 women were included in the study. All the subjects underwent whole-body (WB) PET/MRI (supine WB mode) and dedicated PET/MRI of the breast (prone breast imaging mode) for staging on a simultaneous PET/MRI system. The SUV and TLG values were calculated from 18F-FDG PET data using MRI-based attenuation correction (2-point Dixon sequence for tissue segmentation). Relationships between SUV and TLG values and clinical and histopathologic parameters (i.e., tumor size, tumor grade, Ki-67 status, and hormonal receptor expression status) were evaluated using Spearman correlation coefficient analysis. RESULTS: A significant correlation was observed between mean SUV (SUVmean) and maximum SUV (SUVmax) values derived with WB PET and regional PET of the breasts performed simultaneously with MRI (r = 0.88 and 0.89, respectively). A significant difference (p < 0.05) was observed in SUVmean, SUVmax, and TLG values between the grades and molecular subtypes of breast cancer. High SUVmean, SUVmax, and TLG values were found to correlate with larger tumor size (p < 0.01), higher proliferation index (p < 0.05), higher grade (p < 0.01), and triple-negative hormonal receptor status (p < 0.01, p < 0.05). CONCLUSION: Semiquantitative FDG parameters derived with MRI-based attenuation correction in simultaneous PET/MRI are reliable and correlate with clinicopathologic features such as grade as well as subtype and thus could be used in the prognostication of breast cancer.

Association of pharmacokinetic and metabolic parameters derived using simultaneous PET/MRI: Initial findings and impact on response evaluation in breast cancer.

PURPOSE: To study relationships among pharmacokinetic and 18F-fluorodeoxyglucose (18F-FDG) PET parameters obtained through simultaneous PET/MRI in breast cancer patients and evaluate their combined potential for response evaluation. METHODS: The study included 41 breast cancer patients for correlation study and 9 patients (pre and post therapy) for response evaluation. All patients underwent simultaneous PET/MRI with dedicated breast imaging. Pharmacokinetic parameters and PET parameters for tumor were derived using an in- house developed and vendor provided softwares respectively. Relationships between SUV and pharmacokinetic parameters and clinical as well as histopathologic parameters were evaluated using Spearman correlation analysis. Response to chemotherapy was derived as percentage reduction in size and in parameters post therapy. RESULTS: Significant correlations were observed between SUVmean, max, peak, TLG with Ktrans (ρ=0.446, 0.417, 0.491, 0.430; p≤0.01); with Kep(ρ=0.303, ρ=0.315, ρ=0.319; p≤0.05); and with iAUC(ρ=0.401, ρ=0.410, ρ=0.379; p≤0.05, p≤0.01). The ratio of ve/iAUC showed significant negative correlation to SUVmean, max, peak and TLG (ρ=0.420, 0.446, 0.443, 0.426; p≤0.01). Ability of SUV as well as pharmacokinetic parameters to predict response to therapy matched the RECIST criteria in 9 out of 11 lesions in 9 patients. Maximum post therapy quantitative reduction was observed in SUVpeak, TLG and Ktrans. CONCLUSION: Simultaneous PET/MRI enables illustration of close interactions between glucose metabolism and pharmacokinetic parameters in breast cancer patients and potential of their simultaneity in response assessment to therapy.

Efficacy and Safety of Ibrutinib in Indian Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma: Cases from a Named Patient Program.

CONTEXT: This named patient program evaluated the safety and efficacy of ibrutinib, a selective inhibitor of Bruton's tyrosine kinase in Indian patients with relapsed/refractory chronic lymphocytic leukemia (CLL, with/without chromosome 17 deletion [del17p]) and mantle cell lymphoma (MCL). SUBJECTS AND METHODS: The eight enrolled patients (relapsed/refractory CLL: n = 6 [4/6 patients with del17p] and relapsed/refractory MCL: n = 2) had median age of 55 years (range, 52-60) and had received a median of 3 (CLL patients) and 4 (MCL patients) prior therapies. Patients received once-daily dose of ibrutinib (420 mg: CLL, 560 mg: MCL). RESULTS: In CLL patients, the median time to response was 3 months (range, 0.5-7) and five of six patients had partial response (PR) whereas one achieved complete response (CR). Median time on treatment was 11.5 months (range, 8-14); five patients continued treatment and one was recommended stem cell transplantation (SCT). Of the two MCL patients, one achieved PR and one showed CR and advanced to SCT. In CLL patients, the median (range) hemoglobin level improved from 9.8 g/dL (7.2-11) at baseline to 12.0 g/dL (9.5-13.2) and median (range) platelet count improved from 150,000 cells/µL (21,000-195,000) at baseline to 190,350 cells/µL (130,000-394,000) at the time of analysis (July 2016). Most adverse events (AEs) reported were infections (n = 2). No Grade 3-4 or serious AEs, dose reductions, or treatment discontinuation due to AEs were reported. CONCLUSIONS: In this first real-world experience in Indian patients, ibrutinib demonstrated therapeutic efficacy in relapsed/refractory CLL (with/without del17p) and MCL. Safety results were consistent with the current known profile of ibrutinib.

Summary of the published Indian data on chronic myeloid leukemia.

Chronic myelogenous leukemia (LML) was recognized as a distinct entity in the mid-1800s. Since Nowell and Hunagerford initiated their research on CML in1960 our understanding in CML has been increasing. Imatinib became the preferred treatment from 2000 onwards as a result of its unprecedented success. The lack of structured Indian data on CML led to the formation of a CML data cansortuim which invited CML data albiet retro spartive form around the country including major cancer service providers both government and private. We provide a summary of published Indian data on CML here.

Traumatic Diaphragmatic Injury: A Marker of Serious Injury Challenging Trauma Surgeons.

The objectives of this study are (1) to evaluate prevalence of traumatic diaphragmatic injury (TDI), (2) identify the predictors of mortality, and (3) study the accuracy of investigations in survivors of TDI. Retrospective analysis of prospectively maintained database of TDI from January 2007 to December 2011. Emergency department (ED) records, operative details, and autopsy reports were reviewed to determine injury characteristics, treatment provided, and outcome. Statistical analyses were performed using the SPSS ver.15 software. TDI was identified in 75 individuals. Thirty-two of 75 (42.6 %) cases were brought dead to the hospital, and 43/75 (57.3 %) were survivors presented to emergency department, diagnosed to have TDI intraoperatively. Seven of 43 (16.3 %) died postoperatively. Mortality in TDI was significantly related to age (p = 0.001), injury severity (p < 0.001), site of TDI (p = 0.002), and associated injuries (p = 0.021, odds ratio of 9). Death increased with increase in the number of organ injured (p < 0.001, odds ratio of 12). Multi-detector computer tomography (MDCT) detected TDI in 23/26 (88.5 %) cases preoperatively. Laparotomy (p < 0.001, odds ratio of 22) and thoracotomy (p = 0.021, with odds ratio of 9) were associated with survival benefit when compared to minimal invasive surgery in injured cases. The prevalence of TDI was 2.67 %, TDI's mark severity of injury. Mortality increases with increasing number of organ injured. Right-sided or bilateral injury of diaphragm is associated with increased mortality.

Cytomorphologic significance of marginal vacuoles in diffuse thyroid enlargements.

BACKGROUND: Fine needle aspiration cytology (FNAC) of the thyroid is an established first-line test for thyroid lesions. Marginal vacuoles (MVs) have been associated with hyperactivity of the thyroid, but some studies have pointed towards their nonspecific status. AIMS: To assess the presence of MVs in diffuse thyroid enlargements and evaluate the strength of correlation between MVs, levels of thyroid hormone and cytological diagnosis. MATERIALS AND METHODS: Ninety-seven cases of diffuse thyromegaly were studied. Cytomorphological features were examined with special attention to MVs. MVs were graded as scant, moderate and abundant. Hormonal status of the patients was recorded. The presence and grading of MVs was correlated with cytological diagnosis and hormonal status. The strength of association was studied by applying the Chi-square test and test of proportion; a P ≤ 0.05 was considered significant. RESULTS: Abundant MVs were not associated with hypothyroidism in this study; 79% of these cases were hyperthyroid. The correlation between moderate/insignificant MVs and functional status of the thyroid gland was inconclusive. Further, abundant MVs in thyroid FNACs were seen in cases of primary hyperplasia and Hashimoto's thyroiditis. There was a significant correlation between the presence of abundant/moderate MVs and primary hyperplasia and their absence in colloid goiter (P = 0.01 and 0.004, respectively). CONCLUSIONS: A significant association was found between abundant MVs and a hyperthyroid state. Moderate/absent MVs in diffuse goiters were not found to correlate with thyroid function. Thus, all diffuse goiters with prominent MVs require hormonal evaluation to rule out hyperfunction of the thyroid.

Pressure Sore at an Unusual Site- the Bilateral Popliteal Fossa: A Case report.

Pressure sore is tissue ulceration due to unrelieved pressure, altered sensory perception, and exposure to moisture. Geriatric patients with organic problems and patients with spinal cord injuries are the high-risk groups. Soft tissues over bony prominences are the common sites for ulcer development. About 95% of pressure ulcers occur in the lower part of the body. Ischial tuberosity, greater trochanter, sacrum and heel are common sites. In addition to these, pressure sores at unusual sites like nasal alae, malar eminences, cervical region and medial side of knee have also been described. Only 1.6% of the patients present with sores in areas outside the pelvis and lower extremity. In a paraplegic patient, pressure sores are usually over extensor surface of knee and heel but pressure ulcer over popliteal fossa are extremely rare. We herein report a case of a 36-years-old diabetic and paraplegic male, who presented with multiple bed sores involving the sacral area, heels and bilateral popliteal fossa. Popliteal fossa is an unusual site for pressure sores. Only one similar case has been previously reported in the literature.