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Background: Patients with multiple myeloma (MM) aged ≤ 65 to 70 years, with a good Eastern Cooperative Oncology Group performance status and no major comorbid conditions, are considered potential candidates for autologous stem cell transplant (ASCT) and will be treated with novel agent-based induction therapy for 4 to 6 cycles before ASCT., Patients and Methods: We analyzed the data from 326 patients with MM who had received novel agent-based induction before ASCT at our center to evaluate the effect of induction therapy on ASCT response, stem cell mobilization, engraftment characteristics, and survival. The median age was 52 years (range, 29-72 years), 216 patients were men (66.3%), 32.7% had stage III using the Revised Multiple Myeloma International Staging System, and 15.8% had high-risk cytogenetics. Of the 326 patients, 75 (23.0%) had undergone ASCT in second remission after salvage therapy for relapse. Also, 194 patients (59.5%) had received doublet induction therapy and 132 (40.5%) had received triplet induction therapy., Results: Triplet-based induction therapy was superior to doublet-based therapy for response (95.4% vs. 84.02%; P < .003), stem cell mobilization (CD34 +  ≥ 2 × 10 6 /kg; 88.6% vs. 76.8%; P < .005), and lower 100-day transplant-related mortality (P < .001). The ≥100 day post-ASCT overall response (97.4% vs. 91.7%; P = .124) and complete response (72.5% vs. 68.0%; P = .38) rates were similar. At a median follow-up of 62.5 months, the overall survival (97.5 months vs. 100.0 months; P = .606) and progression-free survival (54.5 months vs. 57 months; P = .515) were similar between the triplet and doublet induction groups., Conclusion: An initial response (chemosensitivity) to induction therapy will prepare patients better for subsequent consolidation therapy and ASCT, leading to favorable outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Before the approval of first-line immune checkpoint inhibitors, platinum doublets were the standard of care in patients with treatment-naïve advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. Pemetrexed-platinum combinations are preferred in non-squamous NSCLC. However, there has been no direct comparison to paclitaxel-carboplatin., Methods: This open-label randomized trial was designed to compare pemetrexed-carboplatin with (weekly) paclitaxel-carboplatin in treatment-naïve advanced/metastatic non-squamous NSCLC without driver mutations. Patients received either pemetrexed 500 mg/m2 and carboplatin AUC 5 every 3 weeks, or paclitaxel 80 mg/m2 on day 1, day 8, and day 15 with carboplatin AUC 5 every 4 weeks for 4 cycles. Patients in both arms were allowed to receive pemetrexed maintenance., Results: A total of 180 patients were enrolled. The study was terminated early; however, at the time of analysis 75.8% of the required events had occurred. Finally, 164 patients were evaluable, 83 in the pemetrexed arm and 81 in the paclitaxel arm. After a median follow-up of 17 months, progression-free survival (PFS) rates at 6 months were not different in the two treatment arms (47.45 vs. 48.64%, p = 0.88). The median PFS values were 5.67 months (95% CI 3.73-7.3) and 5.03 months (95% CI 2.63-7.43) in each arm, respectively (HR 1.13, 95% CI 0.81-1.59, p = 0.44). The median overall survival was also not different: 14.83 months (95% CI 9.5-18.73) and 11.3 (95% CI 8.3-19.7; HR 1.19, 95% CI 0.8-1.78, p = 0.37). All grade toxicities were similar except for alopecia and peripheral neuropathy, which were higher in the paclitaxel arm., Conclusion: Pemetrexed-carboplatin is not superior to (weekly) paclitaxel-carboplatin as the first-line regimen in advanced non-squamous NSCLC in terms of PFS., (© 2021 S. Karger AG, Basel.)

Background: Lung adenocarcinomas present as tight clusters and three-dimensional balls in effusion specimens. Unlike carcinomas of breast and stomach where singly lying malignant cells are seen in effusion samples, lung adenocarcinomas usually show cohesive morphology. This single-cell pattern may also be confused with reactive mesothelial cells. We studied the frequency of pulmonary adenocarcinoma with single-cell pattern cytomorphology in pleural effusion specimens., Materials and Methods: All cases reported as either suspicious or positive for malignancy on pleural effusion cytology (PFC) over the past 1 year were retrieved. The clinical details were obtained from requisition forms. Cases with predominant single-cell pattern, clinically suspicious of carcinoma lung were segregated. These were de-stained and immunocytochemistry (ICC) for TTF-1 was performed., Results: Of 103 cases reported as either suspicious or positive for malignancy on PFC, 29 had a predominant single-cell pattern. Of these, 13 (44.8%) were primary lung carcinoma. The rest were metastasis from ovary (5; 17.2%), breast (2; 6.9%), stomach (2; 6.9%), lymphoma (1; 3.5%), and Ewing's sarcoma (1; 3.5%). Five (17.2%) were those with unknown primary. All cases of lung carcinoma were positive for TTF-1 ICC., Conclusion: Single-cell pattern of pulmonary adenocarcinoma is commoner than popularly believed. This pattern may be difficult to differentiate from carcinoma cells of other sites as well as from reactive mesothelial cells. A high degree of suspicion is therefore needed to perform relevant ICC to clinch the correct diagnosis., (© 2020 Wiley Periodicals LLC.)

Introduction: Inactivating mutations of the SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene and/or loss of the BRG1 (brahma-related gene 1) protein defines SMARCA4-deficient thoracic sarcoma (SMARCA4-dTS), an aggressive neoplasm with a usually fatal outcome. Similar SMARCA4 mutations/BRG1 loss is also seen in a subset of non-small cell lung carcinomas (NSCLCs; SMARCA4-dNSCLCs) that lack alterations in currently targetable oncogenic drivers, that is, EGFR, ALK, and ROS1. There is limited knowledge on the cytomorphological features of these SMARCA4-deficient thoracic neoplasms., Methods: We retrospectively analysed the cytology of 2 cases each of SMARCA4-dNSCLC and SMARCA4-dTS to understand their cytomorphological overlap, if any, and identify features that would prompt testing for BRG1 loss., Results: All 4 patients were males presenting with advanced disease, with a mean age of 41.5 years (SMARCA4-dTS) and 58.5 years (SMARCA4-dNSCLC) at presentation. The cytology of the 2 SMARCA4-dTSs was strikingly similar, showing predominantly singly dispersed rhabdoid phenotype tumour cells with perinuclear cytoplasmic condensations in an inflammatory or necrotic background. The cytology raised suspicion for a wide range of differentials, including melanoma, high-grade lymphoma, germ cell tumour, undifferentiated carcinoma, and undifferentiated sarcoma. SMARCA4-dNSCLCs, on the other hand, were recognizable as poorly differentiated (adeno)carcinomas and were easily distinguished from SMARCA4-dTSs, with both cases showing cohesive clusters of frequently large tumour cells with abundant pale cytoplasm., Conclusion: A diagnosis of SMARCA4-dTS is possible on cytology with appropriate ancillary testing and a high index of suspicion. The cytology of SMARCA4-dNSCLCs does not overlap with SMARCA4-dTS; rather, it resembles that of any poorly differentiated (adeno)carcinoma in the limited numbers analysed in this study., (© 2020 S. Karger AG, Basel.)

Genomic characterization of lung cancer has not only improved our understanding of disease biology and carcinogenesis but also revealed several therapeutic opportunities. Targeting tumor dependencies on specific genomic alterations (oncogene addiction) has accelerated the therapeutic developments and significantly improved the outcomes even in advanced stage of disease. Identification of genomic alterations predicting response to specific targeted treatment is the key to success for this "personalized treatment" approach. Availability of multiple choices of therapeutic options for specific genomic alterations highlight the importance of optimum sequencing of drugs. Multiplex gene testing has become mandatory in view of constantly increasing number of therapeutic targets and effective treatment options. Influence of genomic characteristics on response to immunotherapy further makes comprehensive genomic profiling necessary before therapeutic decision making. A comprehensive elucidation of resistance mechanisms and directed treatments have made the continuum of care possible and transformed this deadly disease into a chronic condition. Liquid biopsy-based approach has made the dynamic monitoring of disease possible and enabled treatment optimizations accordingly. Current lung cancer management is the perfect example of "precision-medicine" in clinical oncology., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Mutations in the tyrosine kinase domain of the epidermal growth factor receptor gene (EGFR) are key driver alterations in lung adenocarcinomas (ADCAs). Exon 19 deletions (exon19del) and exon 21 L858R (L858R) mutations account for 70-90 % of all such alterations and predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs). However, the predictive value of uncommon and compound EGFR mutations for TKIs has not been clearly established., Objective: To assess the spectrum of EGFR mutations in non-small-cell lung carcinoma (NSCLC), and to compare the treatment responses and outcomes among single common, single uncommon, and compound mutations., Method: The study was of combined retrospective (January 2010-December 2015) and prospective (January 2016-February 2020) design spanning 10 years. Tumor samples from TKI-naive NSCLC patients were tested for EGFR mutations by a qPCR-based method. Objective response rates (ORRs) and survival outcomes were analyzed., Result: In total, 1227 tumor samples were tested. EGFR mutations were detected in 391 samples (31.8 %), and included 79.5 % (311/391) single common (exon19del/L858R), 6.6 % (26/391) single uncommon (non-exon19del/L858R), and 13.8 % (54/391) compound mutations. Exon 20 T790M mutations were most prevalent among uncommon/compound mutations (40/391, 10.2 %). Overall, patients with single uncommon/compound mutations responded poorly to both EGFRTKI (47 % ORR) and chemotherapy (43 % ORR), with significantly shorter time to progression (median 7 months) compared to those with exon19del/L858R mutations (median 14.7 months). Patients with baseline T790M mutations (single/compound) were least responsive to EGFR TKIs (11 % ORR) and chemotherapy (27 % ORR) and showed the shortest progression-free survival compared to other uncommon and compound mutations., Conclusion: Approximately one fifth of EGFR-mutant patients harbor uncommon and compound mutations. Unlike those with exon19del/L858R, these patients-particularly those with baseline T790M mutations-show significantly inferior response rates to treatment (EGFR TKI or chemotherapy) and early disease progression., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Early diagnosis is crucial for effective medical management of cancer patients. Tissue biopsy has been widely used for cancer diagnosis, but its invasive nature limits its application, especially when repeated biopsies are needed. Over the past few years, genomic explorations have led to the discovery of various blood-based biomarkers. Tumor Educated Platelets (TEPs) have, of late, generated considerable interest due to their ability to infer tumor existence and subtype accurately. So far, a majority of the studies involving TEPs have offered marker-panels consisting of several hundreds of genes. Profiling large numbers of genes incur a significant cost, impeding its diagnostic adoption. As such, it is important to construct minimalistic molecular signatures comprising a small number of genes., Results: To address the aforesaid challenges, we analyzed publicly available TEP expression profiles and identified a panel of 11 platelet-genes that reliably discriminates between cancer and healthy samples. To validate its efficacy, we chose non-small cell lung cancer (NSCLC), the most prevalent type of lung malignancy. When applied to platelet-gene expression data from a published study, our machine learning model could accurately discriminate between non-metastatic NSCLC cases and healthy samples. We further experimentally validated the panel on an in-house cohort of metastatic NSCLC patients and healthy controls via real-time quantitative Polymerase Chain Reaction (RT-qPCR) (AUC = 0.97). Model performance was boosted significantly after artificial data-augmentation using the EigenSample method (AUC = 0.99). Lastly, we demonstrated the cancer-specificity of the proposed gene-panel by benchmarking it on platelet transcriptomes from patients with Myocardial Infarction (MI)., Conclusion: We demonstrated an end-to-end bioinformatic plus experimental workflow for identifying a minimal set of TEP associated marker-genes that are predictive of the existence of cancers. We also discussed a strategy for boosting the predictive model performance by artificial augmentation of gene expression data.

High-grade neuroendocrine tumors (HGNET) have distinctive tumor biology/behaviour. Newer modalities of treatment (immunotherapy) for them have been included in recent NCCN guidelines. Detection of programmed death receptor-ligand 1 (PD-L1) expression by immunohistochemistry have made easy identification of patients eligible for immunotherapy. We aimed to ascertain expression of PD-L1 on small cell and large cell neuroendocrine carcinomas of lung and review existing literature. Eighty-five cases of HGNET lung (primary/metastatic), were retrieved and reviewed. Immunostaining for PD-L1 using clone SP263 was done. Any amount/intensity of membranous staining of > = 1% tumor cells was cut-off for positivity. Previously published studies using Google and/Pubmed search engines were reviewed. Of 85 cases, 70 were small-cell lung cancer (SCLC), 11 large-cell neuroendocrine carcinoma (LCNEC) and 4 combined SCLC. Median age was 46.5 years with male preponderance. No PD-L1 expression was seen in 91.6% cases. The 7 positive cases were 4 LCNEC, 2 SCLC and 1 combined SCLC. The percentage positivity varied from 1-100%; lower percentage positivity was seen in SCLC. PD-L1 expression on immune cells was seen in 31.3% cases. Sixteen studies evaluating 1992 NET were found; E1L3N PD-L1 clone was commonly used clone. PD-L1 positivity was associated with better prognosis in most studies. There are only a few studies available in literature related to PDL1 expression in high grade neuroendocrine carcinomas of lung. In general, PD-L1 positivity is highly variable and seen in lower percentage of these tumors. With the recent approval of immunotherapy, biomarkers other than PD-L1 should also be investigated in these tumors.

Purpose: Identification of noninvasive blood-based biomarkers is of utmost importance for the early diagnosis and predicting prognosis of advance stage lung cancer patients. MicroRNAs (miRNAs) has been implicated in numerous diseases, however, their role as diagnostic and prognostic biomarkers in Indian lung cancer patients has not been evaluated yet., Methods: For the identification of differentially expressed miRNAs in the serum of non-small cell lung cancer (NSCLC) patients, we performed small RNA sequencing. We validated the expression of 10 miRNAs in 75 NSCLC patients and 40 controls using quantitative reverse transcription polymerase chain reaction (PCR). miRNA expression was correlated with survival and therapeutic response., Results: We identified 16 differentially expressed miRNAs in the serum of NSCLC patients as compared to controls. We observed significant downregulation of miR-15a-5p, miR-320a, miR-25-3p, miR-192-5p, let-7d-5p, let-7e-5p, miR-148a-3p, and miR-92a-3p in the serum of NSCLC patients. The expression of miR-375 and miR-10b-5p was significantly downregulated in lung squamous cell carcinoma patients than controls. The expression of miR-320a, miR-25-3p, and miR-148a-3p significantly correlated with stage. None of the miRNAs were correlated with survival outcome and therapeutic response., Conclusions: We conclude that the relative abundance of miRNAs in serum may be explored for the development of miRNA-based assays for better diagnosis and prognosis of NSCLC. Moreover, further studies are warranted to elucidate the role of some of the less explored miRNAs, such as miR-375 and miR-320a, in the pathogenesis of NSCLC., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Opinion Statement: Immune checkpoint inhibitors (ICIs) have revolutionized the management of metastatic and selected cases of unresectable advanced non-small cell lung cancer (NSCLC). Importantly for patients, this implies that in the absence of a targetable oncogenic driver [especially epidermal growth factor receptor (EGFR) gene mutations and anaplastic lymphoma kinase (ALK) gene rearrangements] and in the presence of high programmed death-ligand 1 (PD-L1) expression (≥ 50%), they are eligible for mono-therapy with pembrolizumab thereby avoiding chemotherapy as the first line of treatment. This mono-immunotherapy approach for high PD-L1 metastatic NSCLC is associated with improved overall survival (OS) and radiological responses (RR) with lesser toxicity as compared with conventional platinum doublet chemotherapy for both non-squamous and squamous histological types.However, majority of NSCLC patients either have no or low expression of PD-L1 (< 50%) and such patients derive greater benefit from a combination of PD-1/PD-L1 ICIs with platinum doublet chemotherapy as compared with chemotherapy alone. Again, benefits are seen for both OS and RRs. However, combining immunotherapy with chemotherapy, in general, does lead to higher toxicity than those seen with either of the two alone.Additionally, for non-squamous NSCLC patients, clinicians should not initiate ICI treatment till the results of common targetable genetic alterations like EGFR mutation, ALK, and ROS1 gene rearrangement testing are known (preferably on broad next generation sequencing) and are negative (even if results of PD-L1 testing are available)-as targeted therapies remain the cornerstone of treatment for patients harboring these oncogenic drivers.It is worth mentioning that PD-1 and PD-L1 ICIs are very expensive, and their usage is associated with occurrence of immune-related adverse events (irAEs) which occasionally can be severe. Hence, it is important to discuss efficacy, toxicity, and cost-related to ICI treatment with each and every patient at diagnosis in order to help them decide if they are willing to go ahead with this form of therapy either singly (for high PD-L1 expressors) or in combination with chemotherapy (for others).

Global deregulation in miRNA expression is a hallmark of cancer cell. An estimated 2300 mature miRNAs are encoded by human genome; role of many of which in carcinogenesis and as cancer biomarkers remains unexplored. In this study, we investigated the utility of miR-3692-3p, miR-3195, and miR-1249-3p as biomarkers in non-small cell lung cancer (NSCLC). For this prospective study, 115 subjects, including 75 NSCLC patients and 40 controls, were recruited. The expression of miR-3692-3p, miR-3195, and miR-1249-3p was checked using qRT-PCR. The miRNA expression was correlated with survival outcome and therapeutic response. There were no significant differences in the mean age of NSCLC patients and controls (56.2 and 55.3 years, respectively; p = 0.3242). Majority of NSCLC patients (67%) were smokers. We observed a significant upregulation of miR-3692-3p expression (p < 0.0001), while the expression of miR-3195 (p = 0.0017) and miR-1249-3p was significantly downregulated (p < 0.0001) in the serum of NSCLC patients as compared to controls. The expression of miR-1249-3p was significantly upregulated in lung adenocarcinoma versus lung squamous cell carcinoma (p = 0.0178). Interestingly, patients who responded to chemotherapy had higher expression of miR-1249-3p than non-responders (p = 0.0107). Moreover, patients with higher expression of miR-3195 had significantly longer overall survival (p = 0.0298). In multivariate analysis, miR-3195 emerged as independent prognostic factor for overall survival. We conclude that the miR-3195 may have prognostic significance, while miR-1249-3p may predict therapeutic response in NSCLC. Further studies are warranted to elucidate the role of these miRNAs in lung carcinogenesis and their utility as candidate cancer biomarkers.

A vast majority of the patients with lung cancer in India present as advanced stage disease and a significant number among them have nonmetastatic locally advanced tumors which require multimodality management with curative intent. We analyzed the treatment outcome of the patients treated with of neoadjuvant chemotherapy followed by surgery approach. This was a retrospective analysis of institutional database of all non-small cell lung cancer patients who underwent neoadjuvant chemotherapy followed by curative intent surgery with/without adjuvant therapy from 2012 to 2018. Patients included were those with N2 disease; T4 or T3 disease requiring pneumonectomy or extensive adjacent structures resection. Mediastinal staging was done by PET-CT (Positron Emission Tomography - Computed Tomography) along with Endobronchial ultrasound in most cases. All the patients received platinum-based doublet chemotherapy for 3-6 cycles before surgery. Response to neoadjuvant chemotherapy and survival were analyzed. A total of 44 patients fulfilled the eligibility criteria. Majority were males (81.8%) and smokers (75%). Squamous cell carcinoma (50%) was the most common subtype. Total 43.2% patients had either T3 or T4 tumors. N2 disease (either single station or multistation) was observed in 67.2% cases. A complete pathologic response was observed in 22.7% cases. In addition, 6.8% patients had ≤10% viable tumor in the resected specimen. Residual disease in N2 nodes were found in 25% cases. Median follow-up was 35.9 months. Patients with residual N2 disease showed a trend toward inferior survival. In multivariate analysis smoking, pretreatment tumor category and final pathologic stage were significant factors for disease free but not for overall survival. This study shows that neoadjuvant chemotherapy is a feasible and effective modality for downstaging locally advanced cases of non-small cell lung cancer among the Indian patients. Patients with less than 10% residual tumor burden had a better survival. The role of surgery in those with persistently N2 needs further evaluation., (Copyright © 2020. Published by Elsevier Inc.)

Background: Anaplastic lymphoma kinase (ALK) rearranged metastatic non-small cell lung cancer (NSCLC) comprises 5%-7% of all lung cancer and carries a good prognosis with available ALK-inhibitors. Majority of registration trials in ALK-inhibitors did not include Indian patients. Hence, this study was planned to analyze the outcome of Indian patients treated with ALK-inhibitors and associated challenges., Methods: This is a multi-center study in 5 major tertiary care cancer centers across India treating ALK-rearranged NSCLC patients from April 2013 to April 2019. ALK rearrangement was determined by Ventana immunohistochemistry with D5F3 clone and/or by break-apart FISH. Patients treated with ALK-inhibitors in any lines of treatment were included in this study. Patients were evaluated for clinicopathologic features, patterns of ALK-inhibitors use and outcome. Progression free-survival (PFS) and overall survival (OS) were calculated and data were censored on April 30, 2019., Results: A total of 274 patients were studied, out of which 250 patients received ALK inhibitor and were analyzed further for outcome. The median age was 50 years (range: 24-82) and male to female ratio of 1.17:1. ALK was evaluated by immunohistochemistry in majority of patients (97%), 3 patients by FISH and 3 more patients were evaluated by both methods. Sixty-five percent (n = 162) of the patients received ALK-inhibitor as first line therapy, 51 patients received ALK-inhibitor as switch maintenance therapy after initial chemotherapy. Crizotinib and Ceritinib were used in 88% and 12%, respectively. One patient received Alectinib. Forty-one percent of patients had CNS progression. After median follow up of 27 months (1-72 months), the median OS was 24.7 months with OS rate of 72%, 51%, and 18% at 1, 2, and 4-years respectively. Median OS was 21.2, 26, and 38 months in the first line ALK-inhibitors use (n = 162), switch maintenance group (n = 51) and second line ALK-inhibitors use (postchemotherapy progression) (n = 33), respectively. No baseline variable predicted PFS. Presence of brain metastasis (P = 0.039) and first line ALK-inhibitors use (P = 0.032) emerged as poor prognostic factor for OS on multivariate analysis. PFS rate was 70%, 47%, and 31% at 6, 12, and 18 months respectively., Conclusion: This is one of the largest real-world data on outcome of ALK inhibitors in ALK-rearranged NSCLC from Asia. In absence of second line ALK inhibitor, initial chemotherapy followed by ALK-inhibitors (switch maintenance) had better outcome. This fact may be studied in individual patient data meta-analysis. Poor performance status and brain metastases at presentation are poor prognostic factors for overall survival. Second-line ALK inhibitor use crucial for better outcome and access to clinical trials are much needed in Indian patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Maintenance chemotherapy (MC) with pemetrexed is a commonly used strategy in nonsquamous non-small cell lung cancer. However, most of the available evidence is from subjects with good performance status (PS), while data on the real-world utility and safety of this strategy in subjects with various categories of PS is limited. We performed a retrospective analysis of multicentric data of 3 centers from India. All patients with advanced nonsquamous non-small cell lung cancer who received MC with pemetrexed after induction chemotherapy were included. Subjects were divided into 2 groups based on baseline Eastern Cooperative Oncology Group score before initiation of induction chemotherapy as good PS (<2) and poor PS (≥2). Progression-free survival, overall survival, and toxicity were assessed in the study population. A total of 290 subjects were included in the study, of whom a significant proportion (n = 104, 35.9%) had poor PS. Survival was better in subjects with good PS as compared to those with poor PS (1-year progression-free survival: 43.5% vs 29.8%, P = 0.021; 1-year overall survival: 61.8% vs 48.1%, P = 0.023). Grade 3/4 toxicity was observed in 14.5% of subjects during MC and was not different between both groups (P = 0.287). Renal dysfunction was more common in subjects who received ≥10 cycles of MC (10.7% vs 4.2%, P = 0.040). MC with pemetrexed appeared to be beneficial and safe in the real-world setting regardless of the baseline PS. However, survival benefit was more pronounced in subjects with good PS at baseline. Renal dysfunction was more frequently encountered in subjects who received prolonged MC., (Copyright © 2020. Published by Elsevier Inc.)

Background: Immune check point inhibitors (ICIs) have changed the treatment paradigm of driver mutation negative non-small cell lung cancer (NSCLC) and they are increasingly incorporated in first-line treatment. Real-world experience of use of these drugs is limited. We aim to evaluate the real-world experience of use of ICIs in patients with advanced NSCLC., Patients and Methods: Medical records of patients with NSCLC treated with ICIs at 4 major academic cancer centers in India between January 2016 and December 2018 were analyzed. The type of ICI taken, response rates, survival, and toxicity profiles were analyzed., Results: The median age at presentation was 60 years (range: 27-79 years). Nivolumab was the most commonly used ICI drug [80%, n = 70] followed by pembrolizumab [10%, n = 9], and atezolizumab [10%, n = 9]. The median number of ICIs cycles received were 4 (range 2-65). Among the evaluable responses in 74 patients, the objective response rates was 25.6% and clinical benefit rate was 46%. Immune related toxicity occurred in 39.9% of patients but, severe toxicity of Grade III and Grade IV occurred in 5 (5.6%) patients. After a median follow-up time of 8.86 months (95%CI 5.2-11.1) the progression-free survival was 4.73 months (95%CI 3.7-8.9), and overall survival was 11.6 months (95%CI 7.33-NR). ECOG PS at the time of start of ICIs was found to be significant determinant of Progression-free survival and overall survival., Conclusion: Our study demonstrates the feasibility of usage of ICIs in advanced NSCLC in Indian setting with acceptable safety profile and comparable responses with the published studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Inc.)

Background: Platinum-based combination chemotherapy is recommended as the standard treatment for patients with advanced non-small-cell lung cancer (NSCLC), but its benefit is limited to patients with performance status (PS) of 0 or 1. However, it is not clear whether these benefits apply to patients with poor performance status (PS 2 and above) and there are no predictors of outcome to suggest whom to treat. The patients with poor performance status (PS 2 and above) accounts for a significant portion (up to 30%) of patients of our practice. In this retrospective analysis, we have analyzed our experience of chemotherapy in patients with poor performance status., Method: A retrospective analysis of patients of advanced NSCLC with poor PS (ECOG PS 2 or more), treated with chemotherapy from October, 2016 to June, 2018 was done. Patients with driver mutations who were treated with first line tyrosine kinase inhibitors were excluded. Hospital case records were reviewed for baseline characteristics, treatment details, and outcome data. Kaplan-Meier curves were drawn to estimate progression free survival. Log-rank test was used to assess factors affecting survival. Data was analyzed using STATA ver 11 (StataCorp. 2009. College Station, TX: StataCorp LP). P value <0.05 was taken as significant., Result: A total of 96 patients were included in the analysis. The median age of the patients was 62 years (range 30-84 years). Majority (67.7%) was males and 65% patients were smokers (current or former). Patients with ECOG PS (Eastern Cooperative Oncology Group Performance Status) of 2 constituted 64.5% of this cohort and 34 patients (33.5%) had an ECOG PS of 3 or 4. The most common chemotherapy regimen used was combination of weekly paclitaxel (60 mg/m 2 ) and carboplatin (AUC2) in 57.8%. Most patients (64%) could complete 4 or more cycles of chemotherapy, however, 15 patients (15.7%) could receive only 1 cycle. Grade 3⁄4 toxicities were observed in 22 (23%) % patients, which were hematological in most cases (anemia and thrombocytopenia). At least one point improvement in ECOG PS from baseline during chemotherapy was observed in 43 patients (45%) after 4 cycles of chemotherapy. Objective response and disease control rates were 20% and 48.42%, respectively. After a median follows-up of 11.2 months, median progression free survival was 6.3 months (95% confidence interval 5-10.63). On univariate analysis, we found that male sex and use of weekly paclitaxel-carboplatin were associated with better progression-free survival PFS., Conclusion: Systemic chemotherapy in modified doses and schedules in advanced NSCLC patients with PS 2 and above is feasible and may be associated with better symptom palliation with clinical benefit and improved survival., (Copyright © 2020. Published by Elsevier Inc.)

Background: The development of various targeted therapies against Epidermal Growth Factor Receptor (EGFR) has been a major step in therapeutic advancements in lung cancer. However, the response to tyrosine kinase inhibitors (TKI) therapy in a real-world setting has not been well elucidated., Methods: As part of a retrospective analysis, patients with EGFR mutated non-small cell lung cancer at 4 tertiary care Institutions in North India between December 2007 and August 2018 were evaluated. The overall response rate, disease control rate, progression-free survival (PFS) and factors affecting PFS were analyzed., Results: A total of 483 patients were included, including 52.4% males, with mean (±SD) age of 56.7 (±12.4) years. Majority (63.8%) had good performance status (Eastern Cooperative Oncology Group 0 or 1) and 77.4% were nonsmokers. Among the EGFR mutations, exon 19 deletion was the most common mutation detected (68.1%), followed by L858R mutation in exon 21 (26.9%). Extra-thoracic metastasis was present in 69.5% patients and majority of them had ≤ 2 metastatic sites (85.1%). TKIs were used as the first-line therapy in 64.8% patients, and gefitinib was the most frequently used TKI (67.3%), followed by erlotinib (26.7%). The overall response rate and disease control rate were 65.9% and 90.7% respectively. The median PFS was 9.3 months and brain was the exclusive site of progression in 18.0% patients. On univariate analysis, the factors that significantly affected PFS were, the number of metastatic sites and the type of EGFR mutation. On multivariate analysis, the number of metastatic sites was the only factor that affected the PFS [HR (95% CI): 2.5 (1.7-3.6); Pvalue <0.001]. Skin toxicity was the most common adverse event (32.3%), followed by involvement of the gastro-intestinal tract (22.5%)., Conclusion: In this one of the largest multicentric Indian study of treatment outcomes in EGFR-mutated non-small cell lung cancer in a real-world setting, we found that increased tumor burden (number of metastatic sites > 2) was the only significant factor associated with a worse PFS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Lead can cause significant biological and neurologic damage, even at small concentrations, and young children are at higher risk. Informal recycling of lead batteries and lead-based workshops/industries have increased the burden of lead toxicity in developing countries, including India. Many informal recycling lead battery workshops have been established by the local people of Patna, Bihar as self-employment opportunities. However, most of the residents are not aware of the risk factors associated with lead poisoning., Objectives: The present pilot study aimed to assess blood lead levels (BLLs) and hemoglobin levels among children aged between 3 to 12 years in the settlement of Karmalichak near Patna, India., Materials and Methods: Children residing near the informal lead battery manufacturing unit were selected for BLL assessment. A total of 41 children were enrolled in the questionnairebased survey., Results: All the children in the present study had detectable lead concentrations in their blood. Only 9% of the studied children had a BLL ≤5 μg/dl, while 91% children had a BLL above >5 μg/dl., Conclusions: The present study carried out in children of Karmalichak region of Patna, India was an attempt to better understand the problem of lead toxicity, describe the epidemiology of its adverse effects, identify sources and routes of exposure, illustrate the clinical effects and develop strategies of prevention so that remedial measures may be taken by government agencies and regulatory bodies. In view of the high lead levels in children in the study area, attempts are being made to develop strategies for future prevention by relocating the informal battery recycling workshops from the area. Moreover, parents have been advised to increase nutritional supplementation of children by providing calcium-, iron- and zinc-rich foods, including milk and vegetables., Participant Consent: Obtained., Ethical Approval: The study was approved by the ethical committee of Era's Lucknow Medical College & Hospital, Era University, Lucknow (India)., Competing Interests: The authors declare no competing financial interests., (© Pure Earth 2020.)

What Is Known and Objective: Oxidative stress and inflammation are known to be high in non-small cell lung cancer (NSCLC). However, association of change in their levels with treatment response remains unaddressed. The present study evaluated change in blood levels of oxidative stress and inflammatory markers in NSCLC patients, after first course of platinum-based chemotherapy., Methods: This prospective cohort study enrolled newly diagnosed NSCLC patients receiving either pemetrexed-carboplatin (group A) or paclitaxel-carboplatin (group B). Blood levels of malondialdehyde (MDA), reduced glutathione (GSH), interleukin-6 (IL-6), C-reactive protein (CRP) and interleukin-10 (IL-10) were measured at baseline and after first cycle. Response to treatment was noted after 2nd or 4th cycle, as available. Subgroup analysis was done (group B), based on paclitaxel dose/formulation., Results: Of the 85 patients screened, 38 were enrolled with a mean age of 56.7 ± 9.2 years. Baseline levels of oxidative and inflammatory markers were not different between the groups and did not change significantly within the groups. Significant reduction in IL-6 was seen with three-weekly paclitaxel-carboplatin (from median 81.3 [range 8.6, 1006] pg/mL to 51.8 [11.4, 99.5] pg/mL; P = .025). C-reactive protein levels reduced with weekly nab-paclitaxel (P = .043). Change in levels did not relate with therapeutic response except for IL-6 which decreased in patients with partial response (from 102.6 [8.1, 1006] pg/mL to 38.9 [8.4, 99.5] pg/mL; P = .036)., What Is New and Conclusion: Although the levels of oxidative and inflammatory markers varied following chemotherapy, trend indicates that IL-6 may be a potential marker of treatment response in NSCLC patients., (© 2019 John Wiley & Sons Ltd.)

Background & Objectives: Advanced epithelial ovarian cancer (EOC) is associated with dismal outcome and progression-free survival (PFS) shortens with each subsequent relapse. For patients with recurrent and platinum refractory disease, therapeutic options are limited. Oral metronomic therapy (OMT) is associated with symptomatic relief and stable response in a significant proportion of patients. We retrospectively evaluated the outcome of patients with EOC treated with OMT at a tertiary care hospital in north India., Methods: Between January 2011 to December 2017, 36 EOC patients received OMT. Patients' median age was 50 yr (range, 38-81 yr) and they had received a median of two lines of prior chemotherapy. OMT regimen included a combination of cyclophosphamide, etoposide (VP-16) and celecoxib with or without pazopanib along with supportive care. Response rates and outcomes were ascertained using the Gynecological Cancer Intergroup Guidelines. The toxicity was graded according to the Common Terminology Criteria for Adverse Events v.4.03., Results: The median CA-125 before initiating OMT was 160 U/ml (range, 42.23-5330 U/ml). The median interval between last chemotherapy and starting OMT regimen was 159 days (range, 1-1211 days). The overall response rate was 50 per cent. The median progression-free survival (PFS) was 8.2 months [95% confidence interval (CI): 5.03-10.33], and the median overall survival was 38 months (95% CI: 25.6-NR). Patients who received two lines of chemotherapy before OMT (P=0.052) and those who received pazopanib-based OMT (P=0.0513) had better PFS., Interpretation & Conclusions: For patients with relapse and refractory EOC, OMT could be a reasonable option. A combination of oral etoposide (VP-16) and pazopanib needs further evaluation in a large number of patients in a randomized trial., Competing Interests: None

Mitogen-Activated Protein (MAP) Kinase pathway involves several oncogenic genes which can serve as potential targets for therapy. Therefore, aim of the present study is to analyze mutations in the MAP Kinase pathway in pulmonary adenocarcinoma (ADCA) of Indian patients along with clinico-pathologic correlation and determination of the survival status in patients receiving therapy. Blocks and slides of 125 pulmonary ADCA of last 5 years were retrieved. Histo-morphology and tumor content were determined. EGFR, KRAS, BRAF and MEK1 genes were analyzed using Sanger sequencing and Real-time polymerase chain reaction (PCR). Clinico-pathologic correlation and survival analysis were performed. Fifty-eight (46.4%) patients harbored genetic mutations of which 49 had single somatic mutations, 5 had multiple exonic and 4 showed coexisting EGFR and KRAS mutations. EGFR mutations were seen in 24.8%, KRAS in 19.2% and BRAF (non-V600E) in 2.4% cases. There was no difference in progression-free survival of wild- type/single mutations when compared with multiple/ coexisting mutations (P = 0.09). However, the P value may indicate borderline correlation. To conclude, EGFR and KRAS mutations may coexist in the same patient in lung ADCA. Multiple exonic mutations of KRAS gene formed substantial percentage of our cohort, requiring further exploration. Lung ADCA harbouring BRAF mutations are commonly non-V600E. Testing of all major genetic driver mutations of lung ADCA irrespective of histology and other demographic characteristics is necessary., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome is a rare multisystem paraneoplastic syndrome characterized by peripheral neuropathy and monoclonal plasmacytosis. Retrospective institutional experiences from the Mayo Clinic as well as Chinese, European, and Japanese series have provided important insights into the characteristics and treatment of this disease, but Indian data are extremely limited. We retrospectively analyzed 49 cases from our institute including 10 patients who underwent autologous stem-cell transplantation (ASCT)., Patients and Methods: We analyzed clinical and laboratory characteristics, treatment details and outcome of all patients diagnosed with POEMS syndrome between 1993 and 2017., Results: Complete medical records were available for 49 patients with a median age of 44 years. Male/female ratio was 38:11. Twenty patients (40.8%) had Eastern Cooperative Oncology Group performance status of 4. Before 2012, melphalan/prednisolone was the most common regimen provided, while bortezomib/dexamethasone and lenalidomide/dexamethasone were used later. Hematologic response was available for 40 patients, 15 (37.5%) of whom experienced complete response, 13 (32.5%) partial response, and 11 (27.5%) stable disease. The median modified Rankin score at baseline was 4 (range, 1-5), which improved to 3 (range, 1-5). Ten patients underwent consolidation ASCT after a median of 4 cycles of induction. Median melphalan dose was 140 mg/m 2 . Engraftment syndrome was observed in 4. After ASCT, all 10 patients experienced hematologic complete response and clinical improvement., Conclusion: This retrospective analysis provides important information on the clinical characteristics of POEMS syndrome in Indian patients, which will help the clinician's decision-making process., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We investigated the impact of renal impairment (RI) on the outcome in multiple myeloma (MM) patients following induction and autologous stem cell transplantation (ASCT). Among 349 patients who received a first ASCT for MM, 86 (24.6%) had RI at diagnosis, defined as estimation of glomerular filtration rate (eGFR) <40 mL/min/1.73 m 2 according to the modification of diet in renal disease (MDRD) formula. Post induction reversal of renal function occurred in 68 (79%) patients including complete renal response in 37.2%. Two hundred and fifty-one patients had received novel agents for induction; posttransplant complete response (CR) rates were 71.4% for patients with renal impairment (RI) versus 67.2% in those without RI, p = 0.23. The quality of stem cell collection and days to engraftment were similar except that patients with RI required higher transfusion numbers of packed red cells ( p < 0.002) and platelets ( p < 0.007). The median overall survival (OS) was 96 months (95% confidence interval [CI] 72.80-119.20) for patients with eGFR ≥40 mL/min, n = 195) versus 62 months (95% CI 28.7-95.3) for 56 patients with RI (eGFR <40 mL/min), p = 0.15. The 5-year OS was 64.6% versus 54.4%, respectively. The median progression-free survival (PFS) was 52 months (95% CI 36.3-67.7) for patients with eGFR ≥40 mL/min versus "not reached" for those with eGFR <40 mL/min p = 0.87; and the 5-year PFS was 48.1% versus 51%, respectively. We conclude that induction with novel agents results in reversal of renal dysfunction in the majority of patients. Consolidation with Hemopoietic Stem Cell Transplantation (HSCT) overcomes the adverse impact of RI on survival., Competing Interests: None declared., (© 2019 International Academy for Clinical Hematology. Publishing services by Atlantis Press International B.V.)

Background & Objectives: Thymomas are rare, but most common anterior mediastinal lesions. The histomorphologic spectrum of thymic epithelial tumours (TETs) in Indian population has not been explored in depth. This study was aimed to assess the histomorphology of TETs in the Indian patients and correlate clinical parameters with pathological features., Methods: It was a retrospective study conducted in a tertiary referral hospital in north India. All morphologically confirmed cases of TETs since 2009 were included. Clinical details and histology slides were reviewed using the Modified Masaoka-Koga staging system and WHO 2015 classification. Clinicopathological correlation and survival analysis were done. A comparative review from other published Indian studies was performed., Results: A total of 219 cases of TETs (138 resections and 81 biopsies) were identified. The most common histomorphologic type was B2, and the most frequent stage was I. Types A/AB were common in older age (P<0.01). Clinically, higher stage tumours were found mostly in men (P<0.01), and these were Type B thymomas (P<0.01). Myasthenia gravis was more common in women (P<0.02) and in lower stages (P<0.05). Survival analysis revealed significant association between recurrence and tumour stage. Although thymic carcinoma was diagnosed on biopsy, no resectable case was identified., Interpretation & Conclusions: Our findings showed that the thymomas in Indian patients were most commonly Stage I tumours of B2 and AB histotypes. Resected thymic carcinomas were conspicuously absent in our study. More studies need to be done to establish the frequency and biology of TETs from India., Competing Interests: None

Background & Objectives: Survival of patients with multiple myeloma (MM) has improved in the past two decades following use of novel agents and autologous stem cell transplantation. To determine predictors of long-term outcome, data of MM patients who underwent autologous stem cell transplantation (ASCT) at a tertiary care centre in north India were retrospectively analyzed., Methods: Between 1995 and 2016, 349 MM patients underwent ASCT. Patients' median age was 52 yr, ranging from 29 to 68 yr, 68.2 per cent were males. Thirty three per cent patients had international staging system (ISS) Stage III and 68.5 per cent had received novel agents-based induction. High-dose melphalan (200 mg/m 2 ) was used for conditioning; patients with renal insufficiency (estimated glomerular filtration rate <40 ml/min) received melphalan 140-150 mg/m 2 ., Results: Post-transplant, 317 of 349 (90.8%) patients responded; complete [complete response (CR)] -213 (61%)], very good partial response (VGPR) -62 (17.8%) and PR in 42 (12%)]. Induction with novel agents, pre-transplant chemosensitive disease, transplant in first remission and serum albumin (≥3.5 g/dl) were predictors of significant response. At a median follow up of 73 months, median overall survival (OS) was 90 months [95% confidence interval (CI) 70.8-109.2], and progression-free survival (PFS) was 41 months (95% CI 33.0-49.0). On multivariate analysis, achievement of CR post-transplant, transplant in first remission, ISS Stages I and II (vs. III), absence of extramedullary disease and serum albumin ≥3.5 g/dl were predictors of prolonged OS. For PFS, achievement of post-transplant CR and transplant in first remission were predictors of superior outcome., Interpretation & Conclusions: Treatment with novel agents, achievement of complete remission post-transplant, ISS Stages I and II, absence of extramedullary disease and transplant in first remission were predictors of long-term survival for patients with MM., Competing Interests: None

Purpose: Biomarker-estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/ neu) -discordance plays an essential role in the management and prognosis of patients with metastatic breast cancer. Rates of discordance have been previously reported around 12% to 35%, 30% to 50%, and 5% to 15%, respectively, in Western literature. Data are sparse regarding the same from developing countries, such as India., Methods: We performed an ambispective review of paired biomarker status in patients with breast cancer-stage I, II, and III as per American Joint Committee on Cancer, 7th edition-who developed metastasis at recurrence (N = 103 patients). Biomarker status and clinical and radiologic parameters were documented at baseline and subsequent follow-up., Results: Discordance was present in 21.3% for ER, 29.1% for PR, and 15.5% for HER2/ neu receptor. In our cohort, 7.8% had positive to negative ER and 13.6% negative to positive. Whereas 21.4% had positive to negative PR, 7.8% had negative to positive PR. Approximately 6.8% had positive to negative HER2/ neu receptor and 8.7% negative to positive. In our cohort, 41 patients (40%) had single-site metastasis-bone, 15.5%; lung, 11.7%; nonregional lymph node, 7.8%; liver, 3.9%; and brain, 0.97%. More than one site of metastasis was present in 62 patients (60%). The most common sites of metastasis were visceral-lung and liver-followed by bone, nonregional lymph node, skin, and brain., Conclusion: The current study demonstrated that metastatic disease evolution in breast cancer is characterized by change in the tumor biology, which leads to discordance in receptor status. Repeat biomarker studies at metastatic recurrence is warranted, especially if treatment plans include hormone and targeted therapy.

Purpose: Approximately 5% to 10% of patients with breast cancer present with up-front metastasis and carry a poor prognosis (5-year survival rates of approximately 20%). To date, little is known about the long-term outcome of patients with metastatic breast cancer from developing nations., Materials and Methods: We performed an ambispective review of approximately 1,800 patients who were registered in breast cancer clinics between January 2012 and August 2018. Approximately 410 (22.8%) patients presented with up-front metastasis. Out of 410, 375 were considered for additional analysis. Clinical, pathologic, and radiologic details were obtained from the medical records., Results: Median age of presentation was 49 years (range, 22 to 80 years), and median duration of symptoms was 6 months (interquartile range, 3-12 months). Baseline receptor status suggested that 234 patients (62.4%) were hormone receptor (HR) positive, 145 (38.6%) were human epidermal growth factor receptor positive, and 69 (18.6%) had triple-negative breast cancer. Various sites of metastasis were: visceral 219 (58.4%), bone only 100 (26.7%), nonregional lymph node metastasis 21 (5.6%), brain 10 (2.7%), and others 25 (5.8%). Approximately 309 patients (82.4%) received up-front chemotherapy, 192 HR-positive patients (82.1%) received endocrine therapy, and 78 human epidermal growth factor receptor-positive patients (53.8%) received targeted agents. Median progression-free survival was 14.2 months (95% CI, 12.7 to 16.8 months), and median overall survival (OS) was 31.7 months (95% CI, 25.8 to 38.2 months) for the cohort. Median time of follow-up was 22.2 months. On multivariable Cox regression analysis, HR-positive disease, good performance status (0 or 1), and oligometastasis were associated with better OS, whereas triple-negative breast cancer and liver and brain metastasis were associated with inferior OS., Conclusion: This is the first comprehensive study, to our knowledge, of metastatic breast cancer from India. HR-positive status, oligometastasis, and good performance status were associated with better outcomes.

Management of cervical cancer has undergone refinement in the past two decades; concurrent chemo-radiation (CCRT) (with cisplatin alone or in combination) is currently the standard treatment approach for patients with locally advanced disease (FIGO stage IIB-IVA). About 30%-40% of such patients fail to achieve complete response; alternative approaches are needed to improve outcome for them. Treatment with bevacizumab (an inhibitor of vascular endothelial growth factor) along with chemotherapy is associated with improved survival in patients with recurrent or metastatic cervical cancer. Weekly paclitaxel and carboplatin for 4-6 weeks as dose dense chemotherapy prior to CCRT is currently under study in a phase III, multicentric trial. Role of adjuvant chemotherapy after CCRT in patients with positive lymph nodes, larger tumor volume and those with stage III-IVA disease needs further exploration. Novel agents targeting molecular pathways are currently being studied. Recent development of immune check point inhibitors is exciting, results of ongoing studies are awaited with interest., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Increased expression of Programmed death ligand-1 (PD-L1) on cancer cells and immune cells predict response to PD-1/PDL1 inhibitors. Data regarding frequency and pattern of PD-L1 expression in NSCLC from India is not available., Objectives: To analyse PD-L1 expression on tumour cells (TC) and immune cells (IC) and to correlate PD-L1 expression with baseline clinico-pathological characteristics, oncogenic drivers and outcome data., Materials and Methods: PD-L1 expression on tumour cells and immune cells was analysed., Results: Eighty-nine cases of resected NSCLC were included. Squamous cell carcinoma was more common than adenocarcinoma. IC were present in almost all cases. Immunopositivity for PD-L1 in TC and IC was 27% and 18% respectively. PD-L1 immunopositivity in TC or IC did not correlate with age, sex, stage or mutation status however sarcomatoid carcinoma and solid predominant adenocarcinomas showed higher positivity rates. PD-L1 immunopositivity in ICs was found to correlate with better disease free survival., Conclusion: PD-L1 immunopositivity was seen in a quarter of NSCLC patients in India. PDL1 positivity on immune cells may be associated with better prognosis in resected NSCLC. However the prognostic value of PD-L1 and clinical response to check point inhibitors in Indian population need to be validated in larger studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Cytology specimens are considered to be a promising alternative for detecting driver mutations in lung cancer patients. We aimed to explore the suitability and utility of various cytology samples of non-small-cell lung cancer (NSCLC) patients for mutation testing. In addition to mutation detection, the importance of preanalytic factors was discussed., Design: A total of 116 cytology samples including 32 controls comprising pleural effusions, bronchial washings, and direct fine-needle aspiration (FNA) smears were included in the study for the detection of EGFR, KRAS, and Her-2/neu gene mutations. Tumor content was checked by microscopic evaluation. Tumor enrichment was done by scraping direct smears. DNA yield was assessed before selecting the method of mutation detection. Sanger sequencing and real-time PCR-based methods were used., Results: Overall, 20.23% EGFR mutations and 2.74% KRAS mutations were observed in this study. Nondriver genetic polymorphisms were observed in EGFR exon 20 in 37% cases. The coexistence of the EGFR mutation and EGFR polymorphism was seen in 7 cases. DNA yield was better in pleural effusions and bronchial washings. Real-time PCR was used in specimens of low DNA yield., Conclusions: Cytology samples are useful in ascertaining molecular diagnostic information for treatment purposes if they are optimized judiciously in their preanalytic phase., (© 2017 S. Karger AG, Basel.)

Competing Interests: The authors have no conflicts of interest to declare.

Objectives: Neuroendocrine tumors of the pancreas (PanNETs) are rare neoplasms, and not much is known about their pathogenesis. We aimed to evaluate ATRX/DAXX immunoexpression in PanNETs a cohort of well-characterized PanNETs., Methods: PanNETs diagnosed over a 10-year period were retrieved and clinicopathogical features reviewed. Immuohistochemistry for pancreatic hormones, and for ATRX and DAXX was performed., Results: Sixty-eight PanNETs were included (30 males and 38 females) with median age of 39 years. Histologically, there were 37 Grade 1 (54.4%), 27 Grade 2 (39.7%), and 4 Grade 3 (5.9%) cases. On immunostaining for hormones, insulin expression was most frequent (22 cases; 38.6%), followed by gastrin (7 cases; 12.3%); 25 cases (43.9%) were negative for all hormones. Loss of ATRX/DAXX immunoexpression was noted in 18 cases (39.1%), and was significantly more frequent in tumors larger than 5 cm. Lymphovascular invasion, infiltrative borders, and infiltration of adjacent organs were also more frequent in tumors with loss of ATRX/DAXX immunoreactivity. A little over half the tumors with ATRX/DAXX loss showed negative immunostaining for all hormones (55.6%)., Conclusion: Loss of ATRX/DAXX expression is frequent in PanNETs, indicating a role in their pathogenesis. As ATRX/DAXX loss is more frequent in larger tumors, and in those with lymphovascular invasion, adjacent organ infiltration and infiltrative borders, this suggests that loss of ATRX/DAXX expression is a late event in pathogenesis and is associated with an aggressive phenotype. Immunohistochemical detection of ATRX/DAXX loss is a simple method for ATRX/DAXX evaluation and can easily be incorporated into routine pathological evaluation of PanNETs.

Background: Survival of myeloma patients has improved considerably in the past decade. However, limited data are available on their long-term outcome. We analysed the data of 225 consecutive patients who underwent autologous stem cell transplantation (ASCT) at our centre., Methods: Between April 1990 and December 2013, a total of 225 patients with multiple myeloma (median age 53 years, range 27-67 years, 69.3% men) underwent ASCT. High-dose melphalan 200 mg/m2 was used for conditioning. Before transplant, the patients received induction therapy with novel agents (thalidomide and dexamethasone, or lenalidomide and dexamethasone, or bortezomib and dexamethasone); or vincristine, doxorubicin, dexamethasone; or alkylating agents (vincristine, melphalan, cyclophosphamide and prednisolone; or melphalan and prednisolone). The response to transplant was evaluated using the European Bone Marrow Transplant criteria, and an intention-to-treat analysis was done., Results: Four-fifths (79.6%) of our patients had Durie Salmon Stage (DSS) IIIA and nearly a quarter (24%) of them had International Stage III disease. Before the transplant, 80.4% of patients had chemosensitive disease. The median interval from diagnosis to transplant was 10 months (range 2-128 months). Following ASCT, 197 (87.5%) patients responded. Complete response was obtained in 54.7%, very good partial response in 19% and partial response in 13.8%. At a median follow-up of 90 months (range 18-266 months), the median progression-free survival (PFS) and overall survival (OS) were 32 and 85.5 months, respectively. The estimated PFS and OS at 10 years were 29.7% and 43.6%, respectively. On multivariate analysis, the presence of extramedullary disease (HR 3.05, p < 0.001), and ISS III (HR 0.50, p < 0.02) predicted inferior OS. Extramedullary disease at diagnosis (HR 1.585, p < 0.03), and more than one regimen pre- transplant (HR 0.53, p < 0.02) predicted an inferior PFS. Complete response was a predictor of superior OS and PFS (p < 0.001)., Conclusion: Complete response following ASCT is associated with good long-term outcome. Alternative treatment strategies are needed to improve results in patients who fail to achieve CR post-transplant and in those with high-risk disease.

The advent of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has led to a paradigm shift in the management of advanced adenocarcinoma of the lung. The key to success of these therapies lies in the precise identification of their molecular targets, i.e. sensitizing EGFR mutations. The variations in the prevalence of these mutations among different ethnicities necessitate regional studies for a better understanding of the molecular epidemiology of the disease and clinical decision-making. This is even more relevant for countries like India where genetic heterogeneity is a rule. Here, we make an attempt to review the epidemiology of EGFR mutations in India versus other Asian countries and the West. We also review the clinical experience with EGFR TKIs and suggest the way forward in a resource-limited setting., (© 2016 S. Karger AG, Basel.)

Background: Lung cancer is one of the commonest and most lethal cancers throughout the world. The majority of the patients present at advance stage and are not suitable for curative intent treatment. Even among patients with localized disease, there has been underutilization of curative treatment modalities. The aim of this study was to analyze the radical treatment utilization rates in patients with non small cell lung cancer (NSCLC) treated at our centre., Materials and Methods: We analyzed case records of 104 patients with a pathologically confirmed diagnosis of NSCLC having stage 1-3B disease who were treated at our centre over last 3 years, to assess the utilization of curative treatment modalities i.e. surgery or radical radiotherapy., Results: The median age of this cohort was 58 years. Out of 104 patients only 33 (31.7%) received curative intent treatment, 14 undergoing curative resection and 19 receiving radical doses of radiotherapy. The baseline characteristics of both the groups (with or without radical treatment) were not different. Major factors associated with underutilization with curative treatment were progressive disease or loss of follow up after chemotherapy and inappropriate use of TKI and/ or palliative radiotherapy in patients with stage 1-3B disease. Patients who did not receive radical treatment had inferior PFS and OS than those who received radical treatment., Conclusions: In our practice we observed gross underutilization of curative intent treatment modalities in patients with NSCLCs which is associated with inferior survival.

BEAM (BCNU, etoposide, cytrabine, melphalan) is the most widely used high dose chemotherapy regimen for autologous transplant in lymphoid malignancies. We report our early experience with an alternative regimen LEAM where BCNU was replaced with the oral analogue CCNU (lomustine) to tide over the non-availability of BCNU. Fifty one patients of relapsed or refractory lymphoma who received BEAM (n= 34) and LEAM (n= 17) from September 2001 to February 2012 were analyzed. From October 2009 onwards LEAM was used as the conditioning regimen instead of conventional BEAM. Patients in the LEAM group had more chemorefractory disease (35% vs 9%, p = 0.045) and high risk comorbidity score (24% vs 0%, p = 0.019). Grade 3 and 4 oral mucositis (67.6% vs. 64.7%, p = 0.834) and diarrhea (47% vs. 41.1%, p = 0.691) were similar. No difference was noted between the two groups in terms of engraftment, documented infections, antibiotic use, cumulative toxicity risk, length of hospital stay and 100 day transplant related mortality. The estimated 2 year overall survival (61.7% vs. 62.7%, p = 0.928) and event free survival (44.6% vs. 41.1%, p = 0.510) of the regimens BEAM and LEAM respectively were comparable. Thus LEAM appeared equivalent to BEAM in terms of toxicity and efficacy and can be used as an alternative to BEAM.

Background: Lung cancer is one of the commonest and most lethal cancers throughout the world. The epidemiological and pathological profile varies among different ethnicities and geographical regions. At present adenocarcinoma is the commonest histological subtype of non-small cell lung cancer (NSCLC) in most of the Western and Asian countries. However, in India squamous cell carcinoma has been reported as the commonest histological type in most of the series. The aim of the study was to analyze the current clinico-pathological profile and survival of lung cancer at our centre., Materials and Methods: We analyzed 434 pathologically confirmed lung cancer cases registered at our centre over a period of three years. They were evaluated for their clinical and pathological profiles, treatment received and outcome. The available histology slides were reviewed by an independent reviewer., Results: Median age was 55 years with a male:female ratio of 4.6:1. Some 68% of patients were smokers. There were 85.3% NSCLC and 14.7% SCLC cases. Among NSCLCs, adenocarcinoma was the commonest histological subtype after the pathology review. Among NSCLC, 56.8% cases were of stage IV while among SCLC 71.8% cases had extensive stage disease. Some 29% of patients could not receive any anticancer treatment. The median overall and progression free survivals of the patients who received treatment were 12.8 and 7.8 months for NSCLC and 9.1 and 6.8 months for SCLC., Conclusions: This analysis suggests that adenocarcinoma may now be the commonest histological subtype also in India, provided a careful pathological review is done. Most of the patients present at advanced stage and outcome remains poor.

In the recent pandemic of H1N1 infection, pediatric patients with haematological malignancies were considered high risk for severe illness. There is paucity of data regarding course of H1N1 infection in this subgroup. We describe H1N1 infection in 3 children with acute leukemia. All three patients presented with neutropenic fever; 2 had probable fungal pneumonia based on chest imaging and galactomanan estimation. Diagnosis of H1N1 infection was delayed in all 3 patients as it was not suspected initially. One patient died despite treatment. H1NI infection may coexist with other infections in febrile neutropenia.

Limited information is available from developing countries about complications, pattern of infections, and long-term outcome of patients following high-dose chemotherapy (HDCT) and autologous blood stem cell transplantation (ASCT). Between April, 1990 and December 2009, 228 patients underwent ASCT. Patients' median age was 48 years, ranging from 11 to 68 years. There were 158 males and 70 females. Indications for transplant included multiple myeloma, n = 143; lymphoma, n = 44 (Hodgkin's, n = 25 and non-Hodgkin's, n = 19); leukemia, n = 22; and solid tumors, n = 18. Patients received HDCT as per standard protocols. Following ASCT, 175 (76.7%) patients responded; complete, 98 (43%); very good partial response, 37 (16.2%); and partial response, 40 (17.5%). Response rate was higher for patients with good Eastern Cooperative Oncology Group (ECOG) performance status (0-2 vs. 3-4, p < 0.001), pretransplant chemo-sensitive disease (p < 0.001) and those with diagnosis of hematological malignancies (p < 0.003). Mucositis, gastrointestinal, renal, and liver dysfunctions were major nonhematologic toxicities, 3.1% of patients died of regimen-related toxicities. Infections accounted for 5.3% of deaths seen before day 30. At a median follow-up of 66 months (range, 9-234 months), median overall (OS) and event-free survival (EFS) were 72 months (95% CI 52.4-91.6) and 24 months (95% CI 17.15-30.9), respectively. For myeloma, OS and EFS were 79 months (95% CI 52.3-105.7) and 30 months (95% CI 22.6-37.4), respectively. Pretransplant good performance status and achievement of significant response following transplant were major predictors of survival. Our analysis demonstrates that such procedure can be successfully performed in a developing country with results comparable to developed countries.

We previously identified several rad51 gain-of-function alleles that partially suppress the requirement for RAD55 and RAD57 in DNA repair. To gain further insight into the mechanism of action of these alleles, we compared the activities of Rad51-V328A, Rad51-P339S and Rad51-I345T with wild-type Rad51, for DNA binding, filament stability, strand exchange and interaction with the antirecombinase helicase, Srs2. These alleles were chosen because they show the highest activity in suppression of ionizing radiation sensitivity of the rad57 mutant, and Val 328 and Ile 345 are conserved in the human Rad51 protein. All three mutant proteins exhibited higher affinity for single-stranded DNA (ssDNA) and showed more robust strand exchange activity with oligonucleotide substrates than wild-type Rad51, with the Rad51-I345T and Rad51-V328A proteins displaying higher activity than Rad51-P339S. However, the Srs2 antirecombinase was able to disrupt Rad51-ssDNA complexes formed with all the mutant proteins. In vivo, the rad51-I345T mutant strain exhibited high resistance to methyl methane sulfonate that was dependent on functional SRS2. These results suggest the Srs2 translocase is able to disrupt Rad51-ssDNA complexes at stalled replication forks, but in the absence of Srs2 the enhanced DNA binding of the Rad51-I345T protein is detrimental to cell survival.

In order to explore the mechanism of geminivirus DNA replication, we show that the Replication initiator (Rep) protein encoded by Mungbean yellow mosaic India virus (MYMIV), a member of the family Geminiviridae, binds specifically to the iterons present in the viral DNA replication origin (CR-A) in a highly ordered manner that might be a prerequisite for the initiation of replication. MYMIV Rep also acts as a helicase during the post-initiation stage and is upregulated in presence of the RPA32 subunit of Replication Protein A. The implication of these findings on the initiation and elongation stages of MYMIV DNA replication has been discussed.

Geminiviruses replicate by rolling circle mode of replication (RCR) and the viral Rep protein initiates RCR by the site-specific nicking at a conserved nonamer (TAATATT downward arrow AC) sequence. The mechanism of subsequent steps of the replication process, e.g. helicase activity to drive fork-elongation, etc. has largely remained obscure. Here we show that Rep of a geminivirus, namely, Mungbean yellow mosaic India virus (MYMIV), acts as a replicative helicase. The Rep-helicase, requiring > or =6 nt space for its efficient activity, translocates in the 3'-->5' direction, and the presence of forked junction in the substrate does not influence the activity to any great extent. Rep forms a large oligomeric complex and the helicase activity is dependent on the oligomeric conformation ( approximately 24mer). The role of Rep as a replicative helicase has been demonstrated through ex vivo studies in Saccharomyces cerevisiae and in planta analyses in Nicotiana tabacum. We also establish that such helicase activity is not confined to the MYMIV system alone, but is also true with at least two other begomoviruses, viz., Mungbean yellow mosaic virus (MYMV) and Indian cassava mosaic virus (ICMV).