Correlation of the Geriatric Assessment with Overall Survival in Older Patients with Cancer.

AIMS: Global guidelines recommend that all older patients with cancer receiving chemotherapy should undergo a geriatric assessment. However, utilisation of the geriatric assessment is often constrained by its time-intensive nature, which limits its adoption in settings with limited resources and high demand. There is a lack of evidence correlating the results of the geriatric assessment with survival from the Indian subcontinent. Therefore, the aims of the present study were to assess the impact of the geriatric assessment on survival in older Indian patients with cancer and to identify the factors associated with survival in these older patients. MATERIALS AND METHODS: This was an observational study, conducted in the geriatric oncology clinic of the Tata Memorial Hospital (Mumbai, India). Patients aged 60 years and older with cancer who underwent a geriatric assessment were enrolled. We assessed the non-oncological geriatric domains of function and falls, nutrition, comorbidities, cognition, psychology, social support and medications. Patients exhibiting impairment in two or more domains were classified as frail. RESULTS: Between June 2018 and January 2022, we enrolled 897 patients. The median age was 69 (interquartile range 65-73) years. The common malignancies were lung (40.5%), oesophagus (31.9%) and genitourinary (12.1%); 54.6% had metastatic disease. Based on the results of the geriatric assessment, 767 (85.4%) patients were frail. The estimated median overall survival in fit patients was 24.3 (95% confidence interval 18.2-not reached) months, compared with 11.2 (10.1-12.8) months in frail patients (hazard ratio 0.54; 95% confidence interval 0.41-0.72, P < 0.001). This difference in overall survival remained significant after adjusting for age, sex, primary tumour and metastatic status (hazard ratio 0.56; 95% confidence interval 0.41-0.74, P < 0.001). In the patients with a performance status of 0 or 1 (n = 454), 365 (80.4%) were frail; the median overall survival in the performance status 0-1 group was 33.0 months (95% confidence interval 24.31-not reached) in the fit group versus 14.4 months (95% confidence interval 12.25-18.73) in the frail patients (hazard ratio 0.50; 95% confidence interval 0.34-0.74, P = 0.001). In the multivariate analysis, the geriatric assessment domains that were predictive of survival were function (hazard ratio 0.68; 95% confidence interval 0.52-0.88; P = 0.003), nutrition (hazard ratio 0.64; 95% confidence interval 0.48-0.85, P = 0.002) and cognition (hazard ratio 0.67; 95% confidence interval 0.49-0.91, P = 0.011). DISCUSSION: The geriatric assessment is a powerful prognostic tool for survival among older Indian patients with cancer. The geriatric assessment is prognostic even in the cohort of patients thought to be the fittest, i.e. performance status 0 and 1. Our study re-emphasises the critical importance of the geriatric assessment in all older patients planned for cancer-directed therapy.

Utility of Indigenously Developed Square Grid Method for Evaluation of Tumor-Stroma Ratio and Stromal Tumor-Infiltrating Lymphocytes in Invasive Breast Carcinoma: A Pilot Study.

Background & Objective: Invasive breast carcinoma (IBC) is the most commonly diagnosed cancer among women in India. The conventional visual method of evaluation of Tumor-Stroma Ratio (TSR) and Stromal Tumor-Infiltrating Lymphocytes (sTIL) appears to be subjective. The present study aims to evaluate the utility of the indigenously designed square grid method for the evaluation of tumor-stroma ratio and stromal tumor-infiltrating lymphocytes in invasive breast carcinoma by assessing the inter-observer variability. Methods: This was a retrospective study conducted at a rural tertiary care referral institute from July 2018 to June 2020. In each case, microphotographs were taken from 10 representative fields in H&E-stained sections for evaluating TSR in low-power and sTIL in high-power. Both the parameters were evaluated employing an indigenously designed square grid applied onto microphotographs in the power-point slides by making use of principles of the Pythagorean theorem. Both parameters were separately evaluated by two pathologists. Cohen kappa statistics was the statistical tool used to analyze inter-observer variability. Results: Thirty cases were analyzed. Invasive breast carcinoma of no special type (IBC-NST) was the most common histopathological type (26 cases (86.67%)). For TRS evaluation, a Kappa value of 0.78 suggested substantial agreement with an agreement of 91.67%. For sTIL evaluation, a Kappa value of 0.51 suggested moderate agreement with an agreement of 88.33%. The P-values were statistically highly significant (P<0.001). Conclusion: Square grid method is a novel technique for evaluating TSR and sTIL in invasive breast carcinoma. It can be considered an example of the application of Pythagoras' theorem in Pathology.

Utility of Indigenous Cytology Technique in the Diagnosis of Oral Cavity Lesions using Normal Saline as a Processing Fluid: A Comparative Study.

Background: Oral cancer is a major health problem in developing countries. Cytology has been widely accepted as a tool in the early diagnosis of cancer. Objectives: To evaluate the diagnostic utility of four different cytology techniques, that is, modified brush cytology (BR) technique, brush cytology cytocentrifugation (BRCC) technique, modified scrape cytology (SR) technique, and scrape cytology cytocentrifugation (SRCC) technique and correlate the cytopathological diagnosis with the available histopathological diagnosis. Materials and Methods: It was a prospective observational study of oral cavity lesions conducted from January 2018 to December 2018 at a rural tertiary care referral institute. Smears prepared by four different techniques, that is, BR technique, BRCC technique, SR technique and SRCC technique were evaluated using a scoring system. Normal saline was used as a processing fluid for cytocentrifugation techniques, and the cytological diagnosis was compared with an available histopathological diagnosis for concordance. Results: Twenty-seven cases of oral cavity lesions were analyzed. Squamous cell carcinoma (55.56%) constituted the most common lesion diagnosed by cytology. Total concordance was 95.65%. Brush cytology techniques were better technique than scrape cytology techniques. Cytocentrifugation techniques were better than modified brush cytology technique and modified scrape cytology technique and the values were statistically highly significant (P<0.0001). Conclusion: The utility of only normal saline as a processing fluid for cytocentrifugation may be considered an unexplored and prudent endeavor. This indigenously designed technique may be employed to improve the quality of cytological preparation for the evaluation of oral cavity lesions.

A Comparative Study of Squash Smear Cytology Diagnosis and Radiological Diagnosis with Histopathology in Central Nervous System Lesions.

Background: Space occupying lesions (SOLs) of central nervous system (CNS) constitutes important cause of neurological morbidity and mortality. Squash cytology is technically a simple and rapid intraoperative diagnostic tool. Radiology is supportive of histopathological diagnosis. Objectives: To enumerate the histopathological patterns of various central nervous system (CNS) lesions, to correlate cytopathological diagnosis with histopathological diagnosis, and to correlate radiological diagnosis with histopathological diagnosis. Materials and Methods: It was a retrospective study of CNS lesion cases from January 2015 to August 2018. Cytological-histopathological concordance and radiological-histopathological concordance were calculated. Chi-square test was the statistical tool used for statistical analysis. Results: Histopathological diagnosis of 50 cases included neoplastic lesions (42 cases [84%]) and non-neoplastic lesions (8 cases [16%]). Correct diagnosis was achieved by squash cytology in 36 cases (72%) and radiological diagnosis in 25 cases (50%) by complete concordance. However, diagnostic accuracy of squash and radiology improved considerably by 90% and 76%, respectively, after applying partial concordance criteria. For the detection of neoplastic lesions, squash cytology had 98% and radiology had 80% diagnostic efficacy. Conclusion: Preoperative radiological investigation and intraoperative squash smear cytology are complementary to each other. A multidisciplinary approach is necessary for the management of patients.

Factors influencing local and distant recurrence following resection of periampullary cancer.

BACKGROUND: Recurrence of periampullary cancer after pancreatoduodenectomy is common. The aim of this study was to investigate patterns of recurrence, incidence, and factors associated with local and distant recurrences. METHODS: This retrospective, single-centre study included consecutive patients with periampullary cancer who underwent resection with curative intent from January 2012 to January 2018. Survival, patterns of recurrence, and factors associated with recurrences were analysed. RESULTS: Median overall survival (OS) and disease-free survival among 398 included patients was 58.4 and 49.5 months respectively. Twenty-three patients (5.8 per cent) developed isolated local recurrences (LR), 50 (12.6 per cent) developed LR along with distant metastasis (DM), and 103 (25.9 per cent) developed isolated DM. Median OS was 40.4 months for patients with isolated LR versus 23 months for those with DM (P < 0.001). Tumour subtype (distal common bile duct (CBD): odds ratio (OR) 6.18, 95 per cent c.i. 2.19 to 17.46) and node-positive status (OR 2.36, 1.26 to 4.43) were independently associated with higher rates of LR. The most common site for isolated LR was along the superior mesenteric artery (12 of 23 patients). Tumour subtype (distal CBD: OR 2.86, 1.09 to 7.52), nodal positivity (OR 2.46, 1.53 to 3.94), and presence of perineural invasion (OR 1.80, 1.02 to 3.18) were independently associated with DM. CONCLUSION: Isolated LR is associated with better survival than DM and occurs most commonly along the superior mesenteric artery.

Economic assessment of starting robot-assisted laparoscopic inguinal hernia repair in a single-centre retrospective comparative study: the EASTER study.

BACKGROUND: There has been a rapid adoption of robot-assisted laparoscopic inguinal hernia repair in the USA, despite a lack of proven clinical advantage and higher material cost. No studies have been published regarding the cost and outcome of robotic inguinal hernia surgery in a European Union setting. METHODS: A retrospective comparative study was performed on the early outcome and costs related to laparoscopic inguinal hernia repair, with either conventional or robot-assisted surgery. RESULTS: The study analysed 676 patients undergoing laparoscopic inguinal hernia repair (272 conventional and 404 robotic repairs). Conventional laparoscopic and robotic repair groups were comparable in terms of duration of surgery (57.6 versus 56.2 min respectively; P = 0.224), intraoperative complication rate (1.1 versus 1.2 per cent; P = 0.990), in-hospital complication rate (4.4 versus 4.5 per cent; P = 0.230) and readmission rate (3.3 versus 1.2 per cent; P = 0.095). There was a significant difference in hospital stay in favour of the robotic approach (P = 0.014), with more patients treated on an outpatient basis in the robotic group (59.2 per cent versus 70.0 per cent for conventional repair). At 4-week follow-up, equal numbers of seromas or haematomas were recorded in the conventional laparoscopic and robotic groups (13.3 versus 15.7 per cent respectively; P = 0.431), but significantly more umbilical wound infections were seen in the conventional group (3.0 per cent versus 0 per cent in the robotic group; P = 0.001). Robotic inguinal hernia repair was significantly more expensive overall, with a mean cost of €2612 versus €1963 for the conventional laparoscopic approach (mean difference €649; P < 0.001). CONCLUSION: Robot-assisted laparoscopic inguinal hernia repair was significantly more expensive than conventional laparoscopy. More patients were treated as outpatients in the robotic group. Postoperative complications were infrequent and mild.

Can Post-Treatment MRI Features Predict Pathological Circumferential Resection Margin (pCRM) Involvement in Low Rectal Tumors.

The MERCURY II study demonstrated the use of MRI-based risk factors such as extramural venous invasion (EMVI), tumor location, and circumferential resection margin (CRM) involvement to preoperatively predict pCRM (pathological CRM) outcomes for lower rectal tumors in a mixed group of upfront operated patients and patients who received neoadjuvant treatment. We aim to study the applicability of results of MERCURY II study in a homogeneous cohort of patients who received neoadjuvant chemoradiation (NACTRT) prior to surgery. After Institutional Review Board approval, post NACTRT restaging MRI of 132 patients operated for low rectal cancer between 2014 and 2018 were retrospectively reviewed by two radiologists for site of tumor, EMVI status, distance from anal verge (< 4 or > 4 cm), and mrCRM positivity. Findings were compared with post surgery pCRM outcomes using Fisher's exact test. Only 9/132(7%) patients showed pCRM involvement on histopathology, 8 of them being CRM positive on MRI (p = 0.01). The positive predictive value (PPV) of mrCRM positive status and pCRM status was 12.7% (95% CI: 9.7-16.5%), while the negative predictive value was 98.5% (95% CI: 91.4-99.8%) (p = 0.01). EMVI positive and anteriorly located tumors showed higher incidence of pCRM positivity but were not found to be significant (15% vs 5.2% and p = 0.13 and 8.6% vs 2.1% and p = 0.28, respectively). Unsafe mrCRM was the only factor significantly associated with pCRM positivity on post neoadjuvant restaging MRI. Tumors less than 4 cm from anal verge, anterior tumor location, and mrEMVI positivity did not show statistically significant results to predict pCRM involvement.

Outcomes of Definitive Treatment of Signet Ring Cell Carcinoma of the Rectum: Is Minimal Invasive Surgery Detrimental in Signet Ring Rectal Cancers?

The outcome of surgery for signet ring adenocarcinoma of rectum is suboptimal with high predilection for locoregional and peritoneal metastases. Lack of intercellular adhesion due to focal loss of epithelial cell adhesion molecule (EpCAM) may account for this. In such patients, whether minimal invasive surgery carries a high risk of dissemination by pneumoperitoneum and tumor implantation remains uncertain. The aim of this study was to compare the outcomes of patients undergoing minimally invasive surgery (MIS) versus open surgery in patients with signet ring cell adenocarcinoma of rectum. A retrospective study was conducted at a tertiary care center over 3 years on 39 patients undergoing open surgery and 40 patients undergoing MIS diagnosed with signet ring cell carcinoma (SRCC) identified from our surgical database. Patient characteristics in terms of demographics, clinicoradiological staging, neoadjuvant therapy, and type of surgery with morbidity were compared in the two groups. Data on patients undergoing adjuvant therapy and 3 years disease-free survival (DFS) and overall survival (OS) were analyzed. Recurrence patterns in both groups were separately identified as locoregional, peritoneal, or systemic. The number of patients undergoing surgery in the two arms was 40 (MIS) and 39 (open). In the MIS arm, mean DFS was 29 months whereas in the open arm, it was 25.8 months. The mean OS was 33.65 months for the MIS arm and that for the open arm was 36.34 months. This retrospective study reveals no significant difference in outcomes of surgery for signet ring cell rectal cancers with either MIS or open approach.

Lysosomal P-gp-MDR1 Confers Drug Resistance of Brentuximab Vedotin and Its Cytotoxic Payload Monomethyl Auristatin E in Tumor Cells.

Antibody-drug conjugates (ADCs) are composed of an antibody linked to cytotoxic anticancer payloads. ADCs recognize tumor-specific cell surface antigens and are internalized into lysosomes where proteolytic enzymes release the cytotoxic payloads. Efflux transporters on plasma membrane that play a significant role on multi-drug resistance in chemotherapy can be internalized on lysosomal membrane and sequester the cytotoxic payloads. In the present study, ATP binding cassette (ABC) efflux transporters including breast cancer resistance protein (BCRP), P-glycoprotein (P-gp-MDR1), multidrug resistance protein (MRP) 2, MRP3 and MRP4 in lysosomal, and plasma membrane of tumor cells were quantified by targeted quantitative proteomics. The cytotoxicity of brentuximab vedotin and its cytotoxic payload monomethyl auristatin E (MMAE) to the tumor cell lines in the presence and absence of elacridar (P-gp-MDR1 inhibitor) or chloroquine (lysosomotropic agent) were evaluated. MMAE is a substrate for P-gp-MDR1, as the apparent efflux ratio in MDR1 transfected MDCK cell monolayers was 44.5, and elacridar abolished the MMAE efflux. Cell lines that highly express P-gp-MDR1 show higher EC50s toward the cell killing effects of MMAE. Co-incubation with chloroquine or elacridar resulted in left shift of MMAE EC50 by 2.9-16-fold and 4.2-22-fold, respectively. Similarly co-incubation with chloroquine or elacridar or in combination of chloroquine and elacridar increased cytotoxic effects of brentuximab vedotin by 2.8- to 21.4-fold on KM-H2 cells that express a specific tumor antigen CD30 and P-gp-MDR1. These findings demonstrate important roles of P-gp-MDR1 on cytotoxic effects of brentuximab vedotin and its payload MMAE. Collectively, ABC transporter-mediated drug extrusion and/or sequestration needs to be early assessed for selection of optimal payloads and linkers when developing ADCs.

Robotic transabdominal retromuscular umbilical prosthetic hernia repair (TARUP): observational study on the operative time during the learning curve.

PURPOSE: The use of extraperitoneal mesh in place of intra-peritoneal mesh is gaining popularity in laparoscopic ventral hernia repair. We have adopted a robotic assisted laparoscopic technique using a lateral single-dock robotic access with retromuscular mesh placement after opening the ipsilateral posterior rectus fascia. In this study, we wanted to evaluate the changes in operative times during the initial experience with this novel technique. METHODS: The initial consecutive patients undergoing robotic assisted transabdominal retromuscular umbilical prosthetic repair (r-TARUP) using a 15 × 15 cm self-fixating mesh were prospectively entered in the study and the operative times during the separate steps of the surgical procedure were recorded. Complications were reported up to 4 week post operatively and quality of life was assessed using the EuraHS-QoL score. RESULTS: Over a 5 month inclusion period, 41 patients with either a primary (n = 34) or a trocar site hernia (n = 7) at the umbilicus were identified. All hernias had a mean diameter of less than 4 cm. The total OR time decreased significantly during the learning curve (tertile 1: 126 min versus tertile 3: 102 min; p = 0.002) due to a decrease in the skin-to-skin operating time (tertile 1: 81 min versus tertile 3:61 min; p = 0.002). The decrease in the retromuscular dissection time was the most significant of all the steps that comprised the console time (p = 0.004). The non-surgical time did not decrease (p = 0.15). The operation was performed on an outpatient basis in 68% of patients and with a one-night-stay in 29%. No complications related to the introduction of the robotic technique for this approach were observed and the early outcome is promising, with favorable quality-of-life evaluation at 4 weeks. CONCLUSIONS: The decrease in operative time during the adoption of r-TARUP was mainly related to the improved efficiency in the dissection phase of the procedure. The technique is reproducible and safe and the operative time compares favorably to published operative times for laparoscopic and open retromuscular umbilical hernia repair.

Physiologically-based pharmacokinetic modelling of a CYP2C19 substrate, BMS-823778, utilizing pharmacogenetic data.

AIMS: Previous studies demonstrated direct correlation between CYP2C19 genotype and BMS-823778 clearance in healthy volunteers. The objective of the present study was to develop a physiologically-based pharmacokinetic (PBPK) model for BMS-823778 and use the model to predict PK and drug-drug interaction (DDI) in virtual populations with multiple polymorphic genes. METHODS: The PBPK model was built and verified using existing clinical data. The verified model was simulated to predict PK of BMS-823778 and significance of DDI with a strong CYP3A4 inhibitor in subjects with various CYP2C19 and UGT1A4 genotypes. RESULTS: The verified PBPK model of BMS-823778 accurately recovered observed PK in different populations. In addition, the model was able to capture the exposure differences between subjects with different CYP2C19 genotypes. PK simulation indicated higher exposures of BMS-823778 in CYP2C19 poor metabolizers who were also devoid of UGT1A4 activity, compared to those with normal UGT1A4 functionality. Moderate DDI with itraconazole was predicted in subjects with wild-type CYP2C19 or UGT1A4. However, in subjects without CYP2C19 or UGT1A4 functionality, significant DDI was predicted when BMS-823778 was coadministered with itraconazole. CONCLUSIONS: A PBPK model was developed using clinical data that accurately predicted human PK in different population with various CYP2C19 phenotypes. Simulations with the verified PBPK model indicated that UGT1A4 was probably an important clearance pathway in CYP2C19 poor metabolizers. DDI with itraconazole is likely to be dependent on the genotypes of CYP2C19 and UGT1A4.

Preoperative Imaging Overestimates the Tumor Size in Pancreatic Neuroendocrine Neoplasms Associated with Multiple Endocrine Neoplasia Type 1.

BACKGROUND: Radiological tumor size of non-functioning pancreatic neuroendocrine neoplasms (Nf-pNENs) associated with multiple endocrine neoplasia type 1 (MEN1) is a crucial parameter to indicate surgery. The aim of this study was to compare radiological size (RS) and pathologic size (PS) of MEN1 associated with pNENs. METHODS: Prospectively collected data of MEN1 patients who underwent pancreatic resections for pNENs were retrospectively analyzed. RS was defined as the largest tumor diameter measured on endoscopic ultrasound (EUS), magnetic resonance imaging (MRI) or computed tomography (CT). PS was defined as the largest tumor diameter on pathological analysis. Student's t test and linear regression analysis were used to compare the median RS and PS. p < 0.05 was considered significant. RESULTS: Forty-four patients with a median age of 37 (range 10-68) years underwent primary pancreatic resections for pNENs. Overall, the median RS (20 mm, range 3-100 mm) was significantly larger than the PS (13 mm, range 4-110 mm) (p = 0.001). In patients with pNENs < 20 mm (n = 27), the size difference (median RS 15 mm vs PS 12 mm) was also significant (p = 0.003). However, the only modality that significantly overestimated the PS was EUS (median RS 14 mm vs 11 mm; p = 0.0002). RS overestimated the PS in 21 patients (21 of 27 patients, 78%). Five of 11 patients (12%) with a Nf-pNEN and a RS > 20 mm had in reality a PS < 20 mm. MRI was the imaging technique that best correlated with PS in the total cohort (r = 0.8; p < 0.0001), whereas EUS was the best correlating imaging tool in pNENs < 20 mm (r = 0.5; p = 0.0001). CONCLUSION: Preoperative imaging, especially EUS, frequently overestimates the size of MEN1-pNENs, especially those with a PS < 20 mm. This should be considered when indicating surgery in MEN1 patients with small Nf-pNENs.

Comparison of paclitaxel-cetuximab chemotherapy versus metronomic chemotherapy consisting of methotrexate and celecoxib as palliative chemotherapy in head and neck cancers.

BACKGROUND: The present match pair analysis was planned to compare the efficacy of cetuximab-paclitaxel-based chemotherapy versus metronomic therapy. MATERIALS AND METHODS: Sixty patients with metastatic/recurrent head and neck squamous cell cancer treated with weekly paclitaxel (80 mg/m2) and cetuximab were matched with sixty patients treated with oral metronomic chemotherapy consisting of methotrexate and celecoxib. The progression-free survival (PFS) and overall survival (OS) between the cohorts were compared using log-rank test. Cox proportional regression model was used to identify independent factors affecting PFS and OS. RESULTS: The median OS was 191 days (95% confidence interval [CI]: 122.2-259.8 days) in metronomic cohort and 256 days (95% CI 177.0-334.9 days) in cetuximab cohort (hazard ratio: 0.58, 95% CI: 0.35-0.95, P = 0.031). On Cox proportional hazard model, Eastern Cooperative Oncology Group Performance Status (0-1 vs. 2) and therapy (cetuximab versus metronomic) had a statistically significant impact on OS. CONCLUSION: Cetuximab-based chemotherapy leads to a significant improvement in OS in the match pair analysis in comparison to metronomic chemotherapy.

Epidermal growth factor receptor positive lung cancer: The nontrial scenario.

PURPOSE: The aim of this study was to report the median overall survival (OS) in epidermal growth factor receptor (EGFR) mutation-positive patients who were managed out of a clinical trial. METHODS: Nonsmall cell lung cancer patients harboring activating EGFR mutations who were either ineligible or refused participation in a clinical trial were selected for this analysis. The reason for not participating in trial, staging, treatment, and outcome details were obtained from a prospective lung cancer database. The Kaplan-Meier method was used to estimate OS. Log-rank test and Cox proportion hazard model were used for univariate and multivariate analysis, respectively. RESULTS: We included 225 patients in this analysis. The median age of the cohort was 56 years (range 29-85 years). A compromised Eastern Cooperative Oncology Group performance status (PS) of >2 was the major reason (83 patients, 36.9%) for ineligibility of patients in a clinical trial. The major reason provided by eligible patients for refusal to participate in a clinical trial was long distance of travel and inability to comply with the study-mandated follow-up visits (65 patients, 28.9%). The median OS in patients with PS 0-2 was 18.17 months (95% confidence interval [CI]: 15.6-20.8 months) and it was 12.1 months (95% CI: 9.0-15.2 months) in patients with PS 3-4 (hazard ratio - 0.579 [95% CI: 0.398-0.843] P = 0.004). CONCLUSION: EGFR positive patients who were ineligible for a clinical trial due to poor PS had lower survival; however, patients with good PS treated off-trial had similar OS to that reported in multiple clinical trials.

Renal Primitive Neuroectodermal Tumour: Case Report of a Rare Entity.

The peripheral Primitive Neuroectodermal Tumour (PNET) is a member of the family of small round cell tumours. PNET is more aggressive in kidney when compared to the other sites. It usually presents in childhood or adolescence. It has an aggressive clinical course and may process towards metastatic disease culminating in death. A 24-year-old female presented with left sided abdominal swelling. Abdominal ultrasound confirmed a heterogeneous left renal mass. Consequently the patient underwent nephrectomy of left kidney and left oophorectomy. Grossly, the tumour involved almost entire kidney, showed multi-lobular, grey, glistening appearance with focal haemorrhagic areas. Histologically, the tumour cells were arranged in diffuse infiltrating sheets, cohesive lobules, Homer-Wright rosettes and perivascular pseudo-rosettes. Individual tumour cells were small round cells with scant cytoplasm and round nuclei having dispersed chromatin. Features were suggestive of PNET. Immunohistochemistry showed tumour cells displaying strong membrane positivity for MIC 2. Renal PNET needs to be differentiated from other primary and metastatic renal round-cell tumours. Most of the cases of renal PNET have poor response to standard treatment of combined surgical resection, post-operative irradiation, and chemotherapy. PNET is a rare primary tumour in the kidney. Histopathological diagnosis has to be confirmed by immunophenotyping of the tumour cells.

Drug-sensitive FGFR3 mutations in lung adenocarcinoma.

Background: Lung cancer is the leading cause of cancer-related deaths across the world. In this study, we present therapeutically relevant genetic alterations in lung adenocarcinoma of Indian origin. Materials and methods: Forty-five primary lung adenocarcinoma tumors were sequenced for 676 amplicons using RainDance cancer panel at an average coverage of 1500 × (reads per million mapped reads). To validate the findings, 49 mutations across 23 genes were genotyped in an additional set of 363 primary lung adenocarcinoma tumors using mass spectrometry. NIH/3T3 cells over expressing mutant and wild-type FGFR3 constructs were characterized for anchorage independent growth, constitutive activation, tumor formation and sensitivity to FGFR inhibitors using in vitro and xenograft mouse models. Results: We present the first spectrum of actionable alterations in lung adenocarcinoma tumors of Indian origin, and shows that mutations of FGFR3 are present in 20 of 363 (5.5%) patients. These FGFR3 mutations are constitutively active and oncogenic when ectopically expressed in NIH/3T3 cells and using a xenograft model in NOD/SCID mice. Inhibition of FGFR3 kinase activity inhibits transformation of NIH/3T3 overexpressing FGFR3 constructs and growth of tumors driven by FGFR3 in the xenograft models. The reduction in tumor size in the mouse is paralleled by a reduction in the amounts of phospho-ERK, validating the in vitro findings. Interestingly, the FGFR3 mutations are significantly higher in a proportion of younger patients and show a trend toward better overall survival, compared with patients lacking actionable alterations or those harboring KRAS mutations. Conclusion: We present the first actionable mutation spectrum in Indian lung cancer genome. These findings implicate FGFR3 as a novel therapeutic in lung adenocarcinoma.

Refinement of screening for familial pancreatic cancer.

OBJECTIVE: Surveillance programmes are recommended for individuals at risk (IAR) of familial pancreatic cancer (FPC) to detect early pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC). However, the age to begin screening and the optimal screening protocol remain to be determined. METHODS: IAR from non-CDKN2A FPC families underwent annual screening by MRI with endoscopic ultrasonography (EUS) in board-approved prospective screening programmes at three tertiary referral centres. The diagnostic yield according to age and different screening protocols was analysed. RESULTS: 253 IAR with a median age of 48 (25-81) years underwent screening with a median of 3 (1-11) screening visits during a median follow-up of 28 (1-152) months. 134 (53%) IAR revealed pancreatic lesions on imaging, mostly cystic (94%), on baseline or follow-up screening. Lesions were significantly more often identified in IAR above the age of 45 years (p<0.0001). In 21 IAR who underwent surgery, no significant lesions (PDAC, pancreatic intraepithelial neoplasia (PanIN) 3 lesions, high-grade intraductal papillary mucinous neoplasia (IPMN)) were detected before the age of 50 years. Potentially relevant lesions (multifocal PanIN2 lesions, low/moderate-grade branch-duct IPMNs) occurred also significantly more often after the age of 50 years (13 vs 2, p<0.0004). The diagnostic yield of potentially relevant lesions was not different between screening protocols using annual MRI with EUS (n=98) or annual MRI with EUS every 3rd year (n=198) and between IAR screened at intervals of 12 months (n=180) or IAR that decided to be screened at ≥24 months intervals (n=30). CONCLUSIONS: It appears safe to start screening for PDAC in IAR of non-CDKN2a FPC families at the age of 50 years. MRI-based screening supplemented by EUS at baseline and every 3rd year or when changes in MRI occur appears to be efficient.