Prachi Patil

Common genetic variation and risk of gallbladder cancer in India: a case-control genome-wide association study

BACKGROUND Gallbladder cancer is highly lethal, with notable differences in incidence by geography and ethnic background. The aim of this study was to identify common genetic susceptibility alleles for gallbladder cancer. METHODS In this case-control genome-wide association study (GWAS), we did a genome-wide scan of gallbladder cancer cases and hospital visitor controls, both of Indian descent, followed by imputation across the genome. Cases were patients aged 20-80 years with microscopically confirmed primary gallbladder cancer diagnosed or treated at Tata Memorial Hospital, Mumbai, India, and enrolled in the study between Sept 12, 2010, and June 8, 2015. We only included patients who had been diagnosed less than 1 year before the date of enrolment and excluded patients with any other malignancies. We recruited visitor controls aged 20-80 years with no history of cancer visiting all departments or units of Tata Memorial Hospital during the same time period and frequency matched them to cases on the basis of age, sex, and current region of residence. We estimated association using logistic regression, adjusting for age, sex, and five eigenvectors. We recruited samples for a replication cohort from patients visiting Tata Memorial Hospital between Aug 4, 2015, and May 17, 2016, and patients visiting the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, between July, 2010, and May, 2015. We used the same inclusion and exclusion criteria for the replication set. We examined three of the most significant single-nucleotide polymorphisms (SNPs) in the replication cohort and did a meta-analysis of the GWAS discovery and replication sets to get combined estimates of association. FINDINGS The discovery cohort comprised 1042 gallbladder cancer cases and 1709 controls and the replication cohort contained 428 gallbladder cancer cases and 420 controls. We observed genome-wide significant associations for several markers in the chromosomal region 7q21.12 harbouring both the ABCB1 and ABCB4 genes, with the most notable SNPs after replication and meta-analysis being rs1558375 (GWAS p=3·8 × 10-9; replication p=0·01; combined p=2·3 × 10-10); rs17209837 (GWAS p=2·0 × 10-8; replication p=0·02; combined p=2·3 × 10-9), and rs4148808 (GWAS p=2·4 × 10-8; replication p=0·008; combined p=2·7 × 10-9). Combined estimates of per-allele trend odds ratios were 1·47 (95% CI 1·30-1·66; p=2·31 × 10-10) for rs1558375, 1·61 (1·38-1·89; p=2·26 × 10-9) for rs17209837, and 1·57 (1·35-1·82; p=2·71 × 10-9) for rs4148808. GWAS heritability analysis suggested that common variants are associated with substantial variation in risk of gallbladder cancer (sibling relative risk 3·15 [95% CI 1·80-5·49]). INTERPRETATION To our knowledge, this study is the first report of common genetic variation conferring gallbladder cancer risk at genome-wide significance. This finding, along with in-silico and biological evidence indicating the potential functional significance of ABCB1 and ABCB4, underlines the likely importance of these hepatobiliary phospholipid transporter genes in the pathology of gallbladder cancer. FUNDING The Tata Memorial Centre and Department of Biotechnology.

Simultaneous gallbladder and bile duct cancers: revisiting the pathological possibilities

The pathogenesis of gallbladder cancer presenting synchronously with malignancy of the bile duct has not been clearly understood. The possible causes for the simultaneous presence of these tumors could be due to local spread, metastases, de novo multifocal origin, or as part of a field change in the extrahepatic biliary apparatus. In this article, we discuss the cases of four patients with simultaneous gallbladder and bile duct malignancies and analyze their individual pathologies to provide an explanation into the mechanisms that may play a role in such conditions.

Escalated radiation dose alone vs. concurrent chemoradiation for locally advanced and unresectable rectal cancers: results from phase II randomized study.

PurposeThis trial was undertaken to compare the rates of resectability between patients treated with neoadjuvant concurrent chemoradiation vs. boosted radiotherapy alone.Materials and methodsPatients with clinically unresectable rectal cancer were randomized to receive external beam radiation therapy (EBRT) to pelvis (45 Gy) with concurrent oral Capecitabine (CRT group; Arm 1) or EBRT to pelvis (45 Gy) alone followed by 20 Gy dose of localized radiotherapy boost to the primary tumor site (RT with boost group, Arm 2). All patients were assessed for resectability after 6 weeks by clinical examination and by CT scan and those deemed resectable underwent surgery.ResultsA total of 90 patients were randomized, 46 to Arm 1 and 44 to Arm 2. Eighty seven patients (44 in Arm 1 and 41 in Arm 2) completed the prescribed treatment protocol. Overall resectability rate was low in both the groups; R0 resection was achieved in 20 (43 %) patients in Arm 1 vs. 15 (34 %) in Arm 2. Adverse factors that significantly affected the resectability rate in both the groups were extension of tumor to pelvic bones and signet ring cell pathology. Complete pathological response was seen in 7 and 11 %, respectively. There was greater morbidity such as wound infection and delayed wound healing in Arm 2 (16 vs. 40 %; p = 0.03).ConclusionEscalated radiation dose without chemotherapy does not achieve higher complete (R0) tumor resectability in locally advanced inoperable rectal cancers, compared to concurrent chemoradiation.

Adenocarcinoma of the Rectum-A Composite of Three Different Subtypes With Varying Outcomes?

INTRODUCTION Adenocarcinoma of the rectum has been classified by the World Health Organization into various histologic subtypes. We analyzed the effect of the histologic subtype (classic, signet ring cell, and mucinous) on the clinical outcomes of patients with rectal cancer. We hypothesized that clinicopathologic outcome measures such as tumor margins, tumor regression grade, recurrence rate, and survival would vary with the histologic subtype. MATERIALS AND METHODS We conducted a retrospective analysis of a prospectively maintained database. All patients with stage I-III rectal adenocarcinoma were included. RESULTS From May 2010 to August 2013, 273 patients underwent curative resection. Both mucin-secreting variants were more common in younger patients and presented at a more advanced stage. Also, 54% and 48% of those with signet ring cell carcinoma (SRCC) and mucinous adenocarcinoma (MAC) had node-positive disease compared with the rate in the classic variant (30%). Circumferential resection margin positivity was 24% with MAC and 19% with SRCC compared with 4% with the classic variant. Disease-free survival for those with the classic and mucinous variants was 38.5 and 37.4 months, respectively. In contrast, it was 28.6 months in the SRCC group. The overall survival did not differ significantly. CONCLUSION Rectal adenocarcinoma presents as a spectrum of disease, with progressively worsening outcomes from classic to MAC to SRCC. These aggressive variants might warrant more aggressive resection. These data from the Indian subcontinent differ from the published data from Western countries.

Clinical Outcome in Definitive Concurrent Chemoradiation With Weekly Paclitaxel and Carboplatin for Locally Advanced Esophageal and Junctional Cancer.

There are little data on the efficacy and safety of taxane/platinum with definitive radiotherapy (RT) for esophageal/GEJ cancer. This article is a retrospective analysis of patients who received weekly paclitaxel 50 mg/m(2) and carboplatin AUC 2 with radical definitive RT for locally advanced esophageal/GEJ cancer. Between February 2011 and July 2014, 179 patients were included. The median age was 54 years. Ninety-two percent of patients had squamous histology. Mean RT dose was 58.7 Gy in 32 fractions over 53 days, with mean of six chemotherapy cycles. Fifty-six percent of patients developed ≥grade 3 acute toxicities, commonly febrile neutropenia (12%) and infection (11%); ≥grade 3 laboratory abnormalities included hyponatremia (38%), leukopenia (49%), neutropenia (27%), and anemia (16%). Twelve percent of patients developed ≥grade 3 chronic toxicity. Fatal toxicities included six during CRT, eight within 30 days of completing CRT, and three chronic. Radiologic response was 49% (CR 5.6%, PR 43%). Follow-up endoscopy showed remission in 53% and residual disease in 14%. At a median follow-up of 28 months, median PFS was 11 months (95% CI: 8-13.9), median OS was 19 months (95% CI: 15.4-22.6), and estimated 1-year, 2-year, and 3-year survivals were 70%, 47%, and 39%, respectively. Weekly paclitaxel-carboplatin concurrently with definitive RT is efficacious with manageable toxicity. [The trial was registered with the Clinical Trials Registry-India (CTRI), registration number: CTRI/2014/07/004776.].

Multimodality therapy of rectal gastrointestinal stromal tumors in the era of imatinib—an Indian series

BACKGROUND Primary objective was to determine if sphincter preservation is possible with the use of neoadjuvant imatinib in cases of rectal gastrointestinal stromal tumor (GIST). Secondary objectives were to determine clinicopathological characteristics and intermediate term oncological outcomes of the cases of rectal GIST. METHODS This is a retrospective review of 13 cases of GIST of the rectum diagnosed between January 1, 2010 and June 30, 2015 at Tata Memorial Centre, Mumbai, India. Clinical parameters that were assessed were duration of the neoadjuvant imatinib therapy, type of surgery performed as well as perioperative morbidity. Pathological parameters that were assessed included the size of the tumor, completeness of resection, mitotic count and mutational analysis. RESULTS Of the 13 patients included, 11 were nonmetastatic at the time of presentation. All the patients received neoadjuvant imatinib in view of locally advanced nature of the tumors. Median distance from anal verge was 2 cm. Median duration of imatinib was 9 months. Of the 9 patients who underwent surgery, three had sphincter preserving surgery (33%) whereas the rest had abdomino-perineal resection. Two patients had perineal wound infections. All the operated patients received adjuvant imatinib therapy for 3 years. Median follow up period was 34 months. One patient developed distant metastasis; otherwise rest had no local or distant recurrence. CONCLUSIONS In cases of rectal GIST, sphincter preservation may not be possible in spite of neoadjuvant therapy with imatinib.

Place of birth and risk of gallbladder cancer in India

CONTEXT Within India, the incidence of gallbladder cancer (GBC) is characterized by marked geographical variation; however, the reasons for these differences are unclear. AIMS To evaluate the role of place of birth, length of residence, and effect of migration from high- to low-risk region on GBC development. SETTINGS AND DESIGN Population-based cancer registries (PBCRs); case-control study. SUBJECTS AND METHODS Data of PBCRs were used to demonstrate geographical variation in GBC incidence rates. A case-control study data examined the role of birth place, residence length, and effect of migration in etiology of GBC. STATISTICAL ANALYSIS Rate ratios for different PBCRs were estimated using Chennai Cancer Registry as the reference population. Odds ratios (ORs) for developing GBC in a high-risk region compared to a low-risk region and associated 95% confidence interval (CI) were estimated through unconditional logistic regression models using case-control study. RESULTS GBC shows marked variation in incidence with risk highest in Northeast regions and lowest in South India. OR of 4.82 (95% CI: 3.87-5.99) was observed for developing GBC for individuals born in a high-risk region compared to those born in a low-risk region after adjusting for confounders. A dose-response relationship with increased risk with increased length of residence in a high-risk region was observed (OR lifetime 5.58 [95% CI: 4.42-7.05]; Ptrend ≤ 0.001). The risk persisted even if study participant migrated from high- to low-risk region (OR = 1.36; 95% CI: 1.02-1.82). CONCLUSIONS The present study signifies the importance of place of birth, length of stay, and effect of migration from high- to low-risk region in the development of GBC. The data indicate role of environmental and genetic factors in etiology of disease.

Factors influencing response to neoadjuvant chemoradiation and outcomes in rectal cancer patients: tertiary Indian cancer hospital experience

BACKGROUND In the treatment of rectal cancers several randomized trials have demonstrated benefits of neoadjuvant chemoradiotherapy (NACRT) in downstaging as well as survival among these patients. We investigated the patient and tumor related variables dictating the outcomes in these patients. METHODS Biopsy proven treatment naive 182 rectal cancer patients underwent NACRT from June 2006 to December 2010. The entire patients received long course conventionally fractionated external beam radiotherapy with concurrent oral Capecitabine. At 6 weeks from completion of NACRT clinico-radiological assessment was carried out for surgical feasibility. All patients were given postoperative adjuvant chemotherapy either single agent or multi drug regimen depending upon biopsy report. RESULTS Among 182 patients, 131 (72%) underwent surgery and initial T stage and signet ring cell morphology were major determinant of operability. Among the 131 operated patients at median follow up of 36 months, 94 (72%) are alive and disease free. With a median follow up of 42 months the 5-year disease free survival (DFS) and overall survival (OS) was 60% and 77%. The majority of the failures were distal but with more advanced disease at presentation both local and distal failures were similar. While assessing survival by multivariate analysis patients having positive nodes post-surgery had a significantly poorer DFS (P=0.001), while signet ring cell morphology and pre-treatment carcino-embryonic antigen (CEA) levels strongly influenced OS (P=0.03). CONCLUSIONS The outcome of our patients were similar to World Literature and signet ring cell morphology, pre-treatment CEA level, and pathological nodal staging all were influential in determining survival. Besides this, the study also highlights the fact that tumours with signet ring cell morphology appearing in younger population with poor survival needs prospective evaluation for more intense CRT regimen and aggressive surgical resections.

Combined brachytherapy and external beam radiation: an effective approach for palliation in esophageal cancer

Purpose Palliation of dysphagia is a challenge in advanced esophageal cancer. The addition of external beam radiotherapy (EBRT) to intraluminal brachytherapy (ILBT) has shown significant improvement in dysphagia relief and symptom scores. The aim of the present study was to evaluate the efficacy of combined use of ILBT and EBRT. Material and methods The medical records of 148 patients with advanced/metastatic esophageal cancer were screened from January 2008 to April 2014, and 74 patients were found eligible for the analysis. All patients received two fractions of 8 Gy each of ILBT, followed by EBRT. Patients were assessed for the symptom scores of dysphagia, odynophagia, regurgitation, and chest pain and weight was recorded periodically. Results For a median follow-up of 6 months, the median OS was 9.5 months (95% CI: 7.5-10.5). The median dysphagia free survival was 6 months (95% CI: 4.8-7.1). The scores for dysphagia significantly improved after completion of 1st ILBT (p = 0.000), 2nd ILBT (p = 0.000), and at 3 months after EBRT compared to ILBT (p = 0.02). Overall 47% had improvement in dysphagia scores and 35% maintained the improvement of scores till last follow up. There was significant improvement in weight after completion of ILBT (p = 0.001) and at 3 months after completion of EBRT (p = 0.00). Twenty nine (39%) patients required nasogastric (NGT) insertions and 12 (16%) needed hospitalization for supportive care. 36.4% had complications in the form of stricture (27%), fistula (5.4%), and bleeding (4%). Conclusions Palliative radiotherapy is an effective alternative for palliation of dysphagia with improvement in symptom scores being evident and sustained. The results of this clinical audit were comparable with those from the trial setting.

Intensity modulated radiation therapy (IMRT) is not superior to three-dimensional conformal radiation (3DCRT) for adjuvant gastric radiation: A matched pair analysis

AIMS To compare three-dimensional conformal radiation (3DCRT) and Intensity Modulated Radiation Therapy (IG-IMRT) for adjuvant gastric irradiation. SUBJECTS AND METHODS From Jan 2010-Aug 2013, all patients undergoing 3DCRT and IG-IMRT were included. Systemic chemotherapy included 1 cycle before and 2 cycles after chemoradiation. Planning Target Volume (PTV) received 45 Gy/25 fractions/5 weeks with concurrent capcetabine 825 mg/m2 bid. Matched pair analysis was performed to evaluate imbalance in two cohorts if any. Common Toxicity Criteria for Adverse Event (CTCAE) vs 3.0 was used to record gastrointestinal (GI), hematological (HL), and renal toxicity during treatment and follow-up. Patterns of recurrence were documented. Mann-Whitney U test was used for statistical comparison. RESULTS Of the 51 patients, 26 received 3DCRT and 25 IMRT. IMRT led to decrease in dose received by right and left kidney (12.4 Gy and 7.1 Gy and 29 Gy vs 8.2 Gy; P<0.001). Overall, 17.6% and 19.6% patients had grade II GI and HL toxicity and 3.9% and 5.9% had grade III GI and HL toxicity. No difference was observed in acute grade II-V GI or HL toxicity (11.5% vs 24%, P=0.07; 7.6% vs 20% P=0.20) or late GI, HL, or renal toxicity between 3DCRT and IMRT. No difference was observed in patterns of local relapse (11.5% vs 12%, P=0.14) or overall survival (39% and 38% (P=0.97)) between 3DCRT and IMRT. CONCLUSIONS 3DCRT and IMRT are equivalent in terms of toxicity and local control.