Prognostic Significance of EMVI in Rectal Cancer in a Tertiary Cancer Hospital in India.

Background Presence of extramural venous invasion (EMVI) is a poor prognostic factor for rectal cancer as per literature. However, India-specific data are lacking. Aim The aim of the study is to determine the prognostic significance of EMVI in locally advanced rectal cancer on baseline MRI. Materials and Methods We retrospectively reviewed 117 MRIs of operable non-metastatic locally advanced rectal cancers in a tertiary cancer institute. Three dedicated oncoradiologists determined presence or absence of EMVI, and its length and thickness, in consensus. These patients were treated as per standard institutional protocols and followed up for a median period of 37 months (range: 2-71 months). Kaplan-Meier curves (95% CI) were used to determine disease-free survival (DFS), distant-metastases free survival (DMFS), and overall survival (OS). Univariate analysis was performed by comparing groups with log-rank test. Results EMVI positive cases were 34/114 (29%). More EMVI-positive cases developed distant metastasis compared with EMVI-negative cases (14/34-41% vs. 22/83-26%). The difference, however, was not statistically significant ( p = 0.146). After excluding signet-ring cell cancers ( n = 14), EMVI showed significant correlation with DMFS ( p = 0.046), but not with DFS or OS. The median thickness and length of EMVI was 6 and 14 mm, respectively in patients who developed distant metastasis, as compared with 5 and 11 mm in those who did not, although this difference was not statistically significant. Conclusion EMVI is a predictor of distant metastasis in locally advanced non-metastatic, non-signet ring cell rectal cancers. EMVI can be considered another high-risk feature to predict distant metastasis.

ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer.

The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number alterations, immunohistochemical, and phospho-proteome array profiling indicates ERBB2 alterations in 40% early-stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n = 25) and recurrent mutations in 14% tumors (n = 44); along with co-occurring KRAS mutation in 7% tumors (n = 44). We demonstrate that ERBB2 heterodimerizes with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2-specific, EGFR-specific shRNA or with a covalent EGFR family inhibitor Afatinib inhibits tumor-associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho-ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo-adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti-EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer.

A cross-sectional study of the distribution of pediatric solid tumors at an Indian tertiary cancer center.

CONTEXT: Pediatric solid tumors include a heterogeneous group of tumors, and the burden of these tumors, especially from resource-challenged countries, is not well described. AIMS: The aim of this study was to describe the distribution of solid tumors in children and the treatment outcome of Wilms tumor and hepatoblastoma. PATIENTS AND METHODS: All patients under 15 years of age with histologically confirmed tumors presenting at a tertiary cancer center from January 2012 to December 2016 were identified from the hospital database. Patients with lymphomas, bone, and central nervous tumors were excluded. The demographic profile including age, sex distribution, and the treatment received were recorded for all patients. RESULTS: The mean age of the eligible 1944 patients was 5.7 years with majority (57.3%) in the 0-4 years age group. The male-to-female ratio was 1.4:1 with a male predominance in all tumors except germ cell tumors. Soft tissue tumors were the most common tumors followed by neuroblastoma and renal tumors, whereas liver tumors formed only 6.7% of all tumors. Seventy percent of the patients received treatment completely or partially at our institute, whereas 18.3% had no cancer-directed treatment. The 3-year overall survival of patients with Wilms tumor and hepatoblastoma was 85.4 and 78.5%, respectively. CONCLUSIONS: Extracranial and extraosseous pediatric solid tumors include a wide range of tumors with a predilection for male sex and children below 4 years of age. Soft tissue tumors, neuroblastoma, and renal tumors are the most common; the outcomes of Wilms tumor and hepatoblastoma are favorable.

Non-typhoidal Salmonella DNA traces in gallbladder cancer.

BACKGROUND: We earlier proposed a genetic model for gallbladder carcinogenesis and its dissemination cascade. However, the association of gallbladder cancer and 'inflammatory stimulus' to drive the initial cascade in the model remained unclear. A recent study suggested infection with Salmonella can lead to changes in the host signalling pathways in gallbladder cancer. FINDINGS: We examined the whole exomes of 26 primary gall bladder tumour and paired normal samples for presence of 143 HPV (Human papilloma virus) types along with 6 common Salmonella serotypes (S. typhi Ty2, S. typhi CT18, S. typhimurium LT2, S. choleraesuis SCB67, S. paratyphi TCC, and S. paratyphi SPB7) using a computational subtraction pipeline based on the HPVDetector, we recently described. Based on our evaluation of 26 whole exome gallbladder primary tumours and matched normal samples: association of typhoidal Salmonella species were found in 11 of 26 gallbladder cancer samples, and non-typhoidal Salmonella species in 12 of 26 gallbladder cancer, with 6 samples were found co-infected with both. CONCLUSIONS: We present the first evidence to support the association of non-typhoidal Salmonella species along with typhoidal strains in gallbladder cancer. Salmonella infection in the chronic carrier state fits the role of the 'inflammatory stimulus' in the genetic model for gallbladder carcinogenesis that may play a role in gallbladder cancer analogous to Helicobacter pylori in gastric cancer.

Massive Liver Trauma-Multidisciplinary Approach and Minimal Invasive Surgery can Salvage Patients.

Management of massive liver trauma (grades IV-VI) is associated with high morbidity and mortality. It can pose serious challenges to treating physician and requires multimodality interventions. For a successful outcome, timing of intervention is crucial. We report a case of grade V hepatic injury treated successfully with angioembolization, laparoscopic lavage, and endoscopic stenting during a time period from admission to discharge on the 24th day. Angioembolization was performed at admission after resuscitation as CT scan showed active extravasation in the arterial phase. Laparoscopic lavage and drainage was performed on the fifth day as abdominal inflammatory response failed to respond to medical management. There was biliary component of abdominal fluid noticed during laparoscopy, which manifested by postoperative localized biliary fistula; hence endoscopic stenting of the bile duct was performed on the seventh day. The patient recovered well with timely minimal invasive approach and was fine at 1 year follow-up.

An autopsy study of coronary atherosclerosis and its relation to anthropometric measurements/indices of overweight and obesity in men.

Atherosclerosis accounts for a large proportion of cardiovascular system associated morbidity and mortality. The present autopsy based study is aimed to study the correlation between coronary atherosclerosis and anthropometric measurements/indices of overweight and obesity such as; Waist Circumference (WC), Hip Circumference (HC), Body Mass Index (BMI), and Waist Hip Ratio (WHR) in men from southern India. The present research also analyses the correlation between anthropometric measurements/indices of overweight and obesity in men with number of coronaries affected with atherosclerosis in individuals. The study included 50 autopsies conducted in the Government District Wenlock Hospital, Mangalore during March and September 2008. The heart was dissected following standard autopsy protocol and a 5 cm section of the right coronary artery (RCA) in the atrio-ventricular groove from its origin, a 5 cm segment of the left anterior descending artery (LADA) distal to the origin of the circumflex artery, but including the region of origin of the circumflex branch and left coronary artery (LCA) from its origin till the circumflex branch were excised, dissected out, fixed in 10% formalin, marked for identification and sent for histopathological analysis. The study shows a positive correlation of WC and WHR with atherosclerotic changes in the RCA. The number of arteries affected with atherosclerosis is found to be well correlated with WC, BMI and WHR. The study confirms an association between anthropometric measurements/indices of obesity, grade of atherosclerosis in the RCA and the number of arteries affected with atherosclerosis. Anthropometric measurements/indices of obesity can be an effective means to identify high risk cases of atherosclerosis at an early stage that can be effective in reducing the associated cardiac morbidity and mortality.

A validated gene expression profile for detecting clinical outcome in breast cancer using artificial neural networks.

Gene expression microarrays allow for the high throughput analysis of huge numbers of gene transcripts and this technology has been widely applied to the molecular and biological classification of cancer patients and in predicting clinical outcome. A potential handicap of such data intensive molecular technologies is the translation to clinical application in routine practice. In using an artificial neural network bioinformatic approach, we have reduced a 70 gene signature to just 9 genes capable of accurately predicting distant metastases in the original dataset. Upon validation in a follow-up cohort, this signature was an independent predictor of metastases free and overall survival in the presence of the 70 gene signature and other factors. Interestingly, the ANN signature and CA9 expression also split the groups defined by the 70 gene signature into prognostically distinct groups. Subsequently, the presence of protein for the principal prognosticator gene was categorically assessed in breast cancer tissue of an experimental and independent validation patient cohort, using immunohistochemistry. Importantly our principal prognosticator, CA9, showed that it is capable of selecting an aggressive subgroup of patients who are known to have poor prognosis.

Relation of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels to growth retardation in extrahepatic portal vein obstruction.

BACKGROUND: Growth retardation has been described in patients with extrahepatic portal vein obstruction (EHPVO). An abnormal growth hormone (GH)-insulin-like growth factor (IGF) axis has been postulated as a possible etiology. We compared anthropometric parameters and IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) levels in patients with EHPVO with their siblings as controls. METHODS AND PATIENTS: Consecutive patients diagnosed with EHPVO who presented to out-patient clinic in Department of Gastroenterology between February 2005 and February 2006 were enrolled along with their siblings whenever possible. After detailed history and clinical examination, anthropometric parameters such as age, height, weight, and mid-parental height were measured in patients and controls. IGF-1 and IGFBP-3 levels were also estimated. RESULTS: Fifty-two patients (40 males, 32 adults) were enrolled. Sibling controls were available for 28 patients. Variceal bleeding was the presenting symptom in 41 of 52 (78.8%) patients. Target height was not achieved in 7 of 32 (22.6%) adults and 6 of 20 (30%) children, showing evidence of growth retardation. The mean IGF-1 levels in patients and controls were 124.71 +/- 65.49 ng/ml and 233 +/- 76.98 ng/ml (P < 0.01), respectively. The mean IGFBP-3 levels in patients and controls were 2.90 +/- 1.07 mug/ml and 4.22 +/- 0.77 mug/ml (P < 0.01), respectively. Hormonal levels between those with and without evidence of growth retardation did not differ significantly. Duration of symptoms, spleen size, platelet count, and age of presentation did not correlate with anthropometry and hormonal levels. CONCLUSIONS: Growth retardation by anthropometry was documented in a quarter of patients with EHPVO. All patients had significantly low IGF-1 and IGFBP-3 levels in comparison with controls despite normal anthropometry in majority of patients (75%).

Hypercoagulable state in idiopathic ulcerative colitis: role of hyperhomocysteinemia and hyperfibrinogenemia.

BACKGROUND: Previous reports on hypercoagulable factors in inflammatory bowel diseases involve heterogeneous populations and patients on various medications. AIMS: To determine the frequency of thrombotic complications in ulcerative colitis (UC); to evaluate for hyperhomocysteinemia and its relationship to vitamin B12 and folate levels and methylene tetrahydrofolate reductase (MTHFR) mutation; and to evaluate for hyperfibrinogenemia and factor V Leiden mutation. METHODS: Eighty-six adult patients with UC were seen during the study period; 28 of them underwent blood tests and constituted the study population. Patients who received medications that affect these factors were among the 58 excluded. Tests were obtained at baseline and after 2 months during remission. Patients received folic acid in addition to treatment for UC. RESULTS: Vascular thrombotic events were noted in 4 patients during follow up. Hyperhomocysteinemia was detected in 11 (39.3%) patients (controls 15/100, p=0.007). Heterozygous state for MTHFR C677T mutation was found in 5 (17.9%) patients (controls: 0.2% homozygous, 13.6% heterozygous, p>0.05). Plasma homocysteine did not correlate with extent, severity or duration of disease, or with MTHFR C677T heterozygous state, but correlated with serum folic acid level (p=0.003) and BMI (p=0.03). With folate supplementation, homocysteine decreased significantly in patients who had hyperhomocysteinemia at baseline. Hyperfibrinogenemia was detected in 3 patients (none in 100 controls). Plasma fibrinogen was not affected by duration, extent or severity of UC and did not decrease with remission of disease. Only one patient had heterozygous factor V Leiden mutation. CONCLUSION: Vascular thrombosis occurred in less than a fifth of the UC population studied. Hyperhomocysteinemia reversible by folate supplementation and hyperfibrinogenemia were observed, but their contribution and that of factor V Leiden mutation appear to be insignificant.

Hepatoblastoma: a single institutional experience of 18 cases.

Hepatoblastomas are the most common liver tumours in children. However, they are rare as compared to other solid malignancies. Thus, there is a need to integrate data from surgical centers around the world to provide a clearer view on the outcomes of multidisciplinary management of these tumours. We set out to retrospectively review our experience of patients with surgically resected hepatoblastomas looking at primary and secondary outcomes. Children diagnosed with hepatoblastoma and managed surgically (along with chemotherapy) at a single institution between 1 January 2000 and 31 May 2007, were analyzed. Out of the 18 patients, there were 12 male and 6 female patients. The median age was 18 months (range 8-72). A palpable mass in abdomen was the presenting symptom in 88% patients. Sixteen patients (88.8%) underwent major liver resection. Sixteen patients (88.8%) received preoperative chemotherapy. Complete gross resection (stage I and II) was achieved in all 18 patients (100%). The mortality and morbidity rates were 0 and 11.2%, respectively. The 80-month disease-free survival was 67%. This series, the largest from India in terms of surgical resections for hepatoblastoma, reaffirms that major liver resection can be performed with minimal perioperative mortality and morbidity and that the use of chemotherapy has definitely helped in down staging tumours for liver resection.

Langerhans cell histiocytosis of mediastinal node.

The predominant clinical and radiological features of Langerhans Cell Histiocytosis (LCH) in children are due to osseous involvement. Extra-osseous disease is far less common, occurring in association with bone disease or in isolation. In the present study, LCH was presumptively diagnosed on Ultrasound guided Fine needle aspiration cytology (FNAC) of the mediastinal lymph node in a 18 month-old child. The diagnosis was confirmed by histological examination of the biopsy material.S-100 protein localization in the LCH cells is often positive on immunohistochemistry.

Endoscopic biliary drainage in patients with amebic liver abscess and biliary communication.

BACKGROUND: Percutaneous drainage or surgery is required when amebic liver abscess (ALA) fails to respond to medical management. In some of these patients, non-response may be due to communication of ALA with the biliary tree. This report describes our experience with the use of endoscopic biliary draining in such patients. METHODS: Medical records of patients with ALA undergoing either needle aspiration or percutaneous pigtail drainage were retrieved; the indications for drainage were: abscess volume exceeding 250 mL, a thin rim of tissue (< 1 cm thick) around the abscess, systemic toxic features and failure to improve on medical treatment. Patients with abscess drain output >25 mL/day persisting for 2 weeks or presence of bile in the drain fluid underwent endoscopic biliary drainage. RESULTS: A total of 115 patients with ALA underwent percutaneous treatment. None of the 25 patients with needle aspiration needed any further treatment. Of the 90 who underwent catheter drainage, the catheter could be removed within one week in 77 patients; the remaining 13 patients (median age 42 years, range 24-65; all men) had an abscess-biliary communication. In them, the median catheter output was 88 mL/day (range 45-347) and 54 mL/day (28-177) at 2 days and 2 weeks after catheter placement. The drain fluid contained bile in all 13 patients and in addition contained pus in 10 patients. Eleven patients had a solitary abscess and two had multiple abscesses. Cholangiogram showed biliary communication in all 13 patients. All patients were treated with placement of 10F biliary endoprosthesis or 10F nasobiliary drain. Pigtail catheter was removed within 1 week in 11 of 13 patients. CONCLUSION: In patients with amebic liver abscess communicating with the biliary tree, biliary stenting may hasten clinical recovery and allow early removal of liver abscess catheter drain.