Biomedical subjects

Sanjay Kakar

Publications and source records attributed to Sanjay Kakar.

28 records · Page 2Linked to original sources

PubMed2004

Mucinous carcinoma of the colon: correlation of loss of mismatch repair enzymes with clinicopathologic features and survival.

Colorectal carcinoma with microsatellite instability (MSI-H) has a characteristic clinicopathologic profile, typically forming right-sided, lymphocyte-rich tumors that are often mucinous. Mucinous histology in general has been linked to adverse prognosis in some studies, but not in others. MSI-H carcinoma, in contrast, has a better prognosis than microsatellite stable carcinoma in most studies. We assessed the relationship between MSI status, clinicopathologic features and outcome for 248 consecutive patients with resected mucinous carcinoma. All cases were reviewed to confirm mucinous histology. Immunohistochemical stains for DNA mismatch repair enzymes hMLH1, hMSH2 and hMSH6 were performed on a representative block from each case. Tumors lacking expression of a mismatch repair enzyme were designated MSI-H; all others were classified as microsatellite stable. Age, sex, tumor size, site, grade, stage, growth pattern, Crohn's-like reaction, vascular invasion and number of tumor-infiltrating lymphocytes were evaluated without knowledge of MSI status or patient outcome. 72 (29.3%) mucinous carcinomas were MSI-H. Compared to microsatellite stable mucinous cancers, they were more likely to be right-sided (83.3 vs 48.6%, P<0.001), have a Crohn's -like reaction (65.7 vs 29.8%, P<0.001) and have many tumor infiltrating lymphocytes (72.2 vs 20.8%, P<0.001). MSI-H mucinous cancers presented more often as localized disease (66.7 vs 38.1%, P<0.001) and less often with lymph node (26.4 vs 44.9%) or distant (4.2 vs 16.5%) metastases. In univariate analysis, MSI had a favorable effect on age-adjusted survival (hazard ratio 0.597, P=0.02). In multivariate analysis, age, grade, Crohn's-like reaction and stage were independent predictors of survival, but MSI status was not. In conclusion, MSI-H mucinous carcinomas are right-sided, low-stage tumors with Crohn's-like reaction and tumor-infiltrating lymphocytes. The outcome for MSI-H mucinous carcinoma is better than that of microsatellite-stable mucinous carcinoma, but MSI status is not an independent predictor of survival.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Sinusoidal dilatation and congestion in liver biopsy: is it always due to venous outflow impairment?

CONTEXT: Impairment of venous outflow manifests as zone 3 sinusoidal dilatation and congestion (SDC) in liver biopsy. However, the finding of SDC is not specific for venous outflow impairment.Objectives.-To determine the specificity of SDC in liver biopsies for venous outflow impairment and to seek an explanation for SDC in patients without clinical or radiologic features of venous outflow impairment. DESIGN: Liver biopsies from 51 patients with sinusoidal dilatation were reviewed. Biopsies from transplant recipients, patients with cirrhosis, and patients with hepatic neoplasms (primary or metastatic) were not included. Clinical records were reviewed for laboratory tests and final clinicopathologic diagnosis. RESULTS: Thirty-four patients (66.7%) had confirmed venous outflow impairment. Of the 17 cases (33.3%) without clinical and/or radiologic evidence of venous outflow impairment, vascular causes were present in 5 cases (9.8%; nodular regenerative hyperplasia in 2 cases and portal vein thrombosis, congenital absence of the portal vein, and sickle cell anemia in 1 case each). Systemic inflammatory disorders were identified in 6 patients (11.8%). These included 2 cases of Castleman disease and 1 each of sarcoidosis, Crohn disease, rheumatoid arthritis, and Still disease. Three patients (5.9%) had tumors without direct involvement of the liver (1 case each of Hodgkin lymphoma, renal cell carcinoma, and pancreatic serous pseudopapillary tumor). In the remaining 3 patients, SDC was identified in wedge liver biopsies performed at the time of surgery, including gastric bypass surgery, cholecystectomy, and splenectomy. No other disease association was apparent in these cases. CONCLUSION: Sinusoidal dilatation and congestion in liver biopsy is associated with venous outflow impairment in two thirds of the cases. In the absence of clinical and/or radiological evidence of venous outflow, diagnostic considerations include other vascular conditions, such as portal vein insufficiency and nodular regenerative hyperplasia. Sinusoidal dilatation and congestion can also occur in the setting of systemic inflammatory diseases, granulomatous disorders, and neoplasms, as well as in wedge biopsies obtained during abdominal surgery.

Arthritis, Rheumatoid↗

PubMed2004

Mice expressing SV40 T antigen directed by the intestinal trefoil factor promoter develop tumors resembling human small cell carcinoma of the colon.

The colonic epithelium contains three major types of mature cells, namely, absorptive, goblet, and enteroendocrine cells. These cells are maintained by a complex process of cell renewal involving progenitor and stem cells, and colon cancers develop when this process goes awry. Much is known about the genetic and epigenetic changes that occur in cancer; however, little is known as to the specific cell types involved in carcinogenesis. In this study, we expressed the SV40 Tag oncogene in the intestinal epithelium under the control of an intestinal trefoil factor (ITF) promoter. This caused tumor formation in the proximal colon with remarkable efficiency. ITFTag tumors were rapidly growing, multifocal, and invasive. ITFTag tumor cells express synaptophysin and contain dense core secretory granules, markers of neuroendocrine differentiation. The cell type involved in the early steps of ITFTag tumorigenesis was studied by examining partially transformed crypts that contained populations of both normal and dysplastic cells. The dysplastic cell population always expressed both Tag and synaptophysin. Cells expressing Tag alone were never observed; however, normal enteroendocrine cells expressing synaptophysin but not Tag were readily visualized. This suggests that ITFTag tumor cells originate from the enteroendocrine cell lineage following a transforming event that results in Tag expression. ITFTag tumors closely resemble human small cell carcinomas of the colon, suggesting the possibility that these tumors might be derived from the enteroendocrine cell lineage as well.

Animals↗

PubMed2003

Frequency of loss of hMLH1 expression in colorectal carcinoma increases with advancing age.

BACKGROUND: The correlation between age at diagnosis and loss of expression of hMLH1 protein in patients with colorectal carcinoma (CRC) has not been evaluated systematically. METHODS: Immunohistochemistry was performed for hMLH1 protein in tumor samples from 867 patients with CRC. The authors defined tumors arising in the cecum, ascending colon, and transverse colon as right-sided and tumors arising in the descending colon, sigmoid colon, and rectum as left-sided. Patients' gender, tumor location (side), and hMLH1 expression were analyzed by age groups. RESULTS: The percentage of tumors with hMLH1 expression loss increased significantly with advancing age (P < 0.0001): There were no tumors in patients age < 40 years that manifested loss of hMLH1 expression, compared with 29% of tumors that manifested loss of hMLH1 expression in patients age > 90 years. Loss of hMLH1 expression occurred more often in patients with right-sided tumors (32.7% vs. 5.2% of patients with left-sided tumors; P < 0.0001) and in tumors from female patients (24.3% vs. 11.5% of tumors from male patients; P < 0.0001). There was no evidence of interaction between gender and tumor location. CONCLUSIONS: Loss of hMLH1 expression in patients with CRC was associated strongly with increasing age. hMLH1 expression loss was more pronounced in tumors from female patients and in tumors that originated on the right side of the colon. Loss of hMLH1 expression in right-sided tumors occurred in nearly 50% of patients age > 90 years. This age-related trend also was observed for males and in tumors that originated in the left colon.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Noninfectious lung pathology in patients with Crohn's disease.

Lung involvement in Crohn's disease is not well characterized. We reviewed our experience with 11 lung biopsies (seven wedge and four transbronchial) from patients with Crohn's disease to study this association further. Negative cultures, special stains for organisms Gomori-methenamine-silver [GMS], acid fast), and polymerase chain reaction for (four cases) were required for inclusion. The group included five women and six men with a mean age of 47 years (range 13-84 years). A diagnosis of Crohn's disease preceded the lung disease in nine patients. In two patients the diagnosis of Crohn's disease followed the diagnosis of their pulmonary disease 1 and 15 months later. Radiologically, eight patients had diffuse infiltrates, two had bilateral nodular infiltrates, and one had a mass. Chronic bronchiolitis with nonnecrotizing granulomatous inflammation was present in four patients, one of whom was taking mesalamine. Two patients had an acute bronchiolitis associated with a neutrophil-rich bronchopneumonia with suppuration and vague granulomatous features. One patient on mesalamine had cellular interstitial pneumonia with rare giant cells. Four patients demonstrated organizing pneumonia with focal granulomatous features, two of whom were taking mesalamine, and one of these two responded to infliximab (anti-tumor necrosis factor) monoclonal antibody therapy. Noninfectious pulmonary disease in patients with Crohn's disease has variable histologic appearances, including granulomatous inflammation and airway-centered disease resembling that seen in patients with ulcerative colitis. Drugs may contribute to pulmonary disease in some patients.

Adult↗

PubMed2003

Colonic ulcers accompanying collagenous colitis: implication of nonsteroidal anti-inflammatory drugs.

OBJECTIVES: A small minority of otherwise typical collagenous colitis (CC) patients also have mucosal ulceration (CC-U). We studied the association of CC-U cases with ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) as a possible explanation for the mucosal ulceration. METHODS: Clinical information and histological features were reviewed in nine cases of biopsy-diagnosed CC-U. Biopsies from 18 unselected cases of CC without ulceration were reviewed for comparison. RESULTS: Of nine patients with CC-U, seven (77.8%) had a history of NSAID ingestion, compared with four of 18 CC controls (20.2%) (p = 0.006). The diarrhea resolved after cessation of NSAID use in four CC-U patients, partially resolved in one patient, and persisted in one patient. The outcome was not available in one patient. Of the two CC-U patients who did not use NSAIDs, one patient was taking lisinopril (angiotensin-converting enzyme inhibitor), and the diarrhea resolved after stopping the drug; the ulceration in the second patient was thought to be ischemic in origin. CONCLUSIONS: Collagenous colitis with ulceration has a strong association with NSAID ingestion. Evaluation of medications and cessation of NSAIDs should be considered as a therapeutic option in cases of collagenous colitis with colonic ulceration.

Adult↗

PubMed2003

Significance of intraepithelial lymphocytosis in small bowel biopsy samples with normal mucosal architecture.

OBJECTIVES: The aim of this study was to determine the specificity of increase in intraepithelial lymphocytes (IELs) with normal villous architecture in small bowel biopsy samples for diagnosis of gluten sensitivity (GS) and its significance in the absence of GS. METHODS: Small bowel biopsy samples from 43 patients with increased IELs and no other pathology were reviewed. Patients with prior diagnosis of GS were excluded. A group of 46 patients with normal duodenal biopsy during the same period served as controls. The clinical records of patients and controls were examined for presenting symptoms, laboratory tests, and final clinicopathological diagnosis. Immunohistochemical characterization of IELs was performed in 13 cases. RESULTS: Four (9.3%) patients had GS based on positive IgA antiendomysial antibodies (n = 3) and favorable response to gluten-free diet (n = 4). One patient (2.2%) had partially treated tropical sprue; six patients (14%) had disorders of immune regulation including Hashimoto's thyroiditis (n = 2) and one case each of Graves' disease, rheumatoid arthritis, psoriasis, and multiple sclerosis; and six patients (14%) were on nonsteroidal anti-inflammatory drugs (NSAIDs). In contrast, none of the control subjects had GS (p = 0.05), tropical sprue, or immunoregulatory disorders (p = 0.011), and one (2.2%) was on NSAIDs (p = 0.04). Increased IELs were also observed in Crohn's disease, lymphocytic/collagenous colitis, and bacterial overgrowth, but the association did not reach statistical significance. Histological features (number and distribution of IELs, crypt mitoses) and immunophenotypic analysis of IELs did not reliably distinguish GS-related from non-GS-related causes of increased IELs. CONCLUSIONS: Intraepithelial lymphocytosis in an otherwise normal small bowel biopsy is somewhat nonspecific, but in nearly 10% of cases can be the initial presentation of GS. Therefore all patients with this finding should be investigated for GS. Increased IELs may also be associated with autoimmune disorders and NSAIDs.

Adolescent↗

PubMed2003

Immunoreactivity of Hep Par 1 in hepatic and extrahepatic tumors and its correlation with albumin in situ hybridization in hepatocellular carcinoma.

We evaluated the expression of Hep Par 1 (hepatocyte paraffin 1 monoclonal antibody) in 42 hepatocellular carcinomas (HCCs), 25 cholangiocarcinomas, 18 tumors metastatic to the liver, and 87 primary extrahepatic tumors. Albumin in situ hybridization (ISH) was performed in the HCC cases. Of 42 cases of HCC, 39 (93%) were positive for Hep Par 1. All cases of cholangiocarcinoma, renal cell carcinoma, adrenocortical carcinoma, and islet cell tumors were negative; 1 case each of primary urinary bladder (n = 10) and pancreatic (n = 10) adenocarcinoma and 3 of 11 cases of primary pulmonary adenocarcinoma showed focal positivity; 7 of 10 gastric and 6 of 8 esophageal adenocarcinomas were strongly positive. Albumin ISH was positive in 39 (93%) HCC cases. All cases of HCC were positive for Hep Par 1 or albumin ISH. Hep Par 1 immunoreactivity has high sensitivity in the diagnosis of HCC. Strong positive staining also occurs in gastroesophageal adenocarcinomas. Cholangiocarcinoma and carcinomas from most other sites are negative for Hep Par 1. Hep Par 1 immunoreactivity shows high correlation with albumin ISH; their combined use for diagnosis of HCC had a sensitivity of 100% in this population.

Albumins↗

PubMed2002

Origin of adenocarcinoma in a transplanted liver determined by microsatellite analysis.

Inadvertent transmission of neoplastic cells from an organ donor can occur at the time of transplantation. Determination of recipient versus donor origin of a tumor is crucial for patient management. This report illustrates the use of microsatellite (MS) analysis to determine the origin of adenocarcinoma arising in a liver transplant. The study patient was a 42-year-old male who had received a liver transplant for hepatitis C and alcohol-related cirrhosis. At the 1-year follow-up visit, a 1.5-cm liver mass was identified during routine ultrasound of the vascular anastamoses. A liver biopsy showed a moderately differentiated adenocarcinoma. Tumor, donor, and recipient DNA were isolated from the paraffin-embedded liver biopsy, pretransplant donor liver biopsy, and the explant liver tissue, respectively. MS analysis was performed by polymerase chain reaction using 5 markers: D5S346, ACTC, D2S123, D18S34, and TP53. The allelic patterns of tumor DNA were identical to those of donor DNA and were distinct from the DNA profile of the recipient. The use of MS analysis clearly established that the adenocarcinoma was of donor origin.

Adenocarcinoma↗

PubMed2002

The fate of low grade dysplasia in ulcerative colitis.

OBJECTIVE: The optimal strategy for the management of definite low grade dysplasia (LGD) detected in surveillance in ulcerative colitis (UC) is unknown, because the natural history of LGD has not been well described. METHODS: We reviewed the Mayo Clinic records of patients with UC found to have flat LGD between 1990 and 1993 in whom a nonoperative strategy was pursued for 2 months or more. RESULTS: Eighteen patients with UC and LGD were observed for a median of 32 months. Nine of 18 patients identified with UC and LGD developed advanced neoplastic lesions during follow-up, which were defined as adenocarcinoma, raised dysplasia, or high grade dysplasia. The cumulative incidence of progression to an advanced lesion was 33% at 5 yr (95% CI = 9-56%). Only one patient developed adenocarcinoma, diagnosed 74 months after his initial finding of LGD and 20 months after his last surveillance exam. Besides this patient, adenocarcinoma was not detected in the colectomy specimens of 13 other patients who underwent surgery. Colectomies were performed for dysplasia or cancer in seven patients, active colitis in five patients, and unknown reasons in two patients. Four patients did not have colectomies. CONCLUSIONS: Neoplastic progression in patients with UC and LGD is common. Total proctocolectomy should be offered to all patients with flat LGD. Our study illustrates numerous pitfalls in the practice of surveillance.

Adult↗