Cholesterol homeostasis and cell proliferation by mitogenic homologs: insulin, benzo-α-pyrene and UV radiation.

Low-Density Lipoprotein (LDL) is known to promote the unregulated proliferation of cells that is progression of cancer. We aimed to investigate the effect of mitogens on the expression of cell cycle proteins, nuclear cholesterol and cell proliferation. We observed that insulin and benzo-α-pyrene (BaP) induced the expression of Low-Density Lipoprotein receptor (LDLR) on HepG2 cells, thereby enhancing the uptake of LDL. The internalized LDL increased the concentration of cholesterol in the cytoplasm and nucleus of the cell. At the same time, insulin and BaP also stimulated the expression of cell cycle proteins viz., Cyclin E and Cdk2, and thus induced more incorporation of Bromodeoxyuridine (BrdU) in cultured cells indicating increased DNA synthesis. Increased expression of cell cycle proteins and DNA synthesis are the indications of DNA replication and new cell synthesis. This suggests a link between the enhanced nuclear cholesterol concentration and new cell formation. On the other hand, UV irradiation with selectively given dose of cell death eventually decreases nuclear cholesterol concentration and LDLR expression. Reduced LDLR shows low functional activity. This, again, repeated the plausibility of the same link between intracellular cholesterol concentration and cell population. The biasness of adverse effect observed by UV irradiation has been compromised by inactivating LDLR with anti-LDLR antibody, resulting in similar effects on Cyclin E expression in the cultured cells. Hence, we concluded that in all the conditions, LDLR expression was found to be a translational event of its transcription factor, SREBP-2, by the induction of insulin, BaP and UV irradiation.

Benevolent Renal Angiomyolipoma with Intra-cardiac Extension-A Challenge in Diagnosis and Management.

While intra-caval and intra-cardiac extension of retroperitoneal tumors is extremely rare, it is almost unheard-of in benign tumors. We report the challenges in diagnosis and management of the first case of a renal angiomyolipoma (AML) with intra-ventricular extension in a young man who presented with pain and a lump in the abdomen.

Glypican-3 mRNA expression level in Wilms tumor: correlation with histological type, stage, and outcome.

PURPOSE: To correlate expression of Glypican-3 in Wilms tumor with histopathology, stage, and outcome. METHODS: Glypican-3 mRNA expression by real-time PCR on tumor and normal germline samples from 75 fresh nephrectomies for Wilms tumor with fold change after normalization against GAPDH was compared. Survival analysis for event-free and overall survival (EFS, OS) with 2-year follow-up for Glypican-3 overexpression (>1.5 times) and clinicopathological parameters was performed. RESULTS: Glypican-3 was overexpressed in 37/75 (49.3%). It was overexpressed in 77% (10/13) cases with blastema predominance or anaplastic histology, as compared to 44% of other histologies (27/62) (p = 0.03). OS was 73 and 93%, respectively (p = 0.016), for those with and without GPC-3 overexpression. EFS was not significantly different with Glypican-3 overexpression (p = 0.11). All 5 deaths among blastema predominant tumors and 4/5 deaths among triphasic tumors had overexpressed Glypican-3. Most deaths in Stage IV, Stage III, and Stage I + II (5/7, 3/3, 1/1) had GPC-3 overexpression. On multivariate analysis, only histology and stage were found to have independent prognostic value. CONCLUSION: Glypican-3 overexpression in Wilms tumor correlates with poor OS on univariate analysis. However, only histology and stage have independent prognostic value. Glypican-3 levels may help to stratify intermediate outcome histology (triphasic) and Stage III Wilms tumors.

Liver biopsy in patients on hemodialysis with hepatitis C virus infection: An important tool.

Hepatitis C virus (HCV) infection is commonest blood borne infection amongst hemodialysis patients. Still, there is paucity of data on liver biopsy in these patients. Our center is doing regular liver biopsy in these patients and thus thought of sharing our experience. In this retrospective study, all patients with HCV infection on hemodialysis were subjected to liver biopsy. Serum bilirubin, liver enzyme, HCV-PCR, genotype and viral load measurement were done in all. Biopsy specimen was stained with H and E, Periodic Acid Schiff, Gomori Stain, Masson Trichrome and Perls Stain. International Working Group scoring system of Ishak et al. was used for Grading and Staging. Of the 270 liver biopsies, mean age of patients was 34.05 ± 10.28 years and 233 (85.3%) were males. Mean duration of hemodialysis was 10.9 ± 7.4 months while of known HCV infection was 5.2 ± 4.0 months. Genotype 3 was commonest followed by 1. All had normal bilirubin and 64 (23.1%) had normal ALT. In 37 (13.3%) patients anti-HCV was not detectable. Mean histology grade was 4.03 ± 1.65 (1-10) and stage was 0.75 ± 0.98 (0-3). Only one patient had cirrhosis on histology. Associated hemosiderosis was seen 10 patients. Only minor complications were observed with no mortality. In conclusion, our study shows that in one-fourth patients with active liver disease, liver enzymes are persistently normal in patients on hemodialysis. Further, carefully performed liver biopsy is reasonably safe procedure though some patients do have non-fatal complications. Liver biopsy helps in assessing disease activity, which otherwise cannot be assessed. Histological grade and stage in these patients is usually mild and cirrhosis is rare. Till such time other non-invasive test is validated, liver biopsy will remain an important test in these patients.

Association of pro-inflammatory cytokines, adipokines & oxidative stress with insulin resistance & non-alcoholic fatty liver disease.

BACKGROUND & OBJECTIVES: The cytokines, adipokines, and oxidative stress have been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD); however, such data remain scarce in India. The present study evaluated pro-inflammatory cytokines, adipokines, and markers of oxidative stress in patients with non-alcoholic fatty liver disease (NAFLD), and their association with degree of adiposity, insulin resistance and markers of disease severity. METHODS: The present prospective cross-sectional pilot study included 79 subjects; 34 NAFLD, 22 chronic hepatitis B (CH-B) and 23 healthy controls (HC). The parameters studied were adiponectin, leptin, tumour necrosis factor α (TNFα), interleukin-1 and 6 (IL-1, IL-6), and systemic markers of oxidative stress. RESULTS: The mean body mass index (kg/m 2 ) in NAFLD patients, CHB, and HC were 26.4±3.7, 21.3±2.3, and 22.3±2.7, respectively. The median serum levels of all pro-inflammatory cytokines were significantly higher (P<0.001) in NAFLD compared to control groups. Compared to HC, levels of adiponectin and leptin were significantly (P<0.05, P<0.01) reduced in both NAFLD and CHB. IL-6 showed marked and selective increase only in NAFLD patients. The levels of IL-6 were significantly (P<0.02) higher in NAFLD patients with advanced histology grade and correlated with IR (r=0.42, P=0.02). In a sub-group, markers of oxidative stress were significantly higher, and that of antioxidant potential were significantly lower among NAFLD patients compared to control subjects. INTERPRETATION & CONCLUSIONS: Patients with NAFLD revealed significantly elevated levels of pro-inflammatory cytokines, increased oxidative stress, and a significant association of IL-6 with IR and advanced histopathology.

Prospective derivation and validation of early dynamic model for predicting outcome in patients with acute liver failure.

OBJECTIVE: It is difficult to predict the outcome in patients with acute liver failure (ALF) using existing prognostic models. This study investigated whether early changes in the levels of dynamic variables can predict outcome better than models based on static baseline variables. DESIGN: 380 patients with ALF (derivation cohort n=244, validation cohort n=136) participated in a prospective observational study. The derivation cohort was used to identify predictors of mortality. The ALF early dynamic (ALFED) model was constructed based on whether the levels of predictive variables remained persistently high or increased over 3 days above the discriminatory cut-off values identified in this study. The model had four variables: arterial ammonia, serum bilirubin, international normalised ratio and hepatic encephalopathy >grade II. The model was validated in a cohort of 136 patients with ALF. RESULTS: The ALFED model demonstrated excellent discrimination with an area under the receiver operator characteristic curve of 0.91 in the derivation cohort and of 0.92 in the validation cohort. The model was well calibrated in both cohorts and showed a similar increase in mortality with increasing risk scores from 0 to 6. The performance of the ALFED model was superior to the King's College Hospital criteria and the Model for End stage Liver Disease score, even when their 3-day serial values were taken into consideration. An ALFED score of ≥4 had a high positive predictive value (85%) and negative predictive value (87%) in the validation cohort. CONCLUSION: The ALFED model accurately predicted outcome in patients with ALF, which may be useful in clinical decision-making.

Antituberculosis therapy-induced acute liver failure: magnitude, profile, prognosis, and predictors of outcome.

UNLABELLED: Antituberculosis therapy (ATT)-associated acute liver failure (ATT-ALF) is the commonest drug-induced ALF in South Asia. Prospective studies on ATT-ALF are lacking. The current study prospectively evaluated the magnitude, clinical course, outcome, and prognostic factors in ATT-ALF. From January 1986 to January 2009, 1223 consecutive ALF patients were evaluated: ATT alone was the cause in 70 (5.7%) patients. Another 15 (1.2%) had ATT and simultaneous hepatitis virus infection. In 44 (62.8%) patients, ATT was prescribed empirically without definitive evidence of tuberculosis. ATT-ALF patients were younger (32.87 [+/-15.8] years), and 49 (70%) of them were women. Most had hyperacute presentation; the median icterus encephalopathy interval was 4.5 (0-30) days. The median duration of ATT before ALF was 30 (7-350) days. At presentation, advanced encephalopathy and cerebral edema were present in 51 (76%) and 29 (41.4%) patients, respectively. Gastrointestinal bleed, seizures, infection, and acute renal failure were documented in seven (10%), five (7.1%), 26 (37.1%), and seven (10%) patients, respectively. Compared with hepatitis E virus (HEV) and non-A non-E-induced ALF, ATT-ALF patients had nearly similar presentations except for older age and less elevation of liver enzymes. The mortality rate among patients with ATT-ALF was high (67.1%, n = 47), and only 23 (32.9%) patients recovered with medical treatment. In multivariate analysis, three factors independently predicted mortality: serum bilirubin (>or=10.8 mg/dL), prothrombin time (PT) prolongation (>or=26 seconds), and grade III/IV encephalopathy at presentation. CONCLUSION: ATT-ALF constituted 5.7% of ALF at our center and had a high mortality rate. Because the mortality rate is so high, determining which factors are predictors is less important. A high proportion of patients had consumed ATT empirically, which could have been prevented.

Aspiration cytology of mesenchymal hamartoma of the chest wall in an infant: a case report.

BACKGROUND: Mesenchymal hamartoma of the chest wall is an extremely uncommon lesion of infants. Radiologic features simulate a malignant neoplasm; however, pathologic examination demonstrates an admixture of fibroblasts, benign cartilage and woven bone. There is a paucity of cytologic reports of this rare entity in the available literature. CASE: A 5-month-old infant presented with a large right chest wall swelling. Radiologic investigation demonstrated lytic destruction of the right 7th, 8th and 9th ribs with a large soft tissue mass. Fine needle aspiration smears showed lobules of hyaline cartilage and a few spindle cells with abundant chondromyxoid matrix. A cytologic diagnosis of a benign chondroid, possibly hamartomatous lesion was given, which was confirmed as mesenchymal hamartoma on histopathologic examination. CONCLUSION: Mesenchymal hamartoma is a rare chest wall lesion that can be diagnosed on cytology, provided that the cytopathologist is aware of this uncommon entity and appreciates the benign cytologic features.

Hepatic epithelioid hemangioendothelioma: A diagnostic pitfall in aspiration cytology.

Hepatic epithelioid hemangioendothelioma (EH) is a rare vascular neoplasm. An accurate radiologic diagnosis is usually difficult due to the presence of multiple nodules, simulating metastatic carcinoma. Though histologic features of this tumor are well described, cytologic reports of hepatic EH are very few in the available literature. We describe a case of a young healthy adult male who was found to have multiple hepatic masses on radiologic investigations. A guided fine needle aspiration demonstrated a poorly differentiated neoplasm. The diagnosis was made on core biopsy assisted by immunohistochemistry, which showed characteristic features of EH. He is doing well 14 months after diagnosis, without surgical excision or chemotherapy. An accurate diagnosis of hepatic EH on aspiration cytology requires an adequate specimen and awareness of its cytologic features, including discohesive atypical cells with intracytoplasmic lumina and intranuclear inclusions. Since this tumor is usually unresectable but has a favorable prognosis as compared to hepatocellular carcinoma, a correct diagnosis is essential for appropriate management and prognostication.

Surgical outcome in relation to duct size at the porta hepatis and the use of cholagogues in patients with biliary atresia.

BACKGROUND: Small ductules communicating with the bile ducts have been described at the porta hepatis in extrahepatic biliary atresia (EHBA) and these form the basis for hepatic portoenterostomy. The use of cholagogues like dehydrocholic acid (DHC) and ursodeoxycholic acid (UDCA) to enhance bile flow postoperatively has been reported. AIMS: This communication describes our experience with the use of cholagogues following surgery in EHBA and attempts to correlate the outcomes with the diameter of the ductules. MATERIAL AND METHODS: Fifty five EHBA patients treated by the Kasai procedure form the basis of this study; 35 patients treated during 1979-1986 and administered DHC (3-5 mg/kg) postoperatively and 20 patients treated during 1999-2002 and administered UDCA (15 mg/kg) postoperatively. The diameter of ductules was measured using an optical micrometer on 5 microm serial sections; the ducts were classified as type I (no demonstrable ducts, n = 14), type II (< 50 microm, n=22) and type III (> 50 microm, n = 19). The clinical outcome was categorized as 1 (jaundice free survival at 5 years follow-up, n = 7), 2 (initial good response but deteriorated after one year, n = 27) and 3 (expired within one year following surgery, n = 21). The response to surgery was monitored using biochemical liver function tests (LFT), hepatobiliary scintigraphy (HIDA scan) and occurrence of cholangitis. RESULTS: Age did not affect the size of ducts in both DHC and UDCA groups but patients in the DHC group were older than those treated with UDCA (mean age DHC: 105.22 +/- 33.53 days, UDCA: 74.68 +/- 23.73 days; p = 0.009). There was no statistically significant difference between duct size and postoperative LFT in both groups (DHC p = 0.1, UDCA p = 0.5). Bile excretion on HIDA scan was significantly better with larger ducts (DHC p = 0.003, UDCA p = 0.025); overall UDCA showed significantly better bile excretion (p = 0.003) but this was not reflected in the surgical outcome. There was no significant difference in the surgical outcome of those treated with DHC or UDCA but a significantly higher incidence of cholangitis was seen with smaller ducts in the UDCA group (p = 0.02). CONCLUSIONS: There was no correlation between duct diameter and postoperative LFT but type III ducts were associated with better bile flow on HIDA scan. Cholangitis was seen more often with type I and II ducts in both DHC and UDCA groups. UDCA administration seemed to be beneficial in patients with type III ducts in increasing bile flow and reducing cholangitis.

Significance of promoter hypermethylation of p16 gene for margin assessment in carcinoma tongue.

BACKGROUND: Loss of p16 expression by promoter hypermethylation has been reported as an early event in the development of oral cancer. The aim of our study was to explore the prognostic implications of presence of promoter hypermethylation of p16 gene in surgical margins in carcinoma tongue. METHODS: A prospective analysis of 38 patients with resectable carcinoma tongue was carried out. DNA from tumor and the surgical margins was assessed by methylation-specific polymerase chain reaction. Follow-up duration was 17 to 37 months. RESULTS: About 86.8% of tumors showed promoter hypermethylation of p16 gene. Out of 30 patients with histologically free margins, 43.3% showed positivity on molecular assessment. Patients with positive molecular margins had a 6.3-fold increased risk of having local recurrence as compared to patients with negative margins. CONCLUSION: Promoter hypermethylation of p16 gene may serve as a useful molecular marker for predicting local recurrence in carcinoma tongue.

Sjogren's syndrome masquerading as nasopharyngeal carcinoma.

OBJECTIVE: The aim of the study was to describe a case of nasopharyngeal involvement by Sjogren's syndrome masquerading as nasopharyngeal carcinoma. METHODS: A description of clinical and radiologic features of facial pain, nasopharyngeal bulge, middle ear effusion, restriction of palatal movement, and infiltrating nasopharyngeal mass on imaging was given. Histologic evaluation, response to treatment with steroids and hydrochloroquine, and long-term follow-up, however, subsequently indicated the mass to be secondary to Sjogren's syndrome. CONCLUSION: A previously undescribed manifestation of Sjogren's syndrome is described.

Cellular mesoblastic nephroma in an infant: report of the cytologic diagnosis of a rare paediatric renal tumor.

Congenital mesoblastic nephroma is a rare pediatric tumor with a favorable clinical outcome. Cytological features of this uncommon tumor and diagnostic difficulties with other commoner pediatric renal neoplasms have been inadequately discussed in the available literature. We describe the case of a 1-year-old girl who presented with a right renal mass. Fine-needle aspiration smears consisted of a few cellular clusters of spindle cells with mitotic activity and mild nuclear pleomorphism. No blastema was identified. A cytologic impression of mesoblastic nephroma was rendered, which was confirmed on histopathological examination of the right nephrectomy specimen as a cellular mesoblastic nephroma. Cytologic diagnosis of mesoblastic nephroma has important prognostic and therapeutic implications. The cytopathologist should carefully evaluate smears from such patients and attempt to differentiate mesoblastic nephroma from Wilms' tumor and clear cell sarcoma.

Association of tuberculous endometritis with infertility and other gynecological complaints of women in India.

Endometrial biopsy samples derived from 393 patients with assorted gynecological complaints were investigated for mycobacterial infection. By employment of four different techniques, mycobacterial pathogens were detected irrespective of the nature/type of clinical complaint. Mycobacterium tuberculosis was the predominant pathogen detected among the samples investigated.

Multifocal osteosarcoma involving unusual sites.

We report a rare case of multifocal osteosarcoma (MFOS) with involvement of skeleton, lung, bone marrow, and soft tissues, presenting with paraparesis, cranial nerve palsies, subcutaneous nodules, anemia, and thrombocytopenia. MFOS with involvement of unusual sites presents problems in diagnosis and has a poor prognosis. The literature on 11 cases of MFOS with extraosseus, extrapulmonary involvement reported previously has been reviewed.

Successful pregnancy outcome with elective caesarean section following two attempts of surgical excision of large giant cell tumor of the lower limb during pregnancy.

CASE REPORT: A 21 year old woman presented at 27 weeks of gestation with history of curettage of large giant cell tumor of distal left femur at 18 weeks of gestation with residual tumor. Repeat excision and bone grafting was performed with isoxsupine tocolysis. An elective caesarean was performed at term and a 3-kg healthy baby boy was delivered. Decision to perform an elective section was taken to avoid fracture of bone and also due to limited abduction of limb. Both mother and baby were discharged from the hospital on the fifth postoperative day. CONCLUSION: Surgical excision of giant cell tumor with tocolysis followed by elective caesarean delivery is recommended for successful pregnancy outcome.

Malignant fibrous histiocytoma of the conjunctiva.

Fibrous histiocytomas are mesenchymal tumours composed of cells with fibroblastic to histiocytic differentiation. They can occur in any part of the body including the orbital tissues. To date, there are 18 cases of fibrous histiocytoma arising from the corneoscleral limbus reported in the literature. Eleven of these were classified as benign, and the rest were malignant fibrous histiocytomas. Benign fibrous histiocytomas have been reported in the orbit, eyelid, episclera and conjunctiva. Malignant fibrous histiocytoma has been well described in the orbit, but rarely as a primary conjunctival tumour. The rarity of the tumour makes its diagnosis and management a challenge. Herein, the clinicopathological features of a case of malignant fibrous histiocytoma are presented and its management with wide excision and cryotherapy followed by ocular reconstruction with amniotic membrane transplant is discussed.

Cavernous hemangiomatous polyp: an unusual case of perimenopausal bleeding.

INTRODUCTION: Significant vascular malformations of uterus are rare but can cause serious menorrhagia. CASE REPORT: We present the case of a 40-year-old multiparous woman who presented with perimenopausal bleeding due to cavernous hemangiomatous polyp successfully treated by polypectomy. CONCLUSION: Cavernous hemangioma can be a rare cause of perimenopausal bleeding. The same found in a polyp may be treated successfully by polypectomy.

Non-alcoholic fatty liver disease may not be a severe disease at presentation among Asian Indians.

AIM: To evaluate the clinical and biochemical profile of patients with non alcoholic fatty liver disease (NAFLD) and to assess their histological severity at presentation. METHODS: Consecutive patients presenting to the liver clinic of All India Institute of Medical Sciences (AIIMS) with raised transaminases to at least 1.5 times upper limit of normal, and histologically confirmed non-alcoholic fatty liver disease were included. Patients who had significant alcohol intake or positive markers of other liver diseases or who were taking drugs known to produce fatty liver were excluded. The clinical, biochemical and histological profile of this group was studied. RESULTS: Fifty-one patients with NAFLD formed the study population. Their median age and BMI were 34(17-58) years and 26.7(21.3-32.5) kg/m(2) respectively and 46 (90.1%) were males. The majority of the patients had mild inflammation, either grade 1 [32 (63%)] or grade 2 [16 (31%)] and only 3 (6%) patients had severe (grade 3) inflammation. Twenty-three (45%), 19 (37%), 8(16%) and 1(2%) patient had stage 0, 1, 2 and 3 fibrosis respectively on index biopsy and none had cirrhosis. On univariate analysis, triglyceride levels more than 150 mg % (OR = 7.1; 95% CI: 1.6-31.5, P = 0.002) and AST/ALT ratio>1 (OR = 14.3; 95% CI: 1.4-678.5, P = 0.008) were associated with high grades of inflammation and none was associated with advanced fibrosis. On multivariate logistic regression analysis, hypertriglyceridemia >150 mg% was the only factor independently associated with presence of high grade of inflammation (OR = 1.6; 95% CI: 1.3-22.7, P = 0.02), while none was associated with advanced fibrosis. Triglyceride levels correlated positively with inflammatory grade (r = 0.412; P = 0.003). CONCLUSION: NAFLD in North Indian patients is a disease of young over-weight males, most of whom are insulin resistant and they tend to have a mild histological disease at presentation.