Purva Gopal

The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: A meta-analysis

Objectives:The PNPLA3 rs738409 single-nucleotide polymorphism is known to promote nonalcoholic steatohepatitis (NASH), but its association with fibrosis severity and hepatocellular carcinoma (HCC) risk is less well-defined. The objectives of this study were to determine the association between PNPLA3 and liver fibrosis severity, HCC risk, and HCC prognosis among patients with liver disease.Methods:We performed a systematic literature review using the Medline, PubMed, Scopus, and Embase databases through May 2013 and a manual search of national meeting abstracts from 2010 to 2012. Two investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios (ORs), according to PNPLA3 genotype, were calculated using the DerSimonian and Laird method for a random effects model.Results:Among 24 studies, with 9,915 patients, PNPLA3 was associated with fibrosis severity (OR 1.32, 95% confidence interval (CI) 1.20–1.45), with a consistent increased risk across liver disease etiologies. Among nine studies, with 2,937 patients, PNPLA3 was associated with increased risk of HCC in patients with cirrhosis (OR 1.40, 95% CI 1.12–1.75). On subgroup analysis, increased risk of HCC was demonstrated in patients with NASH or alcohol-related cirrhosis (OR 1.67, 95% CI 1.27–2.21) but not in those with other etiologies of cirrhosis (OR 1.33, 95% CI 0.96–1.82). Three studies, with 463 patients, do not support an association between PNPLA3 and HCC prognosis but are limited by heterogeneous outcome measures. For all outcomes, most studies were conducted in homogenous Caucasian populations, and studies among racially diverse cohorts are needed.Conclusions:PNPLA3 is associated with an increased risk of advanced fibrosis among patients with a variety of liver diseases and is an independent risk factor for HCC among patients with nonalcoholic steatohepatitis or alcohol-related cirrhosis.

Choroid Plexus Carcinoma

Choroid plexus carcinoma is an uncommon neoplasm of the central nervous system most commonly found in the pediatric population. It is associated with a dismal prognosis, especially if incompletely resected. Accurate histopathologic diagnosis is imperative, and this neoplasm should always be included in the differential diagnosis of a papillary intraventricular tumor. Histopathologic features include blurring of papillary architecture, layers of neoplastic choroid plexus epithelial cells with pleomorphic nuclei, increased nuclear-to-cytoplasmic ratio, increased mitotic activity, areas of necrosis, and brain invasion. Current accepted treatment is gross total surgical resection of the tumor as the goal. Use of adjuvant chemotherapy is controversial at this time; however, it is considered in some cases.

Meta‐analysis: underutilisation and disparities of treatment among patients with hepatocellular carcinoma in the United States

Despite wide availability of treatment options for hepatocellular carcinoma (HCC), several studies have suggested underutilisation in clinical practice.

Human papillomavirus in metastatic squamous carcinoma from unknown primaries in the head and neck: A retrospective 7 year study

GOAL Human Papillomavirus (HPV) is found to be increasingly implicated in head and neck cancers. The objective of this study was to determine the primary site of origin of HPV positive squamous carcinomas metastatic to lymph nodes of the neck. METHODS Surgical pathology records from January 1, 2000 to July 31, 2007 were used to identify surgically removed neck lymph nodes with the diagnosis of metastatic squamous carcinoma. Specimens in formalin-fixed, paraffin-embedded blocks were examined for HPV (+) by analyzing sequencing data generated by PCR and immunostaining for the expression of the p16INK biomarker, which is overexpressed if Rb is not present. H & E stained slides were also reviewed for histological classification. The available retrospective demographics were extracted from the charts to determine trends of confounding factors. RESULTS Of the 43 patient samples, 41 contained adequate DNA to test for HPV. The mean age of the 41 patients was 62 years. All of the patients smoked and 39/41 patients consumed alcohol. The overall HPV (+) incident rate was 27% (11/41) by PCR with strongly diffuse or strong focal p16 staining. 9 of the 34 males and 2 of the 7 females had HPV (+) carcinomas. The average age of the 2 HPV (+) females was 44, compared to the HPV (-) females who averaged 70. The average age of the HPV (+) males was 56 compared with the average age 55 of the HPV (-) males. HPV (+) carcinomas appeared to arise from multiple sites in the oropharynx, particularly the tonsils and tongues, including unknown primaries. By histological exam, most metastatic HPV(+) squamous carcinomas were poorly differentiated (basaloid) microscopically and grossly cystic. CONCLUSION The 27% HPV (+) squamous cancers metastatic to neck lymph node originated from multiple sites in the oropharynx. The HPV (+) female population, although a total of only 2, tended to be much younger than the HPV (-) ones, whereas the HPV (+) male population was similar in age to the HPV (-) male population.

Factors That Affect Accuracy of α-Fetoprotein Test in Detection of Hepatocellular Carcinoma in Patients With Cirrhosis

BACKGROUND & AIMS Measurements of α-fetoprotein (AFP) detect hepatocellular carcinoma (HCC) with low levels of sensitivity and specificity, and therefore are not recommended for use in liver cancer surveillance. However, AFP levels might accurately detect HCC in subgroups of patients. We performed a retrospective case-control study to identify features of patients with cirrhosis in whom levels of AFP correlated with HCC. METHODS We collected data from patients with cirrhosis, with (n = 452) or without (n = 676) HCC, diagnosed at Parkland Hospital in Dallas, Texas, from January 2005 through June 2012. We determined sensitivities and specificities with which different levels of AFP identified those with HCC; multivariate logistic regression was used to associate accurate identification of HCC with patient features (age, sex, race/ethnicity, alcohol intake, smoking, etiology of cirrhosis, presence of decompensation, and laboratory test results). We assessed the overall accuracy of these factors in detecting HCC using receiver operator characteristic curve analysis and the Delong method. We calculated levels of AFP that detect HCC with the highest levels of sensitivity and specificity in subgroups using receiver operator characteristic analysis. RESULTS The most common etiologies of cirrhosis were hepatitis C virus (HCV) infection (60%) and alcohol induced (22%). Nearly 11% of patients were human immunodeficiency virus (HIV)-positive. Levels of AFP greater than 20 ng/mL detected HCC with 70.1% sensitivity and 89.8% specificity. This AFP level identified patients with HCC with a c-statistic of 0.87 (95% confidence interval, 0.85-0.89); it was significantly more accurate in HCV-negative patients than in HCV-positive patients (c-statistic, 0.89 vs 0.83; P = .007). AFP levels of 59 ng/mL or greater most accurately detected HCC in patients with HCV-associated cirrhosis; levels of AFP of 11 ng/mL or greater accurately identified HCC in HCV-negative patients. The level of AFP identified early stage HCC with a c-statistic of 0.62 (95% confidence interval, 0.58-0.66), and had a significantly higher level of accuracy for HIV-positive patients than for HIV-negative patients (c-statistic, 0.81 vs 0.59; P < .001). CONCLUSIONS Based on a retrospective analysis of data from patients with cirrhosis, with or without HCC, AFP level most accurately detects HCC in patients without HCV infection. It detects HCC with a high level of accuracy in patients with cirrhosis and HIV infection.

The Changing Landscape of Hepatocellular Carcinoma: Etiology, Genetics, and Therapy

Hepatocellular carcinoma (HCC) represents one of the leading causes of cancer death and has proved to be highly refractory to treatment. Extensive analysis of the disease has demonstrated that it arises predominantly in response to high-risk etiological challenges, most notably hepatitis virus. However, with evolving vaccination and the obesity epidemic, progressively more cases are associated with underlying metabolic dysfunction. Pathologically diverse forms of HCC are observed, and recent sequencing analysis has defined common events that target well-known cancer pathways including β-catenin/Axin, TP53, and RB/CDKN2A, as well as frequent aberrations in chromatin remodeling factors. However, there are a myriad of low frequency genetic events that make each HCC case unique. Gene expression profiling approaches have successfully been deployed for prognostic assessment of hepatocellular carcinoma and to detect the earliest stages of disease. Despite more extensive research, systemic treatment for HCC is exceedingly limited, with only a handful of drugs providing benefit. Ongoing clinical trials are attempting to exploit specific biological dependencies of HCC to improve the dismal prognosis. Overall, the future of HCC treatment will rely on an understanding of the interplay between etiological factors, molecular features of disease, and rational therapeutic intervention.

Increased cell density decreases cysteine proteinase inhibitor activity and increases invasive ability of two prostate tumor cell lines.

The ability of a cancer cell to metastasis to a distant site is partly dependent on the secretion of matrix degrading enzymes. The lysosomal cysteine proteinases, cathepsins B and L, have been shown to be secreted by a number of cancer cells and have been implicated in metastasis. Cathepsins B and L are regulated by a class of inhibitors known as the cystatins; aberrant cystatin activity has also been shown in a number of cancer cells. Two prostate cancer cell lines, PC3 and DU145, and a normal prostate epithelial cell (NPC) culture were used to determine the importance of cathepsins L+B and cysteine proteinase inhibitor (CPI) activity in the ability of each cell line to invade the reconstituted basement membrane, Matrigel. Cathepsin L+B and CPI activities were evident in the cell extract and conditioned media of PC3, DU145 and NPC; however, only the cancer cell lines PC3 and DU145 exhibited invasive ability. Invasive ability was partially inhibited following exposure of PC3 and DU145 cells to the CPI, E-64. Since environmental factors such as cell-cell interactions are responsible for mediating the expression of a number of genes involved in metastasis, the effects of cell density on cathepsin and CPI activities and invasive ability were also determined. CPI activity decreased and invasive ability increased with increasing cell density. We conclude that cathepsin L+B plays a significant role in the invasive ability of the two prostate cancer cell lines, PC3 and DU145. This may be due to decreased regulation by endogenous CPIs whose activity diminishes at high cell densities.

The clinical significance of focally enhanced gastritis in children.

Focally enhanced gastritis (FEG) was initially described in patients with inflammatory bowel disease (IBD), but subsequent reports found this to be a nonspecific finding in adults. Initial reports suggest that FEG may be more predictive of IBD in pediatric patients, but this has yet to be confirmed. The aim of our study was to characterize and determine clinical correlates of FEG in pediatric patients. Gastric biopsies from pediatric patients who were diagnosed with FEG at a single tertiary care center over a 5-year period were reviewed (5-y cohort study). In a subsequent study, all gastric biopsies from pediatric patients in the single center over a 1-year period were reviewed. Biopsies were reviewed in a blinded manner by 2 pathologists, and histologic data of interest were recorded. Clinical data and follow-up data were recorded from review of the electronic medical records. Of the 25 patients with FEG in the 5-year cohort study, IBD was present in 19 (76%) patients. Crohn disease (CD) was more common than ulcerative colitis (UC) among these patients (68% vs. 16%). In the 1-year review study with 262 gastric biopsies, FEG was present in 31 (11%) cases. Patients with FEG were significantly more likely to have IBD than non-FEG patients (61.3% vs. 11.6%, P⩽0.001). Of the 19 patients with FEG and IBD, 9 patients had CD, 9 patients had UC, and 1 had indeterminate colitis. The presence of FEG is highly associated with IBD in pediatric patients. The presence of FEG does not reliably distinguish between patients with CD and those with UC.

The collagenous gastroenteritides: similarities and differences.

Collagenous gastritis, collagenous sprue, and collagenous colitis share striking histologic similarities and occur together in some patients. They also share some drug and disease associations. Pediatric cases of collagenous gastritis, however, lack most of these associations. The etiologies of the collagenous gastroenteritides are not known, so it is not clear whether they are similar because they share pathogeneses, or because they indicate a common histologic response to varying injuries. The features, disease and drug associations, and the inquiries into the pathogenesis of these disorders are reviewed.

The Synthetic Triterpenoid RTA 405 (CDDO-EA) Halts Progression of Liver Fibrosis and Reduces Hepatocellular Carcinoma Size Resulting in Increased Survival in an Experimental Model of Chronic Liver Injury.

UNLABELLED Patients with cirrhosis have an increased risk of developing liver cancer and a higher rate of mortality. Cirrhosis currently has no known cure, and patients may benefit from new agents aimed at alleviating their complications and slowing down the rate of disease progression. Therefore, the effects of the orally bioavailable synthetic triterpenoid 2-cyano-3,12-dioxooleana- 1,9(11)-dien-28-oate-ethyl amide (CDDO-EA, RTA 405), which has potent antioxidative and antiinflammatory properties, was evaluated in a chronic carbon tetrachloride (CCl(4))-induced model of liver cirrhosis and hepatocellular carcinoma (HCC). Mice were injected with CCl(4) (to induce fibrosis and cirrhosis) or placebo biweekly for 12 weeks followed by CDDO-EA in the diet for 18 weeks with continued biweekly injections of CCl(4). Chronic CCl(4) administration resulted in cirrhosis, ascites, and HCC formation, associated with increased serum transforming growth factor-β1, hepatic hydroxyproline content, and increased serum bilirubin. CDDO-EA, whose administration commenced after establishment of liver fibrosis, decreased liver fibrosis progression, serum bilirubin, ascites, and HCC formation and markedly increased overall survival. CDDO-EA also attenuated -TNFα (tumor necrosis factor-α), α-SMA (alpha smooth muscle actin), augmented -IL-10 levels, and improved histologic and serologic markers of fibrosis. CONCLUSIONS CDDO-EA mitigates the progression of liver fibrosis induced by chronic CCl(4) administration, which is associated with the induction of antifibrogenic genes and suppression of profibrogenic genes.