Microscopic colitis in children with chronic diarrhea.

OBJECTIVE: The aim of the present study was to study microscopic colitis (MC) in children with special reference to its role in chronic diarrhea and changes in mucosal biopsies. METHODS: A total of 100 consecutive children ages 3 to 12 years, with nonbloody diarrhea (passage of ≥3 loose stools per day) of >12 weeks' duration were screened and 26 were enrolled in the study in which no specific etiology could be found and colonoscopy did not reveal any mucosal abnormality. Colonic biopsies were evaluated for the presence of lymphocytic colitis or collagenous colitis and those with the characteristic changes were defined to have MC (group A). Colonic biopsies from patients with MC were compared with biopsies from patients with chronic diarrhea but no evidence of MC (group B). One hundred children ages 3 to 12 years with bleeding per rectum were screened and colonic biopsies from 45 patients (group C) who had colonic mucosal changes but no vascular or polyp lesion were compared with patients with MC. RESULTS: Of the 26 patients with chronic diarrhea, MC was found in 5 (3 lymphocytic colitis and 2 collagenous colitis). Significantly higher polymorphonuclear infiltration was seen in group A as compared with group B (13.8 [5.4-20.6] vs 7.2 [0-19.6]; P = 0.03) or group C (13.8 [5.4-20.6] vs 4 [0-13.4]; P = 0.007). Intraepithelial lymphocytes (12 [4-32] vs 4 [0-24]; P = 0.008) and basement membrane thickening (3.5 [2.9-10.6] vs 2.5 [1.6-5.86]; P = 0.008) were also significantly higher in group A as compared with group C. CONCLUSIONS: MC was found to be present in children with nonbloody chronic diarrhea in children. Further multicentric studies may provide adequate data on its prevalence.

Population-based incidence of intussusception and a case-control study to examine the association of intussusception with natural rotavirus infection among indian children.

BACKGROUND: A rotavirus vaccine previously licensed in the United States was withdrawn because it caused intussusception. Data on background intussusception rates in developing countries are required to plan pre- and postlicensure safety studies for new rotavirus vaccines. Also, it is unclear whether natural rotavirus infection is associated with intussusception. METHODS: Passive surveillance for intussusception in a large, well-defined, poor, urban population in Delhi, India, was conducted in 2 phases. Intussusception was confirmed by ultrasonography or surgery. Fecal samples obtained from patients with intussusception at study hospitals (irrespective of their residence in study areas) and healthy control subjects were tested for rotavirus with use of enzyme immunoassay. If available, resected intestinal tissue samples were tested for rotavirus with use of immunohistochemistical analysis and reverse-transcription polymerase chain reaction. RESULTS: The incidence of intussusception requiring hospitalization was 17.7 cases per 100,000 infant-years of follow-up (95% confidence interval, 5.9-41.4 cases per 100,000 infant-years). Detection rates of rotavirus in stool samples did not differ significantly between case patients and control subjects (4 of 42 case patients vs 6 of 92 control subjects), and no evidence of rotavirus was detected in any of the 22 patients with intussusception for whom intestinal tissue samples were available. CONCLUSIONS: The incidence of intussusception among Indian infants appears to be lower than that reported in other middle- and high-income countries. Natural rotavirus infection does not appear to be a major cause of intussusception in Indian infants.

Clinical significance of altered expression of retinoid receptors in oral precancerous and cancerous lesions: relationship with cell cycle regulators.

Alterations in expression of retinoid receptors are implicated in human cancers. We hypothesized that altered expression of retinoic acid receptors (RARalpha,beta,gamma) and retinoid X receptor RXRalpha and their relationship with cell cycle regulators (p53, p16, p21) is associated with development, progression and prognosis of oral cancer. Immunohistochemical analysis of RAR alpha, beta, gamma and RXRalpha proteins was carried out on serial sections from 244 oral squamous cell carcinomas (OSCCs), 102 potentially malignant lesions (65 hyperplasias, 37 dysplasias), 83 matched histologically normal oral tissues and 29 normal mucosa from non-exposed individuals without oral lesions and correlated with expression of cell cycle regulators p53, p16 and p21 as well as with clinicopathological parameters. Expression of retinoid receptors RARbeta, RARgamma, RXRalpha and cell cycle regulators p16 and p21 was decreased in majority of oral SCCs as well as in potentially malignant lesions. Multivariate stepwise logistic regression analysis carried out for comparison of non-exposed normal oral mucosa with histologically normal oral tissues from patients with oral lesions showed significant loss of RARbeta or p53 accumulation (RARbeta(-)/p53(+) Odd's ratio, OR = 266.6, p = 0.000); non-exposed normal mucosa from individuals without oral lesions with potentially malignant lesion was RARbeta(-)/p21(-)/p53(+) (OR = 215.7, p = 0.000); matched normal to potentially malignant stage was RARalpha(+)/p21(-) (OR = 4.414, p = 0.005); hyperplasia to dysplasia was RARalpha(+)/p53(+) (OR = 4.72, p = 0.005) and potentially malignant to malignant phenotype was RARalpha(+) (OR = 2.061, p = 0.004). The prognostic relevance of these factors was assessed in 115 of these SCC patients who were followed-up for a maximum period of 94 months (median 21 months). Multivariate analysis using Cox's proportional Hazard's model showed that RARalpha(+)/p21(-) phenotype was associated with shorter disease-free survival (Hazard's ratio, HR = 1.863, p = 0.0471). To our knowledge, this is the first large study showing alterations in expression of retinoid receptors at the protein level at different stages in development and progression of oral SCC. It also underscored the prognostic significance of retinoid receptors and their interactions with cell cycle regulators in multistep oral tumorigenesis.

Celiac disease with mild to moderate histologic changes is a common cause of chronic diarrhea in Indian children.

OBJECTIVES: In developed countries, small bowel histology in coeliac disease is a spectrum, ranging from normal with increased intraepithelial lymphocytes to the classic flat mucosa. In developing countries, mild to moderate enteropathies in children with chronic diarrhea and growth failure are assumed to be caused by tropical sprue, persistent infections, or malnutrition with bacterial overgrowth. We report the prevalence and histology of coeliac disease in children with chronic diarrhea at a tertiary referral hospital in North India. METHODS: Two hundred fifty-nine children with symptoms indicating coeliac disease attended the All India Institute of Medical Sciences. Histology was graded after a modified Marsh classification. Serum immunoglobulin A anti-endomysial antibodies (AEA) were assayed using indirect immunofluorescence. Subjects with abnormal histology and positive AEA were put on a gluten free diet (GFD). Coeliac disease was diagnosed on small intestinal biopsy changes and a clinical response to a GFD. RESULTS: Severe enteropathies were present in 63 (24%) subjects, and 58 (92%) responded to a GFD. Sixty-six (25%) had moderate histologic changes, 61 responding to a GFD. AEA was positive in 56 of 63 patients with severe and 65 of 66 with moderate enteropathies. Fifty-seven children had mild enteropathies, and 19 of 20 with positive AEA responded clinically to a GFD. CONCLUSIONS: Coeliac disease is more common than previously believed. It presents a variable histology, and diagnoses may be missed or delayed if based only on severe enteropathies. Serology is a useful adjunct to diagnosis, and diagnostic criteria need to be developed appropriately for coeliac disease in developing countries despite limited facilities.

Alterations of rb pathway components are frequent events in patients with oral epithelial dysplasia and predict clinical outcome in patients with squamous cell carcinoma.

OBJECTIVE: This study was designed to test the hypothesis that alterations in expression of G1/S modulators cyclin D1, p16 and pRb occur in patients with oral epithelial dysplasia, considered to be at increased risk for malignant transformation. In addition, the analysis of expression of all three markers in the same set of oral cancer patients would provide a unique opportunity to determine whether these alterations have cooperative or synergistic effects on oral cancer development and prognosis. PATIENTS AND METHODS: A prospective study was undertaken to carry out immunohistochemical analysis of cyclin D1, p16 and pRb proteins in serial paraffin-embedded tissue sections of 220 oral squamous cell carcinomas (OSCCs), 90 potentially malignant lesions (52 oral hyperplastic lesions, 38 dysplasias) and 81 matched histologically normal oral tissues and correlated them with clinicopathological parameters. Ninety-eight OSCC patients were followed up for a maximum period of 94 months with overall median survival of 21 months. RESULTS: Seventy-five of 90 (83%) potentially malignant lesions and 198 of 220 (90%) OSCCs showed altered expression of at least one of the proteins in the pRb pathway, while 10 of 90 (11%) patients with potentially malignant lesions and 40 (18%) of 220 OSCC patients showed all three alterations. Loss of p16 was the earliest event in oral tumorigenesis. In a multivariate model, loss of pRb was associated with transition from hyperplasia to dysplasia (OR = 3.727, p = 0.005). The transition of potentially malignant lesions to malignant stage was associated with pRb-/cyclin D1+ phenotype (OR = 2.294, p = 0.001) and p53+ phenotype (OR = 2.230, p = 0.002). Loss of pRb and accumulation of p53 (pRb-/p53+) phenotype was associated with histologic progression of the tumors and acquisition of invasive potential. Multivariate analysis using Cox's proportional hazards model revealed that pRb-/p53+ phenotype was the most significant adverse prognosticator for disease-free survival (hazards ratio, (HR) = 2.642, p = 0.004). CONCLUSIONS: Deregulation of the p16/pRb/cyclin D1 pathway is an early event in acquisition of dysplasia, but deregulation of both pRb and p53 pathways is associated with malignant transformation and adverse prognosis in oral tumorigenesis.

Stromelysin 3, Ets-1, and vascular endothelial growth factor expression in oral precancerous and cancerous lesions: correlation with microvessel density, progression, and prognosis.

PURPOSE: Identification of molecular changes characteristic of development and progression of oral cancer are of paramount importance for effective intervention. Stromelysin 3 (MMP11) is a unique matrix metalloproteinase shown to have dual function during cancer progression. The transcription factor Ets-1 and vascular endothelial growth factor (VEGF) are important proangiogenic factors in cancer. This study was designed to test the hypothesis that concomitant expression of stromelysin 3, Ets-1, and/or VEGF affects the development, progression, and prognosis of oral cancer. PATIENTS AND METHODS: Immunohistochemical analysis of stromelysin 3, Ets-1, VEGF, and platelet/endothelial cell adhesion molecule 1 (a marker for intratumoral microvessel density) was carried out in serial paraffin embedded tissue sections of 220 oral squamous cell carcinomas (OSCC), 90 precancerous lesions (59 hyperplasias and 31 dysplasias), and 81 matched histologically normal oral tissues. RESULTS: Ets-1, VEGF, and stromelysin 3 expression independently correlated with increased intratumoral microvessel density in precancerous lesions (P = 0.05, 0.001, and 0.026, respectively) as well as in SCCs (P = 0.005, 0.01, and 0.031, respectively). Logistic regression analysis revealed that concomitant expression of stromelysin 3 and Ets-1 (stromelysin 3(+)/ Ets-1(+) phenotype; odds ratio, 3.7; P = 0.001) was the most significant predictor for transition to precancerous stage, whereas dual expression of stromelysin 3 and VEGF (stromelysin 3(+)/ VEGF(+) phenotype; odds ratio, 2.07; P = 0.004) was the most important predictor for progression from precancerous stage to frank malignancy. Intriguingly, Ets-1 expression was significantly associated with VEGF expression and stromelysin 3 expression in precancerous tissues as well as OSCCs. Follow-up data for 144 patients for a maximum period of 115 months showed that VEGF [hazards ratio (HR), 4.532; P = 0.004] and Ets-1 (HR = 2.182; P = 0.049) expression significantly correlated with reduced disease-free survival in univariate analysis. In bivariate analysis, patients harboring Ets-1(+)/VEGF(+) phenotype had the worst survival (median disease-free survival, 50 months; HR, 2.943; P = 0.003). Multivariate analysis using Cox's proportional hazards model showed that increased VEGF expression was the most significant adverse prognosticator in OSCC patients (HR, 4.470; P = 0.004). CONCLUSIONS: In conclusion, this study provides the first evidence of concomitant expression of stromelysin 3, VEGF, and Ets-1 in clinical specimens in different stages of development of oral cancer. In early stages, concomitant expression of stromelysin 3 and Ets-1 favors the development of a precancerous state, whereas dual expression of stromelysin 3 and VEGF is associated with progression from precancerous to cancerous state. VEGF expression is an adverse prognosticator for disease-free survival.

Prognostic significance of stromelysin-3 and tissue inhibitor of matrix metalloproteinase-2 in esophageal cancer.

OBJECTIVE: Stromelysins (matrix metalloproteinases: MMP-10 or ST-2 and MMP-11 or ST-3) and tissue inhibitors of matrix metalloproteinases (TIMP-1 and 2) have been shown to be associated with human tumor progression, invasion and metastasis. The aim of the present study was to determine the prognostic significance of these proteins in esophageal squamous cell carcinoma (ESCC). METHODS: Immunohistochemical analysis was carried out in 65 surgically resected ESCCs and 49 distant histologically normal esophageal tissues and 16 cases of dysplasias. Statistical analyses were performed to determine the associations between the protein expression and clinicopathological parameters and survival of esophageal cancer patients. RESULTS: Expression of ST-2, ST-3, TIMP-1 and TIMP-2 was observed in 43/65 (66%), 51/65 (78%), 43/65 (66%) and 47/65 (72%) ESCC cases, respectively. Univariate analysis showed that TIMP-2 expression was associated with tumor site (OR = 2.63, p = 0.017). TIMP-1+/TIMP-2+ phenotype was inversely correlated with nodal invasiveness of the tumor (OR = 0.4, p = 0.04). Interestingly, p53 expression was associated with increased levels of ST-3 (OR = 0.11, p = 0.02) and TIMP-1 (OR = 3.2, p = 0.007) suggesting possible involvement of p53 in the regulation of these proteins. An increased expression of ST-2, ST-3, TIMP-1 and TIMP-2 was observed in 11/16 (69%), 7/17 (44%), 11/16 (69%) and 8/16 (50%) dysplasias also suggesting that these alterations are early events in esophageal tumorigenesis. All the ESCC patients were followed up postesophagectomy for a maximum period of 59 months (mean disease-free survival = 12 months). Kaplan-Meier survival analysis showed that patients with ST-3-positive and TIMP-2-negative carcinoma had a significantly shorter disease-free survival (median disease-free survival time of 4 months) as compared to patients in the other groups (median disease-free survival time of 20 months; p = 0.0016). To our knowledge this is the first report showing that ST-3+/TIMP-2- phenotype remained of significant predictive value for disease-free survival (p = 0.0007) in multivariate analysis including a conventional clinicopathological factor, tumor stage (p = 0.051). CONCLUSION: Our results suggest that ST-3+/TIMP-2- phenotype is an adverse prognosticator in esophageal cancer patients.

Xanthogranulomatous pancreatitis: mass lesion of the pancreas simulating pancreatic carcinoma--a report of two cases.

Xathogranulomatous inflammation is well known in the gall bladder and kidney. Xanthogranulomatous pancreatitis has not been previously described. We report two cases of this new clinicopathologic entity. The first was a 50 years old male with cholelithiasis and progressive obstructive jaundice for 5 months. Radiology was suggestive of carcinoma head of pancreas and a Whipples procedure was performed. The second was a 36 years old male with choledocholithiasis and features of chronic pancreatitis. During pancreaticojejunostomy, a mass was found in the tail of pancreas, which was excised with a suspicion of carcinoma. Gross examination of both specimens showed firm grey white masses, demarcated from the surrounding pancreas but with infiltrative margins, and were thought to be carcinoma. Histopathological examination showed localized inflammation with numerous foamy histiocytes along with dilated ducts and microabscesses. A diagnosis of xanthogranulomatous pancreatitis was made in both instances. In view of clinical, radiological, operative and gross appearances of our cases simulating carcinoma, recognition of xanthogranulomatous chronic pancreatitis as a distinct clinicopathological entity seems important, analogous to similar lesions of the kidney and gall bladder.

Combined evaluation of expression of telomerase, survivin, and anti-apoptotic Bcl-2 family members in relation to loss of differentiation and apoptosis in human head and neck cancers.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers, and it accounts for 5% of all adult cancers worldwide. Loss of growth control and a marked resistance to apoptosis are considered major mechanisms driving tumor progression. Little is known about the distribution of inhibitors of apoptosis in HNSCC or how they correlate with other biomarkers of malignancy, such as telomerase, an enzyme that plays a critical role in cellular immortalization. The objective of this study was to assess the protein expression of anti-apoptotic members of Bcl-2 family and survivin and correlate them with telomerase activity. METHODS: We compared anti-apoptotic protein expression in tumor tissue sections of 50 HNSCC patients and 19 histopathologically normal tissues by immunohistochemistry and Western blotting. Apoptotic index was studied by TUNEL assay. Telomerase activity was determined by polymerase chain reaction (PCR)-enzyme-linked immunosorbent assay (ELISA). RESULTS: Bcl-2, Bcl-XL, and survivin were found to be significantly upregulated in tumor tissues as compared with the normal tissue. Protein expression of Bcl-2 and survivin was significantly associated with the loss of differentiation in tumors and that of Bcl-XL with nodal metastasis. Telomerase activity was found to be upregulated in tumors as compared with the normal tissue (p <.001) and was found to be significantly associated with the loss of differentiation in tumors. CONCLUSIONS: Mechanisms that promote both cell proliferation (telomerase activity) and cell survival (expression of inhibitors of apoptosis protein [IAPs]) appear to be activated in HNSCC. This is the first study of its kind to look into the correlation of the apoptotic pathway and proliferation promoting enzyme activity simultaneously in relation to loss of apoptosis and differentiation in HNSCCs. Telomerase activity in these tumors was found to be correlated with Bcl-2, Bcl-XL, and survivin overexpression and with reduced apoptosis, thereby suggesting that novel strategies can be developed to control cancer cell growth by co-targeting telomerase and apoptotic pathways.

Differential expression of retinoic acid receptors in normal and malignant esophageal tissues.

The chemopreventive and chemotherapeutic activities of retinoids may be attributed to their ability to modulate growth, differentiation and apoptosis of epithelial cells, suppress or reverse epithelial carcinogenesis. Many of these effects of retinoids result from modulation of genes by two distinct classes of retinoid receptors: RARs and RXRs, alterations in their expression may lead to tumorigenesis. To determine whether alterations in expression of retinoid receptors are related to the development of esophageal squamous cell carcinomas (ESCCs), the expression of RARalpha, beta, gamma and RXRalpha was studied in 50 untreated primary esophageal carcinomas and 19 distant normal tissues by immunohistochemistry. RARbeta expression was observed in 18/50 (36%) ESCCs, while 16/19 (84%) of matched histologically normal esophageal tissues displayed RARbeta immunopositivity (p=0.001, 0R=3.405). Significant increase in RARalpha immunopositivity was observed in ESCCs (40/50; 80 %) as compared to normal tissues (9/19 cases; 47%) (p=0.008; 0R=2.77). RARgamma expression was observed in ESCCs (37/50cases; 74%) as compared to normal tissues (16/19; 84%); without significant difference. However, poorly differentiated esophageal cancer showed marked decrease in RARy immunopositivity (p=0.017; OR=6.0). Interestingly, increased expression of RXRalpha was observed in 43/50 (86%) ESCCs in comparison with (10/19; 53%) normal tissues (p=0.003; 0R=3.09). Logistic regression analysis revealed RARgamma-/RXRalpha+ phenotype as most significantly associated with dedifferentiation of the tumor (p=0.014; OR=11.0). The hallmark of the study was the significant increase in expression of RARalpha and RXRalpha proteins and loss of expression of RARbeta protein in ESCCs in comparison with the distant normal epithelia.

Stromelysin-3 expression is an early event in human oral tumorigenesis.

Stromelysin-3 (ST3/MMP11) is associated with human tumour progression. To determine the clinical significance of ST3 in oral tumorigenesis, its expression was analysed in different stages of tobacco-associated oral cancer. Immunohistochemical analysis of ST3 expression in 79 oral precancerous lesions, 177 SCCs and 35 histologically normal oral tissues was carried out and corroborated by immunoblotting and RT-PCR. ST3/MMP11 protein expression was observed in 45/79 (57%) precancerous lesions [28/48 (58%) with hyperplasia and 17/31 (55%) with dysplasia] and in 123/177 (70%) oral SCCs. In precancerous lesions, ST3 expression was higher compared to normal oral tissues (p = 0.000) and associated with MVD (p = 0.05), a marker for angiogenesis. ST3 was also expressed in cells cultured from precancerous and cancerous lesions that had undergone epithelial-to-mesenchymal transition. In oral cancer patients, ST3 positivity was associated with lymph node involvement (p = 0.025) and increased intratumoral MVD (p = 0.009). Ninety-eight oral SCC patients were followed up for a period of 94 months (median 22.5 months). Kaplan-Meier survival analysis showed that ST3 expression was not a significant prognostic indicator. ST3 expression in oral hyperplastic and dysplastic lesions suggests its association with progression of phenotypic alterations acquired early during the malignant transformation pathway of oral epithelium and implicates it not only in angiogenesis and invasion but also in tumorigenesis. Thus, ST3 may serve as a potential target for developing molecular therapeutics for early intervention in oral tumorigenesis.

Ets-1 and VEGF expression correlates with tumor angiogenesis, lymph node metastasis, and patient survival in esophageal squamous cell carcinoma.

PURPOSE: Esophageal squamous cell carcinoma (ESCC) in the Indian population exhibits insidious symptomatology, late clinical presentation, aggressive behavior, and high propensity for metastasis. Ets-1, a transcription factor, is expressed in esophageal tumors and associated with poor prognosis. The aim of the present study was to determine the relationship between Ets-1 expression, tumor angiogenesis [vascular endothelial growth factor (VEGF) and microvessel density (MVD)] and the biological behavior of ESCCs. METHODS: In a prospective study the expression of Ets-1, VEGF, and PECAM-1 (CD-31) was determined in 55 ESCCs, by immunohistochemical analysis, correlated with clinicopathological parameters and outcome of the patients. RESULTS: Overexpression of Ets-1 and VEGF proteins was observed in 44/55 (80%) and 38/55 (69%) of ESCCs, respectively. VEGF immunopositivity was associated with lymph node metastasis ( P=0.002). Analysis of mRNA isoforms using RT-PCR revealed increased expression of VEGF 121 transcripts in ESCCs and MVD was correlated with de-differentiation status of the tumors ( P=0.049). Kaplan-Meier survival analysis showed significant correlation between poor disease-free survival and tumor stage ( P=0.02) and with nodal metastasis ( P=0.05). Concomitant expression of VEGF, Ets-1 proteins, and high MVD was correlated with poor disease-free survival ( P=0.004). CONCLUSION: Significant association of Ets-1 and VEGF proteins with tumor angiogenesis (MVD), lymph node invasion, and poor disease-free survival underscores their relevance regarding aggressive tumor behavior and highlights their potential utility as adverse prognostic factors in esophageal carcinomas.

Characterization of apoptosis-related molecular changes in a desmoid tumor of the chest wall: report of a case.

Desmoid tumors are uncommon benign tumors composed of fibrous tissue, which originate from aponeuroses. Little is known about their molecular pathogenesis and the reason that they recur. We report the case of a 20-year-old man with a recurrent desmoid tumor of the chest wall, focusing on our analysis of the apoptosis and its related molecular events. Immunohistochemical examination showed higher expression of antiapoptotic Bcl-2, Bcl-XL, survivin, and the transcription factor, NF-kappaB, in the recurrent tumor than in the adjoining normal tissue. Proapoptotic Bax was not detected in the tumor. Similar findings were obtained in the original primary tumor. Both tumors had a low apoptotic index according to the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. These changes occurred in the absence of cell proliferation, shown by the absence of both Ki-67 staining and increased telomerase activity. This derangement of apoptosis gives the aggressive desmoid tumor cells a proliferative advantage, and presumably, forms the basis of its high recurrence rate. Therefore, inhibitors of apoptosis proteins (IAPs) may be useful for predicting recurrence. The regulation of apoptosis by antisense therapy against these inhibitors could prove beneficial for overcoming repeated recurrence, even after surgery.

Hepatocellular carcinoma in a hepatitis B 'x' transgenic mouse model: A sequential pathological evaluation.

BACKGROUND: The introduction of transgenic technology has made it possible to study the steps of carcinogenesis and directly establish the link between viral subgenomic fragments and specific types of cancer. Research directed at hepatitis B virus (HBV)-related carcinogenesis has benefited from this technology. We present a detailed pathological evaluation of the sequential steps of hepatocarcinogenesis in a hepatitis B 'x' (HBx) transgenic mouse model. In this model, the transgene incorporates the region encoding amino acids 58-154 of the HBV X protein and the murine c-myc gene. This model demonstrated changes in the liver from birth with foci of multicentric dysplasia evolving into nodules and overt hepatocellular carcinoma between 20 and 28 weeks. METHODS AND RESULTS: The hepatocytes were mitotically active and showed increased proliferative capacity soon after birth, with exponential increase thereafter. This was accompanied by a high rate of apoptosis, which later declined as the tumors developed. Other functional and immunophenotypic characteristics included a high c-myc expression in the neoplastic lesions, no alteration in p53 expression, and no alteration in the expression of hepatic enzymes except for diffuse expression of succinic dehydrogenase. CONCLUSION: The entire process illustrates the disturbances of cell growth and death because of the collaborative influence of HBx and c-myc genes that result in the development of hepatocellular carcinoma after a prolonged latent period.

Retinoic acid receptor-alpha as a prognostic indicator in oral squamous cell carcinoma.

Retinoids reverse potentially malignant lesions and inhibit the development of second primary tumors in oral cancer patients by binding to nuclear retinoid receptors. Alterations in the expression of retinoid receptor-alpha are implicated in tumor progression. Herein, we hypothesized that increased expression of RARalpha protein in oral squamous cell carcinoma (SCC) is associated with a poor clinical outcome and thus may serve as a prognostic factor. Retrospective immunohistochemical analysis of RARalpha protein expression was carried out in paraffin-embedded tissue sections from 115 patients with completely resected oral SCCs for whom clinical follow-up data were available. Increased expression of RARalpha protein was observed in 67/115 (58%) oral SCCs (weakly positive in 38 patients and strongly positive in 29 patients). Kaplan-Meier analysis showed that patients with RARalpha positivity had significantly shorter disease-free survival time (median time 40 months vs. 86 months, p = 0.0229). Furthermore, disease-free survival time of the 29 patients with strongly positive RARalpha was significantly worse than for the 86 patients with weak or undetectable levels of RARalpha (p = 0.0328). Strong RARalpha expression in oral SCCs was associated with a significantly worse disease-free survival, suggesting that RARalpha may serve as a prognostic indicator of poor clinical outcome. Further studies are warranted to determine its utility in identifying the subset of patients who would benefit from use of retinoids as adjuvant in chemotherapy or chemopreventive approaches.

Stromelysin-2 overexpression in human esophageal squamous cell carcinoma: potential clinical implications.

The degradation of the extracellular matrix (ECM) is a major step in the process of tumor invasion and metastasis, mediated by matrix metalloproteinases (MMPs). Knowledge of alterations in the expression of stromelysin-2 (ST-2) or MMP-10 in human esophageal squamous cell carcinoma (ESCC) is meager. Immunohistochemical analysis of ST-2 expression was carried out in surgically resected ESCCs (50 cases) and paired distal histologically normal esophageal tissues (50 cases), correlated with clinicopathological parameters. Overexpression of ST-2 protein, in tumor cell cytoplasm and stromal elements, was observed in 37 of the 50 (74%) ESCCs localized in tumor cell cytoplasm and stromal elements. Low levels of ST-2 were observed in 8 of the 50 (16%) matched histologically normal esophageal tissues. Significant associations were observed between ST-2 overexpression and tumor size (r = 0.02, P = 0.04), local invasiveness of the tumor (r = -0.30, P = 0.002) and distant organ metastasis (r = -0.227, P = 0.02), suggestive of its involvement in development and progression of ESCCs. The data underscore the significance of ST-2 expression in context to the aggressive tumor characteristics observed in ESCCs in the Indian population, wherein extremely poor prognosis has been ascribed to extensive local invasion and metastasis.

Pre and post eradication gastric inflammation in Helicobacter pylori-associated duodenal ulcer.

BACKGROUND: Distribution and nature of gastritis are major determinants of clinical outcome of H. pylori infection. The gastric inflammatory changes associated with this infection in developing countries have not been systematically studied. AIMS: To evaluate the inflammatory changes in gastric antrum and corpus in patients with duodenal ulcer and H. pylori infection, before and after H. pylori eradication therapy. METHODS: Histology and H. pylori density were studied in gastric biopsies obtained from 53 consecutive patients with active duodenal ulcer and H. pylori infection. Biopsies were obtained before and 4 weeks after H. pylori eradication therapy, from the anterior and posterior walls of the antrum and corpus, and were evaluated according to the Sydney system. RESULTS: In the pre-H. py/ori eradication antral biopsies, chronic gastritis, active gastritis, atrophy, intestinal metaplasia (IM) and lymphoid follicles / aggregates were seen in 53 (100%), 49 (92%), 11 (21%), 7 (13%) and 28 (53%) patients, respectively. In the corresponding biopsies from gastric corpus, these changes were seen in 49 (92%), 23 (43%), 2 (4%), 2 (4%) and 8 (15%), respectively. All changes except IM were significantly more frequent and of higher grade in the antrum. The grade of chronic gastritis was significantly higher in antrum than corpus; the frequency of gastritis in the antrum and corpus was similar (100% vs. 92%). H. pylori density was also higher in the antrum and correlated well with the grades of chronic gastritis and activity at both sites. Eradication of H. pylori was achieved in 39 patients (74%), and led to significant decrease in gastritis; no change was seen in patients who did not eradicate the organism. CONCLUSIONS: Antral-predominant chronic gastritis and activity are present in more than 90% of patients with H. pylori infection associated with duodenal ulcer, and the grade of gastritis correlates with the density of the organism. Eradication therapy results in improvement of both chronic gastritis and activity.