Asymptomatic colorectal cancer detected by screening

PURPOSE: Colorectal cancer screening has become prevalent. To discuss the efficacy of screening, we studied the characteristics of asymptomatic Colorectal cancer detected by screening. METHODS: This is a retrospective review of patients with colorectal cancer treated at our institution. During the past 20 years, 96 of 1,046 cases of colorectal cancer were asymptomatic and detected by screening. Sixty-one of these cases were detected in the recent five years. The initial screening procedures were fecal occult blood test in 51 cases, sigmoidoscopy or colonoscopy in 18, barium enema in 9, and other tests in 18. RESULTS: Thirteen lesions (14 percent) were smaller than 1.0 cm and 32 (33 percent) were 1–2 cm in size. There were 34 Tis, 21 T1, and 8 T2 tumors. Of the 55 Tis or T1 lesions, 14 showed nonpolypoid growth (5 flat-elevated, 7 flat-elevated with depression, 1 flat, 1 depressed), and 12 of these were detected on endoscopy. Thirty-four cases were TNM Stage 0, 25 were Stage I, 16 were Stage II, 12 were Stage III, and 9 were Stage IV. Sixty-one percent of those detected by screening were in either Stage 0 or Stage I compared with 16 percent in the symptomatic group. Cumulative five-year disease-free survival rates were 100 percent for both Stage 0 and Stage I, 94 percent for Stage II, and 52 percent for Stage III. Overall cumulative five-year survival rate was 87 percent for those detected by screening, compared with 57 percent in symptomatic patients. CONCLUSIONS: Asymptomatic cancers detected by screening were at a less advanced stage. In particular, many nonpolypoid early cancers were detected by endoscopic screening.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Montreal, Quebec, Canada, May 7 to 12, 1995.     

Noc2 is essential in normal regulation of exocytosis in endocrine and exocrine cells

Rab3 is a subfamily of the small GTP-binding protein Rab family and plays an important role in exocytosis. Several potential effectors of Rab3, including rabphilin3 and Rims (Rim1 and Rim2), have been isolated and characterized. Noc2 was identified originally in endocrine pancreas as a molecule homologous to rabphilin3, but its role in exocytosis is unclear. To clarify the physiological function of Noc2 directly, we have generated Noc2 knockout (Noc2(-/-)) mice. Glucose intolerance with impaired insulin secretion was induced in vivo by acute stress in Noc2(-/-) mice, but not in wild-type (Noc2(+/+)) mice. Ca(2+)-triggered insulin secretion from pancreatic isles of Noc2(-/-) mice was markedly impaired, but was completely restored by treatment with pertussis toxin, which inhibits inhibitory G protein Gi/o signaling. In addition, the inhibitory effect of clonidine, an alpha(2)-adrenoreceptor agonist, on insulin secretion was significantly greater in Noc2(-/-) islets than in Noc2(+/+) islets. Impaired Ca(2+)-triggered insulin secretion was rescued by adenovirus gene transfer of wild-type Noc2 but not by that of mutant Noc2, which does not bind to Rab3. Accordingly, Noc2 positively regulates insulin secretion from endocrine pancreas by inhibiting Gi/o signaling, and the interaction of Noc2 and Rab3 is required for the effect. Interestingly, we also found a marked accumulation of secretory granules in various exocrine cells of Noc2(-/-) mice, especially in exocrine pancreas with no amylase response to stimuli. Thus, Noc2, a critical effector of Rab3, is essential in normal regulation of exocytosis in both endocrine and exocrine cells.     

Factors affecting the prognosis of patients with hepatocellular carcinoma invading the portal vein--a retrospective analysis using 952 consecutive HCC patients

BACKGROUND/AIMS: Hepatocellular carcinoma with portal venous invasion has a very poor prognosis. The aim of this study is to clarify the factors contributing to the survival of hepatocellular carcinoma patients with portal venous invasion. METHODOLOGY: Out of 952 patients with hepatocellular carcinoma admitted to Tokyo University hospital and its affiliated hospitals from 1987 to 1999, 53 patients developed portal venous invasion until December 2000. The main portal vein was invaded in 33 patients, and the first branch was invaded in the 20 patients. The factors contributing to the prognosis of hepatocellular carcinoma patients with portal venous invasion were determined by univariate and multivariate analyses using 19 clinicopathological parameters. RESULTS: Overall survival rates of the 53 patients at 6 months, and 1 and 2 years were 40%, 18%, and 12%, respectively. Univariate analysis indicated that the serum albumin level, Child classification, number of tumor foci, portal venous invasion-targeted irradiation, and percutaneous tumor ablation of the parenchymal main tumor were significant. Multivariate analysis showed that percutaneous tumor ablation (P = 0.033; risk ratio = 0.28) was the most important factor contributing to a favorable prognosis followed by number of tumor foci (P = 0.048; risk ratio = 0.41). CONCLUSIONS: This study showed the significance of treatment for the parenchymal main tumor in addition to portal venous invasion in patients with hepatocellular carcinoma involving portal venous invasion. Therefore, the efficacy of combined therapy using portal venous invasion-targeted irradiation and percutaneous tumor ablation for the parenchymal main tumor on survival of hepatocellular carcinoma patients with portal venous invasion is suggested.     

Differential regulation of gene expression and insulin-induced activation of phosphodiesterase 3B in adipocytes of lean insulin-resistant IRS-1 (-/-) mice

Phosphodiesterase (PDE) 3B, a major isoform of PDE in adipocytes, mediates the antilipolytic action of insulin. PDE3B gene expression is generally reduced in adipocytes of either monogenic or polygenic rodent models of obese, insulin-resistance. An increased fat cell size, a common feature of obesity, could account for this reduction. Insulin receptor substrate-1 (IRS-1) (-/-) mice are lean with a reduced fat cell size and have insulin resistance due to a primary defect of insulin signaling. To determine whether the regulation of PDE3B gene expression is correlated with fat cell size, we examined this gene expression in adipose tissues of IRS-1 (-/-) mice. In IRS-1 (-/-) mice, PDE3B mRNA and protein levels were increased 1.24- and 1.35-fold those in C57BL/6J control mice, respectively. Independently, the fold induction of PDE activity by insulin (insulin-induced/basal) was 1.7-fold in control mice, but was reduced to 1.35-fold in IRS-1 (-/-) mice. Thus, PDE3B gene expression may be inversely correlated with a fat cell size, whereas insulin-induced PDE3B activation is mediated through IRS-1.     

Leukemic relapse in the central nervous system after allogeneic stem cell transplantation with complete remission in the bone marrow and donor-type chimerism: report of two cases

We studied two cases with leukemia that relapsed in the central nervous system (CNS) after allogeneic stem cell transplantation. One patient underwent peripheral blood stem cell transplantation (SCT) from a related, yet haplotype-mismatched, donor for chronic myelomonocytic leukemia. She was kept in complete remission (CR) in the bone marrow (BM) for 7 months, until relapse in the cerebrospinal fluid (CSF) was evident. In the other patient, with acute lymphoblastic leukemia, systemic relapse occurred when he was still on immunosuppression 6 months after SCT from an unrelated donor. After induction chemotherapy following cessation of immunosuppression, the BM examination proved CR. During consolidation chemotherapy, however, he developed leukemic dissemination in the CSF, despite the fact that the BM was in CR. Chimerism status in the BM mononuclear cells and fractionated peripheral blood (PB) cells (granulocytes, T-lymphocytes, and the others) was assessed by short tandem repeat analysis. In both patients, the BM cells and all the fractions of the PB cells proved donor-type chimeras. These results seem to suggest that the graft-versus-leukemia effects might not be as effective in the CNS as in the BM, even when complete T-lymphoid chimerism is achieved.     

Bile flow in a mutant Sprague-Dawley rat with defective biliary excretion of glutathione

The Eisai hyperbilirubinemic rat is a mutant strain of Sprague-Dawley origin with hereditary defects in the biliary excretion of bilirubin glucuronide, glutathione, and several other organic anions. The correlation between bile flow and bile acid excretion rates during taurocholate infusion revealed that bile acid-independent flow was smaller in the mutant than in intact Sprague-Dawley rats (19.3 vs 56.0 μl/kg per min), while bile acid-dependent flow was similar. The correlation between bile flow and glutathione excretion rates in Sprague-Dawley rats with modified hepatic glutathione levels revealed that a certain portion of bile flow was proportional to the biliary excretion of glutathione, with a coefficient of 551 bile per 1 mol glutathione. One-third of bile acid-independent bile flow in intact Sprague-Dawley rats was accounted for by glutathione osmosis, which feature was absent in the mutant rats.     

A prospective and comparative cohort study on efficacy and drug resistance during long-term lamivudine treatment for various stages of chronic hepatitis B and cirrhosis

Background and Aims: A prospective , non‐randomized cohort study on long‐term lamivudine treatment , comparing efficacy, drug resistance, and prognosis for various stages of chronic hepatitis B virus (HBV)–related liver disease was performed to elucidate the significance and indication of lamivudine for individual patients at each stage of disease. Methods: A total of 158 cases consisting of 87 chronic hepatitis, 28 compensated cirrhosis, and 43 decompensated cirrhosis, with serum HBV‐DNA > 5 log₁₀ copies/mL and with elevated alanine aminotransferase (ALT) over twice the upper normal limit or complications of hepatic insufficiency, were administered 100 mg of lamivudine daily and monitored for HBV markers, biochemistry, and prognosis. Results: Lamivudine reduced HBV‐DNA and ALT equally in all groups. Serum albumin, prothrombin time (%), and platelet count increased in all groups. The increased margin of albumin was the highest in the decompensated cirrhosis and higher in the compensated cirrhosis than the chronic hepatitis groups. Cumulative incidence of virologic breakthrough was 16%, 42%, 49%, and 53% at 12, 24, 36, and 48 months, respectively, and the strongest predictive factor for lamivudine resistance was persistent HBV‐DNA at 3 months. Ascites, encephalopathy, and jaundice improved in the majority of patients with decompensated cirrhosis. On the other hand, hepatic failure developed or deteriorated in 10 patients after virologic breakthrough, and nine of them had decompensated cirrhosis. Conclusions: Lamivudine was effective in reducing HBV‐DNA and improving hepatic reserve at all stages and was most beneficial and significant for decompensated cirrhosis. Meanwhile, close monitoring of viral load and immediate rescue treatment for lamivudine resistance is necessary to prevent hepatic failure in decompensated cirrhosis.     

Enhancement of endotoxin activity by muramyldipeptide

Synthetic muramyldipeptide (MDP), the minimum structural moiety of bacterial peptidoglycan for adjuvant and related activities, sensitized mice for two types of lethal shock induced by lipopolysaccharide (LPS): an early anaphylactoid shock and late endotoxin shock. In relation to the late reaction in MDP-primed mice, enhanced production of inflammatory cytokines was induced in response to various bacterial components. MDP showed a priming effect in mice not only when administered parentally but also via the oral route. MDP activated human monocytic THP-1 cells in a CD14-, Toll-like receptor 2 (TLR2)- and TLR4-independent manner to increase expression of MyD88, a common adaptor and signaling molecule for TLRs, and exhibited synergistic cytokine inducing effects with TLR4 agonists (LPS, synthetic lipid A), TLR2 agonist (synthetic lipopeptide), and TLR9 agonist (bacterial CpGDNA) in THP-1 cells in culture. Consistent with these findings, MDP primed TLR2 knockout mice as well as wild-type controls, but not TLR4-mutated C3H/HeJ mice, to enhance production of tumor necrosis factor-alpha upon stimulation with synthetic lipid A. In contrast to the BCG- and Propionibacterium acnes-priming system, MDP primed mice in an interferon-gamma-independent manner. Further studies are required to elucidate the mechanisms of the synthetic and priming activities of MDP for various bacterial components.     

Rectal submucosal tumor-like lesion originating from intestinal tuberculosis

We present the case of a 55-year-old man who underwent transsacral local excision for a rectal submucosal tumor-like lesion suspected to originate from tuberculosis. The lesion, 2 cm in size, was found incidentally in the posterior wall of the lower rectum during anal fistulectomy. The lesion was apart from the primary crypt of the anal fistula. Barium enema and colonoscopy revealed a protuberant submucosal growth with a shallow depression of the overlying mucosa. Although computed tomography and magnetic resonance imaging showed a well defined round mass within the rectal wall, digital rectal examination suggested extramural origin. Since repeated endoscopic biopsies were negative, we selected the transsacral approach for excisional biopsy to achieve histological diagnosis. The lesion was confined to the rectal wall and the full-thickness rectal wall was excised. Histologically, a foreign-body granuloma with acute inflammation was the main component of the lesion. Caseating granulomas and Langhans' giant cells, consistent with tuberculosis, were also found.