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Nine patients (seven females, two males) with chronic watery diarrhea and nonspecific colonic mucosal inflammation followed for 1-5 yr are presented. Eight were diagnosed as having collagenous colitis on the basis of marked thickening of the subepithelial collagen layer in at least one set of biopsies. The thickness of the collagen table varied with time in all eight cases. When thickening was minimal, morphological features were indistinguishable from microscopic colitis, signifying that, in most cases, collagenous colitis and microscopic colitis are part of the same spectrum of colonic mucosal response. One of the eight patients had documented collagenous colitis and gluten-associated enteropathy for 12 yr. The colitis and duodenal histology improved synchronously when a gluten-free diet and corticosteroids were administered. The ninth patient had microscopic colitis and enteropathy which did not respond to gluten withdrawal. This patient never exhibited thickening of subepithelial collagen in repeated biopsies over 5 yr, suggesting that an entity of microscopic colitis may exist independent of collagenous colitis. Duodenal mucosal biopsies showed normal histology in four other patients with collagenous colitis. The histological variability of collagenization and inflammation during the course of collagenous colitis and microscopic colitis and the clinical feature of watery diarrhea suggest that these two entities be grouped together as the watery diarrhea-colitis syndrome. [ABSTRACT FROM AUTHOR]

Background: Interleukin-12 (IL-12) and interleukin-23 (IL-23) are inflammatory cytokines linked to the Th-1 and Th-17 phenotypes associated with Crohn's disease (CD). We investigated the activity and safety of apilimod mesylate (formerly STA-5326), an oral IL-12 and IL-23 inhibitor, in patients with active CD., Methods: We performed a multicenter, Phase 2, randomized, double-blinded, placebo-controlled study to evaluate the efficacy of apilimod mesylate in treating 220 adult patients with moderate-to-severe CD (Crohn's Disease Activity Index [CDAI] score 220-450). Patients were stratified according to C-reactive protein (CRP) levels and corticosteroid use and were randomly assigned to receive placebo or apilimod mesylate 50 mg daily or 100 mg daily. The study was divided into an induction phase (43 days) and a maintenance phase (125 days). The primary analysis involved a comparison of the proportion of patients experiencing clinical response, defined as at least a 100-point decrease in CDAI score from baseline at day 29. Data on adverse events were also collected., Results: In all, 220 of the planned 282 patients were enrolled when the Data Monitoring Committee determined that the drug was not efficacious as a treatment and closed enrollment. A clinical response was experienced by 18 patients (24.7%) in the 50-mg daily (QD) group (n = 73) and 19 patients (25.7%) in the 100 mg QD group (n = 74), as compared with 21 patients (28.8%) in the placebo group (n = 73) on day 29 (P = 0.71 for each comparison). No significant adverse safety signal was observed., Conclusions: Apilimod was well-tolerated but did not demonstrate efficacy over placebo in patients with active CD.

The Adenoma Prevention with Celecoxib Trial examined the efficacy and safety of the cyclooxygenase (Cox)-2 inhibitor, celecoxib, for sporadic colorectal adenoma prevention in patients at high risk for colorectal cancer. The trial randomized 2,035 subjects to receive either placebo, celecoxib 200 mg twice daily, or celecoxib 400 mg twice daily. The primary study safety and efficacy analyses involved 3 years of treatment. The results showed significant antitumor effect but also indicated increased cardiovascular adverse events in patients treated with celecoxib compared with placebo. A total of 933 patients participated in an extension of the Adenoma Prevention with Celecoxib Trial, with a planned total treatment and surveillance duration of 5 years. Study medication was stopped early, resulting in a median treatment duration of 3.1 years for those with a year 5 colonoscopy. Patients treated on the placebo arm had a cumulative adenoma incidence of 68.4% over 5 years of observation. This figure was 59.0% (P < 0.0001) for those receiving low-dose celecoxib, and 60.1% (P < 0.0001) for those receiving high-dose celecoxib. The cumulative incidence of advanced adenomas over 5 years was 21.3% of those taking placebo, 12.5% (P < 0.0001) of those taking low dose celecoxib and 15.8% (P < 0.0001) of those taking high-dose celecoxib. Investigator reported treatment emergent adverse events were similar across all treatment groups for categories including renal and hypertensive events and gastrointestinal ulceration and hemorrhage events. For a category composed of cardiovascular and thrombotic events, the risk relative to placebo was 1.6 (95% confidence interval, 1.0, 2.5) for those using 200 mg twice daily celecoxib and 1.9 (95% confidence interval, 1.2, 3.1) for those using 400 mg twice daily celecoxib. Secondary analysis showed an interaction between a baseline history of atherosclerotic heart disease and study drug use with respect to cardiovascular and thrombotic adverse events (P = 0.004). These results confirm the inhibitory effect of celecoxib on colorectal adenoma formation, and provide additional safety data indicating an elevated risk for cardiovascular and thrombotic adverse events, particularly for patients with preexisting atherosclerotic heart disease.

Background: Studies showing that drugs that inhibit cyclooxygenase-2 (COX-2) reduce the number of colorectal adenomas in animals and patients with familial adenomatous polyposis suggest that COX-2 inhibitors may also prevent sporadic colorectal neoplasia., Methods: We randomly assigned patients who had adenomas removed before study entry to receive placebo (679 patients) or 200 mg (685 patients) or 400 mg (671 patients) of celecoxib twice daily. Randomization was stratified for the use of low-dose aspirin. Follow-up colonoscopies were performed at one and three years after randomization. The occurrence of newly detected colorectal adenomas was compared among the groups with the life-table extension of the Mantel-Haenszel test., Results: Follow-up colonoscopies were completed at year 1 in 89.5 percent of randomized patients, and at year 3 in 75.7 percent. The estimated cumulative incidence of the detection of one or more adenomas by year 3 was 60.7 percent for patients receiving placebo, as compared with 43.2 percent for those receiving 200 mg of celecoxib twice a day (risk ratio, 0.67; 95 percent confidence interval, 0.59 to 0.77; P<0.001) and 37.5 percent for those receiving 400 mg of celecoxib twice a day (risk ratio, 0.55; 95 percent confidence interval, 0.48 to 0.64; P<0.001). Serious adverse events occurred in 18.8 percent of patients in the placebo group, as compared with 20.4 percent of those in the low-dose celecoxib group (risk ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P=0.5) and 23.0 percent of those in the high-dose group (risk ratio, 1.2; 95 percent confidence interval, 1.0 to 1.5; P=0.06). As compared with placebo, celecoxib was associated with an increased risk of cardiovascular events (risk ratio for the low dose, 2.6; 95 percent confidence interval, 1.1 to 6.1; and risk ratio for the high dose, 3.4; 95 percent confidence interval, 1.5 to 7.9)., Conclusions: These findings indicate that celecoxib is an effective agent for the prevention of colorectal adenomas but, because of potential cardiovascular events, cannot be routinely recommended for this indication. (ClinicalTrials.gov number, NCT00005094 [ClinicalTrials.gov].)., (Copyright 2006 Massachusetts Medical Society.)

Impaired gallbladder emptying has been associated with gallstone disease but any effect on or from bile acid therapy for gallstone dissolution is unknown. We evaluated gallbladder filling and emptying with low-dose cholecystokinin infusion (0.02 U/kg.h) by computer-assisted cholescintigraphy in 52 controls versus 31 gallstone patients: 17 treated with 12-15 mg/kg.day of chenodeoxycholic acid and 14 with 8-10 mg/kg.day of ursodeoxycholic acid. Thirteen of 31 patients with complete dissolution had four scans: before, after 3 mo of therapy, after stone dissolution, and after discontinuation of bile acids. The 18 failures had three scans: before and after 3 and 15-18 mo of therapy. Before therapy, the 31 gallstone patients had significantly impaired gallbladder emptying compared with controls, but filling was not decreased. Bile acids significantly decreased emptying in both treatment groups after 3 mo of therapy. In the dissolution group, emptying improved once the stones had dissolved and increased further upon discontinuing the bile acids. In the failures, impaired emptying persisted for up to 15-18 mo. Gallbladder filling in the 31 gallstone patients was also significantly decreased after 3 mo of bile acid therapy, particularly in the failure patients, 5 of whom exhibited zero filling. No differences were detected between ursodeoxycholic acid and chenodeoxycholic acid for either gallbladder function or efficiency of dissolution. Thus, bile acid therapy impairs gallbladder filling and emptying in gallstone patients. Gallstone dissolution improves emptying, which is further enhanced when bile acids are discontinued.

Using the fluorescence technique the presence of various immunoglobulin classes (IgG, IgA, IgM) was determined on the surface of peripheral blood lymphocytes obtained from healthy subjects (10 cases) and from patients with chronic lymphatic leukaemia (65 cases). In the investigations the effect of treatment and clinical course on the values of these parameters was taken into consideration. Nearly in all cases of this leukaemia the percent of lymphocytes binding immunoglobulins on their surface was raised in comparison with the lymphocytes of healthy subjects. Presence of one or more classes of immunoglobulins was demonstrated on the surface of leukaemic lymphocytes.

Using the biological test on rats the thrombocytopoietic activity (AT) was determined in sera of 13 patients with idiopathic thrombocytopenia (ITP), 5 patients with pancytopenia and bone marrow hypoplasia, 18 with thrombocytopenia developing during proliferative diseases of the haemopoietic system, and 4 patients with erythremia vera. A high mean thrombocytopoietic activity was demonstrated in ITP and this high activity was accounted for by significantly raised AT in acute thrombocytopenia. Increased AT was observed also in myeloproliferative syndromes associated with thrombocytopenia, while in pancytopenia with bone marrow hypoplasia and in erythremia vera AT seemed not increased independently of the stage of the disease. Greater number of cases will be necessary for drawing reliable conclusions.

Three enzymes concerned in purine degradation, 5'nucleotidase (5'NT), adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) have been measured biochemically in the bone marrow or peripheral blood blasts from 75 patients with acute leukaemia, from 18 patients with blast crisis of chronic granulocytic leukaemia and in the bone marrow and peripheral blood lymphocytes from 14 normal donors. Characteristic patterns among the different sub-types of acute leukaemia have been detected, with high ADA, low 5'NT and PNP in Thy-ALL, high 5'NT and ADA in c-ALL, high PNP and low ADA in AML. The cells in CGL blast transformation resembled the enzymatic pattern of either AML or c-ALL respectively. However, no significant correlation was found between any pair of enzymes in any group of leukaemia, normal bone marrow or peripheral blood lymphocytes studied here.

Rats were given selected doses of rabbit antiplatelet serum (APS) inducing after 6 hours thrombocytopenia at the level of 14% of the initial platelet count followed by a gradual rise in this count (after 12, 24 and 48 hours). Eight hours after APS administration the rats were given transfusion of a concentrate containing 1-2 X 10(9) fresh allogenic platelets (group A) or the same number of previously frozen platelets (group B). Rats receiving no concentrate after APS administration (group C) and rats receiving neither APS nor concentrate (group D) served as controls. Using a bioassay on mice the serum thrombocytopoietic activity (ATS) was determined in the rats and the platelet count was measured by the direct method. These determinations were done before and 24 and 48 hours after the experiment. It was shown that after 24 hours the values of the platelets (p less than 0.1) and ATS (p less than 0.001) were lower in group B than in the remaining groups. This suggests an inhibitory effect of the frozen concentrate on the ATS. After 24 hours the platelet count was highest in group A, and after 48 hours in group C, which suggests that transfusion of fresh concentrate has an immediate effect but in a later phase it inhibits spontaneous mechanisms effacing the thrombocytopenic effect.

Thrombocytopoietic activity (ATS) was determined in tests on mice on the day before and on the 1st, 7th, and 14th days after splenectomy in 18 patients (13 with idiopathic thrombocytopenia, 5 with haemolytic anaemia). It was found that in patients with ITP and high-grade splenic destruction of platelets ATS increased on the first days after splenectomy. On the other hand, in ITP patients with low-grade splenic platelet destruction splenectomy decreased the value of ATS immediately after the operation. Splenectomy performed in cases with normal platelet count caused no greater changes in ATS in the first week. These observations suggest that in patients with increased splenic destruction of platelets ATS may be inhibited and this inhibition may be removed after splenectomy. Absent correlation between ATS and platelet count may indicate that the value of ATS is not of decisive importance in thrombocytopenia regression following splenectomy.

In 40 cases of Hodgkin's disease (24 untreated patients and 16 patients in remission) the immunological humoral and cell-mediated competence was studied using test of hypersensitivity of DNCB and PPD, blastic transformation and the ability of 3H-DNA synthesis in lymphocytes stimulated with PHA and PWM, and in some cases, with PPD. In all patients the concentration of serum immunoglobulins was determined as well. Impairment of immunological reactivity was found in about 40% of patients, on the average, in various stages of the disease and during remissions following treatment with cytostatic agents and radiotherapy. The most frequent abnormality found in 52.5% of cases was impairment of blastic transformation of lymphocytes stimulated with PHA in vitro. In 60% of cases negative results of intradermal test with PPD and in 75% of patients the DNCB test was negative. No correlation could be found between impairment of the immune competence in this disease and the clinical stage and/or type of histological changes in lymph nodes.

By means of a bioassay performed in rats utilizing 75Se-selenomethionine as a platelet marker in vivo, serum thrombocytopoietic activity (STA) was determined in 9 healthy volunteers and in 82 patients with thrombocytopenia, viz. 27 cases of ITP (9 acute and 18 chronic), 19 of aplastic anaemia, 19 of acute leukaemia and 17 of chronic proliferative disorders. STA was the highest in the ITP group (p less than 0.01), particularly in the cases of short duration (p less than 0.001). In acute leukaemia, the STA was remarkably elevated (p less than 0.02) and a negative correlation between STA and blood platelet count could be demonstrated. A negative correlation between STA and the duration of thrombocytopenia was also found in the patients with ITP. No significant increase of STA was observed in patients with ITP after corticosteroid administration. In 5 out of 7 cases who responded satisfactorily to splenectomy a significant fall of STA was demonstrated after surgery. A slight, but statistically significant, rise of the STA value was found in patients with aplastic anaemia (p less than 0.05). No STA elevation was observed in the cases of chronic proliferative disorders with thrombocytopenia.

The clinical course of 38 patients with Hodgkin's disease in the stage of remission was evaluated. The material consisted of two groups of patients: 1. submitted to immunotherapy and 2. control group. In 16 cases immunostimulation was performed with BCG vaccine, including four cases treated with BCG vaccine and levamisole and 3 patients were given levamisole only. In some patients, immunotherapy restored normal immunologic reactivity, as shown by the reversion of negative tests of delayed hypersensitivity. In all patients treated with levamisole caused normal blastic transformation of PHA-stimulated lymphocytes. In the group of patients treated with immunotherapy relapses of malignant lymphogranulomatosis were observed in 10.6% of cases, and in the control group--in 15.7%. The patients of both groups remain under continuous clinical surveillance.

Ecto-5'nucleotidase (5'NT), adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP) and deoxycytidine (CdR), deoxyguanosine (GdR), deoxyadenosine (AdR) and adenosine (AR) kinases have been measured in subpopulations of peripheral blood lymphocytes of eight healthy volunteers. The separation of B, T, T helper/inducer and T suppressor/cytotoxic cells was performed by means of density gradient centrifugation, E rosetting, passage through a nylon-wool column and antibody affinity chromatography utilising OKT8 and OKT4 monoclonal antibodies. ADA was significantly higher in T lymphocytes and 5'NT in B lymphocytes. Among T cell subpopulations, 5'NT activity was significantly higher (P less than 0 . 01) in T suppressor/cytotoxic (OKT8+) cells (32 . 9 units/10(6) cells than in T helper/inducer (OKT4+) cells (9 . 7 units/10(6) cells). Indeed, the 5'NT activity in T suppressor cells was similar to that in B cells. T helper cells tended, however, to have higher PNP and ADA activities than T suppressor cells but the differences were not statistically significant. No major differences were noted in kinase activities between any of the lymphocyte subpopulations.

Ninety-seven patients with autoimmune haemolytic anaemia were observed in the period between 1965 and 1979. Corticosteroids were found to be more effective in the acute phase of haemolysis (68.6%) than in the prolonged treatment (35%). Favourable results with combined treatment (corticosteroids plus azathioprine or cyclophosphamide) were achieved in 60.5% of patients, while the therapeutic potency of corticosteroids alone was 18.6%. Splenectomy was effective in 81% of the patients. No correlation between postsplenectomy results and spleen to liver radioactivity ratio was observed.

A case of a 72-year-old male with a leiomyosarcoma of the inferior vena cava causing Budd-Chiari syndrome is described. Percutaneous decompression of the portal system was attempted but with no success. At autopsy, a large tumor arising from and completely obstructing the inferior vena cava was found, histologically proven to be a leiomyosarcoma. Over 50 cases of leiomyosarcoma of the inferior vena cava have been reported in the literature, the majority of which occurred in women and 1/3 of which were associated with the Budd-Chiari syndrome. Histologically up to two mitotic figures per 10 high power fields have been scored. This case indicates the unreliability of a low mitotic index as an indicator of benign behavior of smooth muscle neoplasms of the venous system.

A medification of the previously described method of thrombocytopoietic activity (ATS) determination is reported using mouse instead of rats as laboratory animals. This makes possible to reduce significantly the volume of blood necessary for ATS determination. The error of the method was 8.6--11.6% when the results were calculated in impulses per 1 mg of platelet protein (imp/mg BP) and 5.5--9.2% when presented as a percentage of total activity adsorbed to the platelets.

The authors present a method of determination of the activity of the thrombocytopoietic factor (AT) by means of biological test on rats using 75-Se-selenomethionine for in vivo labelling of platelets. For suppression of endogenous thrombocytopoiesis the rats received antiplatelet rabbit serum which was used for investigations in the period of reactive hyperthrombocytosis. The thrombocytopoietic activity was expressed in radioactivity impulses per 1 mg of platelet protein of rats which permitted to eliminate the error-fraught determination of platelet count. A statistically significant rise in the thrombocytopoietic activity was demonstrated in rabbits with experimental thrombocytopenia as compared with the AT in healthy rabbits. The error of the method was 9.6-9.8 percent (P less than 0.05).