A 1-year follow-up study on checkpoint inhibitor-induced colitis: results from a European consortium.

BACKGROUND: Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis. MATERIALS AND METHODS: This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed. RESULTS: Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis. CONCLUSIONS: Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes.

Endorectal sonographic appearances of rectal MALT lymphoma, its response to therapy, and local recurrence.

Endorectal sonography may significantly help to evaluate rectal lymphoma. We report the sonographic findings in a case of rectal non-Hodgkin's MALT (mucosa-associated lymphoid tissue) lymphoma, including the monitoring of response to therapy and confirmation of recurrence, in a 45-year-old man. On endorectal sonography of the rectal wall, the mucosa was markedly thickened to 1.1 cm and was diffusely hypoechoic and risen into multiple polypoid folds. The submucosa and muscularis propria appeared normal. Multiple lymph nodes were visualized in the perirectal fat; they were homogeneously hypoechoic, were round or oval, and ranged from 1.0 cm to 2.6 cm. Endoscopic biopsies revealed a grade I non-Hodgkin's MALT lymphoma. Following chemotherapy, endorectal sonography showed that the surface of the rectal mucosa had a smoother appearance and near-normal thickness, but lymph nodes, although smaller, remained visible in the perirectal fat. Four months later, endorectal sonography demonstrated a local relapse of disease, with significant thickening of the rectal mucosa and multiple lymph nodes visible in the perirectal fat. Following high-dose chemotherapy for the recurrence, endorectal sonography demonstrated a near-normal appearance of the rectal mucosa.

Decline with age of the respiratory chain activity in human skeletal muscle.

Mitochondrial respiratory systems have been screened in 63 orthopaedic patients of age ranging between 17 and 91 years. The results show a statistically significant definite decrease with ageing of mitochondrial respiratory activity with pyruvate plus malate, succinate and ascorbate plus TMPD. This pattern is associated with an equally significant decrease with age of the enzymatic activity of complex I, II and IV. No significant decrease with age is, on the contrary, observed in the mitochondrial content of cytochromes a+a3, and c+c1. Preliminary Western blot analysis indicates an altered polypeptide pattern in cytochrome c oxidase. This study provides evidence for a decline with age of mitochondrial respiratory activity in human skeletal muscle, affecting complex I, II and IV.

Human osteoclast-like cells recognize laminin via an RGD independent mechanism.

Interactions between cells from human giant cell tumors of bone and the extracellular matrix protein laminin were studied. Cells were capable of recognizing this substratum via a RGD-independent mechanism. Recognition induces adhesion and spreading onto laminin. This protein triggered the release of cellular FN which in turn enhanced recruitment of the beta 1 chain-containing integrin receptor.

Long-term effects of eating sucrose on metabolic control of type 1 (insulin-dependent) diabetic outpatients.

The aim of the study was to investigate the effects of regularly eating a moderate amount of sucrose (30 g/day) in 12 type 1 (insulin-dependent, IDDM) diabetic outpatients in fair blood glucose and lipid control. Two diets, each lasting two months, were compared in a randomized cross-over study. The former was a high-carbohydrate high-fiber diet for diabetic patients with Italian alimentary habits, the latter had the same composition except that 30 g of sucrose replaced 30 g of complex carbohydrates with high glycemic index (bread). The two diets contained equal amounts of carbohydrates, proteins and lipids; the only difference being the contribution of oligosaccharides to total carbohydrates (22% vs 34%) and cholesterol amount. During the control diet, glycosylated hemoglobin was substantially unchanged in both control and sucrose diet periods (control diet: 6.91 +/- 0.29 (SE) vs 6.80 +/- 0.25%; sucrose diet: 6.75 +/- 0.31 vs 6.91 +/- 0.36%). This was true also for fructosamine (control diet: 3.92 +/- 0.21 vs 3.76 +/- 0.18%; sucrose 3.50 +/- 0.14 vs 3.64 +/- 0.20 mmol/l). Circulating blood lipid levels, body weight and daily insulin dose did not show any significant variations during the study. Moderate amounts of sucrose may be allowed to IDDM patients with Italian alimentary habits without worsening diabetic control.

Podosome expression in osteoclasts: influence of high extracellular calcium concentration.

In this study the effect of high extracellular calcium concentration has been evaluated, by immunofluorescence, on podosome expression in chicken osteoclasts. Cells were cultured in presence of 0.2 and 4 mM calcium for 90 minutes and microfilaments were detected, after fixation and permeabilization, by decoration with rodhamine conjugated phalloidin. Results showed that increased extracellular calcium concentration induces the inhibition of podosome expression indicating that these close-contact areas are capable of calcium-mediated regulation.

Cytoplasmic pH is regulated in isolated avian osteoclasts by a Cl-/HCO3- exchanger.

Osteoclast resorb bone in an acid compartment formed by the bone-attachment site. The low pH of the resorption compartment provides a lysosome-like milieu suitable for acid proteases to degrade collagen. Solubilization of the hydroxyapatite that makes up bone mineral consumes about 2 moles of protons per moles of calcium dissolved, requiring a massive proton flux to maintain a low pH in the resorption compartment. In order to determine how the osteoclast maintains a physiological cytoplasmic pH while secreting massive amounts of acid, we studied the intracellular pH of osteoclasts using esterified fluorescein derivatives while controlling the electrolyte composition of the medium. The principal finding is that osteoclasts have a high capacity for chloride/bicarbonate exchange which enables them to maintain normal intracellular pH in the face of a large loading of base equivalents. Thus, the overall process of proton secretion during bone resorption is similar to the polarized acid elimination by renal epithelia, involving a proton pump on one surface of the cell, and a Cl-/HCO3- exchange to maintain cytoplasmic pH.

Hyperglycemic effect of sucrose ingestion in IDDM patients controlled by artificial pancreas.

The hyperglycemic effect of 28 g sucrose, taken during a mixed meal, was studied in six insulin-dependent diabetes mellitus (IDDM) patients controlled by artificial pancreas. On 2 consecutive days the patients were given, in random order, two Italian meals containing macaroni, bread, meat, vegetables, fruit, olive oil, and an eggnog made with sucrose (meal A) or saccharin (meal B). The two meals were isocaloric and contained equal amounts of carbohydrates. The feedback control on blood glucose continued for 180 min after the meals. Plasma glucose levels and insulin infusion rates delivered by the artificial pancreas after the two test meals did not show any significant differences regarding basal and peak values, peak times, and areas under the curves. A modest amount of sucrose, taken during a mixed meal, does not produce a hyperglycemic effect higher than an equal amount of complex carbohydrates in IDDM patients controlled by artificial pancreas. The same may be expected in well-controlled IDDM patients in conventional therapy because a correlation exists between insulin requirement for conventional therapy and insulin delivered during glucose-controlled insulin infusion.

Possible effectiveness of plasmapheresis and immunosuppressive therapy in reversing subcutaneous insulin resistance: a case report.

Severe resistance to subcutaneous insulin with normal sensitivity to intravenous insulin developed in a 39 year old woman affected by type 1 diabetes mellitus. The patient had been treated for ten months with continuous intravenous or intraperitoneal insulin before undergoing pancreatic transplantation. After surgery repeated plasmapheresis were performed and immunosuppressive therapy was undertaken. When studied again, one month after surgery, the patient showed normal sensitivity to subcutaneous insulin. Our data suggest that plasmapheresis and/or immunosuppressive treatment could have played a role in reversing insulin resistance.

Effects of mixing short- and intermediate-acting insulins on absorption course and biologic effect of short-acting preparation.

The effects of mixing short- and intermediate-acting insulins (Actrapid MC and Monotard MC) were studied in seven diabetic patients. On different days, 0.16 IU/kg of Actrapid and 0.24 IU/kg of Monotard were administered to each subject in separate injections and combined in the same syringe. Free-insulin curves and the biologic effect of insulin, assessed by the glucose-clamp technique, were compared. The absorption rate of regular insulin was higher when injected separately from the intermediate-acting preparation: the incremental areas of free insulin above basal levels, up to 90 min after the administration of the hormone, were 32 +/- 5 vs. 21 +/- 3 microU X ml-1 X min-1 (P less than .02). In the same period, glucose infused to sustain glycemia showed no significant differences (2.8 +/- 0.4 vs. 2.4 +/- 0.3 mg X kg-1 X min-1 after the administration of insulin in separate and combined injection, respectively). The difference in insulin profiles is not translated into a significant difference in glucose requirement. This might be a consequence of a flattening of the insulin dose-response curve due to insulin resistance of diabetic subjects. The slight delay in insulin action of Actrapid when mixed with Monotard is probably irrelevant in clinical practice.