OBJECTIVEClosed-loop (CL) insulin delivery effectively maintains glucose overnight but struggles when challenged with meals. Use of single-day, 30-μg/meal pramlintide lowers meal excursions during CL. We sought to further elucidate the potential benefits of adjunctive agents after 3–4 weeks of outpatient dose titration.RESEARCH DESIGN AND METHODSTwo CL studies were conducted: one evaluating adjunctive pramlintide and the other liraglutide. Ten subjects (age 16–23 years; A1C 7.2 ± 0.6% [55 ± 6.6 mmol/mol]) completed two 24-h sessions: one on CL alone and one on CL plus 60-μg pramlintide (CL + P), after a 3–4-week outpatient dose escalation. Eleven subjects (age 18–27 years; A1C 7.5 ± 0.9% [58 ± 9.8 mmol/mol]) were studied before and after treatment with 1.8 mg liraglutide (CL + L) after a similar 3–4-week dose escalation period. Timing and content of meals during CL were identical within experiments; meals were not announced.RESULTSPramlintide delayed the time to peak plasma glucose (PG) excursion (CL 1.6 ± 0.5 h vs. CL + P 2.6 ± 0.9 h, P < 0.001) with concomitant blunting of peak postprandial increments in PG (P < 0.0001) and reductions in postmeal incremental PG area under the curve (AUC) (P = 0.0002). CL + L also led to reductions in PG excursions (P = 0.05) and incremental PG AUC (P = 0.004), with a 28% reduction in prandial insulin delivery. Outpatient liraglutide therapy led to a weight loss of 3.2 ± 1.8 kg, with a 26% reduction in total daily insulin dose.CONCLUSIONSAdjunctive pramlintide and liraglutide treatment mitigated postprandial hyperglycemia during CL control; liraglutide demonstrated the additional benefit of weight loss in an insulin-sparing manner. Further investigations of these and other adjunctive agents in long-term outpatient CL studies are needed.

OBJECTIVEAn integrated sensor-augmented pump system has been introduced that interrupts basal insulin infusion for 2 h if patients fail to respond to low-glucose alarms. It has been suggested that such interruptions of basal insulin due to falsely low glucose levels detected by sensor could lead to diabetic ketoacidosis. We hypothesized that random suspension of basal insulin for 2 h in the overnight period would not lead to clinically important increases in blood β-hydroxybutyrate levels despite widely varying glucose values prior to the suspension.RESEARCH DESIGN AND METHODSSubjects measured blood glucose and blood β-hydroxybutyrate levels using a meter each night at 9:00 p.m., then fasted until the next morning. On control nights, the usual basal rates were continued; on experimental nights, the basal insulin infusion was reprogrammed for a 2-h zero basal rate at random times after 11:30 p.m.RESULTSIn 17 type 1 diabetic subjects (mean age 24 ± 9 years, diabetes duration 14 ± 11 years, A1C level 7.3 ± 0.5% [56 mmol/mol]), blood glucose and blood β-hydroxybutyrate levels were similar at 9:00 p.m. on suspend nights (144 ± 63 mg/dL and 0.09 ± 0.07 mmol/L) and nonsuspend nights (151 ± 65 mg/dL and 0.08 ± 0.06 mmol/L) (P = 0.39 and P = 0.47, respectively). Fasting morning blood glucose levels increased after suspend nights compared with nonsuspend nights (191 ± 68 vs. 141 ± 75 mg/dL, P < 0.0001), and the frequency of fasting hypoglycemia decreased the morning following suspend nights (P < 0.0001). Morning blood β-hydroxybutyrate levels were slightly higher after suspension (0.13 ± 0.14 vs. 0.09 ± 0.11 mmol/L, P = 0.053), but the difference was not clinically important.CONCLUSIONSSystems that suspend basal insulin for 2 h are safe and do not lead to clinically significant ketonemia even if the blood glucose level is elevated at the time of the suspension.

Background Calcification occurs in 12–27% of hepatic colorectal metastases, but its clinical significance and its influence on prognosis are unknown. Methods All patients diagnosed with colorectal liver metastases at the Ottawa Regional Cancer Centre in 1991 (n = 97), as well as those enrolled in chemotherapy trials in 1990–1992 (n = 51), were entered into a retrospective cohort study. Thirty‐six patients were excluded due to inadequate follow‐up. In the remaining 112, abdominal CT scans and/or ultrasound examinations were used to determine the presence of calcification. Charts were reviewed for variables, including primary tumour pathology, amount of liver involvement by tumour (<25%, 25–50%, >50%), and the chemotherapeutic agents received, and were subjected to multivariate and regression analysis. End point was survival in months or to December 1993 (median follow up 24 months). Results Patients with calcification (n = 31) (28%) were compared to those who did not have calcifications (n = 81). The groups were comparable with respect to sex, age, time to calcification, time to metastases, and treatment type. Calcification occurred independent of the degree of tumour differentiation, the presence of mucinous adenocarcinoma, or the hepatic tumour burden. Nine patients with calcified metastases (30%) had calcification at presentation. Biopsies showed calcification next to viable tumour cells with an absence of an inflammatory reaction. Survival was improved with better primary tumour differentiation and less tumour burden. The presence of calcification had a statistically highly significant improvement in survival (P < 10−6, relative risk = .19) independent of other variables. Conclusions The presence of calcification within a colorectal liver metastasis appears to imply a significantly better prognosis. © 1996 Wiley‐Liss, Inc.

The objective of this study was to evaluate the effectiveness of a brief, office-based educational intervention to increase parent or patient recognition of the early warning signs and symptoms of diabetic ketoacidosis (DKA). Forty-two patients aged > 13 years and 34 parents of children aged 4 13 years were given a pretest questionnaire about their knowledge of signs and symptoms of DKA and sick day management practices. They received a brief refresher course on sick day management specific to their treatment modality (pump vs. injection) and were given a take-home flow sheet of guidelines for diabetes sick day management. Subjects were retested with the same knowledge questionnaire after 6 to 12 months. Patients or parents scored higher on the posttest than the pretest and called the emergency line for assistance more frequently (p ¼ .032) following the intervention. Emergency department visits were significantly reduced in adolescents (p ¼ .024). A short educational intervention and printed management tool is effective in improving sick day and DKA knowledge and appears to be effective in reducing emergency department visits by increasing utilization of a diabetes emergency line for early outpatient intervention.

Background: Calcification occurs in 12-27% of hepatic colorectal metastases, but its clinical significance and its influence on prognosis are unknown.Methods: All patients diagnosed with colorectal liver metastases at the Ottawa Regional Cancer Centre in 1991 (n = 97), as well as those enrolled in chemotherapy trials in [1990][1991][1992] (n = 51), were entered into a retrospective cohort study. Thirty-six patients were excluded due to inadequate follow-up. In the remaining 112, abdominal CT scans and/or ultrasound examinations were used to determine the presence of calcification. Charts were reviewed for variables, including primary tumour pathology, amount of liver involvement by tumour (<25%, 25-50%, >50%), and the chemotherapeutic agents received, and were subjected to multivariate and regression analysis. End point was survival in months or to December 1993 (median follow up 24 months). Results:Patients with calcification (n = 31) (28%) were compared to those who did not have calcifications (n = 8 1). The groups were comparable with respect to sex, age, time to calcification, time to metastases, and treatment type. Calcification occurred independent of the degree of tumour differentiation, the presence of mucinous adenocarcinoma, or the hepatic tumour burden. Nine patients with calcified metastases (30%) had calcification at presentation. Biopsies showed calcification next to viable tumour cells with an absence of an inflammatory reaction. Survival was improved with better primary tumour differentiation and less tumour burden. The presence of calcification had a statistically highly significant improvement in survival (P < Conclusions: The presence of calcification within a colorectal liver metastasis appears to imply a significantly better prognosis. 0 1996 Wiley-Liss, Inc. relative risk = .19) independent of other variables. ~_ _ _ _ _ _ _ _ _ _ _ _ _ _

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Introduction. Malignant mesothelioma is a rare cancer linked to asbestos exposure. It comes from the oncogenic transformation of mesothelioma cells, a protective membrane that covers several internal cavities including the pleura, peritoneum and pericardium. Malignant pleural mesothelioma (MPM) accounts for more than 90% of cases. The average survival of these patients is approximately 8 to 12 months, due to the resistance of tumors towards treatments. A well-known hallmark in cancer is tumor suppression gene inactivation. BAP1 is the most mutated gene in pleural mesothelioma (25-60%). BAP1 has a deubiquitinase activity involved in chromatin modifications, homologous recombination, DNA damage and programmed cell death. Moreover, hypoxia is an important microenvironment component within tumors, and it is demonstrated in patients with MPM. The bio-persistent localization of asbestos in mesothelioma cells has been shown to induce chronic inflammation that activates autophagic flux to survive. Autophagy is induced by several types of cellular stresses, including hypoxia. This suggests that MPM cells are dependent on autophagic flux when subjected to stress to ensure their continuity and proliferation. Hypothesis/Objectives. The hypothesis of this project is that MPM has vulnerabilities in the autophagy/lysosome process, which can thus be targeted by chemical inhibitors to improve treatment response and efficacy. The specific objectives are to i) examine autophagy flux in MPM cells with BAP1 mutations, ii) demonstrate autophagy modulation in MPM cells towards the hypoxic response, and iii) assess the potential for autophagy and lysosome inhibitors in MP cells with mutations on BAP1 or towards the hypoxic response. Methods/Results. To achieve this, molecular biology approaches are used to reintroduce (Gateway system), or repress (CRISRP/Cas9) the expression of BAP1 in Mero-25 and Mero-41 cells, respectively. Models were confirmed by western blot. The hypoxic chamber is used to manipulate cells in 1% O2, in which we confirmed the activation of autophagy in response to hypoxia in a kinetic timeframe of 24, 48 and 72hr. Subsequently, the autophagic flux was studied in presence of Bafilomycin A1 indicating an activation of this cellular process. The potential and cytotoxicity of autophagy or lysosome inhibitors will be evaluated by XTT and clonogenic assays. Conclusion. Malignant pleural mesothelioma has an unmet need in novel therapeutic strategies. Our studies could contribute to improve anticancer treatments using combinatory approaches that modulate autophagy. Citation Format: Chloe Michaud, Sandra Turcotte. Studying the autophagic flux in response to hypoxia in BAP1-mutated pleural mesothelioma cells linked to asbestos exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1379.