Patient-reported outcome (PRO) results from the AGITG DOCTOR trial: a randomised phase 2 trial of tailored neoadjuvant therapy for resectable oesophageal adenocarcinoma.

BACKGROUND: AGITG DOCTOR was a randomised phase 2 trial of pre-operative cisplatin, 5 fluorouracil (CF) followed by docetaxel (D) with or without radiotherapy (RT) based on poor early response to CF, detected via PET, for resectable oesophageal adenocarcinoma. This study describes PROs over 2 years. METHODS: Participants (N = 116) completed the EORTC QLQ-C30 and oesophageal module (QLQ-OES18) before chemotherapy (baseline), before surgery, six and 12 weeks post-surgery and three-monthly until 2 years. We plotted PROs over time and calculated the percentage of participants per treatment group whose post-surgery score was within 10 points (threshold for clinically relevant change) of their baseline score, for each PRO scale. We examined the relationship between Grade 3+ adverse events (AEs) and PROs. This analysis included four groups: CF responders, non-responders randomised to DCF, non-responders randomised to DCF + RT, and "others" who were not randomised. RESULTS: Global QOL was clinically similar between groups from 6 weeks post-surgery. All groups had poorer functional and higher symptom scores during active treatment and shortly after surgery, particularly the DCF and DCF + RT groups. DCF + RT reported a clinically significant difference (-13points) in mean overall health/QOL between baseline and pre-surgery. Similar proportions of patients across groups scored +/- 10 points of baseline scores within 2 years for most PRO domains. Instance of grade 3+ AEs were not related to PROs at baseline or 2 years. CONCLUSIONS: By 2 years, similar proportions of patients scored within 10 points of baseline for most PRO domains, with the exception of pain and insomnia for the DCF + RT group. Non-responders randomised to DCF or DCF + RT experienced additional short-term burden compared to CF responders, reflecting the longer duration of neoadjuvant treatment and additional toxicity. This should be weighed against clinical benefits reported in AGITG DOCTOR. This data will inform communication of the trajectory of treatment options for early CF non-responders. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12609000665235 . Registered 31 July 2009.

Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.

BACKGROUND: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. PATIENTS AND METHODS: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). RESULTS: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. CONCLUSIONS: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. TRIAL REGISTRATION: ACTRN12609000665235.

Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer.

BACKGROUND: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. MATERIALS AND METHODS: Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. RESULTS: Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. CONCLUSION: ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

Reduction of smoking urges with intranasal insulin: a randomized, crossover, placebo-controlled clinical trial.

Many cigarette smokers express a desire to quit smoking, but ~85% of cessation attempts fail. In our attempt to delineate genetic modulators of smoking persistence, we have earlier shown that a locus within an ~250 kb haplotype block spanning the 5' untranslated region region of insulin-degrading enzyme is associated with serum cotinine levels; the study's measure of smoking quantity. Based on our findings, and coupled with recent preclinical studies showing the importance of multiple neuropeptides in reinstatement of drug use, we formulated intranasal insulin to evaluate its efficacy during acute abstinence from smoking. Our original study was a crossover trial including 19 otherwise healthy smokers who abstained from smoking for 36 h. The morning following their second night of abstinence, in random order, study participants received intranasal insulin (60 IU) or placebo (8.7% sodium chloride). The goal of our second study was to replicate the craving findings from the original trial and expand this research by including additional stress-related measures. Thirty-seven study participants abstained from smoking overnight. The next day, they were administered either intranasal insulin (60 IU) or placebo, following which they participated in the Trier Social Stress Test Task. This was a parallel design study focusing on the standard stress subjective, hormonal and cardiovascular measures. We also evaluated any changes in circulating glucose, insulin and c-peptide (a marker of endogenous insulin). In the original study, intranasal insulin significantly reduced morning nicotine craving (b=3.65, P⩽0.05). Similarly, in the second study, intranasal insulin reduced nicotine cravings over time (b=0.065, P⩽0.05) and the effect lasted through the psychosocial stress period. Intranasal insulin also increased circulating cortisol levels (F=12.78, P⩽0.001). No changes in insulin or c-peptide were detected. A significant treatment × time interaction (P⩽0.05) was detected for glucose, but subjects remained well within the euglycemic range. Previous studies have shown that heightened nicotine cravings and blunted response to stress are independent and significant predictors of relapse to smoking. In our study, intranasal insulin normalized the subjective and hormonal response to stress. As such, intranasal insulin should further be studied in a larger clinical trial of smoking cessation. In support of this, we provide evidence that the treatment is safe and effective and, based on absence of peripheral insulin changes, conclude that the pharmacodynamic effect is centrally driven.

Treatment and outcomes of metastatic colorectal cancer in Australia: defining differences between public and private practice.

BACKGROUND: Prior studies have suggested improved outcomes for cancer patients managed in private centres, despite universal healthcare within Australia. AIMS: To compare patient, disease, treatment and survival data for metastatic colorectal cancer (mCRC) managed in private versus public centres. METHODS: Analysis of prospectively collected registry data for consecutive patients with mCRC managed at 16 participating centres from July 2009. RESULTS: Data for 1065 patients were examined. Age, gender and Charlson comorbidity score were similar for public and private patients. Private patients were more commonly Eastern Cooperative Oncology Group performance score 0-1 (85% vs 78%, P = 0.008), in the highest Index of Relative Socioeconomic Advantage and Disadvantage quintile (57% vs 18%, P < 0.001) or had a single metastatic site (62% vs 54%, P = 0.009). Patients treated in private were more likely to receive chemotherapy (84% vs 70%, P < 0.001), bevacizumab (59% vs 50%, P = 0.008), be treated with curative intent (37% vs 26%, P < 0.001) and undergo metastasectomy (30% vs 22%, P = 0.001). These management differences remained statistically significant after adjusting for baseline characteristics. Management in the private setting was associated with superior overall survival (median 27.9 vs 20 months, hazard ratio 0.7, 95% confidence interval: 0.57 to 0.86, P = 0.001), significant in multivariate analysis adjusting for all baseline covariates. CONCLUSIONS: Significant differences in baseline characteristics were noted for private versus public patients. However, these do not explain the higher rates of treatment delivery in the private setting, which likely contributed towards the observed survival difference. Further studies are required to determine if the increased likelihood of intervention in the private setting is driven by patient, clinician and/or institutional factors.

Early onset metastatic colorectal cancer in Australia.

BACKGROUND: Colorectal cancer (CRC) incidence and mortality rates have been increasing among young patients (YP), for uncertain reasons. It is unclear whether YP have a distinct tumor biology or merit a different treatment approach to older patients (OP). METHODS: We reviewed prospectively collected data from consecutive patients with metastatic CRC (MCRC) enrolled in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Australian registry. Clinicopathological features, treatment and survival outcomes were compared between YP (<50 years) and OP (≥50 years). RESULTS: Of 3692 patients diagnosed August 2009 - March 2023, 14 % (513) were YP. YP were more likely than OP to be female (52% vs. 40 %, P < 0.0001), have ECOG performance status 0-1 (94% vs. 81 %, P < 0.0001), to have a left-sided primary (72% vs. 63 %, P = 0.0008) and to have fewer comorbidities (90% vs. 60 % Charleston score 0, P < 0.0001). There were no differences in the available molecular status, which was more complete in YP. YP were more likely to have de novo metastatic disease (71% vs. 57 %, P < 0.0001). YP were more likely to undergo curative hepatic resection (27% vs. 17 %, P < 0.0001), to receive any chemotherapy (93% vs. 78 % (P < 0.0001), and to receive 3+ lines of chemotherapy (30% vs. 24 % (P < 0.0034)). Median first-line progression free survival (10.2 versus 10.6 months) was similar for YP vs OP, but overall survival (32.1 versus 25.4 months, HR = 0.745, P < 0.0001) was longer in YP. CONCLUSION: Known prognostic variables mostly favored YP versus OP with newly diagnosed mCRC, who were also more heavily treated. Consistent with this, overall survival outcomes were improved. This data does not support that CRC in YP represent a distinct subset of mCRC patients, or that a modified treatment approach is warranted.

Uric acid and acute kidney injury in high-risk patients for developing acute kidney injury undergoing cardiac surgery: A prospective multicenter study.

PURPOSE: It is unclear whether preoperative serum uric acid (SUA) elevation may play a role in the development of acute kidney injury (AKI) associated with cardiac surgery (CSA-AKI). We conducted a cohort study to evaluate the influence of preoperative hyperuricemia on AKI in patients at high risk for developing SC-AKI. DESIGN: Multicenter prospective international cohort study. SETTING: Fourteen university hospitals in Spain and the United Kingdom. PARTICIPANTS: We studied 261 consecutive patients at high risk of developing CSA-AKI, according to a Cleveland score ≥ 4 points, from July to December 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: AKIN criteria were used for the definition of AKI. Multivariable logistic regression models and propensity score-matched pairwise analysis were used to determine the adjusted association between preoperative hyperuricemia (≥7 mg/dL) and AKI. Elevated preoperative AUS (≥7 mg/dL) was present in 190 patients (72.8%), whereas CSA-AKI occurred in 145 patients (55.5%). In multivariable logistic regression models, hyperuricemia was not associated with a significantly increased risk of AKI (adjusted Odds Ratio [OR]: 1.58; 95% confidence interval [CI]: 0.81-3; P = .17). In propensity score-matched analysis of 140 patients, the hyperuricemia group experienced similar adjusted odds of AKI (OR 1.05, 95%CI 0.93-1.19, P = .37). CONCLUSIONS: Hyperuricemia was not associated with an increased risk of AKI in this cohort of patients undergoing cardiac surgery at high risk of developing CSA-AKI.

HMGB1 acts as an agent of host defense at the gut mucosal barrier.

Mucosal barriers provide the first line of defense between internal body surfaces and microbial threats from the outside world. 1 In the colon, the barrier consists of two layers of mucus and a single layer of tightly interconnected epithelial cells supported by connective tissue and immune cells. 2 Microbes colonize the loose, outer layer of colonic mucus, but are essentially excluded from the tight, epithelial-associated layer by host defenses. 3 The amount and composition of the mucus is calibrated based on microbial signals and loss of even a single component of this mixture can destabilize microbial biogeography and increase the risk of disease. 4-7 However, the specific components of mucus, their molecular microbial targets, and how they work to contain the gut microbiota are still largely unknown. Here we show that high mobility group box 1 (HMGB1), the prototypical damage-associated molecular pattern molecule (DAMP), acts as an agent of host mucosal defense in the colon. HMGB1 in colonic mucus targets an evolutionarily conserved amino acid sequence found in bacterial adhesins, including the well-characterized Enterobacteriaceae adhesin FimH. HMGB1 aggregates bacteria and blocks adhesin-carbohydrate interactions, inhibiting invasion through colonic mucus and adhesion to host cells. Exposure to HMGB1 also suppresses bacterial expression of FimH. In ulcerative colitis, HMGB1 mucosal defense is compromised, leading to tissue-adherent bacteria expressing FimH. Our results demonstrate a new, physiologic role for extracellular HMGB1 that refines its functions as a DAMP to include direct, virulence limiting effects on bacteria. The amino acid sequence targeted by HMGB1 appears to be broadly utilized by bacterial adhesins, critical for virulence, and differentially expressed by bacteria in commensal versus pathogenic states. These characteristics suggest that this amino acid sequence is a novel microbial virulence determinant and could be used to develop new approaches to diagnosis and treatment of bacterial disease that precisely identify and target virulent microbes.

Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent.

BACKGROUND: CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity. METHODS: This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours. RESULTS: Thirty-one patients received CYT997 over 12 dose levels (7-358 mg m(-2)). Doses up to 202 mg m(-2) were well tolerated. Dose-limiting toxicities were observed at 269 and 358 mg m(-2), consisting of grade 3 prolonged corrected QT interval in two patients and grade 3 hypoxia and grade 4 dyspnea in one patient. All toxicities were reversible. The pharmacokinetics of CYT997 were linear over the entire dose range. Dynamic contrast-enhanced magnetic resonance imaging scans showed significant changes in tumour K(trans) values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of >or=65 mg m(-2). Moreover, plasma levels of von Willebrand factor and caspase-cleaved cytokeratin-18 increased post-treatment at higher dose levels. Among 22 patients evaluable for response, 18 achieved stable disease for >2 cycles. CONCLUSIONS: CYT997 was well tolerated at doses that were associated with pharmacodynamic evidence of vascular disruption in tumours.

Metabolic Effects of Androgen-associated Body Mass in Klinefelter Syndrome.

Patients with Klinefelter Syndrome (KS) are at increased risk for both diabetes and cardiovascular disease. While the anabolic effects of androgen replacement therapy may be associated with weight gain in such patients, the metabolic effects of this weight gain are unknown. Since untreated KS represents a natural example of androgen deprivation, we hypothesized that KS patients who are receiving androgen replacement would have a healthier metabolic risk factor profile, in addition to an increased Body Mass Index (BMI), relative to patients who are not receiving androgen replacement. Using de-identified data collected from Health Facts (a national, consolidated, and relational database of Electronic Health Records), we identified 2,447 adult patients with an ICD-9 billing code for KS. Of these, 262 patients were included in this study based on available anthropometrics, metabolic profiles, and information about androgen replacement. Multiple linear regression analysis was performed using BMI as the dependent variable in a model that included age, androgen replacement therapy (yes or no), A1C, blood pressure, and fasting lipids. Post-hoc comparisons were made using frequency analysis and the unpaired Student's t-test. There were 81 patients with KS who received androgen replacement and 181 patients who did not. In multiple regression, only androgen therapy was positively and significantly associated with BMI while adjusting for other risk factors (p=0.03). Post-hoc comparison of metabolic risk factors revealed no other differences between patients who received androgen replacement and those who did not. These data suggest that androgen replacement therapy in Klinefelter Syndrome is associated with increased BMI, but this increase does not appear to exert a detrimental effect on other metabolic risk factors in this condition.

Randomised positive control trial of NSAID and antimicrobial treatment for calf fever caused by pneumonia.

One hundred and fifty-four preweaning calves were followed between May and October 2015. Calves were fitted with continuous monitoring temperature probes (TempVerified FeverTag), programmed so a flashing light emitting diode (LED) light was triggered following six hours of a sustained ear canal temperature of ≥39.7°C. A total of 83 calves (61.9 per cent) developed undifferentiated fever, with a presumptive diagnosis of pneumonia through exclusion of other calf diseases. Once fever was detected, calves were randomly allocated to treatment groups. Calves in group 1 (NSAID) received 2 mg/kg flunixin meglumine (Allevinix, Merial) for three consecutive days and group 2 (antimicrobial) received 6 mg/kg gamithromycin (Zactran, Merial). If fever persisted for 72 hours after the initial treatment, calves were given further treatment (group 1 received antimicrobial and group 2 received NSAID). Calves in group 1 (NSAID) were five times more likely (P=0.002) to require a second treatment (the antimicrobial) after 72 hours to resolve the fever compared with the need to give group 2 (antimicrobial) calves a second treatment (NSAID). This demonstrates the importance of ongoing monitoring and follow-up of calves with respiratory disease. However, of calves with fever in group 1 (NSAID), 25.7 per cent showed resolution following NSAID-only treatment with no detrimental effect on the development of repeated fever or daily live weight gain. This suggests that NSAID alone may be a useful first-line treatment, provided adequate attention is given to ongoing monitoring to identify those cases that require additional antimicrobial treatment.

Predictors of Physical Fitness among Southwestern Native American Adolescents at Risk for Diabetes.

The prevalence of obesity is increasing among children nationally. Native American children from Zuni Pueblo appear to be at increased risk for obesity, which also increases the risk for the metabolic syndrome, diabetes, and cardiovascular disease. While exercise and physical fitness can prevent or forestall these developments, predictors of physical fitness in this population are unknown. Forty-seven Native American adolescents completed four aspects of the Presidential Fitness Challenge (push-ups, sit-ups, step-ups, and timed walking) during screening for another study, and fitness was empirically summarized with a Presidential Fitness Index. Correlative analyses were subsequently performed to elucidate predictors of fitness. Age was the only independent predictor of the Presidential Fitness Index. Other variables that were not found to be independent predictors included BMI percentile, waist circumference, fat free mass, total body fat, and HDL cholesterol. Among adolescent Southwest Native Americans, older children performed better on the Presidential Fitness Challenge. Additionally, BMI was not found to be an independent predictor of fitness.

An analysis of incidental and symptomatic pulmonary embolism (PE) in medical oncology patients.

AIM: To determine the incidence of symptomatic versus incidental pulmonary embolism (PE) in oncology patients, characterize the nature and extent of incidental PE and the factors contributing to diagnosis. METHODS: Specialized web search engine was used to identify oncology patients with positive imaging studies for PE. PE identified at staging CT scans were classified as incidental PEs, whereas PE diagnosed by CTPA/VQ scan were classified as symptomatic PEs. RESULTS: A total of 111 patients with PE were identified over the period of three years. Of these, 67 (60%) patients had symptomatic whereas 44 (40%) patients had incidental PE. Most PEs were segmental and non-occlusive irrespective of the type of PE or stage of the disease. Incidence of PE was equal with/without chemotherapy. Platinum-based chemotherapy was more commonly associated with PE. Most patients received anticoagulation irrespective of type of PE. CONCLUSION: Forty percent of the diagnosed PEs were incidental, more common in the metastatic group. This may be due to the increased frequency of staging scans performed in patients with metastatic disease, as well as the inherent disease biology of metastatic compared with localized disease. Further prospective analysis of survival by PE subtype and optimal length of anticoagulation in incidental PE is warranted.

An open-source platform to study uniaxial stress effects on nanoscale devices.

We present an automatic measurement platform that enables the characterization of nanodevices by electrical transport and optical spectroscopy as a function of the uniaxial stress. We provide insights into and detailed descriptions of the mechanical device, the substrate design and fabrication, and the instrument control software, which is provided under open-source license. The capability of the platform is demonstrated by characterizing the piezo-resistance of an InAs nanowire device using a combination of electrical transport and Raman spectroscopy. The advantages of this measurement platform are highlighted by comparison with state-of-the-art piezo-resistance measurements in InAs nanowires. We envision that the systematic application of this methodology will provide new insights into the physics of nanoscale devices and novel materials for electronics, and thus contribute to the assessment of the potential of strain as a technology booster for nanoscale electronics.

Lispro insulin: benefits and limitations.

Lispro insulin is the first synthetic insulin analog commercially available for the treatment of diabetes. Its rapid absorption and short half-life results in both advantages and disadvantages to the patient with diabetes. Understanding the physiology of normal insulin secretion and the pathophysiology of diabetes is paramount to optimizing Lispro insulin in patients with diabetes.

Meal composition is a determinant of lispro-induced hypoglycemia in IDDM.

OBJECTIVE: Lispro is a newly FDA-approved analog of human insulin that will be widely used in patients with IDDM. This insulin, however, may have an increased potential for hypoglycemia because of its very rapid subcutaneous absorption, especially in a setting of decreased carbohydrate intake. Using a short-term prospective randomized parallel group-study design, we studied the incidence of hypoglycemia when lispro was given before breakfast compared with regular human insulin. Since carbohydrate intake is a determinant of postprandial glycemia, we administered three isocaloric meals characterized by low, average, and high carbohydrate content. RESEARCH DESIGN AND METHODS: Two groups of six IDDM subjects were randomized to receive 0.15 U/kg of lispro or regular human insulin subcutaneously before the ingestion of three 500-kcal breakfast meals of differing carbohydrate content on separate days. Lispro was administered at mealtime, and regular insulin was administered 30 min before mealtime. RESULTS: Postprandial plasma glucose concentrations were decreased in the lispro group compared with the regular-insulin group for all three meal types (P < 0.05), and hypoglycemia developed more frequently and rapidly in the lispro group, compared with the regular-insulin group by survival analysis. Additionally, peak insulin concentrations were higher (P < 0.001) and peaked more rapidly (P < 0.05) in the lispro group, compared with the regular-insulin group. CONCLUSIONS: We conclude that lispro has a tendency for early postprandial hypoglycemia compared with regular insulin in the setting of reduced carbohydrate intake. This fact should be told to patients who decide to switch from regular insulin to lispro. Health care professionals should instruct their IDDM patients to monitor glucose levels frequently after switching to lispro since adjustments in their carbohydrate intake and/or their lispro dosage may be necessary to avoid hypoglycemia.

A treatable cause of recurrent severe hypoglycemia.

OBJECTIVE: To see if glucocorticoid deficiency might explain increased insulin sensitivity causing severe brittle diabetes in two type I diabetic patients. CASES: We describe two patients who developed brittle diabetes characterized by recurrent severe hypoglycemia on small daily insulin doses with severe hyperglycemia on further insulin dose reduction. In both patients, insulin requirements had fallen markedly. RESULTS: Both patients were found to have glucocorticoid deficiency. In one patient, this was a result of hypopituitarism, in which hypoglycemia was aggravated by growth hormone deficiency. In the other patient, glucocorticoid deficiency was the result of primary adrenal failure. Resolution of brittle diabetes and restoration of normal insulin doses followed steroid replacement therapy in both patients. CONCLUSIONS: These patients emphasize the importance of seeking an organic cause for recurrent severe hypoglycemia. Increasing insulin sensitivity in type I diabetic patients should alert clinicians to the possibility of glucocorticoid deficiency.

Optimal administration of lispro insulin in hyperglycemic type 1 diabetes.

OBJECTIVE: Lispro is a new rapidly absorbed insulin analog. At present, there are no recommendations for the optimal injection time of lispro insulin in hyperglycemic patients. In contrast to normoglycemic patients with diabetes, we hypothesized that injection of lispro insulin 15-30 min before meal ingestion would improve postprandial glucose excursion in hyperglycemic diabetic subjects. RESEARCH DESIGN AND METHODS: In 48 randomized overnight studies, 12 healthy adult type 1 diabetic patients received lispro insulin 0.15 U/kg admixed with human ultralente 0.2 U/kg (as background insulin) subcutaneously at minutes (-30, -15, 0, and +15) relative to the ingestion of an American Diabetes Association breakfast of 8.6 kcal/kg. Pre-breakfast hyperglycemia of 10.2 +/- 0.2 mmol/l was established before the study by continuous overnight infusion of intravenous insulin, which was stopped 30 min before lispro insulin injection. Glucose and insulin levels were measured every 30 min for 5 h after breakfast. RESULTS: Results demonstrated that postprandial glucose excursion was reduced when lispro insulin was administered 15 or 30 min before the meal compared with lispro insulin injected at the meal (P < 0.002). The postprandial glucose excursion (millimoles per liter per hour) was -6.4 +/- 3 for the -30-min group, -5.1 +/- 2.9 for the -15-min group, 3.4 +/- 4.1 for the 0-min group, and 5.7 +/- 4.4 for the +15-min group. Although injecting lispro insulin at 30 min before the meal resulted in a significant reduction in postprandial glycemia, it was accompanied by loss of glucose control at 4 h postmeal in two subjects. CONCLUSIONS: Optimization of lispro insulin in hyperglycemic patients requires timing of the insulin injection at least 15 min before the meal.

Low-dose ethanol predisposes elderly fasted patients with type 2 diabetes to sulfonylurea-induced low blood glucose.

OBJECTIVE: It has previously been demonstrated that the risk of hypoglycemia is low among otherwise healthy elderly fasted patients with type 2 diabetes taking oral sulfonylurea medications. Nevertheless, these agents do cause hypoglycemia in clinical practice, suggesting that accompanying factors must typically be present for hypoglycemia to occur. Ethanol is one putative risk factor that has not been evaluated as a mechanism for low blood glucose among sulfonylurea users. We hypothesized that low concentrations of ethanol would reduce blood glucose concentrations in elderly type 2 diabetic patients receiving sulfonylureas during a short-term fast. RESEARCH DESIGN AND METHODS: A total of 10 type 2 diabetic patients, aged 68 +/- 3 years and receiving 20 mg glyburide daily, participated in a prospective double-blind placebo-controlled in-patient study consisting of two 24-h fasts at least 1 week apart. During hours 14 and 15 of the fasting studies, subjects received intravenous infusions of either 4.35 mmol.kg-1.h-1 ethanol (equivalent to one or two alcoholic beverages) or saline placebo in random order. Ethanol, plasma glucose, insulin, and counterregulatory hormones were assessed very 30-60 min during the final 10 h of the fast. RESULTS: Blood ethanol levels peaked at 17 +/- 2 mmol/l (the lower legal limit of intoxication in New Mexico) during the ethanol study. Plasma glucose concentrations did not differ at baseline (placebo 8.5 +/- 1.8 vs. ethanol 8.7 +/- 1.7 mmol/l; P = 0.50), but nadir plasma glucose was lower after the ethanol infusion compared with placebo (4.4 +/- 1.2 vs. 5.0 +/- 1.4 mmol/l; P = 0.01), and the absolute decline in plasma glucose was also greater during the ethanol study than the placebo study (4.7 +/- 0.9 vs. 3.6 +/- 1.2 mmol/l; P = 0.01). Counterregulatory hormone levels were increased during the ethanol study and nonesterified fatty acid concentrations were suppressed compared with the placebo study. CONCLUSIONS: Low doses of ethanol predispose fasted elderly type 2 diabetic patients to low blood glucose during a short-term fast. This may be one of several mechanisms by which sulfonylurea-induced hypoglycemia occurs in elderly patients.

Apparent heterogeneity of hepatic lysosomes due to membrane-bound acid phosphatase.

Hepatic lysosomes have been fractionated by rate sedimentation and by isopycnic banding. In all experiments, the distribution of acid phosphatase differed from that of the other lysosomal enzymes. Evidence is presented that this difference is due not to the separation of lysosomes from different cell types, but simply reflects the membrane location of a part of the acid phosphatase.