Third Report of the Japan Diabetes Society (JDS)/Japanese Cancer Association (JCA) Joint Committee on diabetes and cancer: summary of the results of a questionnaire survey of oncologists and diabetologists-secondary publication.

The Japan Diabetes Society (JDS) and the Japan Cancer Association (JCA) launched a joint committee and published their "First Joint Committee Report on Diabetes and Cancer" in 2013, compiling recommendations for physicians and healthcare providers as well as for the general population. In 2016, the "Second Joint Committee Report on Diabetes and Cancer" summarized the current evidence on glycemic control and cancer risk in patients with diabetes. The current "Third Joint Committee Report on Diabetes and Cancer", for which the joint committee also enlisted the assistance of the Japanese Society of Clinical Oncology (JSCO) and the Japanese Society of Medical Oncology (JSMO), reports on the results from the questionnaire survey, "Diabetes Management in Patients Receiving Cancer Therapy," which targeted oncologists responsible for cancer management and diabetologists in charge of glycemic control in cancer patients. The results of the current survey demonstrated that there is a general consensus among oncologists and diabetologists with regard to the need for guidelines on glycemic control goals, the relevance of glycemic control, and glycemic control during cancer therapy in cancer patients.

Third Report of the Japan Diabetes Society/Japanese Cancer Association Joint Committee on Diabetes and Cancer: Summary of the results of a questionnaire survey of oncologists and diabetologists-Secondary publication.

The Japan Diabetes Society and the Japan Cancer Association launched a joint committee and published their "First Joint Committee Report on Diabetes and Cancer" in 2013, compiling recommendations for physicians and health-care providers as well as for the general population. In 2016, the "Second Joint Committee Report on Diabetes and Cancer" summarized the current evidence on glycemic control and cancer risk in patients with diabetes. The current "Third Joint Committee Report on Diabetes and Cancer", for which the joint committee also enlisted the assistance of the Japanese Society of Clinical Oncology and the Japanese Society of Medical Oncology, reports on the results from the questionnaire survey, "Diabetes Management in Patients Receiving Cancer Therapy," which targeted oncologists responsible for cancer management and diabetologists in charge of glycemic control in cancer patients. The results of the current survey indicated that there is a general consensus among oncologists and diabetologists with regard to the need for guidelines on glycemic control goals, the relevance of glycemic control, and glycemic control during cancer therapy in cancer patients.

Negative Selection on a SOD1 Mutation Limits Canine Degenerative Myelopathy While Avoiding Inbreeding.

Several hundred disease-causing mutations are currently known in domestic dogs. Breeding management is therefore required to minimize their spread. Recently, genetic methods such as direct-to-consumer testing have gained popularity; however, their effects on dog populations are unclear. Here, we aimed to evaluate the influence of genetic testing on the frequency of mutations responsible for canine degenerative myelopathy and assess the changes in the genetic structure of a Pembroke Welsh corgi population from Japan. Genetic testing of 5,512 dogs for the causative mutation in superoxide dismutase 1 (SOD1) (c.118G>A (p.E40K)) uncovered a recent decrease in frequency, plummeting from 14.5% (95/657) in 2019 to 2.9% (24/820) in 2022. Weir and Cockerham population differentiation (FST) based on genome-wide single-nucleotide polymorphism (SNP) of 117 selected dogs detected the SNP with the highest FST located in the intron of SOD1 adjacent to the c.118G>A mutation, supporting a selection signature on SOD1. Further genome-wide SNP analyses revealed no obvious changes in inbreeding levels and genetic diversity between the 2019 and 2022 populations. Our study highlights that genetic testing can help inform improved mating choices in breeding programs to reduce the frequency of risk variants and avoid inbreeding. This combined strategy could decrease the genetic risk of canine degenerative myelopathy, a fatal disease, within only a few years.

LSD1 promotes the egress of hematopoietic stem and progenitor cells into the bloodstream during the endothelial-to-hematopoietic transition.

During embryonic development, primitive and definitive waves of hematopoiesis take place to provide proper blood cells for each developmental stage, with the possible involvement of epigenetic factors. We previously found that lysine-specific demethylase 1 (LSD1/KDM1A) promotes primitive hematopoietic differentiation by shutting down the gene expression program of hemangioblasts in an Etv2/Etsrp-dependent manner. In the present study, we demonstrated that zebrafish LSD1 also plays important roles in definitive hematopoiesis in the development of hematopoietic stem and progenitor cells. A combination of genetic approaches and imaging analyses allowed us to show that LSD1 promotes the egress of hematopoietic stem and progenitor cells into the bloodstream during the endothelial-to-hematopoietic transition. Analysis of compound mutant lines with Etv2/Etsrp mutant zebrafish revealed that, unlike in primitive hematopoiesis, this function of LSD1 was independent of Etv2/Etsrp. The phenotype of LSD1 mutant zebrafish during the endothelial-to-hematopoietic transition was similar to that of previously reported compound knockout mice of Gfi1/Gfi1b, which forms a complex with LSD1 and represses endothelial genes. Moreover, co-knockdown of zebrafish Gfi1/Gfi1b genes inhibited the development of hematopoietic stem and progenitor cells. We therefore hypothesize that the shutdown of the Gfi1/Gfi1b-target genes during the endothelial-to-hematopoietic transition is one of the key evolutionarily conserved functions of LSD1 in definitive hematopoiesis.

End-of-life impact of concurrent diabetes mellitus and adrenal insufficiency as immune-related adverse events in an advanced non-small cell lung cancer patient.

A 49-year-old man diagnosed with metastatic non-small cell lung cancer was treated with immune checkpoint inhibitor (ICI) combination therapy (nivolumab + ipilimumab) as first-line therapy. During the treatment course, the patient developed ICI-associated diabetes mellitus and adrenal insufficiency, and insulin and hydrocortisone replacement therapy (10 mg/day) were initiated for endocrine toxicity. Despite systemic treatment, the disease progressed. Near the end of the patient's life, he was repeatedly hospitalized for diabetic ketoacidosis and adrenal crisis because he could not physically administer insulin subcutaneously or self-administer oral hydrocortisone due to the deterioration of his general condition as a result of disease progression. This case report demonstrates that it is necessary to evaluate not only the impact of immune-related adverse events on short-term quality of life during ICI treatment but also on the patient's end-of-life care.

Type 1 diabetes associated with immune checkpoint inhibitors for malignant melanoma: A case report and review of 8 cases.

Advanced malignant melanoma (MM) is treated with immune checkpoint inhibitor (ICI) therapy, which often results in several immune-related adverse events. Fulminant type 1 diabetes mellitus (T1DM) is a rare, rapidly progressive, life-threatening disease. Here, we summarize 8 cases of MM with ICI-induced T1DM and describe one case that developed fulminant T1DM due to nivolumab therapy. We retrospectively reviewed patients treated with ICI from 2014 to 2021 at our hospital. The clinical features and risk factors of ICI-induced T1DM were discussed. ICIs were administered to 426 MM patients at our hospital. Among these, nivolumab was administered in 5 cases, pembrolizumab in 1 case, and the combination of nivolumab and ipilimumab in 2 cases. The frequency of ICI-associated T1DM was 1.88%. The mean glycated hemoglobin level at T1DM onset was 8.0 ± 1.0%. Of the patients, 75% were diagnosed with fulminant T1DM, 62.5% developed diabetic ketoacidosis, and 25% had glutamic acid decarboxylase (GAD) antibodies (an early predictive marker for T1DM). The mean interval between the first ICI administration and T1DM development was 201 ± 187 days. The mean duration of resumption was 13 ± 7 days. We should monitor for T1DM development following treatment with ICIs. ICI can be continued to be used to treat MM if insulin therapy successfully controls T1DM. A 67-year-old patient who received adjuvant nivolumab therapy developed fulminant T1DM and thyrotoxicosis 57 days later and tested positive for GAD antibodies. Subsequently, he developed hypophysitis and an isolated adrenocorticotropin deficiency. He continued receiving nivolumab along with self-injected insulin without developing recurrence.

Metformin with Temozolomide for Newly Diagnosed Glioblastoma: Results of Phase I Study and a Brief Review of Relevant Studies.

Glioblastoma (GBM) inevitably recurs due to a resistance to current standard therapy. We showed that the antidiabetic drug metformin (MF) can induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. In this study, we design a phase I/II study to examine the clinical effect of MF. We aim to determine a recommended phase II MF dose with maintenance temozolomide (TMZ) in patients with newly diagnosed GBM who completed standard concomitant radiotherapy and TMZ. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first six weeks after MF initiation. Three patients were treated with 1500 mg/day MF and four patients were treated with 2250 mg/day MF between February 2021 and January 2022. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, all of which were manageable. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up session. The MF dose of up to 2250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to a phase II study with 2250 mg/day MF.

The Effect of a Learning Partner Model-Based Program on Spreading Cancer Prevention Knowledge Using Community Health Volunteers in Japan.

OBJECTIVES: This study examines the implementation and short-term effects of a Learning Partner Model (LPM)-based educational program on cancer prevention and control information for community health volunteers in Japan. METHODS: The program was undertaken by 3 local governments in collaboration with a government initiative and offered a 90-min group workshop to community health volunteers. Community health volunteers (primary participants) recruited in turn friend or family members (secondary participants) with whom they were prepared to share the content of the workshop with the help of printed materials received in the workshop. We conducted self-administered paper and pencil questionnaire surveys before, immediately after, and 3 months after the workshop. The t-test, Fisher's exact test, paired t-test, and McNemar test were used to compare the 2 groups' demographic characteristics and healthy habits at pretest. Repeated measures ANOVA was used to compare cancer prevention knowledge between groups and over time. RESULTS: Of 142 participants, 107 pairs of learning partners (primary and corresponding secondary participant) completed all questionnaires. All primary participants and 37.4% of the secondary participants were women, and 57.9% of the learning partners were spouses. The results showed significantly higher correct answers on the cancer-prevention knowledge questions in the post-workshop and follow-up surveys compared to the pre-workshop survey (P < .001). The increase in knowledge was observed in all learning-partner groups in all 3 sites. CONCLUSION: The study demonstrates a promising strategy that can be adapted to the health needs of the community beyond cancer prevention and control, building on the efforts of local governments and government health initiatives.

Association between diabetes and adjuvant chemotherapy implementation in patients with stage III colorectal cancer.

AIMS/INTRODUCTION: Among colorectal cancer (CRC) patients, pre-existing diabetes is suggested to influence poor prognosis, but the impact on adjuvant chemotherapy implementation is largely unknown. We aimed to compare the implementation rate of adjuvant chemotherapy between CRC patients with and without pre-existing diabetes in a retrospective cohort study. MATERIALS AND METHODS: Colorectal cancer diagnosis information was obtained from the hospital-based cancer registry of patients with stage III CRC who underwent curative surgery in 2013 in Japan (n = 6,344). Health claims data were used to identify diabetes and chemotherapy. We examined the association between diabetes and the implementation rate of adjuvant chemotherapy using a generalized linear model adjusted for age, sex, updated Charlson Comorbidity Index, hospital type and prefecture. Furthermore, we applied a mediation analysis to examine the extent to which postoperative complications mediated the association. RESULTS: Of the 6,344 patients, 1,266 (20.0%) had diabetes. The mean ages were 68.2 and 71.3 years for patients without and with diabetes, respectively. Compared with those without diabetes, patients with diabetes were less likely to receive adjuvant chemotherapy (crude rate 58.9 and 49.8%; adjusted percentage point difference 4.6; 95% confidence interval 1.7-7.5). The difference was evident for patients aged <80 years, and larger for platinum-containing regimens than others. Mediation analysis showed that postoperative complications explained 9.1% of the inverse association between diabetes and adjuvant chemotherapy implementation. CONCLUSIONS: We observed that patients with stage III CRC and diabetes are less likely to receive adjuvant chemotherapy than those without diabetes, and postoperative complications might partially account for the association.

Current Diagnosis and Management of Abetalipoproteinemia.

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by biallelic pathogenic mutations in the MTTP gene. Deficiency of microsomal triglyceride transfer protein (MTTP) abrogates the assembly of apolipoprotein (apo) B-containing lipoprotein in the intestine and liver, resulting in malabsorption of fat and fat-soluble vitamins and severe hypolipidemia. Patients with ABL typically manifest steatorrhea, vomiting, and failure to thrive in infancy. The deficiency of fat-soluble vitamins progressively develops into a variety of symptoms later in life, including hematological (acanthocytosis, anemia, bleeding tendency, etc.), neuromuscular (spinocerebellar ataxia, peripheral neuropathy, myopathy, etc.), and ophthalmological symptoms (e.g., retinitis pigmentosa). If left untreated, the disease can be debilitating and even lethal by the third decade of life due to the development of severe complications, such as blindness, neuromyopathy, and respiratory failure. High dose vitamin supplementation is the mainstay for treatment and may prevent, delay, or alleviate the complications and improve the prognosis, enabling some patients to live to the eighth decade of life. However, it cannot fully prevent or restore impaired function. Novel therapeutic modalities that improve quality of life and prognosis are awaited. The aim of this review is to 1) summarize the pathogenesis, clinical signs and symptoms, diagnosis, and management of ABL, and 2) propose diagnostic criteria that define eligibility to receive financial support from the Japanese government for patients with ABL as a rare and intractable disease. In addition, our diagnostic criteria and the entry criterion of low-density lipoprotein cholesterol (LDL-C) ＜15 mg/dL and apoB ＜15 mg/dL can be useful in universal or opportunistic screening for the disease. Registry research on ABL is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.

Genetic relationships and inbreeding levels among geographically distant populations of Felis catus from Japan and the United States.

Pedigreed cats have traditionally been mated with close relatives, which increases the risks for inbreeding depression and genetic disorders. We evaluated the genome-wide population structure and the degree of inbreeding of 1022 cats, including 13 pedigreed and two random bred populations from Japan and the USA, using single nucleotide polymorphism array-based data. Ancestry structure analysis revealed Japan's American Curl, Norwegian Forest, and Siamese cat populations were genetically distinct from their American counterparts. Furthermore, we found an ancestral genetic component shared between five pedigreed and random bred Japanese cats, suggesting the breeds were admixed with Japanese cats or cats of east Asian origin. Between-country differences in inbreeding estimates based on runs of homozygosity were found for Maine Coon, Siamese, and random bred cats. To reduce the risks of inbreeding depression and genetic disorders, particularly for highly inbred breeds, such as Abyssinian cats, as well as Russian Blue and Siamese cats in the USA, appropriate breeding practices must be observed, including mating practices that increase the genetic diversity.

Clinical characteristics of adrenal insufficiency as an immune-related adverse event in non-small-cell lung cancer.

Adrenal insufficiency (AI) is an immune-related adverse event of immune checkpoint inhibitors and on occasion could be serious. There have been few reports of clinical information regarding AI associated with anti-programmed cell death protein-1 (anti-PD-1) antibody in non-small-cell lung cancer (NSCLC) patients. Patients with advanced NSCLC treated with anti-PD-1 antibodies between December 2015 and October 2017 were identified from the medical records of our institution. We investigated the frequency, symptoms, test results, and treatment outcomes of AI, and prognosis of patients who developed AI. In total, 282 NSCLC patients were treated with anti-PD-1 antibodies, and 4 patients (1.4%) were diagnosed as AI and 6 patients (2.1%) as suspicious of AI according to the laboratory data or clinical findings. The median follow-up period was 13.6 months. All patients with AI and suspicious of AI were treated with corticosteroid replacement, and performance status (PS) was improved in 50% of patients. Two of 10 patients were thought to have central AI. Six patients of 10 patients continued to receive anti-PD-1 antibodies with corticosteroid hormone replacement after diagnosis. The median progression-free survival and overall survival were 10.2 and 15.4 months, respectively. In conclusion, the incidence of AI among NSCLC patients treated with anti-PD-1 antibodies was similar to previous studies. Corticosteroid replacement improved PS, symptoms, and laboratory data of patients with AI and suspicious of AI. Corticosteroid replacement may contribute to continuation of anti-PD-1 antibodies and survival outcome was preferable in patients with AI and suspicious of AI receiving corticosteroid treatment.

Prevalence of diabetes in Japanese patients with cancer.

Cancer patients with diabetes experience a poorer prognosis, yet the population burden of this multimorbidity remains unknown. This study aimed to estimate the latest incidence and prevalence of cancer with diabetes mellitus in Japan. We used projection of cancer incidence and latest survival data from population-based cancer registries. The incidence of cancer associated with diabetes was estimated separately for patients with pre-existing diabetes and those without diabetes, and used to estimate the 5-year cancer prevalence for those with and without diabetes. The prevalence of pre-existing diabetes in cancer patients at any cancer site was estimated to be 20.7% (647,160 men and women). Among cancer sites, diabetes prevalence was high in patients with liver and pancreatic cancers in both sexes. In conclusion, our study shows a large burden of diabetes in cancer patients in Japan, which warrants further attention by health practitioners and policy-makers.

Preceding psychological factors and calorie intake in patients with type 2 diabetes: investigation by ecological momentary assessment.

BACKGROUND: Psychological factors have been reported to have influence on the eating habits of patients with diabetes. However, previous studies have used questionnaires to investigate the association, and thus include recall bias. To overcome this disadvantage, ecological momentary assessment (EMA) can be used to record subjective symptoms and behavior in subjects' daily lives. Therefore, the aim of the present study was to investigate the influence of preceding psychological factors on calorie intake using computerized EMA for 6 months. METHODS: The participants were nine outpatients with type 2 diabetes, aged 34-72. They were instructed to use a personal digital assistant as an electronic diary for 6 months to record subjective symptoms, such as psychological stress, anxiety, and depressive mood, and the food and drink that they consumed. The association between a preceding psychological factor and calorie intake within 5 hours was investigated using multilevel modeling. RESULTS: Preceding psychological stress was positively associated with calorie intake from snacks. Preceding psychological stress, anxiety, and depressive mood were negatively associated with calorie intake from regular meals. CONCLUSIONS: Preceding psychological factors influence the calorie intake of patients with type 2 diabetes. Understanding the role of these factors will be useful for developing psychological interventions to prevent overeating. TRIAL REGISTRATION: The trial registration number: UMIN000002992. Date of registration: 2010/01/07.

Impact of the Duration of Diabetes Mellitus on the Outcome of Metastatic Pancreatic Cancer Treated with Gemcitabine: A Retrospective Study.

Objective To assess the impact of the duration of diabetes mellitus (DM) on the outcomes of pancreatic cancer patients undergoing chemotherapy. Methods We reviewed the medical records of patients with metastatic pancreatic cancer who received gemcitabine monotherapy as the standard therapy before the introduction of combination regimens. The treatment outcomes of gemcitabine were compared among three groups classified according to the duration of DM: no DM, short DM (<4 years), and long DM (≥4 years). Results Among 350 patients, 218, 87, and 45 patients were classified into the no DM, short DM, and long DM groups, respectively. In comparison to the no DM group, the univariate hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were 1.44 [95% confidence interval (CI), 1.02-2.02; p=0.027] and 1.33 (95% CI, 0.93-1.89; p=0.081), respectively, in the long DM group, and 1.12 (95% CI, 0.85-1.46; p=0.426) and 1.06 (95% CI, 0.81-1.40; p=0.678), respectively, in the short DM group; the multivariate-adjusted HRs were 1.33 (95% CI, 0.94-1.89; p=0.103) and 1.37 (95% CI, 0.95-1.98; p=0.095) in the long DM group and 1.12 (95% CI, 0.85-1.47; p=0.410) and 1.10 (95% CI, 0.82-1.46; p=0.533) in the short DM group. The survival outcomes of the long DM group tended to remain poorer in analyses using different cutoffs of DM duration as, well as in hospital-specific analyses. Conclusion Long-standing DM may be associated with shorter PFS and OS in patients with metastatic pancreatic cancer.

Myeloid HMG-CoA (3-Hydroxy-3-Methylglutaryl-Coenzyme A) Reductase Determines Atherosclerosis by Modulating Migration of Macrophages.

Objective- Inhibition of HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is atheroprotective primarily by decreasing plasma LDL (low-density lipoprotein)-cholesterol. However, it is unknown whether inhibition of HMGCR in myeloid cells contributes to this atheroprotection. We sought to determine the role of myeloid HMGCR in the development of atherosclerosis. Approach and Results- We generated mice with genetically reduced Hmgcr in myeloid cells ( Hmgcr m-/m-) using LysM (Cre) and compared various functions of their macrophages to those of Hmgcr fl/fl control mice. We further compared the extent of atherosclerosis in Hmgcr m-/ m- and Hmgcr fl/fl mice in the absence of Ldlr (LDL receptor). Hmgcr m-/ m- macrophages and granulocytes had significantly lower Hmgcr mRNA expression and cholesterol biosynthesis than Hmgcr fl/fl cells. In vitro, Hmgcr m-/ m- monocytes/macrophages had reduced ability to migrate, proliferate, and survive compared with Hmgcr fl/fl monocytes/macrophages. However, there was no difference in ability to adhere, phagocytose, store lipids, or polarize to M1 macrophages between the 2 types of macrophages. The amounts of plasma membrane-associated small GTPase proteins, such as RhoA (RAS homolog family member A), were increased in Hmgcr m-/ m- macrophages. In the setting of Ldlr deficiency, Hmgcr m-/ m- mice developed significantly smaller atherosclerotic lesions than Hmgcr fl/fl mice. However, there were no differences between the 2 types of mice either in plasma lipoprotein profiles or in the numbers of proliferating or apoptotic cells in the lesions in vivo. The in vivo migration of Hmgcr m-/ m- macrophages to the lesions was reduced compared with Hmgcr fl/fl macrophages. Conclusions- Genetic reduction of HMGCR in myeloid cells may exert atheroprotective effects primarily by decreasing the migratory activity of monocytes/macrophages to the lesions.

Association of antithyroglobulin antibodies with the development of thyroid dysfunction induced by nivolumab.

Thyroid dysfunction (TD) induced by immune checkpoint inhibitors is not sufficiently understood. The purpose of this retrospective observational study was to identify risk factors and the clinical course of TD induced by nivolumab. Patients with advanced solid tumors who were treated with nivolumab from March 2009 through to March 2016 at the National Cancer Center Hospital (Tokyo, Japan) were included. Thyroid function and antithyroid Abs from serum samples among all patients were evaluated at baseline and during nivolumab treatment. Overt hypothyroidism was defined as low serum-free T4 together with elevated thyroid-stimulating hormone (TSH) >10 µIU/mL. Thyrotoxicosis was defined as low TSH with elevated free T4 and/or free T3. We defined thyroid autoimmunity as the presence of antithyroid Abs at baseline, including antithyroid peroxidase Abs and antithyroglobulin Abs (TgAb). Twenty-three (14%) of a total of 168 patients developed TD, including 17 cases of hypothyroidism and 20 of thyrotoxicosis. Thyrotoxicosis followed by hypothyroidism occurred in 14 cases. Fourteen of 35 patients (40%) with thyroid autoimmunity developed TD vs 9 of 133 (7%) without (odds ratio 9.19; 95% confidence interval [CI], 3.53-23.9). In multivariate analysis, elevated TSH and TgAb at baseline were significantly associated with the development of TD, with odds ratio of 7.36 (95% CI, 1.66-32.7) and 26.5 (95% CI, 8.18-85.8), respectively. Association between TD and elevated antithyroid peroxidase Abs at baseline was not significant. These results suggest that patients with pre-existing TgAb and elevated TSH at baseline are at high risk of TD.

Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): an open-label, randomised controlled trial.

BACKGROUND: Limited evidence suggests that multifactorial interventions for control of glucose, blood pressure, and lipids reduce macrovascular complications and mortality in patients with type 2 diabetes. However, safe and effective treatment targets for these risk factors have not been determined for such interventions. METHODS: In this multicentre, open-label, randomised, parallel-group trial, undertaken at 81 clinical sites in Japan, we randomly assigned (1:1) patients with type 2 diabetes aged 45-69 years with hypertension, dyslipidaemia, or both, and an HbA1c of 6·9% (52·0 mmol/mol) or higher, to receive conventional therapy for glucose, blood pressure, and lipid control (targets: HbA1c <6·9% [52·0 mmol/mol], blood pressure <130/80 mm Hg, LDL cholesterol <120 mg/dL [or 100 mg/dL in patients with a history of coronary artery disease]) or intensive therapy (HbA1c <6·2% [44·3 mmol/mol], blood pressure <120/75 mm Hg, LDL cholesterol <80 mg/dL [or 70 mg/dL in patients with a history of coronary artery disease]). Randomisation was done using a computer-generated, dynamic balancing method, stratified by sex, age, HbA1c, and history of cardiovascular disease. Neither patients nor investigators were masked to group assignment. The primary outcome was occurrence of any of a composite of myocardial infarction, stroke, revascularisation (coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting), and all-cause mortality. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00300976. FINDINGS: Between June 16, 2006, and March 31, 2009, 2542 eligible patients were randomly assigned to intensive therapy or conventional therapy (1271 in each group) and followed up for a median of 8·5 years (IQR 7·3-9·0). Two patients in the intensive therapy group were found to be ineligible after randomisation and were excluded from the analyses. During the intervention period, mean HbA1c, systolic blood pressure, diastolic blood pressure, and LDL cholesterol concentrations were significantly lower in the intensive therapy group than in the conventional therapy group (6·8% [51·0 mmol/mol] vs 7·2% [55·2 mmol/mol]; 123 mm Hg vs 129 mm Hg; 71 mm Hg vs 74 mm Hg; and 85 mg/dL vs 104 mg/dL, respectively; all p<0·0001). The primary outcome occurred in 109 patients in the intensive therapy group and in 133 patients in the conventional therapy group (hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·094). In a post-hoc breakdown of the composite outcome, frequencies of all-cause mortality (HR 1·01, 95% CI 0·68-1·51; p=0·95) and coronary events (myocardial infarction, coronary artery bypass surgery, and percutaneous transluminal coronary angioplasty; HR 0·86, 0·58-1·27; p=0·44) did not differ between groups, but cerebrovascular events (stroke, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting) were significantly less frequent in the intensive therapy group (HR 0·42, 0·24-0·74; p=0·002). Apart from non-severe hypoglycaemia (521 [41%] patients in the intensive therapy group vs 283 [22%] in the conventional therapy group, p<0·0001) and oedema (193 [15%] vs 129 [10%], p=0·0001), the frequencies of major adverse events did not differ between groups. INTERPRETATION: Our results do not fully support the efficacy of further intensified multifactorial intervention compared with current standard care for the prevention of a composite of coronary events, cerebrovascular events, and all-cause mortality. Nevertheless, our findings suggest a potential benefit of an intensified intervention for the prevention of cerebrovascular events in patients with type 2 diabetes. FUNDING: Ministry of Health, Labour and Welfare of Japan, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Kissei Pharmaceutical, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanwa Kagaku Kenkyusho, Shionogi, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda.

Fulminant type I diabetes mellitus associated with nivolumab in a patient with relapsed classical Hodgkin lymphoma.

We report the case of a patient with relapsed classical Hodgkin lymphoma who developed fulminant type I diabetes mellitus as a severe adverse event of treatment with the anti-programmed cell death-1 (PD-1) antibody, nivolumab. On the first day of the sixth cycle, the blood glucose level was markedly elevated (375 mg/dL). Although neither ketoacidosis nor ketonuria was detected, the markedly acute onset of the hyperglycemia was consistent with the typical clinical course of fulminant type I diabetes mellitus, and this diagnosis was supported by clinical data. All autoantibodies associated with type I diabetes mellitus were negative. The endogenous insulin secretion ceased completely within 2 weeks. After the blood glucose level was brought under control, nivolumab was resumed and continued without other major adverse events. Human leukocyte antigen (HLA) analysis revealed that the patient carried the HLA-B*4002 haplotype, a susceptibility allele for this type of diabetes mellitus. This case suggests that fulminant type I diabetes mellitus may be triggered by nivolumab in patients with a genetic background associated with the condition, warranting careful future consideration of this particular adverse event.