Creation and Validation of Patient-Derived Cancer Model Using Peritoneal and Pleural Effusion in Patients with Advanced Ovarian Cancer: An Early Experience.

Background: The application of personalized cancer treatment based on genetic information and surgical samples has begun in the field of cancer medicine. However, a biopsy may be painful for patients with advanced diseases that do not qualify for surgical resection. Patient-derived xenografts (PDXs) are cancer models in which patient samples are transplanted into immunodeficient mice. PDXs are expected to be useful for personalized medicine. The aim of this study was to establish a PDX from body fluid (PDX-BF), such as peritoneal and pleural effusion samples, to provide personalized medicine without surgery. Methods: PDXs-BF were created from patients with ovarian cancer who had positive cytology findings based on peritoneal and pleural effusion samples. PDXs were also prepared from each primary tumor. The pathological findings based on immunohistochemistry were compared between the primary tumor, PDX, and PDX-BF. Further, genomic profiles and gene expression were evaluated using DNA and RNA sequencing to compare primary tumors, PDXs, and PDX-BF. Results: Among the 15 patients, PDX-BF was established for 8 patients (5 high-grade serous carcinoma, 1 carcinosarcoma, 1 low-grade serous carcinoma, and 1 clear cell carcinoma); the success rate was 53%. Histologically, PDXs-BF have features similar to those of primary tumors and PDXs. In particular, PDXs-BF had similar gene mutations and expression patterns to primary tumors and PDXs. Conclusions: PDX-BF reproduced primary tumors in terms of pathological features and genomic profiles, including gene mutation and expression. Thus, PDX-BF may be a potential alternative to surgical resection for patients with advanced disease.

Lymphatic Complications Following Sentinel Node Biopsy or Pelvic Lymphadenectomy for Endometrial Cancer.

Sentinel node biopsy (SNB) is performed worldwide in patients with endometrial cancer (EC). The aim of this study was to evaluate and compare the occurrence rate of lymphatic complications between SNB and pelvic lymphadenectomy (LND) for EC. The medical records of women who underwent SNB or pelvic LND for EC between September 2012 and April 2022 were assessed. A total of 388 patients were enrolled in the current study. Among them, 201 patients underwent SNB and 187 patients underwent pelvic LND. The occurrence rates of lower-extremity lymphedema (LEL) and pelvic lymphocele (PL) were compared between the patients who underwent SNB and those who underwent pelvic LND. The SNB group had a significantly lower occurrence rate of lower-extremity LEL than the pelvic LND group (2.0% vs. 21.3%, p < 0.01). There were no patients who had PL in the SNB group; however, 4 (2.1%) patients in the pelvic LND group had PL. The occurrence rates of lower-extremity LEL and PL were significantly lower in patients who underwent SNB than those who underwent pelvic LND. SNB for EC has a lower risk of lymphatic complications compared to systemic LND.

A Disproportionality Analysis of the Adverse Effect Profiles of Methimazole and Propylthiouracil in Patients with Hyperthyroidism Using the Japanese Adverse Drug Event Report Database.

Background: Antithyroid drugs (ATDs) are frequently used to achieve euthyroidism in patients with hyperthyroidism. ATDs cause characteristic common and rare adverse events; however, comprehensive comparisons between methimazole (MMI) and propylthiouracil (PTU) in terms of adverse events are limited. Methods: In this study, we thoroughly explored adverse events in association with MMI and PTU use with a disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database and evaluated the prevalence of MMI and PTU prescriptions using the National Database of Health Insurance Claims and Specific Health Checkups (NDB) Open Data Japan. We analyzed 3271 cases of MMI use and 1029 cases of PTU use with respect to 9789 preferred terms (PTs) for adverse events registered in the JADER database by calculating and comparing reporting odds ratios (RORs). Results: We found that 8 PTs, including agranulocytosis (p < 0.0001, 4.01-fold), aplasia cutis congenita (p < 0.0001, 123.22-fold), and exomphalos (p = 0.0002, 22.17-fold), demonstrated significantly higher RORs (more than 4-fold) for MMI use than for PTU use. Nineteen PTs, including anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (p < 0.0001, 29.84), rapidly progressive glomerulonephritis (p < 0.0001, 6.44), and pulmonary alveolar hemorrhage (p < 0.0001, 7.77), had RORs for PTU use more than four times those for MMI use. NDB Open Data Japan showed more frequent PTU prescriptions than MMI prescriptions for women of reproductive age. Conclusions: This large-scale study confirmed that a variety of congenital malformations were identified as having significantly high RORs for MMI use, while diseases related to ANCA-associated vasculitis were specific to PTU.

Cancer-Specific miRNAs Extracted from Tissue-Exudative Extracellular Vesicles in Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinomas (OCCs) arise from endometriotic cysts that many women develop. Biomarkers for early OCC detection need to be identified. Extracellular vesicles have attracted attention as biomarker carriers. This study aims to identify cancer-specific miRNAs as novel OCC biomarkers using tissue-exudative extracellular vesicles (Te-EVs). Te-EVs were collected from four patients with OCC on one side and a normal ovary on the other side. Microarray analysis was performed to identify cancer-specific miRNAs in Te-EVs. Serum samples obtained before and after surgery from patients with OCC and atypical endometrial hyperplasia (AEH) (controls) were compared using real-time PCR to examine changes in the detected EV miRNA levels. Thirty-seven miRNAs were >2-fold upregulated on the OCC side compared with the normal ovarian side. We selected 17 miRNAs and created specific primers for 12 of these miRNAs. The levels of six EV miRNAs were significantly decreased in postoperative OCC serum compared to those in preoperative OCC serum. In contrast, no significant change was observed between the pre and postoperative values in the control group. We identified OCC tissue-specific miRNAs in the EVs secreted by OCC tissues. These EV miRNAs have potential for use as biomarkers for the early diagnosis and detection of OCC.

Validation of a Patient-Derived Xenograft Model for Cervical Cancer Based on Genomic and Phenotypic Characterization.

Patient-derived xenograft (PDX) models are useful tools for preclinical drug evaluation, biomarker identification, and personalized medicine strategies, and can be developed by the heterotopic or orthotopic grafting of surgically resected tumors into immunodeficient mice. We report the PDX models of cervical cancer and demonstrate the similarities among original and different generations of PDX tumors. Fresh tumor tissues collected from 22 patients with primary cervical cancer were engrafted subcutaneously into NOD.CB17-PrkdcSCID/J mice. Histological and immunohistochemical analyses were performed to compare primary and different generations of PDX tumors. DNA and RNA sequencing were performed to verify the similarity between the genetic profiles of primary and PDX tumors. Total RNA in extracellular vesicles (EVs) released from primary and PDX tumors was also quantified to evaluate gene expression. The total tumor engraftment rate was 50%. Histologically, no major differences were observed between the original and PDX tumors. Most of the gene mutations and expression patterns related to carcinogenesis and infiltration were similar between the primary tumor and xenograft. Most genes associated with carcinogenesis and infiltration showed similar expression levels in the primary tumor and xenograft EVs. Therefore, compared with primary tumors, PDX models could be potentially more useful for translational research.

Endometrial Cancer Patient-Derived Xenograft Models: A Systematic Review.

BACKGROUND: Because patient-derived xenograft (PDX) models resemble the original tumors, they can be used as platforms to find target agents for precision medicine and to study characteristics of tumor biology such as clonal evolution and microenvironment interactions. The aim of this review was to identify articles on endometrial cancer PDXs (EC-PDXs) and verify the methodology and outcomes. METHODS: We used PubMed to research and identify articles on EC-PDX. The data were analyzed descriptively. RESULTS: Post literature review, eight studies were selected for the systematic review. Eighty-five EC-PDXs were established from 173 patients with EC, with a total success rate of 49.1%. A 1-10 mm3 fragment was usually implanted. Fresh-fragment implantation had higher success rates than using overnight-stored or frozen fragments. Primary tumors were successfully established with subcutaneous implantation, but metastasis rarely occurred; orthotopic implantation via minced tumor cell injection was better for metastatic models. The success rate did not correspond to immunodeficiency grades, and PDXs using nude mice reduced costs. The tumor growth period ranged from 2 weeks to 13 months. Similar characteristics were observed between primary tumors and PDXs, including pathological findings, gene mutations, and gene expression. CONCLUSION: EC-PDXs are promising tools for translational research because they closely resemble the features of tumors in patients and retain molecular and histological features of the disease.

Comparison of Prognosis between Minimally Invasive and Abdominal Radical Hysterectomy for Patients with Early-Stage Cervical Cancer.

Minimally invasive surgery (MIS) is performed to treat cervical cancer patients; however, a recent study showed that MIS was associated with higher recurrence and death rate compared with abdominal radical hysterectomy (ARH). In the current study, the prognosis of patients with early-stage cervical cancer who underwent MIS with vaginal closure or ARH was evaluated. One hundred and eighty-two patients underwent radical hysterectomy for cervical cancer with stage of IA2, IB1, and IIA1. MIS was performed by laparoscopy or a robot using the vaginal closure method. Disease-free survival (DFS) and overall survival (OS) were evaluated between the groups. Among the patients, 67 underwent MIS and 115 underwent ARH. The recurrence rate was 4.5% in MIS patients and 3.5% in ARH patients with a median follow-up (interquartile range) of 36 (18-60) and 78 (48-102) months, respectively. DFS and OS were not different between the groups (3y-DFS, 95.3% vs. 96.1%, p = 0.6; 3y-OS, 100% vs. 100%, p = 0.06). In early-stage cervical cancer patients, MIS with vaginal closure did not increase the risk for recurrence or death. Surgical techniques and procedures to avoid spillage of tumor cells could be important for a better prognosis.

Patient-Derived Xenograft Models in Cervical Cancer: A Systematic Review.

BACKGROUND: Patient-derived xenograft (PDX) models have been a focus of attention because they closely resemble the tumor features of patients and retain the molecular and histological features of diseases. They are promising tools for translational research. In the current systematic review, we identify publications on PDX models of cervical cancer (CC-PDX) with descriptions of main methodological characteristics and outcomes to identify the most suitable method for CC-PDX. METHODS: We searched on PubMed to identify articles reporting CC-PDX. Briefly, the main inclusion criterion for papers was description of PDX created with fragments obtained from human cervical cancer specimens, and the exclusion criterion was the creation of xenograft with established cell lines. RESULTS: After the search process, 10 studies were found and included in the systematic review. Among 98 donor patients, 61 CC-PDX were established, and the overall success rate was 62.2%. The success rate in each article ranged from 0% to 75% and was higher when using severe immunodeficient mice such as severe combined immunodeficient (SCID), nonobese diabetic (NOD) SCID, and NOD SCID gamma (NSG) mice than nude mice. Subrenal capsule implantation led to a higher engraftment rate than orthotopic and subcutaneous implantation. Fragments with a size of 1-3 mm3 were suitable for CC-PDX. No relationship was found between the engraftment rate and characteristics of the tumor and donor patient, including histology, staging, and metastasis. The latency period varied from 10 days to 12 months. Most studies showed a strong similarity in pathological and immunohistochemical features between the original tumor and the PDX model. CONCLUSION: Severe immunodeficient mice and subrenal capsule implantation led to a higher engraftment rate; however, orthotopic and subcutaneous implantation were alternatives. When using nude mice, subrenal implantation may be better. Fragments with a size of 1-3 mm3 were suitable for CC-PDX. Few reports have been published about CC-PDX; the results were not confirmed because of the small sample size.

The therapeutic potential of exosomal miR-22 for cervical cancer radiotherapy.

Cervical cancer is the fourth-most prevalent malignancy in women. For advanced cervical cancer, radiotherapy is a major treatment. Micro RNAs (miRNAs) are small, noncoding RNAs that negatively regulate the target gene expression posttranscriptionally. miR-22 is frequently downregulated in various cancers including cervical cancer, and is associated with a poor prognosis in cervical cancer. Exosomes are small endosomally secreted vesicles that carry components such as proteins, messenger RNA (mRNA), DNA and miRNA. We investigated whether or not exosomes can efficiently deliver miR-22 to recipient cervical cancer cells and affect the gene expression in the cells, as well as assessed the role of exosomal miR-22 in radiosensitivity. Exosomes containing high levels of miR-22 were extracted by ultracentrifugation and then characterized by Western blotting, a nanoparticle tracking analysis and electron microscopy. The high presence of miR-22 in the exosome was confirmed by real-time polymerase chain reaction. After the administration of the collected exosomal miR-22 to SKG-II and C4-I cervical cancer cells, the level of miR-22 in the cells was significantly increased, indicating the absorption of the exosomal miR-22. When miR-22 encapsulated in exosomes was administered to the SKG-II cells, the level of c-Myc binding protein (MYCBP) and human telomerase reverse transcriptase (hTERT) was significantly decreased in correlation with increased radiosensitivity determined by a clonogenic assay. Taken together, these results suggest that the administration of exosomal miR-22 may be a novel drug delivery system for cervical cancer radiotherapy.

Oncologic outcomes for patients with endometrial cancer who received minimally invasive surgery: a retrospective observational study.

BACKGROUND: Laparoscopic hysterectomy has been performed for patients with endometrial cancer as minimally invasive surgery; however, the long-term outcomes of high-risk disease compared to open surgery remain unclear. METHODS: Eight hundred and eighty-three patients with endometrial cancer who underwent laparoscopic or abdominal hysterectomy were categorized into three groups. Low-risk disease was defined as stage IA disease with endometrioid carcinoma of grade 1 or 2. Uterine-confined disease was defined as stage IA disease with high-grade tumors or stage IB and II disease. Advanced disease was defined as stage III or IV disease. The progression-free survival (PFS) and overall survival (OS) rates were compared between laparoscopic and laparotomic hysterectomy. RESULTS: Among 478 patients with low-risk disease, including 226 with laparoscopy and 252 with laparotomy, the prognosis was not significantly different between the groups (3-year PFS rate, 97.4% vs. 97.1%, p = 0.8; 3-year OS rate, 98.6% vs. 98.3%, p = 0.9). Among the 229 patients with uterine-confined disease, including 51 with laparoscopy and 178 with laparotomy, the prognosis was not significantly different between the groups (3-year PFS rate, 90.5% vs. 85.5%, p = 0.7; 3-year OS rate, 91.3% vs. 92.5%, p = 0.8). Among the 176 patients with advanced disease, including 24 with laparoscopy and 152 with laparotomy, laparoscopic hysterectomy had a higher PFS rate and OS rate than laparotomic hysterectomy (3-year PFS rate, 74.5% vs. 51.5%, p = 0.01; 3-year OS rate, 92.3% vs. 75.1%, p = 0.03). CONCLUSIONS: Laparoscopic procedures are not associated with a poorer outcome than laparotomy in patients with advanced endometrial cancer or uterine-confined endometrial cancer.

Radiocesium distribution in the sediments of the Odaka River estuary, Fukushima, Japan.

Radiocesium that originated from the Fukushima Daiichi Nuclear Power Plant accident was deposited on the ground surface and has been transported via fluvial discharge, primarily in the form of particulates, to downstream areas and eventually to the ocean. During transportation, some of the radiocesium accumulated on the riverbed. In this study, we quantified the radiocesium deposition on the riverbed in the Odaka River estuary and investigated the radiocesium sedimentation process of the river bottom. Our results show that the radiocesium inventory in the seawater intrusion area is larger than those in the freshwater and marine parts of the estuary. Moreover, the particle-size distribution in the seawater intrusion area shows a high proportion of silt and clay particles compared with the distribution in other areas. The increased radiocesium inventory in this area is attributed to the sedimentation of fine particles caused by hydrodynamic factors (negligible velocity of the river flow) rather than flocculation factor by salinity variation.

The differential expression of miRNAs between ovarian endometrioma and endometriosis-associated ovarian cancer.

BACKGROUND: MicroRNAs (miRNAs) have been implicated to play a vital role in development, differentiation, cell proliferation and apoptosis. However, which miRNAs are actually associated with endometriosis-associated ovarian cancer remains controversial. METHODS: Serum and ascites samples were obtained from all patients. Serum samples from 5 cases of ovarian endometrioma and endometriosis-associated ovarian cancer each were submitted for comprehensive miRNA microarray profiling. We investigated the differential expression of miRNAs between the two groups to confirm the pivotal role of miRNAs. Quantitative reverse transcription-polymerase chain reaction validation of five selected miRNAs [miR-92a-3p, miR-486-5p, miR-4484, miR-6821-5p, and miR-7108-5p] was performed, and miR-486-5p expression analysis was followed by proliferation and wound healing assays, depending on the expression of miR-486-5p. RESULT: miR-486-5p expression in serum and ascites samples from endometriosis-associated ovarian cancer patients was significantly higher than that from ovarian endometrioma patients. Moreover, the miR-486-5p level in serum and ascites samples was significantly correlated with the severity of the endometriosis. The upregulation of miR-486-5p in immortalized ovarian endometrioma cells significantly increased proliferation and migration. In contrast, the downregulation of miR-486-5p in these cells significantly decreased proliferation and migration. CONCLUSION: miR-486-5p might function as an oncogenic miRNA in endometriosis-associated ovarian cancer and could be a noninvasive biomarker to prospect the severity of ovarian endometrioma.

The Protective Effect of Testosterone on the Ovarian Reserve During Cyclophosphamide Treatment.

INTRODUCTION: Cyclophosphamide, which is widely used to treat malignant disease, causes ovarian follicular atresia, which leads to premature ovarian insufficiency. The present study evaluated the protective effect of testosterone in preventing the decline in the ovarian reserve during cyclophosphamide treatment. METHODS: Using the COV434 human granulosa cell line, the protective effect of testosterone against cyclophosphamide was evaluated by immunocytochemistry, Western blotting and an MTS assay. The follicles in mouse ovaries and serum anti-Mullerian hormone were also assessed to evaluate the effects of testosterone. RESULTS: Testosterone suppressed the decrease in cell viability and apoptosis caused by cyclophosphamide treatment in vitro. In vivo, the number of atretic follicles in the mouse ovary was significantly lower in the testosterone plus cyclophosphamide group than in the cyclophosphamide alone group (p=0.03). The serum anti-Mullerian hormone was significantly higher in the testosterone plus cyclophosphamide group than in the cyclophosphamide alone group (16.2 [9.7-22.6]) vs 11.2 [8.9-12.1], p<0.01). The rate of cleaved Caspase-3 expression in the testosterone plus cyclophosphamide group was lower than that in the cyclophosphamide alone group (28.4% vs 48.6%, p=0.03). CONCLUSION: These findings indicated that testosterone has the potential to prevent ovarian damage induced by cyclophosphamide by protecting granulosa cells from cyclophosphamide-induced apoptosis.

Serum exosomal microRNA-34a as a potential biomarker in epithelial ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is a leading cause of cancer-related death in women, and thus an accurate diagnosis of the predisposition and its early detection is necessary. The aims of this study were to determine whether serum exosomal microRNA-34a (miR-34a) in ovarian cancer could be used as a potential biomarker. METHODS: Exosomes from OC patients' serum were collected, and exosomal miRNAs were extracted. The relative expression of miR-34a was calculated from 58 OC samples by quantitative real-time polymerase chain reaction. RESULTS: Serum exosomal miR-34a levels were significantly increased in early-stage OC patients compared with advanced-stage patients. Its levels were significantly lower in patients with lymph node metastasis than in those with no lymph node metastasis. Furthermore, its levels in the recurrence group were significantly lower than those in the recurrence-free group. CONCLUSIONS: Serum exosomal miR-34a could be a potential biomarker for improving the diagnostic efficiency of OC.

Effects of liraglutide and empagliflozin added to insulin therapy in patients with type 2 diabetes: A randomized controlled study.

AIMS/INTRODUCTION: Liraglutide and empagliflozin suppress cardiovascular events. However, reports on their long-term combined use with insulin therapy or direct comparisons of these drugs are limited. MATERIALS AND METHODS: This open-label, parallel-group, randomized controlled trial compared the effects of liraglutide and empagliflozin combined with insulin therapy in type 2 diabetes patients. Adult type 2 diabetes outpatients undergoing stable insulin therapy with glycated hemoglobin levels of 7.0-9.5% were enrolled. Participants received 0.9 mg/day liraglutide or 10 mg/day empagliflozin for 24 weeks. The primary end-point was the change in glycated hemoglobin levels from week 0 to 24. Body composition was assessed by dual-energy X-ray absorptiometry. RESULTS: A total of 64 insulin-treated patients were randomized to receive liraglutide or empagliflozin. We analyzed 61 patients (30 liraglutide and 31 empagliflozin) who could be followed up. Liraglutide induced greater changes in glycated hemoglobin and glycated albumin than empagliflozin (glycated hemoglobin -1.24 ± 0.15% vs -0.35 ± 0.11%, P < 0.0001; glycated albumin -4.4 ± 0.6% vs -2.4 ± 0.5%, P < 0.01). Bodyweight (-1.3 ± 0.4 kg vs -1.5 ± 0.3 kg, P = 0.69) or body fat mass/lean tissue mass; urinary albumin excretion (median -5.3 mg/g-creatinine [interquartile range -60.6, 9.9 mg/g-creatinine] vs -12.9 mg/g-creatinine [interquartile range -70.8, -2.0 mg/g-creatinine], P = 0.23); and frequency of hypoglycemia did not differ significantly between the groups over a period of 24 weeks. There were no cases of study discontinuation owing to adverse effects. CONCLUSIONS: Liraglutide addition to ongoing insulin therapy more effectively reduced glycated hemoglobin and glycated albumin levels than empagliflozin in patients with inadequately controlled type 2 diabetes.

MicroRNA-22 enhances radiosensitivity in cervical cancer cell lines via direct inhibition of c-Myc binding protein, and the subsequent reduction in hTERT expression.

MicroRNAs (miRs) influence the expression of their target genes post-transcriptionally and serve an important role in multiple cellular processes. The downregulation of miR-22 is associated with a poor prognosis in cervical cancer. However, the mechanisms underlying miR-22-mediated gene regulation and its function are yet to be elucidated. In the present study, the effect of miR-22 expression on the radiosensitivity of cervical cancer was investigated. First, miR-22 was either up- or downregulated to evaluate the regulation of the MYC-binding protein (MYCBP) in four cervical cancer cell lines (C-4I, SKG-II and SiHa). Notably, MYCBP expression was inversely associated with miR-22 induction. A dual-luciferase reporter gene assay revealed that miR-22 directly targets the MYCBP 3'-untranslated region. Subsequently, the level of human telomerase reverse transcriptase component (hTERT; an E-box-containing c-Myc target gene) was analyzed after the up- or downregulation of miR-22. Notably, miR-22-mediated repression of MYCBP reduced hTERT expression. In addition, the influence of miR-22 on radiosensitivity in C-4I, SKG-II and SiHa cells was examined using a clonogenic assay and in mouse xenograft models. Upregulation of miR-22 was associated with increased radiosensitivity. Furthermore, lentiviral transduction of miR-22 reduced the Ki-67 index while increasing the TUNEL index in xenograft tissue. The current findings indicate the potential utility of miR-22 in radiotherapy for cervical cancer.

Mineral composition characteristics of radiocesium sorbed and transported sediments within the Tomioka river basin in Fukushima Prefecture.

The deposited radiocesium in the Fukushima river basin is transported in the river systems by soil particles and redistributed in the downstream areas. Although predicting the behaviors of minerals that adsorb radiocesium and of radiocesium dissolved in river water within the river systems is essential, the dominant mineral species that adsorb radiocesium have not yet been comprehensively identified. We identify herein such mineral species by investigating the 137Cs distribution and the mineral species in each size fraction that are found in the bedload sediments from an upstream reservoir to an estuary within the Tomioka river basin located east of Fukushima Prefecture in Japan. In the fine sand sediment, which is the dominant fraction in terms of the 137Cs quantity in the river bedload, the 137Cs concentrations of the felsic and mafic minerals are comparable to that of micas. The mafic minerals contain 62% of the 137Cs in the fine sand fraction in the upstream area, while the felsic minerals contain the highest quantities of 137Cs in the downstream area. These results suggest that the quantification of the mineral species and the 137Cs concentration of each size fraction are critically important in predicting the behaviors of the minerals and radiocesium within the Fukushima river basin in the future.

Drug-induced hyperglycemia in the Japanese Adverse Drug Event Report database: association of evelolimus use with diabetes.

Some categories of drugs are known for causing hyperglycemia or diabetes such as steroids, antipsychotics, and immunosuppressant. However, there has been little evidence from studies about the proportion of each drug in the context of drug-induced diabetes. In this study, we used data from the Japanese Adverse Drug Event Report (JADER) database, a spontaneous reporting system database maintained at the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan, reported between April 2004 and June 2017. Among 459,250 reports of adverse drug reactions in JADER database, reported instances of the adverse event of hyperglycemia or diabetes were extracted. After the exclusion of anti-diabetes drugs, the drugs frequently implicated in the development of hyperglycemia or diabetes, including prednisolone, tacrolimus, everolimus, ribavirin, quetiapine, aripiprazole, interferon alfa-2b, risperidone, atorvastatin, dexamethasone, ciclosporin, nilotinib, methylprednisolone, or nivolumab, were identified. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, was manifested as the third most frequently associated drug with hyperglycemia or diabetes (340 cases), following prednisolone (694 cases) and tacrolimus (393 cases), and the reporting odds ratio (ROR 8.56, 95% CI 7.65-9.57) of this drug was higher than that of the two aforementioned drugs (ROR 3.96, 95% CI 3.66-4.28 and ROR 3.51, 95% CI 3.17-3.89). These results suggest that there is a potent association of evelolimus with hyperglycemia in clinical practice in Japan.

Metabolic recovery of lipodystrophy, liver steatosis, and pancreatic ß cell proliferation after the withdrawal of OSI-906.

Growth factor signaling via insulin receptor (IR) and IGF-1 receptor (IGF1R) plays several important roles in the pathogenesis of metabolic syndrome and diabetes. OSI-906 (linsitinib), an anti-tumor drug, is an orally bioavailable dual inhibitor of IR and IGF1R. To investigate the recovery from metabolic changes induced by the acute inhibition of IR and IGF1R in adult mice, mice were treated with OSI-906 or a vehicle for 7 days and the results were analyzed on the last day of injection (Day 7) or after 7 or 21 days of withdrawal (Day 14 or Day 28). On day 7, the visceral white fat mass was significantly reduced in mice treated with OSI-906 accompanied by a reduced expression of leptin and an increased expression of the lipolysis-related genes Lpl and Atgl. Interestingly, the lipoatrophy and the observed changes in gene expression were completely reversed on day 14. Similarly, liver steatosis and ß cell proliferation were transiently observed on day 7 but had disappeared by day 14. Taken together, these results suggest that this model for the acute inhibition of systemic IR/IGF1R signaling may be useful for investigating the recovery from metabolic disorders induced by impaired growth factor signaling.