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Urinary tract infection (UTI) and pyelonephritis cause urosepsis, which can become life threating. Sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors, a class of oral anti-diabetic drugs, may increase the risk of UTI and pyelonephritis, as observed from their mechanism of action. Patients with diabetes receiving SGLT2 inhibitors are often concomitantly administered other antidiabetic, antidyslipidemic, or antihypertensive drugs. To determine if drug-drug interactions (DDIs) between SGLT2 inhibitors and these medications increased the risk of UTI and pyelonephritis, we analyzed the Food and Drug Administration Adverse Event Reporting System (FAERS) database. We applied Norén's and Gosho's methods for detecting DDIs. FAERS contains records describing 14 526 398 patient characteristics, 54 290 663 drug properties, and 47 252 416 reactions/events. We found 23 drug combinations that could induce UTI and pyelonephritis, such as SGLT2 inhibitors administered with dipeptidyl peptidase-4 inhibitors, thiazolidinediones, glinides, statins, angiotensin II receptor blockers, and calcium channel blockers. Combination therapy with the drugs detected in our analyses would show potential interactions that could result in UTI and pyelonephritis in patients with diabetes mellitus. However, owing to various limitations, these results must be confirmed by additional analyses.

Distal bypass combined with a free flap is a frequent surgical option for ischemic ulcers of the lower extremities. Here, we describe a patient in whom there was a change in the direction of blood flow in a distal bypass graft. A 68-year-old male patient with an ischemic ulcer on his left heel was referred to our facility by a local dermatology clinic. Surgical revascularization was performed between the popliteal artery and the dorsalis pedis artery using an ipsilateral great saphenous vein as the graft vessel. The wound site did not heal postoperatively, so it was covered using a free latissimus dorsi muscle flap. At the same time, the thoracodorsal artery was anastomosed to the bypass graft in an end-to-side manner to serve as a nutrient vessel. Initially, blood flow into the thoracodorsal artery from the bypass graft was via the popliteal artery. However, after occlusion of the proximal anastomotic site of the bypass graft, blood flow into the thoracodorsal artery from the bypass graft was via the dorsalis pedis artery, which was the distal anastomotic site. The change in direction of blood flow might have been the result of an increase in blood flow in the collateral vessels in the ischemic lower leg, which eventually overwhelmed the blood flow in the bypass graft.

The primary analysis of the phase 1/2 ISLANDs study in Japanese individuals with relapsed/refractory multiple myeloma (RRMM) showed that isatuximab monotherapy was well tolerated and effective, even in participants with high-risk cytogenetic abnormalities. Here, we report a prespecified second analysis conducted 20 months after the first dosing of the last participant (ClinicalTrials.gov identifier: NCT02812706). The primary objectives were to evaluate the safety and tolerability of isatuximab in phase 1 and to evaluate the efficacy of isatuximab, including assessment of overall response rate (ORR) at the recommended dose (RD), in phase 2. In phase 1, three participants received isatuximab 10 mg/kg every week (QW) for 4 weeks/cycle followed by every 2 weeks (Q2W) and five participants received 20 mg/kg QW/Q2W. Since no dose-limiting toxicities occurred in phase 1, 20 mg/kg QW/Q2W was identified as the RD for the phase 2 study (n = 28). At the time of data cut-off, three participants (one in phase 1 and two in phase 2) continued to receive isatuximab; disease progression and treatment-related adverse events were the most common reasons for treatment discontinuation. The overall safety profile was consistent with the primary analysis. One death, not related to isatuximab treatment, was reported since the first analysis. The ORR and clinical benefit rate remained unchanged from the primary analysis at 36.4% (95% confidence interval [CI]: 20.4%-54.9%) and 54.5% (95% CI: 36.4%-71.9%), respectively. The median progression-free survival (PFS) was 5.6 months, longer than the median PFS reported in the primary analysis (4.7 months), whereas median overall survival was not reached. Overall, isatuximab 20 mg/kg QW/Q2W had an acceptable safety and tolerability profile and showed promising antitumor activity in Japanese individuals with RRMM.

Ferroptosis is a regulated cell death due to the iron-dependent accumulation of lipid peroxide. Ferroptosis is known to constitute the pathology of ischemic diseases, neurodegenerative diseases, and steatohepatitis and also works as a suppressing mechanism against cancer. However, how ferroptotic cells affect surrounding cells remains elusive. We herein report the transfer phenomenon of lipid peroxidation and cell death from ferroptotic cells to nearby cells that are not exposed to ferroptotic inducers (FINs). While primary mouse embryonic fibroblasts (MEFs) and NIH3T3 cells contained senescence-associated β-galactosidase (SA-β-gal)-positive cells, they were decreased upon induction of ferroptosis with FINs. The SA-β-gal decrease was inhibited by ferroptotic inhibitors and knockdown of Atg7, pointing to the involvement of lipid peroxidation and activated autophagosome formation during ferroptosis. A transfer of cell culture medium of cells treated with FINs, type 1 or 2, caused the reduction in SA-β-gal-positive cells in recipient cells that had not been exposed to FINs. Real-time imaging of Kusabira Orange-marked reporter MEFs cocultured with ferroptotic cells showed the generation of lipid peroxide and deaths of the reporter cells. These results indicate that lipid peroxidation and its aftereffects propagate from ferroptotic cells to surrounding cells, even when the surrounding cells are not exposed to FINs. Ferroptotic cells are not merely dying cells but also work as signal transmitters inducing a chain of further ferroptosis.

[Background] Ovarian teratomas are the most common ovarian tumors in children. Fertility-sparing surgery (FSS) is often recommended owing to its advantage of fertility preservation. We examined the validity of FSS in pediatric patients with ovarian teratomas. [Procedure] We retrospectively reviewed the medical records of patients who underwent initial surgery for ovarian teratomas in our department between 1972–2021. Patients were divided into two groups: oophorectomy (OVX) group and FSS group. Clinical characteristics, perioperative characteristics, and outcomes were compared between the groups. [Results] Forty-six patients underwent initial surgery (OVX: 25 patients; FSS: 21 patients). There were no differences between the groups in terms of age, pathological diagnosis, affected side, ovarian torsion, postoperative complications, recurrence rate, or length of postoperative follow-up. Regarding pathological diagnosis, immature teratomas were found only in the OVX group (p = 0.0161). The tumor size was larger in the OVX group (p = 0.0104). Regarding perioperative findings, operation time was longer in the FSS group (p = 0.0071) and bleeding volume was higher in the OVX group (p = 0.0070). The number of days until the start of oral intake and the length of hospital stay postoperatively were shorter in the FSS group (p = 0.0002 and p < 0.0001, respectively). [Conclusion] We demonstrated the advantages of FSS, including its minimally invasive approach and comparable outcomes in terms of tumor recurrence; the operation time was longer. Since both FSS and OVX are associated with a risk of tumor recurrence, long-term follow-up in anticipation of adult transition is necessary.

Isatuximab, an anti‐CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open‐label, single‐arm, multicenter, phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose‐limiting toxicities occurred; the recommended dose for the single‐arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high‐risk cytogenetic abnormalities had comparable results. In phase 2, the median progression‐free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high‐risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as NCT02812706., This open‐label, single‐arm, multicenter phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). The results demonstrated that isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM, including high‐risk cytogenetic patients.

Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors that arise from chromaffin cells. We report the case of an 11-year-old boy with no history of hypertension who presented with an abdominal mass arising from the retroperitoneum. During laparoscopic surgery, the patient developed a hypertensive crisis with a peak systolic blood pressure of over 270 mmHg, although we were able to continue to perform laparoscopic resection. Even if no concomitant symptoms due to catecholamine production are observed before surgery, as in this case, blood pressure may fluctuate during surgery. Intraoperative and postoperative management should be considered in cooperation with anesthesiologists.

In the pivotal phase III, randomized, multicenter ICARIA-MM study (NCT02990338), isatuximab plus pomalidomide and dexamethasone (Isa-Pd) improved progression-free survival and overall response rate versus pomalidomide and dexamethasone (Pd) in the overall population of patients with relapsed/refractory multiple myeloma.In this predefined subgroup analysis, efficacy, and safety between East Asian patients and the overall population were assessed.In total, 36 East Asian patients were included (Japanese, n = 13; Korean, n = 9; Taiwanese, n = 14). At a median follow-up of 11.6 months, median progression-free survival was not reached (95% confidence interval [CI] 5.80-not calculable) in the Isa-Pd arm and was 7.9 months (95% CI 2.90-not calculable) in the Pd arm. The hazard ratio for the between-group difference was 0.52 (95% CI 0.19-1.39), which was similar to the overall population (hazard ratio, 0.60; 95% CI 0.44-0.82). No new safety signals were observed, except that a higher proportion of patients in the East Asian population experienced Grade ≥ 3 neutropenia compared with the overall population.These results confirm the efficacy of Isa-Pd in East Asian patients with relapsed/refractory multiple myeloma, and the related safety data are consistent with those observed in the overall population and are manageable.

We performed distal bypass and free flap transfer in a single-stage operation to repair an extensive soft tissue defect in an ischemic foot of an 84-year-old woman. The nutrient artery of the free flap was anastomosed to the bypass graft in an end-to-side manner. Subsequently, the bypass graft became occluded on several occasions. Although intravascular and surgical interventions were performed each time, the bypass graft eventually became completely occluded. However, despite late occlusion of the nutrient artery, the free flap has remained viable and the patient is ambulatory. The time required for a transplanted free flap to become completely viable without a nutrient artery is likely longer for an ischemic foot compared with a healthy foot. However, the exact period of time required is not known. A period of month was required in our patient. We report this case to help clarify the process by which a free flap becomes viable when applied to an ischemic foot.

Background This study aimed to compare the clinical outcomes of intestinal transplantation (ITX) between 2 groups by using medications for induction treatment and assess the utility of the current protocol. Methods From 2003 to 2020, 11 patients underwent ITX. Recipients were classified into 2 groups: group IL-2Ra (interleukin-2 receptor antagonist therapy, n = 6) and ATG (rabbit antithymocyte globulin therapy, n = 5). We conducted a retrospective review of patient and graft survival rates and the postoperative course. Results The 1-, 5-, and 10-year patient and graft survival rates of the 11 primary grafts in the 11 recipients were 100%, 88.9%, 62.2% and 90.0%, 78.8%, 56.3%, respectively. The median duration of follow-up for the IL-2Ra and ATG groups was 197.3 and 87.3 months, respectively. The 1-, 5-, and 10-year patient survival rates were 100%, 83.3%, 50% and 100%, 100%, 100% for the IL-2Ra and ATG groups, respectively (P = .25) and 83.3%, 66.7%, 33.3% and 100%, 100%, 100% for graft survival in the IL-2Ra and ATG groups, respectively (P = .08). The incidence of moderate and severe acute rejection was 100% and 20% in the IL-2Ra and ATG groups, respectively (P = .02). The 1- and 5-year moderate and severe rejection-free survival rates were 33.3%, 0% and 80%, 80% in the IL-2Ra and ATG groups, respectively (P = .04). Conclusions ATG significantly suppressed moderate and severe acute rejection compared with IL-2Ra, thereby showing better short- and mid-term rejection-free survival rates. Additional clinical experience is needed to determine the optimal regimen for the management of ITX recipients.

Our institution employs rectoplasty with a posterior triangular colonic flap (RPTCF) for classic-type Hirschsprung’s disease. Recently, we employed a modified Soave procedure: transanal endorectal pull-through with rectoanal myotomy (TEPTRAM). In both procedures, the internal sphincter muscle is completely divided vertically at the 6 o’clock position. Unlike RPTCF, TEPTRAM does not require abdominal manipulation. We aimed to verify the usefulness of TEPTRAM. 64 patients with classic-type Hirschsprung’s disease who underwent surgery between 1970 and 2017 were divided into group R (RPTCF, 47 cases) and group T (TEPTRAM, 17 cases). We compared the defecation function of the groups. No patient showed fecal incontinence (R: 0/41, T: 0/10, ns). Three patients (6%) in group R and four (24%) in group T developed postoperative enterocolitis (P = 0.16). Three patients (10%) in group R and one (20%) in group T needed an enema (P = 0.36). There was no adverse effect of rectoanal myotomy; incontinence was not observed in either procedure. Although there was no significant difference, the incidences of enterocolitis and constipation were slightly higher in group T, perhaps because of the residual muscle cuff; therefore, it is necessary to provide best care with attention to constipation immediately after surgery.

While planning clinical trials, when simple formulas are unavailable to calculate sample size, statistical simulations are used instead. However, one has to spend much computation time obtaining adequately precise and accurate simulated sample size estimates, especially when there are many scenarios for the planning and/or the specified statistical method is complicated. In this article, we summarize the theoretical aspect of statistical simulation-based sample size calculation. Then, we propose a new simulation procedure for sample size calculation by fitting the probit model to simulation result data. From the theoretical and simulation-based evaluations, it is suggested that the proposed simulation procedure provide more efficient and accurate sample size estimates than ordinary algorithm-based simulation procedure especially when estimated sample sizes are moderate to large, therefore it would help to dramatically reduce the computational time required to conduct clinical trial simulations.

We proposed a statistical criterion to detect drug-drug interactions causing adverse drug reactions in spontaneous reporting systems. The used criterion quantitatively measures the discrepancy between the observed and expected number of adverse events via chi-square statistics. We compared the performance of our method with that of Noren et al. (Stat Med 2008; 27 (16): 3057–3070) through a simulation study. When the number of events for a combination of two drugs was equal to or lower than two, the false positive rate for our method ranged from 0.01 to 0.08, whereas the rate for Noren’s method ranged from 0.01 to 0.06. The sensitivity for our method ranged from 0.09 to 0.29, whereas the sensitivity for Noren’s method ranged from 0.03 to 0.24. The area-under-the-receiver operating characteristic curve for our method was significantly larger than that for Noren’s methods regardless of simulation settings. The proposed method was also applied to the Food and Drug Administration Adverse Event Reporting System database, and a recognized drug-drug interaction was detected. The proposed criterion controlled false positives at an acceptable level and had higher sensitivity than that of Noren’s method had when events were rare.

A Bayesian confidence propagation neural network (BCPNN) is a signal detection method used by the World Health Organization Uppsala Monitoring Centre to analyze spontaneous reporting system databases. We modify the BCPNN to increase its sensitivity for detecting potential adverse drug reactions (ADRs). In a BCPNN, the information component (IC) is defined as an index of disproportionality between the observed and expected number of reported drugs and events. Our proposed method adjusts the IC value by borrowing information about events that have occurred in drugs defined as similar to the target drug. We compare the performance of our method with that of a traditional BCPNN through a simulation study. The false positive rate of the proposed method was lower than that of the traditional BCPNN method and close to the nominal value, 0.025, around the true difference in ICs between the target drug and similar drugs equal to 0. The sensitivity of the proposed method was much higher than that of the traditional BCPNN method in case in which the difference in ICs between the target drug and similar drugs ranges from 0 to 2. When applied to a database managed by Japanese regulatory authority, the proposed method could detect known ADRs earlier than the traditional method. The proposed method is a novel criterion for early detection of signals if similar drugs have the same tendencies. The proposed BCPNN tends to have higher sensitivity when the true difference is greater than 0.