Association of methotrexate polyglutamates concentration with methotrexate efficacy and safety in patients with rheumatoid arthritis treated with predefined dose: results from the MIRACLE trial.

OBJECTIVES: The usefulness of methotrexate-polyglutamates (MTX-PGs) concentration for management of rheumatoid arthritis has been debated. We aimed to clarify the association of MTX-PGs concentration with efficacy and safety in MTX-naïve patients initiating MTX in a prospective interventional clinical trial. METHODS: The MIRACLE trial enrolled 300 MTX-naïve patients. Oral MTX was initiated and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission according to the Simplified Disease Activity Index at week 24 were randomised to either the continued dose or reduced dose group and were started on subcutaneous adalimumab. We measured the concentrations of MTX-PGs in erythrocytes using liquid chromatography-tandem mass spectrometry and analysed the association of these concentrations with efficacy and safety. RESULTS: The mean concentration of total MTX-PGs increased with an increasing dose of MTX and continued to elevate for another 12 weeks after the dose was fixed. At week 24, the total MTX-PGs concentration was 110.5 (SD 43.8) nmol/L with MTX dose of 12.6 (3.0) mg/week (0.23 (0.07) mg/kg/week). During MTX monotherapy, the higher MTX-PGs concentration was an independent factor for lower disease activity; however, this association disappeared after adalimumab initiation in patients with continued MTX dose. Hepatotoxicity was related to the higher MTX-PGs concentration regardless of adalimumab use. The total MTX-PGs concentration was significantly elevated by lower estimated glomerular filtration rate, serum albumin and body mass index. CONCLUSIONS: The MIRACLE trial demonstrated that higher total MTX-PGs concentration in erythrocytes is related to the higher efficacy and lower safety of MTX. TRIAL REGISTRATION NUMBER: NCT03505008.

Functional Analysis of Seed Dormancy Genes by Biolistic Transient Gene Expression in Immature Embryos of Wheat.

Seed dormancy genes typically suppress germination and cell division. Therefore, overexpressing these genes can negatively affect tissue culture, interfering with the generation of transgenic plants and thus hampering the analysis of gene function. Transient expression in target cells is a useful approach for studying the function of seed dormancy genes. Here, we describe a protocol for transiently expressing genes related to seed dormancy in the scutellum of immature wheat (Triticum aestivum) embryos to analyze their effects on germination.

Analyzing factors affecting positivity in drive-through COVID-19 testing: a cross-sectional study.

BACKGROUND: Demand for COVID-19 testing prompted the implementation of drive-through testing systems. However, limited research has examined factors influencing testing positivity in this setting. METHODS: From October 2020 to March 2023, a total of 1,341 patients, along with their clinical information, were referred from local clinics to the Sasebo City COVID-19 drive-through PCR center for testing. Association between clinical information or factors related to the drive-through center and testing results was analyzed by Fisher's exact test and logistic regression models. RESULTS: Individuals testing positive exhibited higher frequencies of upper respiratory symptoms; cough (OR 1.5 (95% CI 1.2-1.8), p < 0.001, q = 0.005), sore throat (OR 2.4 (95% CI 1.9-3.0), p < 0.001, q < 0.001), runny nose (OR 1.4 (95% CI 1.1-1.8), p = 0.002, q = 0.009), and systemic symptoms; fever (OR 1.5 (95% CI 1.1-2.0), p = 0.006, q = 0.02), headache (OR 1.9 (95% CI 1.4-2.5), p < 0.001, q < 0.001), and joint pain (OR 2.7 (95% CI 1.8-4.1), p < 0.001, q < 0.001). Conversely, gastrointestinal symptoms; diarrhea (OR 0.2 (95% CI 0.1-0.4), p < 0.001, q < 0.001) and nausea (OR 0.3 (95% CI 0.1-0.6), p < 0.001, q < 0.001) were less prevalent among positives. During omicron strain predominant period, higher testing positivity rate (OR 20 (95% CI 13-31), p < 0.001) and shorter period from symptom onset to testing (3.2 vs. 6.0 days, p < 0.001) were observed compared to pre-omicron period. Besides symptoms, contact history with infected persons at home (OR 4.5 (95% CI 3.1-6.5), p < 0.001, q < 0.001) and in office or school (OR 2.9 (95% CI 2.1-4.1), p < 0.001, q < 0.001), as well as the number of sample collection experiences by collectors (B 7.2 (95% CI 2.8-12), p = 0.002) were also associated with testing results. CONCLUSIONS: These findings underscore the importance of factors related to drive-through centers, especially contact history interviews and sample collection skills, for achieving higher rates of COVID-19 testing positivity. They also contribute to enhanced preparedness for next infectious disease pandemics.

Proposal for Classifying the Emetogenicity of Oral Anticancer Agents with a Focus on PARP Inhibitors: A Prospective, Observational, Multicenter Study (JASCC-CINV 2002).

Background: Olaparib and niraparib (poly adenosine diphosphate [ADP]-ribose polymerase [PARP] inhibitors) have significant antitumor action in patients with ovarian cancer. However, the incidence of nausea and vomiting among patients on these drugs in clinical trials is rather high. There are no guidelines on antiemetic treatment for nausea caused by oral anticancer agents. This study aimed to investigate the incidence of nausea and vomiting caused by PARP inhibitors and the actual situation of antiemetic therapy in patients with gynecologic cancer. Methods: Patients with gynecologic cancer who were scheduled to receive PARP inhibitors were enrolled. Data on PARP inhibitor-induced nausea and vomiting were collected from patient diaries for 21 days. The primary endpoint was the incidence of vomiting during the 21 days after starting olaparib and niraparib. Results: Overall, between January 2020 and March 2023, 134 patients were enrolled. Of the 129 patients who were evaluated, 28 (21.7%) received prophylactic antiemetics for 21 days, and 101 (78.3%) did not. The overall incidence of PARP inhibitor-induced vomiting was 16.3%. The incidence of vomiting in the group that did not receive antiemetic prophylaxis was 13.9%. On dividing the group that did not receive antiemetic prophylaxis into the olaparib and niraparib subgroups, the incidence of vomiting was found to be 18.6% for the olaparib group and 10.3% for the niraparib group. Conclusion: The incidence of emesis without antiemetic prophylaxis among patients on olaparib and niraparib ranged from 10% to 30%. Therefore, olaparib and niraparib can be classified in the low emetogenic risk and prophylactic antiemetic therapy at the time of treatment initiation may be unnecessary.

Impact of Nutritional Status on Antibody Titer After Booster mRNA COVID-19 Vaccine Among Elderly Adults in Japan.

BACKGROUND: Published studies on mRNA coronavirus disease 2019 (COVID-19) vaccine effects focus on younger individuals, comprising the majority of the workforce. Studies in elderly adults are sparse. METHODS: In total, 107 subjects were recruited (median age 78; interquartile range [IQR], 58.5-90.5; range, 35-105 years). Factors associated with antibody titer after the third mRNA COVID-19 vaccination were compared between 49 elderly (age ≥80; median, 94; IQR, 86-97; range, 80-105 years) and 58 younger (age ≤79; median, 61; IQR, 46-71; range, 35-79 years) adults. RESULTS: Among body mass index (BMI) categories, the group of underweight elderly adults had a lower antibody titer compared to those with normal weight (P < .01 after 1, 3, and 5 months). Elderly adults were less likely to maintain effective antibody titer (≥4160 AU/mL) compared to younger adults: 76% versus 98%, P < .001 after 1 month, and 45% versus 78%, P < .001 after 3 months. Elderly adults who maintained effective antibody titer for 5 months had a higher BMI (22.9 kg/m2 vs 20.1 kg/m2, P = .02), and were less likely to have underweight BMI (0% vs 31%, P = .02) compared to the subjects who failed to maintain effective antibody titer. CONCLUSIONS: These results highlight the impact of nutritional status and the deleterious effect of underweight BMI on antibody titer and its maintenance among elderly adults following booster mRNA COVID-19 vaccination.

A case of simultaneous breast cancer and ovarian cancer based on a hereditary breast and ovarian cancer syndrome.

We experienced a relatively rare case of synchronous breast and ovarian cancer in a patient with hereditary breast and ovarian cancer syndrome (HBOC). Here, we report the usefulness of laparoscopic examination to determine the subsequent treatment strategy in cases of suspected concurrent multiple carcinomas. Our patient was diagnosed with breast cancer following detection of a right breast mass. She was diagnosed with HBOC as she was found to be harboring a germline pathogenic variant of breast cancer susceptibility gene 1 (BRCA1). Preoperative images suggested the presence of neoplastic masses in the abdominal cavity, and the possibility of metastatic peritoneal dissemination of breast cancer or concurrent overlapping of gynecological malignancies was considered. We decided to employ laparoscopic examination, and if simultaneous overlapping of cancers was suspected, we planned to further evaluate whether primary debulking surgery (PDS) for gynecological cancer was possible or not. Laparoscopy revealed the presence of ovarian cancer with neoplastic lesions on the bilateral ovaries and disseminations in the pelvic and abdominal cavities. The total predictive index was 0; therefore, PDS was considered feasible. We performed a total mastectomy, followed by laparotomy, and optimal surgery was achieved. The final diagnosis was simultaneous stage IIB invasive ductal breast carcinoma and stage IIIC high-grade serous ovarian carcinoma. In this case of suspected concurrent multiple carcinomas, laparoscopy was beneficial for decision-making regarding subsequent surgical treatment. We believe that the use of laparoscopy will enable simultaneous surgery for breast cancer and ovarian cancer to become one of the treatment strategies in the future.

Impact of sex and age on vaccine-related side effects and their progression after booster mRNA COVID-19 vaccine.

In mRNA COVID-19 vaccination, side effects after the first and second dose have been well reported. However, studies about side effects after booster vaccine are sparse. 272 healthcare workers who received the third mRNA COVID-19 vaccine were recruited, and impact of sex, age, and symptoms on the side effect progression was statistically analyzed. Females and younger adults had a higher frequencies of general fatigue, headache, joint pain, chills and axillary pain compared to males and elderly adults, respectively. In longitudinal analysis, prolonged time to recovery from side effects was found among females and younger adults. Finally, between the third and second dose vaccinations, 52% of subjects had a longer duration of side effects following the third vaccine compared to the second, and joint pain was the culprit symptom related to the prolonged duration of side effects. Following the second vaccine dose, 25% of subjects had a longer duration of side effects and asthma and ear fullness, which exacerbated the underlying allergic condition, and COVID arm symptom were the culprit symptoms. These highlight the impact of sex, age, and culprit symptoms on the progress of side effects following the booster mRNA COVID-19 vaccine.

Trastuzumab Deruxtecan for Human Epidermal Growth Factor Receptor 2-Expressing Advanced or Recurrent Uterine Carcinosarcoma (NCCH1615): The STATICE Trial.

PURPOSE: To investigate the efficacy and safety of trastuzumab deruxtecan, an antibody-drug conjugate targeting human epidermal growth factor receptor 2 (HER2) with a topoisomerase I inhibitor payload, in patients with uterine carcinosarcoma (UCS) expressing HER2. PATIENTS AND METHODS: Patients with recurrent UCS with HER2 immunohistochemistry scores ≥1+ previously treated with chemotherapy were included. Patients were assigned to the HER2-high (immunohistochemistry score ≥2+; n = 22) or low (immunohistochemistry score of 1+; n = 10) groups for primary and exploratory analyses, respectively. Trastuzumab deruxtecan 6.4 or 5.4 mg/kg was administered intravenously once every 3 weeks until unacceptable toxicity or disease progression. Dose modification was based on the updated recommended phase II dose for breast cancer to be 5.4 mg/kg. The primary end point was the objective response rate by central review in the HER2-high group. Secondary end points included the overall response rate (ORR) in the HER2-high group by investigator assessment, ORR in the HER2-low group, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: The ORR by central review in the HER2-high and HER2-low groups were 54.5% (95% CI, 32.2 to 75.6) and 70.0% (95% CI, 34.8 to 93.3) and those by investigator assessments were 68.2% and 60.0%, respectively. The median PFS and OS in the HER2-high and HER2-low groups were 6.2 and 13.3 months and 6.7 months and not reached, respectively. Grade ≥ 3 adverse events occurred in 20 patients (61%). Grades 1-2 and 3 pneumonitis/interstitial lung disease occurred in eight (24%) and one (3%) patient, respectively. CONCLUSION: Trastuzumab deruxtecan has efficacy in patients with UCS, regardless of HER2 status. The safety profile was generally consistent with that previously reported. Toxicities were manageable with appropriate monitoring and treatment.

Postoperative transverse colon necrosis due to mesenteric injury during laparoscopic surgery for endometrial carcinoma.

Hemorrhage and organ injury have been frequently reported as complications associated with trocar puncture in laparoscopic surgery. This report presents a case of delayed intestinal necrosis due to mesenteric injury. A 76-year-old woman who had a history of distal gastrectomy and adrenal insufficiency was diagnosed with stage IA endometrial cancer. We performed laparoscopic total hysterectomy and bilateral salpingo-oophorectomy. The upper abdominal wall and mesentery were adhered, and bleeding from the mesentery was noted during the first trocar puncture of the umbilical region, resulting in ligation and hemostasis. Abdominal pain and fever developed on the third postoperative day, and contrast-enhanced computed tomography demonstrated transverse colon perforation. Emergency laparotomy showed necrosis in the proximal transverse colon and a defect in the marginal artery. Mesenteric injury can lead to delayed intestinal necrosis without intraoperative macroscopic findings. In laparoscopic cases where adhesion is expected, trocar placement should be carefully considered.

Association between financial toxicity and health-related quality of life of patients with gynecologic cancer.

OBJECTIVES: Patients often struggle with their financial situation during cancer treatment due to treatment-related costs or loss of income. This resulting negative effect is called financial toxicity, which is a known as a side effect of cancer care. This study aimed to evaluate the association between financial toxicity and health-related quality of life among patients with gynecologic cancer using validated questionnaires. METHODS: In this multicenter study, patients with gynecologic cancer receiving anti-cancer drug treatment for > 2 months were recruited. Patients answered the COmprehensive Score for Financial Toxicity (COST) tool, EORTC-QLQ-C30, disease-specific tools (EORTC-QLQ-OV28/CX24/EN24), and EQ-5D-5L. Spearman's rank correlation coefficient was used to determine associations. RESULTS: Between April 2019 and July 2021, 109 cancer patients completed the COST questionnaire. The mean COST score was 19.82. Strong associations were observed between financial difficulty (r = - 0.616) in the EORTC-QLQ-C30 and body image (r = 0.738) in the EORTC-QLQ-CX24, while weak associations were noted between the global health status/quality of life (r = 0.207), EQ-5D-5L index score (r = 0.252), and several function and symptom scale scores with the COST score. CONCLUSIONS: Greater financial toxicity was associated with worse health-related quality of life scores, such as financial difficulty in gynecologic cancer patients and body image in cervical cancer patients as strong associations, and weakly associated with general health-related quality of life scores and several function/symptom scales.

Reduced versus maximum tolerated methotrexate dose concomitant with adalimumab in patients with rheumatoid arthritis (MIRACLE): a randomised, open-label, non-inferiority trial.

BACKGROUND: Efficacy of combination therapy with methotrexate and biological disease-modifying antirheumatic drugs is well established in the management of patients with rheumatoid arthritis; however, the optimal dose of methotrexate to administer with a tumour necrosis factor inhibitor remains unclear. We aimed to clarify the efficacy and safety of adalimumab combined with reduced methotrexate dose compared with the maximum tolerated methotrexate dose in patients with rheumatoid arthritis and an inadequate response to methotrexate monotherapy. METHODS: In this open-label, randomised controlled trial, we recruited methotrexate-naive patients with rheumatoid arthritis and a disease duration of less than 2 years across 24 secondary or tertiary care hospitals across Japan, South Korea, and Taiwan. At initiation, methotrexate was given orally and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission on the basis of the Simplified Disease Activity Index (SDAI) at week 24 were randomly assigned (1:1) to receive adalimumab (40 mg biweekly) combined with a continued maximum tolerated dose of methotrexate or adalimumab combined with a reduced dose of methotrexate. The primary endpoint was non-inferiority of adalimumab plus reduced-dose methotrexate to adalimumab plus maximal-dose methotrexate based on SDAI remission at week 48, assessed in the modified full-analysis set with a pre-specified non-inferiority margin of -15%, based on a two-sided 90% CI. Adverse events were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03505008 and has been completed. FINDINGS: From April 18, 2018, to June 2, 2020, from 323 patients screened, 300 were enrolled, and 291 patients were included in the full analysis set. The mean age was 57·7 years (SD 15·2), 217 (75%) were female, 74 (25%) were male, and all patients were of Asian ethnicity. The mean SDAI at study enrolment was 26·5 (SD 12·4). 52 patients discontinued the study before week 24 or at week 24 before randomisation. At week 24, 105 (36%) of 291 patients achieved remission and continued methotrexate monotherapy through week 48. 134 (46%) did not achieve remission at week 24 and were randomly assigned to receive adalimumab plus the maximum tolerated dose of methotrexate (n=68) or adalimumab plus reduced-dose methotrexate (n=66). Remission at week 48 was achieved in 25 (38%) of 66 and 27 (44%) of 61 patients, respectively, with an adjusted risk difference of 6·4% (90% CI -7·0 to 19·8), which met the non-inferiority margin of -15%. Adverse events after week 24 tended to be more frequent in the maximum tolerated dose group than in the reduced-dose group (24 [35%] vs 13 [20%], p=0·054). Between week 24 and 48, there were 14 serious adverse events (6 in the methotrexate monotherapy group, 5 in the adalimumab plus maximal-dose methotrexate, and 3 in the adalimumab plus reduced-dose methotrexate group), and no deaths. INTERPRETATION: The MIRACLE study showed that the efficacy of adalimumab combined with reduced methotrexate dose was not inferior to that with the maximum tolerated methotrexate dose, with a tendency to a better safety profile. FUNDING: Eisai.

Impact of Sex and Age on mRNA COVID-19 Vaccine-Related Side Effects in Japan.

mRNA COVID-19 vaccination was initiated worldwide in late 2020, and its efficacy has been well reported. However, studies about vaccine-related side effects are sparse. A total of 262 health care workers who received mRNA COVID-19 vaccine BNT162b2 were recruited, and their vaccine-related side effects were investigated. Impact of sex and age on the side effects was statistically analyzed. A higher number of vaccine-related side effects among females versus males was identified (median 3 versus 2, P < 0.05, after the first dose, and 5 versus 2.5, P < 0.01, after the second dose). General fatigue, headache, chills, and fever were the culprit adverse symptoms. In multivariate analysis, females had an increasing number of side effects after receiving their first (B = 0.7; 95% confidence interval [CI], 0.2 to 1.2) and second (B = 1.5; 95% CI, 0.7 to 2.2) vaccine doses compared to that of males. In age analysis, the older group (≥60 years old) had a lower number of side effects than the younger group (B = -0.5 with a 95% CI of -1.1 to -0.02 after the first vaccine dose, and B = -2.1 with a 95% CI of -2.9 to -1.2 after the second vaccine dose). Additionally, prolonged time to recovery was found among females (P = 0.003 after the first dose; P = 0.008 after the second dose). Specifically, symptoms of general fatigue, headache, itching, swelling at the injection site, and dizziness were the culprit symptoms affecting recovery time. Several cutaneous and membranous symptoms, including "COVID arm," were identified among females. These results highlight the impact of sex and age on side effects from mRNA COVID-19 vaccine and will aid in creating a safer vaccine. IMPORTANCE We demonstrate sex- and age-related impact on mRNA COVID-19 vaccine-related side effects, with a higher number and frequency of side effects and prolonged time to recovery in females compared to males and negative correlation between age and vaccine-related side effects. Identification of unique age- and sex-specific adverse symptoms will provide the opportunity to better understand the nature of sex- and age-associated immunological differences and develop safer and more efficacious vaccines.

Flowering Date1, a major photoperiod sensitivity gene in adzuki bean, is a soybean floral repressor E1 ortholog.

Adzuki bean is an important legume crop originating in temperate regions, with photoperiod in sensitivity being a key factor in its latitudinal adaptation. The Flowering Date1 (FD1) gene has a large effect on the photoperiodic response of flowering time, but the molecular basis for the effect of this locus is undetermined. The present study delimited the FD1 locus to a 17.1 kb sequence, containing a single gene, an E1 ortholog (VaE1). A comparison between Vigna angularis 'Shumari' (photoperiod insensitive) and 'Acc2265' (photoperiod sensitive) identified 29 insertions/deletions and 178 SNPs upstream of VaE1 in the FD1 locus. VaE1 expression in 'Acc2265' was greater under long-day than short-day conditions, whereas VaE1 expression in 'Shumari' was lower regardless of day length. These findings suggested that responsible gene of FD1 is a VaE1, which acts as a floral repressor by being upregulated in response to long-day conditions. The inability to upregulate VaE1 under long-day conditions was linked to its ability to flower under these conditions. These results provide greater understanding of the molecular control of a flowering date and clues enabling the breeding of adzuki bean at higher latitudes.

Outcomes of Pregnancies and Deliveries of Patients Who Underwent Fertility-Preserving Surgery for Early-Stage Epithelial Ovarian Cancer.

Some studies have shown increased risks of preterm birth, low birth weight, and cesarean delivery after oncologic treatment; others have shown the opposite. We evaluated the outcomes of pregnancies and deliveries of patients who underwent fertility-preserving surgery (FSS) for early-stage epithelial ovarian cancer (EOC) and examined their perinatal prognosis. This retrospective study included women with a history of stage IA or IC ovarian cancer reported in our previous study. The primary outcome was preterm birth after cancer diagnosis was considered. Secondary outcomes were neonatal morbidity and severe maternal morbidity. Thirty-one children were born to 25 women who had undergone FSS. The mean number of weeks at delivery was 38.7 ± 0.7, and the mean birth weight of infants was 3021 ± 160 g. With respect to pregnancy outcomes, 5 patients had preterm labor and 26 had full-term labor. The delivery mode was vaginal delivery in 18 patients and cesarean delivery in 13. Complications during pregnancy included placenta previa (one case) and pelvic abscess (one case). Except for three preterm infants with low birth weight, there were no other perinatal abnormalities. Pregnancy after fertility preservation in EOC has an excellent perinatal prognosis, although the cesarean delivery rate is high.

Validity of the COmprehensive Score for financial Toxicity (COST) in patients with gynecologic cancer.

OBJECTIVE: Financial toxicity is a financial burden of cancer care itself, which leads to worse quality of life and higher mortality and is considered an adverse effect. The COmprehensive Score for financial Toxicity (COST) tool is a patient-reported outcome measurement used to evaluate financial toxicity. We aimed to validate the internal consistency and reproducibility of the COST tool in patients with gynecologic cancer. METHODS: In this multicenter study covering the period April 2019 to July 2021, using the COST tool in Japan, patients diagnosed with ovarian, cervical, or endometrial cancer receiving systemic anti-cancer drug therapy for more than 2 months were eligible. Patients with no out-of-pocket costs for direct medical costs were excluded. The patients answered the initial test and a retest, which was completed from 2 to 14 days after the initial test. Internal consistency and reproducibility were assessed using Cronbach's alpha and intraclass correlation coefficient (ICC), respectively. Cronbach's alpha ≥0.8 indicates good internal consistency, and ICC ≥0.8 is highly reliable. RESULTS: A total of 112 patients (ovarian: 50, cervical: 26, endometrial: 36) responded to the initial test, and 89 patients answered the retest from 2 to 14 days after the initial test. The median patient age was 58 (range, 28-78) years. The median COST score was 19. Cronbach's alpha showed good internal consistency at 0.83 (95% CI 0.78 to 0.87). The ICC at 0.850 (95% CI 0.777 to 0.900) showed high reliability. CONCLUSIONS: The COST tool has good internal consistency and reliable reproducibility in patients with gynecologic cancer in Japan. The COST tool quantifies financial toxicity in the insurance system, where patients have limited out-of-pocket direct medical costs. The results support the use of the COST tool in patients with gynecologic cancer.

In Vitro Antibacterial Activity of Imipenem/Relebactam against Clinical Isolates in Japan.

Relebactam is a novel ß-lactamase inhibitor of Ambler class A and C ß-lactamases that has been developed in combination with imipenem/cilastatin for the treatment of carbapenem-resistant bacterial infections. In this study, we evaluated the in vitro antibacterial activity of imipenem/relebactam (IMR) against imipenem-nonsusceptible Enterobacterales and Pseudomonas aeruginosa isolates from Japan. Two sets of antibacterial susceptibility tests were conducted according to the susceptibility testing standard of the Clinical and Laboratory Standards Institute. In the first set, antibacterial susceptibility as measured by the MIC50/90 (MIC range) of IMR was assessed for the following 61 imipenem-nonsusceptible strains: 2 Enterobacter cloacae complex (not determined [0.25 µg/mL]), 33 Klebsiella aerogenes (0.5/1 µg/mL [0.5 to 1 µg/mL]), 2 Serratia marcescens (not determined [1 to 2 µg/mL]), and 24 P. aeruginosa (2/128 µg/mL [0.25 to >128 µg/mL]). In the second set, antibacterial susceptibility was assessed for the following 8 imipenem-nonsusceptible strains: 4 Escherichia coli, 1 E. cloacae complex and 3 Klebsiella pneumoniae. The MIC ranges of IMR for these strains were 0.25 to 0.5 µg/mL, 0.5 µg/mL, and 0.5 to 16 µg/mL, respectively. The antibacterial activity of IMR was similar to or lower than that of amikacin and comparable to or greater than those of other reference drugs. In conclusion, IMR has shown antibacterial activity against clinical isolates from Japan and, therefore, is expected to become a new therapeutic option for carbapenem-resistant infections in Japan. IMPORTANCE Carbapenem-resistant Enterobacterales and carbapenem-resistant Pseudomonas aeruginosa strains pose a global threat. Antibacterial activity of imipenem/relebactam (IMR) against clinical isolates of these bacteria from several global regions has been shown; however, as yet there are no reports on Japanese isolates. In this study, we evaluated the in vitro antibacterial activity of IMR against imipenem-nonsusceptible Enterobacterales and Pseudomonas aeruginosa isolates from Japan. The antibacterial activity of IMR against imipenem-nonsusceptible Enterobacterales was generally comparable to that of amikacin (AMK) and comparable to or higher than those of other reference drugs tested. The antibacterial activity of IMR against imipenem-nonsusceptible P. aeruginosa isolates was lower than that of AMK but comparable to or higher than those of other drugs. These results support the use of IMR as a new treatment option for infections due to Enterobacterales and P. aeruginosa strains that are resistant to existing ß-lactams and other antibacterial agents.

Efficacy and safety of standard of care with/without bevacizumab for platinum-resistant ovarian/fallopian tube/peritoneal cancer previously treated with bevacizumab: The Japanese Gynecologic Oncology Group study JGOG3023.

We investigated the efficacy and safety of further bevacizumab therapy in patients with platinum-resistant ovarian cancer whose disease had progressed after bevacizumab plus chemotherapy. In this multicenter, open-label, phase II trial (JGOG3023), patients were randomized 1:1 to a single-agent chemotherapy alone (either pegylated liposomal doxorubicin [40 or 50 mg/m2 administered intravenously], topotecan [1.25 mg/m2 intravenously], paclitaxel [80 mg/m2 intravenously], or gemcitabine [1000 mg/m2 intravenously]) or single-agent chemotherapy + bevacizumab (15 mg/m2 intravenously). The primary endpoint was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary endpoints were overall survival (OS), objective response rate (ORR), and response rate according to Gynecological Cancer Intergroup cancer antigen 125 criteria. In total, 103 patients were allocated to chemotherapy (n = 51) or chemotherapy + bevacizumab (n = 52). Median investigator-assessed PFS was 3.1 and 4.0 mo in each group, respectively (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.32-0.90, P = .0082). Median OS was 11.3 and 15.3 mo in each group, respectively (HR = 0.67, 95% CI: 0.38-1.17, P = .1556). Respective ORRs were 13.7% and 25.0% (P = .0599) and response rates were 16.7% and 21.4% (P = .8273). The incidence of grade ≥3 treatment-related AEs was 42.0% in the chemotherapy group and 54.9% in the chemotherapy + bevacizumab group; AEs were well tolerated, with only 2 and 12 events leading to discontinuation of therapy, respectively. Bevacizumab was effective beyond progressive disease and AEs were manageable. The observed improvement in PFS requires further verification.

Neoadjuvant chemotherapy for Ewing's sarcoma family tumors of the uterine cervix: A case report.

Ewing's sarcoma family tumors of the uterine cervix are extremely rare and, thus, an optimal treatment strategy has not yet been established. To the best of our knowledge, 28 cases were reported in the English literature between 1996 and 2020, and treatments involved surgery, neoadjuvant chemotherapy, adjuvant chemotherapy, and radiotherapy. The vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide (VDC-IE) protocol increased the survival rate of patients with non-metastatic Ewing's sarcoma family tumors. We herein present a case of a Ewing's sarcoma family tumor of the cervix in a one-month postpartum woman treated with neoadjuvant chemotherapy using the VDC-IE protocol and radical hysterectomy followed by adjuvant chemotherapy, and discussed the diagnosis and treatment of this tumor through a literature review.

Mapping of QTLs controlling epicotyl length in adzuki bean (Vigna angularis).

Epicotyl length (ECL) of adzuki bean (Vigna angularis) affects the efficiency of mechanized weeding and harvest. The present study investigated the genetic factors controlling ECL. An F2 population derived from a cross between the breeding line 'Tokei1121' (T1121, long epicotyls) and the cultivar 'Erimo167' (common epicotyls) was phenotyped for ECL and genotyped using simple sequence repeats (SSRs) and single-nucleotide polymorphism (SNP) markers. A molecular linkage map was generated and fifty-two segregating markers, including 27 SSRs and 25 SNPs, were located on seven linkage groups (LGs) at a LOD threshold value of 3.0. Four quantitative trait loci (QTLs) for ECL, with LOD scores of 4.0, 3.4, 4.8 and 6.4, were identified on LGs 2, 4, 7 and 10, respectively; together, these four QTLs accounted for 49.3% of the phenotypic variance. The segregation patterns observed in F5 residual heterozygous lines at qECL10 revealed that a single recessive gene derived from T1121 contributed to the longer ECL phenotype. Using five insertion and deletion markers, this gene was fine mapped to a ~255 kb region near the end of LG10. These findings will facilitate marker-assisted selection for breeding in the adzuki bean and contribute to an understanding of the mechanisms associated with epicotyl elongation.

Impact of plasma 5-hydroxyindoleacetic acid, a serotonin metabolite, on clinical outcome in septic shock, and its effect on vascular permeability.

Septic shock is characterized by dysregulated vascular permeability. We hypothesized that the vascular permeability of endothelial cells (ECs) would be regulated by serotonin via serotonin-Rho-associated kinase (ROCK) signaling. We aimed to determine the impact of 5-hydroxyindoleacetic acid (5-HIAA) on septic shock as a novel biomarker. Plasma 5-HIAA levels and disease severity indices were obtained from 47 patients with sepsis. The association between 5-HIAA levels and severity indices was analyzed. Permeability upon serotonin stimulation was determined using human pulmonary microvascular ECs. 5-HIAA were significantly higher in septic shock patients than in patients without shock or healthy controls (p = 0.004). These elevated levels were correlated with severity indexes (SOFA score [p < 0.001], APACHE II [p < 0.001], and PaO2:FiO2 [p = 0.02]), and longitudinally associated with worse clinical outcomes (mechanical ventilation duration [p = 0.009] and ICU duration [p = 0.01]). In the experiment, serotonin increased the permeability of ECs, which was inhibited by the ROCK inhibitor (p < 0.001). Serotonin increases vascular permeability of ECs via ROCK signaling. This suggests a novel mechanism by which serotonin disrupts endothelial barriers via ROCK signaling and causes the pathogenesis of septic shock with a vascular leak. Serotonin serves as a novel biomarker of vascular permeability.