Dose Rate Effect on Cell Survival in BNCT.

The output constancy of the accelerator used for boron neutron capture therapy (BNCT) is essential to ensuring anti-tumor efficacy and safety. BNCT as currently practiced requires a wide variety of beam quality assessments to ensure that RBE dose errors are maintained within 5%. However, the necessity of maintaining a constant beam dose rate has not been fully discussed. We therefore clarified the effect of different physical dose rates of the accelerator BNCT on biological effects. SAS and A172 cells exposed to 10B-boronophenylalanine were irradiated using a neutron beam (normal operating current, 100 µA) at the Aomori Quantum Science Center. Thermal neutron flux was attenuated to 50.0 ± 0.96% under 50 µA irradiation compared to that under 100 µA irradiation. Cells were given physical doses of 1.67 and 3.36 Gy at 30 and 60 mC, respectively, and survival was significantly increased after 50 µA irradiation for both cell types (p = 0.0052 for SAS; p = 0.046 for A172, for 60 mC). Differences in accelerator BNCT beam dose rates have non-negligible effects on biological effects. Dose rate fluctuations and differences should not be easily permitted to obtain consistent biological effects.

The Impact of Nutritional Support on Survival Outcomes in Patients with Advanced Gastric Adenocarcinoma Treated with Chemotherapy.

Malnutrition and cachexia occur commonly in patients with advanced gastric cancer (AGC). This study elucidated the effect of nutritional support (NS) on survival outcomes among patients with AGC undergoing chemotherapy. We retrospectively evaluated new AGC cases at our institute between January 2015 and January 2021. Inclusion criteria were unresectable or recurrent chemotherapy-treated gastric adenocarcinoma, ECOG performance status (PS) 0-2, and adequate organ function. Time to treatment failure (TTF) and overall survival (OS) were evaluated, and univariate and multivariate analyses identified prognostic factors. A total of 103 eligible patients were separated into groups: 69 patients (67%) into NS and 34 (33%) into routine care (RC). The median follow-up time was 11.0 mo, (0.5-92). NS was offered to patients with poorer PS (p = 0.03), Glasgow prognostic score (GPS) positivity (p = 0.001), and high neutrophil-to-lymphocyte ratios (cut-off ≤ 3, p = 0.02). Median OS and TTF in the RC and NS groups were 11.6 and 10.4 mo, (p = 0.99) and 4.2 and 5.5 mo, (p = 0.07), respectively. Multivariate analyses identified NS (hazard ratio [HR] = 0.53, p = 0.01) and GPS positivity for TTF, and low body mass index (HR = 2.03, p = 0.007) and GPS positivity (HR = 2.25, p = 0.001) for OS as significant prognostic factors. Thus, NS with chemotherapy is a potentially effective intervention for AGC.

Oscillation of Cdc20-APC/C-mediated CAMDI stability is critical for cortical neuron migration.

Radial migration during cortical development is required for formation of the six-layered structure of the mammalian cortex. Defective migration of neurons is linked to several developmental disorders such as autism and schizophrenia. A unique swollen structure called the dilation is formed in migrating neurons and is required for movement of the centrosome and nucleus. However, the detailed molecular mechanism by which this dilation forms is unclear. We report that CAMDI, a gene whose deletion is associated with psychiatric behavior, is degraded by cell division cycle protein 20 (Cdc20)-anaphase-promoting complex/cyclosome (APC/C) cell-cycle machinery after centrosome migration into the dilation in mouse brain development. We also show that CAMDI is restabilized in the dilation until the centrosome enters the dilation, at which point it is once again immediately destabilized. CAMDI degradation is carried out by binding to Cdc20-APC/C via the destruction box degron of CAMDI. CAMDI destruction box mutant overexpression inhibits dilation formation and neuronal cell migration via maintaining the stabilized state of CAMDI. These results indicate that CAMDI is a substrate of the Cdc20-APC/C system and that the oscillatory regulation of CAMDI protein correlates with dilation formation for proper cortical migration.

Efficacy of modified thoracoabdominal nerves block through perichondrial approach in open gynecological surgery: a prospective observational pilot study and a cadaveric evaluation.

BACKGROUND: Modified thoracoabdominal nerves block through perichondrial approach (M-TAPA) was first described as a peripheral nerve block by Tulgar in 2019. This technique provides an analgesic effective range from Th7-11 with a single puncture per side. Although the efficacy and effective duration of M-TAPA have been reported, further examination is required. Therefore, this study aimed to evaluate the analgesic range and effective duration of M-TAPA in open gynecologic surgery. METHODS: Following approval, 10 adult female patients scheduled for open radical hysterectomy via a vertical incision or laparotomy using a midline incision from under the xiphoid process to the symphysis pubis were enrolled. The primary outcome was the number of anesthetized dermatomes at 2 and 24 h postoperatively. Secondary outcomes included numerical rating scale scores and the total amount of fentanyl used. Cadaveric evaluation was performed to assess the spread of the dye. RESULTS: The median numbers (interquartile range) of anesthetized dermatomes at 2 and 24 h postoperatively were 6 (5-7) and 6.5 (5-7) in the anterior cutaneous branch area and 5 (4-7) and 7 (5-7) in the lateral cutaneous branch area, respectively. There was an 85% chance of simultaneously acquiring analgesia in areas innervated by Th8-11, including complete block in areas innervated by the anterior cutaneous branches of Th9-10. Cadaveric evaluation showed the spread of the dye in Th8-11. CONCLUSIONS: M-TAPA may have analgesic effects in the areas supplied by the anterior cutaneous branches of Th8-11. TRAIL REGISTRATION: IRB approval (No.2700; registered on July 10, 2020) and registration (UMIN Clinical Trials Registry: UMIN000041137 ; registered on July 17, 2020).

Clinical outcomes in pregnant women with coronavirus disease 2019 in a perinatal medical centre in Japan: a retrospective study of the first 1 year of the pandemic.

In this retrospective study, we analysed clinical and demographic data from the medical records of 31 pregnant women with coronavirus disease 2019 (COVID-19) who were treated at our hospital between April 2020 and April 2021. The most common symptom was a fever; ∼10% of patients were asymptomatic. One patient with rapidly worsening pneumonia needed a Caesarean Section at 30 weeks and was admitted for intensive care. Twelve patients received perinatal care in our hospital (10 live births, one stillbirth, and one artificial abortion). Six patients delivered vaginally; the others delivered via caesarean section. Two patients had complications, including severe hypertensive disorders and preeclampsia. All patients recovered from COVID-19. Severe acute respiratory syndrome coronavirus 2 was not detected in the placenta, umbilical cord, cord blood, amniotic fluid, vaginal fluid, or breast milk in any patient. There were no neonatal adverse outcomes. The possibility of transmitting the coronavirus to pregnancy-related samples was low.IMPACT STATEMENTWhat is already known on the subject? COVID-19 has been affecting different countries in diverse ways, and the incidence, mortality, and morbidity rates of patients with COVID-19 vary widely by country or region and race. These differences in results may reflect racial differences and differences in national health care systems. Moreover, the information about the perinatal outcomes of pregnant women with COVID-19 and their newborns from Japan is limited.What do the results of this study add to what is known? We described the perinatal outcomes of 31 Japanese pregnant women with COVID-19 who were managed safely in a perinatal medical centre in Tokyo Japan, during the first 1 year of the pandemic.What are the implications of these findings for clinical practice and/or further research? Severe pneumonia and perinatal complications may occur, although no maternal and neonatal deaths were observed for COVID-19-positive pregnant women in our facility. Therefore, it is important to prevent this infection during pregnancy with the provision of effective medical care.

Integrated molecular and clinical analysis of low-grade gliomas in children with neurofibromatosis type 1 (NF1).

Low-grade gliomas (LGGs) are the most common childhood brain tumor in the general population and in individuals with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Surgical biopsy is rarely performed prior to treatment in the setting of NF1, resulting in a paucity of tumor genomic information. To define the molecular landscape of NF1-associated LGGs (NF1-LGG), we integrated clinical data, histological diagnoses, and multi-level genetic/genomic analyses on 70 individuals from 25 centers worldwide. Whereas, most tumors harbored bi-allelic NF1 inactivation as the only genetic abnormality, 11% had additional mutations. Moreover, tumors classified as non-pilocytic astrocytoma based on DNA methylation analysis were significantly more likely to harbor these additional mutations. The most common secondary alteration was FGFR1 mutation, which conferred an additional growth advantage in multiple complementary experimental murine Nf1 models. Taken together, this comprehensive characterization has important implications for the management of children with NF1-LGG, distinct from their sporadic counterparts.

Alteration of circulating cell-free DNA level by external cephalic version: A potential biomarker for direct evaluation of placental damage.

AIM: To confirm that variations in cell-free fetal DNA (cffDNA) are indicators of external placental damage, we quantitatively investigated cffDNA alterations in maternal peripheral blood during external cephalic version (ECV). METHODS: We recruited 48 singleton pregnant women who underwent ECV in our hospital. Before and immediately after ECV, we harvested 10 ml of maternal peripheral blood samples for cffDNA analysis. cffDNA alterations were assessed based on the fetal fraction (FF) rate. We performed ECV without epidural anesthesia but administered epidural anesthesia if ECV was disrupted due to severe pain. RESULTS: The FF increased from 22.9% ± 5.7% to 27.0% ± 5.7% (p < 0.05) after ECV. The FF increased in both successful (before, 24.4% ± 5.9%; after, 28.1% ± 5.9%; p < 0.05) and unsuccessful (before, 21.8% ± 3.8%; after, 27.3% ± 4.2%; p < 0.05) cases, as well as in patients who received epidural anesthesia (before, 23.9% ± 4.7%; after, 28.5% ± 4.4%; p < 0.05) or underwent ECV more than once (before, 23.5% ± 6.1%; after, 28.4% ± 5.3%; p < 0.05). CONCLUSIONS: FF alterations increased due to external stresses during ECV; the alterations were markedly greater when the strength and duration of external stress increased. These FF alterations may serve as potential biomarkers for the direct assessment of placental damage.

Translation and validation of the Japanese Version of the Quality of Recovery-15 Questionnaire.

PURPOSE: Patient-reported outcomes after surgery and anaesthesia have recently attracted attention. A recent systematic review and a consensus guideline recommend that patients' recovery can be adequately measured using the quality of recovery-15 (QoR-15) during the perioperative period; however, the Japanese version of the QoR-15 (QoR-15J) is not available. We aimed to translate the QoR-15 into Japanese and assess its validity. METHODS: After translating into Japanese, 205 patients who underwent various types of surgery under general anaesthesia were enrolled in the study. QoR-15J was evaluated before surgery and 24 h and 48 h after surgery. Additionally, 30 patients answered the QoR-15J at 25 h after surgery. We assessed the feasibility, reliability, validity, and responsiveness of the QoR-15J. RESULTS: One patient who did not undergo surgery and two patients who were discharged within 24 h were excluded. One hundred and eighty-seven patients answered the QoR-15J at 24 h after surgery (completion rate, 92.6%) and 183 patients with complete data were included in the final analysis. The Cronbach's alpha coefficient for internal reliability and Spearman rank correlation coefficient for test-retest reliability were 0.84 and 0.91, respectively. The Cohen effect size for all items was 1.42. CONCLUSIONS: QoR-15 was translated into Japanese and the Japanese version's validity was assessed in patients undergoing various types of surgery under general anaesthesia. Our results suggest that QoR-15J is feasible, reliable, valid, and responsive.

The incidence and reasons for canceled surgical cases in an academic medical center: a retrospective analysis before and after the development of a preoperative anesthesia clinic.

PURPOSE: The development of a preoperative anesthesia clinic (PAC) can reduce the number of surgical cases canceled on the day of surgery. However, there are only a few studies on the details of cancellations in the operating room. This study aimed to assess the incidence and reasons for surgical cases canceled from admission to the operating room to the start of surgery. METHODS: This retrospective study involved patients who underwent anesthesia performed by anesthesiologists between January 2008 and March 2019. We focused on case cancellations occurring from admission to the operating room to the start of surgery. We classified the reasons for cancellation into four categories: insufficient preoperative anesthetic assessment, anesthetic issues/complications, medical problems related to patients' comorbidity, and others. We evaluated and compared the incidence and reasons for cancellation before and after the establishment of a PAC. RESULTS: Among a total of 48,089 scheduled surgery, 18 (0.037%, 95% confidence interval 0.019-0.055) cases were canceled. The total cancellation rate before and after the development of a PAC was not statistically significant (0.051% vs 0.022%, P = 0.10). Before the development of a PAC, the most common reason was insufficient preoperative anesthetic assessment in 46.1%, followed by anesthetic issues/complications (23.0%), medical problems related to patients' comorbidity (15.3%), and others (15.3%). After the development of a PAC, surgeries were canceled for medical problems related to patients' comorbidity (80.0%) and anesthetic issues/complications (20.0%). CONCLUSIONS: The total incidence of surgical case cancellations was 0.037%. Before and after the development of a PAC, cancellation rate was comparable. After the development of a PAC, none case were canceled due to insufficient preoperative anesthetic assessment.

Neutrophil-to-lymphocyte ratio as indicator to severe complication after pancreaticoduodenectomy or distal pancreatectomy.

BACKGROUND: Pancreaticoduodenectomy and distal pancreatectomy are complex procedures with high rates of post-operative complications. We evaluated the factors associated with post-operative complications, focusing on pre-operative hematologic markers such as the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index. METHODS: Data from patients (≥age 20) who underwent pancreaticoduodenectomy or distal pancreatectomy between January 2013 and December 2017 at a Japanese tertiary hospital were retrospectively reviewed. Patients who failed to complete the operation and those who underwent additional procedure were excluded. The primary outcome was reoperation and unplanned intensive care unit admission before first discharge, and secondary outcome was the length of hospital stay. Multivariate analysis was used to identify explanatory factors associated with post-operative complications. The differences in length of hospital stay were compared with the Mann-Whitney U test. RESULTS: Of 238 eligible patients, 208 with a median age of 71 years were included in the analysis. The median values [1st interquartile range, 3rd interquartile range] of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index were 2.65 [1.69, 4.04], 247 [146, 407], and 46.0 [42.0, 49.7], respectively. Eleven patients (5.3%) experienced post-operative complications. The neutrophil-to-lymphocyte ratio (odds ratio, 1.13; 95% confidence interval, 1.02-1.26; P = 0.03) and blood loss volume (odds ratio per 100 mL, 1.11; 95% confidence interval, 1.00-1.22; P = 0.039) were independently associated with post-operative complications. Post-operative complications contributed to longer hospital stays (19 [15, 28] vs 33 [22, 65] days, P = 0.005). CONCLUSION: The neutrophil-to-lymphocyte ratio and blood loss volume were significantly associated with post-operative complications, leading to prolonged hospitalization.

Associated factors with delayed ambulation after abdominal surgery.

PURPOSE: After abdominal surgery, ambulatory status is an important indicator of postoperative recovery. This study investigated the inability to ambulate on postoperative day 1 and identified associated predictive factors in patients undergoing abdominal surgery, focusing on preoperative hematologic markers such as the neutrophil-to-lymphocyte ratio (NLR) and prognostic nutritional index. METHODS: Adult patients undergoing abdominal surgery from May 2018 to October 2018 were investigated consecutively. Only patients with duration of surgery ≥ 3 h were included for observation. Data on patient characteristics were collected from medical charts and laboratory results. Univariate analysis and multivariate logistic regression were used to determine associations with inability to ambulate without human assistance on postoperative day 1 and postoperative length of stay. RESULTS: Of 416 eligible patients, 217 patients were included in the analysis. Sixty-nine patients (31.7%) were not able to ambulate on postoperative day 1. The NLR (odds ratio, 1.11; 95% confidence interval, 1.01-1.23), duration of surgery (odds ratio per 1 h, 1.27; 95% confidence interval, 1.06-1.43), and American Society of Anesthesiologists physical status of 3 (odds ratio, 4.99; 95% confidence interval, 1.15-21.5) were independently associated with the inability to ambulate without assistance on postoperative day 1, which was also associated with longer hospital stays (13 [11, 22] vs 21 [15, 39] days, P < 0.001). CONCLUSIONS: The NLR, surgical duration, and American Society of Anesthesiologists physical status were significantly associated with the inability to ambulate without human assistance on postoperative day 1 and prolonged hospitalization.

A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress.

New drugs have significantly improved the survival of patients with multiple myeloma (MM), but the prognosis of MM patients with high-risk cytogenetic changes such as t(4; 14), t(14; 16) or del17p remains very poor. A natural product, komaroviquinone (KQN), was originally isolated from the perennial semi-shrub Dracocephalum komarovi and has anti-protozoal activity against Trypanosoma cruzi, the organism causing Chagas' disease. Here we demonstrate that a novel KQN-derivative, GTN024, has an anti-MM effect both in vitro and in vivo. GTN024 induced the apoptosis of MM cell lines including those with high-risk cytogenetic changes. GTN024 produced reactive oxygen species (ROS) and increased phosphorylated eIF2α. The ROS production and subsequent endoplasmic reticulum (ER) stress are thought to play a key role in GTN024-induced apoptosis, as the apoptosis was completely abrogated by anti-oxidant treatment. In a mouse xenograft model, an intraperitoneal injection of 20 mg/kg of GTN024 significantly delayed tumor growth. Hematological toxicity and systemic toxicity as indicated by weight loss were not observed. These results suggest that the novel KQN-derivative GTN024 could become a candidate drug for treating high-risk MM.

Dual Roles of Group IID Phospholipase A2 in Inflammation and Cancer.

Phospholipase A2 enzymes have long been implicated in the promotion of inflammation by mobilizing pro-inflammatory lipid mediators, yet recent evidence suggests that they also contribute to anti-inflammatory or pro-resolving programs. Group IID-secreted phospholipase A2 (sPLA2-IID) is abundantly expressed in dendritic cells in lymphoid tissues and resolves the Th1 immune response by controlling the steady-state levels of anti-inflammatory lipids such as docosahexaenoic acid and its metabolites. Here, we show that psoriasis and contact dermatitis were exacerbated in Pla2g2d-null mice, whereas they were ameliorated in Pla2g2d-overexpressing transgenic mice, relative to littermate wild-type mice. These phenotypes were associated with concomitant alterations in the tissue levels of ω3 polyunsaturated fatty acid (PUFA) metabolites, which had the capacity to reduce the expression of pro-inflammatory and Th1/Th17-type cytokines in dendritic cells or lymph node cells. In the context of cancer, however, Pla2g2d deficiency resulted in marked attenuation of skin carcinogenesis, likely because of the augmented anti-tumor immunity. Altogether, these results underscore a general role of sPLA2-IID as an immunosuppressive sPLA2 that allows the microenvironmental lipid balance toward an anti-inflammatory state, exerting beneficial or detrimental impact depending upon distinct pathophysiological contexts in inflammation and cancer.

Progression-free survival of children with localized ependymoma treated with intensity-modulated radiation therapy or proton-beam radiation therapy.

BACKGROUND: The treatment for childhood intracranial ependymoma includes maximal surgical resection followed by involved-field radiotherapy, commonly in the form of intensity-modulated radiation therapy (IMRT). Proton-beam radiation therapy (PRT) is used at some centers in an effort to decrease long-term toxicity. Although protons have the theoretical advantage of a minimal exit dose to the surrounding uninvolved brain tissue, it is unknown whether they have the same efficacy as photons in preventing local recurrence. METHODS: A retrospective review of medical records from September 2000 to April 2013 was performed. Seventy-nine children with newly diagnosed localized intracranial ependymomas treated with either IMRT (n = 38) or PRT (n = 41) were identified, and progression-free survival (PFS) was analyzed with Kaplan-Meier and Cox multivariate analyses. RESULTS: The median age at diagnosis was 3.7 years for all patients (range, 0.4-18.7 years). There were 54 patients with infratentorial tumors (68% of the total population). Patients treated with PRT were younger (median age, 2.5 vs 5.7 years; P = .001) and had a shorter median follow-up (2.6 vs 4.9 years; P < .0001). Gross total resection (GTR) was achieved in 67 patients (85%) and was more frequent in the PRT group versus the IMRT group (93% vs 76%; P = .043). The 3-year PFS rates were 60% and 82% with IMRT and PRT, respectively (P = .031). CONCLUSIONS: Children with localized ependymomas treated with PRT have a 3-year PFS rate comparable to that of children treated with IMRT. This analysis suggests that local control is not compromised by the use of PRT. The data also support GTR as the only prognostic factor for PFS. Cancer 2017;123:2570-78. © 2017 American Cancer Society.

Synthesis and biological evaluation of the natural product komaroviquinone and related compounds aiming at a potential therapeutic lead compound for high-risk multiple myeloma.

Alternatives of treatments for multiple myeloma (MM) have become increasingly available with the advent of new drugs such as proteasome inhibitors, thalidomide derivatives, histone deacetylase inhibitors, and antibody drugs. However, high-risk MM cases that are refractory to novel drugs remain, and further optimization of chemotherapeutics is urgently needed. We had achieved asymmetric total synthesis of komaroviquinone, which is a natural product from the plant Dracocephalum komarovi. Similar to several leading antitumor agents that have been developed from natural compounds, we describe the antitumor activity and cytotoxicity of komaroviquinone and related compounds in bone marrow cells. Our data suggested that komaroviquinone-related agents have potential as starting compounds for anticancer drug development.

Clinical Results and Prognostic Factors in Boron Neutron Capture Therapy for Recurrent Squamous Cell Carcinoma of the Head and Neck Under the Japan National Health Insurance System: A Retrospective Study of the Initial 47 Patients.

PURPOSE: Recurrent head and neck cancer presents a therapeutic challenge because of cumulative toxicity from initial radiation therapy, limiting reirradiation options. Boron neutron capture therapy (BNCT) offers a promising alternative, selectively delivering a radical dose to tumors while sparing adjacent normal tissue. This study investigates the initial clinical outcomes and prognostic factors associated with BNCT for recurrent squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: This retrospective analysis investigated the initial 47 patients treated with BNCT between May 2020 and February 2021 in Japan. All patients had received radiation therapy with a median dose of 70 Gy (range, 44-176) before BNCT. Median tumor size was 11 cm3 (range, 1-117 cm3), with 23% of tumors larger than 30 cm3, and 87% of patients had prior systemic therapy. The most common prescribed dose to the pharyngeal mucosa was 15 Gy-Eq (36%), followed by 18 Gy-Eq (34%). The minimum dose given to tumor was 27.4 Gy-Eq (range, 13.3-45.2). In 23 patients, 18F-fluoro-borono-phenylalanine positron emission tomography was performed within 1 week before BNCT, and the tumor-to-blood 10B ratio was 3.5 (range, 2.0-8.7). RESULTS: Efficacy analysis revealed a 51% complete response rate and a 74% overall response rate. Disease-free survival rates at 1 and 2 years were 34.6% and 26.6%, respectively. Overall survival rates at 1 and 2 years were 86.1% and 66.5%, respectively. Multivariate analysis revealed that, among the patient characteristics, whether the lesion was mucosal had a significant effect on achieving complete response. CONCLUSIONS: This study provided valuable insights into the early integration of BNCT into routine clinical practice, highlighting its efficacy and safety. Technical improvements are needed to ensure precise dose administration. Ongoing prospective studies, such as the phase II REBIVAL study, will further elucidate the role of BNCT in recurrent head and neck cancer.