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.

Safety of Boron Neutron Capture Therapy with Borofalan(10B) and Its Efficacy on Recurrent Head and Neck Cancer: Real-World Outcomes from Nationwide Post-Marketing Surveillance.

BACKGROUND: This study was conducted to evaluate the real-world safety and efficacy of boron neutron capture therapy (BNCT) with borofalan(10B) in Japanese patients with locally advanced or locally recurrent head and neck cancer (LA/LR-HNC). METHODS: This prospective, multicenter observational study was initiated in Japan in May 2020 and enrolled all patients who received borofalan(10B) as directed by regulatory authorities. Patient enrollment continued until at least 150 patients were enrolled, and adverse events attributable to drugs, treatment devices, and BNCT were evaluated. The patients with LA/LR-HNC were systematically evaluated to determine efficacy. RESULTS: The 162 patients enrolled included 144 patients with squamous cell carcinoma of the head and neck (SCCHN), 17 patients with non-SCCHN (NSCCHN), and one patient with glioblastoma. Treatment-related adverse events (TRAEs) were hyperamylasemia (84.0%), stomatitis (51.2%), sialoadenitis (50.6%), and alopecia (49.4%) as acute TRAEs, and dysphagia (4.5%), thirst (2.6%), and skin disorder (1.9%) as more common late TRAEs. In patients with LA/LR-HNC, the overall response rate (ORR) was 72.3%, with a complete response (CR) in 63 (46.0%) of 137 patients with SCCHN. Among 17 NSCCHN patients, the ORR was 64.7%, with eight cases (47.1%) of CR. One- and two-year OS rates in patients with recurrent SCCHN were 78.8% and 60.7%, respectively. CONCLUSIONS: This post-marketing surveillance confirmed the safety and efficacy of BNCT with borofalan(10B) in patients with LA/LR-HNC in a real-world setting.

Immunotherapy for Unresectable Small Bowel Adenocarcinoma: A Case Series.

BACKGROUND/AIM: The efficacy of systemic therapy for unresectable small bowel adenocarcinoma that is refractory to fluoropyrimidines and oxaliplatin has not yet been established because of the rarity of this cancer. Although immunotherapy with anti-PD-1 antibodies has shown robust efficacy in the treatment of esophagogastric adenocarcinoma, its effectiveness in small bowel adenocarcinoma remains unclear. CASE REPORT: In the first case, a 75-year-old man was diagnosed with metastatic moderately differentiated adenocarcinoma of the jejunum with stable microsatellite instability. After receiving multiple lines of therapy, including fluoropyrimidines plus oxaliplatin, irinotecan, and paclitaxel, the patient was treated with nivolumab and achieved a partial response that lasted for 12 months. In the second case, a 65-year-old man was diagnosed with an unresectable locally advanced duodenal adenocarcinoma. High microsatellite instability was confirmed by polymerase chain reaction-based testing. After showing resistance to 5-fluorouracil and oxaliplatin, the patient received nivolumab and ipilimumab therapy. Although therapy was discontinued because of immune-related colitis and skin rash, a partial response was achieved. CONCLUSION: Treatment with immune checkpoint inhibitors is effective for refractory small bowel adenocarcinoma, irrespective of the microsatellite status.

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.

Investigation of the efficacy of the change ratio of brain natriuretic peptide for predicting the cardiac effects of chemoradiotherapy on esophageal cancer.

The aim of this study was to investigate the effectiveness of brain natriuretic peptide (BNP) as a predictor of radiological effects on the heart. A total of 41 patients with esophageal cancer who underwent chemoradiotherapy (CRT) were retrospectively investigated. The BNP levels were measured on the first day of CRT (pre-CRT) and the last day of CRT (post-CRT), and the median concentration of BNP and dosimetric parameters of the heart were calculated. The change ratio of BNP was calculated as follows: [(BNP post-CRT) - (BNP pre-CRT)]/(BNP pre-CRT). The comparison of BNP pre-CRT with post-CRT was performed using a Wilcoxon signed-rank test. The relationship between dosimetric parameters and change ratio was analyzed using Spearman's correlation coefficient. The median levels of BNP of pre-CRT and post-CRT were 10 and 22 pg/ml, respectively, and the difference was statistically significant (P<0.0001). Significant correlations (all P<0.05) were observed between the change ratio and mean dose, V5, V10, V20, and V30. Of the cohort, 14 patients developed acute-to-subacute cardiac events, such as pericardial effusion, cardiomegaly, acute exacerbation of chronic heart failure, and a decreased ejection fraction. The change ratios of BNP, V5, V10, V20, and V30 were significantly higher in patients who experienced cardiac events compared with those who did not. The results of this study showed that BNP measurement, particularly the change ratio of BNP pre- and post-CRT, may be a useful cardiac event predictor in addition to dosimetric parameters.

Swept Source-Optical Coherence Tomography-Guided Facedown Posturing to Minimize Treatment Burden and Maximize Outcome after Macular Hole Surgery.

We evaluated the closure of full-thickness macular holes (MHs) the day after surgery in minimizing the burden and maximizing patient outcomes. Herein, 25-gauge pars plana vitrectomy, internal limiting membrane peeling, and fluid-gas (20% sulfur hexafluoride) were performed for the treatment. Patients were instructed to remain in the facedown position until the confirmation of MH closure, and the position was discontinued in cases where the closure was confirmed. In total, 43 eyes of 43 patients, whose average age was 69.7 ± 8.6 years, were enrolled in this study. We used swept source (SS)-optical coherence tomography (OCT) for the confirmation of MH closure for gas-filled eyes and used spectral domain (SD)-OCT for the reconfirmation of MH closure after the gas volume was reduced to less than half of the vitreous cavity. MH closure was confirmed in 40 eyes (93%, the closure group) on the next day after surgery. The time from surgery to SS-OCT imaging was 24.7 h. Although facedown positioning was terminated in cases where MH closure was confirmed, there were no cases in which the MH was re-opened afterward. The basal and minimum MH size was significantly larger in the non-closure group than that in the closure group (p = 0.027, p = 0.043, respectively). Therefore, checking with SS-OCT the day after surgery and terminating facedown positioning in cases where MH closure was confirmed would be a useful method, removing a great burden for the elderly without sacrificing the MH closure rate.

Characterization and clinical utility of different collimator shapes in accelerator-based BNCT systems for head and neck cancer.

NeuCure® is the only accelerator-based boron neutron capture therapy (BNCT) system in the world with pharmaceutical approval. Until now, only flat collimators (FCs) on the patient side have been installed. However, in some cases of head and neck cancer patients, positioning the patient close enough to the collimator when using FCs was difficult. Thus, there are concerns about the prolongation of the irradiation time and overdose to normal tissues. To address these issues, a collimator with a convex-extended section on the patient side (extended collimators [ECs]) was developed, and its pharmaceutical approval was obtained in February 2022. This study evaluated the physical characterization and usefulness of each collimator using a simple geometry water phantom model and human model. In the water phantom model, the thermal neutron fluxes at 2 cm depth on the central axis were 5.13 × 108, 6.79 × 108, 1.02 × 109, and 1.17 × 109n/cm2/s for FC(120), FC(150), EC50(120), and EC100(120), respectively, when the distance from the irradiation aperture was kept constant at 18 cm. With ECs, the relative off-axis thermal neutron flux decreased steeply. In the hypopharyngeal cancer human model, the tumor dose changes were within <2%, but the maximum oral mucosa doses were 7.79, 8.51, 6.76, and 4.57 Gy-Eq, respectively. The irradiation times were 54.3, 41.3, 29.2, and 24.8 min, respectively. In cases where positioning the patient close to the collimator is difficult, the use of ECs may reduce the dose to normal tissues and shorten the irradiation time.

GTN057, a komaroviquinone derivative, induced myeloma cells' death in vivo and inhibited c-MET tyrosine kinase.

OBJECTIVE: Despite the development of newly developed drugs, most multiple myeloma (MM) patients with high-risk cytogenetic abnormalities such as t(4;14) or del17p relapse at anin early stage of their clinical course. We previously reported that a natural product,komaroviquinone (KQN), isolated from the perennial semi-shrub Dracocephalum komarovi, i.e., komaroviquinone (KQN) and its derivative GTN024 induced the apoptosis of MM cells by producing reactive oxygen species (ROS), but both exhibited significant hematological toxicity. Aim of this study is to clarify anti-tumor activity, safety and pharmacokinetics of GTN057, an optimization compound of KQN in vivo. METHODS: ICR/SCID xenograft model of KMS11, a t(4;14) translocation-positive MM cell line, was used for in vivo study. Mice pharmacokinetics of GTN057 and the degradation products were analyzed by LC-MS/MS. RESULTS: Herein, our in vitro experiments revealed that GTN057 is much less toxic to normal hematopoietic cells, induced the apoptosis of both MM cell lines andpatient samples, including those with high-risk cytogenetic changes. A xenograft model of a high-risk MM cell line demonstrated that GTN057 significantly delayed the tumor growth with no apparent hematological or systemic toxicities in vivo. The pathological examination of GTN057-treated tumors in vivoshowed revealed apoptosis of MM cells and anti-angiogenesis. In addition to the production of ROS, GTN057 inhibited the downstream signaling of c-MET, a receptor tyrosine kinase a receptor forand hepatocyte growth factor (HGF) receptor. Thus, GTN057 is less toxic and is able tomay be a candidate drug for treating MM patients, via multifunctional mechanisms. We have also extensively studied the pharmacologyical analysis of GTN057. The metabolites of GTN057, (e.g.,such as GTN054), may also have anti-tumorantitumor activity. CONCLUSION: Natural products or and their derivatives can could be good sources of antineoplastic drugs even for high-risk cancer.

Quality of death after elective surgery: a questionnaire survey for the bereaved family.

PURPOSE: Postoperative death is the third leading cause of death in the world, but the quality of death after surgery has been poorly documented. This study aimed to evaluate the feasibility of a questionnaire survey for the bereaved family regarding the postoperative quality of death and the impact of preoperative functional disability on the quality of death. METHODS: Patients aged ≥55 years who underwent scheduled surgery under general anesthesia in a tertiary-care hospital in Japan between April 2016 and December 2018 were enrolled. Patients' functional disability was assessed using the 12-item World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) before surgery and scored based on the sum of the 12 items (0-48). Postoperative deaths were detected in medical records 3 months and 1 year after surgery. When death had occurred, a questionnaire on the quality of death using the short version of the Good Death Inventory (GDI) was sent to the bereaved family, which was scored as the sum of the 10 domains (10-70). RESULTS: Of 4020 eligible patients, 148 patients (3.6 %) died within 1 year after surgery. A hundred and twenty-nine bereaved families were sent the questionnaire, and 83 of them (64.3%) submitted valid responses suggesting the high feasibility of this questionnaire survey. There were no differences between the GDI and WHODAS 2.0 scores (median 49 [interquartile range 41-55] vs. 49 [43-54], respectively, p = 0.90). In addition, multiple regression analysis of related factors using the short version of the GDI as a continuous variable showed that age and death in a facility other than that in which the surgery was performed were associated with lower GDI scores (p = 0.004 and p = 0.04, respectively). CONCLUSION: The completion rate was 64.3%. There was no association between the quality of death and preoperative functional disability; however, older age was associated with a higher quality of death, while death in a facility other than that in which the surgery was performed was associated with lower quality of death.

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.

Association between intraoperative hypotension and postoperative nausea and vomiting: a retrospective analysis of 247 thyroidectomy cases.

BACKGROUND: Postoperative nausea and vomiting (PONV) are major complications after general anesthesia. Although various pathways are involved in triggering PONV, hypotension plays an important role. We hypothesized that intraoperative hypotension during general anesthesia might be responsible for the incidence of PONV. METHODS: We retrospectively investigated patients who underwent thyroidectomy. The initial blood pressure measured before induction of anesthesia was used as the baseline value. The systolic blood pressure measured during the operation from the start to the end of anesthesia was extracted from anesthetic records. The time integral value when the measured systolic blood pressure fell below the baseline value was calculated as area under the curve (AUC) of s100%. RESULTS: There were 247 eligible cases. Eighty-eight patients (35.6%) had PONV. There was no difference in patient background between the patients with or without PONV. Univariate analysis showed that the total intravenous anesthesia (TIVA) (p=0.02), smoking history (p=0.02), and AUC-s100% (p=0.006) were significantly associated with PONV. Multiple logistic regression analysis revealed that TIVA (OR: 0.54, 95% CI: 0.29...0.99), smoking history (OR: 0.60, 95% CI: 0.37...0.96), and AUC-s100% (OR: 1.006, 95% CI: 1.0...1.01) were significantly associated with PONV. CONCLUSION: Intraoperative hypotension evaluated by AUC-s100% was related to PONV in thyroidectomy.

Association between intraoperative hypotension and postoperative nausea and vomiting: a retrospective analysis of 247 thyroidectomy cases

Abstract Background: Postoperative nausea and vomiting (PONV) are major complications after general anesthesia. Although various pathways are involved in triggering PONV, hypotension plays an important role. We hypothesized that intraoperative hypotension during general anesthesia might be responsible for the incidence of PONV. Methods: We retrospectively investigated patients who underwent thyroidectomy. The initial blood pressure measured before induction of anesthesia was used as the baseline value. The systolic blood pressure measured during the operation from the start to the end of anesthesia was extracted from anesthetic records. The time integral value when the measured systolic blood pressure fell below the baseline value was calculated as area under the curve (AUC) of s100%. Results: There were 247 eligible cases. Eighty-eight patients (35.6%) had PONV. There was no difference in patient background between the patients with or without PONV. Univariate analysis showed that the total intravenous anesthesia (TIVA) (p = 0.02), smoking history (p = 0.02), and AUC-s100% (p = 0.006) were significantly associated with PONV. Multiple logistic regression analysis revealed that TIVA (OR: 0.54, 95% CI: 0.29-0.99), smoking history (OR: 0.60, 95% CI: 0.37-0.96), and AUC-s100% (OR: 1.006, 95% CI: 1.0-1.01) were significantly associated with PONV. Conclusion: Intraoperative hypotension evaluated by AUC-s100% was related to PONV in thyroidectomy.

Hypercarbia in a Pediatric Patient With Relapsed Medulloblastoma.

Pediatric medulloblastoma is a common form of pediatric brain tumor and typically presents with progressive signs of increased intracranial pressure and ataxia. Relapse of the disease is most often diagnosed on surveillance imaging. We present the case of a 13-year-old boy with a previous history of medulloblastoma who presented with chronic hypercarbic respiratory failure as a symptom of a recurrent tumor. Imaging demonstrated a left cerebellar enhancing mass with leptomeningeal thickness and extension to the posterior medulla oblongata, which is the center for respiratory control. His hypercarbic respiratory failure represents a unique presentation of a central nervous system (CNS) tumor. Thus, this case illustrates the importance of thorough evaluation for CNS tumors involving the brainstem in patients with respiratory acidosis and no clear pulmonary etiology.

A Novel Suturing Technique for Choroidal Avulsion.

Ocular trauma has been one of the leading causes of visual impairment, and choroidal avulsion is especially devastating. Surgical treatment of choroidal avulsion is challenging, and very few surgical techniques have been reported. We experienced two cases of globe rupture with 360-degree avulsion of the choroid-ciliary body from the peripheral section. After vitrectomy for a globe rupture, the choroid gradually slid down to the posterior pole over time and vision deteriorated even though the retina was attached. We treated the choroidal avulsion using two surgical methods: a mattress suturing technique using a 10-0 proline long needle and a 7-0 nylon single suture technique. In both methods, the retina-choroid, which had slipped down to the posterior pole, was suspended and fixed to the sclera assisted by a wide-angle viewing system, improving visual acuity. These two methods are considered to be useful surgical procedures for the treatment of an avulsed choroid.

Rapidly Progressive Precocious Puberty With an Elevated Testosterone Level in a 5-Year-Old Boy With a ß-Human Chorionic Gonadotropin-Secreting Intracranial Germ Cell Tumor in the Pineal Gland.

Objective: Peripheral precocious puberty (PP) is an infrequent etiology for early sexual development. Intracranial germ cell tumors (GCTs) are rare but can present infrequently with PP with the rate of development affected by the degree of tumor hormone production. Our objective was to describe a young boy with a ß-human chorionic gonadotropin (hCG)-secreting intracranial GCT with an extremely elevated testosterone level, who presented with rapidly progressive PP. Case Report: A 5-year-old boy presented with penile growth plus pubic hair, deepening voice, and body odor for 3 months. Physical examination revealed a height velocity of 16.25 cm/year, Tanner stage 3 pubic hair, and enlarged penis for age. Laboratory results revealed elevated serum and cerebrospinal fluid ß-hCG and 17-hydroxyprogesterone progesterone levels. The testosterone level was above the initial detection range at 2700 ng/dL. Follicle-stimulating hormone and luteinizing hormone were prepubertal with normal serum and cerebrospinal fluid alpha-fetoprotein levels. Imaging showed a pineal mass diagnosed as a ß-hCG-secreting GCT. During chemotherapy, the physical signs of PP remitted and laboratory values normalized. Discussion: Intracranial tumors can cause peripheral PP in boys. If the tumor produces high ß-hCG levels, this could cause severe hyperandrogenemia resulting in the rapid development of secondary sexual signs. GCTs should be considered in male patients with rapidly progressive PP, even in those lacking other signs of a brain tumor. Conclusion: When presented with a boy with PP, a GCT should be considered if workup shows an elevated testosterone level in conjunction with an elevated ß-hCG level, especially if with rapid development.