Carbon-ion radiotherapy for hepatocellular carcinoma with major vascular invasion: a retrospective cohort study.

BACKGROUND: Macroscopic vascular invasion (MVI) significantly impacts survival in patients with hepatocellular carcinoma (HCC), warranting systemic therapy over locoregional therapy. Despite novel approaches, HCC with MVI has a poor prognosis compared to early-to intermediate-stage HCC. This study aimed to evaluate the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for HCC characterized by MVI. METHODS: This retrospective cohort study evaluated HCC patients with MVI treated using C-ion RT with a dose of 45.0-48.0 Gy/2 fractions or 52.8-60.0 Gy/4 fractions between 1995 and 2020 at our institution in Japan. We analyzed the prognostic factors and rates of local recurrence, survival, and adverse events. The local recurrence rate was determined using the cumulative incidence function, with death as a competing event. Survival rates were determined using the Kaplan-Meier method. The log-rank test for univariate analysis and the Cox proportional hazards model for multivariate analysis were used to compare subgroups. RESULTS: In total, 76 patients with a median age of 71 years (range, 45-86 years) were evaluated. Among them, 68 had Child-Pugh grade A while eight had grade B disease. In 17 patients, the vascular tumor thrombus reached the inferior vena cava or main trunk of the portal vein. Over a median follow-up period of 27.9 months (range, 1.5-180.4 months), the 2-year overall survival, progression-free survival, and local recurrence rates were 70.0% (95% confidence interval [CI]: 57.7-79.4%), 32.7% (95% CI: 22.0-43.8%), and 8.9% (95% CI: 1.7-23.5%), respectively. A naïve tumor and a single lesion were significant prognostic factors for overall survival in the univariate analysis. Albumin-bilirubin grade 1 and a single lesion were independent prognostic factors in the multivariate analysis. Overall, four patients (5%) experienced grade 3 late adverse events, with no observed grade 4 or 5 acute or late adverse events. CONCLUSIONS: C-ion RT for HCC with MVI showed favorable local control and survival benefits with minimal toxicity.

Discovery of type II polyketide synthase-like enzymes for the biosynthesis of cispentacin.

Type II polyketide synthases (PKSs) normally synthesize polycyclic aromatic compounds in nature, and the potential to elaborate further diverse skeletons was recently revealed by the discovery of a polyene subgroup. Here, we show a type II PKS machinery for the biosynthesis of a five-membered nonaromatic skeleton contained in the nonproteinogenic amino acid cispentacin and the plant toxin coronatine. We successfully produce cispentacin in a heterologous host and reconstruct its biosynthesis using seven recombinant proteins in vitro. Biochemical analyses of each protein reveal the unique enzymatic reactions, indicating that a heterodimer of type II PKS-like enzymes (AmcF-AmcG) catalyzes a single C2 elongation as well as a subsequent cyclization on the acyl carrier protein (AmcB) to form a key intermediate with a five-membered ring. The subsequent reactions, which are catalyzed by a collection of type II PKS-like enzymes, are also peculiar. This work further expands the definition of type II PKS and illuminates an unexplored genetic resource for natural products.

CYP1A2*F Polymorphism contributes at least partially to the Variability of Plasma Levels of Dehydroaripiprazole, an active Metabolite of Aripiprazole, in Schizophrenic Patients.

AIM: The relationship between CYP1A2 polymorphisms and the steady-state plasma levels of aripiprazole and its active metabolite, dehydroaripiprazole, were investigated in Japanese schizophrenic patients. BACKGROUND: It has been implied that cytochrome P450 (CYP) 1A2 may play a role in the metabolism of aripiprazole. Genetic variations in the CYP1A2 gene have been reported. OBJECTIVE: The authors investigated the relationship between 2 CYP1A2 polymorphisms, CYP1A2*C (-3860G>A) and CYP1A2*F (-163C>A), and the steady-state plasma levels/dose (C/D) ratios of aripiprazole and dehydroaripiprazole in Japanese schizophrenic patients. METHODS: All 89 subjects (46 males and 43 females) had been receiving 2 fixed daily doses of aripiprazole (24 mg; n=56 and 12 mg: n=33) for more than 2 weeks. No other drugs were used except flunitrazepam and biperiden. The plasma drug levels were determined by LC/MS/MS. These CYP1A2 polymorphisms were detected using polymerase chain reaction analysis. RESULTS: The mean C/D ratios of dehydroaripiprazole were significantly (P < 0.05) lower in patients with the A/A allele of CYP1A2*F than in those without the allele. No differences were found in the values of aripiprazole and the combination of aripiprazole and dehydroaripiprazole among the CYP1A2*F genotype. There were no differences in the values of aripiprazole, dehydroaripiprazole, or the combination of the 2 compounds among the CYP1A2*C genotype. The absence of the A allele of CYP1A2*F was correlated with the mean C/D ratios of dehydroaripiprazole (standardized partial correlation coefficient = 0.276, P < 0.01) by multiple regression analysis. CONCLUSION: The findings of this study suggest that the CYP1A2*F polymorphism contributes at least partially to the variability in the steady-state plasma levels of dehydroaripiprazole.

Syntheses of (+)-costic acid and structurally related eudesmane sesquiterpenoids and their biological evaluations as acaricidal agents against Varroa destructor.

Synthesis of (+)-costic acid, isolated from Dittrichia viscosa (L.) W. Greuter as a natural acaricidal sesquiterpenoid, was achieved in 16 steps from (R)-carvone with an overall yield of 4.8%, involving the radical cyclization of selenoester to construct a decalone framework as the key step. Other structurally related natural products, (+)-costal, (+)-costol, and (+)-ß-selinene, were also synthesized. The acaricidal activities of these four natural products and some synthetic intermediates were also evaluated against Varroa destructor. Among them, (+)-costal especially exhibited potent acaricidal activity.

Concurrent chemoradiotherapy using proton beams can reduce cardiopulmonary morbidity in esophageal cancer patients: a systematic review.

This systematic review was performed to investigate the superiority of proton beam therapy (PBT) to photon-based radiotherapy (RT) in treating esophageal cancer patients, especially those with poor cardiopulmonary function. The MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases were searched from January 2000 to August 2020 for studies evaluating one end point at least as follows; overall survival, progression-free survival, grade ≥ 3 cardiopulmonary toxicities, dose-volume histograms, or lymphopenia or absolute lymphocyte counts (ALCs) in esophageal cancer patients treated with PBT or photon-based RT. Of 286 selected studies, 23 including 1 randomized control study, 2 propensity matched analyses, and 20 cohort studies were eligible for qualitative review. Overall survival and progression-free survival were better after PBT than after photon-based RT, but the difference was significant in only one of seven studies. The rate of grade 3 cardiopulmonary toxicities was lower after PBT (0-13%) than after photon-based RT (7.1-30.3%). Dose-volume histograms revealed better results for PBT than photon-based RT. Three of four reports evaluating the ALC demonstrated a significantly higher ALC after PBT than after photon-based RT. Our review found that PBT resulted in a favorable trend in the survival rate and had an excellent dose distribution, contributing to reduced cardiopulmonary toxicities and a maintained number of lymphocytes. These results warrant novel prospective trials to validate the clinical evidence.

Prospective exosome-focused translational research for afatinib (EXTRA) study of patients with nonsmall cell lung cancer harboring EGFR mutation: an observational clinical study.

Background: The exosome-focused translational research for afatinib (EXTRA) study is the first trial to identify novel predictive biomarkers for longer treatment efficacy of afatinib in patients with epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC) via a comprehensive association study using genomic, proteomic, epigenomic, and metabolomic analyses. Objectives: We report details of the clinical portion prior to omics analyses. Design: A prospective, single-arm, observational study was conducted using afatinib 40 mg/day as an initial dose in untreated patients with EGFR mutation-positive NSCLC. Dose reduction to 20 mg every other day was allowed. Methods: Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. Results: A total of 103 patients (median age 70 years, range 42-88 years) were enrolled from 21 institutions in Japan between February 2017 and March 2018. After a median follow-up of 35.0 months, 21% remained on afatinib treatment, whereas 9% had discontinued treatment because of AEs. The median PFS was 18.4 months, with a 3-year PFS rate of 23.3%. The median afatinib treatment duration in patients with final doses of 40 (n = 27), 30 (n = 23), and 20 mg/day (n = 35), and 20 mg every other day (n = 18) were 13.4, 15.4, 18.8, and 18.3 months, respectively. The median OS was not reached, with a 3-year OS rate of 58.5%. The median OS in patients who did (n = 25) and did not (n = 78) receive osimertinib during the entire course of treatment were 42.4 months and not reached, respectively (p = 0.654). Conclusions: As the largest prospective study in Japan, this study confirmed favorable OS following first-line afatinib in patients with EGFR mutation-positive NSCLC in a real-world setting. Further analysis of the EXTRA study is expected to identify novel predictive biomarkers for afatinib. Trial registration: UMIN-CTR identifier (UMIN000024935, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_his_list.cgi?recptno=R000028688.

Clinical and Virologic Impacts of Respiratory Viral Co-infections in Children With Influenza.

BACKGROUND: Advances in multiplex polymerase chain reaction (PCR) methods have enabled the simultaneous detection of multiple respiratory viruses. We aimed to estimate the clinical and virologic impacts of influenza and other respiratory virus co-infection in children. METHODS: We enrolled 38 and 35 children diagnosed with influenza and treated with baloxavir marboxil (baloxavir) and oseltamivir, respectively. We performed quantitative reverse transcription-PCR to detect and measure the levels of noninfluenza viruses from 3 nasopharyngeal swab samples collected before and on days 3 and 5 after the initial antiviral dose. We assessed patients' clinical information using questionnaires. RESULTS: One or more respiratory viruses other than influenza virus were detected in 26 (35.6%) of 73 children before antiviral treatment. The influenza virus load and clinical characteristics on the day of influenza onset were similar between children with and without virus co-infections. Of the 26 and 32 children without the emergence of the reduced baloxavir and oseltamivir susceptible variants after treatment, 8 (30.8%) and 7 (21.9%) children were dually co-infected with human rhinovirus only, respectively. The level of human rhinovirus RNA on day 0 in these children was less than -3 log 10 that of influenza virus RNA, and the human rhinovirus co-infection had no impact on the disease course either clinically or virologically. CONCLUSIONS: When multiple respiratory viruses are detected in the same patient, it is necessary to assess clinical symptoms as well as the levels of detected viruses to determine which virus contributes to the development of illness.

Dosimetric Analysis for Otitis Media With Effusion Due to Eustachian Tube Dysfunction After Carbon-ion Radiation Therapy for Head and Neck Cancers.

Purpose: This study aimed to clarify the predictive factors for otitis media with effusion (OME) due to Eustachian tube dysfunction in patients treated with carbon-ion radiation therapy (CIRT) for head and neck cancers. Methods and Materials: We investigated patients with head and neck cancer whose Eustachian tube was irradiated by CIRT between October 2013 and December 2018 at our institution. OME severity was assessed by the proportion of mastoid cell opacification of magnetic resonance or computed tomography imaging (grade 0: <5% of volume of mastoid cell with opacification by fluid collection; grade 1: 6%-33%; grade 2: 34%-67%; and grade 3: 68%-100%). Clinical factors and dosimetric parameters affecting the development of grade 2 to 3 OME were analyzed using a log-rank test and Cox proportional hazards model. Results: In total, 141 patients were analyzed. The median follow-up period was 25.2 months. Grade 2 to 3 OME was observed in 65 patients, with a median incidence period of 6.5 months. According to the multivariate analysis, the mean dose of the cartilage part was a significant independent predictive parameter of grade 2 to 3 OME. The 2-year incidence rate of patients with a mean dose of the cartilage part of <40.59 Gy (relative biological effectiveness) and ≥40.59 Gy (relative biological effectiveness) was 24.2% (95% confidence interval, 15.1%-37.4%) and 66.4% (95% confidence interval, 54.5%-78.0%), respectively. Conclusions: Our findings may be useful to predict the risk of grade 2 to 3 OME due to Eustachian tube dysfunction before CIRT.

[Treatment Experience of Chemotherapy and Carbon-Ion Radiotherapy followed by Curative Conversion Surgery for Initially Locally Advanced Unresectable Pancreatic Cancer after Distal Gastrectomy].

BACKGROUND: Carbon-ion radiotherapy(CIRT)has an advantage over conventional radiotherapy by its dose distribution and biological effect for locally advanced unresectable pancreatic cancer(UR-PC). Conversion surgery(CS)might be attempted for UR-PC with favorable response by chemotherapy and radiotherapy. CASE PRESENTATION: A 67-year-old female who have a history of distal gastrectomy. CT scan revealed locally advanced UR-PC with invasion to celiac artery, 60 mm in size. Systemic chemotherapy with gemcitabine and nab-paclitaxel was continued for 15 months, showing decrease of tumor markers and radiological shrinkage of the tumor. The patient was referred to our hospital for surgical consultation. Since there was no metastasis in staging laparoscopy, CIRT with gemcitabine was administered for 3 weeks. After completion of CIRT, distal pancreatectomy with celiac axis resection and total remnant gastrectomy for direct invasion of the tumor was performed as CS, resulting R0 resection. Her postoperative course was uneventful with 17 days of hospital stay. DISCUSSION: CS after CIRT was safely performed. Clinical trial of total neoadjuvant therapy with systemic chemotherapy, CIRT, followed by CS for locally advanced CIRT is ongoing in our hospital. CIRT could be an effective treatment in locally advanced UR-PC in the context of multi-modal treatment including CS.

Re-Whole Brain Radiotherapy May Be One of the Treatment Choices for Symptomatic Brain Metastases Patients.

Generally, patients with multiple brain metastases receive whole brain radiotherapy (WBRT). Although, more than 60% of patients show complete or partial responses, many experience recurrence. Therefore, some institutions consider re-WBRT administration; however, there is insufficient information regarding this. Therefore, we aimed to review re-WBRT administration among these patients. Although most patients did not live longer than 12 months, symptomatic improvement was sometimes observed, with tolerable acute toxicities. Therefore, re-WBRT may be a treatment option for patients with symptomatic recurrence of brain metastases. However, physicians should consider this treatment cautiously because there is insufficient data on late toxicity, including radiation necrosis, owing to poor prognosis. A better prognostic factor for survival following radiotherapy administration may be the time interval of > 9 months between the first WBRT and re-WBRT, but there is no evidence supporting that higher doses lead to prolonged survival, symptom improvement, and tumor control. Therefore, 20 Gy in 10 fractions or 18 Gy in five fractions may be a reasonable treatment method within the tolerable total biological effective dose 2 ≤ 150 Gy, considering the biologically effective dose for tumors and normal tissues.

Increased salt intake is associated with diabetes and characteristic dietary habits: a community-based cross-sectional study in Japan.

We investigated the association of salt intake with lifestyle-related diseases and also the association of habitually consumed foods with salt intake. A cross-sectional study was conducted using data from a baseline survey of 2,129 residents of Yonezawa city (980 males and 1,149 females), Yamagata prefecture. The residents were divided into three groups based on their estimated daily salt intake: low, medium, and high. In both genders, the prevalence of hypertension and diabetes increased in the order of high > medium > low salt intake (trend p<0.001). Similar trends were observed in the prevalence of hyperlipidemia in females and metabolic syndrome in males. The prevalence of diabetes in the high salt intake group was significantly higher than that in the control group (matched from the low and medium salt intake groups), even when confounding factors were excluded by propensity score matching (p<0.01). Network analysis showed that the low salt intake group had a greater tendency to habitually consume various vegetables than the high salt intake group. Our findings reveal that the prevalence of lifestyle-related diseases increased with higher salt intake. We speculate that a dietary shift to multiple vegetable consumption could have salt-lowering effects.

MRI Grading Scale Predicts Ambulatory Function After Radiotherapy for Metastatic Spinal Cord Compression: A Prospective Single-Institution Observational Study.

INTRODUCTION: Although magnetic resonance imaging (MRI) is an important modality for the diagnosis of metastatic spinal cord compression (MSCC), there are only a few reports on MSCC findings and symptoms after radiotherapy. We aimed to reveal the factors related to ambulatory function after treatment, including the MRI findings, in a prospective observational study. METHODS: Patients with suspected MSCC who were treated with radiotherapy were included in this study. Orthopedic surgeons evaluated the neurological function according to the Frankel grade. All patients underwent spinal MRI, and the degree of spinal cord compression was assessed by a radiologist and a radiation oncologist using an MRI grading scale. One month after treatment, orthopedic surgeons reassessed the Frankel grade. Twenty-three patients who were evaluated 1 month after radiotherapy were included in the analysis. RESULTS: Before radiotherapy, 17 patients were ambulatory and six were unable to walk. Furthermore, 13 patients were diagnosed with grade 3 compression on MRI (spinal cord compression with no cerebrospinal fluid seen on axial T2-weighted imaging). Patients with grade 3 MSCC were significantly more likely to be non-ambulatory at 1 month. CONCLUSIONS: The MRI grading scale for MSCC may be a prognostic factor for ambulatory function after radiotherapy. MRI findings could aid in determining the indication for radiotherapy.

Endoscopic imaging modalities for diagnosing the invasion depth of superficial esophageal squamous cell carcinoma: a systematic review.

Endoscopic diagnosis of the invasion depth of superficial esophageal squamous cell carcinoma (ESCC) is an important determinant of the treatment strategy. The three endoscopic imaging modalities commonly used to predict the invasion depth of superficial ESCC in Japan are non-magnifying endoscopy (non-ME), magnifying endoscopy (ME), and endoscopic ultrasonography (EUS). However, which of these three modalities is most effective remains unclear. We performed a systematic review of the literature to compare the diagnostic accuracy of the three modalities for prediction of the invasion depth of superficial ESCC. We used Medical Subject Heading terms and free keywords to search the PubMed, Cochrane Central, and Ichushi databases to identify direct comparison studies published from January 2000 to August 2020. The results of direct comparison studies were used to compare the diagnostic accuracy of each modality. The primary outcome was defined as the proportion of overdiagnosis of pT1b-SM2/3 cancers, and the main secondary outcome was the proportion of underdiagnosis of pT1b-SM2/3 cancers. Other secondary outcomes were the sensitivity and specificity values of the modalities. Four articles were finally selected for qualitative evaluation. Although ME showed no significant advantages over non-ME in terms of sensitivity and specificity, it had a slightly lower proportion of overdiagnosis. EUS had sensitivity and specificity similar to those of non-ME and ME, but EUS had a higher proportion of overdiagnosis. Non-ME and ME are useful for the diagnosis of cancer invasion depth. EUS may increase overdiagnosis, and caution is required in determining its indications.

Implementation rate and effects of multidisciplinary team meetings on decision making about radiotherapy: an observational study at a single Japanese institution.

BACKGROUND: Cancer treatment requires a multidisciplinary approach. Therefore, multidisciplinary team meetings (MDTMs) have been widely used to determine the direction of treatment. However, no standard provisions exist for conducting MDTMs, and recommendations discussed in MDTMs are sometimes not implemented. ​This study analyzed the indications for radiotherapy discussed and recommended at MDTMs, identified the rate of radiotherapy recommendations for patients that were not implemented, and clarified the reasons at a single academic center in Japan. METHODS: This was a cross-sectional study that analyzed the minutes and electronic medical records of cases discussed at MDTMs held between April 2012-March 2017 at Yamagata University Hospital. We categorized how radiotherapy was initially presented at MDTMs, determined the rate of radiotherapy recommendations made through MDTMs, analyzed whether treatment recommendations were subsequently implemented, and examined the causes of non-implementation. We performed a statistical analysis to assess some clinical factors (sex, age, number of multidisciplinary team meetings, and classification of planned treatment) associated with the non-implementation of radiotherapy recommendations from MDTMs. RESULTS: A total of 1813 cases were discussed at MDTMs, of which 71% (1293 cases) were presented with treatment plans, including radiotherapy. Further, 66% (1205 cases) were recommended for radiotherapy through the MDTMs. Recommendations from MDTMs were not implemented in 7% (142 cases). The most typical reason for non-implementation was the clinician's opinion (30%), followed by patient preferences (27%) and disease progression (20%). Change in cancer stage and improvement in symptoms were 12% and 4%, respectively. These ratios were similar each year. We could not find the factors associated with the non-implementation of radiotherapy recommendations from MDTMs. CONCLUSIONS: MDTMs had a significant effect on the recommendation of radiotherapy for each patient with a tumor. The primary reason for the non-implementation of decisions made at MDTMs was the opinion of clinicians and the patient's preference. These results were similar to previous studies. We need to establish a monitoring system where patients themselves can decide the treatments based on their choices while using the recommendations from MDTMs.

The potential for reducing alcohol consumption to prevent esophageal cancer morbidity in Asian heavy drinkers: a systematic review and meta-analysis.

Alcohol consumption is a major risk factor for esophageal cancer. In Asia, heavy drinkers are considered to have a higher risk of esophageal cancer than nondrinkers and light drinkers. However, no study has shown an association between alcohol reduction and the morbidity of esophageal cancer in Asian heavy drinkers. Therefore, this study investigated the significance of reducing alcohol consumption to prevent esophageal cancer in Asian heavy drinkers by conducting a systematic review and meta-analysis. The MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases were searched from January 1995 to December 2020. The hazard ratio (HR) and 95% confidence interval (CI) were calculated using a random-effects model. I2 statistics were used to detect heterogeneity. This study included 21 articles in the qualitative synthesis. Light drinkers and heavy drinkers were categorized based on alcohol consumption amount as ≤ 25 ethanol g/day and ≥ 66 ethanol g/day, respectively, as described in many previous studies, and five cohort studies were eligible for this meta-analysis. The HR of esophageal cancer among heavy drinkers versus nondrinkers was 4.18 (95% CI 2.34-7.47, I2 = 74%). On the other hand, the HR of esophageal cancer among light drinkers was 1.82 compared with nondrinkers (95% CI 1.57-2.10, I2 = 0%). Heavy drinkers have a higher esophageal cancer incidence than light drinkers and nondrinker. It is possible that alcohol reduction may decrease the risk of esophageal cancer in Asian heavy drinkers.

Fruit and vegetable consumption and risk of esophageal cancer in the Asian region: a systematic review and meta-analysis.

The consumption of fruit and vegetables was reported to be associated with a reduced risk of esophageal cancer (EC) in many studies of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) from different regions worldwide. Therefore, to provide precise information to reduce the risk of EC in Asia, we performed a systematic review and meta-analysis of studies conducted in the Asian region about fruit and vegetable consumption and the risk of EC. We searched the MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases from January 2010 to December 2020. The summary relative risk (SRR) and 95% CI were calculated using a random-effects model. In addition, I2 statistics were used to detect heterogeneity. Twenty-two studies were eligible for meta-analysis (16 case-control studies and 6 cohort studies). The SRR for the lowest versus highest fruit consumption was 0.64 (95% CI 0.53-0.77, I2 = 82%). That for the lowest versus highest vegetable consumption was 0.61 (95% CI 0.50-0.74, I2 = 81%). Based on subgroup analysis, a validated Food Frequency Questionnaire (FFQ) was significantly associated (SRR for fruit: 0.54; 95% CI 0.40-0.74, SRR for vegetable: 0.60; 95% CI 0.48-0.76) with low heterogeneity (I2 = 48% for fruit, I2 = 0% for vegetables). Egger's funnel plot asymmetry test demonstrated publication bias (P < 0.001 for fruit, P = 0.009 for vegetables). Fruit and vegetable consumption might be associated with a lower risk of EC in the Asian region. However, further substantial prospective studies with a validated FFQ and well-controlled important confounding factors are required to confirm the association.