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Background In definitive chemoradiotherapy (CRTx) for esophageal cancer, a radiotherapy (RT) dose of 50.4 Gy in 28 fractions has been the standard in many countries, while 60 Gy in 30 fractions has been frequently used in Japan. To clarify the optimal RT dose in CRTx for esophageal cancer, we compared clinical outcomes with the two doses using data from the Comprehensive Registry of Esophageal Cancer in Japan by the Japan Esophageal Society (JES). Methods Of the patients enrolled in the registry for 2015–2017 surveys (patients treated between 2009 and 2011), 996 patients who received definitive CRTx with 50.4 Gy or 60 Gy for thoracic esophageal cancer were eligible for analysis. Results The complete response (CR) rates in the 50.4 Gy and 60 Gy groups were 49.1% and 46.4%, respectively (p = 0.5851). The 5-year overall survival (OS) rates in the 50.4 Gy group and 60 Gy group for stages I, II/III and IV were 64.2% and 57.2%, 35.0% and 27.0%, and 18.0% and 15.3%, respectively. Since no significant difference was found between the two groups, the 50.4 Gy group was not inferior to the 60 Gy group with regard to OS. Conclusions The analysis revealed that the 50.4 Gy group had a non-inferior outcome in comparison with the 60 Gy group for stages I, II/III and IV thoracic esophageal cancer. These results were obtained from a large database for the first time in Japan.

Purpose The purpose of this study was to compare carbon-ion (C-ion), proton and photon radiotherapy (RT) plans with regard to dose reduction of the gastrointestinal (GI) tract by using a greater omentum spacer (GO spacer). Methods We retrospectively retrieved data for ten patients who received the GO spacer as surgical spacer placement for abdominal and pelvic tumors. Simulation plans were created on pre-spacer Computed Tomography (CT) and post-spacer CT for C-ion RT, proton RT and photon RT to compare the dose of the GI tract. The plans were normalized so that at least 95% of the planning target volume (PTV) received 70 Gy (relative biological effectiveness equivalent) delivered in 35 fractions. All plans were created with the lowest possible dose to the GI tract under conditions that meet the dose constraints for the PTV and spinal cord (maximum dose Results D2 cc and V10–70 of the GI tract were significantly lower on post-spacer plans than on pre-spacer plans for all three RT modalities. Regarding post-spacer plans, D2 cc of the GI tract was significantly lower on C-ion RT plans and proton RT plans than on photon RT plans (C-ion vs photon p = 0.001, proton vs photon p = 0.002). However, there was no significant difference between C-ion RT plans and proton RT plans for D2 cc of the GI tract (C-ion vs proton p = 0.992). In the photon RT plan for one patient, D2 cc of the GI tract did not meet Conclusions The GO spacer shows a significant dose reduction effect on the GI tract.

Most of the primary sphenoid sinus tumors present with locally advanced stages with involvement of adjacent critical structures and are not amenable to radical resection. We sought to evaluate the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for sphenoid sinus malignancies.

Background Most of the primary sphenoid sinus tumors present with locally advanced stages with involvement of adjacent critical structures and are not amenable to radical resection. We sought to evaluate the safety and efficacy of carbon‐ion radiotherapy (C‐ion RT) for sphenoid sinus malignancies. Methods This is a retrospective analysis of 22 patients of primary sphenoid carcinomas treated with definitive C‐ion RT. Results Adenoid cystic carcinoma was the most common histology (15 patients, 68.2%). The median follow‐up of this cohort was 48.5 months. The actuarial local control and overall survival at 5 years were 51.0% and 62.7%, respectively. Grade 4 visual impairment and grade 4 brain necrosis were seen in six and one patient, respectively. Conclusion C‐ion RT can provide a reasonably good clinical outcome in locally advanced sphenoid sinus malignancies with a marginally higher late toxicity profile because of extremely close proximity of the target volume to critical structures.

Although esophagectomy is the standard treatment for resectable esophageal cancer, chemoradiotherapy or radiotherapy alone is also selected for some cases. However, there have been very few detailed studies conducted on a large scale on the efficacy of these treatments in Japan. Of the patients enrolled in the Comprehensive Registry of Esophageal Cancer in Japan by the Japan Esophageal Society for the 2015–2017 surveys (patients treated between 2009 and 2011), the data of 388 patients treated by definitive radiotherapy alone (RTx) and 1964 patients treated by definitive chemoradiotherapy (CRTx) were analyzed. The median age of the patients was 78 years in the RTx group and 69 years in the CRTx group; thus, the proportion of elderly patients was significantly higher in the RTx group than in the CRTx group (p

Purpose We investigated the efficacy and safety of carbon-ion radiotherapy (C-ion RT) for locally recurrent rectal cancer (LRRC). Patients and methods Data from patients with LRRC treated with C-ion RT from November 2003 to December 2014 at three institutions were retrospectively analyzed. The endpoints of this clinical trial were overall survival (OS), local control (LC), and acute/late toxicity. Results A total of 224 patients' data were collected. The prescribed dose was 70.4 Gy (relative biological effectiveness [RBE]-weighted absorbed dose) or 73.6 Gy (RBE) in 16 fractions. The median follow-up period from the initiation of C-ion RT was 62 months (range 6–169 months). The OS rates were 73% (95% confidence interval [CI], 67%–79%) at 3 years and 51% (95%CI 44%–58%) at 5 years. The LC rates were 93% (95%CI 88%–96%) at 3 years, and 88% (95%CI 82%–93%) at 5 years. Grade 3 acute toxicity was observed in three patients: gastrointestinal toxicity (n = 1) and pelvic infection (n = 2). Grade 3 late toxicity was observed in 12 patients: skin reaction (n = 2), gastrointestinal toxicity (n = 2), neuropathy (n = 1), and pelvic infection (n = 7). There was no grade 4 or 5 acute or late toxicity. Conclusions This first multi-institutional analysis of C-ion RT for LRRC indicated relatively favorable outcomes with limited toxicities.

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.

There are no studies on the risk factors of radiation pneumonitis (RP) after carbon-ion radiotherapy at a dose of 50 Gy (relative biological effectiveness (RBE)) in a single fraction. The objective of this study was to identify factors associated with RP after radiotherapy, including dose–volume parameters. Ninety-eight patients without a history of thoracic radiotherapy who underwent treatment for solitary lung tumors between July 2013 and April 2016 were retrospectively analyzed. Treatment was planned using Xio-N. The median follow-up duration was 53 months, and the median clinical target volume was 32.3 mL. Three patients developed grade 2 RP, and one patient developed grade 3 interstitial pneumonitis. None of the patients developed grade 4 or 5 RP. The dose-volume parameters of the normal lung irradiated at least with 5–30 Gy (RBE), and the mean lung dose was significantly lower in patients with grade 0–1 RP than in those with grade 2–3 RP. Pretreatment with higher SP-D and interstitial pneumonitis were significant factors for the occurrence of symptomatic RP. The present study showed a certain standard for single-fraction carbon-ion radiotherapy that does not increase the risk of RP, however, further validation studies are needed.

Background We aimed to detect influenza variants with reduced susceptibility to baloxavir marboxil (baloxavir) and oseltamivir and identify differences in the clinical course between children with and without these variants after antiviral treatment. Methods During the 2019–2020 influenza season, we enrolled children with confirmed influenza A (20 treated with baloxavir and 16 with oseltamivir). We analyzed patients’ sequential viral RNA loads and infectious virus titers, the drug susceptibilities of clinical isolates, and amino acid substitutions in the viral polymerase acidic protein subunits or neuraminidase. We assessed patients’ clinical information using questionnaires. Results All viral RNA loads and virus titers were significantly decreased after treatment, but we detected baloxavir-resistant and oseltamivir-resistant variants in 5 of 20 and 3 of 16 patients, respectively. The duration of fever was similar between patients with and without the variants, but infectious viral shedding lasted 3 days longer in patients with baloxavir-resistant variants. In addition, the duration to improvement of clinical symptoms was longer in these patients (75.0 vs 29.5 hours; P = .106). Conclusions After antiviral treatment, the emergence of baloxavir-resistant variants may affect the patients’ clinical course, but oseltamivir-resistant variants had no clinical impact.

Background: The prevalence of non-tuberculous mycobacterial (NTM) pulmonary disease is globally increasing. The most common pathogen isolated in Japan is the Mycobacterium avium complex (MAC), and the natural history of MAC pulmonary disease (MAC-PD) remains unclear, even in mild cases of MAC-PD. Our previous study showed that serum dROM (oxidative stress marker) as well as the increase of total cell counts and neutrophil percentages in bronchoalveolar lavage fluid (BALF) were related to the commencement of chemotherapy (CT). Aims: To elucidate whether the level of oxidative stress in BALF reflect the disease severity and can be a marker for initiating CT in mild cases of MAC-PD. Methods: Between June 2016 and March 2019, 34 subjects who were suspected of MAC-PD and underwent diagnostic bronchoscopy were included, and all of patients did not show systemic inflammation. According to the findings of bronchoscopy, subjects were divided into MAC group and Non-MAC group. MAC group were subdivided into Treatment group (MAC-T) and Observation group (MAC-O). We measured malondialdehyde (MDA) in BALF and serum d-ROM as a marker of oxidative stress. Results: Total cell counts as well as neutrophil percentages in BALF were the highest in MAC-T group among three groups (P Conclusions: The level of MDA in BALF seemed to reflect the oxidative tissue damage in mild cases of MAC-PD, and it might be an indicator for disease severity and the commencement of CT.

Hintergrund: Die exzessive Inhalation von Aluminiumstaub führt gelegentlich zu einer überwiegend die Oberlappen betreffenden Lungenfibrose, die einer idiopathischen pleuroparenchymalen Fibroelastose (IPPFE) ähnelt und bei der es sich den Annahmen zufolge um eine sekundäre PPFE handelt. Fallbericht: Ein 67-jähriger Mann, der 50 Jahre lang in einem aluminiumverarbeitenden Unternehmen gearbeitet hatte, stellte sich mit Belastungsdyspnoe in unserer Klinik vor. Die Computertomographie (CT) des Thorax zeigte eine bilaterale dichte subpleurale Konsolidierung in den oberen und mittleren Lungenfeldern entsprechend einer IPPFE; eine etwaige sekundäre PPFE im Zusammenhang mit einer Aluminose wurde jedoch nicht ausgeschlossen. Aufgrund des kritischen Zustands des Patienten erfolgten eine transbronchiale Lungenbiopsie (TBLB) anstatt einer chirurgischen Lungenbiopsie sowie eine Elementaranalyse der entnommenen Gewebeprobe. Da die mittels TBLB gewonnene Probe bedauerlicherweise kein Alveolargewebe enthielt, konnte die Diagnose PPFE nicht pathologisch gesichert werden. Die radiologischen Befunde sprachen jedoch stark für eine PPFE. In der Elementaranalyse wurden hohe Mengen an Aluminium in den Bronchiolarwänden nachgewiesen, so dass die Diagnose einer Aluminose der Atemwege mit wahrscheinlich sekundärer PPFE infolge Aluminiumexposition gestellt wurde. Schlussfolgerungen: Eine TBLB mit Elementaranalyse kann zur Abgrenzung der idiopathischen PPFE von sekundären Ursachen bei staubbedingten Erkrankungen wie Aluminose hilfreich sein. Der vorliegende Fall zeigt, dass die Inhalation von Aluminium eine sekundäre PPFE verursachen kann; ein besonderes Augenmerk sollte auf die Vermeidung einer weiteren Exposition gelegt werden.

BACKGROUND The purpose of the present study was to retrospectively evaluate the safety and efficacy of proton beam therapy (PBT) in patients with second primary lung cancer after lung resection. METHODS Patients who were diagnosed with second primary lung cancer after lung resection and underwent PBT between January 2009 and February 2015 were retrospectively recruited. Toxicities were evaluated using Common Terminology Criteria for Adverse Events version 4.0. RESULTS Nineteen patients were eligible for inclusion in this study. All of the patients completed the treatment. The median age was 75 (range: 63-82) years, and the median follow-up time of living patients was 60 months. The median dose of PBT was 76.8 Gy relative biological effectiveness (range: 66.0-80.0 Gy). The three-year overall survival rate was 63.2% and the three-year local control rate was 84.2%. No grade 4 or 5 toxicities were observed after PBT. CONCLUSIONS Our results suggest that PBT is a safe and feasible treatment for second primary lung cancer compared to surgery or X-ray radiotherapy. PBT may become a treatment choice for patients with second primary lung cancer after lung resection.

Background The purpose of the present study was to retrospectively evaluate the safety and efficacy of proton beam therapy (PBT) in patients with second primary lung cancer after lung resection. Methods Patients who were diagnosed with second primary lung cancer after lung resection and underwent PBT between January 2009 and February 2015 were retrospectively recruited. Toxicities were evaluated using Common Terminology Criteria for Adverse Events version 4.0. Results Nineteen patients were eligible for inclusion in this study. All of the patients completed the treatment. The median age was 75 (range: 63–82) years, and the median follow‐up time of living patients was 60 months. The median dose of PBT was 76.8 Gy relative biological effectiveness (range: 66.0–80.0 Gy). The three‐year overall survival rate was 63.2% and the three‐year local control rate was 84.2%. No grade 4 or 5 toxicities were observed after PBT. Conclusions Our results suggest that PBT is a safe and feasible treatment for second primary lung cancer compared to surgery or X‐ray radiotherapy. PBT may become a treatment choice for patients with second primary lung cancer after lung resection.

Background We conducted a retrospective multicenter study to assess the clinical outcomes of carbon‐ion radiotherapy (CIRT) for head and neck malignancies (Japan Carbon‐Ion Radiation Oncology Study Group [J‐CROS] study: 1402 HN). We aimed to evaluate the safety and efficacy of CIRT in patients with external auditory canal (EAC) and middle ear (ME) carcinomas. Methods Thirty‐one patients treated with CIRT at four Japanese institutions were analyzed. Fourteen patients (45.2%) had squamous cell carcinomas, 13 (41.9%) had adenoid cystic carcinomas, and four (12.9%) had other types. Nineteen (61.3%), six (19.4%), three (9.7%), and three (9.7%) patients had T4, T3, T2, and T1 disease, respectively. All patients had N0M0 status. The median radiation dose was 64 Gy (relative biological effectiveness) in 16 fractions. The median gross tumor volume was 33.3 mL. Results The median follow‐up period was 18.4 months (range, 5.1‐85.6). The 1‐ and 3‐year local control and overall survival rates were 75.0% and 55.0% and 79.3% and 58.7%, respectively. Regarding grade 3 or higher toxicities, three patients (9.7%) had grade 3 dermatitis, one (3.2%) had grade 3 mucositis, and two (6.5%) had grade 3 central nervous necrosis (ie, radiation‐induced brain necrosis). No grade 4 or worse reactions were observed. Conclusion CIRT was effective for EAC and ME carcinomas.

Background This multi‐institutional retrospective study focused on the clinical outcome of carbon‐ion radiotherapy (C‐ion RT) for non‐squamous cell malignant tumors of the nasopharynx. Methods The Japan Carbon‐ion Radiation Oncology Study Group collected and analyzed data for 43 patients with non‐squamous cell malignant tumors of the nasopharynx treated with C‐ion RT at four institutions in Japan. Results Twenty‐nine patients had adenoid cystic carcinomas, seven had malignant melanomas, three had adenocarcinomas, two had mucoepidermoid carcinomas, and two had other pathologies. Twenty‐six of the 43 patients (61%) had T4 tumors. The most common dose‐fractionation schedule was 64 Gy (relative biological effectiveness) in 16 fractions. The median follow‐up period was 30 months. The 2‐year local control (LC) and overall survival (OS) rates were 88% and 84%, respectively. For late toxicity, one patient developed grade 4 optic nerve disorder and two developed grade 5 pharyngeal hemorrhage. Actual incidence of grade 3 or higher late adverse events was 19%, and included cranial nerve dysfunction, jaw bone necrosis, central nervous system necrosis, and ear inflammation. Conclusions C‐ion RT provided good LC and OS rates with acceptable toxicity for treatment of non‐squamous cell malignant tumors of the nasopharynx.

The efficacy and safety of carbon ion radiotherapy (C-ion RT) for locoregional recurrence after surgery for pancreatic cancer were retrospectively evaluated. The results for 30 patients showed that C-ion RT was performed safely with relatively long overall survival, good local control, and minimal toxicity.

Purpose of the guidelines The primary objective of these guidelines is to provide general clinicians with information that would guide them to make informed choices of the available diagnosis/treatment strategies for esophageal cancer (intended for malignant esophageal tumors of epithelial origin, not for any other non-epithelial malignant tumors of the esophagus or metastatic esophageal malignant tumors). Furthermore, these guidelines are also intended as an aid for healthcare professionals other than the physicians, patients, and patients’ family members, to obtain an understanding of the fundamental principles of the diagnosis and treatment of esophageal cancer. These guidelines are intended to allow physicians to undertake diagnosis and treatment of esophageal cancer by sharing the information contained in the guidelines and promote mutual understanding among the healthcare professionals, patients, and their family members.

Purpose The aim of this multi-institutional study was to evaluate the efficacy and safety of carbon-ion radiotherapy (C-ion RT) for locally advanced pancreatic cancer (LAPC). Methods and Materials Patients with LAPC treated with C-ion RT from April 2012 to December 2014 at 3 institutions were retrospectively analyzed. Patients with pathologically-confirmed invasive ductal adenocarcinoma of the pancreas were eligible. The prescribed dose was 52.8 Gy (relative biological effectiveness weighted absorbed dose; RBE) or 55.2 Gy (RBE) in 12 fractions. Overall survival (OS), distant metastasis-free survival (DMFS), local recurrence (LR), and toxicity were evaluated. Results In total, 72 patients were included in this study. Tumors in the head of the pancreas were seen in 30 patients (42%), while those in the body or tail of the pancreas were seen in 42 patients (58%). Fifty-six patients (78%) received concurrent chemotherapy. The OS rates were 73% (95% confidence interval [CI], 62%-84%) at 1 year, and 46% (95% CI, 31%-61%) at 2 years with a median OS of 21.5 months (95% CI, 11.8-31.2 months). The 1- and 2-year DMFS rates were 41% (95% CI, 29%-52%) and 28% (95% CI, 16%-40%), respectively. The 1- and 2-year cumulative incidences of LR were 16% (95% CI, 9%-26%) and 24% (95% CI, 14%-36%), respectively. Nineteen patients (26%) experienced acute grade 3 or 4 hematological toxicities. Two patients (3%) had grade 3 anorexia. Late gastrointestinal (GI) grade 3 toxicity was observed in 1 patient (1%). No patients developed late grade 4 or 5 toxicity. Conclusions The first multi-institutional analysis of C-ion RT for LAPC indicated relatively favorable outcomes with limited toxicities, especially for tumors not in close proximity to GI tract.

A retrospective multicenter study was carried out to assess the clinical outcomes of carbon-ion radiotherapy for head and neck malignancies (Japan Carbon-Ion Radiation Oncology Study Group [J-CROS] study: 1402 HN). We evaluated the safety and efficacy of carbon-ion radiotherapy in patients with major salivary gland carcinoma. Sixty-nine patients treated with carbon-ion radiotherapy at four Japanese institutions were analyzed. Thirty-three patients (48%) had adenoid cystic carcinomas, 10 (14%) had mucoepidermoid carcinomas, and 26 (38%) had other disease types. Three patients (4%) had T1 disease, 8 (12%) had T2, 25 (36%) had T3, and 33 (48%) had T4. The median radiation dose was 64 Gy (relative biological effectiveness) in 16 fractions. The median gross tumor volume was 27 mL. The median follow-up period was 32.7 months. The 3-year local control rate and overall survival rate were 81% and 94%, respectively. Regarding acute toxicities, seven patients had grade 3 mucositis and seven had grade 3 dermatitis. Regarding late toxicities, one patient had grade 3 dysphagia and one had a grade 3 brain abscess. No grade 4 or worse late reactions were observed. In conclusion, definitive carbon-ion radiotherapy was effective with acceptable toxicity for major salivary gland carcinomas.

Background The purpose of the present study was to evaluate retrospectively the efficacy and safety of proton beam therapy for elderly patients (≥80 years of age) with non-small cell lung cancer. Methods Patients diagnosed with T1–4 N0 M0 non-small cell lung cancer and treated with proton beam therapy between January 2009 and 2015 were recruited from our database retrospectively. Toxicity was evaluated using The Common Terminology Criteria for Adverse Events version 4.0. Results Thirty-five patients, including 25 (71%) with clinically inoperable lung cancer, were administered proton beam therapy. The median age was 82 years (range: 80–87 years), and the median follow-up time was 34 months (range: 10–72 months). The median dose of proton beam therapy was 80.0 Gy relative biological effectiveness (RBE) (range: 60.0–80.0 Gy [RBE]), and all patients completed the treatments. All patients were followed for at least 23 months or until their death. The 3-year overall survival rate was 67.2% (90.0% in patients with operable lung cancer, and 58.2% in those with inoperable lung cancer). The 3-year local control rate was 86.5%. Two patients presented with grade 2 pneumonitis. The occurrence rate of grade 2 pneumonitis was significantly correlated with a high lung V20 (p = 0.030), and a high mean lung dose (p = 0.030), and a low ratio of lung volume spared from 0.05 Gy (RBE) dose (total lung volume minus lung volume irradiated at least 0.05 Gy [RBE]) (p = 0.030). However, there were no cases of grade 3 or higher radiation pneumonitis. Conclusions This study suggests that the proton beam therapy was feasible for elderly patients with non-small cell lung cancer and can be considered as one of the treatment choices for elderly patients with lung cancer.

Summary To evaluate the clinical outcomes of patients with mucoepidermoid carcinomas in the head and neck treated with carbon-ion radiotherapy. Data from 26 patients who underwent carbon-ion radiotherapy in four facilities were analyzed in this multi-institutional retrospective study: the Japan Carbon-ion Radiation Oncology Study Group (J-CROS). The median follow-up time was 34 months. One patient experienced local recurrence, and the 3-year local control rate was 95%. One patient developed lymph node recurrence and five developed distant metastases. The 3-year progression-free survival rate was 73%. Five patients died, two of mucoepidermoid carcinoma and three of intercurrent disease. The 3-year overall survival rate was 89%. Acute mucositis and dermatitis of grade 3 or higher were experienced by 19% and 8% of patients, respectively; these improved with conservative therapy. Late mucositis and osteonecrosis of jaw were observed in 12% and 23% of patients, respectively. The 3-year cumulative rate of any late adverse event of grade 3 or higher was 14%. None of the patients died of the acute or late adverse events. Carbon-ion radiotherapy was efficacious and safe for treating mucoepidermoid carcinoma in this multi-institutional retrospective study. We are currently conducting a prospective multicenter study. (UMIN000024473) This article is protected by copyright. All rights reserved.

Smoking cigarettes and drinking alcoholic beverages are considered very important risk factors for adverse health effects, such as many types of cancer and cardiovascular disease. In this study, we evaluated the influence of smoking and drinking cessation on risk of esophageal cancer, by means of meta-analysis. We extracted 205 studies by conducting a systematic literature search. Thirty-five studies that estimated risk reduction following smoking cessation and 18 studies conducted following drinking cessation were identified in the literature review. Former smokers had a significantly lower summary risk ratio (RR) than current smokers [RR 0.74, 95% confidence interval (CI) 0.68–0.80]. In subgroup analysis of Japanese smokers, squamous cell carcinoma, and adenocarcinoma, RRs for former smokers versus current smokers were 0.65 (95% CI 0.51–0.83), 0.60 (95% CI 0.50–0.72), and 0.93 (95% CI 0.84–1.03), respectively. The summary RR between former alcohol drinkers and current drinkers was not significant (RR 1.09, 95% CI 0.94–1.26). In our analysis of time since drinking cessation, drinkers who had stopped consuming alcohol for 5 years or more had a significantly lower summary RR than current drinkers (RR 0.78, 95% CI 0.66–0.93). Summary RR for drinkers who stopped for 10 years or more versus current drinkers was 0.65 (95% CI 0.57–0.74). Our investigation found that smoking cessation lowers esophageal cancer incidence. We also found that esophageal cancer incidence risk could be decreased in current drinkers by cessation of alcohol consumption for 5 years or more.

Aim To evaluate the efficacy of stereotactic body radiotherapy (SBRT) for pulmonary metastasis from colorectal cancer. Patients and methods Data for 104 lesions from 93 patients who underwent SBRT for pulmonary oligometastases from colorectal cancer at ten Institutions were retrospectively analyzed. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0. Results The median calculated biological effective dose using the linear-quadratic model with α/β of 10 Gy (BED10) was 105.6 Gy. Adjuvant chemotherapy after SBRT was performed in 47 patients. The median observation period was 28 months. The 3- and 5-year local control rates were 65.2% and 56.2%, respectively. The 3- and 5-year overall survival rates were 55.9% and 42.7%, respectively. Only two patients had grade 3 radiation pneumonitis. In multivariate analysis for local control, primary site, age, adjuvant chemotherapy after SBRT and BED10 were selected as prognostic factors. Conclusion Dose escalation and adjuvant chemotherapy might improve local control in SBRT for pulmonary oligometastases from colorectal cancer.

BACKGROUND Reportedly, a high plasma concentration of lamotrigine plays a role in the development of lamotrigine-related rash. The relationship between plasma concentrations of lamotrigine at week 2 and the lamotrigine-related rash was prospectively studied in 84 patients (22 males and 62 females) with treatment-resistant depressive disorder during an 8-week treatment of lamotrigine augmentation. METHODS Eighty-four depressed patients with an insufficient response to at least 3 psychotropics, including antidepressants, mood stabilizers, and atypical antipsychotics, were included. The diagnoses were major depressive disorder (n = 39), bipolar I disorder (n = 10), and bipolar II disorder (n = 35). The final doses of lamotrigine were 100 mg/d for 57 subjects who were not taking valproate and 75 mg/d for 27 subjects taking valproate. Blood sampling was performed at week 2. Lamotrigine plasma concentrations were measured using high-performance liquid chromatography. The development of lamotrigine-related rash was assessed during the 8-week treatment. RESULTS Six females developed lamotrigine-related rash. The mean plasma lamotrigine concentrations at week 2 were significantly (P = 0.009) higher in the rash group (4.81 ± 1.23 μmol/L) than in the nonrash group (3.35 ± 1.39 μmol/L). Receiver-operating characteristic analysis indicated that a plasma lamotrigine concentration of 4.38 μmol/L or greater at week 2 was significantly (P < 0.0001) predictive of lamotrigine-related rash. The proportion of patients with a lamotrigine concentration of 4.38 μmol/L or greater was significantly divided by the cutoff point into the rash group and the nonrash group (5/1 versus 13/65, P = 0.001). CONCLUSIONS This study suggests that a high plasma lamotrigine concentration during week 2 is a risk factor for lamotrigine-related rash and a plasma lamotrigine concentration of 4.38 μmol/L may be a considered a threshold for rash in treatment-resistant depressive disorder.

We quantified intra-fractional dose variation and organ movement during CT-based 3D-image guided brachytherapy (3D-IGBT) in cervical cancer patients. Fifteen patients who underwent CT-based 3D-IGBT were studied. For all patients, pre-delivery CT for treatment planning after applicator insertion and post-delivery CT after dose delivery without changing the applicator position were acquired. Pre- and post-delivery CT were rigidly fused by matching the inserted applicator and planned dose on pre-delivery CT (pre-delivery dose) was mapped on post-delivery CT (post-delivery dose). D2, D1, and D0.1 cm3 of the rectum and bladder were compared between pre- and post-delivery doses with contours on each CT image. Organ movement and deformation was evaluated using deformation vector fields calculated by deformable image registration between pre- and post-delivery CT. We also evaluated dose variation and DVF between with and without a catheter to control filling. Differences in all DVH parameters were 15% dose difference was found in 13.8% of the fractions in rectum D2 cm3 and in 11.1% of those in bladder D2 cm3. The mean value of DVF for bladder was larger than that of rectum, especially for the superior-inferior (S-I) direction. Insertion catheters in bladder reduced mean dose and DVF variation compared with that of without catheters. In fraction groups with large dose increasing, DVF in the S-I direction was significantly larger than that of other fraction groups. Our results indicated that preparation is needed to reduce changes in the S-I direction affect dose variation.

During the 2018–2019 influenza seasons, we detected reduced baloxavir marboxil (baloxavir) susceptible variants with I38S or I38T amino acid substitutions on the PA subunit of influenza virus ribonucleic acid polymerase in 7 of 18 baloxavi-treated children and found that virus titer rebounded in some of these children with variants. We also found fever durations to be similar between patients with or without the variants, but the patients with variants shed the virus 3 days longer and took longer to improve clinical symptoms than those without variants. The emergence of these variants should be monitored during future influenza seasons.

Background No-touch environmental disinfection using ultraviolet devices has been highlighted in the past several years to control the transmission of multidrug-resistant organisms (MDROs). However, its effectiveness in non-US healthcare settings is yet to be examined. This study aimed to evaluate the effectiveness of disinfection by portable pulsed xenon ultraviolet (PX-UV) devices in controlling transmission of MDROs in a non-US healthcare setting. Methods All patients admitted in the intensive care unit in a 629-bed tertiary referral hospital in Japan from August 2016 to February 2019 were enrolled. During the study period, PX-UV disinfection was added to manual terminal cleaning after every patient transfer/discharge. For microbiological evaluation, surfaces were selected for sampling by contact plates before/after manual cleaning and after PX-UV. After overnight incubation, colonies on the plates were counted. Results The incidence of newly acquired methicillin-resistant Staphylococcus aureus (MRSA) declined significantly (13.8 to 9.9 per 10,000 patient days, incidence rate ratio 0.71, p = 0.002), as well as that of newly acquired drug-resistant Acinetobacter (48.5 to 18.1, 0.37, p Conclusions PX-UV is effective in further reducing the microbial burden and controlling MDROs in a non-US healthcare setting.

Background: The number of nontuberculous mycobacterial lung disease (NTM) is rapidly increasing. Its natural history seems to be complicated, and it is sometimes difficult to decide when chemotherapy (CT) should be started. Our previous study showed that the increase of total cell counts and neutrophil percentages in bronchoalveolar lavage fluid (BALF) were related to the commencement of CT. Neutrophils produce reactive oxygen species, leading to the increase of oxidative stress. Aims: To elucidate whether oxidative stress as well as neutrophils are useful indicators to initiate CT in NTM patients. Methods: Between June 2016 and January 2019, 69 subjects that underwent diagnostic bronchoscopy were included. According to the finding of bronchoscopy, subjects were divided into NTM group and No-NTM group. NTM group were subdivided into Treatment group (NTM-T) and Observation group (NTM-O). We measured serum d-ROM as a marker of oxidants and serum BAP as a marker of antioxidants through a spectrophotometric procedure (FRAS4). Results: Total cell counts as well as neutrophil percentages in BALF were the highest in NTM-T group (P Conclusions: The current study suggested that the predominance of neutrophil in BALF and/or serum oxidative stress markers seemed to be a potential indicator to initiate CT in NTM patients.

Background Marfan Syndrome (MFS) is a heritable connective tissue disorder with a high degree of clinical variability including respiratory diseases; a rare case of MFS with massive intrathoracic bleeding has been reported recently. Case presentation A 32-year-old man who had been diagnosed with MFS underwent a Bentall operation with artificial valve replacement for aortic dissection and regurgitation of an aortic valve in 2012. Warfarin was started postoperatively, and the dosage was gradually increased until 2017, when the patient was transported to our hospital due to sudden massive haemoptysis. Computed tomography (CT) with a maximum intensity projection (MIP) revealed several giant pulmonary cysts with fluid levels in the apex of the right lung with an abnormal vessel from the right subclavian artery. Transcatheter arterial embolization was performed with angiography and haemostasis was achieved, which suggested that the bleeding vessel was the lateral thoracic artery (LTA) branch. CT taken before the incident indicated thickening of the cystic wall adjacent to the thorax; therefore, it was postulated that the bleeding originated from fragile anastomoses between the LTA and pulmonary or bronchial arteries. It appears that the vessels exhibited inflammation that began postoperatively, which extended to the cysts. Conclusion We experienced a case of MFS with massive haemoptysis from the right LTA. We have to be aware of the possibility that massive haemoptysis could be induced in MFS with inflamed pulmonary cysts.

Background: Excessive inhalation of aluminium powder occasionally results in upper lobe predominant lung fibrosis, which is similar to idiopathic pleuroparenchymal fibroelastosis (IPPFE) and has been suggested to be secondary PPFE. Case presentation: A 67-year-old man who had worked in an aluminum-processing factory for 50 years visited our hospital complaining of exertional dyspnea. Chest computed tomography (CT) showed bilateral dense sub-pleural consolidation in the upper and middle lung fields, which was consistent with IPPFE; however, the possibility of secondary PPFE associated with aluminosis was not ruled out. Considering the patient’s critical condition, trans-bronchial lung biopsy (TBLB) rather than surgical lung biopsy was performed, with elemental analysis of the biopsied specimen. Unfortunately, the specimen obtained by TBLB did not contain alveolar tissue; therefore, pathological diagnosis of PPFE was not possible. However, radiographic findings were highly suggestive of PPFE. On elemental analysis, excessive amounts of aluminum were detected in the bronchiolar walls, establishing a diagnosis of airway aluminosis with likely secondary PPFE resulting from aluminium exposure. Conclusions: TBLB with elemental analysis might be useful in differentiating idiopathic PPFE from secondary causes in dust inhalation related disease, such as aluminosis. This case indicated that inhalation of aluminium might cause secondary PPFE, with attention needing to be paid to avoid further exposure.

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Background/Aims: The present study prospectively examined whether or not a partial response at week 4 predicts subsequent response at week 8 during lamotrigine augmentation therapy in 51 (16 males and 35 females) inpatients with treatment-resistant depressive disorder using an open-study design. Methods: The subjects were 51 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 19), bipolar I disorder (n = 9), and bipolar II disorder (n = 23). The final doses of lamotrigine were 100 mg/day for 29 subjects who were not taking valproate and 75 mg/day for 22 subjects taking valproate. Depressive symptoms were evaluated by the Montgomery-Åsberg Depression Rating Scale (MADRS) before the start of lamotrigine and then at week 4, and finally after the 8th week of treatment. Results: A significant linear relationship was found between percent improvements in MADRS scores at weeks 4 and 8 (r = 0.492, y = 0.438x + 30.223, R2 = 0.226, p < 0.001). The receiver operating characteristics analysis indicated that a percent improvement of 16% or greater at week 4 was significantly (p < 0.01) predictive of response (50% or more reduction in the MADRS score). The patients were significantly divided by the cut-off point into the responders and the nonresponders (18/26 vs. 1/25, p < 0.001). Conclusion: The present study suggests that a partial response at week 4 can predict subsequent outcome at week 8 during lamotrigine augmentation therapy in patients with treatment-resistant depressive disorder, and that the absence of a partial improvement at week 4 is highly predictive of nonresponse.

Background and purpose A multi-institutional observational study (J-CROS1501PR) has been carried out to analyze outcomes of carbon-ion radiotherapy (CIRT) for patients with prostate cancer. Patients and methods Data of the patients enrolled in prospective studies of following 3 CIRT institutions were analyzed: National Institute of Radiological Sciences (NIRS; Chiba, Japan), Gunma University Heavy Ion Medical Center (GHMC; Gunma, Japan), and Ion Beam Therapy Center, SAGA HIMAT Foundation (HIMAT; Saga, Japan). Endpoints of the clinical trial are biochemical recurrence-free survival (bRFS), overall survival (OS), cause-specific survival (CSS), local control rate (LCR), and acute/late adverse effects. Results A total of 2157 patients' data were collected from NIRS ( n =1432), GHMC ( n =515), and HIMAT ( n =210). The number of patients in low-risk, intermediate-risk, and high-risk groups was 263 (12%), 679 (31%), and 1215 (56%), respectively. The five-year bRFS in low-risk, intermediate-risk, and high-risk patients was 92%, 89%, and 92%, respectively. The five-year CSS in low-risk, intermediate-risk, and high-risk patients was 100%, 100%, and 99%, respectively. The incidence of grade 2 late GU/GI toxicities was 4.6% and 0.4%, respectively, and the incidence of ⩾G3 toxicities were 0%. Conclusions Favorable overall outcomes of CIRT for prostate cancer were suggested by the analysis of the first multi-institutional data.

BACKGROUND The authors have previously shown that an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentration and that a plasma lamotrigine concentration of 12.7 μmol/L may be a threshold for a good therapeutic response in treatment-resistant depressive disorder. The present study investigated whether or not an optimal dose of lamotrigine could be predicted from plasma lamotrigine concentration at week 2. METHODS The subjects were 37 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 15), bipolar I disorder (n = 6), and bipolar II disorder (n = 16). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 16 subjects who were not taking valproate and 75 mg/d for 21 subjects taking valproate, respectively. Blood sampling was performed at weeks 2 and 8. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. RESULTS There were significant linear relationships between the plasma lamotrigine concentrations at week 2 (x) and those at week 8 (y) for subjects who were not taking valproate (P < 0.01) and those taking valproate (P < 0.01). Regression equations were y = 2.032x + 2.549 for the former and y = 3.599x + 5.752 for the latter, respectively. Based on the equations, a nomogram to estimate an optimal dose of lamotrigine could be calculated. CONCLUSIONS The present study suggests that an optimal dose of lamotrigine for augmentation therapy in treatment-resistant depressive disorder can be predicted from a plasma lamotrigine concentration at week 2.

Various options are available to treat cervical esophageal cancer (CEC), including primary resection, neo-adjuvant therapy followed by surgery, and definitive chemoradiotherapy (dCRT). However, whether neo-adjuvant therapy or dCRT can improve larynx preservation rates in patients with CEC is unclear. This study investigated results of CEC treatment in clinical practice by a nationwide survey in Japan. We retrospectively investigated results of clinical practices for patients with resectable CEC treated between 2012 and 2014, using a mailed questionnaire as a nationwide survey to 308 institutions recognized by the Japan Esophageal Society and the Japan Broncho-Esophagological Society. We registered 792 patients from 93 institutions, of whom 11.1 % underwent endoscopic resection, 46.0 % underwent surgery, and 39.2 % underwent dCRT. Among patients with CEC who were considered to be poor candidates for laryngeal preservation at initial diagnosis, 24.5 % of the 139 patients treated with neo-adjuvant therapy, and 47.3 % of the 226 patients treated with dCRT preserved their larynxes. This questionnaire survey revealed that multimodality treatment for CEC could decrease laryngectomy rates, especially among patients who were not considered to be laryngeal preservation candidates. These treatment strategies can lead to both laryngeal preservation and postoperative quality of life, and should become more widely used.

Background and objective: If it becomes possible to reduce the prophylactic radiation field by using a personalized radiation field, radiation therapy of esophageal cancer may become safer. In this study, we examined the relationship between expression levels of biomarkers (CD44, COX-2, TWIST, VEGF-C and LOX) and lymph node metastasis and distant metastasis. Materials and methods: We performed retrospective analysis of 14 patients who underwent radical surgery for esophageal cancer between 2009 and 2011 in Yamagata University Hospital. Stain index was used for assessment of biomarker expression. The relationships of stain index with regional recurrence and distant metastasis were evaluated. Results: All patients had squamous cell carcinoma. The median follow-up duration was 38 months. Distant failure was significantly related to low COX-2 expression in the deep part of the tumor (stain index

Background: The purpose of the present study was to evaluate the efficacy and safety of single-fraction carbon-ion radiotherapy (CIRT) in patients with non-small cell lung cancer. Methods: Patients with histologically confirmed non-small cell lung cancer, stage T1-2N0M0, and treated with single-fraction CIRT (50Gy (relative biological effectiveness)) between June 2011 and April 2016 were identified in our database and retrospectively analyzed. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Results: The study included 57 patients, 22 (38.6%) of whom had inoperable cancer. The median age was 75 years (range: 42&ndash, 94 years), and the median follow-up time was 61 months (range: 6&ndash, 97 months). The 3- and 5-year overall survival rates were 91.2% and 81.7%, respectively. All survivors were followed up for more than three years. The 3- and 5-year local control rates were 96.4% and 91.8%, respectively. No case of &ge, grade 2 pneumonitis was recorded. Conclusions: This study suggests that single-fraction CIRT for T1-2N0M0 non-small cell lung cancer patients is feasible and can be considered as one of the treatment choices, especially in medically inoperable patients.

18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) is usually used for staging or evaluation of treatment response rather than for cancer screening. However, 18F-FDG PET/CT has also been used in Japan for cancer screening in people with no cancer symptoms, and accumulating evidence supports this application of 18F-FDG PET/CT. Previously, we have observed a correlation between the saliva and tumor metabolomic profiles in patients with oral cancer. Hence, if salivary metabolites demonstrate a significant correlation with PET parameters such as the maximum standardized uptake value (SUVmax), they may have the potential to be used as a screening tool before PET/CT to identify patients with high SUVmax. Hence, in this study, we aimed to explore the relationship between salivary metabolites and SUVmax of 18F-FDG PET/CT using previously collected data. 18F-FDG PET/CT was performed for staging 26 patients with oral cancer. The collected data were integrated and analyzed along with quantified salivary hydrophilic metabolites obtained from the same patients with oral cancer and controls (n = 44). In total, 11 metabolites showed significant correlations with SUVmax in the delayed phases. A multiple logistic regression model of the two metabolites showed the ability to discriminate between patients with oral cancer and controls, with an area under the receiver operating characteristic curve of 0.738 (p = 0.001). This study uniquely confirmed a relationship between salivary metabolites and SUVmax of PET/CT in patients with oral cancer; salivary metabolites were significantly correlated with SUVmax. These salivary metabolites can be used as a screening tool before PET/CT to identify patients with high SUVmax, i.e., to detect the presence of oral cancer.

BACKGROUND In a previous study, the authors had shown that in treatment-resistant depressive disorder, an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentrations. Lamotrigine is mainly metabolized by UGT1A4 and UGT2B7, and polymorphisms of said UGTs that affect enzyme activities have been reported. This study investigated the effect of these polymorphisms on the steady-state plasma concentrations (Css) of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy. METHODS The subjects were 103 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 46), bipolar II disorder (n = 44), and bipolar I disorder (n = 13). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 67 subjects who were not taking valproate and 75 mg/d for 36 subjects taking valproate, respectively. Blood sampling was performed at the 8th week. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. The genotypes of UGT1A4 142T>G, UGT2B7 -161C>T, and UGT2B7 372A>G were identified by polymerase chain reaction analyses. RESULTS There were no significant relationships between these polymorphisms and the Css of lamotrigine in the subjects regardless of valproate comedication. CONCLUSIONS This study suggests that these genetic polymorphisms do not affect the Css of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy.

Background: Pulmonary hypertension (PH) is defined by a resting mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, on the other hand, the term of mPAP ranging from 21 to 24 mmHg is recognized as “borderline PH”. However, little is known about the clinical importance of borderline PH in interstitial lung disease (ILD). Aims: To evaluate whether borderline PH has an impact on the exercise capacity and the risk of acute exacerbation (AE) in patients with ILD. Methods: Between November 2013 and October 2016, 80 patients with ILD (23 IPF) that underwent right heart catheterization were included. The patients were divided into 3 groups: mPAP ≤ 20mmHg (No-PH group; n = 56), 21 ≤ mPAP ≤ 24mmHg (Bo-PH group; n = 18) and mPAP ≥ 25mmHg (PH group; n = 6). Patients’ characteristics, hemodynamics, 6MWT data, and 1-year incidence of AE were collected. Results: There were no significant differences among 3 groups in patients’ characteristics including pulmonary function. However, both Bo-PH and PH groups had significantly lower 6-min walk distance (p Conclusions: The current study shows that borderline PH is associated with exercise intolerance and increased risk for acute exacerbation in patients with ILD. These results suggest that the presence of borderline PH should be considered the pulmonary vascular disorder in patients with ILD.