Search

Background: Kidney complications associated with anticancer drug therapy have greatly increased recently. We aimed to investigate the real-world clinical outcomes of anticancer drug therapy-associated renal complications in Japan using the national kidney biopsy database, Japan Renal Biopsy Registry (J-RBR)., Methods: From 2018 to 2021, 449 cases from 49 facilities identified as 'drug-induced' histopathology in the J-RBR were screened, of which a total of 135 were confirmed as anticancer drug-related cases and included in the analysis. Overall survival rates were estimated using the Kaplan-Meier method and compared by logrank test. The Cox regression model was used to evaluate the association between variables and deaths., Results: The most common primary sites of malignancies were the lung (33.3%), followed by gastrointestinal (16.3%) and gynaecological (11.1%) cancers. Tubulointerstitial nephritis (TIN; 47.4%) and thrombotic microangiopathy (TMA; 35.6%) were the most frequent diagnoses. All immunoglobulin A nephropathy, minimal change disease and crescentic glomerulonephritis (CrGN) cases were immune checkpoint inhibitor related. All CrGN cases were anti-neutrophil cytoplasmic antibody negative. Antibiotics were most frequently used concomitantly with anticancer drugs in TMA cases among subgroups (TMA versus others: 62.5 versus 27.5%; P  < .001). Among TMA cases, the serum lactate dehydrogenase level tended to be higher in cytotoxic agent-associated TMA (CTx-TMA) than in other TMAs, but was not significant between groups (415.5 versus 219.0 U/l; P  = .06). Overall survival was worse in CTx-TMA than in other TMAs ( P  = .007). The Cox model demonstrated proton pump inhibitor (PPI) use (hazard ratio 2.49, P  = .001) as a significant prognostic factor, as well as the presence of metastasis and serum albumin level., Conclusions: Our registry analysis highlighted various presentations of biopsy-proven kidney complications associated with anticancer drug therapy. Clinicians should be aware of worse outcomes associated with CTx-TMA and the prognostic role of PPI use., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

The present study aimed to summarize and report data on errors related to treatment planning, which were collected by medical physicists. The following analyses were performed based on the 10-year error report data: (1) listing of high-risk errors that occurred and (2) the relationship between the number of treatments and error rates, (3) usefulness of the Automated Plan Checking System (APCS) with the Eclipse Scripting Application Programming Interface and (4) the relationship between human factors and error rates. Differences in error rates were observed before and after the use of APCS. APCS reduced the error rate by ~1% for high-risk errors and 3% for low-risk errors. The number of treatments was negatively correlated with error rates. Therefore, we examined the relationship between the workload of medical physicists and error occurrence and revealed that a very large workload may contribute to overlooking errors. Meanwhile, an increase in the number of medical physicists may lead to the detection of more errors. The number of errors was correlated with the number of physicians with less clinical experience; the error rates were higher when there were more physicians with less experience. This is likely due to the lack of training among clinically inexperienced physicians. An environment to provide adequate training is important, as inexperience in clinical practice can easily and directly lead to the occurrence of errors. In any environment, the need for additional plan checkers is an essential factor for eliminating errors., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

This study assessed the significance of hands-on-training (HoT) and questionnaire-based surveys on 3D image-guided brachytherapy (3D-IGBT) and a combination of intracavitary and interstitial brachytherapy, the so-called 'hybrid' BT (HBT), in uterine cervical cancer. In October 2023, 29 radiation oncologists, nurses, radiologic technologists and medical physicists from 10 Japanese facilities participated in an HoT on 3D-IGBT and HBT. Questionnaires were distributed to each participant before and after the HoT, and feedback was obtained through online channels. The questionnaire response rate was 83% (24/29), with at least one participant responding from each facility. 'Insertion of applicators and needles', 'human resource shortage' and 'pain relief and sedation' were the primary concerns of radiation oncologists. 'Applicator reconstruction', ' optimization of dwell positions', ' treatment planning' and ' human resource shortages ' were the primary concerns of radiological technologists and medical physicists. The HoT content was adjusted according to the results of preliminary surveys. The concerns expressed by the participants were addressed during the lectures and practical training. Significant reductions in anxiety were observed toward all items of the 10-point self-assessment after the HoT, regardless of the profession. The average score on satisfaction with the HoT (on a 10-point scale) was 9.52 (minimum of 8 and maximum of 10). In conclusion, HoT tailored in response to a pre-questionnaire-based survey effectively reduced participants' anxiety regarding the implementation of 3D-IGBT and HBT., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

This study aimed to assess the current state of brachytherapy (BT) resources, practices and resident education in Japan. A nationwide survey was undertaken encompassing 177 establishments facilitating BT in 2022. Questionnaires were disseminated to each BT center, and feedback through online channels or postal correspondence was obtained. The questionnaire response rate was 90% (159/177), and every prefecture had a response in at least one center. The number of centers in each prefecture ranged from 0.6 to 3.6 (median: 1.3) per million population. The annual number of patients in each center ranged from 0 to 272 (median: 31). While most prefectures provided intracavitary (IC) BT for gynecological cancers and interstitial (IS) BT for prostate cancer, only one-third of the prefectures provided IS BT for cancer sites other than the prostate. The institutional image-guided BT implementation rate was 71%. IC and IS BT was performed for 15.4% of IC BT cases of gynecological cancer. Only 47% of the BT training centers answered that they could provide adequate training in BT for residents. The most common reason for this finding was the insufficient number of patients in each center. The results show that, although BT has achieved uniformity in terms of facility penetration, new technologies are not yet widespread enough. Furthermore, IS BT, which requires advanced skills, is limited to a few BT centers, and considerable number of BT training centers do not have sufficient caseloads to provide the necessary experience for their residents., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Cancer is a common complication after kidney transplantation. Kidney transplant recipients (KTR) have a 2- to 4-fold higher risk of developing cancer compared to the general population and post-transplant malignancy is the third most common cause of death in KTR. Moreover, it is well known that certain cancer types are overrepresented after transplantation, especially non-melanoma skin cancer. Immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, with remarkable survival benefit in a subgroup of patients. ICI are monoclonal antibodies that block the binding of specific co-inhibitory signaling molecules. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand programmed cell death ligand 1 (PD-L1) are the main targets of ICI. Solid organ transplant recipients (SOTR) have been excluded from clinical trials owing to concerns about tumor response, allo-immunity, and risk of transplant rejection. Indeed, graft rejection has been estimated as high as 48% and represents an emerging problem. The underlying mechanisms of organ rejection in the context of treatment with ICI are poorly understood. The search for restricted antitumoral responses without graft rejection is of paramount importance. This review summarizes the current knowledge of the use of ICI in KTR, the potential mechanisms involved in kidney graft rejection during ICI treatment, potential biomarkers of rejection, and how to deal with rejection in clinical practice., Competing Interests: B.S. is member of the CKJ Editorial Board. T.V.M., S.B., N.D., and N.M. have no disclosures related to this article, (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

The uterus is known as one of the moving organs. We evaluated the movement of the uterus during irradiation and the effects of changes in the surrounding organs using a magnetic resonance (MR)-guided radiotherapy system. Seven patients with cervical cancer underwent pre- and posttreatment MR imaging to assess changes in the positioning of the uterus and cervix as well as the alterations in bladder and rectal volume. The study revealed that the movements of the uterus were greater than that of the cervix and showed a tendency to correlate with the bladder rather than the rectum. We also examined whether intrafractional motion could lead to insufficient dose coverage of the clinical target volume (CTV), specifically focusing on the D98% of the CTV in the uterine body and cervix. The impact of intrafractional motion on the D98% varied among patients, with one out of the seven patients experiencing an average dosimetric change of -2.6 Gy in the uterus, although larger planning target volume margins of 1.5 cm were applied, therefore, indicating the need for individualized optimal margins in each case. Online adaptive radiotherapy offers the advantage of modifying the treatment plan when irradiating moving organs, such as the uterus. However, it should be noted that this approach may result in longer overall treatment times compared with the traditional methods. Therefore, we must carefully consider the influence of intrafractional organ motions when opting for such a treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

It has been shown that a group of rectal cancer patients will achieve a pathological complete response following preoperative chemoradiotherapy, and non-operative management has recently gained attention. To escalate the tumour dose and increase the likelihood of pathological complete response, brachytherapy can play an important role in safely increasing the total dose. However, at the time this report was published, an applicator dedicated to rectal brachytherapy was unaffordable in Japan. Here, we report two T3 rectal cancer patients who were inoperable or refused surgery and treated by chemoradiotherapy following intracavitary brachytherapy involving a vaginal cylinder applicator with lead shielding., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

An 80-year-old male presented with T1N0M0 myxofibrosarcoma in or next to the humeral canal, which is located between the biceps and triceps of the right upper arm. Because the tumor was close to critical anatomical structures such as the brachial artery, median nerve and ulnar nerve, it was deemed impossible to perform limb-sparing surgery with an adequate resection margin. Therefore, preoperative external beam radiation therapy (EBRT) followed by limb-sparing surgery was offered. Magnetic resonance imaging taken after 40 Gy/20 fractions of EBRT showed an inadequate response, and limb-sparing surgery was not deemed possible at this point. Amputation of the right arm was offered, but the patient refused. Therefore, salvage high-dose-rate interstitial brachytherapy (HDR-ISBT) was offered. Under local anesthesia and sedation, 14 plastic needles were inserted, and 36 Gy in 6 fractions of HDR-ISBT was performed. Although radiation-induced incomplete paralysis of the median nerve was noted, no local progression or distant metastasis was found on the CT that was taken 2 years after the treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Objective: Compared with the implementation speed of image-guided adaptive brachytherapy for uterine cervical cancer, that of intracavitary and interstitial brachytherapy is slow, possible because it requires more invasive procedure of inserting needles directly into tumours. To accelerate the implementation speed of intracavitary and interstitial brachytherapy, a first hands-on seminar for image-guided adaptive brachytherapy and intracavitary and interstitial brachytherapy for uterine cervical cancer was held on 26 November 2022, supported by Japanese Society for Radiology and Oncology. This article deals with this hands-on seminar and difference of degree of confidence of participants in starting intracavitary and interstitial brachytherapy before and after the seminar., Methods: The seminar consisted of lectures regarding intracavitary and interstitial brachytherapy in the morning and hands-on practice of needle insertion and contouring, as well as dose calculation practice using the radiation treatment system in the evening. Prior to and following the seminar, participants completed a questionnaire asking about their level of confidence in performing intracavitary and interstitial brachytherapy, expressed between 0 and 10 (the higher the number, the stronger the confidence)., Results: A total of 15 physicians, six medical physicists and eight radiation technologists from 11 institutions attended the meeting. The median level of confidence before and after the seminar was 3 (range, 0-6) and 5.5 (range, 3-7), respectively, and a statistically significant improvement was observed (P<0.001)., Conclusion: It was suggested that the hands-on seminar on intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer improved the level of confidence of the attendees and propelled their motivation, through which it is expected that the implementation of intracavitary and interstitial brachytherapy will be accelerated., (© Crown copyright 2023.)

Compared with the European or the United States' uterine cervical cancer management guidelines, which aim to deliver >85 Gy EQD2 (the equivalent effective dose in 2 Gy per fraction) to the high-risk clinical target volume (CTVHR) D90 (minimal dose of 90% of the CTVHR), the dose goal of the corresponding Japanese guidelines does not recommend delivering such a high dose to the CTVHR D90. Subsequently, while the rate of late radiation-induced toxicities is reported to be much lower in the Japanese schedule, the local control rate is relatively inferior to that of clinical results reported by the IntErnational study on MRI-guided BRAchytherapy in CErvical cancer study (EMBRACE-I) in which the dose goal for CTVHR D90 was >85 Gy and showed >90% local control regardless of tumor stage. In daily clinical practice, patients with residual disease supposedly due to insufficient total dose delivery are occasionally referred to our hospital for the possibility of re-irradiation, which is not usually recommended because the risk of late severe radiation-induced toxicity is high. In this report, the authors hope to raise a discussion in our community about modifying our treatment guidelines to recommend a higher dose at least for patients with poor response., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Currently, tongue cancers are primarily managed by surgery, and interstitial brachytherapy is only recommended for a selected group of early state T1-2N0 patients who refuse surgery or are medically inoperable. In this report, a case with T3N2cM0 tongue cancer who has been effectively treated by the combination of concurrent chemoradiotherapy involving volumetric arc therapy and boost high-dose rate interstitial brachytherapy is presented. Of course, surgery remains the main treatment strategy for tongue cancer patients; however, the authors believe that if volumetric arc therapy is carefully planned to reduce the mandible dose as much as possible and high-dose rate interstitial brachytherapy with a mouthpiece that protects the mandible is combined, it is possible to treat T3N2 disease, and this can be considered for patients who want to preserve organ function., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The fruit-like aroma of two valine-derived volatiles, isobutanol and isobutyl acetate, has great impact on the flavour and taste of alcoholic beverages, including sake, a traditional Japanese alcoholic beverage. With the growing worldwide interest in sake, breeding of yeast strains with intracellular valine accumulation is a promising approach to meet a demand for sakes with a variety of flavour and taste by increasing the valine-derived aromas. We here isolated a valine-accumulating sake yeast mutant (K7-V7) and identified a novel amino acid substitution, Ala31Thr, on Ilv6, a regulatory subunit for acetohydroxy acid synthase. Expression of the Ala31Thr variant Ilv6 conferred valine accumulation on the laboratory yeast cells, leading to increased isobutanol production. Additionally, enzymatic analysis revealed that Ala31Thr substitution in Ilv6 decreased sensitivity to feedback inhibition by valine. This study demonstrated for the first time that an N-terminal arm conserved in the regulatory subunit of fungal acetohydroxy acid synthase is involved in the allosteric regulation by valine. Moreover, sake brewed with strain K7-V7 contained 1.5-fold higher levels of isobutanol and isobutyl acetate than sake brewed with the parental strain. Our findings will contribute to the brewing of distinctive sakes and the development of yeast strains with increased production of valine-derived compounds., (© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.)

Sinonasal undifferentiated carcinoma (SNUC) is a highly aggressive and uncommon neoplasm that arises from the mucosa of the nasal cavity or paranasal sinuses. The multidisciplinary approach that includes surgery, radiation therapy (RT), and chemotherapy has been proven to improve survival rates. However, there is no established evidence for the efficacy of further (boost) irradiation following definitive RT in SNUC patients with residual primary tumor. We describe a successful case of a patient with SNUC who had an uncontrolled primary tumor following induction chemotherapy and radical concurrent chemoradiotherapy (CCRT) and underwent a high-dose-rate interstitial brachytherapy (HDR-ISBT) boost. A 75-year-old Japanese woman with unresectable locally advanced SNUC (LA-SNUC) received induction chemotherapy followed by radical CCRT. However, because the residual primary tumor was evident after planned external beam RT, she underwent an HDR-ISBT boost, and the tumor decreased significantly. A complete response (the Response Evaluation Criteria in Solid Tumors, ver. 1.1) was achieved 2 months after brachytherapy, and the patient has been disease-free for 2 years following treatment initiation. In conclusion, an HDR-ISBT boost can be a safe and effective treatment option in patients with residual and inoperable LA-SNUC in the maxillary sinus after initial RT., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Recent improvement in treatment and patient survival has opened the eligibility of kidney transplantation to patients who developed end-stage kidney disease (ESKD) from plasma cell dyscrasias (PCDs). Data on clinical outcomes in this population are lacking., Methods: We conducted a retrospective study of United Network for Organ Sharing/Organ Procurement and Transplantation Network dataset (2006-2018) to compare patient and graft outcomes of kidney transplant recipients with ESKD due to PCD versus other causes., Results: Among 168 369 adult first kidney transplant recipients, 0.22-0.43% per year had PCD as the cause of ESKD. The PCD group had worse survival than the non-PCD group for both living and deceased donor types {adjusted hazard ratio [aHR] 2.24 [95% confidence interval (CI) 1.67-2.99] and aHR 1.40 [95% CI 1.08-1.83], respectively}. The PCD group had worse survival than the diabetes group, but only among living donors [aHR 1.87 (95% CI 1.37-2.53) versus aHR 1.16 (95% CI 0.89-1.2)]. Graft survival in patients with PCD were worse than non-PCD in both living and deceased donors [aHR 1.72 (95% CI 1.91-2.56) and aHR 1.30 (95% CI 1.03-1.66)]. Patient and graft survival were worse in amyloidosis but not statistically different in multiple myeloma compared with the non-PCD group., Conclusion: The study data are crucial when determining kidney transplant eligibility and when discussing transplant risks in patients with PCD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Reactive oxygen species (ROS) play a central role in plant responses to biotic and abiotic stresses. ROS stimulate stomatal closure by inhibiting blue light (BL)-dependent stomatal opening under diverse stresses in the daytime. However, the stomatal opening inhibition mechanism by ROS remains unclear. In this study, we aimed to examine the impact of reactive carbonyl species (RCS), lipid peroxidation products generated by ROS, on BL signaling in guard cells. Application of RCS, such as acrolein and 4-hydroxy-(E)-2-nonenal (HNE), inhibited BL-dependent stomatal opening in the epidermis of Arabidopsis thaliana. Acrolein also inhibited H+ pumping and the plasma membrane H+-ATPase phosphorylation in response to BL. However, acrolein did not inhibit BL-dependent autophosphorylation of phototropins and the phosphorylation of BLUE LIGHT SIGNALING1 (BLUS1). Similarly, acrolein affected neither the kinase activity of BLUS1 nor the phosphatase activity of protein phosphatase 1, a positive regulator of BL signaling. However, acrolein inhibited fusicoccin-dependent phosphorylation of H+-ATPase and stomatal opening. Furthermore, carnosine, an RCS scavenger, partially alleviated the abscisic-acid- and hydrogen-peroxide-induced inhibition of BL-dependent stomatal opening. Altogether, these findings suggest that RCS inhibit BL signaling, especially H+-ATPase activation, and play a key role in the crosstalk between BL and ROS signaling pathways in guard cells., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This is the preliminary results of a multi-center prospective clinical trial evaluating the feasibility of the hybrid of intracavitary and interstitial brachytherapy for locally advanced cervical cancer., Methods: Patients with FIGO stage IB2, IIA2, IIB, IIIA, IIIB and IVA uterine cervical cancer pretreatment width of which was ≥5 cm measured by MRI were eligible. Protocol therapy consisted of 30-30.6 Gy in 15-17 fractions of whole pelvic radiotherapy concurrent with weekly CDDP, followed by 24 Gy in 4 fractions of hybrid of intracavitary and interstitial and pelvic radiotherapy with central shield up to 50-50.4 Gy in 25-28 fractions. The primary endpoint of phase I part was that the rate of grade ≥ 3 acute non-hematologic adverse events related to hybrid of intracavitary and interstitial would be <10%., Results: Between October 2015 and October 2019, 74 patients underwent primary registration, with 52 patients eventually proceeding to the secondary registration. The median pretreatment tumor width was 5.7 cm, and FIGO Stages were IB2 10, IIA2 2, IIB 20 and IIIB 20, respectively. The median high-risk clinical target volume D90 was 72.0 Gy (54.8-86.6 Gy, EQD2), rectum D2cc was 53.7 Gy (29.3-80.3 Gy) and bladder D2cc was 69.8 Gy (38.9-84.8 Gy). The rate of grade ≥ 3 non-hematologic adverse events related to hybrid of intracavitary and interstitial was 1.9% (1/52), and 17.3% (9/52) of patients experienced non-hematologic adverse events related to hybrid of intracavitary and interstitial of any grade. In multivariate analysis, high-risk clinical target volume ≥ 35 ml was associated with an increased risk of any grade of acute non-hematologic adverse events related to hybrid of intracavitary and interstitial (P = 0.036)., Conclusion: The feasibility and reproducibility of hybrid of intracavitary and interstitial were demonstrated from a multi-center prospective clinical trial., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although the international study on MRI-guided brachytherapy in cervical cancer (EMBRACE-I) demonstrated excellent local control regardless of the T stage, up to 14.6% of grade 3-5 late radiation-related toxicities were observed, which is unacceptable. While the efficacy of hydrogel spacers has been established in prostate radiotherapy, its implementation speed in cervical cancer brachytherapy is relatively slow, despite the fact that several articles have reported its efficacy in cervical cancer brachytherapy. The authors believe that using a spacer in cervical cancer brachytherapy and brachytherapy for other gynecologic malignancies will reduce late radiation-related toxicity and improve patients' quality of life; therefore, its rapid implementation is required., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Sake is a traditional Japanese alcoholic beverage brewed by the yeast Saccharomyces cerevisiae. Since the consumption and connoisseurship of sake has spread around the world, the development of new sake yeast strains to meet the demand for unique sakes has been promoted. Phenylalanine is an essential amino acid that is used to produce proteins and important signaling molecules involved in feelings of pleasure. In addition, phenylalanine is a precursor of 2-phenylethanol, a high-value aromatic alcohol with a rose-like flavor. As such, adjusting the quantitative balance between phenylalanine and 2-phenylethanol may introduce value-added qualities to sake. Here, we isolated a sake yeast mutant (strain K9-F39) with phenylalanine accumulation and found a missense mutation on the ARO80 gene encoding the His309Gln variant of the transcriptional activator Aro80p involved in the biosynthesis of 2-phenylethanol from phenylalanine. We speculated that mutation of ARO80 would decrease transcriptional activity and suppress the phenylalanine catabolism, resulting in an increase of intracellular phenylalanine. Indeed, sake brewed with strain K9-F39 contained 60% increase in phenylalanine, but only 10% less 2-phenylethanol than sake brewed with the parent strain. Use of the ARO80 mutant in sake brewing may be promising for the production of distinctive new sake varieties., One-Sentence Summary: The ARO80 mutant is appropriate for controlling the content of phenylalanine and 2-phenylethanol., (© The Author(s) 2021. Published by Oxford University Press on behalf of Society of Industrial Microbiology and Biotechnology.)

It has been postulated that the combination of intracavitary and interstitial brachytherapy (IC/IS) is effective and safe for large and irregularly shaped uterine cervical cancer patients. However, due to its invasiveness compared to conventional intracavitary brachytherapy (ICBT), it has to be said that the implementation speed of IC/IS is slow. Until now, there have been no guidelines for required equipment, human resources, and procedural guide focusing solely on IC/IS. The purpose of this guideline is to provide radiation oncologists and medical physicists who wish to start IC/IS with practical and comprehensive guidance for a safe IC/IS introduction and to help accelerate the spread of the utilization of IC/IS nationwide. This is the English translation of the Japanese IC/IS Guidelines, and it was created in an effort to share the Japanese approach to the management of locally advanced uterine cervical cancer worldwide., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

This study is an international multi-institutional retrospective study comparing the clinical outcomes between intracavitary brachytherapy (ICBT) and the hybrid of intracavitary and interstitial brachytherapy (HBT) for locally advanced cervical cancer patients treated with definitive radiation therapy. Locally advanced cervical cancer, the initial size of which is larger than 4 cm and treated by concurrent chemoradiotherapy and image-guided adaptive brachytherapy, were eligible for this retrospective study. Patients who received HBT at least once were included in the HBT group, and patients who received only ICBT were included in the ICBT group. Anonymized data from 469 patients from 13 institutions in Japan, one from Korea and one from Thailand, were analyzed. Two hundred eighty and 189 patients were included in the ICBT group and the HBT group, respectively. Patients in the HBT group had more advanced stage, non-Scc histopathology, a higher rate of uterine body involvement, larger tumor at diagnosis, larger tumor before brachytherapy and a lower tumor reduction ratio. With a median follow-up of 51.3 months (2.1-139.9 months), 4-y local control (LC), progression-free survival (PFS) and overall survival (OS) for the entire patient population were 88.2%, 64.2% and 83%, respectively. The HBT group received a higher HR-CTV D90 than that of the ICBT group (68.8 Gy vs 65.6 Gy, P = 0.001). In multivariate analysis, the non-Scc histological subtype, HR-CTV D95 ≤ 60 Gy, reduction ratio ≤ 29% and total treatment time (TTT) ≥ 9 weeks were identified as the independent adverse prognostic factors for LC. Regarding LC, no difference was found between ICBT and HBT (4-y LC 89.3% vs 86.8%, P = 0.314). After adjustment for confounding factors by propensity score matching, no advantage of applying HBT was demonstrated regarding LC, PFS, or OS. Despite the fact that HBT patients had more adverse clinical factors than ICBT patients, HBT delivered a higher dose to HR-CTV and resulted in comparable LC., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

We suggested de-escalation would be possible for cervical cancer like human papillomavirus (HPV)-related oropharyngeal cancer. However, the classification was based on tumor shrinkage that can be obtained after half of the treatment was finished. Our other article found adverse factors which can be obtained prior to treatment, and they might classify patients earlier., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Although systemic therapy is the standard treatment for metastatic prostate cancer, a randomized controlled trial showed radiotherapy to the prostate improved overall survival of metastatic prostate cancer patients with the low metastatic burden. Additionally, a randomized phase II trial showed that metastasis-directed therapy for oligo-recurrent prostate cancer improved androgen-deprivation therapy (ADT)-free survival. Therefore, administering radiotherapy to both prostate and metastatic regions might result in better outcomes. Thus, we report the treatment results of radiotherapy to both prostate and metastatic regions. Our institutional database was searched for patients who received radiotherapy to the prostate and metastatic regions. We summarized patient characteristics and treatment efficacy and performed statistical analysis to find possible prognostic factors. A total of 35 patients were included in this study. The median age was 66 years, and the median initial prostate-specific antigen (PSA) level was 32 ng/ml. The Gleason score was 7 in 10 patients, 8 in 13 patients, and 9 in 12 patients. The median radiotherapy dose was 72 Gy to the prostate and 50 Gy to the metastatic bone region. The 8-year overall survival, cause-specific survival, progression-free survival, and freedom from biochemical failure rate were 81, 85, 53, and 57%. Among the 35 patients, 12 were disease-free even after ADT was discontinued. In selected patients with metastatic prostate cancer, ADT and radiotherapy to the prostate and metastatic sites were effective. Patients with good response to ADT may benefit from radiotherapy to both prostate and metastatic regions., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Sake is a traditional Japanese alcoholic beverage brewed with the yeast Saccharomyces cerevisiae. Sake taste is affected by sugars, organic acids, and amino acids. We previously isolated mutants resistant to the proline analogue azetidine-2-carboxylate derived from a diploid sake yeast strain. Some of the mutants produced a greater amount of proline in the brewed sake. One of them (strain K-9-AZC) carried a novel mutation in the PRO1 gene encoding the Gln79His variant of the γ-glutamyl kinase Pro1, a key enzyme in proline biosynthesis in S. cerevisiae. This mutation resulted in extreme desensitization to feedback inhibition by proline, leading to proline overproduction. Interestingly, sake brewed with K-9-AZC contained 3.7-fold more proline, but only 25% less succinate than sake brewed with the parent strain. Metabolome analysis suggests that the decrease in succinate was attributable to a lower level of 2-oxoglutarate, which is converted into glutamate. The approach here could be a practical method for breeding of yeast strains involved in the diversity of sake taste.

Surgery is the standard modality for early-stage I-II non-small-cell lung cancer (NSCLC). Generally, patients who are >80 years old tend to have more comorbidities and inferior physical status than younger patients. Stereotactic body radiation therapy (SBRT) may provide an alternative treatment for this group of patients. Here, we report our experience using SBRT to in the management of early-stage NSCLC in patients >80 years old. Patients aged ≥80 years old who were diagnosed with early-stage NSCLC and treated with definitive lung SBRT from January 2000 to January 2018 were retrospectively analysed. Local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), cancer-specific survival (CSS), progression-free survival (PFS), overall survival (OS) and treatment-related toxicities were analysed for patients >80 years old. A total of 153 patients were included, with a median age of 85 years (range, 80-94). The median follow-up period and OS was 39.8 months (range, 10-101 months) and 76 months, respectively. The 3-year OS, PFS, CSS, RRFS and LRFS were 65.3, 58.0, 75.7, 73.9 and 85.3%, respectively. Radiation pneumonitis grade 0-1, grade 2, grade 3 and grade 4 was observed in 135 (88.2%), 13 (8.5%), 4 (2.61%) and 1 (0.6%) patient(s), respectively. On multivariate analyses, tumor size, pretreatment C-reactive protein (CRP) value, histology and pretreatment physical state were significantly associated with OS. Definitive lung SBRT appears to have high LRFS and OS without causing high-grade radiation-related toxicities in early-stage NSCLC patients who were >80 years old., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

The present study aimed to report the efficacy and toxicity of our high-dose-rate (HDR) brachytherapy for early stage lip cancer (LC) using customized dental spacers. A retrospective analysis was performed among six patients with early stage LC treated with HDR interstitial brachytherapy between April 2015 and August 2019 using customized dental spacers. The total treatment dose was 49 Gy/7 fractions or 54 Gy/9 fractions. The median follow-up duration for the patients was 13 (range: 2-52) months. All patients completed the entire brachytherapy protocol safely and have experienced no local recurrence thus far. The CTV D100 and D90 values per fraction were median 100 (range: 98.3-100) % prescribed dose (PD) and median 133.4 (range: 129.3-138.9) % PD, respectively. The D2cc and D0.1cc values per fraction for the mandible were median 1.07 (range, 0.79-1.88) Gy and median 1.65 (range: 1.21-2.83) Gy, D2cc and D0.1cc values per fraction for oral cavity were median 1.48 (range, 1.31-1.72) Gy and median 2.73 (range: 1.79-2.88) Gy, respectively. Acute toxicities encountered were mucositis and lip edema limited to the irradiated area; none of them was beyond grade 2 and all were resolved within 1-2 months after treatment. We did not observe any late grade 2 adverse events or worse. This study shows that the adverse effects of HDR brachytherapy for early stage LC can be minimized using a dental spacer. Cooperation with the dentistry department is essential to make spacers that are individually customized for each patient., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Our previous study by Murakami N, Mori T, Nakamura S, Yoshimoto S, Honma Y, Ueno T, Kobayashi K, Kashihara T, Takahashi K, Inaba K, Okuma K, Igaki H, Nakayama Y, Itami J. (J Radiat Res. 2019 Jul 30. pii: rrz053. doi: 10.1093/jrr/rrz053. [Epub ahead of print]) showed that strong expression of epithelial cell adhesion molecule (EpCAM) was associated with radiation resistance in head and neck squamous cell cancer patients (SCC). In this study, the prognostic impact of histopathologic features including EpCAM for nasopharyngeal cancer (NPC) patients was investigated. Since 2009, our institution has performed chemoradiation for locally advanced NPC patients with intensity modulated radiation therapy (IMRT). Tri-weekly adjuvant cisplatin (CDDP, 80 mg/m2) was administered concurrently with definitive radiation therapy 70 Gy in 35 fractions. One month after radiation therapy, adjuvant chemotherapy of three cycles of CDDP/5 fluorouracil (5-FU) was administered. Using a pretreatment biopsy specimen, EBV-encoded small RNA in situ hybridization (EBER-ISH), EpCAM, p16 and p53 were assessed by immunohistochemical analysis. Between May 2009 and September 2017, 51 NPC patients received definitive radiation therapy. Five, 13, 17 and 16 patients were staged as I, II, III and IV, respectively. The median follow-up period for alive patients was 31.1 months (12.4-109.7 months). Three-year overall survival (OS), progression-free survival (PFS) and locoregional control (LRC) were 87.1, 57.1 and 85.7%, respectively. EpCAM, p16 and p53 were not associated with PFS, OS nor LRC. Three-year PFS for patients with keratinizing and non-keratinizing SCC were 25 and 60.5%, respectively (P = 0.033, hazard ratio 4.851 (95% confidence interval 1.321-17.814)).Prognosis of NPC patients with keratinizing SCC was worse than non-keratinizing SCC patients, suggesting a biological difference between the two types of tumor., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

A reliable biomarker can contribute to appropriate treatment selection in the management of head and neck squamous cell carcinoma (HNSCC). Recently, epithelial cell adhesion molecule (EpCAM) was shown to have prognostic features in several malignancies. However, it remains to be elucidated whether EpCAM predicts prognosis of HNSCC after radiotherapy. Therefore, the prognostic potential of EpCAM in HNSCC patients treated by radiotherapy was investigated in this study. All HNSCCs patients examined between January 2013 and December 2015 were analyzed for the expression of EpCAM. One hundred HNSCC patients were identified who were treated by primary radiotherapy. Intense expression of EpCAM was found in 29 HNSCC patients. Two-year overall survival (OS) for patients with intense EpCAM expression was 62.2%, whereas it was 87.9% for those without (P = 0.011). In multivariate analysis, intense EpCAM expression was found to be an independent prognostic factors for OS (P = 0.036). Overall, EpCAM was found to be an independent prognostic factor for HNSCC., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

The current study retrospectively analyzed the results of radiotherapy for clinically localized sebaceous carcinoma of the eyelid.We reviewed records of 83 patients with histologically confirmed sebaceous carcinoma who were treated radiotherapeutically between 1983 and 2015. Sixty-five patients (78%) were initially treated with radiotherapy of curative intent, while the remaining 18 patients underwent postoperative radiotherapy due to tumor recurrence or positive surgical margins. Thirty-seven patients belonged to T1-2, while 46 belonged to T3-4. All 83 patients were treated with radiotherapy with a median radiation dose of 60 Gy. The median follow-up period was 92.1 months (range, 2.8-310.3 months). At the time of analysis, 13 patients (15.1%) died, and 36 patients (43.3%) had local recurrence. The 7-year overall survival, freedom from neck lymph node recurrence, and local control (LC) rates for all patients were 83.5%, 75.5%, and 52.3%, respectively. Patients with a tumor size ≤10 mm had a higher 7-year LC rate than those with a tumor size >10 mm (58.8% vs 46.6%, P = 0.054). Neck lymph node recurrence was observed in 17 patients (20%) and significantly related to the tumor size. Late toxicity of an eyelid dysfunction of grade 3 was observed in 1 patient with T3 tumor. Radiotherapy for sebaceous carcinoma of the eyelid is a reasonable alternative to surgical resection for tumors <10 mm in size with few severe complications, while larger tumors should be treated with surgery if feasible., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

The aim of the study was to compare incidences of late gastrointestinal adverse events and clinical outcomes between 3D conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) after radical hysterectomy for cervical cancer patients. Between March 2007 and May 2014, 73 cervical cancer patients with high-risk prognostic factors (pelvic lymph node metastasis and/or parametrial invasion) underwent postoperative pelvic radiation therapy (RT) after radical hysterectomy. Of these patients, 33 (45%) and 40 (55%) received 3DCRT and IMRT, respectively. Because the gastrointestinal obstruction rate after postoperative pelvic 3DCRT was high, no concurrent chemotherapy was applied until 2015. The median follow-up period for patients with 3DCRT and IMRT was 82 months (6-113) and 50 months (5-74), respectively. There was no significant difference in overall survival (OS) (4-year OS: 85% vs 78%, P = 0.744) or disease-free survival (DFS) (4-year DFS: 73% vs 64%, P = 0.696) between the two groups. Eleven (33%) and 13 (33%) patients experienced recurrence after 3DCRT and IMRT, respectively. The patients who had vaginal invasion from the postoperative pathological finding more frequently had loco-regional recurrence than the patients who did not have vaginal invasion (2.3% vs 17%, P = 0.033). Gastrointestinal obstruction was observed in 9 (27%) and 3 (7.5%) patients for 3DCRT and for IMRT, respectively (P = 0.026). Severe gastrointestinal obstruction that required surgery was observed in 6 (19%) patients, all of whom received adjuvant RT by 3DCRT. IMRT could reduce the incidence of late severe gastrointestinal obstruction after postoperative pelvic RT with a non-inferior clinical efficacy compared with 3DCRT., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

A single-arm multi-center confirmatory trial was started in Japan to confirm the efficacy and safety of post-radical hysterectomy concurrent chemoradiotherapy using intensity-modulated radiation therapy (IMRT-CCRT) for patients with high-risk uterine cervical cancer, for which the current standard treatment is CCRT using three-dimensional conformal radiation therapy (3DCRT-CCRT). This study began in April 2017 and a total of 220 patients will be accrued from 44 institutions within 3.5 years. The primary endpoint is 3-year relapse-free survival. The secondary endpoints are overall survival, loco-regional relapse-free survival, proportion of late lower gastrointestinal adverse events greater than or equal to grade 3, proportion of lower edema limbs, adverse events, and serious adverse events. This trial was registered at the Japan Registry of Clinical Trials as jRCTs031180194 (https://jrct.niph.go.jp/)., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Perirectal hyaluronate gel injection (HGI) appears to be a promising technique for healthy tissue dose sparing in pelvic radiotherapy. In this analysis, we report our initial experience of HGI in gynecologic brachytherapy, focusing on its safety and effectiveness for dose reduction to the rectum. Between July 2013 and May 2014, 36 patients received HGI for primary/salvage gynecologic brachytherapy. Dosimetric effect analysis was based on pre- and post-HGI computed tomography dataset registration with corresponding dose-volume histogram evaluation. The maximum dose to the most exposed 0.1 cm3 (D0.1cm3) and 2.0 cm3 (D2.0cm3) were used as index values for rectum and bladder dose evaluation. The dose indexes for target volume (TV) coverage were TV D90/V100. In all cases, HGI was well tolerated, with no acute or late adverse events documented at a median follow-up of 220 days (range, 18-1046 days). Rectum D2.0cm3 and D0.1cm3 were significantly decreased by HGI (P < 0.001 and P = 0.003, respectively), with no significant impact on dosimetric parameters of bladder and TV coverage. Factors correlating negatively with the dosimetric effect of HGI were an increasing number of interstitial catheters (P = 0.003) as well as Lcranial100% (P = 0.014) and Lcranial80% (P = 0.001) [i.e. the length from the anal verge to the most cranial point at which the 100% and 80% isodose lines, respectively, crossed the rectum]. The concept of HGI for gynecologic brachytherapy is plausible, and our initial experience indicates it to be an effective technique for rectal dose reduction in radiotherapy of intrapelvic tumours., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Conversion from tacrolimus to belatacept has been shown to be beneficial for an increasing number of kidney transplant (KT) patients. Predicting factors for favorable outcomes are still unknown. We aimed to investigate whether histological vascular lesions at the time of conversion might correlate with greater improvement in renal function post-conversion., Methods: The study was conducted on a retrospective cohort of 34 KT patients converted from tacrolimus to belatacept. All patients underwent an allograft biopsy prior to conversion. We analyzed the evolution of the estimated glomerular filtration rate (eGFR) at 3 and 12 months after conversion., Results: Median time to conversion was 6 (2-37.2) months post-transplant. About 52.9% of patients had moderate-to-severe chronic vascular lesions (cv2-3). We observed an increase in eGFR in the whole cohort from 35.4 to 41 mL/min/1.73 m 2 at 3 months (P = 0.032) and 43.7 at 12 months (P = 0.013). Nine patients experienced acute rejection post-conversion, with one graft loss observed beyond the first year after conversion. Patients with cv2-3 had significant improvement in eGFR at 12 months (+8.6 mL/min/1.73 m 2 ; 31.6 to 40.2 mL/min/1.73 m 2 ; P = 0.047) compared with those without these lesions (+6.8 mL/min/1.73 m 2 ; 40.9 to 47.7 mL/min/1.73 m 2 ; P = 0.148)., Conclusions: Conversion from tacrolimus to belatacept has a beneficial effect in terms of renal function in KT patients. This benefit might be more significant in patients with cv in the biopsy.

There are many reports concerning patient-specific quality assurance (QA) for intensity-modulated radiation therapy (IMRT). However, reports about the statistical results of QA are lacking. Management methods for the results of the QA are needed, even though we have the ESTRO group recommendation that a tolerance limit of 1.96 standard deviation (SD) be established in each institution. The purpose of this study was to establish a management method for determining the tolerance limit and to report the statistical results of patient-specific QA. From April 2006 to March 2015, five linacs in the National Cancer Center, Tokyo, Japan, were used to treat 1185 patients with IMRT. Patient-specific QA was performed using an ion chamber, films, and some detectors. To establish a management method for the results, differences between the measured and calculated doses in the ion chamber were analyzed for each linac, each phantom, and each treatment site. The overall mean dose difference was 0.5 ± 1.3%, and the mean dose difference in each linac was 0.6 ± 1.2%, 0.9 ± 1.3%, -0.4 ± 1.4%, -0.1 ± 1.2% and -0.1 ± 0.9%. The difference between linacs and between treatment sites was significant (P < 0.001 and 0.01, respectively). The proportion of the dose difference within ±3% was 97.7%, and that was improved from 2006 to 2014. The results of the patient-specific QA should be managed for each linac and each treatment site in order to decide the suitable tolerance limit. Reports of statistical results will be helped if a new tolerance limit and action level will be considered., (© The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Objective: The orbital periosteum is considered to be a barrier to tumor spread; however, it is difficult to evaluate microscopic tumor spread during surgery. This study aimed to assess the impact of pathological status in orbital preservation surgery., Methods: We retrospectively analyzed the 3-year local control rate and treatment outcomes of patients with malignant tumors invading the orbit who were treated between 2006 and 2012., Results: In total, 27 patients were reviewed over a median follow-up period of 36 months. Pathologically, 19 had carcinomas and 8 had sarcomas. Treatment was by orbital exenteration in 6 patients and orbital preservation surgery in 21 patients. After orbital preservation surgery, poorer 3-year local control rates were significantly associated with positive surgical margins (negative vs. positive: 91% vs. 41%, P = 0.040) and microscopic orbital periosteum invasion (negative vs. positive: 90% vs. 39%, P = 0.010). These factors were independent risk factors in multivariate analysis. The locations of the positive margin were most common at the horizontal and vertical margins of the orbital periosteum and the posterior margin of the orbital apex. Moreover, in 24% of patients, invasion evaluation by preoperative imaging study was underestimated compared with postoperative microscopic evaluation., Conclusions: The positive surgical margin and microscopic orbital periosteum invasion were the risk factors of orbital recurrence. It is difficult to determine the indications for orbital preservation surgery by preoperative imaging studies because of the unpredictable accurate pathological status before surgery and the limitations of preoperative imaging evaluation., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objective: Antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have recently been associated with immune-mediated necrotizing myopathy, especially in patients with statin exposure. As the data are very limited concerning phenotypes and treatment in paediatric patients, we aimed to identify the paediatric patients positive for anti-HMGCR antibodies and clarify their features and therapeutic strategies., Methods: We screened 62 paediatric patients who were clinically and/or pathologically suspected to have inflammatory myopathy for anti-HMGCR antibodies. We further re-assessed the clinical and histological findings and the treatment of the patients positive for anti-HMGCR antibodies., Results: We identified nine paediatric patients with anti-HMGCR antibodies (15%). This was more frequent than anti-signal recognition particle antibodies (four patients, 6%) in our cohort. The onset age ranged from infancy to 13 years. Five patients were initially diagnosed with muscular dystrophy, including congenital muscular dystrophy. Most patients responded to high-dose corticosteroid therapy first but often needed adjuvant immunosuppressants to become stably controlled., Conclusion: Paediatric necrotizing myopathy associated with anti-HMGCR antibodies may not be very rare. Phenotypes are similar to those of adult patients, but a chronic slowly progressive course may be more frequent. Some patients share the clinicopathological features of muscular dystrophy indicating that recognizing inflammatory aetiology would be challenging without autoantibody information. On the other hand, most patients responded to treatment, especially those who were diagnosed early. Our results suggest the importance of early autoantibody testing in paediatric patients who have manifestations apparently compatible with muscular dystrophy in addition to those who have typical features of inflammatory myopathy., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

The brachytherapy dose calculations used in treatment planning systems (TPSs) have conventionally been performed assuming homogeneous water. Using measurements and a Monte Carlo simulation, we evaluated the dosimetric impact of an air passage on brachytherapy for bronchus cancer. To obtain the geometrical characteristics of an air passage, we analyzed the anatomical information from CT images of patients who underwent intraluminal brachytherapy using a high-dose-rate 192 Ir source (MicroSelectron V2r®, Nucletron). Using an ionization chamber, we developed a measurement system capable of measuring the peripheral dose with or without an air cavity surrounding the catheter. Air cavities of five different radii (0.3, 0.5, 0.75, 1.25 and 1.5 cm) were modeled by cylindrical tubes surrounding the catheter. A Monte Carlo code (GEANT4) was also used to evaluate the dosimetric impact of the air cavity. Compared with dose calculations in homogeneous water, the measurements and GEANT4 indicated a maximum overdose of 5-8% near the surface of the air cavity (with the maximum radius of 1.5 cm). Conversely, they indicated a minimum overdose of ~1% in the region 3-5 cm from the cavity surface for the smallest radius of 0.3 cm. The dosimetric impact depended on the size and the distance of the air passage, as well as the length of the treatment region. Based on dose calculations in water, the TPS for intraluminal brachytherapy for bronchus cancer had an unexpected overdose of 3-5% for a mean radius of 0.75 cm. This study indicates the need for improvement in dose calculation accuracy with respect to intraluminal brachytherapy for bronchus cancer., (© The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Immune-checkpoint inhibitors are emerging as revolutionary drugs for certain malignancies. However, blocking the co-inhibitory signals may lead to immune-related adverse events, mainly in the spectrum of autoimmune diseases including colitis, endocrinopathies and nephritis. Here, we report a case of a 75-year-old man with metastatic malignant melanoma treated with a combination of nivolumab (anti-PD1-antibody) and ipilimumab (anti-CTLA-4 antibody) who developed systemic rash along with severe acute tubulointerstitial nephritis after two doses of combination therapy. Kidney biopsy and peripheral blood immune profile revealed highly proliferative and cytotoxic T cell features. Herein, we discuss the pathophysiology and management of immune checkpoint blockade-related adverse events.

Context: Mitochondrial diabetes is a rare form of diabetes mellitus accounting for up to 1% of all diabetes. Pyruvate therapy has been reported to be a potential therapeutic choice for patients with mitochondrial diseases., Case Description: Water-based sodium pyruvate solutions (0.5 g/kg, thrice daily) were administrated orally to a 32-year-old Japanese male with mitochondrial diabetes and myopathy caused by m.14709T>C mutation. At the age of 20 years, he was diagnosed with diabetes mellitus and started insulin therapy. He tested negative for islet cell and glutamic decarboxylase antibodies. To evaluate favorable therapeutic improvements, we measured the lactate and pyruvate levels in plasma and cerebrospinal fluid; urinary C-peptide, glycated hemoglobin, and glycoalbumin levels; and total daily insulin dose (TDD). The patient experienced no side effects such as diarrhea because of pyruvate therapy. His urinary C-peptide level improved from 4.3 to 17.2 μg/d after 1 day and to 30.2 μg/d after 6 months of pyruvate therapy. TDD decreased from 33 to 20 U/d after 6 months of pyruvate therapy, but the lactate levels of plasma and cerebrospinal fluid and the lactate/pyruvate ratio did not change., Conclusions: Sodium pyruvate improved insulin secretion and resulted in decreased TDD in a patient with mitochondrial diabetes. Pyruvate therapy may be a potential therapeutic choice for patients with mitochondrial diabetes. Clinical trials involving a larger number of patients and long-term evaluation of the therapy are necessary to clarify the efficacy of pyruvate therapy.

Dropped head syndrome (DHS) is a famous but unusual late complication of multimodality treatment for head and neck carcinoma. We reported this early-onset complication and analyzed the dose to the neck extensor muscles. We examined the records of three patients with DHS after radiotherapy. The doses to the neck extensor muscles were compared between three patients with DHS and nine patients without DHS. The mean dose to the neck extensor muscles of the three patients with DHS were 58.5 Gy, 42.3 Gy and 60.9 Gy, while the dose was <50 Gy in all nine patients in the control group. The onset of this syndrome was 5 months, 6 months and 15 months. The early-onset DHS may have something to do with dose to the neck extensor muscles. The proposed dose to the neck extensor muscles might be <46 Gy (or at least <50 Gy)., (© The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Intensity-modulated radiation therapy (IMRT) was recently introduced to the field of gynecologic malignancies; however, its value is not yet validated. A clinical trial is in preparation to investigate the efficacy and feasibility of IMRT for postoperative cervical cancer. The object of this study was to perform a surveillance study of IMRT for post-operative cervical cancer. A questionnaire regarding the precise methods of conducting IMRT was sent to six institutions that had already introduced IMRT for post-operative cervical cancer, and the data were analyzed. Half of the institutions used static IMRT and the others used volumetric-modulated arc therapy (VMAT). Most institutions used body-immobilizing devices for patient fixation. Most institutions instructed patients to fill their bladder before undergoing planning CT or daily treatment. While one institution inserted metallic markers and another one used radio-contrast-soaked gauze to visualize the vaginal cuff, the other institutions used nothing for vaginal cuff visualization. Most institutions defined the clinical target volumes according to the Japan Clinical Oncology Group or the Radiation Therapy Oncology Group guidelines. Only one institution used a prescribed dose based on 95% of the PTV (D(95)), while the rest used the mean dose (D(mean)). This valuable information from six leading institutions will be utilized in a future prospective clinical trial., (© The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Stereotactic body radiotherapy (SBRT) is a relatively new treatment for liver tumor. Outcomes of SBRT for liver tumors unsuitable for ablation or surgical resection were evaluated. A total of 79 patients treated with SBRT for primary hepatocellular carcinoma (HCC) between 2004 and 2012 in six Japanese institutions were studied retrospectively. Patients treated with SBRT preceded by trans-arterial chemoembolization were eligible. Their median age was 73 years, 76% were males, and their Child-Pugh scores were Grades A (85%) and B (11%) before SBRT. The median biologically effective dose (α/β = 10 Gy) was 96.3 Gy. The median follow-up time was 21.0 months for surviving patients. The 2-year overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival were 53%, 40% and 76%, respectively. Sex and serum PIVKA-II values were significant predictive factors for OS. Hypovascular or hypervascular types of HCC, sex and clinical stage were significant predictive factors for PFS. The 2-year PFS was 66% in Stage I vs 18% in Stages II-III. Multivariate analysis indicated that clinical stage was the only significant predictive factor for PFS. No Grade 3 laboratory toxicities in the acute, sub-acute, and chronic phases were observed. PFS after SBRT for liver tumor was satisfactory, especially for Stage I HCC, even though these patients were unsuitable for resection and ablation. SBRT is safe and might be an alternative to resection and ablation., (© The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

During radiotherapy for gastric lymphoma, it is difficult to protect the liver and kidneys in cases where there is considerable overlap between these organs and the target volume. This study was conducted to compare the three radiotherapy planning techniques of four-fields 3D conformal radiotherapy (3DCRT), half-field radiotherapy (the half-beam method) and intensity-modulated radiotherapy (IMRT) used to treat primary gastric lymphoma in which the planning target volume (PTV) had a large overlap with the left kidney. A total of 17 patients with gastric diffuse large B-cell lymphoma (DLBCL) were included. In DLBCL, immunochemotherapy (Rituximab + CHOP) was followed by radiotherapy of 40 Gy to the whole stomach and peri-gastric lymph nodes. 3DCRT, the half-field method, and IMRT were compared with respect to the dose-volume histogram (DVH) parameters and generalized equivalent uniform dose (gEUD) to the kidneys, liver and PTV. The mean dose and gEUD for 3DCRT was higher than for IMRT and the half-beam method in the left kidney and both kidneys. The mean dose and gEUD of the left kidney was 2117 cGy and 2224 cGy for 3DCRT, 1520 cGy and 1637 cGy for IMRT, and 1100 cGy and 1357 cGy for the half-beam method, respectively. The mean dose and gEUD of both kidneys was 1335 cGy and 1559 cGy for 3DCRT, 1184 cGy and 1311 cGy for IMRT, and 700 cGy and 937 cGy for the half-beam method, respectively. Dose-volume histograms (DVHs) of the liver revealed a larger volume was irradiated in the dose range <25 Gy with 3DCRT, while the half-beam method irradiated a larger volume of liver with the higher dose range (>25 Gy). IMRT and the half-beam method had the advantages of dose reduction for the kidneys and liver., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

The influence of deviations in dwell times and source positions for (192)Ir HDR-RALS was investigated. The potential dose errors for various kinds of brachytherapy procedures were evaluated. The deviations of dwell time ΔT of a (192)Ir HDR source for the various dwell times were measured with a well-type ionization chamber. The deviations of source position ΔP were measured with two methods. One is to measure actual source position using a check ruler device. The other is to analyze peak distances from radiographic film irradiated with 20 mm gap between the dwell positions. The composite dose errors were calculated using Gaussian distribution with ΔT and ΔP as 1σ of the measurements. Dose errors depend on dwell time and distance from the point of interest to the dwell position. To evaluate the dose error in clinical practice, dwell times and point of interest distances were obtained from actual treatment plans involving cylinder, tandem-ovoid, tandem-ovoid with interstitial needles, multiple interstitial needles, and surface-mold applicators. The ΔT and ΔP were 32 ms (maximum for various dwell times) and 0.12 mm (ruler), 0.11 mm (radiographic film). The multiple interstitial needles represent the highest dose error of 2%, while the others represent less than approximately 1%. Potential dose error due to dwell time and source position deviation can depend on kinds of brachytherapy techniques. In all cases, the multiple interstitial needles is most susceptible., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

The main purpose of this study was to compare three different treatment plans for locally advanced cervical cancer: (i) the inverse-planning simulated annealing (IPSA) plan for combination brachytherapy (BT) of interstitial and intracavitary brachytherapy, (ii) manual optimization based on the Manchester system for combination-BT, and (iii) the conventional Manchester system using only tandem and ovoids. This was a retrospective study of 25 consecutive implants. The high-risk clinical target volume (HR-CTV) and organs at risk were defined according to the GEC-ESTRO Working Group definitions. A dose of 6 Gy was prescribed. The uniform cost function for dose constraints was applied to all IPSA-generated plans. The coverage of the HR-CTV by IPSA for combination-BT was equivalent to that of manual optimization, and was better than that of the Manchester system using only tandem and ovoids. The mean V100 achieved by IPSA for combination-BT, manual optimization and Manchester was 96 ± 3.7%, 95 ± 5.5% and 80 ± 13.4%, respectively. The mean D100 was 483 ± 80, 487 ± 97 and 335 ± 119 cGy, respectively. The mean D90 was 677 ± 61, 681 ± 88 and 513 ± 150 cGy, respectively. IPSA resulted in significant reductions of the doses to the rectum (IPSA D2cm(3): 408 ± 71 cGy vs manual optimization D2cm(3): 485 ± 105 cGy; P = 0.03) and the bladder (IPSA D2cm(3): 452 ± 60 cGy vs manual optimization D2cm(3): 583 ± 113 cGy; P < 0.0001). In conclusion, combination-BT achieved better tumor coverage, and plans using IPSA provided significant sparing of normal tissues without compromising CTV coverage.

Purpose: To analyze the results of radical radiotherapy by electron beams for squamous cell carcinoma (SCC) of the eyelid and to find the possible prognostic factors., Materials and Methods: Records of 38 patients with histologically confirmed SCC of the eyelid who underwent electron beam radiation therapy between 1964 and 2010 in our institution were retrospectively reviewed. Median tumor size was 15 mm (range, 3-40 mm). T stage was T1 in three, T2a in six, T2b in 14, and T3a in 15 patients. Four patients had nodal metastasis. Of the 38 patients, 14 had relapsed disease after prior treatment. Median radiation dose was 60.0 Gy (range, 45.0-70.4 Gy). Median follow-up was 72.5 months (range, 2.0-369 months)., Results: 5-year local relapse-free, nodal relapse-free, distant metastasis-free and relapse-free rates for all patients were 71.8%, 77.5%, 90.6% and 58.0%, respectively. In seven patients, lymph node metastases occurred in 11 faciocervical regions. The 5-year overall survival was 79.5%. T stage and radiation dose expressed in EQD2 Gy tended to have impacts on local control. Relapsed patients showed unfavorable local relapse-free rate, however this was without statistical significance. Of the 14 patients who died, 12 succumbed to concurrent diseases. Grade 3 or greater severe late morbidities (CTCAE ver4.0) were observed in nine patients. Due to the morbidities, two patients lost their vision., Conclusion: Radical radiotherapy for SCC of the eyelid yielded good results and could be a treatment option. Whether radiation-dose escalation could improve local control in advanced T stages and relapsed patients needs further study.

Brachytherapy plays a significant role in the management of cervical cancer, but the clinical significance of brachytherapy in the management of vaginal cancer remains to be defined. Thus, a single institutional experience in the treatment of primary invasive vaginal carcinoma was reviewed to define the role of brachytherapy. We retrospectively reviewed the charts of 36 patients with primary vaginal carcinoma who received definitive radiotherapy between 1992 and 2010. The treatment modalities included high-dose-rate intracavitary brachytherapy alone (HDR-ICBT; two patients), external beam radiation therapy alone (EBRT; 14 patients), a combination of EBRT and HDR-ICBT (10 patients), or high-dose-rate interstitial brachytherapy (HDR-ISBT; 10 patients). The median follow-up was 35.2 months. The 2-year local control rate (LCR), disease-free survival (DFS), and overall survival (OS) were 68.8%, 55.3% and 73.9%, respectively. The 2-year LCR for Stage I, II, III and IV was 100%, 87.5%, 51.5% and 0%, respectively (P = 0.007). In subgroup analysis consisting only of T2-T3 disease, the use of HDR-ISBT showed marginal significance for favorable 5-year LCR (88.9% vs 46.9%, P = 0.064). One patient each developed Grade 2 proctitis, Grade 2 cystitis, and a vaginal ulcer. We conclude that brachytherapy can play a central role in radiation therapy for primary vaginal cancer. Combining EBRT and HDR-ISBT for T2-T3 disease resulted in good local control.

Background: The favorable response rate of radiotherapy for localized gastric mucosa-associated lymphoid tissue lymphoma refractory to Helicobacter pylori eradication has been demonstrated. However, there are limited data available on the long-term outcomes. The aim of this retrospective study was to evaluate the long-term outcomes of radiotherapy for localized gastric mucosa-associated lymphoid tissue lymphoma refractory to Helicobacter pylori eradication., Methods: Thirty-four consecutive patients with localized gastric mucosa-associated lymphoid tissue lymphoma that were refractory to eradication were treated with radiotherapy (a total dose of 30 Gy). The response and adverse events of radiotherapy were retrospectively analyzed as short-term outcomes, and recurrence-free, overall and disease-specific survival rates were calculated as long-term outcomes., Results: Thirty-three (97.1%) patients achieved complete remission and radiotherapy was well tolerated. One patient underwent emergency gastrectomy due to severe hematemesis. Of the 34 patients during the median follow-up period of 7.5 (1.2-13.0) years, one patient had local recurrence after 8.8 years, one patient underwent surgery for bowel obstruction secondary to small bowel metastasis after 5.1 years and one patient had pulmonary metastasis after 10.9 years. Pathologically, all three recurrences revealed mucosa-associated lymphoid tissue lymphoma without any transformation to high-grade lymphoma. None died of gastric mucosa-associated lymphoid tissue lymphoma. The 5-year recurrence-free survival rate was 97.0%. The 5-year overall survival rates and disease-specific survival rates were 97.0 and 100%, respectively., Conclusions: Radiotherapy in patients with localized gastric mucosa-associated lymphoid tissue lymphoma refractory to Helicobacter pylori eradication can achieve excellent overall survival. However, long-term surveillance is necessary to identify late recurrences.