Multi-institutional prospective observational study of radiotherapy for metastatic bone tumor.

Purpose of this study is to evaluate patient characteristics, treatments and outcomes in bone metastasis radiotherapy practice. Patients for whom radiotherapy for bone metastasis was planned at 26 institutions in Japan between December 2020 and March 2021 were consecutively registered in this prospective, observational study. Study measures included patient characteristics, pain relief, skeletal-related events (SREs), overall survival and incidence of radiation-related adverse events. Pain was evaluated using a numerical rating scale (NRS) from 0 to 10. Irradiated dose was analyzed by the biologically effective dose (BED) assuming α/ß = 10. Overall, 232 patients were registered; 224 patients and 302 lesions were fully analyzed. Eastern Cooperative Oncology Group Performance Status was 0/1/2/3/4 in 23%/38%/22%/13%/4%; 59% of patients had spinal metastases and 84% had painful lesions (NRS ≥ 2). BED was <20 Gy (in 27%), 20-30 Gy (24%), 30-40 Gy (36%) and ≥ 40 Gy (13%); 9% of patients were treated by stereotactic body radiotherapy. Grade 3 adverse events occurred in 4% and no grade 4-5 toxicity was reported. Pain relief was achieved in 52% at 2 months. BED is not related to pain relief. The cumulative incidence of SREs was 6.5% (95% confidence interval (CI) 3.1-9.9) at 6 months; no factors were significantly associated with SREs. With spinal lesions, 18% of patients were not ambulatory at baseline and 50% of evaluable patients in this group could walk at 2 months. The 6-month overall survival rate was 70.2% (95% CI 64.2-76.9%). In conclusion, we report real-world details of radiotherapy in bone metastasis.

Cell-cycle dependence on the biological effects of boron neutron capture therapy and its modification by polyvinyl alcohol.

Boron neutron capture therapy (BNCT) is a unique radiotherapy of selectively eradicating tumor cells using boron compounds (e.g., 4-borono-L-phenylalanine [BPA]) that are heterogeneously taken up at the cellular level. Such heterogenicity potentially reduces the curative efficiency. However, the effects of temporospatial heterogenicity on cell killing remain unclear. With the technical combination of radiation track detector and biophysical simulations, this study revealed the cell cycle-dependent heterogenicity of BPA uptake and subsequent biological effects of BNCT on HeLa cells expressing fluorescent ubiquitination-based cell cycle indicators, as well as the modification effects of polyvinyl alcohol (PVA). The results showed that the BPA concentration in the S/G2/M phase was higher than that in the G1/S phase and that PVA enhances the biological effects both by improving the uptake and by canceling the heterogenicity. These findings might contribute to a maximization of therapeutic efficacy when BNCT is combined with PVA and/or cell cycle-specific anticancer agents.

Quality of palliative radiotherapy assessed using quality indicators: a multicenter survey†.

We sought to identify potential evidence-practice gaps in palliative radiotherapy using quality indicators (QIs), previously developed using a modified Delphi method. Seven QIs were used to assess the quality of radiotherapy for bone metastases (BoM) and brain metastases (BrM). Compliance rate was calculated as the percentage of patients for whom recommended medical care was conducted. Random effects models were used to estimate the pooled compliance rates. Of the 39 invited radiation oncologists, 29 (74%) from 29 centers participated in the survey; 13 (45%) were academic and 16 (55%) were non-academic hospitals. For the QIs, except for BoM-4, the pooled compliance rates were higher than 80%; however, for at least some of the centers, the compliance rate was lower than these pooled rates. For BoM-4 regarding steroid use concurrent with radiotherapy for malignant spinal cord compression, the pooled compliance rate was as low as 32%. For BoM-1 regarding the choice of radiation schedule, the compliance rate was higher in academic hospitals than in non-academic hospitals (P = 0.021). For BrM-3 regarding the initiation of radiotherapy without delay, the compliance rate was lower in academic hospitals than in non-academic hospitals (P = 0.016). In conclusion, overall, compliance rates were high; however, for many QIs, practice remains to be improved in at least some centers. Steroids are infrequently used concurrently with radiotherapy for malignant spinal cord compression.

Factors associated with quality of life in patients receiving palliative radiotherapy for bone metastases: a secondary cross-sectional analysis of data from a prospective multicenter observational study.

OBJECTIVE: To identify factors significantly associated with quality of life (QOL) and determine if these associations are strong enough to predict certain aspects of QOL without measuring them. METHODS: We conducted an exploratory secondary analysis of baseline data of 224 patients (enrolled between December 2020 and March 2021) from a previously published prospective observational study on radiotherapy for bone metastases at 26 centres. Using univariable linear regression, we assessed the association between patient/treatment factors and QOL scale scores as measured by the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 15-Palliative (QLQ-C15-PAL) and the EORTC QOL Questionnaire Bone Metastases module (QLQ-BM22). RESULTS: Age and sex were not significantly associated with QOL. Worse performance status, higher pain scores, and opioid and single-fraction use were significantly associated with most QOL scales; these four factors were associated with worse global QOL, worse functioning status, and more severe symptoms. The coefficients of determination for most QOL scales were less than 0.2, indicating that most of the variability in QOL scores was not explained by any of the explanatory variables. CONCLUSION: Performance status, pain intensity, and opioid and single-fraction use were significantly associated with most QOL scales. However, the associations were not strong enough to estimate QOL. ADVANCES IN KNOWLEDGE: To date, the association between treatment factors and QOL in patients with bone metastases has not been fully studied. We identified the factors that were significantly associated with QOL and found that these associations were not strong enough to predict QOL.

Income and Employment of Patients at the Start of and During Follow-up After Palliative Radiation Therapy for Bone Metastasis.

Purpose: The aim of this study was to understand the income and employment status of patients at the start of and during follow-up after palliative radiation therapy for bone metastasis. Methods and Materials: From December 2020 to March 2021, a prospective multi-institutional observational study was conducted to investigate income and employment of patients at the start of administration of radiation therapy for bone metastasis and at 2 and 6 months after treatment. Of 333 patients referred to radiation therapy for bone metastasis, 101 were not registered, mainly because of their poor general condition, and another 8 were excluded from the follow-up analysis owing to ineligibility. Results: In 224 patients analyzed, 108 had retired for reasons unrelated to cancer, 43 had retired for reasons related to cancer, 31 were taking leave, and 2 had lost their jobs at the time of registration. The number of patients who were in the working group was 40 (30 with no change in income and 10 with decreased income) at registration, 35 at 2 months, and 24 at 6 months. Younger patients (P = 0), patients with better performance status (P = 0), patients who were ambulatory (P = .008), and patients with lower scores on a numerical rating scale of pain (P = 0) were significantly more likely to be in the working group at registration. There were 9 patients who experienced improvements in their working status or income at least once in the follow-up after radiation therapy. Conclusions: The majority of patients with bone metastasis were not working at the start of or after radiation therapy, but the number of patients who were working was not negligible. Radiation oncologists should be aware of the working status of patients and provide appropriate support for each patient. The benefit of radiation therapy to support patients continuing their work and returning to work should be investigated further in prospective studies.

Quality Indicators in Palliative Radiation Oncology: Development and Pilot Testing.

PURPOSE: A quality indicator (QI) is a valuable tool to evaluate the quality of health care systems. In palliative radiation oncology, only a few related QIs have been developed to date. In this study, we sought to develop and pilot test QIs that assess the quality of care in palliative radiation therapy. METHODS AND MATERIALS: A modified Delphi method was used to establish consensus with an expert panel. The panel consisted of 8 radiation oncologists who have expertise in palliative radiation oncology and 1 expert on Delphi methodology. Online panel meetings and e-mail surveys were conducted to develop QIs on palliative radiation therapy for bone and brain metastases. Feasibility of measurement was assessed though pilot surveys that were conducted by radiation oncologists at 5 facilities. RESULTS: After 3 online meetings and 2 e-mail surveys, we developed 4 QIs on bone metastases and 3 QIs on brain metastases. Two email surveys and 2 pilot surveys confirmed the validity of QIs and the feasibility of measurement, respectively. CONCLUSIONS: We developed valid and feasible QIs on palliative radiation therapy for bone and brain metastases. Our work may contribute to reduce the evidence-practice gaps in palliative radiation oncology.

Production of functional sperm from cryopreserved testicular germ cells following intraperitoneal transplantation into allogeneic surrogate in yellowtail (Seriola quinqueradiata).

The aim of this study was to establish a method for the cryopreservation of spermatogonia of the yellowtail (Seriola quinqueradiata), which is the most commonly farmed fish in Japan. Testicular cells were prepared by enzymatic dissociation of testicular fragments containing an abundance of type A spermatogonia and were added to cryomedium containing dimethyl sulfoxide (DMSO), ethylene glycol, glycerol, or propylene glycol at concentrations of 0.5-2.5 M. The cells were then frozen and stored in liquid nitrogen for 3 days. After thawing, their survival and transplantability were evaluated. Testicular cells were most successfully cryopreserved in 1.0 M DMSO as indicated by survival of 34% of cells. Furthermore, in situ hybridization using the yellowtail vasa probe showed that these recovered cells contained a similar proportion of germ cells to fresh testicular cells before freezing. Transplantation of the recovered cells into the peritoneal cavities of allogeneic larvae resulted in 94% of surviving recipients having donor-derived germ cells in their gonads after 28 days. Sperm were then collected from seven randomly selected recipients once they reached 2 years of age and used to fertilize wild-type eggs, which led to an average of 26% of the first filial (F1) offspring being derived from donor fish, as confirmed through the use of microsatellite markers. Thus, we successfully cryopreserved yellowtail spermatogonia and produced functional sperm via intraperitoneal transplantation into allogeneic recipients.

Establishment of novel monoclonal antibodies for identification of type A spermatogonia in teleosts†.

We recently established a germ cell transplantation system in salmonids. Donor germ cells transplanted into the body cavity of recipient embryos migrate toward and are incorporated into the recipient gonad, where they undergo gametogenesis. Among the various types of testicular germ cells, only type A spermatogonia (A-SG) can be incorporated into the recipient gonads. Enriching for A-SG is therefore important for improving the efficiency of germ cell transplantation. To enrich for A-SG, an antibody against a cell surface marker is a convenient and powerful approach used in mammals; however, little is known about cell surface markers for A-SG in fish. To that end, we have produced novel monoclonal antibodies (mAbs) against cell-surface molecules of rainbow trout (Oncorhynchus mykiss) A-SG. We inoculated mice with living A-SG isolated from pvasa-GFP transgenic rainbow trout using GFP-dependent flow cytometry. By fusing lymph node cells of the inoculated mice with myeloma cells, we generated 576 hybridomas. To identify hybridomas that produce mAbs capable of labeling A-SG preferentially and effectively, we screened them using cell ELISA, fluorescence microscopy, and flow cytometry. We thereby identified two mAbs that can label A-SG. By using flow cytometry with these two antibodies, we could enrich for A-SG with transplantability to recipient gonads from amongst total testicular cells. Furthermore, one of these mAbs could also label zebrafish (Danio rerio) spermatogonia. Thus, we expect these monoclonal antibodies to be powerful tools for germ cell biology and biotechnology.

The unusual rainbow trout sex determination gene hijacked the canonical vertebrate gonadal differentiation pathway.

Evolutionary novelties require rewiring of transcriptional networks and/or the evolution of new gene functions. Sex determination (SD), one of the most plastic evolutionary processes, requires such novelties. Studies on the evolution of vertebrate SD revealed that new master SD genes are generally recruited from genes involved in the downstream SD regulatory genetic network. Only a single exception to this rule is currently known in vertebrates: the intriguing case of the salmonid master SD gene (sdY), which arose from duplication of an immune-related gene. This exception immediately posed the question of how a gene outside from the classical sex differentiation cascade could acquire its function as a male SD gene. Here we show that SdY became integrated in the classical vertebrate sex differentiation cascade by interacting with the Forkhead box domain of the female-determining transcription factor, Foxl2. In the presence of Foxl2, SdY is translocated to the nucleus where the SdY:Foxl2 complex prevents activation of the aromatase (cyp19a1a) promoter in cooperation with Nr5a1 (Sf1). Hence, by blocking a positive loop of regulation needed for the synthesis of estrogens in the early differentiating gonad, SdY disrupts a preset female differentiation pathway, consequently allowing testicular differentiation to proceed. These results also suggest that the evolution of unusual vertebrate master sex determination genes recruited from outside the classical pathway like sdY is strongly constrained by their ability to interact with the canonical gonadal differentiation pathway.

The Role of Cancer Boards in the Treatment Decisions Regarding Chemotherapy.

Objective The influence of cancer boards with respect to the treatment decisions regarding chemotherapy remains to be elucidated. In the present study, we investigated the cases that presented at our institutional cancer boards, to assess the effect of cancer boards on the treatment decisions regarding chemotherapy. Methods Data from the cancer boards at Yamagata University Hospital, Yamagata, Japan, were collected. Along with data from the clinical records, the details of the discussions and the chosen plan of treatment of the cancer boards were analyzed. Results From February 2010 to February 2014, 1,541 cases were discussed at our cancer boards. Of these, 811 cases (52.6%) involved discussions about chemotherapy. Of those 811 cases, recommendations were made to alter the treatment plans for 189 cases (23.3%). The reasons for discouraging chemotherapy varied; however, 29/45 (64.4%) cases involved discouragement for the following reasons: old age, a comorbid condition, the physical (performance) status, or insufficient evidence to administer chemotherapy. Eighty-six patients were referred to the medical oncology department through the cancer boards. Conclusion Our results showed that cancer boards have a great influence on the treatment decisions regarding chemotherapy and the prompt referral of cases to medical oncologists as necessary. In terms of future research, we will evaluate the effect of cancer boards on the prognosis and outcomes of cases using the institutional cancer registry.

Modified simultaneous integrated boost radiotherapy for large retroperitoneal malignant tumor: A case report.

The current study reports the case of a large retroperitoneal tumor treated with modified simultaneous integrated boost (SIB) radiotherapy. A 45-year-old female presented to the emergency department complaining of left abdominal pain and fever. A computed tomography scan detected a retroperitoneal tumor of 12×16×16 cm, and a biopsy revealed a poorly-differentiated adenocarcinoma. The patient was diagnosed with a large adenocarcinoma originating from the left ureter, with no distant metastasis. Due to the patient's poor physical condition, surgery was not recommended, and the patient was referred to the Department of Radiation Oncology (Yamagata University Hospital, Yamagata, Japan). Modified SIB radiotherapy was administered following the acquisition of written consent from the patient. The total irradiation dose to the center of the tumor and to the surrounding healthy tissue was ∼96 Gy/33 fractions and <60 Gy/33 fractions, respectively. At the end of the radiotherapeutic course, the tumor volume was reduced by ≥80%, and the residual tumor was surgically resected. As a result of the resection, a complete pathological response was confirmed; the patient has been recurrence-free for >3 years with no complications. Modified SIB radiotherapy may be safely administered, with favorable outcomes. Complete recovery can be achieved with this technique, even in a patient with a large radioresistant tumor.

Modified simultaneous integrated boost radiotherapy for unresectable locally advanced breast cancer: preliminary results of a prospective clinical trial.

BACKGROUND: The purpose of this study was to evaluate the effect of modified simultaneous integrated boost (SIB) radiotherapy for patients with extensive breast cancer. PATIENTS AND METHODS: Patients with macroscopic tumor and histologically proven adenocarcinoma of the breast were enrolled in the study. Patients were included whether they had or did not have previous surgery, chemotherapy, hormone therapy, or molecular targeted therapy; patients with past history of thoracic radiotherapy were excluded. Under conditions of not exceeding the tolerance dose for normal tissue, irradiation to the tumor was increased to the maximum possible extent using the modified SIB technique. RESULTS: Three breast cancer patients were treated with the modified SIB technique. All patients were diagnosed as T4b (median maximum diameter of the tumor: 16 cm; range, 15.5-22 cm), and all patients exhibited symptoms because of the extremely large tumor. The median total dose to the part of tumor tissue was 128.8 Gy (range, 110-140 Gy). Total dose to normal tissue was < 72 Gy in all patients. Although large tumors were radio-resistant, it was macroscopically confirmed that all tumors eventually disappeared. Although skin defects persisted because of tumor disappearance, there were no Grade ≥ 3 toxicities due to radiotherapy. CONCLUSION: Although much care is required in delivering extremely high doses of radiotherapy to the tumor, modified SIB radiotherapy was shown to be effective against extremely large tumors that could not be controlled using conventional radiotherapy. In future, an increase in the number of study patients and establishment of the technique will be required.

Status of radiotherapy in a multidisciplinary cancer board.

Multidisciplinary cancer boards (CBs) for making cancer treatment decisions have become popular in many countries; however, the status of radiotherapy in CBs and the influence of CBs on radiotherapy decisions have not been studied. To clarify these issues, we reviewed the minutes of our CBs from February 2010 to March 2012, and we classified planned treatments discussed at the CBs into five categories and analyzed decisions concerning radiotherapy in each category. The fraction of cases for which radiotherapy was recommended was 536/757 (71%). These cases included 478 cases (63%) for which radiation therapy was planned and four cases (0.5%) for which radiation therapy was unexpectedly recommended. On the other hand, radiation therapy was canceled in 21 cases (4%) for which radiation therapy had been planned. This study showed that radiotherapy was discussed in many cases at CBs and that CBs have a great influence on decisions concerning radiotherapy.

Modified simultaneous integrated boost radiotherapy for an unresectable huge refractory pelvic tumor diagnosed as a rectal adenocarcinoma.

A clinical trial of radiotherapy with modified simultaneous integrated boost (SIB) technique against huge tumors was conducted. A 58-year-old male patient who had a huge pelvic tumor diagnosed as a rectal adenocarcinoma due to familial adenomatous polyposis was enrolled in this trial. The total dose of 77 Gy (equivalent dose in 2 Gy/fraction) and 64.5 Gy was delivered to the center of the tumor and the surrounding area respectively, and approximately 20% dose escalation was achieved with the modified SIB technique. The tumor with an initial maximum size of 15 cm disappeared 120 d after the start of the radiotherapy. Performance status of the patient improved from 4 to 0. Radiotherapy with modified SIB may be effective for patients with a huge tumor in terms of tumor shrinkage/disappearance, improvement of QOL, and prolongation of survival.

Sexual plasticity of ovarian germ cells in rainbow trout.

The sexual plasticity of fish gonads declines after the sex differentiation period; however, information about the plasticity of the germ cells themselves after sex differentiation is limited. Using rainbow trout (Oncorhynchus mykiss), we recently established a novel germ cell transplantation system that provides a unique platform with which to dissect the developmental and cellular mechanisms underlying gametogenesis. Using this technique, we show here that transplanted ovarian germ cells isolated from 6- to 9-month-old donors can colonize sexually undifferentiated embryonic gonads and resume gametogenesis. Ovarian germ cells containing oogonia and early oocytes isolated from female rainbow trout were transplanted into the peritoneal cavities of hatching-stage fry of both sexes and the behavior of the donor cells was observed. The transplanted ovarian germ cells migrated towards the recipient gonads, interacted with embryonic gonadal somatic cells, proliferated rapidly, and eventually differentiated into eggs in female recipients and sperm in male recipients. Furthermore, the donor-derived eggs and sperm obtained from the recipient fish were functional and were able to produce normal offspring. These findings indicate that mitotic germ cells, the oogonia, possess a high level of sexual plasticity.