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.

Clinical outcome, radiological findings, and genetic features of IDH-mutant brainstem glioma in adults.

BACKGROUND: With the recent advent of genetic testing, IDH-mutant glioma has been found among adult brainstem gliomas. However, the clinical outcome and prognosis of IDH-mutant brainstem gliomas in adults have not been elucidated. This study aimed to investigate the clinical outcome, radiological findings, and genetic features of adult patients with IDH-mutant diffuse brainstem gliomas. METHODS: Data from adult patients with brainstem glioma at Hokkaido University Hospital between 2006 and 2022 were retrospectively analyzed. Patient characteristics, treatment methods, genetic features, and prognosis were evaluated. RESULTS: Of 12 patients with brainstem glioma with proven histopathology, 4 were identified with IDH mutation. All patients underwent local radiotherapy with 54 Gray in 27 fractions combined with chemotherapy with temozolomide. Three patients had IDH1 R132H mutation and one had IDH2 R172G mutation. The median progression-free survival and overall survival were 68.4 months and 85.2 months, respectively, longer than that for IDH-wildtype gliomas (5.6 months and 12.0 months, respectively). At the time of initial onset, contrast-enhanced lesions were observed in two of the four cases in magnetic resonance imaging. CONCLUSION: As some adult brainstem gliomas have IDH mutations, and a clearly different prognosis from those with IDH-wildtype, biopsies are proactively considered to confirm the genotype.

Clinical outcomes for olfactory neuroblastoma.

Background: Olfactory neuroblastoma (ONB) is a rare malignant tumor arising from the olfactory neuroepithelium. The standard of care for ONB is surgical resection; however, detailed treatment protocols vary by institution. Our treatment protocol consists of endoscopic skull base surgery (ESBS) for endoscopically resectable cases and induction chemotherapy followed by craniotomy combined with ESBS for locally advanced cases, with postoperative radiotherapy performed for all cases. Chemoradiotherapy (CRT) is performed in unresectable cases. In this study, we evaluate our treatment protocol and outcomes for ONB. Methods: A retrospective review of patients with ONB was conducted. Outcomes included survival outcomes and perioperative data. Results: Fifteen patients (53.6%) underwent ESBS, 12 (42.9%) underwent craniotomy combined with ESBS, and 1 (3.6%) received CRT. The 5- and 10-year overall survival rates for all patients were 92.9% and 82.5%, respectively, with a median follow-up period of 81 months. The 5- and 10-year disease-free survival rates were 77.3% and 70.3%, respectively, and the 5- and 10-year local control rates were 88.2% and 80.2%, respectively. Patients undergoing ESBS demonstrated a significantly shorter operating time, period from operation to ambulation, hospitalization period, and less blood loss than those undergoing craniotomy combined with ESBS. Conclusion: Our treatment protocol was found to afford favorable outcomes. Patients who underwent endoscopic resection showed lower complication rates and better perioperative data than those who underwent craniotomy combined with ESBS. With appropriate case selection, ESBS is considered a useful approach for ONB.

A Single-Institution Prospective Study To Evaluate the Safety and Efficacy of Real- Time Image-Gated Spot-Scanning Proton Therapy (RGPT) for Prostate Cancer.

Purpose: In real-time image-gated spot-scanning proton therapy (RGPT), the dose distribution is distorted by gold fiducial markers placed in the prostate. Distortion can be suppressed by using small markers and more than 2 fields, but additional fields may increase the dose to organs at risk. Therefore, we conducted a prospective study to evaluate the safety and short-term clinical outcome of RGPT for prostate cancer. Methods and Materials: Based on the previously reported frequency of early adverse events (AE) and the noninferiority margin of 10%, the required number of cases was calculated to be 43 using the one-sample binomial test by the Southwest Oncology Group statistical tools with the one-sided significance level of 2.5% and the power 80%. Patients with localized prostate cancer were enrolled and 3 to 4 pure gold fiducial markers of 1.5-mm diameter were inserted in the prostate. The prescribed dose was 70 Gy(relative biologic effectiveness) in 30 fractions, and treatment was performed with 3 fields from the left, right, and the back, or 4 fields from either side of slightly anterior and posterior oblique fields. The primary endpoint was the frequency of early AE (≥grade 2) and the secondary endpoint was the biochemical relapse-free survival rate and the frequency of late AE. Results: Forty-five cases were enrolled between 2015 and 2017, and all patients completed the treatment protocol. The median follow-up period was 63.0 months. The frequency of early AE (≥grade 2) was observed in 4 cases (8.9%), therefore the noninferiority was verified. The overall 5-year biochemical relapse-free survival rate was 88.9%. As late AE, grade 2 rectal bleeding was observed in 8 cases (17.8%). Conclusions: The RGPT for prostate cancer with 1.5-mm markers and 3- or 4- fields was as safe as conventional proton therapy in early AE, and its efficacy was comparable with previous studies.

Cytological Analysis of the Surgical Field During Transanal Total Mesorectal Excision for Rectal Cancer: A Prospective Study.

BACKGROUND: An unexpectedly large number of patients experienced local recurrence with transanal total mesorectal excision in Norway. This appears to be associated with cancer cell spillage during surgery. OBJECTIVE: To investigate the surgical field cytology during transanal total mesorectal excision. DESIGN: This was a prospective cohort study. SETTINGS: This study was conducted at a single center between June and December 2020. PATIENTS: Forty patients with rectal cancer underwent transanal total mesorectal excision. Following the irrigation of the surgical field, the water specimens were cytologically evaluated at six representative steps. The first sample was used as an initial control. The second, third, fourth, fifth, and sixth samples were collected after the 1st purse-string suture, rectotomy, the 2nd purse-string suture, specimen resection, and anastomosis, respectively. The clinicopathological features and intraoperative complications of the patients were reviewed. MAIN OUTCOME MEASURES: The primary outcome was to evaluate the presence of cancer cells in washing cytological samples. RESULTS: Of the 40 consecutive patients enrolled in this study, 18 patients underwent neoadjuvant chemoradiotherapy. Incomplete first pursestring suture and rectal perforation were observed in 4 (10.0%) and 3 (7.5%) cases, respectively. In the first sample, 31 (77.5%) patients had malignant cells. Malignant findings were detected in two patients (5.0%) from the second to fifth samples. None of the sixth sample exhibited any malignant findings. LIMITATIONS: This single center study had a small sample size. CONCLUSIONS: Cancer cells were initially detected by cytology, but only a few were observed throughout the procedure; however, cancer cells were not detected in the final surgical field. Further follow-up and novel studies are required to obtain clinically significant findings using cytology during transanal total mesorectal excision. See Video Abstract.

Cutoff value of the geniohyoid muscle mass to identify sarcopenic dysphagia by ultrasonography.

PURPOSE: Determining the strength and area of the swallowing muscles is important in patients with sarcopenic dysphagia. Although the normative data on the strength of the swallowing muscles have been reported, those of the area of the geniohyoid muscle are poorly investigated. We investigated the cross-sectional area of the geniohyoid muscle in Japanese subjects without dysphagia using ultrasonography to determine the normative and cut-off values. METHODS: 142 subjects without dysphagia were included. The older group (age ≥ 65 years) included 36 (women 27/men 9) subjects, and the younger group (age ≤ 39 years) included 106 (women 54/men 52) subjects. The cross-sectional area of the geniohyoid muscle was measured by ultrasound. The mean of the younger group-2 standard deviation (SD) was calculated and used as a cut-off value for low swallowing muscle mass. RESULTS: The mean (SD) of the area of the geniohyoid muscle of each group was as follows: older women group 167.2 (32.6) mm2, older men group 193.2 (49.5) mm2, younger women group 247.3 (37.4) mm2, younger men group 313.1 (59.2) mm2. The mean 2SD of the geniohyoid muscle area in the younger women group was 172.5 mm2 and in the younger men group 194.7 mm2. CONCLUSION: We found that the cut-off value of the ultrasonographic cross-sectional area of the geniohyoid muscle was 172.5 mm2 for women and 194.7 mm2 for men. These values could be used as cut-off values for the mass of the geniohyoid muscle to identify patients with sarcopenic dysphagia.

Degenerate oligonucleotide primer MIG-seq: an effective PCR-based method for high-throughput genotyping.

Next-generation sequencing (NGS) library construction often involves using restriction enzymes to decrease genome complexity, enabling versatile polymorphism detection in plants. However, plant leaves frequently contain impurities, such as polyphenols, necessitating DNA purification before enzymatic reactions. To overcome this problem, we developed a PCR-based method for expeditious NGS library preparation, offering flexibility in number of detected polymorphisms. By substituting a segment of the simple sequence repeat sequence in the MIG-seq primer set (MIG-seq being a PCR method enabling library construction with low-quality DNA) with degenerate oligonucleotides, we introduced variability in detectable polymorphisms across various crops. This innovation, named degenerate oligonucleotide primer MIG-seq (dpMIG-seq), enabled a streamlined protocol for constructing dpMIG-seq libraries from unpurified DNA, which was implemented stably in several crop species, including fruit trees. Furthermore, dpMIG-seq facilitated efficient lineage selection in wheat and enabled linkage map construction and quantitative trait loci analysis in tomato, rice, and soybean without necessitating DNA concentration adjustments. These findings underscore the potential of the dpMIG-seq protocol for advancing genetic analyses across diverse plant species.

Impact of adaptive radiotherapy on survival in locally advanced nasopharyngeal carcinoma treated with concurrent chemoradiotherapy.

PURPOSE: To investigate the clinical significance of adaptive radiotherapy (ART) in locally advanced nasopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Eligible patients were treated with concurrent chemoradiotherapy using IMRT. Planning computed tomography in ART was performed during radiotherapy, and replanning was performed. Since ART was started in May 2011 (ART group), patients who were treated without ART up to April 2011 (non-ART group) were used as the historical control. The Kaplan-Meier method was used to calculate overall survival (OS), locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). LRFS for the primary tumor (LRFS_P) and regional lymph node (LRFS_LN) were also studied for more detailed analysis. Statistical significance was evaluated using the log-rank test for survival. RESULTS: The ART group tended to have higher radiation doses. The median follow-up period was 127 months (range, 10 to 211 months) in the non-ART group and 61.5 months (range, 5 to 129 months) in the ART group. Compared to the non-ART group, the ART group showed significantly higher 5-year PFS (53.8% vs. 81.3%, p = 0.015) and LRFS (61.2% vs. 85.3%, p = 0.024), but not OS (80.7% vs. 80.8%, p = 0.941) and DMFS (84.6% vs. 92.7%, p = 0.255). Five-year LRFS_P was higher in the ART group (61.3% vs. 90.6%, p = 0.005), but LRFS_LN did not show a significant difference (91.9% vs. 96.2%, p = 0.541). CONCLUSION: Although there were differences in the patient backgrounds between the two groups, this study suggests the potential effectiveness of ART in improving locoregional control, especially in the primary tumor.

Changes in the corrected carotid flow time can predict spinal anesthesia-induced hypotension in patients undergoing cesarean delivery: an observational study.

PURPOSE: Spinal anesthesia is a standard technique for cesarean delivery; however, it possesses a risk of hypotension. We hypothesised that the changes in the corrected flow time induced by the Trendelenburg position could predict the incidence of hypotension after spinal anesthesia for cesarean delivery. METHODS: Patients undergoing elective cesarean delivery under spinal anesthesia were enrolled. Before anesthesia induction, corrected flow time was measured in the supine and Trendelenburg positions (FTc-1 and FTc-2, respectively). Additionally, a percent change in corrected flow time induced by the Trendelenburg position was defined as ΔFTc. The primary endpoint was to investigate the ability of ΔFTc to predict the incidence of spinal anesthesia-induced hypotension until delivery. The receiver operating characteristics curves to assess the ability of FTc-1, FTc-2, and ΔFTc to predict the incidence of hypotension were generated. RESULTS: Finally, 40 patients were included, and of those, 26 (65%) developed spinal anesthesia-induced hypotension. The areas under the curve for FTc-1, FTc-2, and ΔFTc were 0.591 (95% CI: 0.424 to 0.743) (P = 0.380), 0.742 (95% CI: 0.579 to 0.867) (P = 0.004), and 0.882 (95% CI: 0.740 to 0.962) (P < 0.001) respectively, indicating ΔFTc as the best predictor among these three parameters. The best threshold for ΔFTc was 6.4% (sensitivity: 80.8% (95% CI: 53.8 to 96.2), specificity: 85.7% (95% CI: 42.9 to 100.0)). CONCLUSIONS: This study demonstrated that changes in the corrected carotid flow time induced by the Trendelenburg position could serve as a good predictor of spinal anesthesia-induced hypotension for cesarean delivery.

Psychological aspects of rehabilitation nutrition: A position paper by the Japanese Association of Rehabilitation Nutrition (secondary publication).

Psychological aspects of rehabilitation nutrition affect physical, cognitive, and social rehabilitation nutrition. When depression is recognized, not only pharmacotherapy and psychotherapy, but also non-pharmacological therapies such as exercise, nutrition, psychosocial, and other interventions can be expected to improve depression. Therefore, accurate diagnosis and intervention without overlooking depression is important. Psychological aspects of preventive rehabilitation nutrition is also important because depression can be partially prevented by appropriate exercise and nutritional management. Even in the absence of psychological negatives, increasing more psychological positives from a positive psychology perspective can be useful for both patients and healthcare professionals. Positive rehabilitation nutrition interventions can increase more psychological positives, such as well-being, through cognitive-behavioral therapy and mindfulness on their own, as well as through interventions on environmental factors. Consequently, physical, cognitive, and social positives are also expected to be enhanced.

Daily fraction dose-adjusted radiotherapy policy to avoid prolonging the overall treatment time for early glottic squamous cell carcinoma: a single-institutional retrospective study.

The objective of this study was to determine the outcomes of radical radiotherapy for early glottic squamous cell carcinoma (EGSCC) with the policy of increasing the fraction size during radiotherapy when the overall treatment time (OTT) was expected to be prolonged. Patients diagnosed with clinical T1-2N0M0 EGSCC, who were treated with radical radiotherapy between 2008 and 2019 at Hokkaido University Hospital, were included. Patients received 66 Gy in 33 fractions for T1 disease and 70 Gy in 35 fractions for T2 disease as our standard regimen (usual group [UG]). If the OTT was expected to extend for >1 week, the dose fraction size was increased from 2.0 to 2.5 Gy from the beginning or during radiotherapy (adjusted group [AG]). At this time, we performed a statistical analysis between UG and AG. In total, 116 patients were identified, and the treatment schedules of 29 patients were adjusted. The median follow-up was 60.9 months. In the T1 group, the cumulative 5-year local failure rate was 12.0% in the AG and 15.4% in the UG, and in the T2 group, the rate was 40.7% in the AG and 25.3% in the UG. There were no significant differences between the AG and UG. Similarly, no significant differences were observed for overall survival and progression-free survival rates. Our single-institutional retrospective analysis of EGSCC patients suggested that a method of adjusting the radiotherapy schedule to increase fraction size from the beginning or during the course may be effective in maintaining treatment outcomes.

A new predictive parameter for dose-volume metrics in intensity-modulated radiation therapy planning for prostate cancer: Initial phantom study.

BACKGROUND: Organ-at-risk (OAR) sparing is often assessed using an overlap volume-based parameter, defined as the ratio of the volume of OAR that overlaps the planning target volume (PTV) to the whole OAR volume. However, this conventional overlap-based predictive parameter (COPP) does not consider the volume relationship between the PTV and OAR. PURPOSE: We propose a new overlap-based predictive parameter that consider the PTV volume. The effectiveness of proposed overlap-based predictive parameter (POPP) is evaluated compared with COPP. METHODS: We defined as POPP = (overlap volume between OAR and PTV/OAR volume) × (PTV volume/OAR volume). We generated intensity modulated radiation therapy (IMRT) based on step and shoot technique, and volumetric modulated arc therapy (VMAT) plans with the Auto-Planning module of Pinnacle3 treatment planning system (v14.0, Philips Medical Systems, Fitchburg, WI) using the American Association of Physicists in Medicine Task Group (TG119) prostate phantom. The relationship between the position and size of the prostate phantom was systematically modified to simulate various geometric arrangements. The correlation between overlap-based predictive parameters (COPP and POPP) and dose-volume metrics (mean dose, V70Gy, V60Gy, and V37.5 Gy for rectum and bladder) was investigated using linear regression analysis. RESULTS: Our results indicated POPP was better than COPP in predicting intermediate-dose metrics. The bladder results showed a trend similar to that of the rectum. The correlation coefficient of POPP was significantly greater than that of COPP in < 62 Gy (82% of the prescribed dose) region for IMRT and in < 55 Gy (73% of the prescribed dose) region for VMAT regarding the rectum (p < 0.05). CONCLUSIONS: POPP is superior to COPP for creating predictive models at an intermediate-dose level. Because rectal bleeding and bladder toxicity can be associated with intermediate-doses as well as high-doses, it is important to predict dose-volume metrics for various dose levels. POPP is a useful parameter for predicting dose-volume metrics and assisting the generation of treatment plans.

Radiotherapy with or without chemotherapy for locally advanced head and neck cancer in elderly patients: analysis of the Head and Neck Cancer Registry of Japan.

BACKGROUND: Whether concurrent chemotherapy with radiotherapy (CRT) is effective for elderly patients with head and neck cancer is a controversial topic. This study aimed to analyze the effectiveness of CRT vs. radiation therapy (RT) among elderly patients in Japan. METHODS: Data from the Head and Neck Cancer Registry of Japan were extracted and analyzed. Patients with locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, or larynx who received definitive CRT or RT between 2011 and 2014 were included. RESULTS: CRT was administered to 78% of the 1057 patients aged ≥ 70 years and 67% of the 555 patients aged ≥ 75 years. For the patients aged ≥ 75 years, the overall survival (OS) rate was significantly better in the CRT group than in the RT group (P < 0.05), while the progression-free survival (PFS) rate was not significantly different (P > 0.05). The add-on effect of CRT was significantly poor in elderly patients (P < 0.05), and it was not a significant factor in the multivariate analysis for patients aged ≥ 75 years. After propensity score matching, there were no significant differences in the OS and PFS rates between the patients aged ≥ 70 years and those aged ≥ 75 years (all, P > 0.05). CONCLUSION: Although aggressive CRT is administered to elderly patients in Japan, its effectiveness is uncertain. Further prospective randomized trials are needed to verify whether CRT is superior to RT alone for elderly patients.

Usefulness of the GLIM criteria to predict recovery of activities of daily living in older adults with post-acute stroke.

OBJECTIVES: The usefulness of malnutrition diagnosed using the Global Leadership Initiative on Malnutrition (GLIM) criteria as a predictor of recovery of activities of daily living is unclear. This study aimed to investigate whether baseline malnutrition diagnosed using the GLIM criteria was predictive of recovery of activities of daily living in older patients with post-acute stroke. MATERIALS AND METHODS: A retrospective cohort study was conducted in patients aged ≥70 years with post-acute stroke. The outcome was activities of daily living measured using the motor domain of the Functional Independence Measure (FIM-motor) score at discharge. Participants were classified as malnourished or non-malnourished according to the GLIM criteria. Multivariate linear regression analyses were performed to determine whether baseline malnutrition diagnosed using the GLIM criteria was predictive of the FIM-motor score at discharge. The analysis was adjusted for clinically relevant covariates associated with rehabilitation outcomes after stroke. RESULTS: A total of 236 patients (mean age, 80.0 years; female, 54.2%) were included in the analysis. On admission, 83 (35.2%) patients were diagnosed with malnutrition. Multivariate linear regression analyses showed that malnutrition diagnosed using the GLIM criteria was predictive of the FIM-motor score at discharge (ß = -0.347, P < 0.001). CONCLUSIONS: Identifying malnutrition using the GLIM criteria is useful for predicting recovery of activities of daily living in older patients with post-acute stroke.

Deuterium Magnetic Resonance Imaging Using Deuterated Water-Induced 2H-Tissue Labeling Allows Monitoring Cancer Treatment at Clinical Field Strength.

PURPOSE: An accurate and noninvasive assessment of tumor response following treatment other than traditional anatomical imaging techniques is essential. Deuterium magnetic resonance spectroscopic (MRS) imaging has been demonstrated as an alternative for cancer metabolic imaging by high-field MRI using deuterium-labeled molecules. The study aim was to use 2H tissue labeling and deuterium MRI at clinical field strength for tumor visualization and assessment of three anticancer therapies in pancreatic cancer model mice. EXPERIMENTAL DESIGN: MIA PaCa-2 pancreatic carcinoma and C26 colorectal carcinoma models of BALB/c-nu mice was prepared, and repeated deuterium MRI was performed during the first 10 days of free drinking of 30% D2O to track 2H distribution in tissues. 2H accumulation in the tumor after irradiation, bevacizumab administration, or gemcitabine administration was also measured in MIA PaCa-2-bearing mice. Confirmatory proton MRI, ex vivo metabolic hyperpolarization 13C-MRS, and histopathology were performed. RESULTS: The mouse's whole-body distribution of 2H was visible 1 day after drinking, and the signal intensity increased daily. Although the tumor size did not change 1 and 3 days after irradiation, the amount of 2H decreased significantly. The 2H image intensity of the tumor also significantly decreased after the administration of bevacizumab or gemcitabine. Metabolic hyperpolarization 13C-MRS, proton MRI, and 2H-NMR spectroscopy confirmed the efficacy of the anticancer treatments. CONCLUSIONS: Deuterium MRI at 1.5T proved feasible to track 2H distribution throughout mouse tissues during D2O administration and revealed a higher 2H accumulation in the tumor xenografts. This research demonstrated a promising successful method for preliminary assessment of radiotherapy and chemotherapy of cancer.

Efficacy and adverse events of anthracycline and propranolol combination in five dogs with stage 3 hemangiosarcoma.

Background: Canine hemangiosarcoma (HSA), which originates from endothelial cells, is one of the most common malignant neoplasms that frequently develop metastatic lesions. Although anthracycline-based HSA treatment strategies have been widely investigated, reliable therapy for dogs with clinically advanced-stage HSA (stage 3 HSA) has not been established yet. Recently, several studies have demonstrated that propranolol, a beta-adrenergic receptor antagonist, exhibits anti-tumor effects against tumors originating from vascular endothelial cells, indicating the possibility that propranolol is a candidate adjunctive agent for anthracycline-based therapy in dogs with stage 3 HSA. This study aimed to evaluate the clinical efficacy and adverse events (AEs) of anthracycline and propranolol combination in stage 3 HSA-affected dogs. Case Description: We retrospectively investigated five dogs diagnosed with stage 3 HSA which were administered with both anthracycline and propranolol during the same period between January 2020 and August 2021. Clinical benefit was observed in four of five HSA dogs (one of complete response, one of partial response, and two of stable disease) with gross metastatic lesions by anthracycline and propranolol combination. Notably, some or all of the metastatic lesions were reduced in two cases. In all five dogs administered with anthracycline and propranolol combination, no serious and irreversible AEs were observed. Conclusion: Our findings demonstrate the efficacy and safety of anthracycline and propranolol combination in stage 3 HSA-affected dogs. Further studies are needed to establish treatment protocols based on anthracycline and propranolol combination for dogs with advanced HSA.

Therapeutic applications of local injection of hsa-miR-634 into canine spontaneous malignant melanoma tumors.

Malignant melanoma (MM) is one of the most common tumors in both dogs and humans. As canine MM (CMM) and human MM (HMM) have similar clinical characteristics, CMM appears to be a good clinical model for HMM. We previously demonstrated that the introduction of a synthetic double-strand-microRNA-634 (miR-634) mimic triggered apoptotic cell death by directly targeting the genes associated with cytoprotective processes in various human cancer cell lines, including those of HMM. This study aimed to investigate the antitumor effects of the local administration of miR-634 on spontaneous CMMs to provide a basis for future applications of miR-634 formulations in HMM treatment. We found that miR-634 administration induced apoptosis in CMM cell lines in vitro via downregulation of Asct2, Nrf2, and survivin expression, similar to the mechanisms in HMM cell lines. Furthermore, intratumoral miR-634 administration induced antitumor effects in four of seven spontaneous CMM cases, with no adverse effects. Local administration of miR-634 to lung metastasis under ultrasound guidance induced tumor shrinkage. These results confirm the antitumor effect of the local administration of miR-634 in spontaneous CMM, a model for spontaneous HMM, thereby providing a novel treatment strategy for HMM.

First Evidence of Familial Transmission of Hereditary Gastrointestinal Polyposis Associated with Germline APC Variant in Jack Russell Terriers.

Jack Russell terriers (JRTs) with gastrointestinal (GI) neoplastic polyps have been recently reported to harbor an identical germline variant in the adenomatous polyposis coli (APC) gene, c.[462_463delinsTT], in the heterozygous state, which indicates that this disease is an autosomal dominant hereditary disorder. Many individual cases of this disease have been observed in clinical practice; however, familial transmission has not been demonstrated due to the difficulty in tracing the family members of household dogs, especially after the disease's onset in adulthood. Recently, we encountered two cases of GI polyposis in maternal half sisters. These two cases facilitated the identification of additional relatives spanning three generations, including parents, full and half siblings of the dam (aunt and uncle), littermate and non-littermate siblings, and a nephew. Genetic analysis revealed that 11 of the 14 examined JRTs in this family carried the heterozygous germline APC variant, and eight dogs with the variant already had a current and/or past medical history of GI neoplastic polyps. Some cases in the family showed significantly more severe disease phenotypes than those initially reported, suggesting that the severity of this disease can vary considerably among individuals. Moreover, familial aggregation of severe cases suggested that the genetic modifier involved in increasing severity may have been transmitted in this family in addition to the germline APC variant. Furthermore, in addition to this family, we reported two other families of JRTs affected by hereditary GI polyposis that consisted of five full and half siblings and a mother-daughter pair, respectively. These findings unequivocally establish the transgenerational transmission of hereditary GI polyposis associated with the germline APC variant in JRT lineages.