Impact of neoadjuvant androgen deprivation therapy on toxicity in intensity-modulated radiation therapy for prostate cancer.

This study aimed to compare toxicities, prostate volume and dosimetry, between patients who underwent intensity-modulated radiation therapy (IMRT) combined with ≥3 months of neoadjuvant androgen deprivation therapy (NADT) and those without NADT for prostate cancer. In total, 449 patients with intermediate- and high-risk prostate cancer received 78 Gy IMRT in 39 fractions, of which 129 were treated without any ADT (non-ADT group) and 320 with NADT ≥3 months (NADT group). Adverse events and dose-volume indices were compared between the two groups retrospectively. The NADT group had a lower rate of acute grade 2 gastrointestinal (GI) toxicities (17% vs 25%, P = 0.063) and late grade 2 GI toxicities (P = 0.055), including a significantly lower rate of late grade 2 rectal hemorrhage (P = 0.033), compared with the non-ADT group. There were no cases of late grade 3 or higher GI toxicities. The average volume of the prostate in the NADT group was 38% smaller than that in the non-ADT group (43.7 vs 27.0 cm3, P < 0.001). Bladder V40Gy and V50Gy, and rectum V40Gy, V50Gy, V60Gy and V70Gy were significantly smaller in the NADT group. In the NADT group, no significant difference was observed in adverse events or dosimetry between the subgroups with NADT ≥12 and <12 months. Acute and late rectal toxicities were reduced by NADT within ≥3 months in accordance with reduced prostate volume and improved rectal dosimetry. This suggests a merit of administering neoadjuvant ADT ≥3 months for reducing rectal toxicities.

A Case of Radiation-Induced Brachial Plexopathy Below the Tolerance Dose.

This case report details a rare instance of radiation-induced brachial plexopathy (RIBP) occurring below the typical tolerance dose in a 55-year-old woman following chemoradiotherapy for apical non-small cell lung carcinoma. Despite receiving a radiation dose considered safe (47-48 Gray in 25 fractions), she developed sensory abnormalities and motor weakness in the right upper limb. The diagnostic distinction between RIBP and tumor recurrence was achieved using MRI, which showed characteristic features of radiation-induced damage. The patient's medical history included smoking and rheumatoid arthritis, highlighting the role of patient-specific factors in the development of RIBP. The case underscores the importance of recognizing RIBP as a potential diagnosis in patients with new-onset brachial plexopathy post-radiation therapy, even when radiation exposure is within conventional safety limits. This report contributes to the literature by demonstrating that RIBP can occur at lower-than-expected radiation doses, especially in the presence of contributing factors like neurotoxic chemotherapy and individual patient risks. It emphasizes the need for careful assessment and management in such cases to distinguish between RIBP and cancer recurrence.

Treatment planning comparison of high-dose-rate brachytherapy vs. robotic and conventional stereotactic body radiotherapy for ultrahypofractionated treatment of prostate cancer.

Background and purpose: Ultrahypofractionated radiation therapy is increasingly used in the treatment of prostate cancer. High-dose-rate brachytherapy (HDR-BT) and stereotactic body radiotherapy (SBRT) are representative methods of ultrahypofractionation. This study was performed to compare clinically applied treatment plans for patients who had been treated using HDR-BT vs. conventional or robotic SBRT. Materials and methods: Calculated dose-volume indices between HDR-BT without a perirectal spacer (n = 20), robotic SBRT without a spacer (n = 40), and conventional (non-robotic) SBRT with a spacer (n = 40) were compared. Percentages against the prescription dose regarding the planning target volume (PTV), bladder, rectum, and urethra were statistically compared. Results: The D50% of the PTV with HDR-BT (140.5% ± 4.9%) was significantly higher than that with robotic or conventional SBRT (116.2% ± 1.6%, 101.0% ± 0.4%, p < 0.01). The D2cm3 of the bladder with HDR-BT (65.6% ± 6.4%) was significantly lower than those with SBRT (105.3% ± 2.9%, 98.0% ± 1.3%, p < 0.01). The D2cm3 of the rectum with HDR-BT (60.6% ± 6.2%) was also significantly lower than those with SBRT (85.1% ± 8.8%, 70.4% ± 9.6%, p < 0.01). By contrast, the D0.1cm3 of the urethra with HDR-BT (117.1% ± 3.6%) was significantly higher than those with SBRT (100.2% ± 0.7%, 104.5% ± 0.6%, p < 0.01). Conclusions: HDR-BT could administer a higher dose to the PTV and a lower dose to the bladder and rectum, at the cost of a slightly higher dose to the urethra compared with SBRT.

Intensity-modulated radiation therapy for intermediate-risk prostate cancer: does ADT still have an impact in the dose-escalated external beam radiation therapy era?

BACKGROUND: This study aimed to investigate the effect of androgen deprivation therapy (ADT) on the survival of intermediate-risk prostate cancer (IR-PCA) patients treated with dose-escalated external beam radiation therapy (DE-EBRT), and to determine the group that will benefit from ADT. METHODS: We analysed 620 IR-PCA patients treated with DE-EBRT at two institutions. Variables were adjusted using the stabilised inverse probability of treatment weighting method (sIPTW) between radiation therapy (RT) and RT plus ADT groups. Biochemical relapse-free survival (bRFS) rate and overall survival (OS) rate were compared using Kaplan-Meier analysis and log-rank test. Cox proportional hazard analysis (CPH) was conducted to detect unfavorable risk factors. RESULTS: This study included 405 patients; with 217 and 188 patients in the RT and RT plus ADT groups, respectively. The prescribed radiation dose was 78 Gy in 39 fractions. The median follow-up time was 82.0 months. After sIPTW-adjustment, 214.3 and 189.7 patients were assigned to the RT and RT plus ADT groups, respectively. The 7-year bRFS and OS were 89.3% and 94.6% in RT group and 92.3% and 91.0% in RT plus ADT group, respectively. Before and after sIPTW adjustment, no statistically significant differences were found in these endpoints between treatment groups. Multivariate CPH for bRFS revealed Gleason score (GS) 4 + 3 as an unfavorable risk factor, and ADT improved biochemical control of them. CONCLUSION: ADT may not always be effective in all Japanese IR-PCA patients treated with DE-EBRT, but it can improve biochemical control in patients with GS 4 + 3.

Outcomes of intensity-modulated radiation therapy for intermediate- or high-risk prostate cancer: a single-institutional study.

BACKGROUND: There are few reports from Japan about the outcomes of intensity-modulated radiation therapy for localized prostate cancer. This study was aimed at assessing the efficacy and toxicity of intensity-modulated radiation therapy in patients with intermediate- or high-risk prostate cancer. METHODS: We conducted a review of the data, retrieved from our institutional database, of patients who had received intensity-modulated radiation therapy for localized prostate cancer at a radiation dose of 78 Gy in 39 fractions. Data of 201 patients with intermediate-risk prostate cancer and 311 patients with high-risk prostate cancer were analyzed. RESULTS: The median follow-up period after the completion of intensity-modulated radiation therapy was 100 months (range, 24-154). The rates of cause-specific survival, overall survival, metastasis-free survival and biochemical recurrence-free survival in the intermediate-risk patients were 99, 95, 95 and 94% at 5 years and 99, 91, 90 and 86% at 8 years, respectively; the corresponding rates in the high-risk patients were 100, 97, 91 and 84% at 5 years and 96, 92, 84 and 76% at 8 years, respectively. The crude incidence of late grade 2-3 genitourinary toxicity was 28.1%, and that of late grade 3 genitourinary toxicity was 2.0%. The crude incidence of late grade 2 gastrointestinal toxicity was 5.1%, and there were no cases of late grade 3 gastrointestinal toxicity. CONCLUSIONS: Our data demonstrated that intensity-modulated radiation therapy is effective for patients with localized intermediate-risk or high-risk prostate cancer while having minimal toxicity.

Comparison Between Dose-Escalated Intensity Modulated Radiation Therapy and 3-Dimensional Conformal Radiation Therapy for Salvage Radiation Therapy After Prostatectomy.

PURPOSE: To compare long-term outcomes and late toxicity between patients treated with 3-dimensional conformal radiation therapy (3D-CRT) and with dose-escalated intensity modulated radiation therapy (IMRT) as salvage radiation therapy (SRT) after prostatectomy. METHODS AND MATERIALS: A total of 110 patients who had been treated at our institution between 2010 and 2018 with SRT for biochemical recurrence after radical prostatectomy were included. The patients were treated either by 3D-CRT with 64 Gy (59 patients) or by IMRT with 70 Gy (51 patients). The irradiation target was the prostate bed only (106 patients) or the prostate bed and pelvic region (4 patients). Twelve patients (11%) received concurrent androgen deprivation therapy. The differences in clinical outcomes and late gastrointestinal (GI) and genitourinary (GU) toxicity between the 3D-CRT and IMRT groups were retrospectively assessed. Toxicities were recorded using the Common Terminology Criteria for Adverse Events, version 5.0. Prostate-specific antigen (PSA) progression after SRT was defined as an increase in the serum PSA level of 0.2 ng/mL from the PSA nadir after SRT and confirmed by a second PSA measurement that was higher than the first. RESULTS: The median follow-up time was 7.8 years for 3D-CRT (range:,0.3-9.2 years) and 3.1 years for IMRT (range, 0.4-7.2 years). There was no significant difference in the 4-year biochemical no-evidence-of-disease (bNED) rate between the 3D-CRT and IMRT groups (43.5% vs 52.1%; P = .20). Toxicity analysis showed no significant difference in late GI or GU toxicities of grade 2 or greater between the 3D-CRT and IMRT groups. The respective 4-year cumulative rates of toxicity in the 3D-CRT and IMRT groups were as follows: grade ≥2 GI toxicity, 8.8% and 4.4% (P = .42); grade ≥2 GU toxicity, 19.1% and 20.3% (P = .93); and grade ≥2 hematuria, 5.3% and 8.0% (P = .67). In the 3D-CRT group, the 8-year cumulative rates of GI toxicity, GU toxicity, and hematuria of grade 2 or greater were 8.8%, 28.4%, and 12.6%, respectively. CONCLUSIONS: Dose-escalated IMRT showed no improvements in bNED or late toxicity compared with 3D-CRT. In addition, the results suggest that GU toxicity can occur after a long period (even after 6 years), whereas GI toxicity is seldom newly observed after 4 years.

Single axonal morphology reveals high heterogeneity in spinocerebellar axons originating from the lumbar spinal cord in the mouse.

Among the spinocerebellar projections vital for sensorimotor coordination of limbs and the trunk, the morphology of spinocerebellar axons originating from the lumbar cord has not been well characterized compared to those from thoracic and sacral cords. We reconstructed 26 single spinocerebellar axons labeled by biotinylated dextran injections into the gray matter of the lumbar spinal cord in mice. Axon terminals were mapped with the zebrin pattern of the cerebellar cortex. Reconstructed axons were primarily classified into ipsilaterally and contralaterally ascending axons, arising mainly from the dorsal and ventral horns, respectively. The majority of ipsilateral and contralateral axons took the dorsal-medullary and ventral-pontine pathways, respectively. The axons of both groups terminated mainly in the vermal and medial paravermal areas of lobules II-V and VIII-IXa, often bilaterally but predominantly ipsilateral to the axonal origin, with a weak preference to particular portions of zebrin stripes. The ipsilateral axons originating from the medial dorsal horn in the upper lumbar cord (n = 3) had abundant (43-147) mossy fiber terminals and no medullary collaterals. The ipsilateral axons originating from the lateral dorsal horn in the lower lumbar cord (n = 9) and the contralateral axons (n = 14) showed remarkable morphology variations. The number of their mossy fiber terminals varied from 2 to 172. Their collaterals, observed in 17 axons out of 23, terminated mainly in the medial cerebellar nucleus, nucleus X, and lateral reticular nucleus in various degrees. The results indicated that the lumbar spinocerebellar projection contains highly heterogeneous axonal populations regarding their pathway, branching, and termination patterns.

Comparison of Physician-recorded Toxicities and Patient-reported Outcomes of Five Different Radiotherapy Methods for Prostate Cancer.

BACKGROUND/AIM: To compare five radiotherapy methods for prostate cancer. PATIENTS AND METHODS: During 2005-2018, the data of patients with non-metastatic prostate cancer were retrospectively analysed. Patients were treated with high-dose-rate brachytherapy (HDR-BT); low-dose-rate brachytherapy (LDR-BT); or external-beam radiotherapy (EBRT), including conventionally fractionated radiotherapy (CFRT), moderate-hypofractionated radiotherapy (MHRT), and ultra-hypofractionated radiotherapy (UHRT). RESULTS: In total, 496 patients (149, HDR-BT; 100, LDR-BT; 100, CFRT; 97, MHRT, and 50, UHRT) with a median follow-up of 4.3 years were enrolled. The incidence of grade ≥2 acute genitourinary toxicities was significantly lower with HDR-BT (p<0.001) than with any other radiotherapy. The cumulative incidence of late grade ≥2 genitourinary toxicities was the highest with UHRT and significantly higher (p=0.005) with UHRT than with HDR-BT. Higher symptom score peaks were noted 4 weeks after therapy for LDR-BT than for EBRT. CONCLUSION: Physician-recorded toxicities were slightly lower with HDR-BT and patient-reported outcomes tended to be worse with LDR-BT.

Outcomes after reirradiation of spinal metastasis with stereotactic body radiation therapy (SBRT): a retrospective single institutional study.

This study was aimed at assessing the feasibility and toxicity of using stereotactic body radiation therapy (SBRT) for reirradiation of spinal metastatic tumors. We conducted a retrospective review, from our institutional database, of the data of patients who received reirradiation, with overlap of some prescribed isodose lines to the vertebra from the initial radiation therapy, between 2007 and 2019. We identified 40 patients with spinal metastatic tumors, of whom 2 had 2 metastatic vertebral lesions each, totaling up to 42 target lesions. The median dose to spinal cord at the initial radiation therapy was 30 Gy. SBRT based on the intensity-modulated radiation therapy (IMRT) technique was used for reirradiation to spare the spinal cord. All patients received a prescription dose of 25 Gy in 5 fractions to the planning target volume (PTV). Among the 40 cases who had pain, pain relief was obtained in 24 (60%) after reirradiation. Neurologic improvement was obtained in 8 of 15 cases (53%). The adverse events were evaluated using the Common Terminology Criteria for Adverse Events Version 5.0. Reirradiation was well-tolerated, with only 2 patients experiencing adverse events ≥grade 2 in severity, including 1 patient with grade 3 pain, and another patient with grade 3 spinal fracture. None of the patients developed radiation myelopathy. Our data demonstrated that reirradiation of spinal metastasis using SBRT provided effective pain relief and neurologic improvement, with minimal toxicity.

Dense projection of Stilling's nucleus spinocerebellar axons that convey tail proprioception to the midline area in lobule VIII of the mouse cerebellum.

The cerebellar cortex has dual somatotopic representation, broadly in the anterior lobules and narrowly in the posterior lobules. However, the somatotopy has not been well understood in vermal lobule VIII, located in the center of the posterior representation. Here, we examined the axonal projections and somatosensory representation of the midline area of vermal lobule VIII in mice, using the striped zebrin expression pattern as a landmark of intra-lobular compartmentalization. Retrograde tracer injection into this area (zebrin stripes 1+ and 1- in lobule VIII) labeled neuronal clusters, bilaterally, in the pericanal gray matter (Stilling's nucleus) in the sacral spinal cord. Spinocerebellar axons labeled by biotinylated dextran amine injection into the sacral pericanal gray matter terminated bilaterally in stripes 1+ and 1- in lobule VIII, with more than 70 terminals per axon, and the vermal stripes in lobules II-III. Dorsal flexion of the tail and electrical stimulation of the sacral spinal gray matter elicited the firing of mossy fiber terminals in stripes 1+ and 1- in lobule VIII. Anterograde labeling of Purkinje cell axons in this area showed terminals in the medial pole of the medial cerebellar nucleus. Lesioning of this area impaired locomotor performance in the rotarod test. These results demonstrated that stripes 1+ and 1- in lobule VIII receive tail proprioceptive sensation from the Stilling's nucleus as their predominant mossy fiber input. The results also suggest that locomotion-related activity is represented not only in the anterior lobule, but also in lobule VIII in the cerebellar vermis.

Single axonal morphology and termination to cerebellar aldolase C stripes characterize distinct spinocerebellar projection systems originating from the thoracic spinal cord in the mouse.

The spinocerebellar projection has an essential role in sensorimotor coordination of limbs and the trunk. Multiple groups of spinocerebellar projections have been identified in retrograde labeling studies. In this study, we aimed at characterizing projection patterns of these groups using a combination of anterograde labeling of the thoracic spinal cord and aldolase C immunostaining of longitudinal stripes of the cerebellar cortex in the mouse. We reconstructed 22 single spinocerebellar axons, wholly in the cerebellum and brain stem and partly, in the spinal cord. They were classified into three groups, (a) non-crossed axons of Clarke's column neurons (NCC, 8 axons), (b) non-crossed axons of marginal Clarke's column neurons (NMCC, 7 axons), and (c) crossed axons of neurons in the medial ventral horn (CMVH, 7 axons), based on previous retrograde labeling studies. While NCC axons projected mainly to multiple bilateral stripes in vermal lobules II-IV and VIII-IX, and the ipsilateral medial cerebellar nucleus, NMCC axons projected mainly to ipsilateral stripes in paravermal lobules II-V and copula pyramidis, and the anterior interposed nucleus. CMVH axons projected bilaterally to multiple stripes in lobules II-V with a small number of terminals but had abundant collaterals in the spinal cord and medullary reticular nuclei as well as in the vestibular and cerebellar nuclei. The results indicate that, while CMVH axons overlap with propriospinal and spinoreticular projections, NCC and NMCC axons are primarily spinocerebellar axons, which seem to be involved in relatively more proximal and distal sensorimotor controls, respectively.

Morphology of the olivocerebellar projection of the chick: an axonal reconstruction study.

The projection pattern of the olivocerebellar (OC) axons, which terminate mainly as climbing fibers (CFs) in the cerebellar cortex, tightly reflects the compartmental and developmental organization of the cerebellum as revealed by mapping and reconstruction studies in the rat. The avian cerebellum is well lobulated and longitudinally compartmentalized like the mammalian cerebellum. However, the projection pattern of the OC axons has not been studied in detail for most areas of the avian cerebellum. In the present study, we reconstructed labeled chick OC axons resulting from a small focal injection of biotinylated dextran amine into the inferior olive to investigate their morphological characteristics, and to determine their relationship to the general morphology of the chick cerebellum. Labeled CFs were distributed basically in a single longitudinally elongated narrow band-shaped area in lobules I-VIII, but in multiple, transversely widened, band-shaped areas in lobules IX-X. Three of the four reconstructed OC axons terminated in a single longitudinally band-shaped area in lobules IXa-c, whereas the other one terminated in multiple mediolaterally separated areas in lobule IXc, which is part of the flocculus. Single OC axons branched into 14 CFs on average. Two CFs occasionally merged to form a single terminal arbor. Axons also had thin, non-CF collaterals that projected either to a cerebellar nucleus or to the cortex. The results indicate that the morphological characteristics of OC axons, including branching and termination, are basically conserved between the chick and the rat.