UNASSIGNED: Adding stereotactic radiosurgery (SRS) to combined immune checkpoint therapy with ipilimumab and nivolumab (IPI + NIVO) has led to promising results for patients with melanoma brain metastases (MBM). This study retrospectively analyzes the toxicity profile depending on the timing of SRS with regard to IPI + NIVO.
UNASSIGNED: For this study, the clinical database was searched for all patients with MBM who were treated with SRS and IPI + NIVO. The patients were separated into three groups: group A completed IPI + NIVO (usually up to four cycles) >14 days before SRS, in group B IPI + NIVO was initiated>14 days after SRS, and group C received SRS concurrently to IPI + NIVO. Treatment related toxicity was obtained from clinical and neuroradiological records. Analyses were performed using the Fisher-Yates-test.
UNASSIGNED: 31 patients were assessed including six (19.4 %), seven (22.6 %) and 18 (58.1 %) patients, in groups A, B and C, respectively. Baseline prognostic markers between groups were balanced. In total, five (16.1 %) patients experienced neurological grade 3 toxicities related to SRS. All of these five patients were in group C, which was near-significantly correlated with a risk for grade 3 toxicities (p = 0.058). Post-hoc analyses showed that a maximum time period of seven days between SRS and IPI + NIVO was significantly correlated with grade 3 toxicity (p = 0.048).
UNASSIGNED: Application of SRS to IPI + NIVO within a seven-day span was related to higher toxicity rates in this retrospective analysis. After previous studies focused on immune checkpoint monotherapies with SRS and declared it as safe, this study indicates that concomitant application of IPI + NIVO and SRS might increase side effects. Prospective validation is warranted to corroborate these findings.

UNASSIGNED: To evaluate the feasibility of subsequent elective nodal radiotherapy (ENRT) for nodal recurrences after previous radiotherapy with a defined planning approach for a gapless radiation field junction.
UNASSIGNED: Patients with 1) previous radiotherapy of prostate or prostatic fossa and subsequent pelvic ENRT or 2) previous pelvic radiotherapy and subsequent ENRT to paraaortic lymph nodes (LN) and gapless junction of both radiation fields were analyzed. The cumulative maximum dose (Dmax-cum) and the maximum cumulative dose in 1 cc (D1cc-cum) were estimated. Absolute toxicity and the toxicity exceeding baseline were evaluated.
UNASSIGNED: Twenty-two patients with PSMA-PET/CT-staged nodal oligorecurrence after prior radiotherapy were treated with pelvic (14 patients) or paraaortic ENRT (9 patients). One patient was treated sequentially at both locations. Median time between first and second RT was 20.2 months. Median doses to the lymphatic pathways and to PET-positive LN were 47.5 Gy and 64.8 Gy, respectively. The planning constraint of an estimated Dmax-cum ≤ 95 Gy and of D1cc-cum < 90 Gy were achieved in 23/23 cases and 22/23 cases, respectively. Median follow-up was 33.5 months. There was no additional acute or late toxicity ≥ grade 3. Worst acute toxicity exceeding baseline was grade 1 in 68.2% and grade 2 in 22.7% of patients. Worst late toxicity exceeding baseline was grade 1 in 31.8% and grade 2 in 18.2% of patients.
UNASSIGNED: ENRT for nodal recurrences after a previous radiotherapy with gapless junction of radiation fields seems to be feasible, applying the dose constraints Dmax-cum ≤ 95 Gy and D1cc-cum < 90 Gy without grade 3 acute or late toxicities exceeding baseline.

A man with non-small-cell lung cancer who was negative for anti-nuclear antibodies was admitted for dyspnea after immune checkpoint inhibitor (ICI) administration. Computed tomography (CT) showed complexed radiologic features, including subpleural and basal predominant reticular shadow with cystic structures and peribronchovascular consolidation. Although we treated him with high-dose steroid under a diagnosis of ICI-related pneumonitis, he developed acute exacerbation of pneumonitis with progressive fibrosis and volume loss. A re-evaluation identified anti-aminoacyl-tRNA synthetase antibody in the serum collected before ICI administration. This case highlights the importance of re-evaluating pre-existing autoimmune disorders in patients who develop ICI-related pneumonitis with atypical radiologic features.

UNASSIGNED: The impact of stroma-targeting therapy on tumor immune suppression is largely unexplored. An RNA oligonucleotide, STNM01, has been shown to repress carbohydrate sulfotransferase 15 (CHST15) responsible for tumor proteoglycan synthesis and matrix remodeling. This phase I/IIa study aimed to evaluate the safety and efficacy of STNM01 in patients with unresectable pancreatic ductal adenocarcinoma (PDAC).
UNASSIGNED: This was an open-label, dose-escalation study of STNM01 as second-line therapy in gemcitabine plus nab-paclitaxel-refractory PDAC. A cycle comprised three 2-weekly endoscopic ultrasound-guided locoregional injections of STNM01 at doses of 250, 1,000, 2,500, or 10,000 nM in combination with S-1 (80-120 mg twice a day for 14 days every 3 weeks). The primary outcome was the incidence of dose-liming toxicity (DLT). The secondary outcomes included overall survival (OS), tumor response, changes in tumor microenvironment on immunohistopathology, and safety (jRCT2031190055).
UNASSIGNED: A total of 22 patients were enrolled, and 3 cycles were repeated at maximum; no DLT was observed. The median OS was 7.8 months. The disease control rate was 77.3%; 1 patient showed complete disappearance of visible lesions in the pancreas and tumor-draining lymph nodes. Higher tumoral CHST15 expression was associated with poor CD3+ and CD8+ T cell infiltration at baseline. STNM01 led to a significant reduction in CHST15, and increased tumor-infiltrating CD3+ and CD8+ T cells in combination with S-1 at the end of cycle 1. Higher fold increase in CD3+ T cells correlated with longer OS. There were 8 grade 3 adverse events.
UNASSIGNED: Locoregional injection of STNM01 was well tolerated in patients with unresectable PDAC as combined second-line therapy. It prolonged survival by enhancing T cell infiltration in tumor microenvironment.
UNASSIGNED: The present study was supported by the Japan Agency for Medical Research and Development (AMED).

UNASSIGNED: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States.
UNASSIGNED: This prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient\'s primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections.
UNASSIGNED: The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57-0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44-0.89]; p > 0.05; CI for difference: -0.18-0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim.
UNASSIGNED: This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone.
UNASSIGNED: was provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.

UNASSIGNED: To report the results of the Single Fraction Early Prostate Irradiation (SiFEPI) phase 2 prospective trial.
UNASSIGNED: The SiFEPI trial (NCT02104362) evaluated a single fraction of high-dose rate brachytherapy (HDB) for low- (LR) and favorable-intermediate (FIR) risk prostate cancers. After rectal spacer placement, a single fraction of 20 Gy was delivered to the prostate. Oncological outcome (biochemical (bRFS) and local (lRFS) relapses, disease-free (DFS) and overall (OS) survivals and toxicity (acute/late genito-urinary (GU), gastro-intestinal (GI) and sexual (S) toxicities were investigated.
UNASSIGNED: From 03/2014 to 10/2017, 35 pts were enrolled, of whom 33 were evaluable. With a median age of 66 y [46-79], 25 (76 %) and 8 (24 %) pts were LR and FIR respectively. With a MFU of 72.8 months [64-86], 6y-bRFS, lRFS and mRFS were 62 % [45-85], 61 % [44-85] and 93 % [85-100] respectively while 6y-DFS, CSS and OS were 54 % [37-77], 100 % and 89 % [77-100] respectively. Late GU, GI and S toxicities were observed in 11 pts (33 %;18G1), 4 pts (12 %;4G1) and 7 pts (21 %;1G1,5G2,1G3) respectively. Biochemical relapse (BR) was observed in 11 pts (33 %;7LR,4FIR) with a median time interval between HDB and BR of 51 months [24-69]. Nine of these pts (82 %) presented a histologically proven isolated local recurrence.
UNASSIGNED: Long-term results of the SiFEPI trial show that a single fraction of 20 Gy leads to sub-optimal biochemical control for LR/FIR prostate cancers. The late GU and GI toxicity profile is encouraging, leading to consideration of HDB as a safe irradiation technique.

UNASSIGNED: Systemic glucocorticoids are first-line treatment options for autoimmune blistering diseases; however, their long-term use is associated with significant toxicities.
UNASSIGNED: To evaluate the side effects of steroid-sparing agents and compare them with those of steroids.
UNASSIGNED: We searched Cochrane Reviews, Embase, MEDLINE, and Scopus between October 1978 and May 2020 using the keywords \"bullous pemphigoid,\" \"pemphigus,\" \"autoimmune blistering diseases,\" and \"side effects.\" A total of 31 randomized controlled trials and retrospective case series were critically appraised.
UNASSIGNED: This review includes a total of 1685 patients with autoimmune blistering diseases, of whom 781 had bullous pemphigoid and 904 had either pemphigus vulgaris or pemphigus foliaceous.
UNASSIGNED: A major limitation is that because adjuvants are generally used in combination with steroids, only 12 of the studies reviewed included a \"steroid-only\" arm to allow for a direct comparison of side effects. Additionally, there is inadequate literature and lack of standardized grade reporting of specific side effects of each steroid-sparing agent.
UNASSIGNED: In the future, researchers should consider implementing the Common Terminology Criteria for Adverse Events, version 5.0, for reporting of all side effects to allow for consistency and standardization. It would be useful to have an index similar to the Glucocorticoid Toxicity Index to quantify these side effects.

The past decade has witnessed a change in landscape of cancer management with the advent of precision oncology. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and have played an important role in improving patient survival. While the patients are living longer, treatment with ICIs are sometimes associated with adverse effects, some of which could be fatal. Radiologists can play a crucial role by early identification of some of these adverse effects during restaging scans. Our paper focuses on the imaging features of commonly occurring ICI toxicities based on organ system.

UNASSIGNED: Giant-cell tumor of bone (GCTB) is a relatively benign, but locally aggressive osteoclastogenic stromal tumour of the bone. Although denosumab has been approved as an monoclonal antibody against RANK ligand for the treatment of GCTB, few clinical trials of the benefit in tumor response have been conducted to prove the efficiency in Chinese population.
UNASSIGNED: In this multicentric, random controlled, clinical trial, 160 patients were enrolled to compare the therapeutic efficacy and safety of denosumab and zoledronic acid treatment in patients with surgically unsalvageable GCTB.
UNASSIGNED: Between 2nd Jan 2015 and 1st Jan 2018, 160 adults (aged ≥ 18 years) with ①surgically unsalvageable GCTB, ②surgically salvageable GCTB with planned surgery expected to result in severe morbidity were included in this randomized clinical trial. Patients received either subcutaneous denosumab (DB group; 120 mg once every 4 weeks with loading doses of 120 mg subcutaneously admininstered on days 8 and 15; n = 80) or intravenous zoledronic acid (ZA group; 4 mg once every 4 weeks; n = 80) for six cycles. Disease status, clinical benefits, treatment-emergent adverse effects, overall survival, and cost of treatment were evaluated during the follow-up period. Statistical significance was determined using 95% confidence intervals.
UNASSIGNED: Denosumab and zoledronic acid had similar tumor responses (p = 0.118) and clinical benefits (p = 0.574). Disease progression was observed in fewer patients in the DB group (12.5%) than ZA group (15.0%). Denosumab caused fatigue (p = 0.001) and back pain (p < 0.0001), while zoledronic acid caused hypocalcemia (p < 0.0001), flu-like symptoms (p = 0.059) and hypotension (p = 0.059). Denosumab treatment was markedly more expensive than zoledronic acid treatment (p < 0.0001). The cost to manage treatment-emergent adverse effects was the same for the ZA group and the DB group (p = 0.425). The accumulate recurrence-free survival rate at 4-year follow-up is higher in DB group (p = 0.035).
UNASSIGNED: Denosumab is a safe but costly alternative to zoledronic acid for treatment of surgically unsalvageable GCTB.

The use of available treatments for Fabry disease (FD) (including enzyme replacement therapy [ERT]) may be restricted by their limited symptom improvement and mode of administration. Lucerastat is currently being investigated in the MODIFY study as oral substrate reduction therapy for the treatment of FD. By reducing the net globotriaosylceramide (Gb3) load in tissues, lucerastat has disease-modifying potential to improve symptoms and delay disease progression. MODIFY is a multicenter, double-blind, randomized, placebo-controlled, parallel-group Phase 3 study (ClinicalTrial.gov: NCT03425539); here we present the rationale and design of this study. Eligible adults with a genetically confirmed diagnosis of FD and FD-specific neuropathic pain entered screening. Patients were randomized (2:1) to receive either oral lucerastat twice daily or placebo for 6 months; treatment allocation was stratified according to sex and ERT treatment status. The main objectives of MODIFY are to assess the effects of lucerastat on neuropathic pain, gastrointestinal (GI) symptoms, FD biomarkers, and determine its safety and tolerability. Neuropathic pain and GI symptoms are key features of FD that have a significant impact on quality of life. Despite various tools available to assess pain and GI symptoms, there are currently limited tools available to assess neuropathic and GI symptoms in FD, validated according to health authority guidelines. Based on FDA recommendations, we undertook a patient-reported outcome (PRO) validation study, using a novel eDiary-based PRO tool to assess the validity of evaluating neuropathic pain as a primary efficacy endpoint in MODIFY. Results from the PRO validation study are included. To date, MODIFY is the largest Phase 3 clinical study conducted in patients with FD. Enrollment to MODIFY is now complete, with 118 patients randomized. Results will be presented in a separate publication. Long-term effects of lucerastat are being assessed in the ongoing open-label extension study (NCT03737214).