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The occurrence, second-line management and outcome of sr/sd-irAEs was investigated in patients with skin cancer. All skin cancer patients treated with immune checkpoint inhibitors (ICIs) between 2013 and 2021 at a tertiary care center were analyzed retrospectively. Adverse events were coded by CTCAE version 5.0. The course and frequency of irAEs were summarized using descriptive statistics. A total of 406 patients were included in the study. In 44.6% (n = 181) of patients, 229 irAEs were documented. Out of those, 146 irAEs (63.8%) were treated with systemic steroids. Sr-irAEs and sd-irAEs (n = 25) were detected in 10.9% of all irAEs, and in 6.2% of ICI-treated patients. In this cohort, infliximab (48%) and mycophenolate mofetil (28%) were most often administered as second-line immunosuppressants. The type of irAE was the most important factor associated with the choice of second-line immunosuppression. The Sd/sr-irAEs resolved in 60% of cases, had permanent sequelae in 28% of cases, and required third-line therapy in 12%. None of the irAEs were fatal. Although these side effects manifest in only 6.2% of patients under ICI therapy, they impose difficult therapy decisions, especially since there are few data to determine the optimal second-line immunosuppression.

Graft‐versus‐host disease (GVHD) is a complication of allogeneic haematopoietic cell transplantation. Endothelial injury is crucial as pathophysiological substrate for GVHD. GVHD first‐line treatment is high‐dose corticosteroids, although some patients are steroid‐refractory. Through the present study, we compared the endothelial proteomic profiles in response to serum from steroid‐refractory acute GVHD (SR‐aGVHD) and steroid‐sensitive acute GVHD (SS‐aGVHD) patients. Blood samples from SR‐aGVHD (n = 4) and SS‐aGVHD (n = 8) patients were collected at aGVHD diagnosis. Endothelial cell cultures were exposed (48 h) to patients' serum. Protein extraction and proteomic analysis were performed. Differences were statistically evaluated by multivariate analysis. Forty‐four proteins contributed to separate all samples into the two study groups, among which 15 participated significantly (p < 0.05), 10 exhibiting a fold change >1.2. Differentially expressed proteins were mainly associated with oxidative phosphorylation (Cytochrome C oxidase subunit 6B1, CX6B1), inflammation and angiogenesis (Apolipoprotein D, APOD), cell survival (Rapamycin‐insensitive companion of mTOR, RICTR), and oxidative stress (Riboflavin kinase, RIFK). This pilot study used a novel approach to distinguish the aGVHD response to steroid treatment. The proteins differentially expressed could constitute potential biomarkers for steroid‐treatment response. These findings signify a step forward to identify the mechanisms of response to steroids, of high clinical relevance considering the SR‐aGVHD elevated mortality.

We report a 67‐year‐old man with a relapse characterised by fever, respiratory failure and bilateral infiltrates following completion of a short‐term empirical methylprednisolone regimen for a similar episode. Serum, upper respiratory tract and bronchoalveolar lavage samples were negative for infection, whereas an extensive antibody panel showed no remarkable findings. The presence of migratory opacities on chest imaging, a mixed cellular lavage pattern and prior steroid responsiveness supported a provisional diagnosis of cryptogenic organising pneumonia. During outpatient follow‐up, frequent exacerbations occurred, barring any steroid tapering attempts. An individualised pathophysiological hypothesis is proposed for the recalcitrant course following incidental detection of mannose‐binding lectin deficiency. Given the potential role of mannose binding lectin in apoptotic cell clearance and modulation of inflammation, we postulate an impingement on the disease trajectory, which has been previously observed in chronic obstructive pulmonary disease, bronchiectasis and bronchiolitis obliterans post‐transplant.

Steroid‐refractory immune‐related pneumonitis is a clinical challenge with limited evidence‐based treatment strategies. Current guidelines recommend the use of immunosuppressants; however, the optimal type and dosage of these agents remain unclear. Herein, we report a case of steroid‐refractory immune‐related pneumonitis that was successfully treated with mycophenolate mofetil (MMF). The patient did not respond to high‐dose steroid therapy as initial treatment but showed significant improvement in both subjective symptoms and imaging findings after the additional administration of MMF. Subsequent tapering of the MMF dose led to worsening imaging findings, which improved upon re‐escalation of the MMF dose. This case highlights the potential efficacy of MMF for the treatment of steroid‐refractory immune‐related pneumonitis and provides valuable insights into the administration of MMF and its potential role in managing similar cases. Herein, we report the case of an 82‐year‐old male with pleural mesothelioma who developed steroid‐refractory immune‐related pneumonitis after treatment with ipilimumab and nivolumab, which was successfully managed by mycophenolate mofetil treatment.

Cyclosporine is considered a safe and effective treatment of severe steroid-refractory ulcerative colitis (UC). However, few data are available concerning its safety profile in pregnant women. We report here the experience of 5 GETAID centers.MethodsIn a retrospective study data on patients with severe UC treated with cyclosporine during pregnancy were extracted from medical records of consecutive patients treated between 2001 and 2007.ResultsEight patients (median age 30.5 years old) were identified. At the time of flare-up the median duration of pregnancy was 11.5 weeks of gestation (range 4–25). Seven patients had pancolitis. All patients had more than 3 commonly used clinical and biological severity criteria. Three patients had severe endoscopic lesions and 5 patients had not. All patients received intravenous corticosteroids for at least 7 days before introduction of cyclosporine. Two patients received azathioprine during treatment with cyclosporine. No severe infections or other complications due to treatment were observed. Treatment was effective in 7/8 patients. One patient received infliximab due to cyclosporine therapy failure with a good outcome. No colectomy was performed during pregnancy. Seven pregnancies were conducted to term, but 1 in utero death occurred due to maternal absence of S-protein. Two newborns were premature, including 1 case of hypotrophy. No malformations were observed.ConclusionsIn our experience, treatment with cyclosporine for steroid-refractory UC during pregnancy can be considered safe and effective.

SummaryWe report the experience of 11 patients (of 60 planned patients) enrolled in a double-blind, placebo-controlled clinical trial of infliximab in patients with severe, active steroid-refractory ulcerative colitis. The study was terminated prematurely because of slow enrollment. Patients having active disease for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids were eligible to receive a single intravenous infusion of infliximab at 5, 10, or 20 mg/kg body weight. The primary endpoint used in this study was treatment failure at 2 weeks after infusion. Treatment failure was defined as 1) unachieved clinical response as defined by a modified Truelove and Witts severity score, 2) increase in corticosteroid dosage, 3) addition of immunosuppressants, 4) colectomy, or 5) death. Safety evaluations included physical examination, clinical chemistry and hematology laboratory tests, and occurrence of adverse experiences. Four of 8 patients (50%) who received infliximab were considered treatment successes at 2 weeks, compared with none of 3 patients who received placebo. Improvement in erythrocyte sedimentation rates and serum concentrations of C-reactive protein and interleukin-6 correlated with the clinical response observed in patients receiving infliximab. Infusion with infliximab produced no significant adverse events. Infliximab was well tolerated and may provide clinical benefit for some patients with steroid-refractory ulcerative colitis.

At Saitama Medical Center, for remission induction in active ulcerative colitis (UC) patients with endoscopic evidence of severe disease, we tend to preferentially use tacrolimus (TAC) over anti-tumor necrosis factor (TNF)-α agents. We conducted this study to evaluate the validity of our therapeutic strategies. This retrospective study was conducted in 52 steroid-refractory active UC patients with a Clinical Activity Index (CAI) score of ≥7 who were receiving remission induction therapy with TAC or anti-TNF-α agents. The patients were divided into a TAC treatment group (TAC group, n = 29) and an anti-TNF-α agent treatment group (anti-TNF group, n = 23). The CAI, Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and incidence of events (relapse, hospitalization and surgery) were retrospectively analyzed. At treatment initiation, the CAI score was 12.6 in the TAC group and 11.5 in the anti-TNF group ( = 0.09), while the corresponding values of the UCEIS were 6.5 and 5.1, respectively ( = 0.0035). The clinical remission rate at 12 weeks was 55% (65% when only the subgroup that received rapid induction therapy was included in the analysis) in the TAC group and 57% in the anti-TNF group, with no significant difference. The cumulative event-free rates at 1, 6 and 12 months were 65.5%, 39.4%, and 39.4%, respectively, in the TAC group and 95.7%, 77.2% and 71.7%, respectively, in the anti-TNF group ( = 0.0037). Rapid induction therapy with TAC tended to be selected for active UC patients with endoscopic evidence of severe disease, and the present study supported the validity of this therapeutic approach. However, transition to the remission-maintenance phase was more favorable in the anti-TNF group.

IntroductionSteroid-refractory (SR) hepatic acute graft-versus-host disease (aGVHD) remains a life-threatening complication following allogeneic hematopoietic stem cell transplantation, characterized by limited responsiveness to both first- and second-line therapies and an overall poor prognosis. This study aimed to evaluate the efficacy and safety of cyclophosphamide (CTX) as a salvage treatment for SR- hepatic aGVHD.MethodsA total of 50 patients with SR-hepatic aGVHD who underwent CTX treatment were retrospectively included in the analysis. Seventeen patients (34.0%) received CTX as second-line therapy, whereas the majority (n=33, 66.0%) were administered CTX as salvage therapy following failure of prior second-line interventions.ResultsThe overall response rate (ORR) at day 28 was 70.0%, with a durable ORR of 66.0% at day 56. Patients with the hepatitic variant of aGVHD showed a superior response compared to those with the classic variant (complete response: 6 of 8 [75.0%] vs. 14 of 42 [33.3%], P = 0.042). The probabilities of overall survival (OS) and nonrelapse mortality (NRM) at 3 years after CTX treatment were 36.9% (95% CI, 24.8%–54.9%) and 56.5% (95% CI, 41.4%–71.6%). Using propensity score matching (PSM), we compared 35 patients receiving CTX with 35 BAT (best available treatment) controls during the same study period. CTX initiation occurred later than BAT (median line: 3 vs 2, P < 0.001). Response rates and survival outcomes were comparable between two groups and CTX demonstrated consistent efficacy even when used as later-line therapy. Additionally, CTX did not significantly increase the risk of adverse events compared to the BAT group up to day 28. The most common adverse events in both groups were neutropenia (71.4% in the CTX group vs. 62.9% in the BAT group, P = 0.445), anemia (68.6% vs. 60.0%, P = 0.454), and cytomegalovirus infection (51.4% vs. 45.7%, P = 0.632).DiscussionThese findings suggest that CTX is a promising and well-tolerated treatment option for patients with SR-hepatic aGVHD.

Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer care with incredible reductions in mortality. One of the most devastating complications of treatment is ICI-related pneumonitis (ICI-p). Despite this, little is known regarding risk factors for severe pneumonitis and treatment effectiveness of various therapeutic options for steroid-refractory disease. To address this, we conducted a retrospective study on patients with cancer who developed ICI-p. Methods We examined consecutive patients who received ICIs and developed ICI-p. Risk factors of interest for severe disease and steroid-refractory ICI-p, including pre-treatment pulmonary function tests (PFTs) and chest imaging, were compared between patients with severe (grades 3-5) and mild (grades 1-2) pneumonitis. The clinical and treatment courses for patients with steroid-refractory ICI-p were recorded. Results A total of 132 patients developed ICI-p, with 60 patients having mild and 72 with severe disease. We found that lower forced vital capacity percent predicted (66.24 vs 85.05, P = .05), lower total lung capacity percent predicted (85.23 vs 99.71, P = .13), and specific radiographic patterns on pre-treatment chest imaging were predictors of severe disease. Initial corticosteroid dose of less than 1 milligram per kilogram prednisone equivalent (P = .14) was correlated with partially steroid-responsive or steroid-refractory ICI-p. Ten patients had steroid refractory ICI-p, and those who received IVIG alone as the immune suppressant beyond corticosteroids had improved survival (P = 05). Conclusions We are the first to identify pre-treatment PFTs and chest imaging abnormalities as risk factors for severe ICI-p. We also found that lower corticosteroid doses were associated with partially steroid-responsive and steroid-refractory ICI-p. Larger, prospective studies are needed to validate our results. Little is known about risk factors for severe pneumonitis and the treatment effectiveness of various therapeutic options for steroid-refractory disease. This retrospective study focused on cancer patients who developed immune checkpoint inhibitor treatment-related pneumonitis.

Ruxolitinib is an important treatment for steroid refractory graft-versus-host disease (SR-GVHD). Therefore, we reported the updated results of a systematic review and meta-analysis of ruxolitinib as treatment for SR-GVHD. In addition, we wanted to compare the efficacy and safety between children and adults with SR-GVHD. Overall response rate (ORR) after ruxolitinib treatment was chosen as the primary end point. Complete response rate (CRR), infection, myelosuppression, and overall survival (OS) were chosen as secondary end points. A total of 37 studies were included in this meta-analysis, and 1,580 patients were enrolled. ORR at any time after ruxolitinib treatment was 0.77 [95% confidence interval (CI): 0.68–0.84] and 0.78 (95% CI: 0.74–0.81), respectively, for SR-aGVHD and SR-cGVHD. CRR at any time after ruxolitinib treatment was 0.49 (95% CI: 0.40–0.57) and 0.15 (95% CI: 0.10–0.23), respectively, for SR-aGVHD and SR-cGVHD. The ORRs at any time after treatment was highest in mouth SR-cGVHD, followed by skin, gut, joints and fascia, liver, eyes, esophagus, and lung SR-cGVHD. The incidence rate of infections after ruxolitinib treatment was 0.61 (95% CI: 0.45–0.76) and 0.47 (95% CI: 0.31–0.63), respectively, for SR-aGVHD and SR-cGVHD. The incidence rates of overall (grades I–IV) and severe (grades III–IV) cytopenia were 53.2% (95% CI: 16.0%–90.4%) and 31.0% (95% CI: 0.0–100.0%), respectively, for SR-aGVHD, and were 28.8% (95% CI:13.0%–44.6%) and 10.4% (95% CI: 0.0–27.9%), respectively, for SR-cGVHD. The probability rate of OS at 6 months after treatment was 63.9% (95% CI: 52.5%–75.2%) for SR-aGVHD. The probability rates of OS at 6 months, 1 year, and 2 years after treatment were 95% (95% CI: 79.5%–100.0%), 78.7% (95% CI: 67.2%–90.1%), and 75.3% (95% CI: 68.0%–82.7%), respectively, for SR-cGVHD. The ORR, CRR, infection events, and myelosuppression were all comparable between children and adults with SR-GVHD. In summary, this study suggests that ruxolitinib is an effective and safe treatment for SR-GVHD, and both children and adults with SR-GVHD could benefit from ruxolitinib treatment.