The Rad51 paralog complex Rad55-Rad57 acts as a molecular chaperone during homologous recombination.

Homologous recombination (HR) is essential for maintenance of genome integrity. Rad51 paralogs fulfill a conserved but undefined role in HR, and their mutations are associated with increased cancer risk in humans. Here, we use single-molecule imaging to reveal that the Saccharomyces cerevisiae Rad51 paralog complex Rad55-Rad57 promotes assembly of Rad51 recombinase filament through transient interactions, providing evidence that it acts like a classical molecular chaperone. Srs2 is an ATP-dependent anti-recombinase that downregulates HR by actively dismantling Rad51 filaments. Contrary to the current model, we find that Rad55-Rad57 does not physically block the movement of Srs2. Instead, Rad55-Rad57 promotes rapid re-assembly of Rad51 filaments after their disruption by Srs2. Our findings support a model in which Rad51 is in flux between free and single-stranded DNA (ssDNA)-bound states, the rate of which is controlled dynamically though the opposing actions of Rad55-Rad57 and Srs2.

Are 6 more accurate than 4? The influence of different modes of delivery on postpartum depression and PTSD.

BACKGROUND: Empirical evidence shows that 4.6-6.3% of all women develop a post-traumatic stress disorder (PTSD) and approximately 10-15% postpartum depression (PPD) following childbirth. This study explores the relationship between delivery mode and the occurrence of PTSD and PPD, specifically examining four distinct caesarean section (CS) modes: primary on maternal request (Grade 4), medically indicated primary (Grade 3), secondary CS from relative indication (Grade 2) and emergency secondary CS (Grade 1), compared to vaginal and assisted vaginal delivery (AVD). The research aims to understand how these six subcategories of delivery modes impact PPD and PTSD levels. Common predictors, including the need for psychological treatment before childbirth, fear of childbirth, planning of pregnancy, induction of labor, birth debriefing, and lack of social support after childbirth, will be analyzed to determine their association with postpartum mental health outcomes. METHODS: The study was planned and carried out by a research team of the psychology department at the Medical School Hamburg, Germany. Within an online-study (cross-sectional design) N = 1223 German speaking women with a baby who did not die before, during or after birth were surveyed once between four weeks and twelve months postpartum via an anonymous online questionnaire on demographic and gynecological data, delivery mode, PTSD (PCL-5) and PPD (EPDS). RESULTS: For both psychiatric disorders, ANOVA revealed significant differences between delivery mode and PPD and PTSD. With weak effects for PPD and medium to strong effects for PTSD. Post-hoc tests showed increased levels of PPD for two CS types (Grade 1, Grade 3) compared to vaginal delivery. For PTSD, secondary CS from relative indication (Grade 2), emergency secondary CS (Grade 1) and assisted vaginal delivery (AVD) were associated with elevated levels of PTSD. Regression analysis revealed delivery mode as a significant predictor of EPDS- (medium effect size) and PCL-5-Score (medium to high effect size). LIMITATION: Delivery was considered as the potential traumatic event, and any previous traumas were not documented. Additionally, the categorization of delivery modes relied on subjective reports rather than medical confirmation. CONCLUSION: The study highlights the influence of delivery mode on the mental health of postpartum mothers: different modes influence postpartum disorders in various ways. However, the definition of delivery mode was only stated subjectively and not medically confirmed. Further research should investigate which aspects of the different delivery modes affect maternal mental health and explore how the perception of childbirth may be influenced by specific delivery experiences.

The soluble form of CD160 acts as a tumor mediator of immune escape in melanoma.

Melanoma is responsible for 90% of skin cancer-related deaths. Major therapeutic advances have led to a considerable improvement in the prognosis of patients, with the development of targeted therapies (BRAF or MEK inhibitors) and immunotherapy (anti-CTLA-4 or -PD-1 antibodies). However, the tumor constitutes an immunosuppressive microenvironment that prevents the therapeutic efficacy and/or promotes the development of secondary resistances. CD160 is an activating NK-cell receptor initially described as delineating the NK and CD8+ T-cell cytotoxic populations. Three forms of CD160 have been described: (1) the GPI isoform, constitutively expressed and involved in the initiation of NK-cells' cytotoxic activity, (2) the transmembrane isoform, neo-synthesized upon cell activation, allowing the amplification of NK cells' cytotoxic functions and (3) the soluble form, generated after cleavage of the GPI isoform, which presents an immuno-suppressive activity. By performing immunohistochemistry analyses, we observed a strong expression of CD160 at the primary cutaneous tumor site of melanoma patients. We further demonstrated that melanoma cells express CD160-GPI isoform and constitutively release the soluble form (sCD160) into the tumor environment. sCD160 was shown to inhibit the cytotoxic activity of NK-cells towards their target cells. In addition, it was found in the serum of melanoma patients and associated with increased tumor dissemination. Altogether these results support a role for sCD160 in the mechanisms leading to the inhibition of anti-tumor response and immune surveillance in melanoma.

Occurrence of type 1 and type 2 diabetes in patients treated with immunotherapy (anti-PD-1 and/or anti-CTLA-4) for metastatic melanoma: a retrospective study.

Anti-PD-1 and anti-CTLA-4 antibodies cause immune-related side effects such as autoimmune type 1 diabetes (T1D). It has also been suggested that by increasing TNF-α, IL-2 and IFN-γ production, anti-PD-1 and/or anti-CTLA-4 treatment could affect pancreatic beta cell function and insulin sensitivity. This study was based on a retrospective observational analysis from 2 July 2014 to 27 June 2016, which evaluated the occurrence of T1D and changes in glycemia and C-reactive protein (CRP) plasma concentrations in patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma at the Saint Louis Hospital. All cases of T1D that developed during immunotherapy registered in the French Pharmacovigilance Database (FPVD) were also considered. Among the 132 patients included, 3 cases of T1D occurred. For the remaining subjects, blood glucose was not significantly affected by anti-PD-1 treatment, but CRP levels (mg/l) significantly increased during anti-PD-1 treatment (p = 0.017). However, 1 case of type 2 diabetes (T2D) occurred (associated with a longer therapy duration). Moreover, glycemia of patients pretreated (n = 44) or concomitantly treated (n = 8) with anti-CTLA-4 tended to increase during anti-PD-1 therapy (p = 0.068). From the FPVD, we obtained 14 cases of T1D that occurred during immunotherapy and were primarily characterized by the rapidity and severity of onset. In conclusion, in addition to inducing this rare immune-related diabetes condition, anti-PD-1 treatment appears to increase CRP levels, a potential inflammatory trigger of insulin resistance, but without any short-term impact on blood glucose level.

Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review.

Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect.

Genetic reporters to detect and quantify homologous recombination in yeast.

Homologous recombination is a conserved process that cells use to repair damaged DNA. Many genetic assays have been developed in Saccharomyces cerevisiae to measure and characterize different types of recombination events, as well as identify proteins acting in such recombination events. Here, we describe two intrachromosomal reporters that utilize ade2 heteroalleles, whereby homologous recombination can be detected by colony color and adenine prototrophy. We detail the use of these reporters to measure recombination frequency, as well as to characterize the types of recombination events.

The separation pin distinguishes the pro- and anti-recombinogenic functions of Saccharomyces cerevisiae Srs2.

Srs2 is an Sf1a helicase that helps maintain genome stability in Saccharomyces cerevisiae through its ability to regulate homologous recombination. Srs2 downregulates HR by stripping Rad51 from single-stranded DNA, and Srs2 is also thought to promote synthesis-dependent strand annealing by unwinding D-loops. However, it has not been possible to evaluate the relative contributions of these two distinct activities to any aspect of recombination. Here, we used a structure-based approach to design an Srs2 separation-of-function mutant that can dismantle Rad51-ssDNA filaments but is incapable of disrupting D-loops, allowing us to assess the relative contributions of these pro- and anti-recombinogenic functions. We show that this separation-of-function mutant phenocopies wild-type SRS2 in vivo, suggesting that the ability of Srs2 to remove Rad51 from ssDNA is its primary role during HR.

Mechanism for inverted-repeat recombination induced by a replication fork barrier.

Replication stress and abundant repetitive sequences have emerged as primary conditions underlying genomic instability in eukaryotes. To gain insight into the mechanism of recombination between repeated sequences in the context of replication stress, we used a prokaryotic Tus/Ter barrier designed to induce transient replication fork stalling near inverted repeats in the budding yeast genome. Our study reveals that the replication fork block stimulates a unique recombination pathway dependent on Rad51 strand invasion and Rad52-Rad59 strand annealing activities, Mph1/Rad5 fork remodelers, Mre11/Exo1/Dna2 resection machineries, Rad1-Rad10 nuclease and DNA polymerase δ. Furthermore, we show recombination at stalled replication forks is limited by the Srs2 helicase and Mus81-Mms4/Yen1 nucleases. Physical analysis of the replication-associated recombinants revealed that half are associated with an inversion of sequence between the repeats. Based on our extensive genetic characterization, we propose a model for recombination of closely linked repeats that can robustly generate chromosome rearrangements.

Failure of Initial Curative Treatment for Non-Metastatic Anal Squamous Cell Carcinoma: From Prognostic Factors Analysis to Stratified Treatment.

In squamous cell anal canal neoplasms, persistent disease or recurrence after initial chemoradiotherapy are not the rule, yet their occurrence deserves to be analyzed to better identify prognostics factors. The aim of our study was to describe the patterns of failures of the initial treatment, their subsequent evolution and to identify prognostic factors in these relapsed patients. All patients with non-metastatic anal squamous cell carcinoma initially treated with curative intent at the Centre Antoine Lacassagne between 1999 and 2019, and who presented persistent disease or recurrence were analyzed. The median follow-up was 44 months. Univariate and multivariate analyses were performed to identify prognostic factors. From our database of 528 patients, 77 patients were eligible: 25 with persistent disease and 52 with recurrence after complete response. The median overall survival was 39 months (95% CI: 25.5-52.3 months) from the date of treatment failure. In univariate analysis, prognostic factors were gender, initial lymph node status, type of failure, response to treatment's failure. In multivariate analysis, only female gender remained statistically significant (HR 0.43- P=0.016). 32% of patients with persistent disease had metastatic status. 17.3% and 5.8% of recurrences respectively occurred after three and five years of follow-up. Systematic imaging could be performed after initial treatment because of distant lesions in one third of patients with persistent disease. The follow-up should not be interrupted before five years, given the significant frequency of late recurrences. In multivariate analysis, only female gender was statistically significant. Stratified treatment based on prognostic factors could be envisaged, the details of which remain to be defined.

A High Postoperative Atropinic Burden is Associated with Postoperative Delirium in Elderly Patients with Hip Fracture: Results of the Prospective, Observational, ATROPAGE Trial.

Background: Postoperative delirium frequently occurs in the elderly after hip fracture surgery and is associated with poor outcomes. Our aim was to identify a correlation between the atropinic burden (AB) due to drugs with clinical antimuscarinic effect and the occurrence of postoperative delirium. Methods: We carried out a prospective, monocentric, observational study including 67 patients over 65 years of age who underwent hip fracture surgery. The addition of the anticholinergic weight of each drug was calculated at different time points to distinguish the prehospital, intra- and postoperative part of the AB. A multivariate analysis was carried out to identify the explanatory variables associated with postoperative delirium. Results: Patients were 78 [71-86] years old. The time from admission to surgery was 12 [12-24] hours. The ADL and CIRS scores were 6 [5.5-6] and 6 [4-9], respectively. The total (prehospital plus intraoperative plus postoperative) AB was 5 [3-9]. The incidence of postoperative delirium was 54% (36/67). The demographic characteristics were comparable between delirium and no delirium groups. Univariate analysis showed statistically significant differences between no delirium and delirium groups concerning the number of prehospital atropinic drugs, prehospital AB, the number of postoperative atropinic drugs, postoperative AB, in-hospital AB and the MMSE calculated on postoperative day 5. Using multivariate analysis, postoperative AB, but not pre- and in-hospital ABs, was associated with postoperative delirium with an odds ratio of 1.84 (95% CI: 1.25-2.72; p = 0.002). A postoperative AB > 2 was associated with a postoperative delirium with an area under ROC curve of 0.73 (95% CI: 0.61-0.83; p = 0.0001). Conclusion: Contrary to a prior exposure to atropinic drugs, a postoperative atropinic burden >2 was associated with postoperative delirium in elderly patients with hip fracture. Postoperative administration of (new) antimuscarinic drugs is a precipitating factor of delirium that could be avoided.

Diagnosis and treatment of Merkel cell carcinoma: European consensus-based interdisciplinary guideline - Update 2022.

Merkel cell carcinoma (MCC) is a rare skin cancer, accounting for less than 1% of all cutaneous malignancies. It is found predominantly in white populations and risk factors include advanced age, ultraviolet exposure, male sex, immunosuppression, such as AIDS/HIV infection, haematological malignancies or solid organ transplantation, and Merkel cell polyomavirus infection. MCC is an aggressive tumour with 26% of cases presenting lymph node involvement at diagnosis and 8% with distant metastases. Five-year overall survival rates range between 48% and 63%. Two subsets of MCC have been characterised with distinct molecular pathogenetic pathways: ultraviolet-induced MCC versus virus-positive MCC, which carries a better prognosis. In both subtypes, there are alterations in the retinoblastoma protein and p53 gene structure and function. MCC typically manifests as a red nodule or plaque with fast growth, most commonly on sun exposed areas. Histopathology (small-cell neuroendocrine appearance) and immunohistochemistry (CK20 positivity and TTF-1 negativity) confirm the diagnosis. The current staging systems are the American Joint Committee on Cancer/Union for international Cancer control 8th edition. Baseline whole body imaging is encouraged to rule out regional and distant metastasis. For localised MCC, first-line treatment is surgical excision with postoperative margin assessment followed by adjuvant radiation therapy (RT). Sentinel lymph node biopsy is recommended in all patients with MCC without clinically detectable lymph nodes or distant metastasis. Adjuvant RT alone, eventually combined with complete lymph nodes dissection is proposed in case of micrometastatic nodal involvement. In case of macroscopic nodal involvement, the standard of care is complete lymph nodes dissection potentially followed by post-operative RT. Immunotherapy with anti-PD-(L)1 antibodies should be offered as first-line systemic treatment in advanced MCC. Chemotherapy can be used when patients fail to respond or are intolerant for anti-PD-(L)1 immunotherapy or clinical trials.

[Online psychotherapy in times of coronavirus disease 2019]. / Onlinepsychotherapie in Zeiten der Corona-Pandemie: Querschnittsbefragung deutscher Psychotherapeuten.

Theoretical background: As a reaction to the coronavirus diseases 2019 (COVID-19) pandemic, in individual settings psychotherapy could be conducted online to an unlimited extent in Germany. The attitudes and experiences of psychotherapists with respect to online therapy (OT) have so far been generally poorly studied and particularly with a view to the situation during the pandemic. Objective: The aim of the study was to examine 1) the frequency of utilization of OT during the first lockdown, 2) the satisfaction with OT versus face-to-face therapy and 3) the technology acceptance experience overall and with respect to the guideline procedures. Material and methods: German psychotherapists licensed and in training, cognitive-behavioral (CB 45.6%), analytic (AP 14%), depth-psychological (DP 34.5%), systemic (SYS 5.8%), were invited to participate in an online survey on demographic and therapeutic data, use of OT, satisfaction with OT vs. face-to-face therapy (Zufriedenheitsfragebogen für Therapeuten, ZUF-THERA) and technology acceptance (Unified Theory of Acceptance and Use of Technology 2 Questionnaire, UTAUT). Results: The 174 participating psychotherapists (mean age = 44.73 years, SD ±â€¯12.79; female 81.6%) reported that the average proportion of OT in the total therapeutic activity during the lockdown was 43.09%, with significant differences between guideline procedures (DP, CB > AP). The satisfaction with OT proved to be significantly lower than with face-to-face therapy and did not differ between the procedures. Prior experience with OT was reported by 23.6% of therapists overall and was higher among those working systemically compared to CB or AP therapists. Therapists working in CB experienced more enjoyment with OT than those working in DP and AP as well as perceived a stronger social influence (e.g. through colleagues) in the use of OT than therapists working in DP. Conclusion: The frequency of use of OT soared during the first lockdown (March-May 2020, 43% in comparison to the former limit covered by health insurances of 20%). In principle, therapists were highly satisfied with OT but significantly lower than with face-to-face therapy. Further studies analyzing the reasons for this in detail are urgently recommended.

When steroids are not enough in immune-related hepatitis: current clinical challenges discussed on the basis of a case report.

Immune-related hepatitis (IRH) is a frequent but poorly understood immune-related adverse event and its frequency increases since the use of combination therapy in several cancer types. Therefore, there is an urgent need to develop adapted guidelines to manage IRH.In the present letter, based on Ziogas et al report entitled 'When steroids are not enough in immune-related hepatitis: current clinical challenges discussed on the basis of a case report', several points are discussed: assessment of IRH severity and liver biopsy indication, immune-related cholangitis as a differential diagnosis for some IRH presentation, the need of steroids for IRH management or the indication for second line immunosuppressive treatment and finally, the possibility of immunotherapy resumption.

["Achieving closeness in video treatment despite distance"]. / "In Videobehandlungen trotz Distanz Nähe schaffen": Wie erlebten Psychotherapeuten die Durchführung von Videobehandlungen in Zeiten von COVID-19?

Background: As a result of the contact ban issued at the beginning of the coronavirus disease 2019 (COVID-19) outbreak in March 2020, psychotherapists provided significantly more video-based therapy (VBT) and most of them provided it the first time. To date, there is little research on how therapists experienced VBT during the pandemic and no studies are available that look at possible procedure-specific features. Objective: The aim was to analyze what subjective experiences therapists of different guideline procedures had with the implementation of VBT in times of the COVID 19 pandemic and what advantages and disadvantages they experienced. Methods: This was a mixed methods study with a cross-sectional online survey. In addition to quantitative data, seven open-ended questions were used to collect therapists' subjective experiences with conducting VBT and analyzed using qualitative content analysis. The identified categories were subjected to a frequency analysis. Data from 174 medical or psychological psychotherapists were included in the analysis. Results: Particularly frequently mentioned advantages were flexibility of location and time, continuity of contact during pandemic periods and avoidance of risk of infection. The most commonly cited disadvantage was the lack of sensory input, facial expressions, gestures, eye contact, and nonverbal communication. The VBT was well-accepted by most, but not all, patients. Technical problems made the implementation difficult. Conclusion: For many therapists VBT remained a stopgap solution that was not designed to last; however, VBT could help to solve known care problems (e.g., underprovision in rural areas) beyond the pandemic period. The results of the study make an important contribution to weighing up the opportunities and risks of VBT for psychotherapeutic care and for keeping an eye on possible dangers and difficulties.

Assessment of Childbirth-Related PTSD: Psychometric Properties of the German Version of the City Birth Trauma Scale.

Background: About 3-4% of women in community samples suffer from childbirth-related posttraumatic stress disorder (PTSD). Surprisingly, the recently developed City Birth Trauma Scale (City BiTS) was the first diagnostic tool for childbirth-related PTSD covering DSM-5 criteria for PTSD. Since no questionnaire on childbirth-related PTSD is available in German, we aimed to validate a German translation of the City BiTS and to provide information on its psychometric properties. Methods: A community sample of 1,072 mothers completed an online survey, which included questions on sociodemographic and obstetric characteristics, the German version of the City BiTS, the Impact of Event Scale-Revised (IES-R), the PTSD Checklist for DSM-5 (PCL-5), Edinburgh Postnatal Depression Scale (EPDS), and the anxiety subscale of the Depression, Anxiety, and Stress Scale (DASS-Anxiety). Results: Exploratory factor analysis (EFA) on a random split-half sample confirmed the previously reported two-factorial structure of the City BiTS. The factors "Childbirth-related symptoms" and "General symptoms" explained about 53%, 52% of variance. Internal consistency was good to excellent for the subscales and the total scale (Cronbach's Alpha = 0.89-0.92). In a confirmatory factor analysis (CFA) in the holdout sample the two-factorial solution reached the best model fit out of three models. Correlation analyses showed convergent validity of the City BiTS (total scale and subscales) with the IES-R and PCL-5 and divergent validity with the EPDS and the DASS-Anxiety. Limitations: Data were acquired in a community sample and prevalence rates might not be representative for mothers of high-risk groups, e.g., after preterm birth. Conclusions: The German version of the City BiTS is the first German questionnaire which allows to assess symptoms of childbirth-related PTSD according to DSM-5 criteria. Besides an improvement in clinical routine it will help to make data on prevalence of childbirth-related PTSD internationally comparable. In addition, this work provides a basis to assess childbirth-related PTSD in studies conducted with a longitudinal study design or in high-risk samples.

Apart From the Diet, the Ruminal Microbiota of Lambs Is Modified in Relation to Their Genetic Potential for Feed Efficiency or Feeding Behavior.

Using two successive types of diets (100% concentrate and 67% forage), this study explores the relationship between the ruminal microbiota of 78 Romane lambs and their feed efficiency (residual feed intake trait) or feeding behavior (feeding rate trait). Analysis was carried out phenotypically by correlating feed efficiency or feeding behavior traits with the relative abundance of bacteria at the phylum, family, and genus levels, and then genetically by comparing the microbiota of lambs selected for extreme breeding values for residual feed intake or feeding rate. Our results confirmed the major effect of diet on the ruminal microbiota composition. The microbiota of lambs consuming a forage-based diet was distinguished by higher microbial diversity and also by higher relative abundance of Firmicutes, whereas Bacteriodetes and Actinobacteria were relatively more abundant in the microbiota of lambs consuming a concentrate-based diet. Moreover, the comparison of lambs divergent for residual feed intake breeding values revealed that regardless of diet, more efficient lambs possessed a ruminal microbiota enriched in Coprococcus, Moryella, [Eubacterium] Brachy group, and [Eubacterium] hallii group, but depleted in Lachnospiraceae FD2005 and Shuttleworthia. The connection between microbiota composition and feeding rate was more tenuous, with no link between the abundance of particular genera and lambs genetically divergent for feeding rate.

Severe immune-related hepatitis induced by immune checkpoint inhibitors: Clinical features and management proposal.

BACKGROUND: Immune-related hepatitis (IRH) occurs in 1 to 18% of immune checkpoint inhibitor (ICI)-treated patients. Steroids are usually recommended for grade≥3 IRH, but their impact on IRH resolution and patient survival remains unclear. METHODS: We retrospectively analyzed a prospective cohort of 339 patients treated at Saint-Louis Hospital (Paris, France) with ICIs for advanced melanoma. Cases of grade≥3 IRH were collected and analyzed. Two groups were compared for their biological features and time for IRH resolution and survival: patients who received steroids (steroids group: SG) and patients who did not (nonsteroids group: NSG). FINDINGS: Grade≥3 IRH was observed in 21 patients. Thirteen were treated with steroids (SG), and 8 were not (NSG). The median time for toxicity resolution was 49 days in SG and 24 days in NSG (P=0.62). All but one patient showed a favorable outcome. Two-year survival was 56% in SG and 54% in NSG (P=0.83). Higher transaminase (P=0.002) and bilirubin (P=0.008) and lower prothrombin (P=0.035) levels were observed in SG than in NSG. For 8 (4 SG/4 NSG) patients, ICI was resumed without any hepatitis relapse. INTERPRETATION: Favorable outcomes may be achieved spontaneously and with no steroids in patients with severe IRH. Steroid initiation should be discussed in cases of high bilirubin levels and decreased prothrombin levels. ICI could be resumed without hepatitis relapse. We propose a management algorithm for grade≥3 IRH that should be validated in larger and prospective cohorts.