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In surgery, indications for artificial nutrition comprise prevention and treatment of catabolism and malnutrition. Thus in general, food intake should not be interrupted postoperatively and the re-establishing of oral (e.g. after anastomosis of the colon and rectum, kidney transplantation) or enteral food intake (e.g. after an anastomosis in the upper gastrointestinal tract, liver transplantation) is recommended within 24 h post surgery. To avoid increased mortality an indication for an immediate postoperatively artificial nutrition (enteral or parenteral nutrition (PN)) also exists in patients with no signs of malnutrition, but who will not receive oral food intake for more than 7 days perioperatively or whose oral food intake does not meet their needs (e.g. less than 60–80%) for more than 14 days. In cases of absolute contraindication for enteral nutrition, there is an indication for total PN (TPN) such as in chronic intestinal obstruction with a relevant passage obstruction e.g. a peritoneal carcinoma. If energy and nutrient requirements cannot be met by oral and enteral intake alone, a combination of enteral and parenteral nutrition is indicated. Delaying surgery for a systematic nutrition therapy (enteral and parenteral) is only indicated if severe malnutrition is present. Preoperative nutrition therapy should preferably be conducted prior to hospital admission to lower the risk of nosocomial infections. The recommendations of early postoperative re-establishing oral feeding, generally apply also to paediatric patients. Standardised operative procedures should be established in order to guarantee an effective nutrition therapy.

This article represents the views of an international group of surgeons on the need for pre-operative optimisation of patient's nutritional status prior to elective surgery as a means of reducing post-operative infective complications. [ABSTRACT FROM AUTHOR]

Purpose: Late alopecia, defined as incomplete hair regrowth > 6 months following cytotoxic chemotherapy or > 6 months from initiation of endocrine therapy, negatively impacts quality of life and may affect dose intensity of adjuvant therapy. This study investigates the effect of oral minoxidil in women with chemotherapy and/or endocrine therapy-induced late alopecia., Methods: The rate of clinical response was assessed by standardized photography and quantitated with trichoscopy., Results: Two hundred and sixteen patients (mean age 57.8 ± 13.7) were included. The most common cancer diagnosis was breast, in 170 patients (79.1%). Alopecia developed after chemotherapy in 31 (14.4%) patients, endocrine monotherapy in 65 (30.1%) patients, and chemotherapy followed by endocrine therapy in 120 (55.6%) patients. In 119 patients, standardized photography assessments were used to determine clinical change in alopecia after a median of 105 (IQR = 70) days on oral minoxidil and revealed improvement in 88 (74%) patients. Forty-two patients received quantitative trichoscopic assessments at baseline and at follow-up after a median of 91 (IQR = 126) days on oral minoxidil. Patients had clinically and statistically significant increases in frontal hair shaft density (from 124.2 hairs/cm 2 at initial to 153.2 hairs/cm 2 at follow-up assessment, p = 0.008) and occipital shaft density (from 100.3 hairs/cm 2 at initial to 123.5 hairs/cm 2 at follow-up assessment. p = 0.004). No patients discontinued oral minoxidil due to adverse events., Conclusions: Overall, oral minoxidil was well tolerated by patients and may benefit both frontal and occipital late alopecia in cancer survivors treated with cytotoxic and/or endocrine therapy by increasing hair shaft and follicle density., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: There is a need for unified guidance in the management of acneiform rash induced by epidermal growth factor receptor inhibitors (EGFRi) among dermatologists., Objective: To establish unified international guidelines for the management of acneiform rash caused by EGFR inhibitors, based on an experts' Delphi consensus., Methods: The initiative was led by five members of the European Academy of Dermatology and Venereology Task Force 'Dermatology for Cancer Patients' who developed a questionnaire that was circulated to a group of 32 supportive oncodermatology experts in Europe, Canada, Argentina, the US States and Asia. The questionnaire consisted of 84 statements in total, regarding diagnosis and treatment of EGFRi-induced acneiform rash. Experts responded to an anonymous 5-point Likert scale survey. The coordinators collected the first-round responses that were checked for consensus (≥75% agreement in positive [agree or strongly agree] or in negative [disagree or strongly disagree] vote). The statements that did not reach strong consensus in the first round were revised, according to experts' feedback, for a second-round survey., Results: Strong consensus was reached in 75/84 (89.3%) of the statements, whilst moderate consensus was achieved in 6/84 elements. Key points include consideration of low-dose isotretinoin for refractory grade II/III acneiform rash, use of topical steroid-sparing agents like topical pimecrolimus in the maintenance phase and use of doxycycline in either 100 or 200 mg per day as prophylactic treatment. Interestingly, experts did not recommend topical antibiotics, neither for prevention, nor for treatment. Consensus failure in 3/84 objects is mostly related to the lack of robust data on these topics., Conclusion: This consensus offers crucial insights often overlooked by radiotherapists, general practitioners, dermatologists and oncologists, and it is expected to improve the management of oncologic patients treated with EGFRi in different settings and continents., (© 2024 European Academy of Dermatology and Venereology.)

Purpose: Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood., Experimental Design: Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays., Results: Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P < 0.0001) and psoriasiform dermatitis (P < 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P < 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P < 0.001), lichenoid (P < 0.0001), bullous dermatitis (P < 0.05), and MPR (P < 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine-targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo., Conclusions: Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions., (©2024 The Authors; Published by the American Association for Cancer Research.)

Combined immune checkpoint blockade (ICB) for cancer exhibits good efficacy in a subset of patients but also associates with immune-related adverse events. Xue et al. use an elegant drug screening strategy to identify the antimicrobial drug clofazimine as an agent that both potentiates ICB efficacy and decreases immune-related adverse events., Competing Interests: Declaration of interests J.D.W. is a consultant for Apricity; Ascentage Pharma; AstraZeneca; BeiGene; Bicara Therapeutics; Bristol Myers Squibb; Daiichi Sankyo; Dragonfly; Imvaq; Larkspur; Psioxus, Recepta; Takeda; Tizona; Trishula Therapeutics; and Sellas (ended 3/22). J.D.W. receives grant/research support from Bristol Myers Squibb and Enterome. J.D.W. has Equity in: Apricity, Arsenal IO/CellCarta; Ascentage; Imvaq; Linneaus; Georgiamune; Maverick; Tizona Therapeutics; Xenimmune. J.D.W. is an inventor on the following patents: Xenogeneic DNA Vaccines; Newcastle Disease viruses for Cancer Therapy; Myeloid-derived suppressor cell (MDSC) assay; (prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment); Anti-PD1 Antibody; Anti-CTLA4 antibodies; Anti-GITR antibodies and methods of use thereof. T.M. is a consultant for Daiichi Sankyo Co, Leap Therapeutics, Immunos Therapeutics, and Pfizer, and a co-founder of Imvaq Therapeutics. T.M. has equity in Imvaq therapeutics. T.M. reports grants from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alphavirus-based vaccines, neo-antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. D.H. and T.M. are co-inventors on patent applications related to OX40 antibodies. L.K. is an intermittent consultant with Janssen and received travel support from Sanofi., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors (BRAF/MEKi) have drastically changed the outcomes of advanced melanoma patients in both the resectable/adjuvant and unresectable/metastatic setting. In this follow-up analysis of real-world data, we aimed to investigate the clinical management and outcomes of advanced melanoma patients in a tertiary referral center in Switzerland approximately a decade after the introduction of ICIs and BRAF/MEKi into clinical use. Moreover, we aimed to compare the results with seminal phase 3 trials and to identify areas of high unmet clinical need., Methods: This single-center retrospective cohort study analyzed the melanoma registry of the University Hospital Zurich, a tertiary cancer center in Switzerland, and included patients treated in the resectable/adjuvant (n = 331) or unresectable/metastatic setting (n = 375)., Results: In the resectable setting, adjuvant anti-PD1 or BRAF/MEKi showed a 3-year relapse-free survival (RFS) of 53% and 67.6%, respectively, and the overall median RFS was 50 months. Patients with lymph node plus in-transit metastases or with distant metastases prior to commencing adjuvant treatment had a significantly reduced overall survival (OS). In 10.9% of patients, the treatment was stopped due to toxicity, which did not affect RFS/OS, unless the duration of the treatment was <3 months. Following a relapse of the disease during the first adjuvant treatment, the median progression-free survival (PFS2) was only 6.6 months; outcomes were particularly poor for relapses that were unresectable (median PFS2 3.9 months) or occurred within the first 2 months (median PFS2 2.7 months). A second adjuvant treatment for patients with resectable relapses still showed efficacy (median RFS2 43.7 months). Elevated LDH levels in patients with an unresectable relapse was correlated with a strong reduction in OS2 (HR 9.84, p = 0.018). In the unresectable setting, first-line anti-PD1, anti-CTLA4/PD1 combination, or BRAF/MEKi showed a 5-year OS of 46.5%, 52.4%, and 49.2%, respectively. In a multivariate analysis, elevated LDH levels or the presence of brain metastases substantially shortened OS (HR > 1.78, p < 0.035). There was a non-significant trend for the improved survival of patients treated with anti-CTLA4/PD1 compared to anti-PD1 (HR 0.64, p = 0.15). After a progression on first-line therapy, the median OS2 was reduced to below two years. Elevated LDH (HR 4.65, p < 0.001) levels and widespread disease with at least three metastatic sites, particularly bone metastases (HR 2.62, p = 0.026), affected OS2., Conclusion: Our study offers real-world insights into the clinical management, treatment patterns, and outcomes of advanced melanoma patients in both the adjuvant and unresectable setting. Early relapses in patients undergoing adjuvant treatment pose a particular challenge but these patients are generally excluded from first-line trials. The approved first-line metastatic treatments are highly effective in the real-world setting with 5-year OS rates around 50%. However, outcomes remain poor for patients with brain metastases or who fail first-line treatment.

Purpose: This study aimed to validate the chemotherapy-induced alopecia distress scale (CADS) in a diverse English-speaking population and patients with endocrine treatment- induced alopecia (EIA)., Objective: Chemotherapy and endocrine therapy commonly cause alopecia in breast cancer patients, leading to significant psychological and social challenges. The CADS was developed to assess the psychosocial impact of alopecia, but its generalizability beyond Korean patients requires further investigation., Methods: Data from the CHANCE study ( NCT02530177 ), which focused on non-metastatic breast cancer, was used. The cohort included 256 patients, and CADS data were collected at baseline, six months after chemotherapy completion, or 12 months after initiating endocrine therapy. The CADS questionnaire comprised 17 items covering physical and emotional health, daily activities, and relationships. Reliability was assessed using Cronbach's alpha, and responsiveness was measured by effect size., Results: The CADS exhibited good reliability, with a Cronbach's alpha of 0.91 for the overall score, indicating acceptable internal consistency in both chemotherapy (0.89) and endocrine therapy (0.86) groups. Longitudinal responsiveness was supported by an effect size of 0.49 between decreasing satisfaction with hair growth and increasing emotional distress. Cross-sectional validity was confirmed, with effect sizes of 0.91 and 0.92 for satisfaction with hair growth and emotional and activity domains, respectively., Conclusion: The CADS is a valid and responsive tool for assessing the psychosocial impact of chemotherapy-induced alopecia and endocrine treatment-induced alopecia in a diverse Western patient population.

Recent progress in the treatment of advanced melanoma has led to the improved survival of affected patients. However, novel treatments also lead to considerable and distinct skin toxicity. To further characterize cutaneous adverse events (AE) of systemic treatments, we conducted a single-center retrospective study of biopsy-proven cutaneous adverse events of melanoma treatment over a period of 10 years at the University Hospital of Zurich, Switzerland. In 102 identified patients, 135 individual skin AEs developed. Immune checkpoint blockade (ICB) was causal for 81 skin AEs, and 54 were related to targeted therapies (TT). Recorded types of skin AEs included lichenoid, maculopapular, acneiform, urticarial, panniculitis, folliculitis, psoriasiform, granulomatous, eczematous, and others. The incidence of skin AEs was higher with TT (18.54%) than with ICB (9.64%, p = 0.0029). Most AEs were low-grade, although 19.21% of AEs were common terminology criteria for adverse events (CTCAE) Grades 3 or 4. A large spectrum of skin AEs was documented during treatment of advanced melanoma, and distinct phenotypes were observed, depending on treatment classes. AEs occurred earlier during treatment with TT than with ICB, and distinct types of skin AEs were associated with respective treatment classes. This study comprehensively describes skin AEs occurring during systemic treatment for melanoma at a single center.

Immune checkpoint inhibitors (ICI) target the PD-1/PD-L1 and CTLA-4 pathways and allows the immune system to deliver antitumor effects. However, it is also associated with well-documented immune-related cutaneous adverse events (ircAEs), affecting up to 70-90% of patients on ICI. In this study, we describe the characteristics of and patient outcomes with ICI-associated steroid-refractory or steroid-dependent ircAEs treated with dupilumab. Patients with ircAEs treated with dupilumab between March 28, 2017, and October 1, 2021, at Memorial Sloan Kettering Cancer Center were included in this retrospective study, which assessed the rate of clinical response of the ircAE to dupilumab and any associated adverse events (AEs). Laboratory values were compared before and after dupilumab. All available biopsies of the ircAEs were reviewed by a dermatopathologist. Thirty-four of 39 patients (87%, 95% CI: 73% to 96%) responded to dupilumab. Among these 34 responders, 15 (44.1%) were complete responders with total ircAE resolution and 19 (55.9%) were partial responders with significant clinical improvement or reduction in severity. Only 1 patient (2.6%) discontinued therapy due to AEs, specifically, injection site reaction. Average eosinophil counts decreased by 0.2 K/mcL (p=0.0086). Relative eosinophils decreased by a mean of 2.6% (p=0.0152). Total serum immunoglobulin E levels decreased by an average of 372.1 kU/L (p=0.0728). The most common primary inflammatory patterns identified on histopathological examination were spongiotic dermatitis (n=13, 33.3%) and interface dermatitis (n=5, 12.8%). Dupilumab is a promising option for steroid-refractory or steroid-dependent immune-related cutaneous adverse events, particularly those that are eczematous, maculopapular, or pruritic. Among this cohort, dupilumab was well-tolerated with a high overall response rate. Nonetheless, prospective, randomized, controlled trials are warranted to confirm these observations and confirm its long-term safety., Competing Interests: Competing interests: YJ receives research funding from Bayer, Bristol-Myers Squibb, Cycle for Survival, Department of Defense, Eli Lilly, Fred’s Team, Genentech/Roche, Merck, NCI, RGENIX, is on the advisory board or serves as a consultant for Amerisource Bergen, Arcus Biosciences, AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Geneos Therapeutics, GlaxoSmithKline, Imedex, Imugene, Lynx Health, Merck, Merck Serono, Mersana Therapeutics, Michael J. Hennessy Associates, Paradigm Medical Communications, PeerView Institute, Pfizer, Research to Practice, RGENIX, Seagen, Silverback Therapeutics, Zymeworks Inc., and has stock options with RGENIX. EAQ receives royalties from UpToDate. PC is a consultant for Merck, Immunocore, AstraZeneca, and Pfizer and has equity interest in Rgenix. MEL has a consultant role with Johnson and Johnson, Novocure, QED, Bicara, Janssen, Novartis, F. Hoffmann-LaRoche AG, EMD Serono, AstraZeneca, Innovaderm, Deciphera, DFB, Azitra, Kintara, RBC/La Roche Posay, Trifecta, Varsona, Genentech, Loxo, Seattle Genetics, Lutris, On Quality, Azitra, Roche, Oncoderm, NCODA, and Apricity. MEL receives research funding from Lutris, Paxman, Novocure, J&J, US Biotest, OQL, Novartis, and AstraZeneca. AM receives research funding from Incyte Corporation and Amryt Pharma; consults for Blueprint Medicines, ADC Therapeutics, Alira Health, OnQuality, Protagonist Therapeutics, and Janssen; and receives royalties from up to date., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4 + T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4 + T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants., Competing Interests: Declaration of interests T.M. is a consultant for Daiichi Sankyo, Leap Therapeutics, Immunos Therapeutics, and Pfizer and co-founder of Imvaq Therapeutics. T.M. has equity in Imvaq Therapeutics. T.M. reports grants from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. D.H. and S.B. have received royalties from Agenus. R.Z. is an inventor on patent applications related to work on GITR, PD-1, and CTLA-4; has received grant support from Bristol-Myers Squibb; and is a consultant for Leap Therapeutics. J.D.W. is a consultant for Apricity, Ascentage Pharma, AstraZeneca, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dragonfly, Georgiamune, Imvaq, Larkspur, Psioxus, Recepta, Tizona, and Sellas. J.D.W. received grant/research support from Bristol Myers Squibb and Sephora. J.D.W. has equity in Apricity, Arsenal IO, Ascentage, Beigene, CellCarta, Imvaq, Linneaus, Larkspur, Georgiamune, Maverick, Tizona Therapeutics, and Xenimmune. J.D.W. is an inventor on the following patents: xenogeneic DNA vaccines, alphavirus replicon particles expressing TRP2, myeloid-derived suppressor cell (MDSC) assay, Newcastle disease virus for cancer therapy, genomic signature to identify responders to ipilimumab in melanoma, engineered vaccinia viruses for cancer immunotherapy (with T.M.), anti-CD40 agonist mAb fused to monophosphoryl lipid A (MPL) for cancer therapy (with T.M.), CAR(+) T cells targeting differentiation antigens as a means to treat cancer, anti-PD-1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies, and methods of use thereof. D.H. and T.M. are co-inventors on patent applications related to OX40 antibodies. M.E. is a member of the research advisory board for brensocatib for Insmed, Inc.; a member of the scientific advisory board for Vividion Therapeutics, Inc.; and a consultant for Protalix, Inc. and holds shares in Agios Pharmaceuticals, Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Response to immunotherapies can be variable and unpredictable. Pathology-based phenotyping of tumors into 'hot' and 'cold' is static, relying solely on T-cell infiltration in single-time single-site biopsies, resulting in suboptimal treatment response prediction. Dynamic vascular events (tumor angiogenesis, leukocyte trafficking) within tumor immune microenvironment (TiME) also influence anti-tumor immunity and treatment response. Here, we report dynamic cellular-level TiME phenotyping in vivo that combines inflammation profiles with vascular features through non-invasive reflectance confocal microscopic imaging. In skin cancer patients, we demonstrate three main TiME phenotypes that correlate with gene and protein expression, and response to toll-like receptor agonist immune-therapy. Notably, phenotypes with high inflammation associate with immunostimulatory signatures and those with high vasculature with angiogenic and endothelial anergy signatures. Moreover, phenotypes with high inflammation and low vasculature demonstrate the best treatment response. This non-invasive in vivo phenotyping approach integrating dynamic vasculature with inflammation serves as a reliable predictor of response to topical immune-therapy in patients., (© 2022. The Author(s).)

Background and Aims: This experimental study assesses the influence of different gases and insufflation pressures on the portal, central-venous and peripheral-arterial pH during experimental laparoscopy., Methods: Firstly, 36 male WAG/Rij rats were randomized into six groups (n = 6) spontaneously breathing during anaesthesia: laparoscopy using carbon dioxide or helium at 6 and 12 mmHg, gasless laparoscopy and laparotomy. 45 and 90 min after setup, blood was sampled from the portal vein, vena cava and the common femoral artery with immediate blood gas analysis. Secondly, 12 animals were mechanically ventilated at physiological arterial pH during 90 min of laparotomy (n = 6) or carbon dioxide laparoscopy at 12 mmHg (n = 6) with respective blood gas analyses., Results: Over time, in spontaneously breathing rats, carbon dioxide laparoscopy caused significant insufflation pressure-dependent portal acidosis (pH at 6 mmHg, 6.99 [6.95-7.04] at 45 min and 6.95 [6.94-6.96] at 90 min, pH at 12 mmHg, 6.89 [6.82-6.90] at 45 min and 6.84 [6.81-6.87] at 90 min; p < 0.05) compared to laparotomy (portal pH 7.29 [7.23-7.30] at 45 min and 7.29 [7.20-7.30] at 90 min; p > 0.05). Central-venous and peripheral-arterial acidosis was significant but less severely reduced during carbon dioxide laparoscopy. Laparotomy, helium laparoscopy and gasless laparoscopy showed no comparable acidosis in all vessels. Portal and central-venous acidosis during carbon dioxide laparoscopy at 12 mmHg was not reversible by mechanical hyperventilation maintaining a physiological arterial pH (pH portal 6.85 [6.84-6.90] (p = 0.004), central-venous 6.93 [6.90-6.99] (p = 0.004), peripheral-arterial 7.29 [7.29-7.31] (p = 0.220) at 90 min; Wilcoxon-Mann-Whitney test)., Conclusion: Carbon dioxide laparoscopy led to insufflation pressure-dependent severe portal and less severe central-venous acidosis not reversible by mechanical hyperventilation., (© 2021. The Author(s).)

Immune-related adverse events (irAEs) frequently complicate treatment with immune checkpoint blockade (ICB) targeting CTLA-4, PD-1, and PD-L1, which are commonly used to treat solid and hematologic malignancies. The skin and gastrointestinal (GI) tract are most frequently affected by irAEs. While extensive efforts to further characterize organ-specific adverse events have contributed to the understanding and management of individual toxicities, investigations into the relationship between multi-organ toxicities have been limited. Therefore, we aimed to conduct a characterization of irAEs occurring in both the skin and gut. A retrospective analysis of two cohorts of patients treated with ICB at Memorial Sloan Kettering Cancer Center was conducted, including a cohort of patients with cutaneous irAEs (ircAEs) confirmed by dermatologists ( n = 152) and a cohort of patients with biopsy-proven immune-related colitis ( n = 246). Among both cohorts, 15% (61/398) of patients developed both skin and GI irAEs, of which 72% (44/61) patients had ircAEs preceding GI irAEs ( p = 0.00013). Our study suggests that in the subset of patients who develop both ircAEs and GI irAEs, ircAEs are likely to occur first. Further prospective studies with larger sample sizes are needed to validate our findings, to assess the overall incidence of co-incident irAEs, and to determine whether ircAEs are predictors of other irAEs. This analysis highlights the development of multi-system dermatologic and gastrointestinal irAEs and underscores the importance of oncologists, gastroenterologists, and dermatologists confronted with an ircAE to remain alert for additional irAEs.

Metastatic uveal melanoma (UM) remains challenging to treat, with objective response rates to immune checkpoint blockade (ICB) being much lower than in primary cutaneous melanoma (CM). Besides a lower mutational burden, the overall immune-excluded tumor microenvironment of UM might contribute to the poor response rate. We therefore aimed at targeting deficiency in argininosuccinate synthase 1, which is a key metabolic feature of UM. This study aims at investigating the safety and tolerability of a triple combination consisting of ipilimumab and nivolumab immunotherapy and the metabolic therapy, ADI-PEG 20. Nine patients were enrolled in this pilot study. The combination therapy was safe and tolerable with an absence of immune-related adverse events (irAE) of special interest, but with four of nine patients experiencing a CTCAE grade 3 AE. No objective responses were observed. All except one patient developed anti-drug antibodies (ADA) within a month of the treatment initiation and therefore did not maintain arginine depletion. Further, an IFNg-dependent inflammatory signature was observed in metastatic lesions in patients pre-treated with ICB compared with patients with no pretreatment. Multiplex immunohistochemistry demonstrated variable presence of tumor infiltrating CD8 lymphocytes and PD-L1 expression at the baseline in metastases.

Purpose: Patients with prostate cancer (PCa) treated with apalutamide frequently develop rash. We aim to characterize apalutamide-related dermatological adverse events (dAEs) and management., Materials and Methods: We assessed 303 patients with PCa treated with apalutamide. DAE frequency and time to onset were calculated and clinicopathological features and management described. Associations between dAE occurrence and clinical trial participation, as well as abiraterone/prednisone exposure were detected using logistic regression models., Results: Seventy-one (23.4%) patients had all-grade dAE occurring at a median of 77 (IQR: 30-135) days post-exposure. Twenty (6.6%) dAE-related therapy interruptions included: 8 (2.6%) with dose maintained on rechallenge, 7 (2.3%) with dose reduction and 5 (1.7%) with discontinuation. Common dAEs were maculopapular rashes (33.8%) and xerosis (32.4%). Seven (77.8%) of 9 histological analyses of skin biopsies supported a drug reaction. No significant differences in laboratory hematological, hepatic and renal function were detected between dAE and no dAE cohorts. Most treated grade 1/2 dAEs (29, 40.8%) required topical steroids (14, 19.7%); few required oral steroids (3, 4.2%) ± oral antihistamines. Most grade 3 dAEs (8, 11.3%) required oral/topical steroids (5, 7.0%); few required topical steroids (3, 4.2%) ± oral antihistamines. Clinical trial patients (180, 59.4%) were more likely to report dAEs than those in the off-trial setting (OR=5.1 [95% CI 2.55-10.12]; p <0.001). Of clinical trial patients, concomitant abiraterone/prednisone recipients (109 of 180, 60.6%) were more likely to report dAEs (OR=3.1 [95% CI 1.53-6.17]; p=0.002)., Conclusions: Apalutamide-related dAEs are frequent and can be managed with topical ± oral steroids. With expanded approval of apalutamide, dAE identification and management are essential.

The discovery and clinical implementation of immune-checkpoint inhibitors (ICIs) targeting CTLA4, PD-1 and PD-L1 has revolutionized the treatment of cancer, as recognized by the 2018 Nobel Prize for Medicine and Physiology. This groundbreaking new approach has improved the outcomes of patients with various forms of advanced-stage cancer; however, the majority of patients receiving these therapies, even in combination, do not derive clinical benefit. Further development of agents targeting additional immune checkpoints, co-stimulatory receptors and/or co-inhibitory receptors that control T cell function is therefore critical. In this Review, we discuss the translational potential and clinical development of agents targeting both co-stimulatory and co-inhibitory T cell receptors. Specifically, we describe their mechanisms of action, and provide an overview of ongoing clinical trials involving novel ICIs including those targeting LAG3, TIM3, TIGIT and BTLA as well as agonists of the co-stimulatory receptors GITR, OX40, 41BB and ICOS. We also discuss several additional approaches, such as harnessing T cell metabolism, in particular via adenosine signalling, inhibition of IDO1, and targeting changes in glucose and fatty acid metabolism. We conclude that further efforts are needed to optimize the timing of combination ICI approaches and, most importantly, to individualize immunotherapy based on both patient-specific and tumour-specific characteristics., (© 2021. Springer Nature Limited.)

Objective: To familiarize the reader with the most common cutaneous adverse events with immune checkpoint inhibitors (CPIs) and their grading and treatment., Data Sources: Recent research articles, relevant review articles, and case series/reports in English from the PubMed database mostly, from 2010 onward., Study Selections: Most data are from retrospective studies and case series. Older studies regarding the mechanism were included if they were of particular importance., Results: An understanding of this review should enable the reader to identify specific skin disorders in patients receiving immune CPIs, grade the adverse event, and be able to treat or refer the patient as needed., Conclusion: Allergists/immunologists need to be familiar with these immune-related cutaneous adverse events because their incidence will increase with the ever-expanding use of CPIs and, in particular, because patients will certainly continue to be referred suspecting drug allergies., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: Treatments with Food and Drug Administration-approved blocking antibodies targeting inhibitory cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death protein 1 (PD-1) receptor, or programmed cell death ligand 1 (PD-L1), collectively named checkpoint inhibitors (CPIs), have been successful in producing long-lasting remissions, even in patients with advanced-stage cancers. However, these treatments are often accompanied by undesirable autoimmune and inflammatory side effects, sometimes bringing severe consequences for the patient. Rapid expansion of clinical applications necessitates a more nuanced understanding of CPI function in health and disease to develop new strategies for minimizing the negative side effects, while preserving the immunotherapeutic benefit., Data Sources: This review summarizes a new paradigm-shifting approach to cancer immunotherapy with the focus on the mechanism of action of immune checkpoints (CTLA4, PD-1, and its ligands)., Study Selections: We performed a literature search and identified relevant recent clinical reports, experimental research, and review articles., Results: This review highlights our understanding of the CPI mechanism of action on cellular and molecular levels. The authors also discuss how reactivation of T cell responses through the inhibition of CTLA4, PD-1, and PD-L1 is used for tumor inhibition in cancer immunotherapy., Conclusion: Mechanisms of PD-1 and CTLA4 blockade and normal biological functions of these molecules are highly complex and require additional studies that will be critical for developing new approaches to dissociate the benefits of checkpoint blockade from off-target effects of the immune reactivation that leads to immune-related adverse events., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)