Immunotherapy efficacy and toxicity: Reviewing the evidence behind patient implementable strategies.

The use of immune checkpoint inhibitors (ICI) in cancer treatment is expanding, offering promising outcomes but with an important risk of immune-related adverse events (irAEs). These events, stemming from an overstimulated immune system attacking healthy cells, can necessitate immunosuppressant treatment, disrupt treatment courses, and impact patients' quality of life. The analysis of ICI efficacy data has led to a better understanding of the characteristics of responders. Similarly, we are gaining clearer insights into the characteristics of patients who develop irAEs, prompting an increasing emphasis on modifiable factors associated with irAE risk. These factors include lifestyle choices and the composition of the gut microbiome. Despite comprehensive reviews exploring the microbiome's role in therapy efficacy, understanding its connection with immune-related toxicity remains incomplete. While endeavours to identify predictive biomarkers continue, lifestyle modifications emerge as a promising avenue for enhancing treatment outcomes. This review consolidates the current evidence regarding the impact of the gut microbiome on irAE occurrence. Furthermore, it focuses on actionable strategies for mitigating these adverse events, elucidating the evidence supporting dietary adjustments, supplementation, medication management, and physical activity. With the expanding range of indications for ICI therapy, a significant proportion of oncology patients, including those in early disease stages, are now exposed to these treatments. Acknowledging the importance of averting irAEs in this context, our review offers timely insights crucial for addressing the evolving challenges associated with immunotherapy across diverse oncological settings.

Corticosteroids and other immunosuppressants for immune-related adverse events and checkpoint inhibitor effectiveness in melanoma.

BACKGROUND: Recent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus far, we assessed the association of immunosuppressant type and dose with survival in melanoma patients with irAEs. METHODS: Patients with advanced melanoma who received immunosuppressants for irAEs induced by first-line anti-PD-1 ± anti-CTLA-4 were included from 18 hospitals worldwide. Associations of cumulative and peak dose corticosteroids and use of second-line immunosuppression with survival from start of immunosuppression were assessed using multivariable Cox proportional hazard regression. RESULTS: Among 606 patients, 404 had anti-PD-1 + anti-CTLA-4-related irAEs and 202 had anti-PD-1-related irAEs. 425 patients (70 %) received corticosteroids only; 181 patients (30 %) additionally received second-line immunosuppressants. Median PFS and OS from starting immunosuppression were 4.5 (95 %CI 3.4-8.1) and 31 (95 %CI 15-not reached) months in patients who received second-line immunosuppressants, and 11 (95 %CI 9.4-14) and 55 (95 %CI 41-not reached) months in patients who did not. High corticosteroid peak dose was associated with worse PFS and OS (HRadj 1.14; 95 %CI 1.01-1.29; HRadj 1.29; 95 %CI 1.12-1.49 for 80vs40mg), while cumulative dose was not. Second-line immunosuppression was associated with worse PFS (HRadj 1.32; 95 %CI 1.02-1.72) and OS (HRadj 1.34; 95 %CI 0.99-1.82) compared with corticosteroids alone. CONCLUSIONS: High corticosteroid peak dose and second-line immunosuppressants to treat irAEs are both associated with impaired survival. While immunosuppression is indispensable for treatment of severe irAEs, clinicians should weigh possible detrimental effects on survival against potential disadvantages of undertreatment.

Immunosuppressive therapy management in cancer patients with autoimmune diseases treated with immune checkpoint inhibitors: A case series and systematic literature review.

INTRODUCTION: Prescribing immune checkpoint inhibitors (ICIs) to cancer patients with an autoimmune disease (AID) is presumed safe when cautious adverse event management is applied. However, guidelines on immunosuppressant (IS) adaptations are limited and real-world evidence is scarce. METHODS: Current practice of IS adaptations is described in a case series of AID patients treated with ICIs in a tertiary university hospital in Belgium (1/1/2016-31/12/2021). Patient, drug and disease-related data were documented using retrospective chart review. A systematic search of the PubMed database was performed to identify similar cases (1/1/2010-30/11/2022). RESULTS: Sixteen patients were described in the case series (62% with active AID). Systemic IS were changed before ICI initiation in 5/9 patients. Four patients continued therapy, of which one achieved partial remission. Patients who had IS (partially) stopped before ICI start (n = 4) had AID flares in two cases; immune-related adverse events in three cases. In the systematic review, 37 cases were identified in 9 articles. Corticosteroids (n = 12) and non-selective IS (n = 27) were continued in, respectively, 66% and 68% of patients. Methotrexate was frequently discontinued (13/21). Biologicals, excluding tocilizumab and vedolizumab, were withheld during ICI treatment. Out of all patients with flares (n = 15), 47% had stopped IS therapy before ICI start and 53% had continued their AID drugs. CONCLUSIONS: A detailed overview of IS management in patients with AID receiving ICI therapy is presented. Expanding the knowledge base germane to IS management with ICI therapy in the diverse population is essential to evaluate their mutual impact, thus advancing responsible patient care.

HistoSnap: A Novel Software Tool to Extract m/z-Specific Images from Large MSHC Datasets.

We describe an informatics tool for comfortable browsing through highly complex, multi-gigabyte mass spectrometry histochemistry (MSHC) datasets, via clever ion-specific image extraction.The package is developed particularly for the untargeted localization/discovery of biomolecules such as endogenous (neuro)secretory peptides on histological sections of biobanked formaldehyde-fixed paraffin-embedded (FFPE) samples straight from tissue banks.Atmospheric pressure-MALDI-Orbitrap MSHC data of sections through human pituitary adenomas in which two well-known human neuropeptides are detected are used as an example to demonstrate the key features of the novel software, named HistoSnap.

MS1-Based Data Analysis Approaches for FFPE Tissue Imaging of Endogenous Peptide Ions by Mass Spectrometry Histochemistry (MSHC).

Ambiguous reports in the literature exist regarding the use and usefulness of formalin-fixed paraffin-embedded (FFPE) tissues in mass spectrometry imaging (MSI). Especially for the study of endogenous (non-tryptic) peptides, several studies have concluded that MSI on archived FFPE tissue bank samples is virtually impossible. We here illustrate that by employing a variant of MSI, called mass spectrometry histochemistry (MSHC), biomolecular tissue localization data are obtained that unequivocally comprise endogenous peptides. We here discuss different informatics steps in a data analysis workflow to help filter peptide-related features out of large and complex datasets generated by atmospheric pressure matrix-assisted laser desorption/ionization high-resolution (Orbitrap mass analyzer) MSHC. These include, in addition to accurate mass measurements, Kendrick mass defect filtering and isotopic distribution scrutiny.

Recommendations of the International Society of Geriatric Oncology on skin cancer management in older patients.

INTRODUCTION: Non-melanoma skin cancer (NMSC) is becoming ever more prevalent among older adults. However, older adults with NMSC are often underrepresented in clinical trials and guidelines on effective management is still unclear. The International Society of Geriatric Oncology (SIOG) created a multi-disciplinary task force to explore the potential in developing practical guidelines for the treatment of older patients with basal cell carcinoma (BCC) and skin (cutaneous) squamous cell carcinoma (cSCC). MATERIALS AND METHODS: A systematic literature search to identify relevant and up-to-date literature on treatment of NMSC in older adults was conducted on various databases including MEDLINE, Embase, CINAHL, Cochrane, and PubMed. The resulting papers were discussed by an expert panel, leading to a consensus recommendation. RESULTS: A total of 154 articles were identified for the expert panel to utilise in generating consensus recommendations. A major focus on geriatric assessment and management options including surgery, radiotherapy, systemic therapy, clinical monitoring, and medical/medicophysical therapy were reviewed for recommendations. DISCUSSION: Patient age should not be the sole deciding factor in the management of patients with NMSC. Assessment from a multidisciplinary team (MDT) is crucial, and the decision-making process should consider the patient's lifestyle, needs, and expectations. A comprehensive geriatric assessment should also be considered. Patients should feel empowered to advocate for themselves and have their views considered a part of the MDT discussion.

Steroid-dependent pericarditis following anti-PD1 immunotherapy in a metastatic melanoma patient: a case report.

Background: Immune-related adverse events are increasingly prevalent in the oncologist's practice. Cardiac adverse events are rare but can be life-threatening. Case reports of immune checkpoint inhibitor (ICI)-related pericarditis are scarce and so is the scientific evidence for its management. This is the first report of a steroid-dependent pericarditis. Case summary: We present a case of a woman with lung metastatic melanoma who developed pericarditis after two infusions of pembrolizumab. The initial response to steroids and colchicine was favourable, and steroids were successfully tapered, after which the immunotherapy was reintroduced. A complete metabolic remission was achieved after six cycles of pembrolizumab, but pericarditis symptoms recur each time the steroid dose is lowered below 10 mg. After introduction of azathioprine, steroids were successfully tapered over the course of 6 months. Discussion: Because of the chronicity of the pericarditis, it was hypothesized that an underlying auto-immune pericarditis was triggered by the checkpoint inhibitor and the general guidelines for recurrent idiopathic pericarditis were followed, successfully adding azathioprine to taper steroids to stop.

Systemic treatment and radiotherapy for patients with non-small cell lung cancer (NSCLC) and HIV infection - A systematic review.

Lung cancer is the most common non-AIDS defining cancer among people living with HIV (PLWH), but there is a paucity of data regarding the efficacy and toxicity of radiotherapy and systemic regimens, including immunotherapy, in the treatment of these patients. In order to answer this question, we have performed a systematic search of the literature in Ovid Medline until March 17, 2022. We included 21 publications, enrolling 513 PLWH with non-small cell lung cancer (NSCLC), mostly male (75-100%), (ex-)smokers (75-100%) and with stage III-IV at diagnosis (65-100%). The overall response rate (ORR) to chemotherapy (n = 186 patients, mostly receiving platinum-based regimens) was highly variable (17 %-83 %), with a substantial hematological toxicity. ORR varied between 13 % and 50 % with single-agent immunotherapy (n = 68), with median overall survival between 9 and 11 months and a very acceptable toxicity profile, in line with studies in the HIV non-infected population. All five patients receiving tyrosine kinase inhibitors (TKIs; gefitinib or erlotinib) showed a partial response and long overall survival. Yet, combination of TKIs with antiretroviral therapy using pharmacological boosters, such as ritonavir, should be avoided. Radiotherapy was evaluated among 42 patients, showing high ORR (55 %-100 %), but 18 % of patients had a pneumonitis. This systematic review shows that radiotherapy and systemic therapy are effective and safe among PLWH with controlled infection diagnosed with NSCLC. Nonetheless, most reports were small and heterogeneous and larger studies are needed to confirm these encouraging findings. Moreover, clinical trials should not restrict the inclusion of PLWH, as more data is needed regarding the long-term efficacy and safety of treatments among this underserved population, especially of immunotherapy.

Spatially Resolved Neuropeptide Characterization from Neuropathological Formalin-Fixed, Paraffin-Embedded Tissue Sections by a Combination of Imaging MALDI FT-ICR Mass Spectrometry Histochemistry and Liquid Extraction Surface Analysis-Trapped Ion Mobility Spectrometry-Tandem Mass Spectrometry.

To make the vast collections of well-documented human clinical samples archived in biobanks accessible for mass spectrometry imaging (MSI), recent developments have focused on the label-free top-down MS analysis of neuropeptides in sections of formalin-fixed, paraffin-embedded (FFPE) tissues. In analogy to immunohistochemistry (IHC), this variant of MSI has been designated MSHC (mass spectrometry histochemistry). Besides the detection and localization of neuropeptide and other biomolecular MS signals in these FFPE samples, there is great interest in their molecular identification and full characterization. We here used matrix assisted laser desorption ionization (MALDI) MSI employing ultrahigh-resolution FT-ICR MS on 2,5-dihydroxybenzoic acid (DHB) coated five-micron sections of human FFPE pituitary to demonstrate clear isotope patterns and elemental composition assignment of neuropeptides (with ∼1 ppm mass accuracy). Besides tandem MS fragmentation pattern analysis to deduce or confirm amino acid sequence information (Arg-vasopressin for the case presented here), there is a need for orthogonal primary structure characterization of the peptide-like MS signals of biomolecules desorbed directly off FFPE tissue sections. In the present work, we performed liquid extraction surface analysis (LESA) extractions on consecutive (uncoated) tissue slices. This enables the successful characterization by ion mobility MS of vasopressin present in FFPE material. Differences in sequence coverage are discussed on the basis of the mobility selected collision induced dissociation (CID), electron capture dissociation (ECD), and UV photodissociation (UVPD) MS/MS. Using Arg-vasopressin as model case (a peptide with a disulfide bridged ring structure), we illustrate the use of LESA in combination with a reduction agent for effective sequencing using mobility selected CID, ECD, and UVPD MS/MS.