Exploring risk factors for endocrine-related immune-related adverse events: Insights from meta-analysis and Mendelian randomization.

This study utilized meta-analysis and Mendelian randomization (MR) to identify risk factors for endocrine-related immune-related adverse events (EirAEs) and to ascertain whether EirAEs confer better prognosis of immunotherapy. The meta-analysis identified several risk factors for EirAEs, including elevated baseline TSH (OR = 1.30, 95% CI 1.10-1.53), positive TgAb (OR = 14.23, p < .001), positive TPOAb (OR = 3.75, p < .001), prior thyroid-related medical history (OR = 4.19), increased BMI (OR = 1.11), combination immune checkpoint inhibitors (ICIs) therapy with targeted treatment (OR = 2.71, 95% CI 2.11-3.47), and dual ICI therapy (OR = 3.26, 95% CI 2.22-4.79). MR analysis further supported causalities between extreme BMI, hypothyroidism, and irAEs from a genetic perspective. In addition, cancer patients who experienced EirAEs exhibited significantly prolonged PFS (HR = 0.84, 95% CI 0.73-0.97) and OS (HR = 0.59, 95% CI 0.45-0.76) compared to those without. These findings provide valuable insights for clinical decision-making among healthcare professionals and offer direction for future research in this field.

Evaluation of the safety of PD-1/PD-L1 inhibitors for immunotherapy in patients with malignant tumors after COVID-19 infection: A single-center cohort study.

INTRODUCTION: An increasing body of evidence suggests a close association between COVID-19 infection and the safety of PD-1/PD-L1 inhibitor therapy in cancer patients. However, the available data concerning these impacts remain limited and occasionally contradictory. MATERIAL AND METHODS: We conducted a retrospective analysis of cancer patients who received PD-1/PD-L1 inhibitor therapy at the same institution from November 2022 to May 2023. After excluding patients with missing information, a total of 224 cases were included. In our study, immune-related adverse events (irAEs) that occurred during the hospitalization of patients were included in the analysis. Further analysis of inter-subgroup differences was conducted following a 1:2 propensity score matching. Statistical analyses were performed using the Fisher's exact, chi-squared, and Mann-Whitney U-tests. RESULT: The results showed that no statistically significant differences between the two subgroups in the incidence of irAEs, changes in immune function before and after using PD-1/PD-L1 inhibitors, and alterations in hepatic and renal function (p > 0.05). CONCLUSION: Our findings suggest that infection with COVID-19 does not significantly impact the safety of PD-1/PD-L1 inhibitors in cancer patients. Most cancer patients used PD-1/PD-L1 inhibitors during COVID-19 infection (asymptomatic or mild infection) did not experience exacerbation of their underlying condition, nor did they exhibit a substantial increase in toxic side effects.

A Meta-Analysis of Efficacy and Safety of Neoadjuvant Immunotherapy Plus Chemotherapy for Resectable Non-Small Cell Lung Cancer.

INTRODUCTION: Neoadjuvant immunotherapy plus chemotherapy has ushered in a new era for surgical treatment for patients with NSCLC. This study aimed to examine the efficacy and safety of neoadjuvant immunotherapy plus chemotherapy in NSCLC. METHODS: Eligible studies were identified from PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and conference meeting abstracts. The endpoints included major pathological response (MPR), complete pathological response (pCR), surgical resection rate, R0 resection, treatment-related adverse events (TRAEs), severe adverse events (SAEs), surgical complications, treatment discontinuation, surgical delay, and treatment-related death. Stata 18 software was used for statistical analysis, and p < 0.05 was considered statistically significant. Twenty-two studies including a total of 1108 patients were eligible for this study. RESULTS: Among the patients who received neoadjuvant immunotherapy plus chemotherapy, the pooled MPR rate was 51% (95% CI [0.44-0.58]), and pCR rate was 34% (95% CI [0.28-0.40]). The pooled surgical resection rate was 85% (95% CI [0.81-0.89]), and the pooled R0 rate was 94% (95% CI [0.91-0.96]). The pooled rate of pathological tumor downstaging was 84% (95% CI [0.79-0.88]), and the pooled rate of pathological nodal downstaging was 38% (95% CI [0.23-0.57]). During the treatment of neoadjuvant immunotherapy plus chemotherapy with or without surgery, the pooled rate of TRAEs (any grade) was 84% (95% CI [0.73-0.91]), and the pooled rate of SAEs was 29% (95% CI [0.21-0.38]). Surgical complications pooled rate was 25% (95% CI [0.14-0.41]). The pooled rate of treatment discontinuation (11%, 95% CI [0.09-0.13]), surgical delay (3%, 95% CI [0.02-0.05]), and treatment-related death (2%, 95% CI [0.02-0.03]) were conducted. CONCLUSION: Neoadjuvant immunotherapy plus chemotherapy provides a high pathological response, surgical resection rate, R0 resection rate, and pathological downstage rate and has a low risk of increasing the incidence of SAEs, surgical complications, treatment discontinuation, surgical delay, and treatment-related death. The validation of prospective and large sample studies is needed to confirm this conclusion.

Reconceptualization of immune checkpoint inhibitor-associated gastritis.

In recent years, with the extensive application of immunotherapy in clinical practice, it has achieved encouraging therapeutic effects. While enhancing clinical efficacy, however, it can also cause autoimmune damage, triggering immune-related adverse events (irAEs). Reports of immunotherapy-induced gastritis have been increasing annually, but due to its atypical clinical symptoms, early diag-nosis poses a certain challenge. Furthermore, it can lead to severe complications such as gastric bleeding, elevating the risk of adverse outcomes for solid tumor patients if immunotherapy is interrupted. Therefore, gaining a thorough under-standing of the pathogenesis, clinical manifestations, diagnostic criteria, and treatment of immune-related gastritis is of utmost importance for early identification, diagnosis, and treatment. Additionally, the treatment of immune-related gastritis should be personalized according to the specific condition of each patient. For patients with grade 2-3 irAEs, restarting immune checkpoint inhibitors (ICIs) therapy may be considered when symptoms subside to grade 0-1. When restarting ICIs therapy, it is often recommended to use different types of ICIs. For grade 4 irAEs, permanent discontinuation of the medication is necessary.

Toxicity in the era of immune checkpoint inhibitor therapy.

Immune checkpoint inhibitors (ICIs) reinvigorate anti-tumor immune responses by disrupting co-inhibitory immune checkpoint molecules such as programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4). Although ICIs have had unprecedented success and have become the standard of care for many cancers, they are often accompanied by off-target inflammation that can occur in any organ system. These immune related adverse events (irAEs) often require steroid use and/or cessation of ICI therapy, which can both lead to cancer progression. Although irAEs are common, the detailed molecular and immune mechanisms underlying their development are still elusive. To further our understanding of irAEs and develop effective treatment options, there is pressing need for preclinical models recapitulating the clinical settings. In this review, we describe current preclinical models and immune implications of ICI-induced skin toxicities, colitis, neurological and endocrine toxicities, pneumonitis, arthritis, and myocarditis along with their management.

Unraveling the obesity paradox in small cell lung cancer immunotherapy: unveiling prognostic insights through body composition analysis.

Background: The advent of immunotherapy has changed the landscape of SCLC treatment, although the identification of reliable prognostic biomarkers remains a formidable challenge. Our objective was to investigate the prognostic implications of obesity and body composition in SCLC immunotherapy while seeking a straightforward anthropometric measure. Methods: This retrospective study analyzed data from patients with SCLC who underwent immunotherapy between 2019 and 2023. Body composition and waist circumference (WC) were analyzed using 3D slicer software on baseline CT images. Quantitative measures, including skeletal muscle index (SMI), total adipose tissue index (TATI), and other indicators at the L3 level, along with body shape index (BSI) and additional indicators based on WC, were obtained. The relationships between these indicators, response, PFS, OS, and their interconnections were examined. Results: A total of 145 SCLC patients who received immunotherapy were identified, of whom 133 met the inclusion criteria. In univariate analysis, a BMI≥28 kg/m2 was associated with a PFS advantage (HR 0.42, p=0.04), but this trend vanished in multivariate analysis. Body measurements exhibited stronger correlations with adipose tissue content, with BSI showing the highest correlation with muscle. In multivariate analysis, lower BSI was associated with poorer OS (HR 1.79, p=0.02). The association between muscle composition and prognosis was robust in univariate analysis but dissipated in multivariate analysis. However, accounting for a high TATI background significantly heightened the adverse effect of SMI on prognosis in the multivariate model. Conclusion: No clear association between BMI and SCLC immunotherapy prognosis was observed. However, high adiposity exacerbated the adverse effects of sarcopenia in SCLC immunotherapy, and BSI demonstrated potential as a straightforward prognostic measure.

Evaluating the efficacy and safety of different neoadjuvant immunotherapy combinations in locally advanced HNSCC: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors have demonstrated promising therapeutic outcomes in recurrent/metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC), prompting numerous clinical trials to investigate the safety and efficacy of this approach in neoadjuvant therapy. This systematic review aims to consolidate and analyze the findings from various clinical trials combining neoadjuvant immunotherapy for HNSCC, with the goal of identifying the most effective neoadjuvant immunotherapy regimen. Methods: The system conducted searches across electronic databases including PubMed, Embase, the Cochrane Library and Web of science from their inception to July 1, 2024. The primary focus was on evaluating efficacy (particularly pathological complete response (pCR), major pathological response (MPR), and overall response rate (ORR)) and safety (primarily assessed by grade 3-4 treatment-related adverse reactions). Results: A total of 1943 patients from 32 studies were analyzed. Combining neoadjuvant immunotherapy with chemotherapy or radiotherapy demonstrated superiority over neoadjuvant immunotherapy alone in terms of the MPR rate, while showing no statistically significant difference in the pCR rate. Furthermore, the combination of neoadjuvant immunotherapy with chemotherapy or radiotherapy exhibited a lower CR rate compared to neoadjuvant immunotherapy with radiotherapy alone, but a higher PR rate and SD rate. Apart from the neoadjuvant immunotherapy group in isolation, there were no statistically significant differences in grade ≥3 treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) among the other three combination therapy groups. Conclusion: This systematic review and meta-analysis indicate that patients with locally advanced HNSCC might benefit from neoadjuvant immunotherapy, particularly when used in conjunction with chemotherapy or radiotherapy. Nonetheless, additional data is required to definitively confirm its efficacy. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=553753, identifier CRD42024553753.

Evaluating the efficacy of immunotherapy in gastric cancer: Insights from immune checkpoint inhibitors.

The emergence of immunotherapy, particularly immune checkpoint inhibitors (ICIs), represents a groundbreaking approach to treating gastric cancer (GC). However, the prognosis of GC patients receiving ICI treatment is influenced by various factors. This manuscript identified sarcopenia and myosteatosis as inde-pendent prognostic factors impacting the outcomes of GC patients treated with ICIs. Additionally, this study introduced a visual predictive model to estimate the prognosis of GC patients. If confirmed by further studies, this observation could provide valuable insights to propel the advancement of personalized clinical medicine and the integration of precision medicine practices.

Cancer therapy-related salivary dysfunction.

Salivary gland dysfunction is a common side effect of cancer treatments. Salivary function plays key roles in critical daily activities. Consequently, changes in salivary function can profoundly impair quality of life for cancer patients. We discuss salivary gland anatomy and physiology to understand how anticancer therapies such as chemotherapy, bone marrow transplantation, immunotherapy, and radiation therapy impair salivary function. We discuss approaches to quantify xerostomia in the clinic, including the advantages and limitations of validated quality-of-life instruments and approaches to directly measuring salivary function. Current and emerging approaches to treat cancer therapy-induced dry mouth are presented using radiation-induced salivary dysfunction as a model. Limitations of current sialagogues and salivary analogues are presented. Emerging approaches, including cellular and gene therapy and novel pharmacologic approaches, are described.

Systemic Inflammation Indexes and Risk of Immune-related Adverse Events in Patients With Metastatic Urothelial Carcinoma Treated With Immunotherapy.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic urothelial carcinoma (mUC). However, they could be associated with immune-related adverse events (irAEs), which may be clinically significant. Identifying clinical characteristics that may be associated with a higher risk of irAEs is of great importance. PATIENTS AND METHODS: We retrospectively collected data from all patients who received anti-PD1 or anti-PD-L1 for metastatic UC at our Institution from January 2017 to December 2022. Patients were dichotomized according to baseline neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and platelet-to-lymphocyte ratio (PLR) values. We performed univariate and multivariate logistic regression to determine the association between baseline characteristics and the development of irAEs. RESULTS: A total of 119 patients were identified. At a median follow-up of 29.6 months, 96 patients progressed and 82 died. Forty-five patients developed irAEs of any grade, 8 patients developed grade 3 toxicities. In the univariate analysis PS of 0 (p<0.01), baseline NLR <3.52, baseline PLR <194 (p=0.04) and baseline SII <906 (p=0.01) were significantly associated with a higher risk of developing irAEs, whereas in the multivariate analysis only PS=0 (p<0.01) and NLR <3.52 (p=0.03) maintained their correlation. Median progression-free survival (mPFS) and overall survival (mOS) were significantly longer in patients with NLR <3 (mPFS 3.8 vs. 2.6 months, p=0.01; mOS 15.3 vs. 5.6 months, p=0.002) and PS=0 (mPFS 4.8 vs. 2.1 months, p<0.001; mOS 15.3 vs. 3.8 months, p<0.001). CONCLUSION: Low baseline NLR, PLR, and SII and good PS are associated with a higher risk of developing irAEs in patients treated with ICIs for mUC.

Risk of bowel obstruction in patients with colon cancer responding to immunotherapy: an international case series.

BACKGROUND: Immunotherapy is used routinely for treating deficient mismatch repair (dMMR) colon cancer (CC). This case series highlights an emerging safety issue, where patients develop bowel obstruction associated with immunotherapy response. PATIENTS AND METHODS: Patients with dMMR CC who developed bowel obstruction while responding to immunotherapy were retrospectively identified. Data on patient, disease, treatment, and response-specific factors were explored for potential risk factors. Overall treatment numbers were used to estimate incidence. RESULTS: Nine patients from eight European centres were included. Common features were hepatic flexure location (5/9), T4 radiological staging (6/9), annular shape (8/9), radiological stricturing (5/9), and endoscopic obstruction (6/9). All received pembrolizumab and obstructed between 45 and 652 days after starting treatment. Seven patients underwent surgical resection; one was managed with a defunctioning stoma; and one was managed conservatively. One patient died from obstruction. Radiological response was seen in eight patients, including two complete responses. Pathological response was seen in all seven who underwent resection, including four complete responses. The overall incidence of immunotherapy response-related obstruction in these centres was 1.51%. CONCLUSIONS: Bowel obstruction associated with immunotherapy response may represent a rare treatment-related complication in dMMR CC. Clinicians must recognise this safety signal and share experience to maintain patient safety.

IL-2 based cancer immunotherapies: an evolving paradigm.

Discovered over 4 decades ago in the supernatants of activated T cells, interleukin-2 (IL-2) is a potent pleiotropic cytokine involved in the regulation of immune responses. It is required for effector T cell expansion and differentiation as well as for peripheral tolerance induced by regulatory T cells. High-dose IL-2 treatment was the first FDA-approved immunotherapy for renal cell carcinoma and melanoma, achieving single agent complete and durable responses, albeit only in a small proportion of patients. The therapeutic potential of wild type IL-2 is clinically limited by its short half-life and severe vascular toxicity. Moreover, the activation of regulatory T cells and the terminal differentiation of effector T cells on IL-2 pose additional restrictions. To overcome the toxicity of IL-2 in order to realize its full potential for patients, several novel engineering strategies are being developed and IL-2 based immunotherapy for cancer has emerged as a burgeoning field of clinical and experimental research. In addition, combination of IL-2 with PD-1/L1 pathway blockade shows vastly improved anti-tumor efficacy over either monotherapy in preclinical tumor models. In this review we discuss the biological characteristics of IL-2 and its receptors, as well as its efficacy and treatment limiting toxicities in cancer patients. We also explore the efforts aimed at developing novel and safer IL-2 therapies to harness the full therapeutic potential of this cytokine.

INDIVIDUAL ARTICLE: NECOM 4: Algorithm Integrating Skincare for the Management of Immunotherapy-Related Cutaneous Adverse Events for Cancer Patients and Survivors.

BACKGROUND: In the Nordic European Countries, cancer is the leading cause of death. The last decade has brought revolutionizing cancer treatments including immune checkpoint inhibitors (ICIs). Patients on ICIs have a high risk of developing cutaneous immune-related adverse events. Treating these side effects is of high importance to improve patient's quality of life (QoL) and continue the anti-cancer treatment. METHODS: The Nordic European Cutaneous Oncodermatology Management (NECOM) project develops tools to prevent and treat cancer therapy-related cutaneous adverse events (cAEs). The first 2 NECOM papers presented various cAEs and skincare regimens involving hygiene, moisturization, sun protection, and camouflage products for preventing and managing cAEs. The NECOM 3 practical algorithm was on the prevention and treatment of acute radiation dermatitis. This NECOM 4 practical algorithm is intended to prevent and manage cutaneous immunotherapy-related adverse events (cirAEs), improving cancer patients' QoL and outcomes. RESULTS: The NECOM advisors discussed the results of a systematic literature review and obtained consensus on the evidence and expert opinion-based practical algorithm for cirAEs to support all healthcare providers treating cancer patients in the Nordic European Countries. The algorithm starts with a simple skincare regimen of cleansing, moisturizing, and protection, followed by the exclusion of severe cutaneous adverse reactions, and then specific interventions to treat the most common cirAEs (pruritus, maculopapular eruption, eczematous eruption, psoriasis, lichenoid eruption, and bullous eruption). CONCLUSIONS: CirAEs are the most common side effects induced by ICIs and may lead to cancer treatment interruption or even discontinuation. Patient education on the prevention of cirAEs using a skincare regimen and treatment recommendations given in the NECOM 4 algorithm may help prevent and manage cirAEs and improve the QoL and outcome of patients receiving ICIs. J Drugs Dermatol. 2024;23:8(Suppl 2):s4-10.

Evaluation of the association between predictive factors and the development of immune-related adverse events and prognostic factors for chemoimmunotherapy in patients with non-small cell lung cancer: A multicenter retrospective study.

INTRODUCTION: Chemoimmunotherapy is widely used as the first-line management of advanced non-small cell lung cancer (NSCLC) in clinical settings. However, predictive factors associated with the development of immune-related adverse events (irAEs) and prognostic factors for NSCLC patients undergoing chemoimmunotherapy remains largely unexplored. Therefore, in this study, we aimed to evaluate predictive factors for irAE development and prognostic factors associated with chemoimmunotherapy in NSCLC patients. METHODS: This study enrolled 199 patients with advanced and recurrent NSCLC who underwent chemoimmunotherapy across eight institutions in Nagano prefecture from December 2018 to January 2023. We examined predictive factors associated with irAE development and prognostic factors associated with overall survival (OS). RESULTS: Among the patients, 106 experienced irAEs, while 93 patients did not. A total of 44 (22.1%) patients developed multiple irAEs. High serum albumin levels (Alb >3.5 g/dL) emerged as an independent predictive factor associated with irAE development in logistic regression analysis (odds ratio; 2.35, 95% confidence interval 1.27-4.34, p = 0.007). Furthermore, the development of multiple irAEs (p = 0.016), lower lactate dehydrogenase level (<223 U/L, p = 0.002), and decreased neutrophil-to-lymphocyte ratio (<3, p = 0.049) were identified as independent favorable prognostic factors associated with OS in multivariate Cox hazard analyses. CONCLUSION: The study results suggest that high serum Alb is a predictive factor for irAE development and that the presence of multiple irAEs is a favorable prognostic indicator for NSCLC patients undergoing chemoimmunotherapy.

Immune-targeted therapy with transarterial chemo(embolization) for unresectable HCC: a systematic review and meta-analysis.

Background: Transarterial chemo(embolization) is preferred for treating unresectable hepatocellular carcinoma (uHCC); however, because of emerging immune-targeted therapies, its efficacy is at stake. This systematic review pioneers to evaluate the clinical efficacy and safety of transarterial chemo(embolization) combined with immune-targeted therapy for uHCC patients. Methods: PubMed, Embase, and Cochrane Library were searched for studies comparing immune-targeted therapy with or without transarterial chemo(embolization) until 31 May 2024. The complete response (CR) rate, objective response rate (ORR), and disease control rate (DCR) were considered to be the primary outcomes calculated for the clinical outcomes of transarterial chemo(embolization) combined with immune-targeted therapy, along with progression-free survival (PFS) and overall survival (OS). The incidence of treatment-related severe adverse events was set as the major measure for the safety outcome. Results: Sixteen studies, encompassing 1,789 patients receiving transarterial chemo(embolization) plus immune-targeted therapy and 1,215 patients receiving immune-targeted therapy alone, were considered eligible. The combination of transarterial chemo(embolization) and immune-targeted therapy demonstrated enhanced outcomes in CR (OR = 2.12, 95% CI = 1.35-3.31), ORR (OR = 2.78, 95% CI = 2.15-3.61), DCR (OR = 2.46, 95% CI = 1.72-3.52), PFS (HR = 0.59, 95% CI = 0.50-0.70), and OS (HR = 0.51, 95% CI = 0.44-0.59), albeit accompanied by a surge in ALT (OR = 2.17, 95% CI = 1.28-3.68) and AST (OR = 2.28, 95% CI = 1.42-3.65). The advantages of additional transarterial chemo(embolization) to immune-targeted therapy were also verified in subgroups of first-line treatment, intervention techniques, with or without extrahepatic metastasis, Child-Pugh grade A or B, and with or without tumor thrombus. Conclusion: The combination of transarterial chemo(embolization) and immune-targeted therapy seems to bolster local control and long-term efficacy in uHCC, albeit at the expense of hepatic complications. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO/, identifier 474669.

Comparative Efficacy and Safety of Immunotherapy on Non-Small Cell Lung Cancer Patients With Brain Metastases: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Growing evidence suggests that immunotherapy has a positive effect on non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). However, it remains unclear which type of immunotherapy is more efficient. The aim of this network meta-analysis (NMA) was to compare the efficacy and safety of different immunotherapy types and determine the optimal option. METHOD: Four databases (PubMed, Cochrane Library databases, Embase, and Web of Science) and ClinicalTrial.gov were searched from inception until January 26, 2023. Randomized controlled trials (RCTs), prospective nonrandomized trials, or observational studies investigating NSCLC patients with BMs treated by immunotherapy were included. The quality of the included studies was evaluated using the Cochrane risk of bias (ROB) tool and the Newcastle-Ottawa Scale (NOS). The efficacy of immunotherapy on NSCLC patients with BMs was evaluated using frequentist random-effects NMA. RESULT: Eleven studies from 1560 citations, encompassing 1437 participants, were included in this NMA. Statistical analysis showed that pembrolizumab (SMD = 4.35, 95% CI [2.21, 6.60]) and nivolumab+ipilimumab (SMD = 3.81, 95% CI [1.21, 6.40]) could improve overall survival (OS). Pembrolizumab (SMD = 3.32, 95% CI [2.75, 3.90]) demonstrated better effects in improving the overall response rate (ORR). No significant difference in adverse event (AE) was observed between immunotherapy and chemotherapy. CONCLUSION: Our findings indicated that pembrolizumab was the most promising immunotherapy for NSCLC patients with BMs. Nivolumab+ipilimumab might be an alternative choice to improve OS. LIMITATION: Inconsistency tests were not performed because of the scarcity of direct comparison. Besides, high heterogeneity was observed in our NMA.

Real-world efficacy, safety data and predictive clinical parameters for treatment outcomes in advanced soft tissue sarcoma treated with combined immunotherapy and antiangiogenic therapy.

BACKGROUND: The combination of immunotherapy and antiangiogenic therapy has shown potential in the treatment of numerous malignant tumors, but limited evidence was available for soft tissue sarcomas (STS). Therefore, the aim of the present study is to assess the efficacy and safety of immunotherapy in conjunction with antiangiogenic therapy in patients diagnosed with advanced STS (aSTS). METHODS: The study enrolled patients with aSTS from January 2014 to October 2022. Eligible participants had previously received anthracycline-based chemotherapy, presented with an anthracycline-resistant sarcoma subtype, or were ineligible for anthracycline treatment due to medical conditions. Following enrollment, these patients received a combination of immunotherapy and antiangiogenic therapy. The primary endpoints were the objective response rate (ORR) and progression-free survival (PFS), while the secondary endpoints included the disease control rate (DCR), overall survival (OS), and the incidence of adverse events. RESULTS: Fifty-one patients were included in this cohort study. The median duration of follow-up was 15.8 months. The ORR and DCR were 17.6%, and 76.5%, respectively. The median PFS (mPFS) was 5.8 months (95% CI: 4.8-6.8) for all patients, and the median OS had not been reached as of the date cutoff. Multivariate analysis indicated that Eastern Cooperative Oncology Group performance status of 0-1 and ≤ second-line treatment were positive predictors for both PFS and OS. Patients with alveolar soft part sarcoma or clear cell sarcoma had longer mPFS (16.2 months, 95% CI: 7.8-25.6) when compared to those with other subtypes of STS (4.4 months, 95% CI: 1.4-7.5, P < 0.001). Among the observed adverse events, hypertension (23.5%), diarrhea (17.6%), and proteinuria (17.6%) were the most common, with no treatment-related deaths reported. CONCLUSION: The combination of immunotherapy and antiangiogenic agents showed promising efficacy and acceptable toxicity in patients with aSTS, especially those with alveolar soft part sarcoma or clear cell sarcoma.

The impact of chronic obstructive pulmonary disease on the risk of immune-related pneumonitis in lung cancer patients undergoing immunotherapy: a systematic review and meta-analysis.

BACKGROUND: Lung cancer, a leading cause of cancer mortality, poses significant treatment challenges. The use of immune checkpoint inhibitors (ICIs) has revolutionized therapy, but it is associated with immune-related pneumonitis (IRP). This study systematically reviews and analyzes the impact of Chronic Obstructive Pulmonary Disease (COPD) on the risk of IRP in lung cancer patients undergoing immunotherapy. METHODS: Adhering to PRISMA guidelines and using the PICO framework, a comprehensive search across PubMed, Embase, Web of Science, and the Cochrane Library was conducted. Inclusion criteria encompassed peer-reviewed studies involving lung cancer patients treated with ICIs, comparing those with and without COPD. The primary outcome was the incidence and risk of IRP. The Newcastle-Ottawa Scale evaluated study quality. The effect size was calculated using random or fixed-effects models based on the observed heterogeneity. We assessed the heterogeneity between studies and conducted a sensitivity analysis. RESULTS: The search identified 1026 articles, with six meeting the criteria for inclusion. Studies varied in design and geography, predominantly retrospective cohort studies. Patients with COPD had an increased risk of IRP (OR = 1.54, 95% CI [1.24, 1.92, P < 0.01). Subgroup analysis based on radiation therapy exposure (< 40% and ≥ 40%) also indicated a heightened IRP risk in COPD patients. Sensitivity analysis affirmed the robustness of the results, and publication bias was not significant. CONCLUSIONS: Lung cancer patients with COPD undergoing immunotherapy have a significantly increased risk of developing IRP. This highlights the necessity for vigilant monitoring and individualized treatment strategies to improve the safety and effectiveness of immunotherapy in this group.

Toxicity profile of camrelizumab-based immunotherapy in older adults with advanced cancer.

Immune checkpoint inhibitors (ICIs) have become an important cornerstone of many tumour treatments. However, the toxicity profile of immune-chemotherapy combination treatment approaches among older adult cancer patients is still unclear. Patients with any cancer who received camrelizumab-based immunotherapy were eligible for inclusion. The primary endpoints were adverse events (AEs) and immune-related adverse events (irAEs), which were defined based on Naranjo's algorithm. Patients were stratified by age (≥ 70 years and < 70 years), and comparisons were made based on the type of camrelizumab-based therapy (monotherapy, combined chemotherapy, or combined anti-VEGF therapy). A total of 185 patients were administered camrelizumab-based immunotherapy, 55 (30%) of whom were ≥ 70 years old. A total of 146 (78.9%) patients received camrelizumab-based combination treatment. The incidence of all-grade AEs was 56.8% (105 patients), while that of irAEs was 36.8% (68 patients). There was no difference in the percentage of patients experiencing any grade or grade ≥ 3 AEs between age groups. However, the frequency of irAEs (both any grade and grade ≥ 3) significantly differed by age group (P = 0.001 and 0.009, respectively). The results of multivariable analysis revealed that age ≥ 70 years was the only independent risk factor for irAEs. The results of subgroup analysis revealed that the incidence of irAEs was higher in older patients treated with camrelizumab-chemotherapy, while the incidence rates were similar between age groups in the monotherapy and combination anti-VEGF treatment subgroups. Immune-related diabetes mellitus occurred more frequently among older adults. The spectrum of irAEs showed that combination immunotherapy had more widely effects on the organ system than monotherapy. In this study, older (≥ 70 years) patients had a higher risk of all-grade and high-grade irAEs when receiving camrelizumab chemotherapy combination treatment. Notably, long-term random glucose monitoring should be performed during ICI-based immunotherapy in older cancer patients.

Tofacitinib for the treatment of immune-related adverse events in cancer immunotherapy: a multi-center observational study.

BACKGROUND: Treatment strategy against immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) frequently requires other immunosuppressive agents. Tofacitinib is a rapidly acting JAK-STAT inhibitor with proven efficacy in multiple autoimmune diseases. We aimed to evaluate the efficacy and safety of tofacitinib in the management of irAEs in cancer patients. METHODS: Cancer patients who received ICIs and were treated with tofacitinib for the management of irAEs at 6 institutions were retrospectively included in this study. Demographic and clinical characteristics were obtained from electronic medical records. Longitudinal assessment of cardiac troponin T (cTnT) with clinical assessment was utilized to evaluate the benefit of tofacitinib treatment in patients with ICI myocarditis. Overall survival (OS) was also assessed. RESULTS: Fifty-three patients were included in this study. The median time from irAE onset to tofacitinib therapy was 17 (range, 2-186) days and the median duration of tofacitinib treatment was 52.5 (range, 3-277) days. Enrolled patients were subdivided into 3 groups based on clinical severity and steroid responsiveness including 11 life-threatening cases, 30 steroid-resistant cases, and 12 cases with steroid taper failure. Clinical remission rate in each group was 54.5%, 96.7%, and 100%, respectively (P < 0.01). Tofacitinib was well-tolerated with 4 patients (7.5%) developing infectious events. From the ICI initiation, the overall median OS was 16.1 (95% CI 7.8-26.9) months. CONCLUSION: Tofacitinib showed promising clinical efficacy in patients experiencing irAEs, particularly in patients who failed to respond to steroids or experienced relapse during steroid tapering. Moreover, and most importantly, tofacitinib exhibited a favorable safety profile in cancer patients developing irAEs in terms of both toxicity and anti-tumor activity. Future prospective studies are warranted.