Proton pump inhibitors and cancer treatments: Emerging evidence against coadministration.

BACKGROUND: Proton pump inhibitors (PPIs) are widely used in cancer patients despite accumulating data showing that they can impact the efficacy of major anticancer drugs. This is particularly important with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (CPIs). RESULTS: Most TKIs require gastric acidity for their absorption and some retrospective series demonstrated that coprescription decreases the survival benefit of some TKI use (erlotinib, gefitinib and pazopanib). Relations between microbiota, the immune system, and the efficacy of immunotherapy are now obvious, just as modifications to gut flora after PPIs use are well-known. Many retrospective articles, including articles based on individual-participant data from randomized studies, demonstrated that patients treated with CPIs have a poorer outcome (overall survival, progression-free survival and response rate) when they received PPIs concomitantly, while there was no impact of such coprescription among patients in control arms, not treated with immunotherapies. Similar data were also observed in patients treated with palbociclib. CONCLUSION: For these interactions, it is very important to use the precautionary principle and warn patients and physicians about this. In patients who require acid suppression because of severe symptoms, using antacids or H2 blockers could be recommended.

Neoadjuvant Chemoradiotherapy Upregulates the Immunogenicity of Cold to Hot Tumors in Esophageal Cancer Patients.

Objective: To test the hypothesis that neoadjuvant chemoradiotherapy (NACRT) is more effective against hot esophageal squamous cell carcinoma (ESCC) and that it may upregulate tumor immunogenicity. Background: There have been several recent reports showing the efficacy of immune check-point inhibitors (ICIs) against esophageal cancer, especially immunologically hot tumors. In addition, several studies have suggested that chemotherapy and radiotherapy may convert cold tumors to hot tumors. Methods: Of 105 ESCC patients who underwent surgery after NACRT between 2010 and 2018 at our hospital, 99 whose biopsy tissue samples were obtained were enrolled. Based on immunohistochemical analysis, tumors that were FOXA1 (+) and/or EYA2 (+) were defined as hot tumors, others were cold tumors. We then investigated the association between tumor immunogenicity and clinicopathological features. Results: The 29 patients with hot tumors before NACRT had a significantly better 5-year disease-specific survival (DSS) rate than the remaining 70 patients with cold tumors (85% vs 64%; P = 0.036). In a multivariate analysis, tumor immunogenicity was a significant independent predictor of DSS. Of 68 patients without a pathological complete response (non-pCR) in their primary tumor, 51 (75%) had hot tumors after NACRT. Moreover, 75% (36/48) of tumors that were cold before NACRT were converted to hot tumors after NACRT. Conclusions: Patients with hot ESCC tumors treated with NACRT plus esophagectomy had a better prognosis than those with cold tumors. NACRT upregulated cold tumor immunogenicity to hot tumors, suggesting NACRT may increase the sensitivity of ESCC to adjuvant ICIs.

Acute kidney injury associated with anti-PD-1 and anti-PD-L1 drugs: a meta-analysis of randomized clinical trials.

BACKGROUND: Immune Checkpoint Inhibitors (ICI) have been widely used in treating different types of cancer. They increase survival in many oncologic patients and enable cancer-specific therapy. Acute Kidney Injury (AKI) is one of the adverse effects associated with using ICI, where knowledge of the prevalence and renal histological findings are still reasons for discussion. OBJECTIVE: Therefore, this meta-analysis evaluates the association between ICI use and AKI. METHODS: The search was performed in PubMed, Lilacs, and Cochrane platforms. Studies published up to December 1, 2022, were included. RESULTS: A total of 16 studies met the established PICOT criteria and were included in this review. Comparing the ICI plus chemotherapy against chemotherapy alone, the relative risk (RR) for AKI's development with ICI use was 2.89 (95%CI 1.37-6.10). In the analyses by class and drug type, programmed cell death 1 monoclonal antibody (anti-PD-1) showed an increased risk of 2.11 (95%CI 1.26-3.52), and pembrolizumab demonstrated a risk of AKI (RR= 2.77, 95%CI 1.46-5.26). Likewise, regarding the severity of AKI, AKI grade 3 or higher was more common in the ICI plus chemotherapy compared to the chemotherapy group: 3.66 (95%CI 1.19-11.30), while the subgroup analyses pooled studies comparing ICI alone versus chemotherapy alone in the control group did not demonstrate an association with AKI. CONCLUSIONS: These findings suggest that ICI use is associated with an increased risk of AKI and that anti-PD-1 use is associated with a higher incidence of renal adverse events than programmed cell death ligand 1 monoclonal antibody (anti-PD-L1). Studies with adequate power and well-defined criteria for acute interstitial nephritis, nowadays taken as a synonym for AKI related to ICI, are necessary.

Combining immunotherapy and radiation therapy in gastrointestinal cancers: A review.

INTRODUCTION AND PURPOSE: With a significant global impact, treatment of gastrointestinal (GI) cancers still presents with challenges, despite current multimodality approaches in advanced stages. Clinical trials are expanding for checkpoint inhibition (ICI) combined with radiation therapy (RT). This review intends to offer a comprehensive image of the current data regarding the effectiveness of this association, and to reflect on possible directions to further optimize the results. RESULTS: Several early phase studies demonstrated encouraging potential. However, translating preclinical outcomes to clinical settings proves challenging, especially in immunologically "cold" environments. GI cancers exhibit heterogeneity, requiring tailored approaches based on disease stage and patient characteristics. Current results, though promising, lack the power of evidence to influence the general practice. CONCLUSIONS: Finding biomarkers for identifying or converting resistant cancers is essential for maximizing responses, moreover in this context strategic RT parameters need to be carefully considered. Our review emphasizes the significance of having a thorough grasp of how immunology, tumour biology, and treatment settings interact in order to propose novel research avenues and efficient GI cancer therapy.

Recent trends in bone metastasis treatments: A historical comparison using the new Katagiri score system.

BACKGROUND: Bone metastasis has various negative impacts. Activities of daily living (ADL) and quality of life (QOL) can be significantly decreased, survival may be impacted, and medical expenses may increase. It is estimated that at least 5% cancer patients might be suffering from bone metastases. In 2016, we published the Comprehensive Guidelines for the Diagnosis and Treatment of Bone Metastasis. Since then, the therapeutic outcomes for patients have gradually improved. As life expectancy is a major determinant of surgical intervention, the strategy should be modified if the prolongation of survival is to be achieved. AIM: To monitor how bone metastasis treatment has changed before and after launch of our guidelines for bone metastasis. METHODS: For advanced cancer patients with bone metastasis who visited the Department of Clinical Oncology at Akita University hospital between 2012 and 2023, parameters including the site and number of bone metastases, laboratory data, and survival time, were extracted from electronic medical records and the Katagiri score was calculated. The association with survival was determined for each factor. RESULTS: Data from 136 patients were obtained. The 1-year survival rate for the poor prognosis group with a higher Katagiri score was 20.0% in this study, which was 6% and an apparent improvement from 2014 when the scoring system was developed. Other factors significantly affecting survival included five or more bone metastases than less (P = 0.0080), and treatment with chemotherapy (P < 0.001), bone modifying agents (P = 0.0175) and immune checkpoint inhibitors (P = 0.0128). In recent years, advances in various treatment methods have extended the survival period for patients with advanced cancer. It is necessary not only to simply extend survival time, but also to maintain ADL and improve QOL. CONCLUSION: Various therapeutic interventions including surgical approach for bone metastasis, which is a disorder of locomotor organs, are increasingly required. Guidelines and scoring system for prognosis need to be revised promptly.

Phase I pharmacokinetic, safety, and preliminary efficacy study of tiragolumab in combination with atezolizumab in Chinese patients with advanced solid tumors.

PURPOSE: Tiragolumab is an immunoglobulin G1 monoclonal antibody targeting the immune checkpoint T cell immunoreceptor with immunoglobulin and immunoreceptor ITIM domains. Targeting multiple immune pathways may improve anti-tumor responses. The phase I YP42514 study assessed the pharmacokinetics (PK), safety, and preliminary efficacy of tiragolumab plus atezolizumab in Chinese patients with advanced solid tumors. METHODS: Adult patients from mainland China with Eastern Cooperative Oncology Group performance score 0/1, life expectancy of ≥ 12 weeks, and adequate hematologic/end organ function were eligible. Patients received tiragolumab 600 mg and atezolizumab 1200 mg intravenous every 3 weeks. Key endpoints were PK (serum concentrations of tiragolumab and atezolizumab) and safety. Results from this study were compared with the global phase I study, GO30103 (NCT02794571). RESULTS: In this study, 20 patients received a median of five doses of tiragolumab plus atezolizumab. Median age was 57.5 years, 85.0% of patients were male and the most common tumor type was non-small cell lung cancer. Exposures in Chinese patients were comparable to the global GO30103 population: geometric mean ratio was 1.07 for Cycle 1 tiragolumab area under the concentration-time curve0-21 and 0.92 and 0.93 for Cycle 1 peak and trough atezolizumab exposure, respectively. Treatment-related adverse events were consistent across the Chinese and global populations. Two patients (10.0%) in this study achieved a partial response. CONCLUSION: In this study, tiragolumab plus atezolizumab was tolerable and demonstrated preliminary anti-tumor activity. There were no meaningful differences in the PK or safety of tiragolumab plus atezolizumab between the Chinese and global populations. CLINICAL TRIAL REGISTRATION NUMBER: China Clinical Trial Registry Identifier CTR20210219/YP42514. Date of registration 16 March 2021.

Utility of molecular markers in predicting local control specific to lung cancer spine metastases treated with stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: We report outcomes following spine stereotactic body radiotherapy (SBRT) in metastatic non-small cell lung cancer (NSCLC) and the significance of programmed death-ligand 1 (PD-L1) status, epidermal growth factor receptor (EGFR) mutation and timing of immune check point inhibitors (ICI) on local failure (LF). MATERIALS AND METHODS: 165 patients and 389 spinal segments were retrospectively reviewed from 2009 to 2021. Baseline patient characteristics, treatment and outcomes were abstracted. Primary endpoint was LF and secondary, overall survival (OS) and vertebral compression fracture (VCF). Multivariable analysis (MVA) evaluated factors predictive of LF and VCF. RESULTS: The median follow-up and OS were: 13.0 months (range, 0.5-95.3 months) and 18.4 months (95% CI 11.4-24.6). 52.1% were male and 76.4% had adenocarcinoma. Of the 389 segments, 30.3% harboured an EGFR mutation and 17.0% were PD-L1 ≥ 50%. The 24 months LF rate in PD-L1 ≥ 50% vs PD-L1 < 50% was 10.7% vs. 38.0%, and in EGFR-positive vs. negative was 18.1% vs. 30.0%. On MVA, PD-L1 status of ≥ 50% (HR 0.32, 95% CI 0.15-0.69, p = 0.004) significantly predicted for lower LF compared to PD-L1 < 50%. Lower LF trend was seen with ICI administration peri and post SBRT (HR 0.41, 95% CI 0.16-1.05, p = 0.062). On MVA, polymetastatic disease (HR 3.28, 95% CI 1.84-5.85, p < 0.0001) and ECOG ≥ 2 (HR 1.87, 95% CI 1.16-3.02, p = 0.011) significantly predicted for worse OS and absence of baseline VCF predicted for lower VCF rate (HR 0.20, 95% CI 0.10-0.39, p < 0.0001). CONCLUSION: We report a significant association of PD-L1 ≥ 50% status on improved LC rates from spine SBRT in NSCLC patients.

Association of Microsatellite Instability and Gene Expression Profile in Colorectal Carcinoma and Potential Implications for Therapy.

Background and Objective: In sporadic colorectal carcinomas (CRC), microsatellite instability (MSI) pathways play important roles. Previously, we showed differences in DNA methylation patterns in microsatellite stable (MSS) colorectal carcinomas and MSI-CRC. In the current study, we explore the similarities and differences in gene expression profiles in MSS and MSI at the gene level and at the pathway level to better understand CRC pathogenesis and/or the potential for therapeutic opportunities. Material and Methods: Seventy-one CRC patients (MSI = 18, MSS = 53) were studied. Paired tumor and adjacent normal tissues were used for genome-wide gene expression assays. Result: At the gene level, we compared the list of differentially expressed genes (fold change (FC) ≥ 3 and FDR < 0.05) in tumor tissues compared to corresponding normal tissue in CRC patients with MSI tumors (190 genes) and MSS tumors (129 genes). Of these, 107 genes overlapped. The list of genes that were differentially expressed in MSI tumors only showed enrichment predominantly in two broad categories of pathways-(a) Inflammation-related pathways including the interleukin-17 (IL-17) signaling pathway, tumor necrosis factor (TNF) signaling pathway, chemokine signaling, nuclear factor kappa B (NFκB) signaling, and cytokine-cytokine interactions, and (b) metabolism-related pathways, including retinol metabolism, steroid hormone biosynthesis, drug metabolism, pentose and glucoronate interconversions, and ascorbate and aldarate metabolism. The genes in inflammation-related pathways were up-regulated whereas genes in metabolism-related pathways were down-regulated in MSI tumor tissue. Pathway-level analysis also revealed similar results confirming the gene enrichment findings. For example, the 150 genes involved in the IL-17 signaling pathway were on average up-regulated by 1.19 fold (CI 1.16-1.21) in MSI compared to 1.14 fold (CI 1.13-1.16) in MSS patients (interaction p = 0.0009). Conclusions: We document an association between MSI status and differential gene expression that broadens our understanding of CRC pathogenesis. Furthermore, targeting one or more of these dysregulated pathways could provide the basis for improved therapies for MSI and MSS CRC.

Immune-related serious adverse events with immune checkpoint inhibitors: Systematic review and network meta-analysis.

PURPOSE: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, though uncertainty exists regarding their immune-related safety. The objective of this study was to assess the comparative safety profile (odds ratio) of ICIs and estimate the absolute rate of immune-related serious adverse events (irSAEs) in cancer patients undergoing treatment with ICIs. METHODS: We searched for randomized trials till February 2021, including all ICIs for all cancers. Primary outcome was overall irSAEs, and secondary outcomes were pneumonitis, colitis, hepatitis, hypophysitis, myocarditis, nephritis, and pancreatitis. We conducted Bayesian network meta-analyses, estimated absolute rates and ranked treatments according to the surface under the cumulative ranking curve (SUCRA). RESULTS: We included 96 trials (52,811 participants, median age 62 years). Risk of bias was high in most trials. Most cancers were non-small cell lung cancer (28 trials) and melanoma (15 trials). The worst-ranked ICI was ipilimumab (SUCRA 14%; event rate 848/10,000 patients) while the best-ranked ICI was atezolizumab (SUCRA 82%; event rate 119/10,000 patients). CONCLUSION: Each ICI showed a unique safety profile, with certain events more frequently observed with specific ICIs, which should be considered when managing cancer patients.

Prognostic role of PD-L1 expression in head and neck squamous cell carcinoma: An institutional experience from India.

BACKGROUND: Squamous cell carcinoma accounts for > 90% of Head and neck cancers and has a poor 5-year survival rate of only 50%. Immunosuppressive agents like PD-L1 inhibitors have been found to improve survival in many tumour types, including advanced/recurrent head and neck squamous cell carcinoma (HNSCC). The PD-L1 expression in this tumour can also predict clinical outcome. However, this fact still remains to be proven. AIM: The aim was to study the expression of PD-L1 in HNSCC, correlate with clinicopathological parameters and outcome. MATERIAL AND METHOD: This prospective study was conducted between March 2021 to June 2023 in department of Pathology of a tertiary care centre located in northern India. A total of 65 histologically confirmed cases of HNSCC were included. Expression of PD-L1 was determined by immunohistochemistry. The combined positive (CPS) and tumour proportion (TP) scores were calculated. The results were correlated with clinicopathological parameters and outcome using appropriate statistical tools. RESULTS: Considering CPS, 42 (64.6%) cases showed expression of PD-L1. A high score of ≥ 20% was seen in 10 cases (15.4%). PD-L1 expression did not correlate with any of the clinical parameters including age, gender, addiction, site, TNM stage and HPV status. Conventional HNSCC had significantly higher expression of PD-L1. The cases with positive PD-L1 expression had a higher mean survival and a lower mortality, but the difference was not statistically significant. CONCLUSION: PD-L1 expression is more likely to be seen in conventional HNSCC histomorphology. PD-L1 expression is a predictor of better prognosis in HNSCC.

Distinct changes to pancreatic volume rather than pancreatic autoantibody positivity: insights into immune checkpoint inhibitors induced diabetes mellitus.

BACKGROUND: Immune checkpoint inhibitors (ICI) are promising treatment options for various cancers. However, their use is associated with immune-related adverse events (irAEs), including ICI-induced diabetes mellitus (ICI-DM). This study aimed to investigate the clinical features of ICI-DM, with a particular focus on alterations to pancreatic volume. METHODS: We conducted a retrospective review of 2829 patients who received ICI treatment at the Chang Gung Memorial Hospital, Linkou, between January 2014 and December 2021. New-onset diabetes or diabetic ketoacidosis (DKA) was identified in ten patients receiving ICI therapy. Pancreatic volumes were assessed by manual segmentation of computed tomography (CT) images before and after ICI-DM diagnosis. RESULTS: Among these ten patients, nivolumab was the most commonly used ICI (50.0%), followed by pembrolizumab (30.0%) and atezolizumab (20.0%). One patient received combination therapy with nivolumab and ipilimumab. The median age was 63.01 years (range: 40.1 - 87.8). ICI-DM developed after a median of 13.5 cycles (range: 2 - 42) of ICI treatment or 9.85 months (range:1.5 - 21.3) since ICI initiation. The initial presentation was DKA in 60.0% of patients. All patients had low or undetectable C-peptide levels (range: <0.033 - 0.133 nmol/L) and were negative for most type 1 diabetes mellitus (T1DM)-related autoantibodies; only one patient tested positive for glutamic acid decarboxylase antibodies. CT imaging revealed significant pancreatic atrophy, with a median pancreatic volume decrease of 19.92% (P = 0.038) from baseline and sustained significant decline at last follow-up (median - 37.14%, P = 0.012). CONCLUSIONS: ICI-DM is often accompanied by pancreatic atrophy and approximately two-thirds of patients initially present with DKA. Although the majority of ICI-DM patients lack T1DM-related autoantibodies, identifying diminished pancreatic volumes through CT imaging provides valuable clues into the subclinical aspects of ICI-DM development, aiding in the prevention of diabetic emergencies. TRIAL REGISTRATION: Not applicable.

Novel uses of complement inhibitors in myasthenia gravis-Two case reports.

INTRODUCTION/AIMS: Myasthenia gravis (MG) is a rare, life-threatening immune-related adverse effect (irAE) of immune checkpoint inhibitor (ICI) treatment. C5-complement inhibitors are effective treatments for acetylcholine receptor antibody (AChR ab) positive generalized MG. We describe the use of eculizumab/ravulizumab in two patients with MG receiving concomitant pembrolizumab. METHODS: This was a retrospective review of two medical records. RESULTS: Patient 1: An 80-year-old male with recurrent, non-muscle invasive transitional cell carcinoma of the bladder developed ICI-induced AChR ab positive MG (ICI-MG), myositis, and myocarditis 2 weeks after the first dose of pembrolizumab. Myositis responded to corticosteroids. MG responded to eculizumab, followed by ravulizumab. He died of metastatic cancer 8 months later. Patient 2: A 58-year-old male had refractory thymoma-associated AChR ab-positive MG, which responded to eculizumab. He developed metastatic Merkel cell cancer necessitating pembrolizumab. MG remained stable on eculizumab. He had no irAEs for 22 months, with positron emission tomographic resolution of cancer. He then developed mild, indolent retinal vasculitis, which responded to prednisone. Discontinuation of pembrolizumab for 5 months resulted in cancer recurrence; pembrolizumab was resumed with peri-infusion pulse prednisone. MG remained stable and he continues eculizumab. DISCUSSION: In the first patient, eculizumab, followed by ravulizumab, improved ICI-MG. In the second patient, eculizumab treatment may have had a prophylactic effect on the development of ICI-induced irAEs. The effect of complement inhibition on cancer outcomes of ICI therapy is unknown. A possible biologic basis for complement inhibitors in reducing irAEs of ICI, especially in the presence of underlying autoimmune disease, merits evaluation.

Immunotherapy for endocrine tumours: a clinician's perspective.

Immunotherapy has revolutionised the treatment of oncological patients, but its application in various endocrine tumours is rather limited and is mainly used when conventional therapies have failed. Immune checkpoint inhibitors (ICIs) have been employed in progressive adrenocortical carcinoma, primarily utilizing the anti-PD-L1 agent pembrolizumab, obtaining overall response rates ranging between 14% and 23%. In contrast, the response rate in phaeochromocytoma/paraganglioma was substantially less at 9%, considering the small number of patients treated. Similarly, the response rate in advanced differentiated thyroid carcinomas treated with pembrolizumab was also low at 9%, although the combination of ICIs with tyrosine kinase inhibitors showed higher efficacy. Low response rates to ICIs have also been observed in progressive medullary thyroid cancer, except in tumours with a high mutation burden (TMB). Pembrolizumab or spartalizumab can be utilized in patients with high TMB anaplastic thyroid cancer, obtaining better response rates, particularly in patients with high PD-L1 expression. Immunotherapy has also been used in a few cases of parathyroid carcinoma, showing limited antitumour effect. Pituitary carcinomas may exhibit a more favourable response to ICIs compared to aggressive pituitary tumours, particularly corticotroph tumours. Patients with advanced neuroendocrine tumours achieve an overall response rate of 15%, which varies according to the primary tumour site of origin, degree of differentiation, and therapeutic regimen utilised. Future research is needed to evaluate the potential role of immunohistochemical biomarkers, such as programmed death 1/programmed death ligand 1 and TMB, as predictors for the response to immunotherapy. Furthermore, randomised prospective studies could provide more robust data on the efficacy and side effects of ICIs.

Nothing Great Comes Without Its Risks: A Rare Case of Pembrolizumab-Induced Hypophysitis.

Pembrolizumab is an immune checkpoint inhibitor that targets the programmed cell death protein 1 and enhances immune activity against cancer cells. This has emerged as a powerful tool in the treatment of cancer in patients with severe metastatic disease. Despite this, immune checkpoint inhibitors are associated with many immune-related adverse effects. Reported endocrinopathies include thyroid dysfunction, insulin-deficient diabetes mellitus, primary adrenal insufficiency, and hypophysitis. Hypophysitis is more commonly associated with cytotoxic T-lymphocyte associated antigen 4 inhibitors like ipilimumab and rarely with pembrolizumab. A high clinical suspicion is needed to pursue a diagnosis of immune checkpoint inhibitorinduced hypophysitis, and prompt diagnosis is of immense importance due to the potentially life-threatening nature of endocrinopathies. We present a case of a 64-year-old Caucasian male individual undergoing treatment with pembrolizumab for undifferentiated lung carcinoma who subsequently developed hypophysitis.

Molecular pathology of non-small cell carcinoma.

Currently, lung cancer is treated by the highest number of therapeutic options and the benefits are based on multiple large-scale sequencing studies, translational research and new drug development, which has promoted our understanding of the molecular pathology of lung cancer. According to the driver alterations, different characteristics have been revealed, such as differences in ethnic prevalence, median age and alteration patterns. Consequently, beyond traditional chemoradiotherapy, molecular-targeted therapy and treatment with immune check-point inhibitors (ICI) also became available major therapeutic options. Interestingly, clinical results suggest that the recently established therapies target distinct lung cancer proportions, particularly between the EGFR/ALK and PD-1/PD-L1-positive subsets, e.g. the kinase inhibitors target driver mutation-positive tumours, whereas driver mutation-negative tumours respond to ICI treatment. These therapeutic efficacy-related differences might be explained by the molecular pathogenesis of lung cancer. Addictive driver mutations promote tumour formation with powerful transformation performance, resulting in a low tumour mutation burden, reduced immune surveillance, and subsequent poor response to ICIs. In contrast, regular tobacco smoke exposure repeatedly injures the proximal airway epithelium, leading to accumulated genetic alterations. In the latter pathway, overgrowth due to alteration and immunological exclusion against neoantigens is initially balanced. However, tumours could be generated from certain clones that outcompete immunological exclusion and outgrow the others. Consequently, this cancer type responds to immune check-point treatment. These pathogenic differences are explained well by the two-compartment model, focusing upon the anatomical and functional composition of distinct cellular components between the terminal respiratory unit and the air-conducting system.

Acute Tubulointerstitial Nephritis and Secondary Renal Amyloidosis: A Rare Complication of Atezolizumab.

Lung cancer is the second most common malignancy in both genders and the most common cause of cancer-related deaths worldwide. Broadly, lung cancer is divided into two types: small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Non-small cell lung cancer accounts for 85% of the diagnoses of lung cancer. It is necessary to check for any targetable mutations, which can help in deciding the treatment plan for the patients. The patient we are reporting is a 70-year-old male with multiple co-morbidities diagnosed with non-small cell carcinoma, favoring adenocarcinoma on histopathology. He was started on Atezolizumab/Bevacizumab/Carboplatin/Paclitaxel (ABCP). He was switched to maintenance Atezolizumab/Bevacizumab after four cycles due to poor tolerance to carboplatin and paclitaxel. The patient presented with neutropenic colitis and acute kidney injury (AKI), requiring admission. workup revealed nephrotic range proteinuria with a high urinary albumin-to-creatinine ratio. He underwent a renal biopsy to ascertain the cause of his proteinuria, which showed marked acute and chronic tubulo-interstitial nephritis (TIN), amyloidosis, and global glomerulosclerosis. Secondary (AA) amyloidosis is characterized by the extracellular deposition of misfolded proteins. Although interstitial nephritis is a reported side effect of immune checkpoint inhibitors, AA amyloidosis is a rarer side effect. So, to determine the exact cause and early therapeutic intervention in immune checkpoint inhibitor-related kidney injury, large retrospective or prospective studies should be done.

[Onconephrology in Renal Transplant Patient: A Challenge for the Transplant Nephrologist].

Onconephrology, an emerging field in modern medicine, is gaining importance due to its intricate challenges derived from the mixing field of tumorous and renal diseases. The growing incidence of tumors in transplant patients requires preventive strategies and accurate monitoring. Pre-transplant screening is crucial, focusing on subjects with oncological history. Post-transplant follow-up must be personalized, tailoring screenings for patients with cancer history. Immunosuppressive therapy, although essential to prevent organ rejection, represents a delicate balance between controlling the immune response and cancer risk management. Immune checkpoint inhibitors emerge as a fascinating potential for cancer therapy, but their use in transplant patients requires caution and further research to carefully evaluate their safety and effectiveness, balancing potential benefits with actual risk of rejection. In summary, onconephrology is a growing field that requires an interdisciplinary approach and constant research, aimed at successfully addressing the complex challenges associated with oncological diseases in renal and transplant patients.

Stress Keratin 17 Is a Predictive Biomarker Inversely Associated with Response to Immune Check-Point Blockade in Head and Neck Squamous Cell Carcinomas and Beyond.

Low response rates in immune check-point blockade (ICB)-treated head and neck squamous cell carcinoma (HNSCC) drive a critical need for robust, clinically validated predictive biomarkers. Our group previously showed that stress keratin 17 (CK17) suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors, correlating with decreased response rate to pembrolizumab-based therapy in a pilot cohort of ICB-treated HNSCC (n = 26). Here, we performed an expanded analysis of the predictive value of CK17 in ICB-treated HNSCC according to the REMARK criteria and investigated the gene expression profiles associated with high CK17 expression. Pretreatment samples from pembrolizumab-treated HNSCC patients were stained via immunohistochemistry using a CK17 monoclonal antibody (n = 48) and subjected to spatial transcriptomic profiling (n = 8). Our findings were validated in an independent retrospective cohort (n = 22). CK17 RNA expression in pembrolizumab-treated patients with various cancer types was investigated for predictive significance. Of the 48 patients (60% male, median age of 61.5 years), 21 (44%) were CK17 high, and 27 (56%) were CK17 low. A total of 17 patients (35%, 77% CK17 low) had disease control, while 31 patients (65%, 45% CK17 low) had progressive disease. High CK17 expression was associated with a lack of disease control (p = 0.037), shorter time to treatment failure (p = 0.025), and progression-free survival (PFS, p = 0.004), but not overall survival (OS, p = 0.06). A high CK17 expression was associated with lack of disease control in an independent validation cohort (p = 0.011). PD-L1 expression did not correlate with CK17 expression or clinical outcome. CK17 RNA expression was predictive of PFS and OS in 552 pembrolizumab-treated cancer patients. Our findings indicate that high CK17 expression may predict resistance to ICB in HNSCC patients and beyond.

Acute liver failure following immune checkpoint inhibitors.

We report the case of a 64-year-old man admitted to intensive care unit for liver failure secondary to immune-mediated hepatitis. This patient suffered from a progressing laryngeal squamous cell carcinoma. A treatment was started with immune checkpoint inhibitors combining anti PD-L1 plus novel anti-TIGIT or placebo (ATEZOLIZUMAB plus TIRAGOLUMAB or placebo), as part of a clinical trial. The patient then developed immune-mediated hepatitis, proven by liver biopsy. Despite 14 days of corticosteroids at 2 mg/kg the condition of the patient worsened, with the development of liver failure. The patient was admitted to intensive care unit, treated with plasma exchange, and made a complete recovery from this life-threatening condition. To our knowledge this is the case of a successful use of plasma exchange to treat ATEZOLIZUMAB +/- TIRAGOLUMAB induced liver toxicity. INSIGHTS: Plasma exchange could be a potential lifesaving treatment to severe immune-mediated hepatitis.

Modern Approach to Melanoma Adjuvant Treatment with Anti-PD1 Immune Check Point Inhibitors or BRAF/MEK Targeted Therapy: Multicenter Real-World Report.

BACKGROUND: The landscape of melanoma management changed as randomized trials have launched adjuvant treatment. MATERIALS AND METHODS: An analysis of data on 248 consecutive melanoma stage III and IV patients given adjuvant therapy in eight centers (February 2019 to January 2021) was conducted. RESULTS: The analyzed cohort comprised 147 melanoma patients given anti-PD1 (33% nivolumab, 26% pembrolizumab), and 101 (41%) were given dabrafenib plus trametinib (DT). The 2-year overall survival (OS), relapse-free survival (RFS), and distant-metastases-free survival (DMFS) rates were 86.7%, 61.4%, and 70.2%, respectively. The disease stage affected only the RFS rate; for stage IV, it was 52.2% (95% CI: 33.4-81.5%) vs. 62.5% (95% CI: 52.3-74.8%) for IIIA-D, p = 0.0033. The type of lymph node surgery before adjuvant therapy did not influence the outcomes. Completion of lymph node dissection cessation after positive SLNB did not affect the results in terms of RFS or OS. Treatment-related adverse events (TRAE) were associated with longer 24-month RFS, with a rate of 68.7% (55.5-84.9%) for TRAE vs. 56.6% (45.8-70%) without TRAE, p = 0.0031. For TRAE of grade ≥ 3, a significant decline in OS to 60.6% (26.9-100%; p = 0.004) was observed. CONCLUSIONS: Melanoma adjuvant therapy with anti-PD1 or DT outside clinical trials appears to be effective and comparable with the results of registration studies. Our data support a de-escalating surgery approach in melanoma treatment.