Immunotherapy and Cancer: The Multi-Omics Perspective.

Immunotherapies have revolutionized cancer treatment approaches. Because not all patients respond positively to immune therapeutic agents, it represents a challenge for scientists who strive to understand the mechanisms behind such resistance. In-depth exploration of tumor biology, using novel technologies such as omics science, can help decode the role of the tumor immune microenvironment (TIME) in producing a response to the immune blockade strategies. It can also help to identify biomarkers for patient stratification and personalized treatment. This review aims to explore these new models and highlight their possible pivotal role in changing clinical practice.

Mismatch Repair system protein deficiency as a resistance factor for locally advanced rectal adenocarcinoma patients receiving neoadjuvant chemo-radiotherapy.

BACKGROUND: Available data on Mismatch Repair system (MMR) deficiency are conflicting and derived from small studies. Our study aimed to evaluate the therapeutic implications of MMR status in patients with locally advanced rectal cancer (LARC). METHODS: We retrospectively collected data from 318 patients affected by LARC treated in Italy at the Medical Oncology Units of the University Hospital of Cagliari, Istituto Nazionale dei Tumori Milan, and AOU Ospedali Riuniti Ancona. All patients underwent neoadjuvant chemoradiotherapy. The primary objective was major TRG while secondary objectives were pathological complete response, disease-free survival (DFS) and overall survival (OS). RESULTS: One hundred sixty patients (148 pMMR and 12 dMMR) were included in the exploratory cohort and 158 (146 pMMR and 12 dMMR) were included in the validation cohort. A major TRG has been shown in 42.6% and 43.1% patients with pMMR in exploratory and validation cohort, respectively; while no major TRG have been shown in dMMR patients in both cohorts. Exploratory and validation cohorts showed a statistically significant higher mDFS in pMMR patients compared to dMMR: NR vs. 14 months and NR vs. 17 months, respectively. CONCLUSION: Our results indicated an association between dMMR and poor response to preoperative chemoradiotherapy and they represent a hypothesis-generating data for new neoadjuvant strategies.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: An early exploratory analysis of real-world data.

BACKGROUND: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed death cell ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer. The present study investigated the efficacy and safety of this new standard treatment in a real-world setting. METHODS: The analysed population included patients with unresectable, locally advanced or metastatic adenocarcinoma of the biliary tract treated with durvalumab in combination with gemcitabine and cisplatin at 17 Italian centres. The primary endpoint of the study was progression-free survival (PFS), whereas secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. Unadjusted and adjusted hazard ratios (HRs) by baseline characteristics were calculated using the Cox proportional hazards model. RESULTS: From February 2022 to November 2022, 145 patients were enrolled. After a median follow-up of 8.5 months (95% CI: 7.9-13.6), the median PFS was 8.9 months (95% CI: 7.4-11.7). Median OS was 12.9 months (95% CI: 10.9-12.9). The investigator-assessed confirmed ORR was 34.5%, and the disease control rate was 87.6%. Any grade adverse events (AEs) occurred in 137 patients (94.5%). Grades 3-4 AEs occurred in 51 patients (35.2%). The rate of immune-mediated AEs (imAEs) was 22.7%. Grades 3-4 imAEs occurred in 2.1% of the patients. In univariate analysis, non-viral aetiology, ECOG PS >0 and NLR ≥3 correlated with shorter PFS. CONCLUSION: The results reported in this first real-world analysis mostly confirmed the results achieved in the TOPAZ-1 trial in terms of PFS, ORR and safety.

Understanding the User's Point of View: When the Doctor Gets Sick with Cancer and Seeks Help.

Background: When physicians confront a serious personal illness, they may discover that the transition to the "sick" role is challenging and not easy. We conducted a qualitative study in which a group of doctors with cancer (DP) was compared with a group of patients with cancer, not doctors (NDP) but with a degree of education, qualifications, and a professional role comparable to that of a doctor. Objectives: The main objective was to evaluate the effect of the diagnosis and the treatment of cancer on both the patient's personal and professional life. It was also designed to understand the effect that the experience of cancer may have on the subsequent clinical practice of DP. Methods: The eligibility criteria included diagnosis of tumors of different sites and at any stage of disease treated with local (surgery, radiotherapy) or systemic (chemotherapy, hormonal, target) therapies or a combination of both; patients actively working. A semi-structured interview was used to collect information about the patient's cancer experiences. In both groups, six main themes and ten subthemes were identified. Results: From July to November 2021, 59 patients were enrolled in the study. Among them, 29 were DP and 30 were NDP. The median age and gender were 55.9 years ± 9.3 SD (range 38-82 y), M/F ratio 12/17 for DP, and 56.3 years ± 8.9 SD (range 40-83 y), M/F ratio 11/19 for NDP, respectively. The main themes were: theme 1, practical aspects related to diagnosis: most of the DP did not encounter difficulties in performing the tests necessary to confirm the diagnosis of cancer, unlike what was observed in NDP. Theme 2, cancer diagnosis experience: Many DP and NDP felt prepared for their own cancer experience. Two-thirds of DP already knew their cancer prognosis from their previous background knowledge and one-third of NDP did not want to discuss the prognosis in depth with their referring oncologists for the fear of learning that their cancer had a poor prognosis. Theme 3, treatment experience: for many DP, having a professional background contributed to more active participation in care and also in the management of side effects of treatments. Most NDP were satisfied with the treatment received in the hospital and the relationship with the health professionals. Theme 4, changes in work: None of the patients from both the groups stopped working permanently or lost their job because of the disease. A higher number of DP and NDP reported a loss of interest in their job. Theme 5, changes in personal/family life and friendships: more than half of the patients in both groups developed a new perspective on their private lives. Theme 6, comfort from faith: most of the patients in both groups who followed a faith, found comfort in that faith. For DP only, we explored the theme of the change in the doctor/patient relationship. Important findings from our study included positive changes in the doctor's clinical practice including having a more empathic relationship with patients, greater consideration of the psychological impact of cancer, and greater attention to certain symptoms of cancer reported by patients. Conclusion: This study suggests the need to know the special needs of professional patients, in particular, related to the emotional difficulties, maintenance of privacy, and the need for support on their return to work. These results can help to foster improvements in current cancer care practices.

Circulating DNA in the neoadjuvant setting of early stage colon cancer.

BACKGROUND: While circulating tumour (ct)DNA is an indicator of minimal residual disease and negative prognostic factor in stage II-III colon cancer, no study has ever analysed the value of this biomarker in colon cancer patients treated with neoadjuvant chemotherapy. We sought to fill this gap by using prospectively collected plasma samples from 80 stage III colon cancer patients, receiving one cycle of neoadjuvant FOLFOX followed by surgery +/- adjuvant FOLFOX in the PePiTA trial. MATERIAL AND METHODS: Samples were collected at baseline, 2 weeks and surgery. NPY and WIF1 were selected as universal methylation markers for ctDNA, and analysed with ddPCR technology. ROC curves were applied for cut-off points, and outcome measures included 5-year disease-free survival (DFS) and 6-year overall survival (OS). RESULTS: After a median follow-up of 52.5 months, baseline circulating-free (cf) DNA was an independent prognostic factor for DFS (HR 3.35, 95% CI: 1.15-9.77, p = .03), and a trend towards a similar association was observed for relative cfDNA changes between baseline and surgery (HR 2.57, 95% CI: 0.94-7.05, p = .07). Among 60 ctDNA assessable patients, 25 (42%) had detectable ctDNA at baseline. While detection of ctDNA at any pre-operative timepoint was not associated with outcome, patients with ctDNA increase (change of the worst trending methylation marker ≥11%, or mean ctDNA change of NPY and WIF1 ≥ 0%) between baseline and surgery showed a trend towards worse 5-year DFS (HR 3.66, 95% CI: 0.81-16.44, p = .09). CONCLUSION: This is the first study of ctDNA in the neoadjuvant setting of early-stage colon cancer. Results are hypothesis-generating and should be confirmed in larger series.

BRCA-mutant pancreatic ductal adenocarcinoma.

Despite continued research, pancreatic ductal adenocarcinoma (PDAC) remains one of the main causes of cancer death. Interest is growing in the role of the tumour suppressors breast cancer 1 (BRCA1) and BRCA2-typically associated with breast and ovarian cancer-in the pathogenesis of PDAC. Indeed, both germline and sporadic mutations in BRCA1/2 have been found to play a role in the development of PDAC. However, data regarding BRCA1/2-mutant PDAC are lacking. In this review, we aim to outline the specific landscape of BRCA-mutant PDAC, focusing on heritability, clinical features, differences between BRCA1 and 2 mutations and between germline and sporadic alterations, as well as established therapeutic strategies and those that are still under evaluation.

Impact of Aspirin on clinical outcome in advanced HCC patients receiving sorafenib and regorafenib.

BACKGROUND AND AIM: The aim of our retrospective study is to evaluate the prognostic significance of aspirin in patients with advanced HCC treated with sorafenib. METHODS: 304 patients with HCC,consecutively treated with sorafenib from May 2007 to September 2018, were included in the clinical study. Of Them 93 patients token aspirin. Progression-free survival (PFS)and overall survival (OS)were estimated with the Kaplan-Meier method and compared with the log-rank test. RESULTS: The concomitant use of sorafenib and aspirin was associated with a median OS of 18.3 months compared to 8.8 months of patients who did not receive aspirin (HR 0.57; P < 0.0001). The concomitant use of sorafenib and aspirin was associated with a median PFS of 7.3 months compared to 3.0 months of patients who did not receive aspirin (HR 0.61; P = 0.0003). In the multivariate analysis, the use of aspirin maintained an independent prognostic value for OS(HR 0.61; P = 0.0013). In second line the concomitant use of regorafenib and aspirin was associated with a median OS of 16.9 months compared to 8.0 months of patients who did not receive aspirin (HR 0.30; P = 0.02). CONCLUSION: Globally, our data seem to suggest that aspirin use may improve the clinical outcome of patients with advanced hepatocellular carcinoma receiving sorafenib and regorafenib.

Feasibility and clinical impact of routine molecular testing of gastrointestinal cancers at a tertiary centre with a multi-gene, tumor-agnostic, next generation sequencing panel.

BACKGROUND: High-throughput sequencing technologies are increasingly used in research but limited data are available on the feasibility and value of these when routinely adopted in clinical practice. MATERIAL AND METHODS: We analyzed all consecutive cancer patients for whom genomic testing by a 48-gene next-generation sequencing (NGS) panel (Truseq Amplicon Cancer Panel, Illumina) was requested as part of standard care in one of the largest Belgian cancer networks between 2014 and 2019. Feasibility of NGS was assessed in all study patients, while the impact of NGS on the decision making was analyzed in the group of gastrointestinal cancer patients. RESULTS: Tumor samples from 1064 patients with varying tumor types were tested, the number of NGS requests increasing over time (p < .0001). Success rate and median turnaround time were 91.4% and 12.5 days, respectively, both significantly decreasing over time (p ≤ .0002). Non-surgical sampling procedure (OR 7.97, p < .0001), tissue from metastatic site (OR 2.35, p = .0006) and more recent year of testing (OR 1.79, p = .0258) were independently associated with NGS failure. Excluding well-known actionable or clinically relevant mutations which are recommended by international guidelines and commonly tested by targeted sequencing, 57/279 (20.4%) assessable gastrointestinal cancer patients were found to have tumors harboring at least one actionable altered gene according to the OncoKB database. NGS results, however, had a direct impact on management decisions by the treating physician in only 3 cases (1.1%). CONCLUSIONS: Our findings confirm that NGS is feasible in the clinical setting with acceptably low failure rates and rapid turnaround time. In gastrointestinal cancers, however, NGS-based multiple-gene testing adds very little to standard targeted sequencing, and in routine practice the clinical impact of NGS panels including genes which are not routinely recommended by international guidelines remains limited.

Colorectal Cancer Early Detection in Stool Samples Tracing CpG Islands Methylation Alterations Affecting Gene Expression.

Colorectal cancer (CRC) is a major cause of cancer mortality. Early diagnosis is relevant for its prevention and treatment. Since DNA methylation alterations are early events in tumourigenesis and can be detected in cell-free DNA, they represent promising biomarkers for early CRC diagnosis through non-invasive methods. In our previous work, we identified 74 early altered CpG islands (CGIs) associated with genes involved in cell cross-talking and cell signalling pathways. The aim of this work was to test whether methylation-based biomarkers could be detected in non-invasive matrices. Our results confirmed methylation alterations of GRIA4 and VIPR2 in CRC tissues, using MethyLight, as well as in stool samples, using a much more sensitive technique as droplet digital PCR. Furthermore, we analysed expression levels of selected genes whose promoter CGIs were hypermethylated in CRC, detecting downregulation at mRNA and protein levels in CRC tissue for GRIA4, VIPR2, SPOCK1 and SLC6A3. Most of these genes were already lowly expressed in colon normal tissues supporting the idea that cancer DNA methylation targets genes already barely expressed in the matched normal tissues. Our study suggests GRIA4 and VIPR2 as biomarkers for early CRC diagnosis using stool samples and confirms downregulation of genes hypermethylated in CRC.

CDK4/6 inhibition in hormone receptor-positive/HER2-negative breast cancer: Biological and clinical aspects.

A dysregulated cell division, one of the key hallmarks of cancer, results in uncontrolled cellular proliferation. This aberrant process, mediated by a dysregulated cell-cycle machinery and overactivation of cyclin-dependent kinase (CDK) 4 and 6, can potentially promote tumorigenesis. The clinical application of CDK 4/6 inhibitors, developed to inhibit cell-cycle progression, in the treatment regimens of breast cancer (BC) patients is expanding. Currently, three agents, ribociclib, palbociclib, and abemaciclib, are approved for treating patients with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic BC. In addition, abemaciclib is FDA and EMA-approved for patients with hormone receptor-positive HER2-negative, node-positive, early BC at high risk of recurrence. Emerging data suggest potential anti-tumor effects beyond cell cycle arrest, providing novel insights into the agent's mechanisms of action. As a result, a broader application of the CDK4/6 inhibitors in patients with cancer is achieved, contributing to enhanced optimized treatment in the adjuvant and neoadjuvant settings. Herein, the immunomodulatory activities of CDK4/6 inhibitors, their impact on the cell's metabolic state, and the effect on the decision of the cell to undergo quiescence or senescence are discussed. Moreover, this review provides an update on clinical trial outcomes and the differences in the underlying mechanisms between the distinct CDK4/6 inhibitors.

CD44: A New Prognostic Marker in Colorectal Cancer?

Cluster of differentiation 44 (CD44) is a non-kinase cell surface glycoprotein. It is overexpressed in several cell types, including cancer stem cells (CSCs). Cells overexpressing CD44 exhibit several CSC traits, such as self-renewal, epithelial-mesenchymal transition (EMT) capability, and resistance to chemo- and radiotherapy. The role of CD44 in maintaining stemness and the CSC function in tumor progression is accomplished by binding to its main ligand, hyaluronan (HA). The HA-CD44 complex activates several signaling pathways that lead to cell proliferation, adhesion, migration, and invasion. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The different functional roles of CD44s and specific CD44v isoforms still need to be fully understood. The clinicopathological impact of CD44 and its isoforms in promoting tumorigenesis suggests that CD44 could be a molecular target for cancer therapy. Furthermore, the recent association observed between CD44 and KRAS-dependent carcinomas and the potential correlations between CD44 and tumor mutational burden (TMB) and microsatellite instability (MSI) open new research scenarios for developing new strategies in cancer treatment. This review summarises current research regarding the different CD44 isoform structures, their roles, and functions in supporting tumorigenesis and discusses its therapeutic implications.

Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging.

Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical outcomes. Nevertheless, not all patients respond to treatment and some develop resistance. Therefore, the identification of predictive factors able to predict response to angiogenesis pathway blockade is required in order to identify the best candidates to receive these agents. Unfortunately, no predictive biomarkers have been prospectively validated to date. Over the years, research has focused on biologic factors such as genetic polymorphisms, circulating biomarkers, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and microRNA. Moreover, research efforts have evaluated the potential correlation of molecular biomarkers with imaging techniques used for tumor assessment as well as the application of imaging tools in clinical practice. In addition to functional imaging, radiomics, a relatively newer technique, shows real promise in the setting of correlating molecular medicine to radiological phenotypes.

Durvalumab Plus Gemcitabine and Cisplatin Versus Gemcitabine and Cisplatin in Biliary Tract Cancer: a Real-World Retrospective, Multicenter Study.

BACKGROUND: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed cell death ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). OBJECTIVE: The present study investigated for the first time the impact on survival of adding durvalumab to cisplatin/gemcitabine compared with cisplatin/gemcitabine in a real-world setting. PATIENTS AND METHODS: The analyzed population included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab in combination with cisplatin/gemcitabine or with cisplatin/gemcitabine alone. The impact of adding durvalumab to chemotherapy in terms of overall survival (OS) and progression free survival (PFS) was investigated with univariate and multivariate analysis. RESULTS: Overall, 563 patients were included in the analysis: 213 received cisplatin/gemcitabine alone, 350 received cisplatin/gemcitabine plus durvalumab. At the univariate analysis, the addition of durvalumab was found to have an impact on survival, with a median OS of 14.8 months versus 11.2 months [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50-0.80, p = 0.0002] in patients who received cisplatin/gemcitabine plus durvalumab compared to those who received cisplatin/gemcitabine alone. At the univariate analysis for PFS, the addition of durvalumab to cisplatin/gemcitabine demonstrated a survival impact, with a median PFS of 8.3 months and 6.0 months (HR 0.57, 95% CI 0.47-0.70, p < 0.0001) in patients who received cisplatin/gemcitabine plus durvalumab and cisplatin/gemcitabine alone, respectively. The multivariate analysis confirmed that adding durvalumab to cisplatin/gemcitabine is an independent prognostic factor for OS and PFS, with patients > 70 years old and those affected by locally advanced disease experiencing the highest survival benefit. Finally, an exploratory analysis of prognostic factors was performed in the cohort of patients who received durvalumab: neutrophil-lymphocyte ratio (NLR) and disease stage were to be independent prognostic factors in terms of OS. The interaction test highlighted NLR ≤ 3, Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0, and locally advanced disease as positive predictive factors for OS on cisplatin/gemcitabine plus durvalumab. CONCLUSION: In line with the results of the TOPAZ-1 trial, adding durvalumab to cisplatin/gemcitabine has been confirmed to confer a survival benefit in terms of OS and PFS in a real-world setting of patients with advanced BTC.

Effect of Cancer-Related Cachexia and Associated Changes in Nutritional Status, Inflammatory Status, and Muscle Mass on Immunotherapy Efficacy and Survival in Patients with Advanced Non-Small Cell Lung Cancer.

Immune checkpoint inhibitor (ICI)-based immunotherapy has significantly improved the survival of patients with advanced non-small cell lung cancer (NSCLC); however, a significant percentage of patients do not benefit from this approach, and predictive biomarkers are needed. Increasing evidence demonstrates that cachexia, a complex syndrome driven by cancer-related chronic inflammation often encountered in patients with NSCLC, may impair the immune response and ICI efficacy. Herein, we carried out a prospective study aimed at evaluating the prognostic and predictive role of cachexia with the related changes in nutritional, metabolic, and inflammatory parameters (assessed by the multidimensional miniCASCO tool) on the survival and clinical response (i.e., disease control rate) to ICI-based immunotherapy in patients with advanced NSCLC. We included 74 consecutive patients. Upon multivariate regression analysis, we found a negative association between IL-6 levels (odds ratio (OR) = 0.9036; 95%CI = 0.8408-0.9711; p = 0.0025) and the miniCASCO score (OR = 0.9768; 95%CI = 0.9102-0.9999; p = 0.0310) with the clinical response. As for survival outcomes, multivariate COX regression analysis found that IL-6 levels and miniCASCO-based cachexia severity significantly affected PFS (hazard ratio (HR) = 1.0388; 95%CI = 1.0230-1.0548; p < 0.001 and HR = 1.2587; 95%CI = 1.0850-1.4602; p = 0.0024, respectively) and OS (HR = 1.0404; 95%CI = 1.0221-1.0589; p < 0.0001 and HR = 2.3834; 95%CI = 1.1504-4.9378; p = 0.0194, respectively). A comparison of the survival curves by Kaplan-Meier analysis showed a significantly lower OS in patients with cachexia versus those without cachexia (p = 0.0323), as well as higher miniCASCO-based cachexia severity (p = 0.0428), an mGPS of 2 versus those with a lower mGPS (p = 0.0074), and higher IL-6 levels (>6 ng/mL) versus those with lower IL-6 levels (≤6 ng/mL) (p = 0.0120). In conclusion, our study supports the evidence that cachexia, with its related changes in inflammatory, body composition, and nutritional parameters, is a key prognostic and predictive factor for ICIs. Further larger studies are needed to confirm these findings and to explore the potential benefit of counteracting cachexia to improve immunotherapy efficacy.

Fibroblast growth factor receptors as targets for anticancer therapy in cholangiocarcinomas and urothelial carcinomas.

Cholangiocarcinomas and urothelial carcinomas are lethal tumors worldwide and only a minority of patients are eligible for surgery at diagnosis. Moreover, patients are poorly responsive to current therapeutic strategies, including chemotherapy, radiotherapy, immunotherapy, and multimodality treatments. Recently, several advances have been made in precision medicine and these results are modifying the treatment paradigm for patients diagnosed with cholangiocarcinomas and urothelial carcinoma. These histotypes exhibit a high rate of multiple fibroblast growth factor receptor (FGFR) genetic alterations and numerous preclinical and clinical studies support FGFR as a highly attractive novel therapeutic target. Moreover, identifying specific genetic alterations may predict the tumor's response to conventional and novel FGFR-targeted drugs. Recent clinical studies showed promising data for FGFR-targeted therapy in reducing tumor volume and led to the United States Food and Drug Administration (FDA) approval of, e.g., pemigatinib, infigratinib, futibatinib, and erdafitinib. Moreover, FGFR inhibitors show promising results in the first-line setting of cholangiocarcinomas and urothelial carcinomas. Pemigatinib (FIGHT-302) and futibatinib (FOENIX-CAA3) are being evaluated in phase III trials that compare these agents to current first-line gemcitabine and cisplatin in FGFR2-rearranged cholangiocarcinoma. However, complexity in targeting the FGFR signaling pathway is observed. Herein, we describe the characteristics of the FDA-approved and other investigational FGFR-targeted therapeutics, evaluate the most recent preclinical and clinical studies focusing on targeting FGFR genomic alterations in the treatment of cholangiocarcinomas and urothelial cancer, and provide insight into factors involved in response and (acquired) resistance to FGFR inhibition.

New Horizons in Metastatic Colorectal Cancer: Prognostic Role of CD44 Expression.

BACKGROUND: The transmembrane glycoprotein CD44, the major hyaluronan (HA) receptor, has been proven to regulate cell growth, survival, differentiation, and migration. It is therefore widely considered to be involved in carcinogenesis. Its role as a new therapeutic target in solid tumors is under evaluation in clinical trials. The prognostic value remains controversial. Here, we aimed to investigate the correlation between CD44 expression and the clinicopathological features and survival in metastatic colorectal cancer (mCRC) patients. METHODS: Data from 65 mCRC patients of the Medical Oncology Unit, University Hospital and University of Cagliari were retrospectively collected from 2008 to 2021. Immunohistochemical analysis was performed at the Pathology Division, University Hospital of Cagliari on 3 µm thick sections obtained from paraffin blocks. The intensity of immunohistochemical staining was subclassified into four groups: score 0 if negative or weak membrane staining in less than 10% of tumor cells; score 1+ if weak membrane staining in at least 10% of tumor cells or moderate membrane staining in less than 10% of tumor cells; score 2+ if moderate membrane staining in at least 10% of tumor cells or intensive membrane staining in less than 10% of tumor cells; score 3+ if intense membrane staining in at least 10% of tumor cells. Based on this score, we distinguished patients into low CD44 expression (score 0, 1+, 2+) and high CD44 expression (score 3+). Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; association between categorical variables: Fisher's exact test). RESULTS: Patients' median age was 66 years (range 49-85). Regarding CD44 expression, score was 0 in 18 patients, 1+ in 15 patients, 2+ in 18 patients, and 3+ in 14 patients. Median overall survival (mOS) was 28.1 months (95%CI: 21.3-101). CD44 overexpression (3+) was correlated with poor prognosis (p = 0.0011; HR = 0.2), with a mOS of 14.5 months (95%CI 11.7 to 35.9) versus 30.7 months (95%CI 27.8 to 101) in lower CD44 expression. Higher CD44 expression was associated with clinically poor prognostic features: age ≥ 70 years (p = 0.0166); inoperable disease (p = 0.0008); stage IV at diagnosis (p = 0.0241); BRAF mutated (p = 0.0111), high-grade tumor (p = 0.0084). CONCLUSIONS: CD44 markedly correlated with aggressive tumor behavior and contributed to the earlier progression of disease, thus suggesting its role as a novel prognostic marker and potential therapeutic target for mCRC patients.

Influence of antidiabetic drugs on glucose metabolism and immune response in patients with metastatic pancreatic ductal adenocarcinoma receiving gemcitabine plus nab-paclitaxel as first-line treatment.

BACKGROUND: Association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated. Indeed, DM2 can be both an epiphenomenon of PDAC and a risk factor. The present study aimed to investigate the correlation between overall survival (OS) and antidiabetic drugs in patients with metastatic pancreatic ductal adenocarcinoma and DM2. METHOD: Data from 232 patients were collected retrospectively from 2014 to 2021. 174 from AOU Cagliari Medical Oncology and 58 from AOU Ancona Medical Oncology. All patients received gemcitabine plus nab-paclitaxel first-line chemotherapy. We aimed to evaluate the correlation between DM2, anti-diabetic medications and overall survival. Survival distribution was assessed by Kaplan-Meier curves. RESULTS: Median age was 68±9, 127 (55%) were male. 138/232 (59%) patients were not affected by DM2, 94/232 (41%) were affected by DM2. 57 were insulin-treated and 37 were metformin-treated. DM2 treated patients showed an higher median overall survival (26 vs 12 months, p = 0,0002). Among DM2 patients insulin-treated and metformin-treated showed an mOS of 21 months and 33 months, respectively. CONCLUSIONS: Results showed a correlation between treated DM2 and higher mOS in patients with mPDAC. Limitations due to retrospective data collection must be considered. Further studies in this setting are needed.

Primary adrenal insufficiency induced by immune checkpoint inhibitors: biological, clinical, and radiological aspects.

Immune checkpoint inhibitors (ICI) have become a cornerstone in medical oncology, with evolving therapeutic strategies and applications. These monoclonal antibodies, designed to enhance immune responses, have revealed a spectrum of immune-related adverse events (irAEs). While many irAEs exhibit favorable responses to corticosteroid or immunosuppressive therapy, most ICI-related endocrinopathies necessitate lifelong replacement therapy and pose significant clinical challenges. Adrenal insufficiency (AI), a noteworthy endocrine irAE, can manifest as primary AI (PAI) or secondary AI (SAI), resulting from adrenal or pituitary gland dysfunction, respectively. ICI-induced AI, albeit relatively infrequent, occurs in 1-2% of patients receiving single-agent anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) or Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) therapies and in a higher range of 4-9% when ICIs are used in combinations. Recognizing and addressing ICI-induced PAI is crucial, as it often presents with acute and potentially life-threatening symptoms, especially considering the expanding use of ICI therapy. This review provides an updated overview of ICI-induced PAI, exploring its clinical, diagnostic, and radiological aspects.