Uncovering key targets of success for immunotherapy in pancreatic cancer.

INTRODUCTION: Despite available treatment options, pancreatic ductal adenocarcinoma (PDAC) is frequently lethal. Recent immunotherapy strategies have failed to yield any notable impact. Therefore, research is focussed on unearthing new drug targets and therapeutic strategies to tackle this malignancy and attain more positive outcomes for patients. AREAS COVERED: In this perspective article, we evaluate the main resistance mechanisms to immune checkpoint inhibitors (ICIs) and the approaches to circumvent them. We also offer an assessment of concluded and ongoing trials of PDAC immunotherapy. Literature research was performed on Pubmed accessible through keywords such as: 'pancreatic ductal adenocarcinoma,' 'immunotherapy,' 'immunotherapy resistance,' 'immune escape,' 'biomarkers.' Papers published between 2000 and 2021 were selected. EXPERT OPINION: The tumor microenvironment is a critical variable of treatment resistance because of its role as a physical barrier and inhibitory immune signaling. Promising therapeutic strategies appear to be a combination of immunotherapeutics with other targeted treatments. Going forward, predictive biomarkers are required to improve patient selection. Biomarker-driven trials could enhance approaches for assessing the role of immunotherapy in PDAC.

Emerging treatment evolutions and integrated molecular characteristics of biliary tract cancers.

Biliary tract cancers (BTCs) consist of a group of highly heterogeneous malignancies that are characterized by genomic differences among tumors from different anatomic sites. The current treatment for BTC includes surgery, chemotherapy, target therapy, and immunotherapy. Although surgery remains the primary option for localized disease, representing the only potential curative treatment, a high risk of recurrence cannot be neglected. Chemotherapy has been considered the standard of care for both advanced and metastatic disease and in adjuvant settings. However, drug resistance is a major obstacle associated with chemotherapy. The development of genetic testing technologies, including next-generation sequencing, has opened the door for the identification of drug targets and candidate molecules. A series of preclinical studies has demonstrated the role of gene mutations, abnormal signaling pathways, and immunosuppression in the pathogenesis of BTC, laying the foundation for the application of targeted therapy and immunotherapy. A variety of molecularly targeted agents, including pemigatinib, have shown promising survival benefits in patients with advanced disease. The rapidly evolving role of multimodal therapy represents the subject of this review.

The Difficult Task of Diagnosing Depression in Elderly People with Cancer: A Systematic Review.

Background: Depression is a common psychiatric problem in the elderly and oncology patients. In elderly people with cancer, depression has a peculiar phenomenology. It has a significant impact on the quality of life. Moreover, it is associated with poor adherence to treatments, increased risk of suicide, and mortality. Nevertheless, the topic of depression in elderly people with cancer remains unexplored. Objective: The main goal of this article is to review the literature from the past 20 years on the relationships between depression, cancer, and aging. Methods: The methods followed the Prisma model for eligibility of studies. The articles in which the keywords "depression", "cancer", " elderly, aging, or geriatric" were present, either in the text or in the abstract, were selected. 8.056 articles, by matching the keywords "depression and elderly and cancer," were identified. Only 532 papers met the eligibility criteria of search limits and selection process. Out of 532 papers, 467 were considered irrelevant, leaving 65 relevant studies. Out of 65 suitable studies, 39 (60.0%) met our quality criteria and were included. Results: The risk factors associated with depression in elderly people with cancer can be divided into 4 groups: 1) tumor-related; 2) anticancer treatment-related; 3) patients-related; 4) number and type of comorbidity. The main obstacles in diagnosing depression in elderly patients with cancer are the overlap of the symptoms of cancer and side effects of treatment with the symptoms of depression but also the different ways of reporting depressive symptoms of elderly people and the different clinical types of depression. There is a lack of data regarding validated scales to assess depression in geriatric patients with cancer. Any mental illness, specifically co-occurring anxiety and depression, increases the risk of diagnosis delay and anticancer treatment adherence. Cancer and the diagnosis of mental disorders prior to cancer diagnosis correlate with an increased risk for suicide. A non-pharmacological therapeutic approach, pharmacological treatment and/or a combination of both can be used to treat elderly patients with cancer, but a detailed analysis of comorbidities and the assessment of polypharmacy is mandatory in order to avoid potential side-effects and interactions between antidepressants and the other drugs taken by the patients. Conclusion: Future research should be conducted with the aim of developing a modified and adapted assessment method for the diagnosis and treatment of depression in elderly people with cancer in order to improve their clinical outcomes and quality of life.

Introducing immunotherapy for advanced hepatocellular carcinoma patients: Too early or too fast?

Advanced hepatocellular carcinoma (HCC) is the most frequent liver cancer. Immunotherapy has been explored in this disease in order to improve survival outcomes. Nowadays, scientific research is focusing especially on immune checkpoint inhibitors, in particular anti-PD1, anti-PD-L1 and anti-CTLA4 monoclonal antibodies (mAbs), as single-agent or in combination with other immunotherapy agents, target therapies, anti-vascular endothelial growth factor (VEGF) and other agents targeting specific molecular pathways. Other immunotherapy strategies have been assessed or are under investigation in advanced HCC, namely cytokines, adoptive cell therapy, oncolytic virus, cancer vaccines. Each treatment presents specific efficacy and toxicity profiles, strictly related to their mechanism of action and to advanced HCC tumour microenvironment (TME). The aim of this review is to outline the state-of-the-art of immunotherapy in advanced HCC treatment, highlighting data on already investigated treatment strategies, safety and toxicity (including HBV/HCV-related HCC), and ongoing clinical trials focusing on new promising therapeutic weapons.

Retrospective survival analysis in patients with metastatic pancreatic ductal adenocarcinoma with insulin-treated type 2 diabetes mellitus.

INTRODUCTION: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated and the role of antidiabetic medications such as metformin has also been investigated. The objective of this study was to examine the association between insulin use and overall survival (OS) in patients with advanced PDAC and DM2. METHODS: We retrospectively collected data from 164 patients, including an exploratory cohort of 96 patients from Medical Oncology Unit, University Hospital and University of Cagliari, Italy, and a validation cohort of 68 patients from Medical Oncology of Modena University Hospital. Patients had metastatic disease and received a first-line gemcitabine-based chemotherapy and, subsequently, a second-line fluoropyrimidines-based chemotherapy. We performed univariate analysis to evaluate correlation between long-term diabetes and overall survival. Then we performed multivariate analysis, adjusting for sex, metastatic sites, Eastern Cooperative Oncology Group Performance Status, Ca19.9 levels, N/L ratio, and lactate dehydrogenase levels at diagnosis, to confirm the independence of the variable. RESULTS: In the exploratory cohort, DM2 was significantly associated with higher median OS at univariate analysis (16 vs 10 months; p = 0.004). This result was confirmed by validation cohort (11 months vs 6 months; p = 0.01). In multivariate analysis, insulin-treated patients compared with non diabetic patients showed a significantly increased survival of 4.6 months (p = 0.03). CONCLUSIONS: Patients with insulin-treated metastatic PDAC showed better OS than non diabetic patients, as demonstrated by both cohorts. The correlation between OS and insulin-treated DM2 should be investigated further through a prospective clinical trial.

Molecular-Biology-Driven Treatment for Metastatic Colorectal Cancer.

BACKGROUND: Metastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients. METHODS: A review of clinical trials, retrospective studies and case reports was performed regarding molecular biomarkers with therapeutic implications. RESULTS: RAS wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of RAS status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for BRAFV600E mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (POLE-1) mutant patients. Data are still lacking on NTRK, RET, MGMT, and TGF-ß, which require further research. CONCLUSION: Several molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients.

Immune Checkpoint Inhibitors in the Treatment of HCC.

Hepatocellular carcinoma (HCC) is the typical inflammation-induced neoplasia. It often prospers where a chronic liver disease persists, thus leading a strong rationale for immune therapy. Several immune-based treatments, including immune checkpoint inhibitors (ICI), cytokines, adoptive cell transfer, and vaccines, have been tested in the treatment of HCC. In this review, we summarize the role of the ICI in HCC patients in various sets of treatment. As for advanced HCC, the anti-Programmed cell Death protein 1 (PD1) antibodies and the anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibodies have been examined in patients with enthusiastic results in phase I-II-III studies. Overall, this led the Food and Drug Administration (FDA) to approve pembrolizumab, nivolumab, and nivolumab + ipilimumab in the second-line setting. The anti- Programmed Death-Ligand 1 (PDL-1) antibodies have also been evaluated. Thanks to the results obtained from phase III IMbrave study, atezolizumab + bevacizumab is now the standard of care in the first-line advanced setting of HCC. As for localized HCC, the putative immunological effect of locoregional therapies led to evaluate the combination strategy with ICI. This way, chemoembolization, ablation with radiofrequency, and radioembolization combined with ICI are currently under study. Likewise, the study of adjuvant immunotherapy following surgical resection is underway. In addition, the different ICI has been studied in combination with other ICI as well as with multikinase inhibitors and anti-angiogenesis monoclonal antibody. The evidence available suggests that combining systemic therapies and locoregional treatments with ICI may represent an effective strategy in this context.

New therapeutic targets in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor survival. Of all newly diagnosed patients, only about 20% can benefit from a potentially curative surgical resection, the remaining 80% presenting with unresectable locally advanced (LAPC) or metastatic (MPC) disease. Currently, there are limited therapeutic options for LAPC and MPC patients. Furthermore, despite intensive research efforts to better understand the molecular bases of PDAC and the biological relevance of its tumor microenvironment, treatments still largely consist of classical cytotoxic chemotherapy agents. Several studies of genetic and epigenetic sequencing have demonstrated the existence of 4 molecular PDAC subtypes, with heterogeneous genetic characteristics and different biological behaviour: squamous, pancreatic progenitor, immunogenic and aberrantly differentiated endocrine exocrine (ADEX). These distinct subtypes derive from alterations at multiple levels. Apart from the DNA repair pathway, however, none of these has so far been validated as a clinically relevant therapeutic target. Also, PDAC is unique from an immunological perspective and many studies have recently tried to elucidate the role of intratumoral effector T-cells, RAS oncogene, immunosuppressive leukocytes and desmoplastic reaction in maintaining the immunological homeostasis of this disease. However, there still remains much to be learned about the mechanisms whereby the pancreatic immune microenvironment promotes immune escape of cancer cells. Furthermore, while therapies targeting the stroma as well as immunotherapies hold promise for the future, these are not yet standard of care. This review aims to outline the state-of-the-art of LAPC and MPC treatment, highlighting data on the target therapies failure and current ongoing clinical trials on new promising therapeutic strategies.

BRAF-mutant colorectal cancer, a different breed evolving.

INTRODUCTION: BRAF mutant colorectal cancer (BRAF MT CRC) is a unique category of colorectal tumour with peculiar molecular, pathological and clinical features and poor prognosis; despite recent research, BRAF mutation predictive value and standard treatment of BRAF MT CRC still have to be defined. In this review, we focused on this challenging topic. Areas covered: The potential use of BRAF mutational status among recent additional prognostic and predictive indicators and current treatment strategy in use in these patients is discussed. Moreover, implications and characteristics of new BRAF mutations other than BRAFV600E are analyzed. An in-deep outlook on the immediate future for clinical and translational research in this subgroup of patients is also presented, such as combination therapy with agents targeting the RAS/RAF/MEK/ERK pathway and standard chemotherapy in order to overcome resistance. We performed a research on Pubmed typing 'BRAF mutation', 'colorectal cancer', 'predictive and prognostic value', 'targeted therapy', 'BRAF inhibition'. Expert commentary: BRAFV600E mutation represents a strong, independent negative prognostic factor in II-III stage MSS CRC and mCRC. The best treatment still has to be identified; currently, in good performance status patients, an intensive-chemotherapy-combination remains the standard of care. Further investigations are warranted to explore new horizons to change BRAF MT mCRC outcomes.