Estimating survival in patients with melanoma brain metastases: prognostic value of lactate dehydrogenase.

Patients with melanoma brain metastases (MBM) have poor prognosis, albeit advances in locoregional and systemic treatments. The melanoma-specific Graded Prognostic Assessment (GPA) effectively stratifies survival for patients with MBM. Nevertheless, lactate dehydrogenase (LDH), a well known prognostic factor for patients with melanoma, is not represented in the GPA scores and might add prognostic information for patients with MBM. In this study, 150 consecutive patients with MBM were retrospectively analyzed with the aim of evaluating independent prognostic factors for MBM patients, including LDH. Furthermore, we implemented a disease-specific prognostic score and estimated survival according to treatment modalities. On the basis of multivariable Cox regression analyses, six prognostic factors (age, BRAF status, number of MBM, number of extracranial metastatic sites, performance status, and LDH level) resulted statistically significant in terms of survival and were combined in a prognostic score to stratify patients in distinct prognostic groups ( P  < 0.0001). Among treatment modalities, a multimodal approach with stereotactic radiosurgery or neurosurgery associated with systemic therapy showed the best outcome (median overall survival: 12.32 months, 95% confidence interval, 7.92-25.30). This is the first study to demonstrate that LDH has independent prognostic value for patients with MBM and might be used to improve prognostic stratification, albeit external validation is mandatory. Survival of patients with MBM is affected by both disease-specific risk factors and treatment modalities, with locoregional treatments associated with better outcomes.

Preoperative treatments in borderline resectable and locally advanced pancreatic cancer: Current evidence and new perspectives.

Surgery is the only curative treatment for non-metastatic pancreatic adenocarcinoma, but less than 20 % of patients present a resectable disease at diagnosis. Treatment strategies and disease definition for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) vary in the different cancer centres. Preoperative chemotherapy (CT) is the standard of care for both BRPC and LAPC patients, however literature data are still controversial concerning the type, dose and duration of the different CT regimens, as well as regarding the integration of radiotherapy (RT) or chemoradiation (CRT) in the therapeutic algorithm. In this unsettled debate, we aimed at focusing on the therapeutic regimens currently in use and relative literature data, to report international trials comparing the available therapeutic options or explore the introduction of new pharmacological agents, and to analyse possible new scenarios in microenvironment evaluation before and after neoadjuvant therapies or in patients' selection at a molecular level.

An Integrated Pharmacological Counselling Approach to Guide Decision-Making in the Treatment with CDK4/6 Inhibitors for Metastatic Breast Cancer.

A wide inter-individual variability in the therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) has been reported. We herein present a case series of five patients treated with either palbociclib or ribociclib referred to our clinical pharmacological counselling, including therapeutic drug monitoring (TDM), pharmacogenetics, and drug-drug interaction analysis to support clinicians in the management of CDKis treatment for metastatic breast cancer. Patients' plasma samples for TDM analysis were collected at steady state and analyzed by an LC-MS/MS method for minimum plasma concentration (Cmin) evaluation. Under and overexposure to the drug were defined based on the mean Cmin values observed in population pharmacokinetic studies. Polymorphisms in selected genes encoding for proteins involved in drug absorption, distribution, metabolism, and elimination were analyzed (CYP3A4, CYP3A5, ABCB1, SLCO1B1, and ABCG2). Three of the five reported cases presented a CDKi plasma level above the population mean value and were referred for toxicity. One of them presented a low function ABCB1 haplotype (ABCB1-rs1128503, rs1045642, and rs2032582), possibly causative of both increased drug oral absorption and plasmatic concentration. Two patients showed underexposure to CDKis, and one of them was referred for early progression. In one patient, a CYP3A5*1/*3 genotype was found to be potentially responsible for more efficient drug metabolism and lower drug plasma concentration. This intensified pharmacological approach in clinical practice has been shown to be potentially effective in supporting prescribing oncologists with dose and drug selection and could be ultimately useful for increasing both the safety and efficacy profiles of CDKi treatment.

Multidisciplinary Team Meeting Proposal and Final Therapeutic Choice in Early Breast Cancer: Is There an Agreement?

Background: A multidisciplinary team meeting (MDM) approach in breast cancer (BC) management is a standard of care. One of the roles of MDMs is to identify the best diagnostic and therapeutic strategies for patients (pts) with new diagnosis of early BC. The purpose of this study was to define whether there was an agreement between the planned program (i.e., MDMs-based decision) and that actually applied. In addition, the study explored factors associated with discordance. Methods: We conducted a retrospective study of a consecutive series of 291 patients with new diagnosis of early BC, discussed at MDMs at the University Hospital of Udine (Italy), from January 2017 to June 2018. The association between clinico-biological factors and discordance between what was decided during the MDMs and what was consequently applied by the oncologist was explored through uni- and multivariate logistic regression analyses. Results: The median age was 62 years (range 27-88 years). Among invasive early BC patients, the most frequent phenotype was luminal A (38%), followed by luminal B (33%), HER2-positive (12%), and triple-negative (5%). In situ carcinoma (DCIS) represented 12% of cases. The median time from MDM discussion to first oncologic examination was 2 weeks. The rate of discordance between MDM-based decision and final choice, during a face-to-face consultation with the oncologist, was 15.8% (46/291). The most frequent reason for changing the MDM-based program was clinical decision (87%). Follow-up was preferred to the chemotherapy (CT) proposed within the MDMs in 15% of cases, and to the endocrine therapy (ET) in 39% of cases (among these, 44.5% had a diagnosis of DCIS). Therapeutic change from sequential CT-ET to ET alone was chosen in 16/46 pts (35%): among these patients, seven had a luminal B disease and six had an HER2-positive disease. On univariate analysis, factors associated with discordance were values of Ki-67 14%-30% (OR 3.91; 95% CI 1.19-12.9), age >70 years (OR 2.44, 95% CI 1.28-4.63), housewife/retired status (OR 2.35, 95% CI 1.14-4.85), polypharmacy (OR 1.95; 95% CI 1.02-3.72), postmenopausal status (OR 4.15; 95% CI 1.58-10.9), and high Charlson Comorbidity Index (OR 1.31; 95% CI 1.09-1.57). The association with marital status, educational level, alcohol and smoke habits, presence of a caregiver, parity, grading, histotype and phenotype, and stage was not statistically significant. On multivariate analysis, only Ki-67 value maintained its statistical significance. Conclusion: The results of our study could be useful for enhancing the role of MDMs in the clinical decision-making process in early BC.

BRAF and MEK Inhibitors and Their Toxicities: A Meta-Analysis.

PURPOSE: This meta-analysis summarizes the incidence of treatment-related adverse events (AE) of BRAFi and MEKi. METHODS: A systematic search of Medline/PubMed was conducted to identify suitable articles published in English up to 31 December 2021. The primary outcomes were profiles for all-grade and grade 3 or higher treatment-related AEs, and the analysis of single side effects belonging to both categories. RESULTS: The overall incidence of treatment-related all-grade Aes was 99% for Encorafenib (95% CI: 0.97-1.00) and 97% for Trametinib (95% CI: 0.92-0.99; I2 = 66%) and Binimetinib (95% CI: 0.94-0.99; I2 = 0%). In combined therapies, the rate was 98% for both Vemurafenib + Cobimetinib (95% CI: 0.96-0.99; I2 = 77%) and Encorafenib + Binimetinib (95% CI: 0.96-1.00). Grade 3 or higher adverse events were reported in 69% of cases for Binimetinib (95% CI: 0.50-0.84; I2 = 71%), 68% for Encorafenib (95% CI: 0.61-0.74), and 72% for Vemurafenib + Cobimetinib (95% CI: 0.65-0.79; I2 = 84%). The most common grade 1-2 AEs were pyrexia (43%) and fatigue (28%) for Dabrafenib + Trametinib and diarrhea for both Vemurafenib + Cobimetinib (52%) and Encorafenib + Binimetinib (34%). The most common AEs of grade 3 or higher were pyrexia, rash, and hypertension for Dabrafenib + Trametinib (6%), rash and hypertension for Encorafenib + Binimetinib (6%), and increased AST and ALT for Vemurafenib + Cobimetinib (10%). CONCLUSIONS: Our study provides comprehensive data on treatment-related adverse events of BRAFi and MEKi combination therapies, showing related toxicity profiles to offer a helpful tool for clinicians in the choice of therapy.

NAFLD-Related Hepatocarcinoma: The Malignant Side of Metabolic Syndrome.

Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the second leading cause of cancer-related mortality. HCC typically arises within a cirrhotic liver, but in about 20% of cases occurs in absence of cirrhosis. Among non-cirrhotic risk factors, non-alcoholic fatty liver disease (NAFLD) currently represents the most important emerging cause of HCC in developed countries. It has been estimated that annual incidence of HCC among patients with non-cirrhotic NAFLD is approximately 0.1-1.3 per 1000 patients/year and ranges from 0.5% to 2.6% among patients with non-alcoholic steatohepatitis (NASH) cirrhosis. However, only a few clinical trials enrolling HCC patients actually distinguished NAFLD/NASH-related cases from other non-cirrhotic causes and therefore evidence is still lacking in this subset of patients. This review aims to describe the biology underpinning NAFLD development, to investigate the main molecular pathways involved in its progression to NASH and HCC and to describe how different pathogenetic mechanisms underlying the onset of HCC can have an impact in clinical practice. We hereby also provide an overview of current HCC treatment options, with a particular focus on the available data on NAFLD-related cases in practice-changing clinical trials.

CDK4/6 Inhibitors in Melanoma: A Comprehensive Review.

Historically, metastatic melanoma was considered a highly lethal disease. However, recent advances in drug development have allowed a significative improvement in prognosis. In particular, BRAF/MEK inhibitors and anti-PD1 antibodies have completely revolutionized the management of this disease. Nonetheless, not all patients derive a benefit or a durable benefit from these therapies. To overtake this challenges, new clinically active compounds are being tested in the context of clinical trials. CDK4/6 inhibitors are drugs already available in clinical practice and preliminary evidence showed a promising activity also in melanoma. Herein we review the available literature to depict a comprehensive landscape about CDK4/6 inhibitors in melanoma. We present the molecular and genetic background that might justify the usage of these drugs, the preclinical evidence, the clinical available data, and the most promising ongoing clinical trials.

First- and second-line treatment strategies for hormone-receptor (HR)-positive HER2-negative metastatic breast cancer: A real-world study.

BACKGROUND: Endocrine therapy (ET) plus cyclin-dependent-kinases 4/6 inhibitors (CDK4/6i) represents the standard treatment for luminal-metastatic breast cancer (MBC). However, prospective head-to-head comparisons are still lacking for 1st line (L) options, and it is still crucial to define the best strategy between 1st and 2nd L. MATERIALS AND METHODS: 717 consecutive luminal-MBC pts treated between 2008 and 2020 were analyzed at the Oncology Department of Aviano and Udine, Italy. Differences about survival outcomes (OS, PFS and PPS) were tested by log-rank test. The attrition rate (AR) between 1st and 2ndL was calculated. RESULTS: At 1stL, pts were treated with ET (49%), chemotherapy (CT) (31%) and ET-CDKi (20%) while, at 2ndL, 33% received ET, 33% CT and 8% ET-CDKi. Overall AR was 10%, 7% for CT, 8% for ET and 17% for ET-CDKi. By multivariate analysis, 1stL ET-CDK4/6i showed a better mPFS1 and OS. Moreover, 2ndL ET-CDK4/6i demonstrated better mPFS2 compared to ET and CT. Notably, 1stL ET-CDKi resulted in higher mPFS than 2ndL ET-CDKi. Intriguingly, 1stL ET-CDK4/6i was associated with worse mPPS compared to CT and ET. Secondarily, 1stL ET-CDK4/6i followed by CT had worse OS compared to 1stL ET-CDK4/6i followed by ET. Notably, none of baseline characteristics at 2ndL influenced 2ndL treatment choice (ET vs. CT) after ET-CDKi. CONCLUSION: Our real-world data demonstrated that ET-CDKi represents the best option for 1stL luminal-MBC compared to ET and CT. Also, the present study pointed out that 2ndL ET, potentially combined with other molecules, could be a feasible option after CDK4/6i failure, postponing CT on later lines.