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Background: Breast cancer remains the leading cause of cancer-related deaths among women despite advances in early detection. Neoadjuvant chemotherapy (NACT) is now standard for early-stage BC, with vitamin D (VD) emerging as a potential prognostic biomarker considering its positive pleiotropic effects. This review and meta-analysis assess the impact of baseline VD levels on outcomes in BC patients undergoing NACT. Methods: Inclusion criteria required patients to be over 18 years of age, have a pathologically confirmed BC diagnosis, and have their VD levels assessed prior to chemotherapy. Studies were included if they reported odds ratios (ORs) for response and/or hazard ratios (HRs) for PFS with 95% confidence intervals (CIs). A comprehensive literature search of PubMed/MEDLINE and Scopus/ELSEVIER (2014-2024) was conducted, and data were analyzed using fixed- and random-effects models, with Forest plots illustrating the results. Study quality and potential biases were assessed using the MINORS, NOS, and RoB2 scales, and statistical heterogeneity was evaluated with I 2 statistics and funnel plots. Results: Six studies were included in the analysis. All studies addressed stages II and III, with three also including stage I. The meta-analysis covered data from 722 patients regarding NACT response and 1033 patients for PFS. The results revealed a 22% reduction in the likelihood of non-response to NACT associated with adequate VD levels (low/deficient VD vs. high/sufficient VD; OR: 0.78; 95% CI: 0.30-1.25; p = 0.001) and a 35% reduction in progression risk with sufficient baseline VD levels (low/deficient VD vs. high/sufficient VD; HR: 0.65; 95% CI: 0.33-0.97; p < 0.001). Conclusions: These findings highlight the significance of maintaining adequate vitamin D levels in BC treatment and encourage further studies to unravel the role of VD on cancer biology.

Anthracycline-induced cardiomyopathies and sarcopenia are frequently seen in cancer patients, affecting their overall survival and quality of life; therefore, new cardioprotective and anti-sarcopenic strategies are needed. Vericiguat is a new oral guanylate cyclase activator that reduces heart failure hospitalizations or cardiovascular death. This study highlighted the potential cardioprotective and anti-sarcopenic properties of vericiguat during anthracycline therapy. Human cardiomyocytes and primary skeletal muscle cells were exposed to doxorubicin (DOXO) with or without a pre-treatment with vericiguat. Mitochondrial cell viability, LDH, and Cytochrome C release were performed to study cytoprotective properties. Intracellular Ca ++ content, TUNEL assay, cGMP, NLRP-3, Myd-88, and cytokine intracellular levels were quantified through colorimetric and selective ELISA methods. Vericiguat exerts significant cytoprotective and anti-apoptotic effects during exposure to doxorubicin. A drastic increase in cGMP expression and reduction in NLRP-3, MyD-88 levels were also seen in Vericiguat-DOXO groups vs. DOXO groups ( p < 0.001) in both cardiomyocytes and human muscle cells. GCa vericiguat reduces cytokines and chemokines involved in heart failure and sarcopenia. The findings that emerged from this study could provide the rationale for further preclinical and clinical investigations aimed at reducing anthracycline cardiotoxicity and sarcopenia in cancer patients.

The current surgical guidelines recommend an optimal margin width of 2 mm for the management of patients diagnosed with ductal carcinoma in situ (DCIS). However, there are still many controversies regarding re-excision when the optimal margin criteria are not met in the first resection. The purpose of this study is to understand the importance of surgical margin width, re-excision, and treatments to avoid additional surgery on locoregional recurrence (LRR). The study is retrospective and analyzed surgical margins, adjuvant treatments, re-excision, and LRR in patients with DCIS who underwent breast-conserving surgery (BCS). A total of 197 patients were enrolled. Re-operation for a close margin rate was 13.5%, and the 3-year recurrence was 7.6%. No difference in the LRR was reported among the patients subjected to BCS regardless of the margin width ( p = 0.295). The recurrence rate according to margin status was not significant ( p = 0.484). Approximately 36.9% (n: 79) patients had resection margins < 2 mm. A sub-analysis of patients with margins < 2 mm showed no difference in the recurrence between the patients treated with a second surgery and those treated with radiation ( p = 0.091). The recurrence rate according to margin status in patients with margins < 2 mm was not significant ( p = 0.161). The margin was not a predictive factor of LRR p = 0.999. Surgical re-excision should be avoided in patients with a focally positive margin and no evidence of the disease at post-surgical imaging.

The use of Vascular Endothelial Growth Factor inhibitors (VEGFi) has become prevalent in the field of medicine, given the high incidence of various pathological conditions necessitating VEGF inhibition within the general population. These conditions encompass a range of advanced neoplasms, such as colorectal cancer, non-small cell lung cancer, renal cancer, ovarian cancer, and others, along with ocular diseases. The utilization of VEGFi is not without potential risks and adverse effects, requiring healthcare providers to be well-prepared for identification and management. VEGFi can be broadly categorized into two groups: antibodies or chimeric proteins that specifically target VEGF (bevacizumab, ramucirumab, aflibercept, ranibizumab, and brolucizumab) and non-selective and selective small molecules (sunitinib, sorafenib, cabozantinib, lenvatinib, regorafenib, etc.) designed to impede intracellular signaling of the VEGF receptor (RTKi, receptor tyrosine kinase inhibitors). The presentation and mechanisms of adverse effects resulting from VEGFi depend primarily on this distinction and the route of drug administration (systemic or intra-vitreal). This review provides a thorough examination of the causes, recognition, management, and preventive strategies for VEGFi toxicities with the goal of offering support to oncologists in both clinical practice and the design of clinical trials.

KRAS is frequently mutated in tumors. It is mutated in approximately 30% of all cancer cases and in nearly 50% of cases of metastatic colorectal cancer (CRC), which is the third leading cause of cancer-related deaths worldwide. Recent advancements in understanding CRC biology and genetics have highlighted the significance of KRAS mutations in the progression of CRC. The KRAS gene encodes a small GTPase (Guanosine TriPhosphatases) that plays a key role in signaling pathways associated with important proteins involved in amplifying growth factor and receptor signals. Mutations in KRAS are frequently observed in codons 12 and 13, and these mutations have oncogenic properties. Abnormal activation of KRAS proteins strongly stimulates signals associated with various cancer-related processes in CRC, including cell proliferation, migration and neoangiogenesis. In this review, we explore the distinct prognostic implications of KRAS mutations. Specifically, the KRAS p.G12C mutation is associated with a worse prognosis in metastatic CRC. The correlation between structure, conformation and mutations is visually presented to emphasize how alterations in individual amino acids at the same position in a single protein can unexpectedly exhibit complex involvement in cancer. Last, KRAS p.G12C is discussed as an emerging and promising therapeutic target in metastatic CRC, providing a concise overview of available clinical data regarding the use of new inhibitors.

Background: Vitamin D (VD) has been implicated in several diseases, including colorectal cancer (CRC). This study aimed to determine whether there is an association between VD levels and time-to-outcome in stage III CRC patients through a systematic review and meta-analysis., Methods: The study adhered to the PRISMA 2020 statement. Articles were searched in PubMed/MEDLINE and Scopus/ELSEVIER. Four articles were selected, with the primary objective of providing a pooled estimate of the risk of death specifically in stage III CRC patients based on pre-operative VD levels. Study heterogeneity and publication bias were analyzed using Tau 2 statistics and funnel plots., Results: The selected studies showed significant heterogeneity regarding time-to-outcome, technical assessments, and serum VD concentration measures. The pooled analysis of 2628 and 2024 patients revealed a 38% and 13% increase in the risk of death (HR: 1.38, 95% CI: 0.71-2.71) and recurrence (HR: 1.13; 95% CI: 0.84-1.53), respectively, for random-effects models among patients with lower levels of VD., Conclusions: Our findings suggest that a low concentration of VD has a significant negative impact on time-to-outcome in stage III CRC.

Some cancer patients display a less aggressive form of metastatic disease, characterized by a low tumor burden and involving a smaller number of sites, which is referred to as "oligometastatic disease" (OMD). This review discusses new biomarkers, as well as methodological challenges and perspectives characterizing OMD. Recent studies have revealed that specific microRNA profiles, chromosome patterns, driver gene mutations ( ERBB2 , PBRM1 , SETD2 , KRAS , PIK3CA , SMAD4 ), polymorphisms ( TCF7L2 ), and levels of immune cell infiltration into metastases, depending on the tumor type, are associated with an oligometastatic behavior. This suggests that OMD could be a distinct disease with specific biological and molecular characteristics. Therefore, the heterogeneity of initial tumor burden and inclusion of OMD patients in clinical trials pose a crucial methodological question that requires responses in the near future. Additionally, a solid understanding of the molecular and biological features of OMD will be necessary to support and complete the clinical staging systems, enabling a better distinction of metastatic behavior and tailored treatments.

Cancer patients treated with immune checkpoint inhibitors (ICIs) are exposed to a high risk of atherosclerosis and cardiometabolic diseases due to systemic inflammatory conditions and immune-related atheroma destabilization. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein involved in metabolism of low-density lipoprotein (LDL) cholesterol. PCSK9 blocking agents are clinically available and involve monoclonal antibodies, and SiRNA reduces LDL levels in high-risk patients and atherosclerotic cardiovascular disease events in multiple patient cohorts. Moreover, PCSK9 induces peripheral immune tolerance (inhibition of cancer cell- immune recognition), reduces cardiac mitochondrial metabolism, and enhances cancer cell survival. The present review summarizes the potential benefits of PCSK9 inhibition through selective blocking antibodies and siRNA in patients with cancer, especially in those treated with ICIs therapies, in order to reduce atherosclerotic cardiovascular events and potentially improve ICIs-related anticancer functions.

CAM is used by about 40% of cancer patients in Western Countries, with peaks of 80% for breast cancer patients. Cancer patients use CAM to boost immune function, to control cancer symptoms and treatment-related side effects, and to improve health-related quality of life (HR-QoL) and survival. Unfortunately, self-prescription of natural remedies in cancer patients can lead to unexpected toxicities and can reduce the effectiveness of cancer therapy. Although CAM usually refers to all the "natural or organic" products/methods that are generally considered less toxic, there are concerns about drug interactions, especially in patients participating in clinical trials with experimental agents. Despite the claims of the promising and potential benefits made by prescribers, many CAMs lack clear scientific evidence of their safety and efficacy. Given the widespread use of CAM-both clearly declared and overt-in this review, we focused on the most important known data on the risk of interactions between biologics and oncology drugs with the goal of opening up CAM in accordance with the meaning of integrative medicine., Competing Interests: The Authors declare no conflict of interest.

Background: HIV-infected patients now have long life expectation since the introduction of the highly active antiretroviral therapy (HAART). Liver diseases, especially cirrhosis and hepatocellular carcinoma (HCC), currently represent a leading cause of death in this setting of patients., Aim: To address the results of liver transplantation (LT) for HCC in HIV-infected patients., Methods: All patients with and without HIV infection who underwent LT for HCC (n = 420) between 2001 and 2021 in our center were analyzed with the intent of comparing graft and patient survival. Cox regression analysis was used to determine prognostic survival factors and logistic regression to determine the predictor factors of post-LT recurrence., Results: Among 1010 LT, 32 were HIV-infected recipients. With an average follow-up of 62 ± 51 months, 5-year overall survival in LT recipients with and without HIV-infection was 71.6% and 69.9%, respectively ( p = ns), whereas 5-year graft survival in HIV-infected and HIV-non infected was 68.3% and 68.2%, respectively ( p = ns). The independent predictive factor of survival in the study group was: HCV infection (HR 1.83, p = 0.024). There were no significant differences in the pathological characteristics of HCC between the two groups. The logistic regression analysis of the study population demonstrated that microvascular invasion (HR 5.18, p < 0.001), HCC diameter (HR 1.16, p = 0.028), and number of HCC nodules (HR 1.26, p = 0.003) were predictors of recurrence post-LT., Conclusion: Our study shows that HIV patients undergoing LT for HCC have comparable results in terms of post-LT survival. Excellent results can be achieved for HIV-infected patients with HCC, as long as a strategy of close surveillance and precise treatment of the tumor is adopted while on the waiting list.

Background: Immune checkpoint inhibitors (ICI) plus radiotherapy (RT) have been suggested as an emerging combination in non-small cell lung cancer (NSCLC) patients. However, little is known about the magnitude of its benefits and potential clinical predictors., Objective: To assess the effects of this combination on the increase in overall and progression-free survival., Data Sources: The MEDLINE and CANCERLIT (1970-2020) electronic databases were searched, and the reference lists of included studies were manually searched., Study Selection: Studies were included if they were comparative studies between combination ICI-RT and ICI or RT alone in advanced or metastatic NSCLC patients. Overall survival (OS) was analyzed according to the treatment strategy., Data Extraction: Data on population, intervention, and outcomes were extracted from each study, in accordance with the intention-to-treat method, by two independent observers and combined using the DerSimonian method and Laird method., Results: Compared to ICI or RT alone, ICI-RT significantly increased the 1-year and 3-year OS RR by 0.75 (95% CI 0.64-0.88; p = 0.0003) and 0.85 (95% CI 0.78-0.93; p = 0.0006), respectively. Furthermore, there was a statistically significant benefit on 1- and 3-year progression-free survival (RR 0.73 (95% CI, 0.61-0.87; p = 0.0005) and RR 0.82 (95% CI 0.67-0.99; p = 0.04), respectively)., Conclusions: In patients with advanced or metastatic NSCLC, combination ICI-RT increases 1- and 3-year OS and progression-free survival compared to ICI or RT alone.

The anti-HER2 monoclonal antibody trastuzumab is a key drug for the treatment of HER2-positive gastric cancer (GC); however, its activity is often limited by the onset of resistance and mechanisms of resistance are still poorly understood. Several targeted agents showed synergistic activity by concomitant use with trastuzumab in vitro and are under clinical investigation. The aim of this study was to assess the antitumor activity of duligotuzumab, an anti HER3/EGFR antibody or ipatasertib, an AKT inhibitor, combined with trastuzumab in a panel of HER2-positive human gastric cancer cells (GCC), and the efficacy of such combinations in HER2-resistant cells. We have assessed the efficacy of duligotuzumab or ipatasertib and trastuzumab in combination, analyzing proliferation, migration and apoptosis and downstream intracellular signaling in vitro on human HER2-positive GCC (NCI-N87, OE33, OE19) and in negative HER2 GCC (MKN28). We observed a reduction of proliferation, migration and apoptotic rate in HER2-positive OE33, OE19 and N87 cell lines with the combination of duligotuzumab or ipatasertib plus trastuzumab. In particular, in OE33 and OE19 cell lines, the same combined treatment inhibited the activation of proteins downstream of HER2, HER3, AKT and MAPK pathways. Targeting both HER2 and HER3, or HER2 and AKT, results in an improved antitumor effect on HER2-positive GCC.

The coronavirus disease-2019 (COVID-19) is a highly transmissible viral illness caused by SARS-CoV-2, which has been defined by the World Health Organization as a pandemic, considering its remarkable transmission speed worldwide. SARS-CoV-2 interacts with angiotensin-converting enzyme 2 and TMPRSS2, which is a serine protease both expressed in lungs, the gastro-intestinal tract, and cardiac myocytes. Patients with COVID-19 experienced adverse cardiac events (hypertension, venous thromboembolism, arrhythmia, myocardial injury, fulminant myocarditis), and patients with previous cardiovascular disease have a higher risk of death. Cancer patients are extremely vulnerable with a high risk of viral infection and more negative prognosis than healthy people, and the magnitude of effects depends on the type of cancer, recent chemotherapy, radiotherapy, or surgery and other concomitant comorbidities (diabetes, cardiovascular diseases, metabolic syndrome). Patients with active cancer or those treated with cardiotoxic therapies may have heart damages exacerbated by SARS-CoV-2 infection than non-cancer patients. We highlight the cardiovascular side effects of COVID-19 focusing on the main outcomes in cancer patients in updated perspective and retrospective studies. We focus on the main cardio-metabolic risk factors in non-cancer and cancer patients and provide recommendations aimed to reduce cardiovascular events, morbidity, and mortality.

Direct-acting antivirals (DAAs) induce a rapid virologic response (SVR) in up to 99% of chronic hepatitis C patients. The role of SVR by DAAs on the incidence or recurrence of hepatocellular carcinoma (HCC) is still a matter of debate, although it is known that SVR does not eliminate the risk of HCC. In this review, we made an updated analysis of the literature data on the impact of SVR by DAAs on the risk of HCC as well as an assessment of risk factors and the role of epigenetics. Data showed that SVR has no impact on the occurrence of HCC in the short-medium term but reduces the risk of HCC in the medium-long term. A direct role of DAAs in the development of HCC has not been demonstrated, while the hypothesis of a reduction in immune surveillance in response to the rapid clearance of HCV and changes in the cytokine pattern influencing early carcinogenesis remains to be further elucidated. HCV induces epigenetic alterations such as modifications of the histone tail and DNA methylation, which are risk factors for HCC, and such changes are maintained after HCV clearance. Future epigenetic studies could lead to identify useful biomarkers and therapeutic targets. Cirrhosis has been identified as a risk factor for HCC, particularly if associated with high liver stiffness and α-fetoprotein values, diabetes and the male sex. Currently, considering the high number and health cost to follow subjects' post-HCV clearance by DAAs, it is mandatory to identify those at high risk of HCC to optimize management., Competing Interests: The authors declare no conflict of interest.