Aim The aim of this study is to investigate the incidence and risk of hepatic toxicity in patients receiving tyrosine kinase inhibitors (TKIs) through a large up‐to‐date meta‐analysis of available clinical trials. Methods PubMed was reviewed for phase III randomized trials with axitinib, pazopanib, sorafenib, sunitinib, regorafenib or vandetanib. The characteristics of each study and incidence of all and high grades of ALT, AST and total bilirubin increase were collected. Results A total of 3691 patients was available for meta‐analysis, 1170 had metastatic renal cell carcinoma; 950 had advanced non‐small cell lung carcinoma, 454 had hepatocarcinoma, 753 had metastatic colorectal cancer and 362 had metastatic soft‐tissue sarcoma. The incidence of ALT, AST and bilirubin increase of any grade in patients treated with TKIs was 34.0% (95% CI 31.6, 36.3), 39.2% (95% CI 36.7, 41.6) and 21.8% (95% CI 19.9, 23.7), respectively. The incidence of the high grade increase was 5.2% (95% CI 4.2, 6.4), 5.0% (95% CI, 3.8, 6.2) and 1.7% (95% CI 1.1, 2.4), respectively. The relative risk of ALT, AST and total bilirubin increase was 1.85, 2.19 and 1.79 for any grade and 2.75, 2.39 and 1.65 for high grade, respectively. Conclusions Hepatotoxicity is a relative common event occurring in 23–40% of patients treated with TKIs. Despite this, only 5% of patients have had high grade of toxicity. A better knowledge of this phenomenon may prevent high grade toxicity and reduce treatment discontinuation due to this adverse event.

Unresectable recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) has a very poor prognosis. Soluble immune checkpoints (sICs) are circulating proteins that result from the alternative splicing of membrane proteins and can modulate the immune response to cancer cells. The aim of our pilot study was to determine the possible role of a comprehensive evaluation of sICs in the classification of prognosis and response to treatment in patients with advanced disease. We evaluated several sICs (CD137, CTLA-4, PD-1, PD-L1, PD-L2, TIM3, LAG3, GITR, HVEM, BTLA, IDO, CD80, CD27, and CD28) from peripheral blood at baseline and investigated the association with clinical characteristics and outcomes. A high baseline soluble LAG3 (sLAG3 > 377 pg/mL) resulted in an association with poor PFS and OS (p = 0.047 and p = 0.003, respectively). Moreover, sLAG3 emerged as an independent prognostic factor using an MVA (p = 0.005). The evaluation of sICs, in particular sLAG3, may be relevant for identifying patients with worse prognoses, or resistance to treatments, and may lead to the development of novel targeted strategies.

Background. mTOR inhibitors are currently used in the treatment of solid malignancies. Since their approval, several cases of pulmonary toxicity (PT) have been described. This analysis aims to report the incidence and the risk of PT in published randomized controlled trials. Material and methods. PubMed and Scopus were reviewed for phase II–III randomized controlled trials with temsirolimus and everolimus. The characteristic of each study and incidence of all- and high-grades PT were collected. Results. A total of 2233 patients were available for meta-analysis: 989 had breast cancer, 833 had neuroendocrine tumor and 411 had metastatic renal cell carcinoma. In patients taking mTOR inhibitors, the incidence of all- and high-grades PT was 10.4% and 2.4%, respectively. Compared to controls, the relative risk for all- and high-grades PT was 31- and 8.8-folds, respectively. No significant heterogeneity was observed between the studies. Not any relationship was found between the incidence of lung metastases, treatment exposure and the incidence of PT. Conclusions. The high grade PT is a rare event and 10% of patients may experience mild grade toxicity with a worsening of quality of life and interruption of therapy in some cases. We recommend monitoring of PT in patients treated with mTOR inhibitors.

Immune checkpoint inhibitors have revolutionized treatment and outcome of melanoma and many other solid malignancies including non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Unfortunately, only a minority of patients have a long-term benefit, while the remaining demonstrate primary or acquired resistance. Recently, it has been demonstrated that the prevalence of programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) varies based on the anatomical site of metastases. In particular, liver seems to have more immunosuppressive microenvironment while both the presence of lymph nodal disease and lung metastases seem to have the highest prevalence of PD-L1 and TILs. The aim of the present study is to investigate the possible role of site of metastases as a predictive factor for response or resistance to immunotherapy in several types of cancer. In this multicenter retrospective study, we enrolled patients with metastatic NSCLC, melanoma, RCC, urothelial, merkel carcinoma, and colon cancer who received immunotherapy from April 2015 to August 2019. Major clinicopathological parameters were retrieved and correlated with patients’ survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision-making process. A total of 291 patients were included in this study. One hundred eighty-seven (64%) patients were male and 104 (36%) female. The tumor histology was squamous NSCLC in 56 (19%) patients, non-squamous NSCLC in 99 (34%) patients, melanoma in 101 (35%) patients, RCC in 28 (10%) patients, and other tumors in the remaining 7 (2%) patients. The number of metastatic sites was 1 in 103 patients (35%), 2 in 104 patients (36%) and 3 in 84 patients (29%). Out of 183 valuable patients, the entity of response was complete response (CR), partial response (PR), stable disease (SD), and progression disease (PD) in 15, 53, 31, and 79 patients, respectively. Using an univariate analysis (UVA), tumor burden (p = 0.0004), the presence of liver (p = 0.0009), bone (p = 0.0016), brain metastases (p < 0.0001), the other metastatic sites (p = 0.0375), the number of metastatic sites (p = 0.0039), the histology (p = 0.0034), the upfront use of immunotherapy (p = 0.0032), and Eastern Cooperative Oncology Group (ECOG) Perfomance status (PS) ≥ 1 (p < 0.0001) were significantly associated with poor overall survival (OS). Using a multivariate analysis (MVA) the presence of liver (p = 0.0105) and brain (p = 0.0026) metastases, the NSCLC diagnosis (p < 0.0001) and the ECOG PS (p < 0.0001) resulted as significant prognostic factors of survival. Regarding the progression free survival (PFS), using a UVA of the tumor burden (p = 0.0004), bone (p = 0.0098) and brain (p = 0.0038) metastases, the presence of other metastatic sites (p = 0.0063), the number of metastatic sites (p = 0.0007), the histology (p = 0.0007), the use of immunotherapy as first line (p = 0.0031), and the ECOG PS ≥ 1 (p ≤ 0.0001) were associated with a lower PFS rate. Using an MVA, the presence of brain (p = 0.0088) and liver metastases (p = 0.024) and the ECOG PS (p < 0.0001) resulted as predictors of poor PFS. Our study suggests that the site of metastases could have a role as prognostic and predictive factor in patients treated with immunotherapy. Indeed, regardless of the histology, the presence of liver and brain metastases was associated with a shorter PFS and OS, but these results must be confirmed in further studies. In this context, a deep characterization of microenvironment could be crucial to prepare patients through novel strategies with combination or sequential immunotherapy in order to improve treatment response.

The aim of the study is to observe retrospectively the correlation between Oral Squamous Cell Carcinoma (OSCC) and risk factors; including tobacco, alcohol and Family History of Cancer (FHC). A total of 478 patients were included retrospectively from the database of the Department of Oral Sciences and Maxillofacial Surgery, Sapienza University of Rome. A Test Group (TG) consisted of 239 patients with a confirmed diagnosis of OSCC. A Control Group (CG) consisted of 239 patients without history and/or diagnosis of oral cancer. The logistic regression models were used to calculate the adjusted Odd Ratios (ORs) associated with alcohol, tobacco and FHC; including the General Family History of Cancer (GFHC) and Family History of Head and Neck Cancer (FHHNC) and their 95% Confidence Intervals (CI). The high rate of tobacco consumption was associated with an OR of 1.035 (95% CI 1.001–1.070) and a statistical significance (p = 0.041). Drinker patients showed a significant risk of developing OSCC (p = 0.05) and the OR was 1.035 (95% CI 1.010–1.061). The GFHC was associated with a marginal risk of OSCC with an OR of 1.095 (95% CI 0.953–1.259), without significance (p = 0.199). The FHHNC showed a notable risk increase with an OR of 1.871 (95% CI 0.902–3.882), without significance (p = 0.092). Alcohol and tobacco may be associated with an increase in the risk of OSCC.