The Impact of Drug-Drug Interactions on the Toxicity Profile of Combined Treatment with BRAF and MEK Inhibitors in Patients with BRAF-Mutated Metastatic Melanoma.

BACKGROUND: BRAF and MEK inhibition is a successful strategy in managing BRAF-mutant melanoma, even if the treatment-related toxicity is substantial. We analyzed the role of drug-drug interactions (DDI) on the toxicity profile of anti-BRAF/anti-MEK therapy. METHODS: In this multicenter, observational, and retrospective study, DDIs were assessed using Drug-PIN software (V 2/23). The association between the Drug-PIN continuous score or the Drug-PIN traffic light and the occurrence of treatment-related toxicities and oncological outcomes was evaluated. RESULTS: In total, 177 patients with advanced BRAF-mutated melanoma undergoing BRAF/MEK targeted therapy were included. All grade toxicity was registered in 79% of patients. Cardiovascular toxicities occurred in 31 patients (17.5%). Further, 94 (55.9%) patients had comorbidities requiring specific pharmacological treatments. The median Drug-PIN score significantly increased when the target combination was added to the patient's home therapy (p-value < 0.0001). Cardiovascular toxicity was significantly associated with the Drug-PIN score (p-value = 0.048). The Drug-PIN traffic light (p = 0.00821) and the Drug-PIN score (p = 0.0291) were seen to be significant predictors of cardiotoxicity. Patients with low-grade vs. high-grade interactions showed a better prognosis regarding overall survival (OS) (p = 0.0045) and progression-free survival (PFS) (p = 0.012). The survival analysis of the subgroup of patients with cardiological toxicity demonstrated that patients with low-grade vs. high-grade DDIs had better outcomes in terms of OS (p = 0.0012) and a trend toward significance in PFS (p = 0.068). CONCLUSIONS: DDIs emerged as a critical issue for the risk of treatment-related cardiovascular toxicity. Our findings support the utility of DDI assessment in melanoma patients treated with BRAF/MEK inhibitors.

A network approach to define the predictive role of immune profile on tumor response and toxicity of anti PD-1 single agent immunotherapy in patients with solid tumors.

Background: The immune profile of each patient could be considered as a portrait of the fitness of his/her own immune system. The predictive role of the immune profile in immune-related toxicities (irAEs) development and tumour response to treatment was investigated. Methods: A prospective, multicenter study evaluating, through a multiplex assay, the soluble immune profile at the baseline of 53 patients with advanced cancer, treated with immunotherapy as single agent was performed. Four connectivity heat maps and networks were obtained by calculating the Spearman correlation coefficients for each group: responder patients who developed cumulative toxicity (R-T), responders who did not develop cumulative toxicity (R-NT), non-responders who developed cumulative toxicity (NR-T), non-responders who did not develop cumulative toxicity (NR-NT). Results: A statistically significant up-regulation of IL-17A, sCTLA4, sCD80, I-CAM-1, sP-Selectin and sEselectin in NR-T was detected. A clear loss of connectivity of most of the soluble immune checkpoints and cytokines characterized the immune profile of patients with toxicity, while an inversion of the correlation for ICAM-1 and sP-selectin was observed in NR-T. Four connectivity networks were built for each group. The highest number of connections characterized the NR-T. Conclusions: A connectivity network of immune dysregulation was defined for each subgroup of patients, regardless of tumor type. In patients with the worst prognosis (NR-T) the peculiar connectivity model could facilitate their early and timely identification, as well as the design of a personalized treatment approach to improve outcomes or prevent irAEs.

Immune-related toxicity and soluble profile in patients affected by solid tumors: a network approach.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have particular, immune-related adverse events (irAEs), as a consequence of interfering with self-tolerance mechanisms. The incidence of irAEs varies depending on ICI class, administered dose and treatment schedule. The aim of this study was to define a baseline (T0) immune profile (IP) predictive of irAE development. METHODS: A prospective, multicenter study evaluating the immune profile (IP) of 79 patients with advanced cancer and treated with anti-programmed cell death protein 1 (anti-PD-1) drugs as a first- or second-line setting was performed. The results were then correlated with irAEs onset. The IP was studied by means of multiplex assay, evaluating circulating concentration of 12 cytokines, 5 chemokines, 13 soluble immune checkpoints and 3 adhesion molecules. Indoleamine 2, 3-dioxygenase (IDO) activity was measured through a modified liquid chromatography-tandem mass spectrometry using the high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method. A connectivity heatmap was obtained by calculating Spearman correlation coefficients. Two different networks of connectivity were constructed, based on the toxicity profile. RESULTS: Toxicity was predominantly of low/moderate grade. High-grade irAEs were relatively rare, while cumulative toxicity was high (35%). Positive and statistically significant correlations between the cumulative toxicity and IP10 and IL8, sLAG3, sPD-L2, sHVEM, sCD137, sCD27 and sICAM-1 serum concentration were found. Moreover, patients who experienced irAEs had a markedly different connectivity pattern, characterized by disruption of most of the paired connections between cytokines, chemokines and connections of sCD137, sCD27 and sCD28, while sPDL-2 pair-wise connectivity values seemed to be intensified. Network connectivity analysis identified a total of 187 statistically significant interactions in patients without toxicity and a total of 126 statistically significant interactions in patients with toxicity. Ninety-eight interactions were common to both networks, while 29 were specifically observed in patients who experienced toxicity. CONCLUSIONS: A particular, common pattern of immune dysregulation was defined in patients developing irAEs. This immune serological profile, if confirmed in a larger patient population, could lead to the design of a personalized therapeutic strategy in order to prevent, monitor and treat irAEs at an early stage.

Twenty Years' Experience in Retroperitoneal Lymph Node Dissection for Testicular Cancer in a Tertiary Referral Center.

Background and Objectives: The aim of this article is to present a single-surgeon, open retroperitoneal lymph node dissection (RPLND) series for testicular cancer in a high-volume center. Materials and Methods: We reviewed data from patients who underwent RPLND performed by an experienced surgeon at our institution between 2000 and 2019. We evaluated surgical and perioperative outcomes, complications, Recurrence-Free Survival (RFS), Overall Survival (OS), and Cancer-Specific Survival (CSS). Results: RPLND was performed in primary and secondary settings in 21 (32%) and 44 (68%) patients, respectively. Median operative time was 180 min. Median hospital stay was 6 days. Complications occurred in 23 (35%) patients, with 9 (14%) events reported as Clavien grade ≥ 3. Patients in the primary RPLND group were significantly younger, more likely to have NSGCT, had higher clinical N0 and M0, and had higher nerve-sparing RPLND (all p ≤ 0.04) compared to those in the secondary RPLND group. In the median follow-up of 120 (56-180) months, 10 (15%) patients experienced recurrence. Finally, 20-year OS, CSS, and RFS were 89%, 92%, and 85%, respectively, with no significant difference in survival rates between primary vs. secondary RPLND subgroups (p = 0.64, p = 0.7, and p = 0.31, respectively). Conclusions: Open RPLND performed by an experienced high-volume surgeon achieves excellent oncological and functional outcomes supporting the centralization of these complex procedures.

The role of immune profile in predicting outcomes in cancer patients treated with immunotherapy.

Background: Despite the efficacy of immunotherapy, only a small percentage of patients achieves a long-term benefit in terms of overall survival. The aim of this study was to define an immune profile predicting the response to immune checkpoint inhibitors (ICIs). Methods: Patients with advanced solid tumors, who underwent ICI treatment were enrolled in this prospective study. Blood samples were collected at the baseline. Thirteen soluble immune checkpoints, 3 soluble adhesion molecules, 5 chemokines and 11 cytokines were analyzed. The results were associated with oncological outcomes. Results: Regardless of tumor type, patients with values of sTIM3, IFNα, IFNγ, IL1ß, IL1α, IL12p70, MIP1ß, IL13, sCD28, sGITR, sPDL1, IL10 and TNFα below the median had longer overall survival (p<0.05). By using cluster analysis and grouping the patients according to the trend of the molecules, two clusters were found. Cluster A had a significantly higher mean progression free survival (Cluster A=11.9 months vs Cluster B=3.5 months, p<0.01), a higher percentage of disease stability (Cluster A=34.5% vs. Cluster B=0%, p<0.05) and a lower percentage of disease progression (Cluster A=55.2% vs. Cluster B = 94.4%, p=0.04). Conclusion: The combined evaluation of soluble molecules, rather than a single circulating factor, may be more suitable to represent the fitness of the immune system status in each patient and could allow to identify two different prognostic and predictive outcome profiles.

Genomic and Immune Approach in Platinum Refractory HPV-Negative Head and Neck Squamous Cell Carcinoma Patients Treated with Immunotherapy: A Novel Combined Profile.

INTRODUCTION: Only a minority of patients with platinum refractory head and neck squamous cell carcinoma (PR/HNSCC) gain some lasting benefit from immunotherapy. METHODS: The combined role of the comprehensive genomic (through the FoundationOne Cdx test) and immune profiles of 10 PR/HNSCC patients treated with the anti-PD-1 nivolumab was evaluated. The immune profiles were studied both at baseline and at the second cycle of immunotherapy, weighing 20 circulating cytokines/chemokines, adhesion molecules, and 14 soluble immune checkpoints dosed through a multiplex assay. A connectivity map was obtained by calculating the Spearman correlation between the expression profiles of circulating molecules. RESULTS: Early progression occurred in five patients, each of them showing TP53 alteration and three of them showing a mutation/loss/amplification of genes involved in the cyclin-dependent kinase pathway. In addition, ERB2 amplification (1 patient), BRCA1 mutation (1 patient), and NOTCH1 genes alteration (3 patients) occurred. Five patients achieved either stable disease or partial response. Four of them carried mutations in PI3K/AKT/PTEN pathways. In the only two patients, with a long response to immunotherapy, the tumor mutational burden (TMB) was high. Moreover, a distinct signature, in terms of network connectivity of the circulating soluble molecules, characterizing responder and non-responder patients, was evidenced. Moreover, a strong negative and statistically significant (p-value ≤ 0.05) correlation with alive status was evidenced for sE-selectin at T1. CONCLUSIONS: Our results highlighted the complexity and heterogeneity of HNSCCs, even though it was in a small cohort. Molecular and immune approaches, combined in a single profile, could represent a promising strategy, in the context of precision immunotherapy.

Weekly chemotherapy as first line treatment in frail head and neck cancer patients in the immunotherapy era.

OBJECTIVE: First-line therapy for metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) has been revolutionized by the introduction of anti-checkpoint monoclonal antibodies, which have shown a significant improvement in overall survival (OS) gaining approval in a first line setting. Efficacy and safety of first-line weekly chemotherapy, compared to 3-weeks treatment, was retrospectively evaluated in a frail patient population with R/M HNSCC with the aim to evaluate its role as part of a personalized first-line approach. METHODS: A total of 124 patients with locally incurable R/M HNSCC receiving weekly (21) or three-weekly (103) chemotherapy plus cetuximab in a first line setting from December 2010 to September 2020 were retrospectively reviewed. Treatment outcomes in terms of objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicities were analysed. RESULTS: Patients in the three-week subgroup were ECOG PS 0 (39) and 1 (64) while patients in weekly group (21) were all PS 2. No significant differences were reported in terms of age, sex, smoking and previous alcohol abuse considering the two distinct subgroups. Moreover, no statistically significant difference was found in PFS and OS between the two treatment subgroups. The response rate was 35% (36 patients) and 34% (7 patients) in three-week and weekly treatment group, respectively. Seventy patients (68%) in the three-week group experienced chemotherapy-related toxicities, predominantly G3. In the weekly group a predominantly low-grade toxicity was found in a lower number of patients (52%). CONCLUSION: The weekly schedule appears to be an active and safe strategy in frail patients with R/M HNSCC. Based on these data, a weekly schedule could be considered as a first line treatment in all frail patients excluded from pembrolizumab treatment and a study on the combination of weekly chemotherapy and immunotherapy should be performed.

Standard of Care and Promising New Agents for the Treatment of Mesenchymal Triple-Negative Breast Cancer.

The pathologic definition of triple negative breast cancer (TNBC) relies on the absence of expression of estrogen, progesterone and HER2 receptors. However, this BC subgroup is distinguished by a wide biological, molecular and clinical heterogeneity. Among the intrinsic TNBC subtypes, the mesenchymal type is defined by the expression of genes involved in the epithelial to mesenchymal transition, stromal interaction and cell motility. Moreover, it shows a high expression of genes involved in proliferation and an immune-suppressive microenvironment. Several molecular alterations along different pathways activated during carcinogenesis and tumor progression have been outlined and could be involved in immune evasion mechanisms. Furthermore, reverting epithelial to mesenchymal transition process could lead to the overcoming of immune-resistance. This paper reviews the current knowledge regarding the mesenchymal TNBC subtype and its response to conventional therapeutic strategies, as well as to some promising molecular target agents and immunotherapy. The final goal is a tailored combination of cytotoxic drugs, target agents and immunotherapy in order to restore immunocompetence in mesenchymal breast cancer patients.

Primary squamous cell carcinoma of major salivary gland: "Sapienza Head and Neck Unit" clinical recommendations.

Primary squamous cell carcinoma of salivary gland (SCG) is an extremely rare type of malignant salivary gland tumor, which in turn results in scarcity of data available regarding both its treatment and associated genetic alterations. A retrospective analysis of 12 patients with primary SCG was conducted, along with analysis of the association between treatment, clinical/pathological characteristics, and outcomes. Most patients (8) were staged IVa, with the majority of them (10) having G3 fast growing cancer. Local and systemic recurrence were reported in only three out of nine parotid cases (0 out of 2 submandibular SCGs). In two out of eight patients local relapse occurred after integrated treatment, while recurrence occurred in two out of three patients undergoing exclusive surgery. Five patients eventually died. Treatment of resectable disease must be aggressive and multimodal, with achievement of loco-regional control in order to reduce rate of recurrence and improve outcomes. Metastatic disease would require a therapeutic strategy tailored to the molecular profile in order to improve the currently disappointing results.

The 5-Ws of immunotherapy in head and neck cancer.

The immune checkpoint inhibitors, a class of drugs able to block immune suppressive pathways in order to prime an anticancer immunity, revolutionized standard of care in platinum-refractory recurrent and/or metastatic head and neck carcinoma (R/M HNSCC). The PD-1/ PD-L1 axis is involved in the genesis, maintenance and progression of HNSCC and represents the target of checkpoint inhibitors. HNSCC is an immunosuppressive disease with a high inflammatory component in tumor microenvironment. Recent clinical trials showed that only a small subset of patients really benefits from immunotherapy. This review aims to highlight the five W-points of immunotherapy: why immunotherapy is promising in HNSCC, what is currently available in daily clinical practice, when immunotherapy can be integrated into the therapeutic strategy, where it can be useful according to predictive response biomarker, who, among patients, could get the best benefit from immunotherapy and how improve the achieved results.

Accessory Auricles: Systematic Review of Definition, Associated Conditions, and Recommendations for Clinical Practice.

Accessory auricles are rare congenital abnormalities embryologically derived from the first branchial arch. Presentation may be variable with locations grouped into anatomical zones based on the frequency of location found in the literature. This study reviewed the papers between 1981 and 2017. Findings included an association with syndromes including Goldenhar, VACTERL, Treacher-Collins, Townes-Brocks, and Wolf-Hirschhorn. Based on histological and embryological evidence, the term "accessory auricle" is best used as an umbrella term to define this difference. Finally, indications are provided for imaging and laboratory investigations to guide the physician treating patients with accessory auricles.

Concept design and simulation study on a "phantom" anvil for circular stapler.

INTRODUCTION: Complications and challenges arising from the intraoperative double-stapling technique are seldom reported in colorectal surgery literature. Partial or full-thickness rectal injuries can occur during the introduction and the advancement of the circular stapler along the upper rectum. The aim of this study is to address some of these issues by designing and optimizing a "phantom" anvil manufactured to overcome difficulties throughout the rectal introduction and advancement of the circular stapler for the treatment of benign and malignant colon disease. METHODS: The design of the "phantom" anvil has been performed using computer-aided modeling techniques, finite element investigations, and 2 essential keynotes in mind. The first one is the internal shape of the anvil, which is used for the connection to the gun. The second is the shape of the cap, which makes possible the insertion of the gun through the rectum. The "phantom" anvil has 2 functional requirements, which have been taken into account. The design has been optimized to avoid colorectal injuries, neoplastic dissemination (ie, mechanical seeding) and to reduce the fecal contamination. RESULTS: Numerical simulations show that a right combination of both top and bottom fillet radii of the shape of the anvil can reduce the stress for the considered anatomic configuration of >90%. Both the fillet radii at the top and the bottom of the device influence the local stress of the colon rectum. CONCLUSIONS: A dismountable device, which is used only for the insertion and advancement of the stapler, allows a dedicated design of its shape, keeping the remainder of the stapler unmodified. Computer-aided simulations are useful to perform numerical investigations to optimize the design of this auxiliary part for both the safety of the patient and the ease of the stapler advancement through the rectum.