Principles of medical and oncological management of giant masses of the mediastinum: a narrative review.

Background and Objective: Giant mediastinal tumors are represented by well-defined histological variants originating from different structures and compartments while their clinical presentation may be similar and characterized by the same set of symptoms, the well-known mediastinal syndrome (MS). In 80% of cases the MS is caused by malignant neoplasms, such as lung tumors, in 10-18% of cases by hematological neoplasms and in 2-3% by benign causes. In this review we investigated the medical treatment of main giant mediastinal tumors, focusing our interest on the objective response rate (ORR), as it represents the most suitable parameter to predict the volumetric reduction of the neoplasm and, consequently, the regression of their most severe complication, the MS. We will also cover the supportive and symptomatic treatment of MS. Methods: We performed a deep analysis of the recent international literature published on PUBMED, UpToDate and Medline. The literature search was undertaken from origin until November 30th, 2021, and we only considered publications in English. Key Content and Findings: Considering the variety of pathologies that can occur in the mediastinum, a rapid histological characterization of the neoplasm is mandatory. In fact, the treatment of these neoplasms includes different approaches, sometimes used in combination, which include chemotherapy, radiotherapy, and surgery. The vena cava syndrome (VCS), due to its high mortality, is considered an oncological emergency and, therefore, requires effective treatments carried out urgently, evaluated in multidisciplinary meeting. Conclusions: The treatment of MS includes both antiblastic treatments and therapies directed to the symptoms. Among the former, chemotherapy, target therapy, radiation and surgery may be used, according to the etiology of MS. Among the latters, supportive therapies, interventional radiology procedures such as stenting may help manage this syndrome, despite the prognosis is poor in most cases and linked to the histology of the tumor, which therefore represents the most important prognostic factor.

Monitoring tumor growth rate to predict immune checkpoint inhibitors' treatment outcome in advanced NSCLC.

INTRODUCTION: Radiological response assessment to immune checkpoint inhibitor is challenging due to atypical pattern of response and commonly used RECIST 1.1 criteria do not take into account the kinetics of tumor behavior. Our study aimed at evaluating the tumor growth rate (TGR) in addition to RECIST 1.1 criteria to assess the benefit of immune checkpoint inhibitors (ICIs). METHODS: Tumor real volume was calculated with a dedicated computed tomography (CT) software that semi-automatically assess tumor volume. Target lesions were identified according to RECIST 1.1. For each patient, we had 3 measurement of tumor volume. CT-1 was performed 8-12 weeks before ICI start, the CT at baseline for ICI was CT0, while CT + 1 was the first assessment after ICI. We calculated the percentage increase in tumor volume before (TGR1) and after immunotherapy (TGR2). Finally, we compared TGR1 and TGR2. If no progressive disease (PD), the group was disease control (DC). If PD but TGR2 < TGR1, it was called LvPD and if TGR2 ⩾ TGR1, HvPD. RESULTS: A total of 61 patients who received ICIs and 33 treated with chemotherapy (ChT) were included. In ICI group, 18 patients were HvPD, 22 LvPD, 21 DC. Median OS was 4.4 months (95% CI: 2.0-6.8, reference) for HvPD, 7.1 months (95% CI 5.4-8.8) for LvPD, p = 0.018, and 20.9 months (95% CI: 12.5-29.3) for DC, p < 0.001. In ChT group, 7 were categorized as HvPD, 17 as LvPD and 9 as DC. No difference in OS was observed in the ChT group (p = 0.786). CONCLUSION: In the presence of PD, a decrease in TGR may result in a clinical benefit in patients treated with ICI but not with chemotherapy. Monitoring TGR changes after ICIs administration can help physician in deciding to treat beyond PD.

Emerging Novel Therapeutic Approaches for Treatment of Advanced Cutaneous Melanoma.

The prognosis of patients with advanced cutaneous melanoma has radically changed in the past decade. Nevertheless, primary or acquired resistance to systemic treatment occurs in many cases, highlighting the need for novel treatment strategies. This review has the purpose of summarizing the current area of interest for the treatment of metastatic or unresectable advanced cutaneous melanoma, including data from recently completed or ongoing clinical trials. The main fields of investigation include the identification of new immune checkpoint inhibitors (anti-LAG3, GITR agonist and anti-TIGIT), adoptive cell therapy, vaccines, engineered TCR therapy, IL-2 agonists, novel targets for targeted therapy (new MEK or RAF inhibitors, HDAC, IDO, ERK, Axl, ATR and PARP inhibitors), or combination strategies (antiangiogenetic agents plus immune checkpoint inhibitors, intra-tumoral immunotherapy in combination with systemic therapy). In many cases, only preliminary efficacy data from early phase trials are available, which require confirmation in larger patient cohorts. A more in-depth knowledge of the biological effects of the molecules and identifying predictive biomarkers remain crucial for selecting patient populations most likely to benefit from novel emerging treatment strategies.

Drug-induced colitis on BRAF and MEK inhibitors for BRAF V600E-mutated non-small cell lung cancer: a case report.

INTRODUCTION: The combination of BRAF and MEK inhibitors has deeply changed the treatment of BRAF V600-mutant non-small cell lung cancer patients. These agents demonstrated high antitumor activity as well as safe and manageable toxicity profile. Hypertension, pyrexia and increased liver enzymes are the most common adverse events. Gastrointestinal toxicities are rare, and mainly consist of mild grade vomiting and diarrhea. CASE REPORT: We report the case of 70-year-old man affected by BRAF V600-mutant NSCLC with bilateral lung and bone metastases. First-line treatment with encorafenib (450 mg once daily) and binimetinib (45 mg twice daily) was administered within a clinical trial. At the first radiological assessment, computed tomography (CT) scan showed a partial response and signs of intestinal inflammation were reported. The investigational treatment was timely withheld. The subsequent colonoscopy demonstrated the presence of ulcerative lesions at the caecal tract, and the histological diagnosis suggested a drug-induced colitis. No specific treatment was given as the patient did not report abdominal disturbances. Forty-five days after treatment interruption a new CT scan showed the resolution of bowel inflammation and investigational treatment was resumed at the same doses. The patient is still alive and free of toxicity recurrence after 11 months from treatment initiation. Conclusion. Severe gastrointestinal toxicities are uncommon with BRAF and MEK inhibitors, although cases of colitis and intestinal perforation have already been reported in literature. The pathogenesis seems to be related to the MAPK pathway inhibition performed by MEK inhibitors. These adverse events should be accounted given the potential to evolve into life-threatening conditions.

PD-L1 Expression in Circulating Tumor Cells as a Promising Prognostic Biomarker in Advanced Non-small-cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Circulating tumor cells (CTCs) are a promising source of biological information in cancer. Data correlating PD-L1 expression in CTCs with patients' response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are still lacking. METHODS: This is a prospective single-center cohort study enrolling patients with advanced NSCLC. CTCs were identified and counted with the CellSearch system. PD-L1 expression on CTCs was assessed with phycoerythrin-conjugated anti-human PD-L1 antibody, clone MIH3 (BioLegend, USA). Primary endpoint was the correlation between the CTCs PD-L1 expression and overall survival (OS). Among secondary objectives, we evaluated the correlation between PD-L1 expression on CTCs and matched tumor tissue and the correlation of CTC number and baseline tumor size (BTS). RESULTS: Thirty-nine patients treated with anti-PD-1/PD-L1 agents as second- or third-line therapy were enrolled. Patients were divided into 3 groups: no CTC detectable (CTCnull, n = 15), PD-L1 positive CTC (CTCpos, n = 13), and PD-L1 negative CTC (CTCneg, n = 11). Median OS in patients with CTCneg was 2.2 months, 95% confidence interval (CI), 0.8-3.6 (reference) versus 3.7 months, 95% CI, 0.1-7.5 (hazard ratio [HR] 0.33; 95% CI, 0.13-0.83; P = .019) in patients with CTCpos versus 16.0 months, 95% CI, 2.2-29.8 (HR 0.17; 95% CI, 0.06-0.45; P< .001) in patients with CTCnull. No correlation was found between PD-L1 expression on CTCs and on tumor tissue. CTC number was correlated with BTS. CONCLUSION: PD-L1 expression on CTCs is a promising biomarker in patients with NSCLC treated with ICIs. Further validation as predictive biomarker is needed.

Comparative effectiveness of first-line immune checkpoint inhibitors plus tyrosine kinase inhibitors according to IMDC risk groups in metastatic renal cell carcinoma: a meta-analysis.

Aim: Immune checkpoint inhibitor (ICI)-based combinations have become the new standard of primary systemic treatment for metastatic renal cell carcinoma patients. We performed a meta-analysis aimed at evaluating ICIs plus tyrosine kinase inhibitors (TKIs) combinations across International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups. Materials & methods: All the relevant randomized clinical trials were retrieved through Cochrane library, PubMed/Med and EMBASE; three Phase III randomized clinical trials were included. Results: ICI-TKI combinations significantly decreased the risk of death in IMDC poor- and intermediate-risk patients. Conversely, a nonstatistically significant benefit was observed in favorable-risk patients. Conclusion: Our results suggest that IMDC poor-risk patients benefit most from ICI-TKI combinations, while a proportion of metastatic renal cell carcinoma patients could respond to targeted agent monotherapy.

Comparison of Sequential Testing and Next Generation Sequencing in advanced Lung Adenocarcinoma patients - A single centre experience.

OBJECTIVES: Molecular diagnosis determines therapeutic strategies for patients with non-small-cell lung cancer - adenocarcinoma (NSCLC-A) but depends on resources availability. We compared a sequential single-gene testing algorithm to next generation sequencing in NSCLC-A to assess differences in terms of effectiveness, costs, tissue consumption and time. MATERIALS AND METHODS: We analyzed a retrospective cohort of advanced NSCLC-A patients treated at the Sant'Orsola-Malpighi University Hospital. The sequential testing includes a first analysis of EGFR and KRAS status with further molecular testing physician driven. The available NGS panel detects 35 hotspot mutations,19 amplifications and 23 rearrangements. RESULTS: We included 1758 patients; 1221 characterized with the sequential algorithm between January 2014 to February 2019 and 537 with Next Generation Sequencing (NGS) until January 2020. The prevalence of EGFR, ALK and KRAS alterations was similar between the stepwise and NGS group (16.5% vs 14.3%, 6.3% vs 6.3% and 36% vs 33.5%, respectively). Differently, ROS-1 rearrangements prevalence was higher in stepwise respect to NGS group (4.7% vs 0.7%). Similarly, the stepwise group presented higher prevalence than NGS for MET amplification (11.2% vs 2.2%), MET mutations (9.0% vs 2.4%), HER2 amplification (3.3% vs 1.9%) and mutations (9.8% vs 3.0%), and BRAF mutations (4.5% vs 5.6%). Among the NGS group other mutations were found in 141 patients (26.3%) and the presence of concurrent mutations in 131 (24.4%). The stepwise algorithm presented a relevant dropout rate that increased at each step, with 11.4%, 16.4% and 49.3% respectively for ALK, ROS1 and other analysis. Sequential testing's expenditure was 1375 € per patient, vs 770 € for NGS. Moreover, NGS testing can be performed with just a 25 µm slide respect to an estimated 33.3 µm slide for sequential strategy. CONCLUSION: NGS offered a less expensive and more reliable model of diagnosis respect to sequential one for patients affected by NSCLC-A.

Roles of IL-1 in Cancer: From Tumor Progression to Resistance to Targeted Therapies.

IL-1 belongs to a family of 11 members and is one of the seven receptor-agonists with pro-inflammatory activity. Beyond its biological role as a regulator of the innate immune response, IL-1 is involved in stress and chronic inflammation, therefore it is responsible for several pathological conditions. In particular, IL-1 is known to exert a critical function in malignancies, influencing the tumor microenvironment and promoting cancer initiation and progression. Thus, it orchestrates immunosuppression recruiting pro-tumor immune cells of myeloid origin. Furthermore, new recent findings showed that this cytokine can be directly produced by tumor cells in a positive feedback loop and contributes to the failure of targeted therapy. Activation of anti-apoptotic signaling pathways and senescence are some of the mechanisms recently proposed, but the role of IL-1 in tumor cells refractory to standard therapies needs to be further investigated.

Atezolizumab in a CoHort of pretreated, advanced, non-small cell lung cancer patients with rare HistologiCal SubtypEs (CHANCE trial).

BACKGROUND: Although immunotherapy with immune-checkpoint inhibitors (ICIs) has profoundly changed the therapeutic scenario in the treatment of advanced non-small cell lung cancer (NSCLC), trials of ICIs only enrolled NSCLC patients with common histology. Atezolizumab was approved by the United States Food and Drug Administration (US FDA) in October 2016 and by the European Medicines Agency (EMA) in September 2017 for the treatment of patients with metastatic NSCLC whose disease progressed during or following platinum-containing chemotherapy, regardless of PD-L1 expression. METHODS: We designed a single-arm, multicenter, two-stage phase II study and plan to enroll 43 patients. The primary objective of the study is to evaluate the antitumor activity of atezolizumab in advanced NSCLC patients with rare histology subtypes. Patients with prior atezolizumab or ICI treatment and with untreated, symptomatic, or progressing brain metastases will be excluded. The primary endpoint is disease control rate. Secondary objectives are toxicity and safety, overall response rate, progression-free survival, overall survival, and time to progression. Diagnosis of NSCLC with rare histology will be confirmed by central pathology revision, and will include: colloid carcinoma, fetal adenocarcinoma, non-endocrine large cell carcinoma, sarcomatoid carcinoma, salivary gland-type tumor, lymphoepithelioma-like carcinoma, and NUT-nuclear protein in testis carcinoma. Archival tumor tissue is required for correlative studies of PD-L1 expression on tumor cells and tumor infiltrating lymphocytes. CONCLUSIONS: Therapeutic options in NSCLC with rare histology subtypes, to be assessed in specifically designed trials, are an unmet need. This trial will help elucidate the role of atezolizumab as a viable option in this setting.

A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy.

Cetuximab (CTX) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), commonly used to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, objective remissions occur only in a minority of patients and are of short duration, with a population of cells surviving the treatment and eventually enabling CTX resistance. Our previous study on CRC xenopatients associated poor response to CTX with increased abundance of a set of pro-inflammatory cytokines, including the interleukins IL-1A, IL-1B and IL-8. Stemming from these observations, our current work aimed to assess the role of IL-1 pathway activity in CTX resistance. We employed a recombinant decoy TRAP IL-1, a soluble protein combining the human immunoglobulin Fc portion linked to the extracellular region of the IL-1-receptor (IL-1R1), able to sequester IL-1 directly from the medium. We generated stable clones expressing and secreting a functional TRAP IL-1 into the culture medium. Our results show that IL-1R1 inhibition leads to a decreased cell proliferation and a dampened MAPK and AKT axes. Moreover, CRC patients not responding to CTX blockage displayed higher levels of IL-1R1 than responsive subjects, and abundant IL-1R1 is predictive of survival in patient datasets specifically for the consensus molecular subtype 1 (CMS1). We conclude that IL-1R1 abundance may represent a therapeutic marker for patients who become refractory to monoclonal antibody therapy, while inhibition of IL-1R1 by TRAP IL-1 may offer a novel therapeutic strategy.