Angioside: The role of Angiogenesis and Hypoxia in Lung Neuroendocrine Tumours According to Primary Tumour Location in Left or Right Parenchyma.

Well-differentiated lung neuroendocrine tumours (Lu-NETs), classified as typical (TC) and atypical (AC) carcinoids, represent 30% of NETs. Angiogenesis plays an essential role in NET development and progression. A higher vascular network is a marker of differentiation, with positive prognostic implications. Materials and Methods: We retrospectively evaluated microvessel density (MVD) by CD34 immunohistochemical (IHC) staining and hypoxia by IHC staining for Hypoxia-inducible factor 1α (HIF-1α), comparing right- and left-lung parenchyma in 53 lung NETs. Results: The median age was 66 years (39−81), 56.6% males, 24.5% AC, 40.5% left-sided tumours and 69.8% TNM stage I. The mitotic count was <2/10 per 10 HPF in 79.2%, and the absence of necrosis in 81.1%, 39.6% with Ki67, was ≤2%. The MVD, the number of vessels and the average vessel area median values were significantly higher in the right than the left parenchyma (p: 0.025, p: 0.019, p: 0.016, respectively). Hypoxia resulted present in 14/19 (73.6%) left tumours and in 10/20 (50%) right tumours in the parenchyma (p: 0.129). Conclusions: This study suggests a biological rationale for a different angiogenesis and hypoxia according to the Lu-NETs' location. In our study, left primary tumours were less vascularized and most likely to present hypoxia than right primary tumours. This finding could have potentially useful prognostic and predictive implications for Lu-NETs.

Prognostic impact of early tumor shrinkage and depth of response in patients with microsatellite instability-high metastatic colorectal cancer receiving immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the new standard of care in microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC). Since tumor response dynamic parameters already shown a strong association with survival outcomes in patients with mCRC treated with first-line therapy, we investigated the association of early tumor shrinkage (ETS) and depth of response (DoR) in patients with MSI-H/dMMR mCRC treated with ICIs. METHODS: This is a retrospective, multicenter, cohort study in patients with dMMR and/or MSI-high mCRC treated with ICIs (anti-PD-1/PD-L1 with or without anti-CTLA-4 agents) with measurable disease and at least one post-baseline radiological disease reassessment. The Kaplan-Meier method and Cox proportional-hazards regression models were used for survival analyses. A maximally selected statistics method in a Cox regression model for progression-free survival (PFS) was used to determine the optimal cut-offs for ETS and DoR. RESULTS: We included a total of 169 patients: 116 (68.6%) were treated with anti-PD-1 monotherapy, whereas 53 (31.4%) with anti-PD-1 plus anti-CTLA-4 agents. Patients with primary progressive disease (N=37, 21.9%), experienced an extremely poor overall survival (OS) and were evaluated separately. In patients with clinical benefit, we observed a significant association between ETS and DoR with both OS and PFS, and we identified a relative reduction of at least 1% as the optimal cut-off for ETS and a relative reduction of at least 50% as the optimal cut-off for DoR. CONCLUSIONS: ETS and DoR are important prognostic factors in patients with MSI-high mCRC treated with ICIs that might be useful to design treatment intensification/deintensification strategies. A prospective validation of both is warranted.

Outcome of patients with colorectal cancer undergoing lung metastases resection: a single-institution retrospective analysis.

INTRODUCTION: This study was undertaken to review a single-institution cohort of patients with metastatic colorectal cancer undergoing lung resection after a multidisciplinary evaluation and to investigate the main prognostic factors for survival. METHODS: Medical records of 129 patients undergoing lung metastasectomy for colorectal cancer with curative intent from 2001 to 2017 were reviewed. Tissue samples from the primary tumor were analyzed with a multiplex genotyping system for the detection of mutations in RAS and BRAF genes. Survival analyses were carried out by the Kaplan-Meier method. Univariate and multivariable analyses were performed using the log-rank test and the Cox regression model. RESULTS: Postoperative morbidity and mortality were 13.2% and 0%, respectively. At a median follow-up time of 62.5 months, median overall survival was 90.5 months and median relapse-free survival was 42.8 months. Multivariable analysis for overall survival identified synchronous versus metachronous metastatic presentation as the only prognostic factor, whereas relapse-free survival was independently associated with synchronous versus metachronous metastatic presentation, number of metastases, and postoperative chemotherapy. CONCLUSIONS: This study shows particularly favorable survival outcomes for patients undergoing lung metastasectomy. The validity of some of the main prognostic factors was confirmed and a positive effect of postoperative chemotherapy on relapse-free survival was shown. Contrary to other reports, the presence of KRAS mutations was not associated with significant survival differences. Further studies are needed in order to clarify the interactions between molecular, clinical, and pathologic characteristics and treatment-related factors.

An overview on clinical, pathological and molecular features of lung metastases from colorectal cancer.

Introduction: Lung metastases occur in 10-20% of patients with colorectal cancer (CRC). Most of them are treated with palliative intent and have a poor prognosis. Pulmonary metastasectomy may be a curative option for carefully selected patients with 5-year survival rates ranging from 25% to 60%. However, up to 70% of patients develop recurrence after pulmonary metastasectomy. Therefore, the identification of prognostic factors is essential in CRC patients with resectable lung metastases. Areas covered: This review aims at summarizing the actual body of knowledge available on lung metastases from CRC focusing on their clinical, pathological and molecular profile. Moreover, we provide an update on experts' attitudes towards lung metastasectomy, adjuvant or perioperative chemotherapy. Expert opinion: Traditional clinical prognosticators such as the total number of pulmonary metastases, carcinoembryonic antigen (CEA) serum levels before surgery, and presence of lymph node metastases cannot provide reliable criteria to predict survival after lung metastasectomy. Indeed, research efforts have been directed in recent years toward studying the biological characteristics of lung lesions to better define prognosis and response to treatment, and ultimately shed new light on their proper local and systemic management.

Immunotherapy in Gastrointestinal Cancers.

Gastrointestinal cancers represent a major public health problem worldwide. Immunotherapeutic strategies are currently under investigation in this setting and preliminary results of ongoing trials adopting checkpoint inhibitors are striking. Indeed, although a poor immunogenicity for GI has been reported, a strong biological rationale supports the development of immunotherapy in this field. The clinical and translational research on immunotherapy for the treatment of GI cancers started firstly with the identification of immune-related mechanisms possibly relevant to GI tumours and secondly with the development of immunotherapy-based agents in clinical trials. In the present review a general overview is firstly provided followed by a focus on major findings on gastric, colorectal, and hepatocellular carcinomas. Finally, pathological and molecular perspectives are provided since many efforts are ongoing in order to identify possible predictive biomarkers and to improve patients' selection. Many issues are still unsolved in this field; however, we strongly believe that immunotherapy might positively affect the natural history of a subgroup of GI cancer patients improving outcome and the overall quality of life.

Anti-EGFR monoclonal antibody panitumumab for the treatment of patients with metastatic colorectal cancer: an overview of current practice and future perspectives.

INTRODUCTION: Targeted agents alone or in combination with chemotherapy are current standard of treatment for metastatic colorectal cancer (mCRC). Panitumumab is a fully human monoclonal antibody which inhibits the epidermal growth factor receptor (EGFR). It is currently approved in combination with chemotherapy in first- and second-line and as a monotherapy in chemorefractory patients. RAS gene mutations confer resistance to anti-EGFR agents; thus, panitumumab is restricted to the treatment of RAS wild-type (WT) tumors. Areas covered: This review explores the available data on panitumumab and presents new perspectives on predictive markers of anti-EGFR efficacy including primary tumor sidedness and BRAF mutations. Other details covered include panitumumab's mechanism of action, pharmacokinetics, pharmacodynamics and safety aspects of the therapy as well as mechanisms of secondary resistance and future prospects of treatment in different settings. Expert opinion: Panitumumab has significantly added to the treatment armamentarium for RAS WT mCRC. The effort spent in identifying predictive biomarkers of panitumumab efficacy has been of pivotal importance to development of the molecular selection of patients with mCRC. Primary and secondary resistance, however, still represent important issues. Novel strategies to overcome those issues are currently underway with promising results which highlight the potential use of panitumumab in combination with other targeted agents in the future.

Multimodality treatment of gynecomastia in patients receiving antiandrogen therapy for prostate cancer in the era of abiraterone acetate and new antiandrogen molecules.

Gynecomastia is a pathological enlargement of male breasts due to hormonal imbalance and elevation of estrogens at the expense of testosterone. It is very important to diagnose this disease precociously because it can be the expression of different underlying pathologies. Besides genetic, chromosomal or chronic diseases, drugs often represent the principal cause of this hormonal disequilibrium. In the elderly population, antiandrogen therapy for prostate cancer frequently induces gynecomastia, thus negatively affecting the patients' compliance to treatment because of physical and psychological discomfort deriving from this condition; gynecomastia can in fact be associated with severe breast pain, and it can modify how patients see their own body. During the past decades and even today, many different surgical, radiotherapeutic or clinical approaches have been proposed to prevent or treat this hypertrophy. This article focuses on gynecomastia associated with antiandrogen-based hormonal treatment and shortly reviews the currently most often used therapeutic options for preventing and treating this pathology.

Clinical and pathological features of primary renal synovial sarcoma: analysis of 64 cases from 11 years of medical literature.

OBJECTIVE: To describe, for the first time, the clinical characteristics of primary renal synovial sarcoma (SS) and to examine the association of histological features with the expression of immunohistochemical markers. PATIENTS AND METHODS: We collated published data on all cases of primary renal SS, from its first description in 2000 to September 2011. Data on clinical and pathological characteristics were extracted and used to create a database. Disease-free survival (DFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method with Rothman's 95% confidence intervals (CIs) and compared across the groups using the log-rank test. The associations between tumour extension and histological features were evaluated using the non-parametric Spearman rank test. A chi-squared test was used to assess the differences between groups. RESULTS: In the overall cohort, the median OS was 48 months (95% CI, 14.1-81.9). Cox analysis showed that the risk of death at diagnosis was greatly increased in patients with metastatic disease compared with those with non-metastatic disease (hazard ratio [HR]: 343.9, 95% CI, 2.8-42,000; P= 0.017). The median DFS was 33.0 months (95% CI, 16.8-49.2), and patients who develop metastatic disease have a very poor prognosis with a median survival of 6 months (95% CI, 5.1-6.9). Microscopic features were monophasic, biphasic and poorly differentiated synovial sarcoma in 76, 16 and 8% of patients, respectively. Significant differences in expression of immunohistochemical markers or genetic mutation were found between different subtypes. CONCLUSIONS: Despite its retrospective nature, this study shows that renal SS comprises different histological subtypes, which are characterized by specific immunohistochemical stains and by specific translocations. When diagnosed at metastatic stage, the prognosis was very poor compared with that for non-metastatic disease, even though one out of three patients with non-metastatic disease had disease relapse. Cooperative efforts and publication of cases with adequate follow-up are necessary to better define prognosis and therapeutic strategies for this rare disease.