Publications by authors named "Massimo Milione"

139 Publications

miR-17 Epigenetic Modulation of LKB1 Expression in Tumor Cells Uncovers a New Group of Patients With Poor-Prognosis NSCLC.

J Thorac Oncol 2021 09;16(9):e68-e70

Tumor Genomics Unit, Department of Research, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan, Italy.

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http://dx.doi.org/10.1016/j.jtho.2021.06.032DOI Listing
September 2021

Prognostic features of gastro-entero-pancreatic neuroendocrine neoplasms in primary and metastatic sites: Grade, mesenteric tumour deposits and emerging novelties.

J Neuroendocrinol 2021 Aug 16;33(8):e13000. Epub 2021 Jul 16.

1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Updates in classification of gastro-entero-pancreatic neuroendocrine neoplasms better reflect the biological characteristics of these tumours. In the present study, we analysed the characteristics of neuroendocrine tumours that could aid in a more precise stratification of risk groups. In addition, we have highlighted the importance of grade (re)assessment based on investigation of secondary tumour lesions. Two hundred and sixty-four cases of neuroendocrine tumours of gastro-entero-pancreatic origin from three centres were included in the study. Tumour morphology, mitotic count and Ki67 labelling index were evaluated in specimens of primary tumours, lymph node metastases and distant metastases. These variables were correlated with overall survival (OS) and relapse-free survival (RFS). Tumour stage, number of affected lymph nodes, presence of tumour deposits and synchronous/metachronous metastases were tested as possible prognostic features. Mitotic count, Ki-67 labelling index, primary tumour site, tumour stage, presence of tumour deposits and two or more affected lymph nodes were significant predictors of OS and RFS. At the same time, mitotic count and Ki-67 labelling index can be addressed as continuous variables determining prognosis. We observed a very high correlation between the measures of proliferative activity in primary and secondary tumour foci. The presence of isolated tumour deposits was identified as an important determinant of both RFS and OS for pancreatic (hazard ratio [HR] = 7.61, 95% confidence interval [CI] = 3.96-14.6, P < 0.0001 for RFS; HR = 3.28, 95% CI = 1.56-6.87, P = 0.0017 for OS) and ileal/jejunal neuroendocrine tumours (HR = 1.98, 95% CI = 1.25-3.13, P = 0.0036 for RFS and HR 2.59, 95% CI = 1.27-5.26, P = 0.009 for OS). The present study identifies the presence of mesenterial tumour deposits as an important prognostic factor for gastro-entero-pancreatic neuroendocrine tumours, provides evidence that proliferative parameters need to be treated as continuous variables and further supports the importance of grade determination in all available tumour foci.
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http://dx.doi.org/10.1111/jne.13000DOI Listing
August 2021

Preventive Anti-inflammatory Diet to Reduce Gastrointestinal Inflammation in Familial Adenomatous Polyposis Patients: A Prospective Pilot Study.

Cancer Prev Res (Phila) 2021 Oct 12;14(10):963-972. Epub 2021 Jul 12.

Unit of Hereditary Digestive Tract Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Familial adenomatous polyposis (FAP) is an autosomal-dominant hereditary condition associated with germline mutations in the adenomatous polyposis coli gene. Patient management involves prophylactic surgery and intensive life-long endoscopic surveillance. Diet is a major concern for patients with FAP, who are generally free of symptoms before surgery but tend to have issues related to bowel function postoperatively. We hypothesized that a low-inflammatory diet based on the principles and recipes of the Mediterranean diet would reduce markers of local and systemic inflammation. Twenty-eight patients with FAP over 18 years of age who underwent rectum-sparing prophylactic colectomy and were included in our surveillance program participated in a pilot dietary intervention study. Blood and stool samples at baseline (T0), at the end of the dietary intervention (T1, three months), and at the end of the study (T2, six months after T0) were collected. Gastrointestinal inflammation markers including fecal calprotectin, cyclooxygenase-2, and 15-hydroxyprostaglandin dehydrogenase were evaluated. Serum calprotectin, insulin, insulin-like growth factor-1, C-reactive protein, and glycated hemoglobin were also assessed. Significant changes in serum calprotectin, insulin, and insulin-like growth factor-1 levels occurred over time. Borderline significant changes were observed in the neutrophil-lymphocyte ratio. These changes were noticeable immediately at the end of the 3-month active dietary intervention (T1). A significant increase in 15-hydroxyprostaglandin dehydrogenase expression in the normal crypts of matched samples was also observed between T0 and T2. This pilot study supports the hypothesis that a low-inflammatory diet can modulate gastrointestinal markers of inflammation in individuals with FAP. PREVENTION RELEVANCE: Cancer is known to be related to inflammatory conditions. This study suggests that anti-inflammatory dietary intervention may potentially prevent adenomas and cancer in FAP patients by reducing systemic and tissue inflammatory indices.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0076DOI Listing
October 2021

Case Report: Exceptional Response to Avelumab After Failure of Electrochemotherapy in a Patient With Rapidly Progressive, PD-L1-Negative Merkel Cell Carcinoma.

Front Oncol 2021 17;11:628324. Epub 2021 Jun 17.

Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy.

This case report shows, for the first time, a patient experiencing a complete response after one dose of avelumab following extensive disease progression with prior electrochemotherapy (ECT) treatment. We suggest that ECT may help to establish a tumor microenvironment favorable to immunotherapy. Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with seldom durable chemotherapy responses. ECT has recently emerged as a potential treatment option for several malignancies, including MCC. Avelumab, an anti-programmed cell death-ligand 1 (PD-L1) monoclonal antibody, became the first approved treatment for patients with metastatic MCC. ECT has been shown to activate the immune response, but it is still unknown how ECT may affect patient's response to subsequent immunotherapy. We report a case of a patient with MCC who presented with a rapidly growing skin nodule of the right cheek and experienced extensive disease progression following surgical debulking and ECT treatment. The patient received a flat dose of 800 mg avelumab intravenously every 2 weeks showing complete tumor regression after only one dose. Immunohistochemical analysis of surgical and post-ECT biopsies collected from the primary lesion revealed tumor expression of programmed cell death protein-1 (PD-1), but not PD-L1. Analysis of the tumor samples also revealed no expression of Merkel cell polyomavirus (MCPyV). Comparison of the biopsies showed a decrease in myeloid and T-cell markers after ECT but an increase in major histocompatibility complex (MHC) class I expression on tumor cells. Additionally, the patient experienced an increase in neutrophil-to-lymphocyte ratio and lactate dehydrogenase values post-ECT, which subsequently decreased with avelumab treatment. As of 30 October 2019, the patient was still receiving avelumab treatment and had an ongoing complete response. In this case report, a patient with PD-L1-negative and MCPyV-negative MCC who had disease progression following ECT experienced complete tumor regression with avelumab treatment, suggesting, for the first time to our knowledge, that ECT may help to establish a tumor microenvironment favorable to immunotherapy a potential abscopal effect. Tumor-intrinsic PD-1 expression and modulation of MHC class I antigens after ECT may contribute to the clinical efficacy of avelumab in this context.
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http://dx.doi.org/10.3389/fonc.2021.628324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248546PMC
June 2021

COVID-19 Pandemic: Huge Stress Test for Health System Could Be a Great Opportunity to Update the Workflow in a Modern Surgical Pathology.

Cancers (Basel) 2021 Jun 30;13(13). Epub 2021 Jun 30.

First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori Milano, 20133 Milan, Italy.

Background: On December 2019, an outbreak of atypical pneumonia, known as COVID-19, was identified in Wuhan, China. This disease, characterized by the rapid human-to-human transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly in more than 200 countries. Northern Italy's regions have been hit hard in terms of deaths. Here, we report the experience of the Pathology Department of the Fondazione IRCCS Istituto Nazionale Tumori (INT) in Milan, the first Italian public cancer center, in the period of the lockdown that took place in Lombardy from March to May 2020.

Method: The variation in terms of exams was calculated in two different timeframes: December 2019-February 2020 (pre-COVID-19) and March-May 2020 (COVID-19). During these periods, Turn-Around-Time (TAT) metrics released by the Lombardy Region were calculated to assess if changes applied to guarantee the safeguarding of workers affected the average diagnosis time.

Results: In the COVID-19 period, there was a decrease for all the performed exams. The most considerable decrease was observed for PAP tests (-81.6%), followed by biopsies (-48.8%), second opinions (-41.7%), and surgical (-31.5%), molecular (-29.4%) and cytological (-18.1%) tests. Measures applied within the Pathology Department, such as digital pathology, remote working, rotations and changes in operating procedures, improved the diagnostic performance as required by the guidelines of the Lombardy Region in terms of TAT. At the same time, the measures applied for the safeguarding of the personnel turned out to be feasible and did not affect the overall performance of the Pathology Department.

Conclusions: The sharp slowdown in cancer screening during the first wave of COVID-19 could seriously endanger cancer prevention in the near future.
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http://dx.doi.org/10.3390/cancers13133283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268969PMC
June 2021

Cotargeting of miR-126-3p and miR-221-3p inhibits PIK3R2 and PTEN, reducing lung cancer growth and metastasis by blocking AKT and CXCR4 signalling.

Mol Oncol 2021 Jun 9. Epub 2021 Jun 9.

Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Lung cancer is the leading cause of cancer-related death worldwide. Late diagnosis and metastatic dissemination contribute to its low survival rate. Since microRNA (miRNA) deregulation triggers lung carcinogenesis, miRNAs might represent an interesting therapeutic tool for lung cancer management. We identified seven miRNAs, including miR-126-3p and miR-221-3p, that are deregulated in tumours compared with normal tissues in a series of 38 non-small-cell lung cancer patients. A negative correlation between these two miRNAs was associated with poor patient survival. Concomitant miR-126-3p replacement and miR-221-3p inhibition, but not modulation of either miRNA alone, reduced lung cancer cell viability by inhibiting AKT signalling. PIK3R2 and PTEN were validated as direct targets of miR-126-3p and miR-221-3p, respectively. Simultaneous miRNA modulation reduced metastatic dissemination of lung cancer cells both in vitro and in vivo through CXCR4 inhibition. Systemic delivery of a combination of miR-126-3p mimic and miR-221-3p inhibitor encapsulated in lipid nanoparticles reduced lung cancer patient-derived xenograft growth through blockade of the PIK3R2-AKT pathway. Our findings reveal that cotargeting miR-126-3p and miR-221-3p to hamper both tumour growth and metastasis could be a new therapeutic approach for lung cancer.
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http://dx.doi.org/10.1002/1878-0261.13036DOI Listing
June 2021

A novel CXCR4 antagonist counteracts paradoxical generation of cisplatin-induced pro-metastatic niches in lung cancer.

Mol Ther 2021 Oct 21;29(10):2963-2978. Epub 2021 May 21.

Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite experimental evidence of its potential to induce long-term detrimental effects, including the promotion of pro-metastatic microenvironments. In this study, we investigated the interconnected pathways underlying the promotion of cisplatin-induced metastases. In tumor-free mice, cisplatin treatment resulted in an expansion in the bone marrow of CCR2CXCR4Ly6C inflammatory monocytes (IMs) and an increase in lung levels of stromal SDF-1, the CXCR4 ligand. In experimental lung metastasis assays, cisplatin-induced IMs promoted the extravasation of tumor cells and the expansion of CD133CXCR4 metastasis-initiating cells (MICs). Peptide R, a novel CXCR4 inhibitor designed as an SDF-1 mimetic peptide, prevented cisplatin-induced IM expansion, the recruitment of IMs into the lungs, and the promotion of metastasis. At the primary tumor site, cisplatin treatment reduced tumor size while simultaneously inducing tumor release of SDF-1, MIC expansion, and recruitment of pro-invasive CXCR4 macrophages. Co-recruitment of MICs and CCR2CXCR4 IMs to distant SDF-1-enriched sites also promoted spontaneous metastases that were prevented by CXCR4 blockade. In clinical specimens from NSCLC patients SDF-1 levels were found to be higher in platinum-treated samples and related to a worse clinical outcome. Our findings reveal that activation of the CXCR4/SDF-1 axis specifically mediates the pro-metastatic effects of cisplatin and suggest CXCR4 blockade as a possible novel combination strategy to control metastatic disease.
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http://dx.doi.org/10.1016/j.ymthe.2021.05.014DOI Listing
October 2021

Target therapies plus somatostatin analogs in NETs: a network meta-analysis.

Endocr Relat Cancer 2021 Jun 17;28(7):467-479. Epub 2021 Jun 17.

Department of Medical Oncology ENETS Center of Excellence, Fondazione IRCCS Istituto Tumori Milano, Milan, Italy.

Although combination therapy is not recommended in patients with gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs), this strategy is widely used in clinical practice. This network meta-analysis of randomized trials evaluates targeted therapies and somatostatin analogues in GEP-advanced NETs, either alone or in combination, comparing the efficacy of different, single or combined treatment strategies in terms of progression-free survival (PFS). Interventions were grouped as analogs, everolimus, everolimus plus SSAs, sunitinib and placebo. In a secondary analysis, we also assessed the efficacy of individual-specific pharmacological treatments vs placebo or each other. From 83 studies identified, 8 randomized controlled trials were selected, with a total of 1849 patients with either functioning or non-functioning NETs. The analysis confirmed the superiority of all treatments over placebo (HR ranging from 0.34, 95% CI: 0.24-0.37 with the combination of everolimus plus SSAs to 0.42, 0.31-0.57 with the analogs; moderate quality of evidence). On ranking analysis, the combination of everolimus plus SSA (P score = 0.86) and then everolimus alone (P score = 0.65) ranked highest in increasing PFS. On comparative evaluation of different interventions, pasireotide (P score = 0.96) and everolimus + octreotide (P score = 0.82) ranked as the best pharmacological treatment options. Our findings support the use of combination therapy in the treatment of functioning and non-functioning GEP NETs. The role of pasireotide should be explored in selected subgroups of patients. Lastly, the combination of everolimus and octreotide appears promising and should be more widely considered in clinical practice.
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http://dx.doi.org/10.1530/ERC-20-0492DOI Listing
June 2021

Myeloid and T-Cell Microenvironment Immune Features Identify Two Prognostic Sub-Groups in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms.

J Clin Med 2021 Apr 17;10(8). Epub 2021 Apr 17.

1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.

High-grade Gastroenteropancreatic Neuroendocrine neoplasms (H-NENs) comprehend well-differentiated tumors (NET G3) and poorly differentiated carcinomas (NEC) with proliferative activity indexes as mitotic count (MC) >20 mitoses/10 HPF and Ki-67 >20%. At present, no specific therapy for H-NENs exists and the several evidences of microenvironment involvement in their pathogenesis pave the way for tailored therapies. Forty-five consecutive cases, with available information about T-cell, immune, and non-immune markers, from surgical pathology and clinical databases of 2 Italian institutions were immunostained for Arginase, CD33, CD163 and CD66 myeloid markers. The association between features was assessed by Spearman's correlation coefficient. A unsupervised K-means algorithm was used to identify clusters of patients according to inputs of microenvironment features and the relationship between clusters and clinicopathological features, including cancer-specific survival (CSS), was analyzed. The H-NEN population was composed of 6 (13.3%) NET G3 and 39 (86.7%) NEC. Overall, significant positive associations were found between myeloid (CD33, CD163 and Arginase) and T/immune markers (CD3, CD4, CD8, PD-1 and HLA-I). Myeloid and T-cell markers CD3 and CD8 identified two clusters of patients from unsupervised K-means analysis. Cases grouped in cluster 1 with more myeloid infiltrates, T cell, HLA and expression of inhibitory receptors and ligands in the stroma (PD-1, PD-L1) had significantly better CSS than patients in cluster 2. Multivariable analysis showed that Ki-67 (>55 vs. <55, HR 8.60, CI 95% 2.61-28.33, < 0.0001) and cluster (1 vs. 2, HR 0.43, CI 95% 0.20-0.93, = 0.03) were significantly associated with survival. High grade gastroenteropancreatic neuroendocrine neoplasms can be further classified into two prognostic sub-populations of tumors driven by different tumor microenvironments and immune features able to generate the framework for evaluating new therapeutic strategies.
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http://dx.doi.org/10.3390/jcm10081741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072982PMC
April 2021

Postrecurrence Survival After Liver Transplantation for Liver Metastases From Neuroendocrine Tumors.

Transplantation 2021 Apr 27. Epub 2021 Apr 27.

HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy Pathology Unit 1, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy.

Background: Liver metastases from neuroendocrine tumors (NETs) is an accepted indication for liver transplantation (LT). Despite strict patient selection, post-LT recurrence is observed in 30-50% of cases. Postrecurrence survival is poorly investigated as well as factors influencing postrecurrence outcomes.

Methods: Consecutive patients treated at a single Institution for post-LT recurrence of NET between Jan 1st, 2004 and Dec 31th, 2018 were included. Baseline patients' characteristics, data on the primary tumor, pretransplant therapies, posttransplant recurrence and treatments and long-term outcomes were prospectively collected and retrospectively analyzed.

Results: Thirty-two patients presented with post-LT NET recurrence occurring 82.9 months (IQR 29.4-119.1) from LT, and the most common sites were abdominal lymph nodes (59.4%), peritoneum (6.3%) and lungs (6.3%). Fourteen patients (43.8%) underwent surgery with radical intent. Five- and 10-years survival after recurrence were 76.3% and 45.5%, respectively. Only time from LT to recurrence had a significant impact on post recurrence survival, being 5-years OS 89.5% versus 0% for patients recurring > 24 months after LT versus ≤ 24 months, respectively (p=.001). Moreover, for patients with Mib-1 > 2% at recurrence, 5-years OS was 87.5% versus 0% for those undergoing surgery versus loco-regional or systemic treatments (p=0.011).

Conclusions: The presented results, although based on a retrospective and relatively small series, show that excellent long-term survival is observed after post-LT NET recurrence, particularly in those patients recurring long after LT (> 24 months). An aggressive surgical treatment might result in a new chance of cure for a selected subgroup of patients.
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http://dx.doi.org/10.1097/TP.0000000000003802DOI Listing
April 2021

Heme catabolism by tumor-associated macrophages controls metastasis formation.

Nat Immunol 2021 05 26;22(5):595-606. Epub 2021 Apr 26.

Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy.

Although the pathological significance of tumor-associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. Here we show that a distinct subset of TAMs (F4/80CD115C3aRCD88), endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), plays a critical role in shaping a prometastatic tumor microenvironment favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. This population originates from F4/80HO-1 bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-κB1-CSF1R-C3aR axis. Inhibition of F4/80HO-1 TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients. Overall, these results identify a distinct cancer-induced HO-1 myeloid subgroup as a new antimetastatic target and prognostic blood marker.
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http://dx.doi.org/10.1038/s41590-021-00921-5DOI Listing
May 2021

LKB1 Down-Modulation by miR-17 Identifies Patients With NSCLC Having Worse Prognosis Eligible for Energy-Stress-Based Treatments.

J Thorac Oncol 2021 08 19;16(8):1298-1311. Epub 2021 Apr 19.

Tumor Genomics Unit, Department of Research, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan, Italy.

Introduction: Preclinical models recently unveiled the vulnerability of LKB1/KRAS comutated NSCLC to metabolic stress-based treatments. Because miR-17 is a potential epigenetic regulator of LKB1, we hypothesized that wild-type LKB1 (LKB1) NSCLC with high miR-17 expression may be sensitive to an energetic stress condition, and eligible for metabolic frailties-based therapeutic intervention.

Methods: We took advantage of NSCLC cell lines with different combinations of KRAS mutation and LKB1 deletion and of patient-derived xenografts (PDXs) with high (LKB1/miR-17 high) or low (LKB1/miR-17 low) miR-17 expression. We evaluated LKB1 pathway impairment and apoptotic response to metformin. We retrospectively evaluated LKB1 and miR-17 expression levels in tissue specimens of patients with NSCLC and PDXs. In addition, a lung cancer series from The Cancer Genome Atlas data set was analyzed for miR-17 expression and potential correlation with clinical features.

Results: We identified miR-17 as an epigenetic regulator of LKB1 in NSCLC and confirmed targeting of miR-17 to LKB1 3' untranslated region by luciferase reporter assay. We found that miR-17 overexpression functionally impairs the LKB1/AMPK pathway. Metformin treatment prompted apoptosis on miR-17 overexpression only in LKB1 cell lines, and in LKB1/miR-17 high PDXs. A retrospective analysis in patients with NSCLC revealed an inverse correlation between miR-17 and LKB1 expression and highlighted a prognostic role of miR-17 expression in LKB1 patients, which was further confirmed by The Cancer Genome Atlas data analysis.

Conclusions: We identified miR-17 as a mediator of LKB1 expression in NSCLC tumors. This study proposes a miR-17 expression score potentially exploitable to discriminate LKB1 patients with NSCLC with impaired LKB1 expression and poor outcome, eligible for energy-stress-based treatments.
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http://dx.doi.org/10.1016/j.jtho.2021.04.005DOI Listing
August 2021

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.

Gut 2021 Apr 13. Epub 2021 Apr 13.

Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Objective: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown.

Design: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS).

Results: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%).

Conclusions: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.
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http://dx.doi.org/10.1136/gutjnl-2020-322595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511349PMC
April 2021

EGFR Amplification in Metastatic Colorectal Cancer.

J Natl Cancer Inst 2021 Apr 7. Epub 2021 Apr 7.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy.

Background: EGFR amplification occurs in about 1% of metastatic colorectal cancers (mCRCs) but is not routinely tested as a prognostic or predictive biomarker for patients treated with anti-EGFR monoclonal antibodies (mAbs). Herein, we aimed to characterize the clinical and molecular landscape of EGFR-amplified metastatic colorectal cancer (mCRC).

Methods: In this multinational cohort study, we compared clinical data of 62 patients with EGFR-amplified vs. 1459 EGFR non-amplified mCRC, as well as comprehensive genomic data of 35 EGFR-amplified vs. 439 EGFR non-amplified RAS/BRAF wild-type and microsatellite stable (MSS) tumor samples.

Results: EGFR amplification was statistically significantly associated with left primary tumor sidedness and RAS/BRAF wild-type status. All EGFR-amplified tumors were MSS and HER2 non-amplified. Overall, EGFR-amplified samples had higher median fraction of genome altered compared to EGFR non-amplified, RAS/BRAF wild-type MSS cohort. Patients with EGFR-amplified tumors reported longer overall survival (OS) (median OS = 71.3 months; 95% confidence interval [CI] = 50.7-NA) vs. EGFR non-amplified ones (24.0 months; 95% CI = 22.8-25.6; hazard ratio [HR] = 0.30, 95% CI = 0.20-0.44, P<.001; adjusted HR = 0.46, 95%CI = 0.30-0.69, P<.001). In the subgroup of patients with RAS/BRAF wild-type mCRC exposed to anti-EGFR-based therapy, EGFR amplification was again associated with better OS (median OS = 54.0 months [95% CI = 35.2-NA] vs. 29.1 months [95% CI = 27.0-31.9], respectively; HR = 0.46, 95%CI = 0.28-0.76, P=.002).

Conclusion: Patients with EGFR-amplified mCRC represent a biologically defined subgroup and merit dedicated clinical trials with novel and more potent EGFR targeting strategies beyond single-agent monoclonal antibodies.
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http://dx.doi.org/10.1093/jnci/djab069DOI Listing
April 2021

Does ProCore fine needle biopsy really improve the clinical outcome of endoscopic ultrasound-guided sampling of pancreatic masses?

Dig Dis 2021 Mar 29. Epub 2021 Mar 29.

Introduction: Fine Needle Biopsy (FNB) has been suggested to provide better histological samples as compared to endoscopic ultrasound fine needle aspiration (EUS-FNA). However, studies comparing EUS-FNA and EUS-FNB for pancreatic lesions reported contrasting results. The aim of this study was to compare the clinical performance of EUS-FNA versus EUS-FNB with ProCore needle for the investigation of pancreatic lesions.

Methods: We reviewed all patients undergoing EUS for the investigation of pancreatic lesions from August 2012 to September 2018. From August 2012 to January 2015 all procedures were performed with standard needles, whereas from February 2015 to September 2018 the use of ProCore needles had been introduced. Data on diagnostic accuracy, number of needle passes and/or adverse events were collected.

Results: 324 patients were retrospectively evaluated: 190 (58.6%) underwent EUS-FNA and 134 (41.4%) EUS-FNB. Both EUS-FNA and EUS-FNB showed high diagnostic accuracy for malignancy [94% (CI 95%:89-97%) vs 94% (CI 95%:89-98%)]. Notable, there were no differences between EUS-FNA and EUS-FNB in terms of sensitivity, specificity, positive and negative likelihood ratio, histological core tissue retrieval, adverse events or number of needle passes. However, subgroup analysis noted a higher diagnostic accuracy for 25G EUS-FNB as compared to 25G EUS-FNA (85,7% vs 55,5%; *p=0.023).

Conclusion: EUS-FNB with ProCore needle is safe and feasible in pancreatic lesions. ProCore needle did not provide any advantage in terms of diagnostic accuracy, sensitivity, specificity, positive and/or negative likelihood ratio, or acquisition of core specimen, therefore its routine application is not.
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http://dx.doi.org/10.1159/000516177DOI Listing
March 2021

Neuroendocrine neoplasms of the duodenum, ampullary region, jejunum and ileum.

Pathologica 2021 Feb;113(1):12-18

Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy.

Neuroendocrine neoplasms of the small intestine are some of the most frequently occurring along the gastrointestinal tract, even though their incidence is extremely variable according to specific sites. Jejunal-ileal neuroendocrine neoplasms account for about 27% of gastrointestinal NETs making them the second most frequent NET type. The aim of this review is to classify all tumors following the WHO 2019 classification and to describe their pathologic differences and peculiarities.
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http://dx.doi.org/10.32074/1591-951X-228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138699PMC
February 2021

Recent Advances in the Management of Typical and Atypical Lung Carcinoids.

Clin Lung Cancer 2021 05 17;22(3):161-169. Epub 2020 Dec 17.

Department of Medical Oncology.

Neuroendocrine neoplasms of the lung represent about 20% to 30% of all neuroendocrine tumors. On the basis of clinical and pathologic characteristics, 2 different categories of tumors may be defined: poorly differentiated neuroendocrine neoplasms, characterized by a high rate of recurrences and poor prognosis, and well-differentiated neuroendocrine neoplasms (typical carcinoids and atypical carcinoids), which generally display an indolent course. Lung carcinoids represent only 1% to 5% of all lung malignancies, but their incidence has significantly increased over the past 30 years. Surgery is the reference standard of treatment for lung carcinoids with locoregional disease. For advanced or unresectable lung carcinoids, several therapeutic options are available, but the choice should be shared within a multidisciplinary team to ensure optimal therapeutic outcomes. We describe the current management of these rare neoplasms.
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http://dx.doi.org/10.1016/j.cllc.2020.12.004DOI Listing
May 2021

Synaptophysin expression in mutated advanced colorectal cancers identifies a new subgroup of tumours with worse prognosis.

Eur J Cancer 2021 03 16;146:145-154. Epub 2021 Feb 16.

Department of Oncology, University of Turin at Umberto I "Ordine Mauriziano" Hospital, Turin, Italy.

Background: Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting.

Methods: We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests.

Results: Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001).

Conclusions: Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.
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http://dx.doi.org/10.1016/j.ejca.2021.01.016DOI Listing
March 2021

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association.

Commun Biol 2021 02 3;4(1):155. Epub 2021 Feb 3.

University of Sydney, Sydney, New South Wales, 2006, Australia.

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
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http://dx.doi.org/10.1038/s42003-020-01469-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859232PMC
February 2021

Beyond Traditional Morphological Characterization of Lung Neuroendocrine Neoplasms: In Silico Study of Next-Generation Sequencing Mutations Analysis across the Four World Health Organization Defined Groups.

Cancers (Basel) 2020 Sep 24;12(10). Epub 2020 Sep 24.

1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS (Scientific Institute for Research, Hospitalization and Healthcare) Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy.

Lung neuroendocrine neoplasms (LNENs) represent a rare and heterogeneous population of lung tumors. LNENs incidence rate has increased dramatically over the past 30 years. The current World Health Organization LNENs classification (WHO 2015), distinguished four LNENs prognostic categories, according to their morphology, necrosis amount and mitotic count: typical carcinoid (TC), atypical-carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC). At present, due to their rarity and biological heterogeneity there is still no consensus on the best therapeutic approach. Next-generation-sequencing analysis showed that WHO 2015 LNENs classes, could be characterized also by specific molecular alterations: frequently mutated genes involving chromatin remodeling and generally characterized by low mutational burden (MB) are frequently detected in both TC and AC; otherwise, and tumor suppressor genes alterations and high MB are usually detected in LCNEC and SCLC. We provide an overview concerning gene mutations in each WHO 2015 LNENs class in order to report the current LNENs mutational status as potential tool to better understand their clinical outcome and to drive medical treatment.
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http://dx.doi.org/10.3390/cancers12102753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600757PMC
September 2020

Prognostic Impact of Primary Side and RAS/RAF Mutations in a Surgical Series of Colorectal Cancer with Peritoneal Metastases.

Ann Surg Oncol 2021 Jun 24;28(6):3332-3342. Epub 2020 Sep 24.

Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Selecting patients with colorectal cancer peritoneal metastases (CRC-PMs) for surgery is still a concern. Biological features have the potential to improve prognostic stratification, but their significance in this clinical setting is still unclear. We assessed the prognostic impact of primary side and KRAS/NRAS/BRAF/PIK3CA mutations in patients treated with either cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) or CRS alone.

Methods: We reviewed a prospective database of 152 CRC-PM patients selected to undergo perioperative systemic chemotherapy and CRS with or without HIPEC. Extensive mutational analysis of KRAS, NRAS, BRAF, and PIK3CA was performed by polymerase chain reaction (PCR). In 68 patients, Ion Torrent next-generation sequencing technology was used to characterize the hotspot regions of 50 genes.

Results: The primary tumor was right-sided in 61 patients (40.1%) and left-sided in 91 patients (59.9%). Right-sided primaries were associated with mutated KRAS (p = 0.01) and normal carcinoembryonic antigen (CEA; p = 0.03). KRAS was mutated in 71/152 patients (46.7%), NRAS in 7/152 patients (4.6%), BRAF in 10/152 patients (6.6%), PIK3CA in 17/78 patients (25.0%), TP53 in 37/68 patients (54.4%), APC in 25/68 patients (36.7%), SMAD4 in 13/68 patients (19.1%), and FBXW7 in 5/68 patients (7.4%). Median follow-up was 54.9 months and median survival from PM diagnosis was 45.1 months. The right-sided primary (hazard ratio [HR] 1.62, 95% confidence interval [CI] 0.43-0.89; p = 0.011), BRAF mutations (HR 2.21, 95% CI 1.05-4.63; p = 0.038), and Peritoneal Cancer Index (HR 1.47, 95% CI 1.03-2.10; p = 0.036) independently correlated with poorer survival, while APC mutations univariately correlated with better survival (p = 0.03).

Conclusions: BRAF mutations and right-sided primary are adverse prognostic factors that may be used to optimize therapeutic strategies. APC may be involved in CRC-PM development and progression.
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http://dx.doi.org/10.1245/s10434-020-09161-7DOI Listing
June 2021

The potential role of metformin in the treatment of patients with pancreatic neuroendocrine tumors: a review of preclinical to clinical evidence.

Therap Adv Gastroenterol 2020 31;13:1756284820927271. Epub 2020 Jul 31.

Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy University of Milan, Milan, Italy.

The incidence of pancreatic neuroendocrine tumors (panNETs) has increased worldwide in the last two decades. Given the indolent nature of these tumors, several patients are diagnosed with metastatic disease, which partially impairs the long-term efficacy of currently available treatments and reduces survival rates. The search for new therapeutic strategies for cancer patients has pushed towards the retrospective analysis of studies involving patients who concomitantly received other drugs together with standard anticancer agents. In this light, several retrospective analyses have shown that metformin use is associated with improved prognosis in patients with different tumor types treated with standard antitumor agents. Metformin, the cornerstone oral agent for the treatment of type 2 diabetes, plays a role in modulating glucose cell metabolism. Its potential ability to interfere with tumors may derive from the tight relationship between metabolic reprogramming in cancer cells and tumor progression. Indications for metformin use as an anticancer drug result from pre-clinical and clinical observations. In particular, metformin use in diabetic patients with advanced panNETs has been associated with better progression-free survival in patients treated with somatostatin analogues with or without metformin.
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http://dx.doi.org/10.1177/1756284820927271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406937PMC
July 2020

Colorectal Adenocarcinomas Harboring ALK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 12 Cases and Review of the Literature.

Am J Surg Pathol 2020 09;44(9):1224-1234

Surgical Pathology, Holycross Cancer Center.

This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.
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http://dx.doi.org/10.1097/PAS.0000000000001512DOI Listing
September 2020

Histopathological landscape of rare oesophageal neoplasms.

World J Gastroenterol 2020 Jul;26(27):3865-3888

Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padua, Padua 35121, Italy.

The landscape of neoplastic pathology of the oesophagus is dominated by malignancies of epithelial origin, in particular by oesophageal adenocarcinoma and oesophageal squamous cell carcinoma. However, several other histopathological variants can be distinguished, some associated with peculiar histopathological profiles and prognostic behaviours and frequently underrecognized in clinical practice. The aim of this review is to provide a comprehensive characterization of the main morphological and clinical features of these rare variants of oesophageal neoplastic lesions.
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http://dx.doi.org/10.3748/wjg.v26.i27.3865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385561PMC
July 2020

The Pathologic and Molecular Landscape of Esophageal Squamous Cell Carcinogenesis.

Cancers (Basel) 2020 Aug 4;12(8). Epub 2020 Aug 4.

Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy.

Esophageal squamous cell carcinoma represents the most common histotype of epithelial neoplasm occurring within esophageal mucosa worldwide. Despite the comprehensive molecular characterization of this entity, to date no significant targeted therapy has been introduced into clinical practice. In this review, we describe the molecular landscape of esophageal squamous cell carcinoma based on the most recent literature. Moreover, we focus on other rare variants and on the relationship with head and neck squamous cell carcinomas.
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http://dx.doi.org/10.3390/cancers12082160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465394PMC
August 2020

Differential Diagnosis and Management of Diarrhea in Patients with Neuroendocrine Tumors.

J Clin Med 2020 Aug 1;9(8). Epub 2020 Aug 1.

Department of Medical Oncology, Gastro-entero-pancreatic and Neuroendocrine Unit 1, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.

Diarrhea is a recurrent symptom in patients with neuroendocrine tumors (NETs) and can represent different etiologies; thus, differential diagnosis is challenging. This paper distinguishes the different causes of chronic diarrhea in patients with gastroenteropancreatic NETs, with the aim to identify the most appropriate therapeutic approach. Underlying causes of diarrhea can be multifactorial, including not only diarrhea that is related to specific hormonal hypersecretory syndromes, but also diarrhea that is secondary to the following: extensive surgery which can cause pancreatic exocrine insufficiency or short bowel syndrome, treatment with somatostatin analogs or other antineoplastic agents, and bile acid malabsorption. After initial management of diarrhea with general treatments (dietary modification, use of antidiarrheals), a proper differential diagnosis is necessary to treat patients with specific etiology-driven therapeutic approaches, such as somatostatin analogs, pancreatic enzyme replacement therapy, and tryptophan hydroxylase inhibitors. In conclusion, NETs should be considered in the differential diagnosis of patients suffering from chronic diarrhea, after the exclusion of more common etiologies. Furthermore, physicians should keep in mind that several different etiologies might be responsible for diarrhea occurrence in NET patients. A prompt diagnosis of the actual cause of diarrhea is necessary to guide the treatment and a multidisciplinary approach is mandatory.
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http://dx.doi.org/10.3390/jcm9082468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464810PMC
August 2020

Reply to E. Hindié.

J Clin Oncol 2020 09 23;38(27):3238-3240. Epub 2020 Jul 23.

Andrea Maurichi, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Rosalba Miceli, PhD, Medical Statistics, Biometry and Bioinformatics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Hanna Eriksson, MD, PhD, Department of Oncology, Theme Cancer, Karolinska University Hospital, and Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; Julia Newton-Bishop, MD, FRCP; Jérémie Nsengimana, PhD; and May Chan, PGD, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom; Andrew J. Hayes, MA, MBBS, MD, PhD and Kara Heelan, MB, BCH, BAO, MRCPI, MD, Sarcoma and Melanoma Units and Skin Unit, The Royal Marsden National Health Service (NHS) Foundation Trust, London, United Kingdom; David Adams, PhD, Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Roberto Patuzzo, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Francesco Barretta, MS, PhD, Medical Statistics, Biometry and Bioinformatics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Gianfranco Gallino, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Catherine Harwood, MA, MD, PhD, FRCP and Daniele Bergamaschi, PhD, Queen Mary University of London, London, United Kingdom; Dorothy Bennett, FMedSci, PhD, Molecular and Clinical Sciences Research Institute, St George's, University of London, London, United Kingdom; Konstantinos Lasithiotakis, MD, PhD, York Teaching Hospital NHS Foundation Trust, York, United Kingdom and Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Paola Ghiorzo, MD, PhD and Bruna Dalmasso, MD, University Hospital of Genoa, Genoa, Italy; Ausilia Manganoni, MD and Francesca Consoli, MD, University Hospital of Brescia, Brescia, Italy; Ilaria Mattavelli, MD; Consuelo Barbieri, MD; and Andrea Leva, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Umberto Cortinovis, MD, Plastic and Reconstructive Surgical Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Vittoria Espeli, MD and Cristina Mangas, MD, PhD, Istituto Oncologico Svizzera Italiana, Ospedale Regionale Bellinzona e Valli, Bellinzona, Switzerland; Pietro Quaglino, MD; Simone Ribero, MD, PhD; and Paolo Broganelli, MD, University Hospital of Turin, Turin, Italy; Giovanni Pellacani, MD, University Hospital of Modena, Modena, Italy; Caterina Longo, MD, Arcispedale S. Maria Nuova, Reggio Emilia, Italy; Corrado Del Forno, MD, University Hospital of Pavia, Pavia, Italy; Lorenzo Borgognoni, MD and Serena Sestini, MD, Ospedale S. Maria Annunziata, Tuscan Cancer Institute, Florence, Italy; Nicola Pimpinelli, MD, PhD and Sara Fortunato, MD, Division of Dermatology, University of Florence, Florence, Italy; Alessandra Chiarugi, MD and Paolo Nardini, MD, Institute for Cancer Research and Prevention, Florence, Italy; Elena Morittu, PhD and Antonio Florita, PhD, Scientific Director's Office, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Mara Cossa, MD, PhD; Barbara Valeri, MD; Massimo Milione, MD, PhD; and Giancarlo Pruneri, MD, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Odysseas Zoras, MD, PhD, University Hospital of Heraklion, Heraklion, Greece; Andrea Anichini, PhD and Roberta Mortarini, PhD, Immunobiology of Human Cancers Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; and Mario Santinami, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

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http://dx.doi.org/10.1200/JCO.20.01460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499609PMC
September 2020

Improved Prognostic Prediction in Never-Smoker Lung Cancer Patients by Integration of a Systemic Inflammation Marker with Tumor Immune Contexture Analysis.

Cancers (Basel) 2020 Jul 7;12(7). Epub 2020 Jul 7.

Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy.

Almost 25% of lung cancers (LCs) occur in never-smokers. LC inflammatory profile, based on plasma C-reactive protein levels (CRP), predicts mortality, independently by smoking-status. We hypothesized that: CRP could be associated with tumor immune contexture (TIC) in never-smokers and both these two parameters may improve their prognosis. Sixty-eight never-smokers LC patients with high or low CRP were selected. The programmed cell death protein 1 (PD-1) and its ligand (PD-L1), the human leukocyte antigens (HLA-DR and HLA-I), CD8, CD4, CD3, CD33, CD163, and CD68 were evaluated by immunohistochemistry on surgical samples given TIC evaluation. The classification model based on TIC scores was generated by Classification and Regression Tree analysis. Tumor mutational burden was evaluated by targeted next-generation sequencing. Exclusively high CRP (H-CRP) subset showed PD-L1 expression in 35% of LC as well as lower HLA-I and HLA-DR in their stromal cells. CD3, CD4, CD8, HLA-I, HLA-DR tumor cells staining were associated with a "low inflammatory profile" subset. CRP and LC immune profiles drive clinical outcome: 5-year survival 88% against 8% was associated with low and high-risk profiles ( < 0.0001). Clinical outcome prediction in never-smoker LC patients may be improved by both CRP and tumor immune contexture evaluation.
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http://dx.doi.org/10.3390/cancers12071828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408913PMC
July 2020

Prognostic impact of immune-microenvironment in colorectal liver metastases resected after triplets plus a biologic agent: A pooled analysis of five prospective trials.

Eur J Cancer 2020 08 15;135:78-88. Epub 2020 Jun 15.

Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy. Electronic address:

Background: Immune-contexture of tumour microenvironment (TME) influences prognosis of colorectal cancer (CRC) patients and can be altered by cytotoxic and targeted agents. Limited data are available regarding the immune-TME of CRC after treatment.

Methods: An extensive immunohistochemistry evaluation of immunological parameters on tumour cells and TME of colorectal liver metastases from 106 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (5-fluorouracil, oxaliplatin and irinotecan) or COI (capecitabine, oxaliplatin and irinotecan) plus bevacizumab (N = 59) or cetuximab (N = 47) in five first-line no-profit clinical trials was performed.

Results: No substantial differences were reported in immunological parameters according to administered targeted agent, RAS/BRAF mutational status and histopathological or Response Evaluation Criteria in Solid Tumours response. Stromal expression of Cyclooxygenase-2 (COX-2) (p = 0.002), Human leukocyte antigen (HLA) (p = 0.003) and Programmed cell death protein 1 (PD1) (p = 0.002) were independent prognostic factors for longer relapse-free survival (RFS) at multivariate analysis with a positive trend for post-resection overall survival (OS). Patients whose metastases expressed stromal COX-2, HLA and PD1 (inflamed-score positive) reported longer RFS (25.5 versus 9.8 months; p < 0.001) and post-resection OS (64.3 versus 37.7 months; p = 0.003) as compared with others. In addition, patients with higher expression of CD4 and CD8 T-cells in tumour core and invasive margin (CD4/CD8-score) showed a better post-resection OS (not-reached versus 41.6 months; p = 0.032). A combined score of inflamed-score and CD4/CD8-score (combo-score) showed a clear prognostic role.

Conclusions: The present study emphasises the role of immune-TME as independent predictor of survival in patients resected after triplets plus biologic. Inflamed-, CD4/C8- and combo-scores should be confirmed as prognostic factors in further studies.
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http://dx.doi.org/10.1016/j.ejca.2020.04.045DOI Listing
August 2020

Are Cyclin-Dependent Kinase 4/6 Inhibitors Without Future in Neuroendocrine Tumors?

Oncologist 2020 08 16;25(8):e1257-e1258. Epub 2020 Jun 16.

Department of Medical Oncology, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

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http://dx.doi.org/10.1634/theoncologist.2020-0298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418349PMC
August 2020
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