Prognostic Factors across Poorly Differentiated Neuroendocrine Neoplasms: A Pooled Analysis.

INTRODUCTION: Poorly differentiated neuroendocrine carcinomas (NECs) are characterized by aggressive clinical course and poor prognosis. No reliable prognostic markers have been validated to date; thus, the definition of a specific NEC prognostic algorithm represents a clinical need. This study aimed to analyze a large NEC case series to validate the specific prognostic factors identified in previous studies on gastro-entero-pancreatic and lung NECs and to assess if further prognostic parameters can be isolated. METHODS: A pooled analysis of four NEC retrospective studies was performed to evaluate the prognostic role of Ki-67 cut-off, the overall survival (OS) according to primary cancer site, and further prognostic parameters using multivariable Cox proportional hazards model and machine learning random survival forest (RSF). RESULTS: 422 NECs were analyzed. The most represented tumor site was the colorectum (n = 156, 37%), followed by the lungs (n = 111, 26%), gastroesophageal site (n = 83, 20%; 66 gastric, 79%) and pancreas (n = 42, 10%). The Ki-67 index was the most relevant predictor, followed by morphology (pure or mixed/combined NECs), stage, and site. The predicted RSF response for survival at 1, 2, or 3 years showed decreasing survival with increasing Ki-67, pure NEC morphology, stage III-IV, and colorectal NEC disease. Patients with Ki-67 <55% and mixed/combined morphology had better survival than those with pure morphology. Morphology pure or mixed/combined became irrelevant in NEC survival when Ki-67 was ≥55%. The prognosis of metastatic patients who did not receive any treatment tended to be worse compared to that of the treated group. The prognostic impact of Rb1 immunolabeling appears to be limited when multiple risk factors are simultaneously assessed. CONCLUSION: The most effective parameters to predict OS for NEC patients could be Ki-67, pure or mixed/combined morphology, stage, and site.

Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis.

BACKGROUND: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation. METHODS: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component. RESULTS: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05). CONCLUSIONS: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.

CT texture analysis for prediction of EGFR mutational status and ALK rearrangement in patients with non-small cell lung cancer.

PURPOSE: To develop a CT texture-based model able to predict epidermal growth factor receptor (EGFR)-mutated, anaplastic lymphoma kinase (ALK)-rearranged lung adenocarcinomas and distinguish them from wild-type tumors on pre-treatment CT scans. MATERIALS AND METHODS: Texture analysis was performed using proprietary software TexRAD (TexRAD Ltd, Cambridge, UK) on pre-treatment contrast-enhanced CT scans of 84 patients with metastatic primary lung adenocarcinoma. Textural features were quantified using the filtration-histogram approach with different spatial scale filters on a single 5-mm-thick central slice considered representative of the whole tumor. In order to deal with class imbalance regarding mutational status percentages in our population, the dataset was optimized using the synthetic minority over-sampling technique (SMOTE) and correlations with textural features were investigated using a generalized boosted regression model (GBM) with a nested cross-validation approach (performance averaged over 1000 resampling episodes). RESULTS: ALK rearrangements, EGFR mutations and wild-type tumors were observed in 19, 28 and 37 patients, respectively, in the original dataset. The balanced dataset was composed of 171 observations. Among the 29 original texture variables, 17 were employed for model building. Skewness on unfiltered images and on fine texture was the most important features. EGFR-mutated tumors showed the highest skewness while ALK-rearranged tumors had the lowest values with wild-type tumors showing intermediate values. The average accuracy of the model calculated on the independent nested validation set was 81.76% (95% CI 81.45-82.06). CONCLUSION: Texture analysis, in particular skewness values, could be promising for noninvasive characterization of lung adenocarcinoma with respect to EGFR and ALK mutations.

Efficacy of nivolumab in pre-treated non-small-cell lung cancer patients harbouring KRAS mutations.

BACKGROUND: The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations. METHODS: Clinical data and KRAS mutational status were analysed in patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events. RESULTS: Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3-4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively. CONCLUSIONS: Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations.

Texture features of colorectal liver metastases on pretreatment contrast-enhanced CT may predict response and prognosis in patients treated with bevacizumab-containing chemotherapy: a pilot study including comparison with standard chemotherapy.

PURPOSE: Bevacizumab added to chemotherapy can improve survival in patients with metastatic colorectal cancer, but no predictive factors of efficacy are available in clinical practice. The aim of this study is to assess the predictive and prognostic value of texture analysis on pretreatment contrast-enhanced CT in patients affected by colorectal liver metastases. MATERIALS AND METHODS: Forty-three patients with colorectal liver metastases were retrospectively included in the study: 23 treated with bevacizumab-containing chemotherapy (group A), and 20 with standard chemotherapy (group B). Target liver lesions were analyzed by texture analysis of pretreatment contrast-enhanced CT. Texture analysis produced the parameter uniformity, describing lesion heterogeneity. Radiological response was classified after 3 months according to RECIST-1.1. Overall survival (OS) and progression-free survival (PFS) were considered to be outcome indicators. Multivariable logistic regression and survival analysis were performed. RESULTS: Uniformity was lower in responders than in nonresponders (p < 0.001) in group A but not in group B. Lesion CT density was lower in nonresponders in both groups (p = 0.03 and 0.02, respectively). In group A, uniformity was independently correlated with radiological response (odds ratio = 20, p = 0.01), OS and PFS (relative risks 6.94 and 5.05, respectively; p = 0.005 and p = 0.004, respectively). In group B, no variables were correlated with radiological response, OS or PFS. CONCLUSION: Texture analysis on contrast-enhanced CT stratified response probability and prognosis in patients with colorectal liver metastases treated with bevacizumab-containing therapy. This result was specific for the bevacizumab group.

Eribulin in Heavily Pretreated Metastatic Breast Cancer Patients in the Real World: A Retrospective Study.

OBJECTIVES: The aim of this study was to investigate efficacy and safety of eribulin in heavily pretreated patients with advanced breast cancer (BC) in a real-life setting. METHODS: This retrospective monocentric study included patients with HER-2-negative metastatic BC, pretreated with anthracyclines and taxanes, who were referred to the Oncology Department of Spedali Civili of Brescia from May 2012 to April 2017. Patients received the same dose of eribulin as that used in the EMBRACE trial: 1.4 mg/m2 on days 1 and 8 every 21 days. RESULTS: In a total of 53 patients, 32% obtained a partial response, 11% a stable disease, and 43% a clinical benefit (CB). After a median follow-up of 36 months, median progression-free survival (PFS) was 4.7 months and median overall survival (OS) 13.53 months. Median PFS was significantly longer in patients who reported a CB compared to those with no CB, while survival outcomes (PFS and OS) were better in patients who received > 6 cycles of eribulin. Eribulin showed a good tolerability profile with acceptable toxicities, similar to those reported in EMBRACE. CONCLUSIONS: Our experience in a real-world setting confirms the activity, efficacy, and good tolerability profile of eribulin in heavily pretreated BC patients.

Hepatoprotective effect of N-acetylcysteine in trabectedin-induced liver toxicity in patients with advanced soft tissue sarcoma.

PURPOSE: Trabectedin is one of the few active agents in soft tissue sarcoma (STS) but hepatotoxicity is frequent and represents a dose-limiting factor. Protective strategies aiming at counteracting this important side effect have a crucial clinical impact. Due to its antioxidant properties, N-acetylcysteine (NAC) has a recognized hepatoprotective effect and this provides the rationale for testing NAC in the management of trabectedin-induced hepatotoxicity. METHODS: Patients with recurrent or metastatic soft tissue sarcoma, consecutively observed at our institution, who were considered eligible to trabectedin, received concomitant NAC if they had impaired hepatic or renal function at baseline or developed hepatotoxicity during treatment. The study aim was to retrospectively explore trabectedin administration in terms of number of cycles, mean dose, and dose intensity (DI) in patients who received NAC as compared with those who did not. Secondary end points were progression-free survival (PFS) and overall survival (OS). RESULTS: A total number of 18 patients were enrolled in this study. Nine received NAC and nine did not. The median number of administered trabectedin cycles, mean trabectedin dose/cycles, and median DI was comparable in the two groups (p = 0.450, p = 0.534, and p = 0.450, respectively). The PFS and OS curves overlapped. CONCLUSION: This explorative study suggests that NAC can have a hepatoprotective activity in patients receiving trabectedin allowing to maintain an adequate dose intensity and continuative administration in patients with impaired liver and renal function or developing treatment-induced hepatotoxicity. A prospective randomized trial is warranted.

Amiloride Is Effective in the Management of Abiraterone-Induced Mineralocorticoid Excess Syndrome without Interfering with Its Antineoplastic Activity.

BACKGROUND: The administration of abiraterone acetate (abiraterone) leads to an adrenocorticotropic hormone (ACTH)-driven increase in mineralocorticoid hormones, requiring glucocorticoid supplementation that may stimulate the growth of prostate cancer (PCa). Amiloride is a drug that selectively reduces the aldosterone-sensitive Na+/K+ exchange and could be effective in the management of mineralocorticoid excess syndrome (MCES). METHODS: The efficacy of amiloride + hydrochlorothiazide (HCT) in the clinical management of abiraterone-induced MCES was assessed in 5 consecutive patients with castration-resistant PCa (CRPC). Then, using the in vitro experimental model of PCa cell lines, the possible effects of drugs usually used in the clinical management of CRPC patients on PCa cell viability were investigated. RESULTS: Amiloride/HCT led to a complete disappearance of all clinical and biochemical signs of abiraterone-induced MCES in the 5 treated patients. The in vitro study showed that abiraterone treatment significantly decreased cell viability of both androgen receptor (AR)-expressing VCaP (vertebral-cancer of the prostate) and LNCaP (lymph node carcinoma of the prostate) cells, with no effect on AR-negative PC-3 cells. Prednisolone, spironolactone, and eplerenone increased LNCaP cell viability, while amiloride reduced it. The non-steroid aldosterone antagonist PF-03882845 did not modify PCa cell viability. CONCLUSIONS: The combination of amiloride/HCT was effective in the management of abiraterone-induced MCES. Amiloride did not negatively interfere with the abiraterone inhibition of PCa cell viability in vitro.

Echocardiographic evaluation in subjects with α1-Antitrypsin deficiency.

BACKGROUND: α1-Antitrypsin (AAT) deficiency (AATD) is a genetic condition associated with early-onset panacinar emphysema and, less often, vascular disease. Recently, abnormal elastic properties of ascending aortic wall were described in ZZ genotype AATD subjects who incidentally showed an increased left ventricular mass. MATERIALS AND METHODS: To evaluate biventricular dimensions, valvular apparatus, systolic and diastolic function, 33 AATD subjects with ZZ genotype and 33 healthy subjects matched for age and sex underwent a complete echocardiographic assessment. RESULTS: Compared to controls, AATD subjects showed increased left ventricular mass (160 ± 59 g vs. 121 ± 70 g, P < 0.001), a higher incidence of left and right ventricular diastolic dysfunction (30% vs. 16%, P < 0.001 and 45% vs. 20%, P < 0.001, respectively) and mitral valve prolapse (35% vs. 6%, P < 0.001). In contrast, there was no difference between the two groups in diameters and systolic function of both ventricles and in the ejection fraction of left ventricle. The functions of aortic and tricuspidal valves were also similar. CONCLUSIONS: In the presence of greater left ventricular mass, a significantly higher incidence of left and right ventricular diastolic dysfunction and mitral valve prolapse occurs in AATD subjects (ZZ genotype). These findings strongly suggest an abnormal remodelling process in cardiac tissue in AATD.