Clustering blood donors via mixtures of product partition models with covariates.

Motivated by the problem of accurately predicting gap times between successive blood donations, we present here a general class of Bayesian nonparametric models for clustering. These models allow for the prediction of new recurrences, accommodating covariate information that describes the personal characteristics of the sample individuals. We introduce a prior for the random partition of the sample individuals, which encourages two individuals to be co-clustered if they have similar covariate values. Our prior generalizes product partition models with covariates (PPMx) models in the literature, which are defined in terms of cohesion and similarity functions. We assume cohesion functions that yield mixtures of PPMx models, while our similarity functions represent the denseness of a cluster. We show that including covariate information in the prior specification improves the posterior predictive performance and helps interpret the estimated clusters in terms of covariates in the blood donation application.

A Dramatic Response to Second-Line Nivolumab and Ipilimumab in BRAF-V600-Mutated Metastatic Melanoma.

Introduction: Current treatment options for BRAF V600-mutated unresectable stage III/IV melanoma include anti-PD-1 monotherapy or combination with anti-CTLA-4 or anti-LAG-3 agents, BRAF/MEK inhibitors, and clinical trials. The strategy of combination immunotherapy with nivolumab and ipilimumab has shown promising results, achieving higher response rates, longer duration of response, improved progression-free survival, and enhanced overall survival. The optimal sequence of treatments remains a topic of interest, with preliminary data suggesting a greater effectiveness of immunotherapy as the first-line approach. Preclinical trials have indicated that the efficacy of this sequence may be due to the modification of the immune environment by BRAF kinase inhibitors, leading to immune escape by tumor cells and resistance to immune checkpoint inhibitors. Case Presentation: We present a case of a 72-year-old woman with high-burden metastatic melanoma who failed to respond to prior targeted therapy with BRAF/MEK inhibitors and exhibited a successful response to the second-line treatment with ipilimumab and nivolumab. We discuss the potential reasons for this positive outcome contributing to the current debate concerning treatment sequences, resistance mechanisms, and biomarkers predictive of response to immune checkpoint inhibitors in metastatic melanoma. Conclusion: We believe that in few years the therapeutic algorithms in BRAF V600-mutated unresectable stage III/IV melanoma will be more complex since they will define clearly the correct therapeutic sequences with the inclusion of new immune checkpoint inhibitor drugs and multiple predictive biomarkers of response to better select patients eligible to immunotherapy.

Prospective, Multicenter Phase II Trial of Non-Pegylated Liposomal Doxorubicin Combined with Ifosfamide in First-Line Treatment of Advanced/Metastatic Soft Tissue Sarcomas.

Doxorubicin is a widely used anticancer agent as a first-line treatment for various tumor types, including sarcomas. Its use is hampered by adverse events, among which is the risk of dose dependence. The potential cardiotoxicity, which increases with higher doses, poses a significant challenge to its safe and effective application. To try to overcome these undesired effects, encapsulation of doxorubicin in liposomes has been proposed. Caelyx and Myocet are different formulations of pegylated (PLD) and non-pegylated liposomal doxorubicin (NPLD), respectively. Both PLD and NPLD have shown similar activity compared with free drugs but with reduced cardiotoxicity. While the hand-foot syndrome exhibits a high occurrence among patients treated with PLD, its frequency is notably reduced in those receiving NPLD. In this prospective, multicenter, one-stage, single-arm phase II trial, we assessed the combination of NPLD and ifosfamide as first-line treatment for advanced/metastatic soft tissue sarcoma (STS). Patients received six cycles of NPLD (50 mg/m2) on day 1 along with ifosfamide (3000 mg/m2 on days 1, 2, and 3 with equidose MESNA) administered every 3 weeks. The overall response rate, yielding 40% (95% CI: 0.29-0.51), resulted in statistical significance; the disease control rate stood at 81% (95% CI: 0.73-0.90), while only 16% (95% CI: 0.08-0.24) of patients experienced a progressive disease. These findings indicate that the combination of NPLD and ifosfamide yields a statistically significant response rate in advanced/metastatic STS with limited toxicity.

Epithelioid Mesothelioma Patients with Very Long Survival Display Defects in DNA Repair.

AIM: DNA repair has an important role in malignant pleural mesothelioma (MPM) tumorigenesis and progression. Prognostic/predictive biomarkers for better management of MPM patients are needed. In the present manuscript, we analyzed the expression of more than 700 genes in a cohort of MPM patients to possibly find biomarkers correlated with survival. METHODS: A total of 54 MPM patients, all with epithelioid histology, whose survival follow-up and formalin-fixed paraffin-embedded tumors were available, were included in the study. Gene expression profiles were evaluated using a Nanostring platform analyzing 760 genes involved in different cellular pathways. The percentages of proliferating tumor cells positive for RAD51 and BRCA1 foci were evaluated using an immunofluorescence assay, as a readout of homologous recombination repair status. RESULTS: Patient median survival time was 16.9 months, and based on this value, they were classified as long and short survivors (LS/SS) with, respectively, an overall survival ≥ and <16.9 months as well as very long and very short survivors (VLS/VSS) with an overall survival ≥ than 33.8 and < than 8.45 months. A down-regulation in the DNA damage/repair expression score was observed in LS and VLS as compared to SS and VSS. These findings were validated by the lower number of both RAD51 and BRCA1-positive tumor cells in VLS as compared to VSS. CONCLUSIONS: The down-regulation of DNA repair signature in VLS was functionally validated by a lower % of RAD51 and BRCA1-positive tumor cells. If these data can be corroborated in a prospective trial, an easy, cost-effective test could be routinely used to better manage treatment in MPM patients.

Oral Problems in Oncology Patients Undergoing Chemotherapy for Solid Tumors: A Prospective Observational Study.

PURPOSE: Oral problems in a group of oncological patients undergoing chemotherapy (CT) for solid tumors have been examined. Incidence and severity of patients' self-reported oral problems have been evaluated along their interaction with age, gender, tumor diagnosis and stage, presence of mestastasis, CT agent type, and number of CT cycle. We also analyzed the presence of paraesthesia and anaesthesia and their predisposing factors associated with clinical and treatment-related variables. METHODS: Patients were asked to fill in a questionnaire to evaluate the onset and the intensity of oral and perioral pain, oral mucositis, salivary gland hypofunction, dysgeusia, dysphagia, dysphonia, and sensitivity neuropathy (paraesthesia or dysaesthesia) since the last CT infusion. We also investigated which types of medications have possibly been used and who recommended it, as well as patients' degree of awareness about the possibility of oral problems arising during CT. RESULTS: We recruited 194 patients and obtained 491 questionnaires. We found that a metastatic disease was a risk factor for OM (OR 2.02, p = 0.026) and salivary gland hypofunction (OR 1.66, p = 0.042) and that platinum agents, compared to mitotic inhibitors, increased the risk of developing salivary gland hypofunction (OR 2.16, p = 0.013), dysphagia (OR 3.26, p = 0.001), and anaesthesia (OR 5.16, p = 0.041). Young age was a slight protective factor for most symptoms. The 80% of enrolled patients were informed by the oncologist about possible oral problems arising during CT. CONCLUSIONS: Our study highlighted the importance of collecting observational data from the patients' perspective on oral problems arising during the routine oncology practice, across a range of solid tumors and CT regimens. The relevance of these findings focused on the key role of the multidisciplinary team in advising the patients on the possible occurrence of oral problems, also by recommending their management.

Cardiotoxicity from Capecitabine Chemotherapy: Prospective Study of Incidence at Rest and During Physical Exercise.

BACKGROUND: Physical activity may increase the risk of cardiotoxicity (myocardial ischemia, major arrhythmias) of 5-Fluorouracil, but this risk has never been investigated for its prodrug capecitabine. PATIENTS AND METHODS: One hundred and ninety-two consecutive patients undergoing capecitabine chemotherapy from December 1, 2010 through July 31, 2016 were prospectively evaluated. The baseline evaluation included electrocardiography (ECG) and echocardiography (2DE); a follow-up evaluation, including ECG and exercise stress testing (2DE in case of ECG abnormalities), was done after ≥10 days of treatment. Cardiotoxicity was suspected from ischemic ECG changes, new kinetic abnormalities at 2DE, Lown classification ≥2 ventricular arrhythmia, symptomatic arrhythmias, or positive stress test, and confirmed by a negative stress test after capecitabine washout. RESULTS: Cardiotoxicity was diagnosed in 32 patients (16.7%): six at rest and 26 during exercise. All 32 patients had ECG abnormalities: ST-segment changes (24 patients), negative T-waves (2) and/or arrhythmias: ventricular arrhythmias (14 cases), supraventricular tachycardia (2), complete heart block (1). Eight patients had typical symptoms, 6 had atypical symptoms, 1 had syncope, 17 (53%) were asymptomatic. Cardiotoxicity was more common in patients with atypical symptoms during daily life (OR = 15.7) and in those on a therapeutic schedule of 5 days/week (OR = 9.44). CONCLUSION: Capecitabine cardiotoxicity is frequent, and often elicited by physical effort. Oncologists, cardiologists, and general practitioners should be aware of this risk. Active cardiotoxicity surveillance with ECG (and echocardiogram and/or stress testing in suspected cases) during therapy is recommended. CLINICAL TRIALS REGISTRATION NUMBER: CRO-2010-17.

Focal electroretinogram and microperimetry testing of photoreceptor-retinal pigment epithelium function in intermediate age-related macular degeneration.

PURPOSE: To compare the performance of focal electroretinogram (FERG) and fast mesopic microperimetry in evaluating macular function of intermediate age-related macular degeneration (iAMD) subjects with preserved visual acuity. METHODS: Cross-sectional, observational study. Participants with drusen >125 µm and VA ≥80 ETDRS letters and age- and sex-comparable healthy subjects were consecutively enrolled in the study. Three photopic FERG recordings of the central 9° of the macula with luminance modulated stimuli flickering at 42.5 Hz and a fast mesopic microperimetry with a custom pattern of 3 central (CS) and 3 paracentral (pCS) stimuli at 1.2° and 6° from fixation were acquired. RESULTS: Overall, 112 eyes of 77 participants (age 73.0 ± 7.1 years, 47 iAMD eyes) were analysed. Mean FERG amplitude, CS and pCS (all p < 0.05) were lower in the iAMD group. A significant association was observed between FERG amplitude and iAMD (OR 9.58, p < 0.001) in multiple logistic regression analysis. Z-scores of FERG were lower than microperimetry in iAMD (p = 0.002) but not for healthy participants. AUC of the ROC curve was greater for FERG than microperimetry (0.895 versus 0.644 and 0.675, both p < 0.05). CONCLUSION: Focal ERG objectively measures a cumulative response originating from the photoreceptor-RPE complex of the central 9° of the macula and demonstrated high accuracy in identifying decreased central macular function in iAMD patients with preserved visual acuity, performing better than fast mesopic microperimetry. Focal ERG should be considered a reliable technique for measuring retinal sensitivity of iAMD patients.

What the Cardiologist Needs to Consider in the Management of Oncologic Patients with STEMI-Like Syndrome: A Case Report and Literature Review.

In pre-hospital care, an accurate and quick diagnosis of ST-segment elevation myocardial infarction (STEMI) is imperative to promptly kick-off the STEMI network with a direct transfer to the cardiac catheterization laboratory (cath lab) in order to reduce myocardial infarction size and mortality. Aa atherosclerotic plaque rupture is the main mechanism responsible for STEMI. However, in a small percentage of patients, emergency coronarography does not reveal any significant coronary stenosis. The fluoropyrimidine agents such as 5-Fluorouracil (5-FU) and capecitabine, widely used to treat gastrointestinal, breast, head and neck cancers, either as a single agent or in combination with other chemotherapies, can cause potentially lethal cardiac side effects. Here, we present the case of a patient with 5-FU cardiotoxicity resulting in an acute coronary syndrome (ACS) with recurrent episodes of chest pain and ST-segment elevation.. Our case report highlights the importance of widening the knowledge among cardiologists of the side effects of chemotherapeutic drugs, especially considering the rising number of cancer patients around the world and that fluoropyrimidines are the main treatment for many types of cancer, both in adjuvant and advanced settings.

Joint modeling of recurrent events and survival: a Bayesian non-parametric approach.

Heart failure (HF) is one of the main causes of morbidity, hospitalization, and death in the western world, and the economic burden associated with HF management is relevant and expected to increase in the future. We consider hospitalization data for HF in the most populated Italian Region, Lombardia. Data were extracted from the administrative data warehouse of the regional healthcare system. The main clinical outcome of interest is time to death and research focus is on investigating how recurrent hospitalizations affect the time to event. The main contribution of the article is to develop a joint model for gap times between consecutive rehospitalizations and survival time. The probability models for the gap times and for the survival outcome share a common patient specific frailty term. Using a flexible Dirichlet process model for %Bayesian nonparametric prior as the random-effects distribution accounts for patient heterogeneity in recurrent event trajectories. Moreover, the joint model allows for dependent censoring of gap times by death or administrative reasons and for the correlations between different gap times for the same individual. It is straightforward to include covariates in the survival and/or recurrence process through the specification of appropriate regression terms. The main advantages of the proposed methodology are wide applicability, ease of interpretation, and efficient computations. Posterior inference is implemented through Markov chain Monte Carlo methods.

Bayesian Autoregressive Frailty Models for Inference in Recurrent Events.

We propose autoregressive Bayesian semi-parametric models for gap times between recurrent events. The aim is two-fold: inference on the effect of possibly time-varying covariates on the gap times and clustering of individuals based on the time trajectory of the recurrent event. Time-dependency between gap times is taken into account through the specification of an autoregressive component for the frailty parameters influencing the response at different times. The order of the autoregression may be assumed unknown and is an object of inference. We consider two alternative approaches to perform model selection under this scenario. Covariates may be easily included in the regression framework and censoring and missing data are easily accounted for. As the proposed methodologies lie within the class of Dirichlet process mixtures, posterior inference can be performed through efficient MCMC algorithms. We illustrate the approach through simulations and medical applications involving recurrent hospitalizations of cancer patients and successive urinary tract infections.

Tumour infiltrating lymphocytes and immune-related genes as predictors of outcome in pancreatic adenocarcinoma.

BACKGROUND: We investigated the correlation between pancreatic ductal adenocarcinoma patient prognosis and the presence of tumour infiltrating lymphocytes and expression of 521 immune system genes. METHODS: Intratumoural CD3+, CD8+, and CD20+ lymphocytes were examined by immunohistochemistry in 12 PDAC patients with different outcomes who underwent pancreaticoduodenectomy. The results were correlated with gene expression profile using the digital multiplexed NanoString nCounter analysis system (NanoString Technologies, Seattle, WA, USA). RESULTS: Twenty immune system genes were significantly differentially expressed in patients with a good prognosis relative to patients with a worse prognosis: TLR2 and TLR7 (Toll-like receptor superfamily); CD4, CD37, FOXP3, PTPRC (B cell and T cell signalling); IRF5, IRF8, STAT1, TFE3 (transcription factors); ANP32B, CCND3 (cell cycle); BTK (B cell development); TNF, TNFRF1A (TNF superfamily); HCK (leukocyte function); C1QA (complement system); BAX, PNMA1 (apoptosis); IKBKE (NFκB pathway). Differential expression was more than twice log 2 for TLR7, TNF, C1QA, FOXP3, and CD37. DISCUSSION: Tumour infiltrating lymphocytes were present at higher levels in samples from patients with better prognosis. Our findings indicate that tumour infiltrating lymphocyte levels and expression level of the immune system genes listed above influence pancreatic ductal adenocarcinoma prognosis. This information could be used to improve selection of best responders to immune inhibitors.

Advances in systemic therapy for malignant mesothelioma: future perspectives.

Malignant mesothelioma is a rare and aggressive form of cancer affecting the mesothelium. This mainly occupational disease is becoming more common in those countries where asbestos has been used for industrial applications. Notwithstanding the progress made in the field, patients do not survive more than 12 months on average with standard treatment. With the advent of next generation sequencing, it is now possible to study the mutational landscape of each tumor with the aim of identifying the genetic aberrations driving tumorigenesis. This review encompasses the latest research in the field, with particular attention to new chemotherapy combinatorial regimens, molecular targets and immunotherapies, providing a comprehensive picture of the current and future treatment options for malignant mesothelioma patients.

Is still there a role for IL-2 for solid tumors other than melanoma or renal cancer?

AIM: IL-2 is one of the first immunomodulating cytokines to be tested in the treatment of cancer patients. The effects of this agent in the treatment of solid tumors other than renal cancer and melanoma are poorly understood. MATERIALS & METHODS: We have carried out a meta-analysis of randomized studies. We fixed the response rate as the primary outcome. RESULTS: The pooled risk ratio for an objective response with IL-2 plus chemotherapy versus chemotherapy alone was 1.43 (95% CI: 1.12-1.81; p = 0.004), in favor of colorectal cancer. CONCLUSION: Further investigation in the treatment of patients with colorectal cancer or other solid malignancies with IL-2 is required, alone or in combination with chemotherapy.

A Simple Class of Bayesian Nonparametric Autoregression Models.

We introduce a model for a time series of continuous outcomes, that can be expressed as fully nonparametric regression or density regression on lagged terms. The model is based on a dependent Dirichlet process prior on a family of random probability measures indexed by the lagged covariates. The approach is also extended to sequences of binary responses. We discuss implementation and applications of the models to a sequence of waiting times between eruptions of the Old Faithful Geyser, and to a dataset consisting of sequences of recurrence indicators for tumors in the bladder of several patients.

Second-line therapy for advanced colorectal cancer.

The availability of irinotecan and oxaliplatin has dramatically altered both first- and second-line treatment of advanced colorectal cancer (CRC) compared with the era in which the sole treatment option in advanced disease was 5-fluorouracil (5-FU). Treatment options and strategies are becoming ever more enriched and complex with the recent availability of biologic agents such as bevacizumab and cetuximab. This article reviews randomized clinical trials assessing second-line treatment after failure of first-line single-agent 5-FU, irinotecan-based treatment, or oxaliplatin-based treatment. A number of conclusions can be drawn based on available data. (1) Second-line chemotherapy with active agents is superior to best supportive care alone. (2) Following 5-FU failure, active regimens include irinotecan, FOLFIRI, FOLFOX, and IROX, with IROX appearing to be superior to FOLFIRI. (3) Following irinotecanbased first-line treatment, FOLFOX is in general the best choice, and the combination of FOLFOX plus bevacizumab appears to be superior to FOLFOX alone. (4) Following first-line FOLFOX, irinotecan and FOLFIRI are currently the most appropriate options. Irinotecan plus cetuximab should emerge as an effective regimen. Further study is needed to define the best options in second-line therapy following the FOLFOXIRI triplet or the combination of bevacizumab plus chemotherapy. Studies are ongoing to determine optimal use of biologic agents, both in terms of when they should be used and in what combinations.

Sequential chemotherapy with paclitaxel plus cisplatin, followed by vinorelbine, followed by gemcitabine in advanced non-small cell lung cancer: an Alpe-Adria Thoracic Oncology Multidisciplinary group study (ATOM 001).

Aim of this study was to determine the activity and toxicity of a sequential chemotherapy regimen in advanced non-small cell lung cancer (NSCLC). Fifty-one previously untreated stage IIIB/IV NSCLC patients were enrolled to receive two cycles of cisplatin plus paclitaxel (80/175 mg/m(2) every 21 days), followed by two cycles of vinorelbine (30 mg/m(2) on days 1 and 8 every 21 days), followed by two cycles of gemcitabine (1000 mg/m(2) on days 1, 8, and 15 every 28 days). Forty-one patients (82%) completed the planned six cycles. Grade 3-4 neutropenia was the major toxicity (41% of patients) and it was mainly associated with vinorelbine administration. Response rate after cisplatin plus paclitaxel was 18%; this percentage increased to 41% after vinorelbine, and it reached 43% upon completion of the entire six cycle treatment program. Median survival time was 14.4 months, 1-year survival rate was 53%, and 2-year survival rate was 18%. Median time to disease progression was 6.8 months. This sequential chemotherapy regimen is feasible and active in patients with advanced NSCLC. This pilot experience provides the basis for an ongoing randomized phase III trial comparing our sequential regimen versus cisplatin plus gemcitabine.