Post-traumatic stress symptoms in long-term disease-free cancer survivors and their family caregivers.

BACKGROUND: The experience of cancer is highly stressful and potentially traumatic. We assessed the presence of Post-Traumatic Stress Symptoms (PTSS) in long-term cancer survivors and their caregivers, while examining the association between PTSS and clinical, demographic and psychological variables in the long term. METHODS: In this cross-sectional study 212 survivor-family caregiver dyads completed measures of post-traumatic stress symptoms (PTSS) (Impact of Event Scale), depression and anxiety (Hospital Anxiety Depression Scale). Coping strategies, fatigue, cognitive decline, stressful life events and psychopathological history were also assessed among survivors. Data were analyzed using mixed models, accounting both for individual and dyadic effects. RESULTS: Cancer survivors and their caregivers were assessed after a mean of 6 years after treatment. Twenty per cent of survivors and 35.5% of caregivers had possible posttraumatic stress disorder (PTSD), while 23 patients (11.0%) and 33 caregivers (15.6%) had probable PTSD. Among cancer patients, the severity of post-traumatic symptoms was associated with an anxious coping style, previous psychopathology and depression (p < 0.001), whereas among caregivers it was associated with depression and having a closer relationship with patients (p < 0.001). Patients' depression was associated with caregivers' intrusion symptoms. CONCLUSIONS: High levels of cancer-related PTSS were still present several years after treatment in both survivors and caregivers. Psychopathology may derive from complex interactions among coping, previous disorders and between-person dynamics.

Unveiling mutational dynamics in non-small cell lung cancer patients by quantitative EGFR profiling in vesicular RNA.

The mutational status of the epidermal growth factor receptor (EGFR) guides the stratification of non-small cell lung cancer (NSCLC) patients for treatment with tyrosine kinase inhibitors (TKIs). A liquid biopsy test on cell-free DNA is recommended as a clinical decision-supporting tool, although it has limited sensitivity. Here, we comparatively investigated the extracellular vesicle (EV)-RNA as an independent source for multidimensional and longitudinal EGFR profiling in a cohort of 27 NSCLC patients. We introduced and validated a new rapid, highly specific EV-RNA test with wild-type (WT) and mutant-sensitive probes (E746-A750del, L858R, and T790M). We included a cohort of 20 NSCLC patients with EGFR WT tumor tissues and systematically performed molecular EV-RNA and circulating tumor DNA analyses with clinical data statistics and biophysical profiles of EVs. At the single-patient level, we detected variegated tumor heterogeneity dynamics supported by combinations of driver EGFR mutations. EV-RNA-based mutation analysis showed an unprecedented sensitivity of over 90%. The resistance-associated mutation T790M frequently pre-existed at baseline with a gained EV-transcript copy number at progression, while the general mutational burden was mostly decreasing during the intermediate follow-up. The biophysical profile of EVs and the quantitative assessment of T790M revealed an association with tumor size determined by the sum of the longest diameters in target lesions. Vesicular RNA provides a validated tool suitable for use in clinical practice to investigate the dynamics of common driver EGFR mutations in NSCLC patients receiving TKIs.

Induction chemotherapy plus concomitant chemoradiotherapy in nasopharyngeal carcinoma: An updated network meta-analysis.

BACKGROUND: Induction chemotherapy (IC) added to concurrent chemoradiotherapy (CCRT) appears to be superior to CCRT alone for locally-advanced nasopharyngeal carcinoma (NPC). The main objective of this network meta-analysis (NMA) was to assess the impact of different IC regimens on patient outcome. PATIENTS AND METHODS: We systematically searched and extracted data from randomized, controlled trials involving stage III-IV NPC patients randomly assigned to receive IC + CCRT vs. CCRT alone. Overall survival (OS), locoregional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) in the two arms were compared using hazard ratios (HRs). RESULTS: Eight clinical trials were identified including 2362 patients. OS-benefit from doublet IC regimens, in particular platinum-docetaxel and platinum-gemcitabine regimens, was seen. With regard to LRFS, docetaxel-platinum-5FU regimen showed a greater impact than the others. An indirect comparison between taxane- and gemcitabine-based IC regimens showed a benefit of the latter in terms of OS and DMFS. CONCLUSIONS: Although CCRT with cisplatin has been the gold standard of treatment in NPC for several years. Docetaxel + cisplatin-IC and cisplatin + gemcitabine-IC regimens have a positive impact on survival in locally-advanced NPC and should be considered the new standard option.

Ki67 and PR in Patients Treated with CDK4/6 Inhibitors: A Real-World Experience.

CDK4/6 inhibitors (CDK4/6i) are recommended in patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer (ABC). Up to now, no prognostic biomarkers have been identified in this setting. We retrospectively analyzed the expression of progesterone receptor (PR) and Ki67, assessed by immunohistochemistry, in 71 ABC patients treated with CDK4/6i and analyzed the impact of these markers on progression-free survival (PFS). The majority of patients 63/71 (88.7%) received palbociclib, 4 (5.6%) received ribociclib, and 4 (5.6%) received abemaciclib. A higher median value of Ki67 was observed in cases undergoing second-line treatment (p = 0.047), whereas the luminal B subtype was more prevalent (p = 0.005). In the univariate analysis of the first-line setting, luminal A subtype showed a trend towards a correlation with a longer PFS (p = 0.053). A higher continuous Ki67 value led to a significantly shorter PFS. When the interaction between pathological characteristics and line of treatment was considered, luminal B subtype showed a significantly (p = 0.043) worse outcome (Hazard Ratio (HR) 2.84; 1.03-7.82 95% Confidence Interval (CI)). PFS in patients undergoing endocrine therapy plus CDK4/6i was inversely correlated with Ki67 expression but not with PR, suggesting that tumor proliferation has a greater impact on cell cycle inhibitors combined with endocrine therapy than PR expression.

Compound optimal allocations for survival clinical trials.

The aim of the present paper is to provide optimal allocations for comparative clinical trials with survival outcomes. The suggested targets are derived adopting a compound optimization strategy based on a subjective weighting of the relative importance of inferential demands and ethical concerns. The ensuing compound optimal targets are continuous functions of the treatment effects, so we provide the conditions under which they can be approached by standard response-adaptive randomization procedures, also guaranteeing the applicability of the classical asymptotic inference. The operating characteristics of the suggested methodology are verified both theoretically and by simulation, including the robustness to model misspecification. With respect to the other available proposals, our strategy always assigns more patients to the best treatment without compromising inference, taking into account estimation efficiency and power as well. We illustrate our procedure by redesigning two real oncological trials.

Cauliflower Mosaic Virus TAV, a Plant Virus Protein That Functions like Ribonuclease H1 and is Cytotoxic to Glioma Cells.

Recent comparisons between plant and animal viruses reveal many common principles that underlie how all viruses express their genetic material, amplify their genomes, and link virion assembly with replication. Cauliflower mosaic virus (CaMV) is not infectious for human beings. Here, we show that CaMV transactivator/viroplasmin protein (TAV) shares sequence similarity with and behaves like the human ribonuclease H1 (RNase H1) in reducing DNA/RNA hybrids detected with S9.6 antibody in HEK293T cells. We showed that TAV is clearly expressed in the cytosol and in the nuclei of transiently transfected human cells, similar to its distribution in plants. TAV also showed remarkable cytotoxic effects in U251 human glioma cells in vitro. These characteristics pave the way for future analysis on the use of the plant virus protein TAV, as an alternative to human RNAse H1 during gene therapy in human cells.

Phase-II Trials of Pazopanib in Metastatic Neuroendocrine Neoplasia (mNEN): A Systematic Review and Meta-Analysis.

Background: Several phase-II trials have been designed to evaluate tyrosine kinase inhibitors (TKIs), in particular, pazopanib in neuroendocrine neoplasia (NEN), but its efficacy has not yet been demonstrated in a randomised-controlled Phase III trial. A systematic review of the published clinical trials of metastatic NEN patients could reduce the possible bias of single phase II studies. The present systematic review focuses on the efficacy and safety of pazopanib in patients with metastatic and locally advanced NEN. Methods: A systematic search in the major databases Medline/PubMed, Cochrane and Embase and in supplementary material from important international Meetings was performed to identify publications on pazopanib for the treatment of neuroendocrine neoplasia. English language was defined as a restriction. Four authors of the present review independently performed the study selection, assessed the risk of bias and extracted study data. Four published clinical trials and 2 abstracts were identified. One trial was excluded because the topic was Von-Hippel Landau disease and one abstract was eliminated because of the lack of information on meeting proceedings. Results: In all of the trials pazopanib was orally administered at a dose of 800 mg daily continuously with a 28-day cycle. The intention-to-treat population for efficacy was composed of 230 patients with a median age of 62 years. The partial response rate was 10.7% (95% confidence interval 2.6-20.5). The rate for stable disease was 79.6% (range: 61.7-92.1%) with a disease control rate (DCR) of 90.3%. Progressive disease was reported in 9.7% (range 5.2-17.6) of patients. No complete responses were observed. Median progression-free survival was 11.6 months (95% CI: 9.2-13.9). Overall survival from all the trials was 24.6 (95% CI: 18.7-40.8) months. Severe adverse events (grade III-IV) included hypertension 31%, 16% increase in AST/ALT, diarrhoea 10% and fatigue 10%. Conclusions: Pazopanib monotherapy achieved a DCR of 90.3% in patients with locally advanced and/or metastatic neuroendocrine neoplasia, with an overall response rate comparable to other TKIs and mTOR inhibitors and a safety profile similar to that of drugs of the same class.

Is There an Optimal Choice in Refractory Colorectal Cancer? A Network Meta-Analysis.

BACKGROUND: In the absence of head-to-head comparison studies, the present network meta-analysis evaluated and compared the efficacy of 4 therapeutic alternatives for refractory colorectal cancer. MATERIALS AND METHODS: The search focused on results from phase III randomized controlled trials. Separate (subgroup) network meta-analyses were conducted to obtain drug comparisons stratified by various patient characteristics. The principal outcome of interest was overall survival (OS). RESULTS: No difference in OS was found between regorafenib and TAS-102. For a rectal primary location, TAS-102 conferred benefit versus placebo (hazard ratio [HR], 0.671), but regorafenib did not (HR, 0.950). For patients aged > 65 years, TAS-102 showed benefit versus placebo (HR, 0.579) but regorafenib did not (HR, 0.816). For patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 in the indirect comparison, regorafenib showed benefit versus placebo (HR, 0.687), as did TAS-102 (HR, 0.756) but with a lower advantage. For patients with RAS wild type not previously treated with anti-EGFR antibodies, panitumumab was the optimal choice for OS. CONCLUSIONS: No differences in OS were found between regorafenib and TAS-102. Possible greater efficacy was found for TAS-102 compared with regorafenib for patients with a rectal primary location, ECOG PS > 0, and age > 65 years. In contrast, regorafenib showed possible greater effectiveness for patients with ECOG PS 0 and age < 65 years. In the RAS WT population, the anti-EGFR drug showed superiority with respect to TAS-102 and regorafenib. These results should be viewed as only exploratory, and further prospective studies are warranted to validate these data.

Should Tumor Infiltrating Lymphocytes, Androgen Receptor, and FOXA1 Expression Predict the Clinical Outcome in Triple Negative Breast Cancer Patients?

Tumor-infiltrating lymphocytes (TILs) are a valuable indicator of the immune microenvironment that plays the central role in new anticancer drugs. TILs have a strong prognostic role in triple negative breast cancer (TNBC). Little is known about the interaction with the androgen receptor (AR) and forkhead box A1 (FOXA1). We analyzed the relationships between TIL levels, AR, and FOXA1 expression and their clinical significance in TNBC patients. Further, we investigated their interaction with other biomarkers like programmed cell death ligand-1 (PD-L1), breast cancer type 1 susceptibility protein (BRCA1), poly (ADP-Ribose) polymerase 1 (PARP1), and Na+/H+ exchanger regulatory factor 1 (NHERF1). The expression of the proteins was evaluated by immunohistochemistry in 124 TNBC samples. TILs were performed adhering to International TILs Working Group 2014 criteria. Cox proportional hazards models were also used to identify risk factors associated with poor prognosis. Multivariate analysis identified TILs as independent prognostic factor of disease free survival (DFS; p = 0.045). A Kaplan-Meyer analysis revealed that the patients with high TILs had a better DFS compared to patients with low TILs (p = 0.037), and the phenotypes TILs-/AR+ and TILs-/FOXA1- had a worse DFS (p = 0.032, p = 0.001 respectively). AR was associated with FOXA1 expression (p = 0.007), and the tumors FOXA1+ presented low levels of TILs (p = 0.028). A poor DFS was observed for AR+/FOXA1+ tumors compared to other TNBCs (p = 0.0117). Low TILs score was associated with poor patients' survival, and TILs level in combination with AR or FOXA1 expression affected patient's clinical outcome. In addition, AR+/FOXA1+ phenotype identified a specific subgroup of TNBC patients with poor prognosis. These data may suggest new ways of therapeutic intervention to support current treatments.

Texture analysis in 177Lu SPECT phantom images: Statistical assessment of uniformity requirements using texture features.

The purpose of this study was to apply texture analysis (TA) to evaluate the uniformity of SPECT images reconstructed with the 3D Ordered Subsets Expectation Maximization (3D-OSEM) algorithm. For this purpose, a cylindrical homogeneous phantom filled with 177Lu was used and a total of 24 spherical volumes of interest (VOIs) were considered inside the phantom. The location of the VOIs was chosen in order to define two different configurations, i.e. gravity and radial configuration. The former configuration was used to investigate the uniformity of distribution of 177Lu inside the phantom, while the latter configuration was used to investigate the lack of uniformity from center towards edge of the images. For each VOI, the trend of different texture features considered as a function of 3D-OSEM updates was investigated in order to evaluate the influence of reconstruction parameters. TA was performed using CGITA software. The equality of the average texture feature trends in both spatial configurations was assumed as the null hypothesis and was tested by functional analysis of variance (fANOVA). With regard to the gravity configuration, no texture feature rejected the null hypothesis when the number of subsets increased. For the radial configuration, the statistical analysis revealed that, depending on the 3D-OSEM parameters used, a few texture features were capable of detecting the non-uniformity of 177Lu distribution inside the phantom moving from the center of the image towards its edge. Finally, cross-correlation coefficients were calculated to better identify the features that could play an important role in assessing quality assurance procedures performed on SPECT systems.

Prognostic Role of Circulating miRNAs in Early-Stage Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related death worldwide, with a low 5-year survival rate even in fully resected early-stage disease. Novel biomarkers to identify patients at higher risk of relapse are needed. We studied the prognostic value of 84 circulating microRNAs (miRNAs) in 182 patients with resected early-stage NSCLC (99 adenocarcinoma (ADC), 83 squamous cell carcinoma (SCC)) from whom peripheral blood samples were collected pre-surgery. miRNA expression was analyzed in relation to disease-free survival (DFS) and overall survival (OS). In univariable analyses, five miRNAs (miR-26a-5p, miR-126-3p, miR-130b-3p, miR-205-5p, and miR-21-5p) were significantly associated with DFS in SCC, and four (miR-130b-3p, miR-26a-5p, miR-126-3p, and miR-205-5p) remained significantly associated with OS. In ADC, miR-222-3p, miR-22-3p, and mir-93-5p were significantly associated with DFS, miR-22-3p remaining significant for OS. Given the high-dimensionality of the dataset, multivariable models were obtained using a regularized Cox regression including all miRNAs and clinical covariates. After adjustment for disease stage, only miR-126-3p showed an independent prognostic role, with higher values associated with longer DFS in SCC patients. With regard to ADC and OS, no miRNA remained significant in multivariable analysis. Further investigation into the role of miR-126 as a prognostic marker in early-stage NSCLC is warranted.

NHERF1 and tumor microenvironment: a new scene in invasive breast carcinoma.

BACKGROUND: Tumor microenvironment (TME) includes many factors such as tumor associated inflammatory cells, vessels, and lymphocytes, as well as different signaling molecules and extracellular matrix components. These aspects can be de-regulated and consequently lead to a worsening of cancer progression. In recent years an association between the scaffolding protein Na+/H+ exchanger regulatory factor 1 (NHERF1) and tumor microenvironment changes in breast cancer (BC) has been reported. METHODS: Subcellular NHERF1 localization, vascular endothelial growth factor (VEGF), its receptor VEGFR1, hypoxia inducible factor 1 alpha (HIF-1α), TWIST1 expression and microvessel density (MVD) in 183 invasive BCs were evaluated, using immunohistochemistry on tissue microarrays (TMA). Immunofluorescence was employed to explore protein interactions. RESULTS: Cytoplasmic NHERF1(cNHERF1) expression was directly related to cytoplasmic VEGF and VEGFR1 expression (p = 0.001 and p = 0.027 respectively), and inversely to nuclear HIF-1α (p = 0.021) and TWIST1 (p = 0.001). Further, immunofluorescence revealed an involvement of tumor cells with NHERF1 positive staining in neo-vascular formation, suggesting a "mosaic" structure development of these neo-vessels. Survival analyses showed that loss of nuclear TWIST1 (nTWIST1) expression was related to a decrease of disease free survival (DFS) (p < 0.001), while nTWIST1-/mNHERF1+ presented an increased DFS with respect to nTWIST1+/mNHERF1- phenotype (p < 0.001). Subsequently, the analyses of nTWIST1+/cNHERF1+ phenotype selected a subgroup of patients with a worse DFS compared to nTWIST1-/cNHERF1- patients (p = 0.004). CONCLUSION: Resulting data suggested a dynamic relation between NHERF1 and TME markers, and confirmed both the oncosuppressor role of membranous NHERF1 expression and the oncogene activity of cytoplasmic NHERF1.

Is the classical Wald test always suitable under response-adaptive randomization?

The aim of this paper is to analyze the impact of response-adaptive randomization rules for normal response trials intended to test the superiority of one of two available treatments. Taking into account the classical Wald test, we show how response-adaptive methodology could induce a consistent loss of inferential precision. Then, we suggest a modified version of the Wald test which, by using the current allocation proportion to the treatments as a consistent estimator of the target, avoids some degenerate scenarios and so it should be preferable to the classical test. Furthermore, we show both analytically and via simulations how some target allocations may induce a locally decreasing power function. Thus, we derive the conditions on the target guaranteeing its monotonicity and we show how a correct choice of the initial sample size allows one to overcome this drawback regardless of the adopted target.

Sarcopenia and sarcopenic obesity in patients with muscular dystrophy.

Aging sarcopenia and muscular dystrophy (MD) are two conditions characterized by lower skeletal muscle quantity, lower muscle strength, and lower physical performance. Aging is associated with a peculiar alteration in body composition called "sarcopenic obesity" characterized by a decrease in lean body mass and increase in fat mass. To evaluate the presence of sarcopenia and obesity in a cohort of adult patients with MD, we have used the measurement techniques considered golden standard for sarcopenia that is for muscle mass dual-energy X-ray absorptiometry (DXA), for muscle strength hand-held dynamometry (HHD), and for physical performance gait speed. The study involved 14 adult patients with different types of MD. We were able to demonstrate that all patients were sarcopenic obese. We showed, in fact, that all were sarcopenic based on appendicular lean, fat and bone free, mass index (ALMI). In addition, all resulted obese according to the percentage of body fat determined by DXA in contrast to their body mass index ranging from underweight to obese. Skeletal muscle mass determined by DXA was markedly reduced in all patients and correlated with residual muscle strength determined by HHD, and physical performances determined by gait speed and respiratory function. Finally, we showed that ALMI was the best linear explicator of muscle strength and physical function. Altogether, our study suggests the relevance of a proper evaluation of body composition in MD and we propose to use, both in research and practice, the measurement techniques that has already been demonstrated effective in aging sarcopenia.