Search

Purpose: The optimal anesthetic approach in the endovascular treatment (EVT) of patients with posterior circulation large vessel occlusion (PC-LVO) strokes is not clear. Little data has been published and no randomized clinical trials have been conducted so far. We aimed to perform an updated meta-analysis to compare clinical and procedural outcomes between conscious sedation (CS) and general anesthesia (GA). Methods: We reviewed the literature of the studies reporting CS and GA in patients with endovascularly-treated PC-LVO. The primary outcome was the functional outcome at 3 months measured using the modified Rankin Scale (mRS). A good functional outcome was defined as having a mRS 0–2. Secondary outcomes were mortality at 3 months, final successful recanalization (modified Thrombolysis in Cerebral Infarction (mTICI) scale from 2b to 3) and complete recanalization (mTICI of 3) and times from stroke onset to EVT completion. Random-effects models were completed to pool the outcomes and the I2 value was calculated to assess heterogeneity. Findings: Eight studies with a total of 1351 patients were included. The pooled results reveal that CS use was associated with higher rates of good outcome (OR 2.41, 95% CI 1.58–3.64, I2 = 49.67%) and with lower mortality at 3 months (OR 0.48, 95% CI 0.28–0.82, I2 =57.11%). No significant differences were observed in the final reperfusion rates, procedural duration, and time from stroke onset to EVT completion. Conclusion: In this meta-analysis, GA was associated with significantly lower rates of functional independence at 3 months in patients with PC-LVO strokes.

Aim: Some clinical and biological characteristics have been described as prognostic factors for clinical conversion into clinically definite multiple sclerosis in radiologically isolated syndrome (RIS) population. The aim of this study was to assess signatures of circulating miRNAs in those patients according to their conversion status after 5 years of follow-up. Patients & methods: OpenArray plates assessing 216 miRNA candidates were run in 15 RIS patients, and their relative abundances were analyzed. Results: A specific profile of deregulated circulating miRNAs (miR-144-3p, miR-448 and miR-653-3p in cerebrospinal fluid and miR-142-3p, miR-338-3p, miR-363-3p, miR-374b-5p, miR-424-5p, miR-483-3p in plasma) differentiated individuals who remained as RIS after 5 years of follow-up. Conclusion: Circulating miRNAs might be used as prognostic biomarkers for RIS patients.

Laparoscopic surgery for rectal cancer is technically complex. This study aimed to identify risk factors for suboptimal laparoscopic surgery (involved margins, incomplete mesorectal excision, and/or conversion to open surgery) in patients with rectal cancer. We included patients undergoing laparoscopic anterior resection for rectal cancer between June 2009 and June 2018. We defined the outcome variable suboptimal laparoscopic surgery as conversion to open surgery or inadequate histopathological specimens (margins < 1 mm or involved and/or poor-quality mesorectal excision). To identify independent predictors of suboptimal laparoscopic surgery, we analyzed 15 prospectively recorded demographic, clinical, and anthropometric variables obtained from our rectal cancer unit’s database. Subanalyses examined the same variables with respect to conversion and to inadequate histopathological specimens. Of the 323 patients included, 91 (28.2%) had suboptimal laparoscopic surgery. In the multivariate analysis, the independent factors associated with all suboptimal laparoscopic surgery were tumor location ≤ 5 cm from the anal verge (OR = 2.95, 0.95% CI 1.32–6.60; p = 0.008) and the intertuberous distance (OR = 0.79, 0.95% CI 0.65–0.96; p = 0.019). In the subanalyses, the promontorium-retropubic axis was an independent predictor of conversion (OR 0.70, 0.95% CI 0.51–0.96; p = 0.026), and tumor location ≤ 5 cm from the anal verge (OR 3.71, 0.95% 1.51–9.15; p = 0.004) was an independent predictor of inadequate histopathological specimens. Predictive factors for suboptimal laparoscopic anterior resection for rectal cancer were tumor location and the intertuberous distance. These results could help surgeons decide whether to use other surgical approaches in complex cases. The study was registered at Clinicaltrials.org (No. NCT03107650).

Purpose To validate a novel device developed at our institution for deep inspiration breath hold (DIBH) within a phase 2 clinical trial for left-sided breast cancer and to evaluate the dosimetric benefits of its use. Methods and Materials The device uses an external mechanical reference for guiding the patient to the desired breath level and gives acoustic and visual feedback to the patient and the radiation therapists, respectively. A phase 2 clinical trial was performed for its validation. The thoracic amplitude was used as a surrogate of the inspiration level. The stability, repeatability, reproducibility, and reliability of DIBH using the device were analyzed. The dosimetric parameters of the heart, the left anterior descending coronary artery, the ipsilateral lung, the contralateral breast, and the target coverage using free breathing and DIBH were compared. Results Thirty-eight patients were included in the analysis. The maximum population value of stability and repeatability were 1.7 mm and 3.3 mm, respectively. The reproducibility mean value was 1.7 mm, and population systematic and random errors were 0.3 mm and 0.9 mm, respectively. The reliability was 98.9%. Statistically significant dose reductions were found for the heart, the left anterior descending coronary artery, and the ipsilateral lung dosimetric parameters in DIBH, without losing dose coverage to the planning target volumes. Conclusions The validation of the device within the phase 2 clinical trial demonstrates that it offers reliable, stable, repeatable, and reproducible breast cancer treatments in DIBH with its dosimetric benefits.

We currently do not know the optimal time interval between the end of chemoradiotherapy and surgery. Longer intervals have been associated with a higher pathological response rate, worse pathological outcomes and more morbidity. The aim of this study was to evaluate the effect and safety of the current trend of increasing time interval between the end of chemoradiotherapy and surgery (

In this study, we examined normative data and diagnostic accuracy of a pictorial screening test to detect memory impairment for mild cognitive impairment (MCI) and Alzheimer’s disease (AD) in Spanish-speaking adults with intellectual disability (ID). A total of 94 volunteers with ID (60 controls, 17 MCI, and 17 AD), were evaluated by neuropsychological tests including the PMIS-ID in a cross-sectional validation study. Discriminative validity between the MCI, AD, and control group was analyzed by the area under the ROC curve. A cut-off score of 4.5 on the immediate recall trial had a sensitivity of 69% and a specificity of 80% to detect memory impairment (AUC = 0.685; 95% CI = 0.506–0.863) in the AD group. The PMIS-ID is a useful screening test to rule out a diagnosis of memory decline in people with moderate level of ID and AD, and it shows good psychometric properties.

Breast cancer (BC) is globally the most frequent cancer in women. Adherence to endocrine therapy (ET) in hormone-receptor-positive BC patients is active and voluntary for the first five years after diagnosis. This study examines the impact of adherence to ET on 10-year excess mortality (EM) in patients diagnosed with Stages I to III BC (N = 2297). Since sample size is an issue for estimating age-and stage-specific survival indicators, we developed a method, ComSynSurData, for generating a large synthetic dataset (SynD) through probabilistic graphical modeling of the original cohort. We derived population-based survival indicators using a Bayesian relative survival model fitted to the SynD. Our modeling showed that hormone-receptor-positive BC patients diagnosed beyond 49 years of age at Stage I or beyond 59 years at Stage II do not have 10-year EM if they follow the prescribed ET regimen. This result calls for developing interventions to promote adherence to ET in patients with hormone receptor-positive BC and in turn improving cancer survival. The presented methodology here demonstrates the potential use of probabilistic graphical modeling for generating reliable synthetic datasets for validating population-based survival indicators when sample size is an issue This work was supported by Instituto de Salud Carlos III PI18/01836 funded by FEDER funds/European Regional Development Fund (ERDF)-a way to Build Europe-//FONDOS FEDER “una manera de hacer Europa”

Risk of sudden cardiac death (SCD) increases with age, and several studies have examined the impact of different drugs on cardiovascular function. However, few studies have integrated epidemiological drug consumption data and genetic background in the context of cardiac death. We performed a retrospective population-based study in forensic sudden death cases from a 9-year period in Catalonia. The young cohort included 924 cases 18-50 years old, 566 of which had a cardiac cause of death. Complete autopsy, toxicological, and histopathological studies were performed. Molecular autopsy using next-generation sequencing was performed in nearly 400 cardiac cases. Cases related with fatal acute intoxication were excluded. Drug consumption prevalence was similar between forensic cases of cardiac and non-cardiac origin (62.5% versus 69.5%), with the exception of alcohol, which was more prevalent in the cardiac group than in the non-cardiac group (23.3% versus 17.1%). Individuals in the toxicology-positive group were carriers of more rare genetic variants and were significantly younger than the toxicology-negative group. Psychopharmacological drugs were identified in 22.3% of cardiac cases, and molecular autopsy identified an association between antiepileptic drugs or caffeine and pathogenic or likely pathogenic variants in arrhythmogenic genes. Specific substances could therefore play an essential role as triggers of SCD in genetically predisposed young people.

Background The availability of diverse and sophisticated surgical options to treat spine conditions is compounded by the scarcity of high-level evidence to guide decision-making. Although studies on discrete treatments are frequently published, little information is available regarding real-world surgical practice. We intended to survey spine surgeons to assess clinical management of common spine diagnosis in day-to-day settings. Methods An online survey was distributed among neurosurgeons and orthopaedic surgeons worldwide. The obtained assessment of common surgical practice is contextualized in a review of the best available evidence. Results The survey was answered by more than 310 members of several European, Australasian, and South African professional societies. The submitted responses translate a surgical practice generally grounded on evidence, favoring well-tried techniques, providing comprehensive treatment for the most severe diagnoses. Such practice comes mostly from neurosurgeons focused on spine surgery, practicing in teaching hospitals. Conclusion We believe that the pragmatic, day-to-day approach to spine conditions captured in the present survey offers an informative insight to involved surgeons.

Background An association has been found between the presence of lipid‐specific oligoclonal IgM bands (LS‐OCMB) in cerebrospinal fluid and a more severe clinical multiple sclerosis course. Objective To investigate lipid‐specific oligoclonal IgM bands as a prognostic biomarker of cognitive impairment in the early stages of multiple sclerosis. Methods Forty‐four patients underwent neuropsychological assessment at baseline and 4 years. Cognitive performance at follow‐up was compared adjusting by age, education, anxiety–depression, and baseline performance. Results LS‐OCMB+ patients only performed worse for Long‐Term Storage in the Selective Reminding Test (p = .018). Conclusion There are no remarkable cognitive differences between LS‐OCMB– and LS‐OCMB+ patients in the early stages of MS., Although an association has been reported between the presence of lipid‐specific oligoclonal IgM bands (LS‐OCMB) in cerebrospinal fluid and a more severe clinical multiple sclerosis course, no remarkable cognitive differences were found in this study between LS‐OCMB– and LS‐OCMB+ patients in the early stages of MS.

Mortality from cardiovascular disease (CVD), second tumours, and other causes is of clinical interest in the long-term follow-up of breast cancer (BC) patients. Using a cohort of BC patients (N = 6758) from the cancer registries of Girona and Tarragona (north-eastern Spain), we studied the 10-year probabilities of death due to BC, other cancers, and CVD according to stage at diagnosis and hormone receptor (HR) status. Among the non-BC causes of death (N = 720), CVD (N = 218) surpassed other cancers (N = 196). The BC cohort presented a significantly higher risk of death due to endometrial and ovarian cancers than the general population. In Stage I, HR− patients showed a 1.72-fold higher probability of all-cause death and a 6.11-fold higher probability of breast cancer death than HR+ patients. In Stages II–III, the probability of CVD death (range 3.11% to 3.86%) surpassed that of other cancers (range 0.54% to 3.11%). In Stage IV patients, the probability of death from any cancer drove the mortality risk. Promoting screening and preventive measures in BC patients are warranted, since long-term control should encompass early detection of second neoplasms, ruling out the possibility of late recurrence. In patients diagnosed in Stages II–III at an older age, surveillance for preventing late cardiotoxicity is crucial.

Background and ObjectivesPrimary progressive multiple sclerosis (PPMS) displays a highly variable disease progression with a characteristic accumulation of disability, what makes difficult its diagnosis and efficient treatment. The identification of microRNAs (miRNAs)-based signature for the early detection in biological fluids could reveal promising biomarkers to provide new insights into defining MS clinical subtypes and potential therapeutic strategies. The objective of this cross-sectional study was to describe PPMS miRNA profiles in CSF and serum samples compared with other neurologic disease individuals (OND) and relapsing-remitting MS (RRMS).MethodsFirst, a screening stage analyzing multiple miRNAs in few samples using OpenArray plates was performed. Second, individual quantitative polymerase chain reactions (qPCRs) were used to validate specific miRNAs in a greater number of samples.ResultsA specific profile of dysregulated circulating miRNAs (let-7b-5p and miR-143-3p) was found downregulated in PPMS CSF samples compared with OND. In addition, in serum samples, miR-20a-5p and miR-320b were dysregulated in PPMS against RRMS and OND, miR-26a-5p and miR-485-3p were downregulated in PPMS vs RRMS, and miR-142-5p was upregulated in RRMS compared with OND.DiscussionWe described a 2-miRNA signature in CSF of PPMS individuals and several dysregulated miRNAs in serum from patients with MS, which could be considered valuable candidates to be further studied to unravel their actual role in MS.Classification of EvidenceThis study provides Class II evidence that specific miRNA profiles accurately distinguish PPMS from RRMS and other neurologic disorders.

The presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in cerebrospinal fluid is associated with a more severe clinical multiple sclerosis (MS) course.To investigate LS-OCMB as a prognostic biomarker of cognitive long-term outcomes in MS.Ninety-nine patients underwent neuropsychological assessment. Cognitive performance between LS-OCMB- and LS-OCMB+ patients was compared adjusting by age, education, anxiety-depression, disease duration, and disability.LS-OCMB+ patients of ∼13 years of disease duration performed worse on Symbol Digit Modalities Test (SDMT) (p = 0.005).LS-OCMB+ perform worse on information processing speed and working memory (SDMT), suggesting that LS-OCMB could be a useful biomarker for long-term cognitive outcomes.

Unexpected cardiac deaths are a current challenge to healthcare systems. In adults, coronary artery disease and acquired cardiomyopathies are the most frequent causes of sudden cardiac death while in younger than 35 years old, the main cause is represented by non-ischemic diseases, usually inherited. Nowadays, around 10%-15% of unexpected deaths remain without a definite cause of decease after a complete autopsy, then classified as deaths potentially due to an inherited arrhythmia. Discrete abnormalities in some of the heart measures have been considered as potential predictors or risk factors for sudden cardiac death. However, role of non-benign genetic variants in these scattered heart alterations remains to be clarified, especially if variants are classified of ambiguous role. Clinicians usually only take into consideration pathogenic variants for decision-making. It is yet unclear what the role of VUS genetic variants in modifying the anatomical parameters of the heart. We hypothesize that some heart measures might be influenced by polygenic components as some variants may individually confer minor risk but may actually produce additive effects when combined with others. Our aim was to investigate whether carrying non-benign rare variants in genes related to inherited arrhythmias may contribute to scattered cardiac alterations in anatomical normal hearts. The study is composed by 761 samples collected from autopsies of SD suffered by adults from 18 to 50 years of age who occurred in Catalonia (Spain) in a 9-year period. Complete medico-legal autopsy was performed to determine the cause of death. Molecular autopsy was performed as part of our forensic protocol, including genes associated with inherited diseases.To evaluate the effect of genetic rare variants into hearts measures we performed a linear regression model and data were presented as regression. This study showed, for the first time, that rare variants, regardless of significance (pathogenic, probably pathogenic or uncertain significance), may contribute to interventricular septum width in the structurally normal heart. While the cohort is based on sudden death cases, further studies and case-control studies will be necessary to conclude that the genetic determinants of septal thickness contributes to sudden cardiac death. We conclude that non-benign rare variants contribute to modify scattered septum width in structural normal hearts, being a potential risk factor of arrhythmia in genetic harbors. These evidence support the current recommendation in forensic protocols of including histologic analysis of septum when inherited arrhythmogenic disease is suspicious cause of decease.

Simple Summary Nintedanib is an anti-angiogenic agent that has received approval in the European Union for the treatment of non-small cell lung cancer (NSCLC) after first-line chemotherapy. Here, we explore the possibility that the flavonolignan silibinin—the major bioactive component from the seeds of the milk thistle herb (Silybum marianum)—can provide clinical benefit in patients with advanced NSCLC treated with nintedanib. In vitro studies revealed that silibinin targets biological functions important for the therapeutic efficacy of nintedanib; specifically, activation of the transcription factor STAT3 and sequestration into lysosomal “safe houses”. Supplementation with the silibinin-based nutraceutical Legasil® to patients with NSCLC receiving nintedanib/docetaxel was associated with increased clinical responses and a significantly longer time to treatment failure. Our findings provide a biological and clinical rationale for combining silibinin with nintedanib in a patient population for whom few effective second-line chemotherapy regimens are available. Abstract The anti-angiogenic agent nintedanib has been shown to prolong overall and progression-free survival in patients with advanced non-small-cell lung cancer (NSCLC) who progress after first-line platinum-based chemotherapy and second-line immunotherapy. Here, we explored the molecular basis and the clinical benefit of incorporating the STAT3 inhibitor silibinin—a flavonolignan extracted from milk thistle—into nintedanib-based schedules in advanced NSCLC. First, we assessed the nature of the tumoricidal interaction between nintedanib and silibinin and the underlying relevance of STAT3 activation in a panel of human NSCLC cell lines. NSCLC cells with poorer cytotoxic responses to nintedanib exhibited a persistent, nintedanib-unresponsive activated STAT3 state, and deactivation by co-treatment with silibinin promoted synergistic cytotoxicity. Second, we tested whether silibinin could impact the lysosomal sequestration of nintedanib, a lung cancer cell-intrinsic mechanism of nintedanib resistance. Silibinin partially, but significantly, reduced the massive lysosomal entrapment of nintedanib occurring in nintedanib-refractory NSCLC cells, augmenting the ability of nintedanib to reach its intracellular targets. Third, we conducted a retrospective, observational multicenter study to determine the efficacy of incorporating an oral nutraceutical product containing silibinin in patients with NSCLC receiving a nintedanib/docetaxel combination in second- and further-line settings (n = 59). Overall response rate, defined as the combined rates of complete and partial responses, was significantly higher in the study cohort receiving silibinin supplementation (55%) than in the control cohort (22%, p = 0.011). Silibinin therapy was associated with a significantly longer time to treatment failure in multivariate analysis (hazard ratio 0.43, p = 0.013), despite the lack of overall survival benefit (hazard ratio 0.63, p = 0.190). Molecular mechanisms dictating the cancer cell-intrinsic responsiveness to nintedanib, such as STAT3 activation and lysosomal trapping, are amenable to pharmacological intervention with silibinin. A prospective, powered clinical trial is warranted to confirm the clinical relevance of these findings in patients with advanced NSCLC.

Progressive lacunar syndromes (PLS) occur in up to 20-30% of patients with lacunar strokes, increasing the risk of long term dependency. Our aim is to develop a predictive score to identify patients at high risk of presenting PLS.We derived a risk score for PLS in a cohort of consecutive patients (n=187) presenting with one of the five classic lacunar syndromes (LS) and absence of vascular occlusion, perfusion deficit or symptomatic stenosis. A risk score was developed using the coefficients from the logistic regression model, and receiver operating characteristic (ROC) analysis was conducted to assess the prognostic value of the risk score. Sensitivity, specificity and accuracy were estimated for each total point score.Out of 187 patients included in our sample, 52 (27.8%) presented PLS. Previous history of diabetes mellitus (1 point), diastolic blood pressure at admission (2 points), clinical deficits consistent with a pure motor syndrome (1 point) and asymptomatic intracranial atheromatosis or stenosis in non-symptomatic territory (1 point) were independent predictors for PLS. The estimated area under the ROC curve for this model was 0.77 (95% CI,0.68 - 0.84).This score could be a useful tool in routine clinical practice to predict the occurrence of PLS, allowing the identification of those patients with LS who are at high risk of long term dependency due to early neurological worsening, and who would benefit the most from an intensive treatment.

The cytoplasmic rods-rings (RR) pattern is found in hepatitis C (HCV) patients treated with interferon-ribavirin when studied with ANA-IIF. Ribavirin aggregates/induces antigenic changes in IMPDH-2, an enzyme necessary for ribavirin action.Prospective search for anti-RR autoantibodies (HEp-2, INOVA) in patients treated with direct-acting antivirals (DAAs) from October 2015 to June 2017. HCV-negative patients from up to June 2016 acted as controls. Anti-RR was analyzed at baseline and, mainly, during treatment and follow-up. The Chi-square test, Student's t-test and a logistic regression analysis were performed.Between October 2015 and June 2016, 1258 men and 2389 women who were HCV-negative and 137 men and 112 women who were HCV-positive patients were studied. Approximately 22.9% of HCV-negative and 13.2% of HCV-positive were ANA-IIF-positive (p0.05). Three HCV-negative (0.08%) and 23 (9.2%) HCV-positive patients had anti-RR (p0.001). A total of 122 patients received DAAs; 30 received DAA+RBV; 46 pre-treated with IFN-RBV received DAA; 31 pre-treated with IFN-RBV received DAA+RBV; 16 received IFNpeg-RBV; and 24 received IFN-RBV-DAA. None of the 122 DAA-treated patients showed anti-RR; anti-RR were identified in 14.8% of those treated with DAA-RBV; in 25.9% of those pre-treated with IFN-RBV receiving DAA; in 22.2% of IFN-RBV-pre-treated patients who received DAA+RBV; in 7.4% of those treated with IFNpeg-RBV and in 29.6% of those treated with IFNpeg-RBV-DAA. The multivariate analysis showed significant associations between anti-RR and "Exposure to IFN" and "Time of exposure to RBV".Anti-RR autoantibodies were detected only in patients with current or past treatments with RBV, even in cases in which only DAAs were later administered.

The METTEN study assessed the efficacy, tolerability, and safety of adding metformin to neoadjuvant chemotherapy plus trastuzumab in early HER2-positive breast cancer (BC). Women with primary, non-metastatic HER2-positive BC were randomized (1:1) to receive metformin (850 mg twice-daily) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus trastuzumab, followed by four cycles of 3-weekly FE75C plus trastuzumab (arm A), or equivalent regimen without metformin (arm B), followed by surgery. Primary endpoint was the rate of pathological complete response (pCR) in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% CI: 47.3–80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7–74.5]; OR 1.34 [95% CI: 0.46–3.89], P = 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (P = 0.089), respectively. Blood metformin concentrations (6.2 μmol/L, 95% CI: 3.6–8.8) were within the therapeutic range. Seventy-six percent of patients completed the metformin-containing regimen; 13% of patients in arm A dropped out because of metformin-related gastrointestinal symptoms. The most common adverse events (AEs) of grade ≥3 were neutropenia in both arms and diarrhea in arm A. None of the serious AEs was deemed to be metformin-related. Addition of anti-diabetic doses of metformin to a complex neoadjuvant regimen was well tolerated and safe. Because the study was underpowered relative to its primary endpoint, the efficacy data should be interpreted with caution.

International audience; Purpose To assess the dosimetric impact of switching from the Analytical Anisotropic Algorithm (AAA) to Acuros XB (AXB) for both dose-to-medium (Dm) and dose-to-water (Dw) in VMAT for HandN patients. To study whether it should be linked to a change in the dose prescriptions to the PTVs and in the constraints to the OARs. Methods 110HandN patients treated with VMAT were included. Calculations were performed with AAA and AXB. PTV54, PTV60, PTV70, spinal cord, brainstem, brain, larynx, oral cavity, cochleas, parotid glands and mandible were delineated. Clinically-relevant dose-volume parameters were compared. Paired t-tests were used to analyze the differences in mean values. The Pitman-Morgan dispersion test was computed to evaluate inter-patient variability of these differences. Results AAA overestimated all dose-volume parameters compared to AXB Dm (0.2 Gy to 2.4 Gy). No systematic trend was observed in the differences between AAA and AXB Dw (-5.3 Gy to 0.6 Gy). Dose-volume parameters were significantly higher for AXB Dw compared to AXB Dm (0.1 Gy to 6.6 Gy). In all cases, the largest absolute differences (4%–14%) were found for maximum absorbed doses to the cochleas and the mandible. The number of parameters with significant inter-patient variability was greater when switching from AAA to AXB Dw than from AAA to AXB Dm. Conclusions There are important differences between AXB and AAA in VMAT planning for HandN cancer. The systematic differences and their inter-patient variability identified may help to facilitate decision-making about the dose prescriptions to the PTVs and the constraints to the OAR. © 2018 Associazione Italiana di Fisica Medica

Triple-negative/basal-like breast cancer (BC) is characterized by aggressive biological features, which allow relapse and metastatic spread to occur more frequently than in hormone receptor-positive (luminal) subtypes. The molecular complexity of triple-negative/basal-like BC poses major challenges for the implementation of targeted therapies, and chemotherapy remains the standard approach at all stages. The matricellular protein cysteine-rich angiogenic inducer 61 (CCN1/CYR61) is associated with aggressive metastatic phenotypes and poor prognosis in BC, but it is unclear whether anti-CCN1 approaches can be successfully applied in triple-negative/basal-like BC. Herein, we first characterized the prevalence of CNN1 expression in matched samples of primary tumors and metastatic relapse in a series of patients with BC. We then investigated the biological effect of CCN1 depletion on tumorigenic traits in vitro and in vivo using archetypal TNBC cell lines. Immunohistochemical analyses of tissue microarrays revealed a significant increase of the highest CCN1 score in recurrent tissues of triple-negative/basal-like BC tumors. Stable silencing of CCN1 in triple-negative/basal-like BC cells promoted a marked reduction in the expression of the CCN1 integrin receptor α(v)β(3), inhibited anchorage-dependent cell growth, reduced clonogenicity, and impaired migration capacity. In an orthotopic model of triple-negative/basal-like BC, silencing of CCN1 notably reduced tumor burden, which was accompanied by decreased microvessel density and concurrent induction of the luminal epithelial marker E-cadherin. Thus, CNN1/CYR61-targeting strategies might have therapeutic value in suppressing the biological aggressiveness of triple-negative/basal-like BC.

Background and objectives: Diffuse idiopathic skeletal hyperostosis (DISH) is a bone formation disease in which only skeletal signs are considered in classification criteria. The aim of the study was to describe different phenotypes in DISH patients based on clinicoradiological features. Materials and Methods: We evaluated 97 patients who met the Resnick or modified Utsinger classification criteria for DISH and were diagnosed at our hospital from 2004 to 2015. Patients were stratified into: (a) peripheral pattern (PP)—Resnick criteria not met but presenting ≥3 peripheral enthesopathies, (b) axial pattern (AP)—Resnick criteria met but &lt, 3 enthesopathies, and (c) mixed pattern (MP)—Resnick criteria met with ≥3 enthesopathies. Statistical analysis was carried out to identify variables that might predict classification in a given group. Results: Fifty-six of the 97 patients included (57.7%) were male and 72.2% fulfilled the Resnick criteria. Applying our classification, 39.7% were stratified as MP, 30.9% as AP and 29.4% as PP. Clinical enthesopathy was reported in 40.2% of patients during the course of the disease. Sixty-eight patients were included in a comparative analysis of variables between DISH patterns. The results showed a predominance of women (p &lt, 0.004), early onset (p &lt, 0.03), hip involvement (p &lt, 0.003) and enthesitis (p &lt, 0.001) as hallmarks of PP. Asymptomatic patients were most frequently observed in AP (28.6%, MP 3.8%, PP 5.0%) while MP was characterized by a more extensive disease. Conclusions: We believe DISH has distinct phenotypes and describe a PP phenotype that is not usually considered. Extravertebral manifestations should be included in the new classification criteria in order to cover the entire spectrum of the disease.

COVID-19, the illness caused by infection with the novel coronavirus SARS-CoV-2, is a rapidly spreading global pandemic in urgent need of effective treatments. Here we present a comprehensive examination of the host- and virus-targeted functions of the flavonolignan silibinin, a potential drug candidate against COVID-19/SARS-CoV-2. As a direct inhibitor of STAT3—a master checkpoint regulator of inflammatory cytokine signaling and immune response—silibinin might be expected to phenotypically integrate the mechanisms of action of IL-6-targeted monoclonal antibodies and pan-JAK1/2 inhibitors to limit the cytokine storm and T-cell lymphopenia in the clinical setting of severe COVID-19. As a computationally predicted, remdesivir-like inhibitor of RNA-dependent RNA polymerase (RdRp)—the central component of the replication/transcription machinery of SARS-CoV-2—silibinin is expected to reduce viral load and impede delayed interferon responses. The dual ability of silibinin to target both the host cytokine storm and the virus replication machinery provides a strong rationale for the clinical testing of silibinin against the COVID-19 global public health emergency. A randomized, open-label, phase II multicentric clinical trial (SIL-COVID19) will evaluate the therapeutic efficacy of silibinin in the prevention of acute respiratory distress syndrome in moderate-to-severe COVID-19-positive onco-hematological patients at the Catalan Institute of Oncology in Catalonia, Spain.

Resumen: Objetivo: Analizar la supervivencia poblacional del cáncer de mama (CM) en estadios precoces, estimando la tendencia temporal del exceso de mortalidad (EM) a largo plazo en periodos anuales y quinquenales, y determinando, si es posible, una proporción de pacientes que puedan considerarse curadas. Método: Se incluyó la cohorte de pacientes diagnosticadas de CM en estadios I y II antes de los 60 años de edad en Gerona y Tarragona (N = 2453). Se calcularon la supervivencia observada (SO) y la supervivencia relativa (SR) al CM hasta los 20 años de seguimiento. Para valorar el EM se estimó la SR a intervalos anuales (SRI) y quinquenales (SR5). Los resultados se presentan por grupos de edad (≤49 y 50-59), estadio (I/II) y periodo de diagnóstico (1985-1994 y 1995-2004). Resultados: En el estadio I, la SO y la SR fueron mayores en 1995-2004 que en 1985-1994: 3,5% a los 15 años de seguimiento y 4,5% a los 20 años. La SO superó el 80% en el estadio I y se mantuvo inferior al 70% en el estadio II. Sin embargo, el EM a largo plazo no desapareció (SRI

Resumen: La supervivencia relativa se ha utilizado habitualmente como medida de la evolución temporal del exceso de riesgo de mortalidad en cohortes de pacientes diagnosticados de cáncer, teniendo en cuenta la mortalidad de una población de referencia. Una vez estimado el exceso de riesgo de mortalidad pueden calcularse tres probabilidades acumuladas a un tiempo T: 1) la probabilidad de fallecer asociada a la causa de diagnóstico inicial (enfermedad en estudio), 2) la probabilidad de fallecer asociada a otras causas, y 3) la probabilidad de supervivencia absoluta en la cohorte a un tiempo T. Este trabajo presenta la aplicación WebSurvCa (https://shiny.snpstats.net/WebSurvCa/), mediante la cual los registros de cáncer de base hospitalaria y poblacional, y los registros de otras enfermedades, estiman dichas probabilidades en sus cohortes seleccionando como población de referencia la mortalidad de la comunidad autónoma que consideren. Abstract: Relative survival has been used as a measure of the temporal evolution of the excess risk of death of a cohort of patients diagnosed with cancer, taking into account the mortality of a reference population. Once the excess risk of death has been estimated, three probabilities can be computed at time T: 1) the crude probability of death associated with the cause of initial diagnosis (disease under study), 2) the crude probability of death associated with other causes, and 3) the probability of absolute survival in the cohort at time T. This paper presents the WebSurvCa application (https://shiny.snpstats.net/WebSurvCa/), whereby hospital-based and population-based cancer registries and registries of other diseases can estimate such probabilities in their cohorts by selecting the mortality of the relevant region (reference population). Palabras clave: Cáncer de mama, Supervivencia neta, Supervivencia relativa, Exceso de mortalidad, Riesgos competitivos, Keywords: Breast cancer, Net survival, Relative survival, Excess mortality, Competing risk

Background MicroRNAs (miRNAs) have been reported as deregulated in active brain lesions derived from patients with multiple sclerosis (MS). In there, these post-transcriptional regulators may elicit very important effects but proper identification of miRNA candidates as potential biomarkers and/or therapeutic targets is scarcely available. Objective The aim of the study was to detect the presence of a set of candidate miRNAs in cell-free cerebrospinal fluid (CSF) and to determine their association with gadolinium-enhancing (Gd+) lesions in order to assess their value as biomarkers of MS activity. Methods Assessment of 28 miRNA candidates in cell-free CSF collected from 46 patients with MS (26 Gd+ and 20 Gd− patients) was performed by TaqMan assays and qPCR. Variations in their relative abundance were analyzed by the Mann-Whitney U test and further evaluated by receiver operating characteristic (ROC) analysis. Signaling pathways and biological functions of miRNAs were analyzed using bioinformatic tools (miRTarBase, Enrichr, REVIGO, and Cytoscape softwares). Results Seven out of 28 miRNA candidates were detected in at least 75% of CSF samples. Consistent increase of miR-21 and miR-146a/b was found in Gd+ MS patients. This increase was in parallel to the number of Gd+ lesions and neurofilament light chain (NF-L) levels. Gene Ontology enrichment analysis revealed that the target genes of these miRNAs are involved in biological processes of key relevance such as apoptosis, cell migration and proliferation, and in cytokine-mediated signaling pathways. Conclusion Levels of miR-21 and miR-146a/b in cell-free CSF may represent valuable biomarkers to identify patients with active MS lesions.

Background We provide population-based long-term survival indicators of breast cancer patients by quantifying the observed survival, and the probabilities of death due to breast cancer and to other causes by age and tumor stage at diagnosis. Methods We included a total of 10,195 female patients diagnosed before 85 years with invasive primary breast cancer in Girona and Tarragona during the periods 1985–1994 and 1995–2004 and followed-up until December 31st 2014. The survival indicators were estimated at 5, 10, 15 and 20 years of follow-up comparing diagnostic periods. Results Comparing diagnostic periods: I) the probability of death due to other causes did not change; II) the 20-year survival for women diagnosed ≤ 49 years increased 13% (1995–2004 = 68%; 1985–1994:55%), whereas their probability of death due to breast cancer decreased at the same pace (1995–2004 = 29%; 1985–1994 = 42%); III) at 10 years of follow-up, decreases in the probabilities of death due to breast cancer across age groups switched from 11 to 17% resulting in a risk of death reduction of 19% after adjusting by stage. During 1995–2004, the stage-specific 10-year probabilities of death due to breast cancer switched from: 3–6% in stage I, 18–20% in stage II, 34–46% in stage III and surpassed 70% in stage IV beyond 5 years after diagnosis. Conclusions In our study, women diagnosed with breast cancer had higher long-term probability to die from breast cancer than from other causes. The improvements in treatment and the lead-time bias in detecting cancer in an early stage resulted in a reduction of 19% in the risk of death between diagnostic periods. Electronic supplementary material The online version of this article (10.1007/s12094-018-1852-1) contains supplementary material, which is available to authorized users.

Resumen Introduccion El objetivo de este estudio observacional, prospectivo, multicentrico y multinivel ha sido evaluar los resultados oncologicos (recidiva local, metastasis y supervivencia global) del Proyecto del Cancer de Recto de la Asociacion Espanola de Cirujanos (AEC) 10 anos despues de su inicio, comparando los resultados con los registros escandinavos. Metodos La base de datos del proyecto docente de la AEC incluye hasta la fecha a 17.620 pacientes, de los cuales 4.508 fueron operados con una reseccion potencialmente curativa entre marzo de 2006 y diciembre de 2010. Todos ellos son provenientes de los primeros 59 hospitales incluidos en el proyecto, y por tanto seguidos al menos durante 5 anos, y constituyen el objeto del presente estudio. Resultados La incidencia acumulada de recidiva local fue 7,3 (IC 95%: 8,2-6,5), la de metastasis fue 21,0 (IC 95%: 22,4-19,7) y la de supervivencia global, 72,3 (IC 95%: 80,3-77,6). El analisis de regresion multinivel, con la variable hospital como un efecto aleatorio, mostro una variacion significativa entre los hospitales para las variables de resultado oncologico: supervivencia general, recidiva local y metastasis (δ2 = 0,053). Conclusiones Este estudio indica que los resultados observados en el Proyecto del Cancer de Recto de la AEC son inferiores a los observados en los registros de Escandinavia a los que tratamos de emular y que ello es atribuible a la variabilidad de la practica en algunos centros.

Purpose Our purpose was to assess the dosimetric effect of switching from the analytical anisotropic algorithm (AAA) to Acuros XB (AXB), with dose-to-medium (Dm) and dose-to-water (Dw) reporting modes, in lung stereotactic body radiation therapy patients and determine whether planning-target-volume (PTV) dose prescriptions and organ-at-risk constraints should be modified under these circumstances. Methods and Materials We included 54 lung stereotactic body radiation therapy patients. We delineated the PTV, the ipsilateral lung, the contralateral lung, the heart, the spinal cord, the esophagus, the trachea, proximal bronchi, the ribs, and the great vessels. We performed dose calculations with AAA and AXB, then compared clinically relevant dose-volume parameters. Paired t tests were used to analyze differences of means. We propose a method, based on the composition of the involved structures, for predicting differences between AXB Dw and Dm calculations. Results The largest difference between the algorithms was 4%. Mean dose differences between AXB Dm and AXB Dw depended on the average composition of the volumes. Compared with AXB, AAA underestimated all PTV dose-volume parameters (-0.7 Gy to -0.1 Gy) except for gradient index, which was significantly higher (4%). It also underestimated V5 of the contralateral lung (-0.3%). Significant differences in near-maximum doses (D2) to the ribs were observed between AXB Dm and AAA (1.7%) and between AXB Dw and AAA (-1.6%). AAA-calculated D2 was slightly higher in the remaining organs at risk. Conclusions Differences between AXB and AAA are below the threshold of clinical detectability (5%) for most patients. For a small subgroup, the difference in maximum doses to the ribs between AXB Dw and AXB Dm may be clinically significant. The differences in dose volume parameters between AXB Dw and AXB Dm can be predicted with reference to structure composition

// Ariadna Giro-Perafita 1, * , Ariadna Sarrats 1, * , Ferran Perez-Bueno 1, 2 , Gloria Oliveras 1, 3 , Maria Buxo 4 , Joan Brunet 1, 3 , Gemma Vinas 1, 3 and Teresa Puig Miquel 1 1 New Terapeutics Targets Laboratory (TargetsLab), Department of Medical Sciences, University of Girona, Girona, Spain 2 Pathology Department, Dr. Josep Trueta Hospital and Catalan Institute of Health (ICS), Girona, Spain 3 Medical Oncology Department, Catalan Institute of Oncology (ICO), Girona, Spain 4 Girona Biomedical Research Institute (IDIBGI), Girona, Spain * These authors have contributed equally to this work Correspondence to: Teresa Puig Miquel, email: teresa.puig@udg.edu Gemma Vinas, email: G.vinyes@iconcologia.net Keywords: EGFR, breast cancer molecular subtypes Received: January 25, 2017 Accepted: May 05, 2017 Published: August 10, 2017 ABSTRACT Triple-Negative Breast Cancer (TNBC) has poor prognosis and no approved targeted therapy. We previously showed that the enzyme fatty acid synthase (FASN) was largely expressed in a small TNBC patients’ cohort and its inhibition synergized with cetuximab in TNBC preclinical mouse models. Here, we evaluated FASN and EGFR expression in a cohort of TNBC patients and we study their prognostic role and their association with clinico-histopathological features, intrinsic TNBC subtypes and survival. FASN, EGFR, CK5/6 and vimentin expression were retrospective evaluated by Immunohistochemistry in 100 primary TNBC tumors. FASN expression was classified into high and low FASN groups. EGFR, CK5/6 and vimentin expression were used in TNBC intrinsic subtypes classification. FASN was expressed in most of the TNBC patients but did not correlate with overall survival or disease-free survival in this cohort. High FASN group was significantly associated with positive node status. FASN expression was significantly higher in Basal-Like patients than in Mesenchymal-Like ones. EGFR expression was positive in 50% of the tumors, and those patients showed poorer DFS. Altogether, our findings provide a rationale for further investigation the prognostic role of FASN and EGFR expression in a larger cohort of TNBC patients.

Background Two common issues may arise in certain population-based breast cancer (BC) survival studies: I) missing values in a survivals’ predictive variable, such as “Stage” at diagnosis, and II) small sample size due to “imbalance class problem” in certain subsets of patients, demanding data modeling/simulation methods. Methods We present a procedure, ModGraProDep, based on graphical modeling (GM) of a dataset to overcome these two issues. The performance of the models derived from ModGraProDep is compared with a set of frequently used classification and machine learning algorithms (Missing Data Problem) and with oversampling algorithms (Synthetic Data Simulation). For the Missing Data Problem we assessed two scenarios: missing completely at random (MCAR) and missing not at random (MNAR). Two validated BC datasets provided by the cancer registries of Girona and Tarragona (northeastern Spain) were used. Results In both MCAR and MNAR scenarios all models showed poorer prediction performance compared to three GM models: the saturated one (GM.SAT) and two with penalty factors on the partial likelihood (GM.K1 and GM.TEST). However, GM.SAT predictions could lead to non-reliable conclusions in BC survival analysis. Simulation of a “synthetic” dataset derived from GM.SAT could be the worst strategy, but the use of the remaining GMs models could be better than oversampling. Conclusion Our results suggest the use of the GM-procedure presented for one-variable imputation/prediction of missing data and for simulating “synthetic” BC survival datasets. The “synthetic” datasets derived from GMs could be also used in clinical applications of cancer survival data such as predictive risk analysis.