BackgroundIn patients with acute coronary syndromes (ACS), current guidelines recommend a low-density lipoprotein cholesterol (LDL-C) level < 1.4 mmol/L (<55 mg/dL). MethodsThe JET-LDL is a multicenter, observational, prospective registry created to investigate levels of LDL-C in consecutive patients with ACS undergoing PCI at 35 Italian hospitals, and to report their lipid lowering therapies (LLT). Follow-up was planned at 1 and 3 months. LDL-C reduction >50% from baseline or level < 55 mg/dL at 1-month was the primary endpoint. ResultsA total of 1095 patients were included: median age was 67 (58–75); 33.7% were already on LLT. Baseline LDL-C levels was 105 (76.5–137) mg/dL. At hospital discharge all patients were on LLT: 98.1% received statins (as mono or combination therapy), ezetimibe and PCSK9i were used in 60.1% and 8.5% of cases, respectively. Primary endpoint was achieved in 62% (95% CI 58–65) of cases. At 1-month LDL-C levels dropped to 53 (38–70) mg/dL (p < 0.001 vs baseline) and it was <55 mg/dL in 53% (95% CI 49–57) of patients; however, PCSK9i were added to 7 further cases. At 3-months 58% (95% CI 55–62) of patients achieved the target level, but PCSK9i was added to only 11 new patients. ConclusionsIn this real-world registry of ACS patients undergoing PCI, recommend LDL-C levels were obtained in 62% of patients, but PCSK9i prescription was limited to 10% of cases. As LLT pattern appeared mainly improved at hospital discharge, an early and strong treatment should be considered.

We present a case involving a 32-year-old man who ingested chlorine bleach with self-defeating intent. The ingestion of bleach can lead to a wide range of consequences, from mild mucosal burns to severe complications, rarely resulting in death. This case highlights the association between chlorine bleach ingestion and the development of hepatic portal venous gas (HPVG), a radiological finding traditionally thought to carry poor prognoses. The HPVG in this case resolved spontaneously within 24 h with conservative management, indicating its transient nature. The exact pathophysiological mechanisms responsible for HPVG after the ingestion of toxic substances .remain only partially understood. One hypothesis suggests that extensive damage to the gastrointestinal wall caused by caustic agent may allow enteric gas to enter the portal system. While HPVG after toxic ingestion is often transient, its consequences and potential risks should be carefully considered. Hyperbaric oxygen therapy is suggested in cases with neurological symptoms. In conclusion, HPVG is not a specific disease but rather a manifestation of various underlying factors, and its development in the context of chlorine bleach ingestion represents an additional insight to its understanding. It can be associated with severe medical conditions, but it is also found in less severe cases that can be managed conservatively.

Introduction: Hemostatic biomarkers have been widely explored in different cancer types as possible predictors of specific cancer outcomes, including survival, malignant disease recurrence, and progression. Results from many small and single-center studies are promising, stimulating confirmatory data from large, prospective studies. In a large cohort of high-risk breast cancer patients enrolled in the prospective, observational, multicenter HYPERCAN study, we aim to establish whether prechemotherapy hemostatic levels can predict disease recurrence (DR). Methods: TheHYPERCAN study (ClinicalTrials.gov ID#NCT02622815) is a prospective, observational, multicenter study, specifically designed to evaluate the role of hemostatic biomarkers in relation to disease recurrence, disease progression, mortality response to therapy and thrombosis. Patients with surgically resected high-risk breast cancer enrolled between 2012 and 2019, from the HYPERCAN study were analyzed. Blood samples collected at enrollment, before starting anticancer treatment, were tested for thrombin generation (TG) by both the ST-Genesia system (STG-ThromboScreen reagent, with and without thrombomodulin) and the calibrated automated thrombogram (CAT) at 5 pM TF. D-dimer, fibrinogen, prothrombin fragment 1+2 (F1+2), and proteins C and free protein S (FPS) were also measured. Outcome analyzed was early-DR (E-DR) within 2 years. Results: A total of 1,059 patients (15M/1,044F), mean age 53 years (SD±11) were analyzed. Breast conserving-resection was performed in 53% and mastectomy in 47% of patients. HER-2 expression was positive in 26% of tumor specimens. The most frequent molecular subtype was Luminal B HER2 negative (32%), followed by Luminal A (22%), Luminal B HER2 positive (19%), Triple negative (13%) and HER2 positive (8%). The largest proportion of tumors were classified as invasive ductal carcinoma, diagnosed in 86% of subjects. All patients were eligible for systemic adjuvant chemotherapy, and for receiving trastuzumab in case of HER-2 positivity. Within 2 years from enrollment, 53 (5.5 %) patients experienced an E-DR, 8 died, while 92 were lost at follow-up. E-DR patients were characterized by worse stage (IIIC), more frequently triple-negative, and less often Luminal-B/HER2-positive molecular subtypes (p&amp;lt;0.05). In addition, E-DR subjects were characterized by increased pre-chemotherapy levels of D-dimer (p=0.004), and peak of TG performed by both Genesia (p=0.001), with and without thrombomodulin, and by CAT (p&amp;lt;0.001) assays. The remaining coagulation parameters were not significantly different between the two groups. The competitive multivariable proportional hazard regression model, corrected for age and surgery status, identified D-dimer and TG peak (by both methods) as independent risk factors for E-DR. This model was internally validated by 1,000-bootstrapping resampling correction. A continuous risk score was therefore generated including D-dimer and TG, which provided a ROC AUC of 0.652 (p&amp;lt;0.001). By this score the patients were significantly stratified in a high- vs low-risk for E-DR (HR 23 vs 0%: Log-rank &amp;lt;0.001). Conclusions: In this large prospective cohort of surgically resected breast cancer patients at high-risk of DR, we could generate and internally validate a risk assessment model based on pre-treatment values of TG and D-dimer, able to identify those subjects at higher risk of DR in the first 2 years after tumor resection. This score, if externally validated, may help the clinical surveillance and serve as treatment guidance in patients with primary breast cancer that are at high risk of recurrence, avoiding overtreatment in those at low risk.

The purpose of this study was to investigate the effects of partial-body cryostimulation on middle-distance runners before two 3000-m tests at the speed of the first and second ventilatory threshold, and before a time to exhaustion test at 110% of the maximal aerobic speed. Twelve amateur runners (age: 46 ± 9 years; VO2max: 51.7 ± 4.9 ml·kg-1·min-1) completed six running testing sessions in a randomized counterbalanced cross-over fashion: three of them were preceded by a partial-body cryostimulation and the other three by a control condition. The testing sessions consisted of: 1) a 3000-m continuous running test at the speed of the first ventilatory threshold; 2) a 3000-m continuous running test at the speed of the second ventilatory threshold; 3) a time to exhaustion test at 110% of the maximal aerobic speed. Heart rate, ratings of perceived exertion and visual analogue scale relative to muscle pain were recorded throughout the tests. Total quality recovery was evaluated 24-48 h after the end of each test. Distance to exhaustion was higher after partial-body cryostimulation than control condition (p = 0.018; partial-body cryostimulation: 988 ± 332 m, control: 893 ± 311 m). There were differences in the ratings of perceived exertion during each split of the 3000-m continuous running test at the speed of the second ventilatory threshold (p = 0.001). Partial-body cryostimulation can be positively considered to enhance middle-distance running performance and reduce perception of effort in amateur runners.

Sepsis and septic shock are major challenges and economic burdens to healthcare, impacting millions of people globally and representing significant causes of mortality. Recently, a large number of quality improvement programs focused on sepsis resuscitation bundles have been instituted worldwide. These educational initiatives have been shown to be associated with improvements in clinical outcomes. We aimed to evaluate the impact of a multi-faceted quality implementing program (QIP) on the compliance of a "simplified 1-h bundle" (Sepsis 6) and hospital mortality of severe sepsis and septic shock patients out of the intensive care unit (ICU). Emergency departments (EDs) and medical wards (MWs) of 12 academic and non-academic hospitals in the Lombardy region (Northern Italy) were involved in a multi-faceted QIP, which included educational and organizational interventions. Patients with a clinical diagnosis of severe sepsis or septic shock according to the Sepsis-2 criteria were enrolled in two different periods: from May 2011 to November 2011 (before-QIP cohort) and from August 2012 to June 2013 (after-QIP cohort). The effect of QIP on bundle compliance and hospital mortality was evaluated in a before-after analysis. We enrolled 467 patients in the before-QIP group and 656 in the after-QIP group. At the time of enrollment, septic shock was diagnosed in 50% of patients, similarly between the two periods. In the after-QIP group, we observed increased compliance to the "simplified rapid (1 h) intervention bundle" (the Sepsis 6 bundle - S6) at three time-points evaluated (1 h, 13.7 to 18.7%, p = 0.018, 3 h, 37.1 to 48.0%, p = 0.013, overall study period, 46.2 to 57.9%, p < 0.001). We then analyzed compliance with S6 and hospital mortality in the before- and after-QIP periods, stratifying the two patients' cohorts by admission characteristics. Adherence to the S6 bundle was increased in patients with severe sepsis in the absence of shock, in patients with serum lactate <4.0 mmol/L, and in patients with hypotension at the time of enrollment, regardless of the type of admission (from EDs or MWs). Subsequently, in an observational analysis, we also investigated the relation between bundle compliance and hospital mortality by logistic regression. In the after-QIP cohort, we observed a lower in-hospital mortality than that observed in the before-QIP cohort. This finding was reported in subgroups where a higher adherence to the S6 bundle in the after-QIP period was found. After adjustment for confounders, the QIP appeared to be independently associated with a significant improvement in hospital mortality. Among the single S6 procedures applied within the first hour of sepsis diagnosis, compliance with blood culture and antibiotic therapy appeared significantly associated with reduced in-hospital mortality. A multi-faceted QIP aimed at promoting an early simplified bundle of care for the management of septic patients out of the ICU was associated with improved compliance with sepsis bundles and lower in-hospital mortality.

The role of coronary calcification on clinical outcomes among different revascularization strategies in patients presenting with acute coronary syndromes (ACSs) has been rarely investigated. The aim of this investigation is to evaluate the role of coronary calcification, detected by coronary angiography, in the whole spectrum of patients presenting with acute ACS. The present study was a post hoc analysis of the MATRIX programme. The primary endpoint was major adverse cardiovascular events (MACE), defined as the composite of all-cause mortality, myocardial infarction (MI), or stroke up to 365 days. Among the 8404 patients randomized in the MATRIX trial, data about coronary calcification were available in 7446 (88.6%) and therefore were included in this post hoc analysis. Overall, 875 patients (11.7%) presented with severe coronary calcification, while 6571 patients (88.3%) did not present severe coronary calcification on coronary angiography. Fewer patients with severe coronary calcification underwent percutaneous coronary intervention whereas coronary artery bypass grafting or medical therapy-only was more frequent compared with patients without severe calcification. At 1-year follow-up, MACE occurred in 237 (27.1%) patients with severe calcified coronary lesions and 985 (15%) patients without severe coronary calcified lesions [hazard ratio (HR) 1.91; 95% confidence interval (CI) 1.66-2.20, P < 0.001]. All-cause mortality was 8.6% in patients presenting with and 3.7% in those without severe coronary calcification (HR 2.38, 1.84-3.09, P < 0.001). Patients with severe coronary calcification incurred higher rate of MI (20.1% vs. 11.5%, HR 1.81; 95% CI 1.53-2.1, P < 0.001) and similar rate of stroke (0.8% vs. 0.6%, HR 1.35; 95% CI 0.61-3.02, P = 0.46). Patients with ACS and severe coronary calcification, as compared to those without, are associated with worse clinical outcomes irrespective of the management strategy.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have an extremely important impact on the treatment of hormone-sensitive breast cancer (BC) and have radically changed the first-line treatment for metastatic disease with increased rates of treatment response, overall survival (OS), and progression-free survival (PFS). We performed a pooled analysis of randomized trials to validate or refute the hypothesis that there is a significant survival benefit of adding anti-CDK4/6 inhibitors to standard endocrine therapy (ET) in older patients with advanced BC. We selected only English-language phase II/III randomized controlled trials that compared ET alone with ET with anti-CDK4/6 inhibitors in the treatment of advanced BC, with subgroups reporting the outcomes of elderly patients (usually at least 65 years). The primary endpoint was OS. The review process led to the inclusion of 12 articles and two meeting abstracts, including a total of 10 trials. The addition of CDK4/6 inhibitors to ET (letrozole or fulvestrant) significantly reduced mortality risk by 20% in younger patients (fixed-effect model; HR 0.80; 95% CI 0.72-0.9; p<0.01) and 21% in older BC patients (HR 0.79; 95% CI 0.69-0.91; p<0.01). No OS data were available for patients ≥70 years. This large, pooled analysis is the first to demonstrate that CDK4/6 inhibitors confer OS and PFS benefits in elderly patients (those aged ≥65 years) with advanced ER+BC and to indicate that it should be discussed with and offered to all patients after geriatric assessment and according to the toxicity profile.

Low human epidermal growth factor receptor 2 expression (HER2-low: 1+/2+ by immunohistochemistry without HER2 amplification) is emerging as defining a specific breast cancer (BC) subgroup owing to its distinct biological features. However, its prognostic role has not been confirmed in clinical practice. We conducted a systematic review and meta-analysis to determine the prognostic role of HER2-low status in patients with estrogen receptor-positive (ER+) early BC. We searched PubMed, EMBASE, and the Cochrane Library for prospective or retrospective studies that reported data on overall (OS) or disease-free (DFS) survival for HER2-low compared to HER2-negative BC. Data were pooled using hazard ratios (HR) with confidence intervals (CI) for OS/DFS of HER2-low vs. HER2-negative subgroups according to the random-effects model. OS was the primary outcome measure, and DFS and pathological complete response were the secondary endpoints. An analysis was made of 25 studies collected, including 34,965 patients with HER2-low BC. A HER2-low status was associated with an HR for OS of 0.83 (95% CI=0.76-0.9, p<0.0.01). Similarly, a pooled HR of 0.89 (95% CI=0.840.94, p<0.0.01) showed that patients with HER2-low BC had an increased DFS. Pathological complete response was significantly lower in HER2-low BC in 13 studies (OR=0.72, 95% CI=0.58-0.91; p<0.01). Based on these data, HER2-low status should be identified as a potential prognostic factor in early stage ER+ BC. This should be taken into account when considering treatment in (neo)adjuvant settings, and it should be a potential stratification factor in future investigations.

(1) Background: Venous thromboembolism (VTE) is a frequent complication in ambulatory lung cancer patients during chemotherapy and is associated with increased mortality. (2) Methods: We analyzed 568 newly diagnosed metastatic lung cancer patients prospectively enrolled in the HYPERCAN study. Blood samples collected before chemotherapy were tested for thrombin generation (TG) and a panel of hemostatic biomarkers. The Khorana risk score (KRS), new-Vienna CATS, PROTECHT, and CONKO risk assessment models (RAMs) were applied. (3) Results: Within 6 months, the cumulative incidences of VTE and mortality were 12% and 29%, respectively. Patients with VTE showed significantly increased levels of D-dimer, FVIII, prothrombin fragment 1 + 2, and TG. D-dimer and ECOG performance status were identified as independent risk factors for VTE and mortality by multivariable analysis and utilized to generate a risk score that provided a cumulative incidence of VTE of 6% vs. 25%, death of 19% vs. 55%, and in the low- vs. high-risk group, respectively (p < 0.001). While all published RAMs significantly stratified patients for risk of death, only the CATS and CONKO were able to stratify patients for VTE. (4) Conclusions: A new prediction model was generated to stratify lung cancer patients for VTE and mortality risk, where other published RAMs failed.