Sentinel lymph node biopsy before and after neoadjuvant chemotherapy in cN0 breast cancer patients: impact on axillary morbidity and survival-a propensity score cohort study.

PURPOSE: In patients with clinically lymph node-negative (cN0) breast cancer, performing sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NACT) has been preferentially embraced in comparison to before NACT. However, survival outcomes associated with both strategies remain understudied. We aimed to compare the axillary lymphadenectomy (ALND) rate, disease-free survival (DFS), and overall survival (OS), between two strategies. METHODS: We included 310 patients in a retrospective observational study. SNLB was performed before NACT from December 2006 to April 2014 (107 cases) and after NACT from May 2014 to May 2020 (203 patients). An inverse probability of treatment weighting (IPTW) method was applied to homogenize both groups. Hazard ratios (HR) and odd ratios (OR) are reported with 95% confidence intervals (95%CI). RESULTS: The lymphadenectomy rate was 29.9% before NACT and 7.4% after NACT (p < 0.001), with an OR of 5.35 95%CI (2.7-10.4); p = .002. After 4 years of follow-up, SLNB after NACT was associated with lower risk for DFS, HR 0.42 95%CI (0.17-1.06); p = 0.066 and better OS, HR 0.21 CI 95% (0.07-0.67); p = 0.009 than SLNB before NACT. After multivariate analysis, independent adverse prognostic factors for OS included SLNB before NACT, HR 3.095 95%CI (2.323-4.123), clinical nonresponse to NACT, HR 1.702 95% CI (1.012-2.861), and small tumors (cT1) with high proliferation index, HR 1.889 95% (1.195-2.985). CONCLUSION: Performing SLNB before NACT results in more ALND and has no benefit for patient survival. These findings support discontinuing the practice of SLNB before NACT in patients with cN0 breast cancer.

Axillary lymph node dissection versus radiotherapy in breast cancer with positive sentinel nodes after neoadjuvant therapy (ADARNAT trial).

Introduction: Breast cancer surgery currently focuses on de-escalating treatment without compromising patient survival. Axillary radiotherapy (ART) now replaces axillary lymph node dissection (ALND) in patients with limited sentinel lymph node (SLN) involvement during the primary surgery, and this has significantly reduced the incidence of lymphedema without worsening the prognosis. However, patients treated with neoadjuvant systemic treatment (NST) cannot benefit from this option despite the low incidence of residual disease in the armpit in most cases. Data regarding the use of radiotherapy instead of ALND in this population are lacking. This study will assess whether ART is non-inferior to ALND in terms of recurrence and overall survival in patients with positive SLN after NST, including whether it reduces surgery-related adverse effects. Methods and analyses: This multicenter, randomized, open-label, phase 3 trial will enroll 1660 patients with breast cancer and positive SLNs following NST in approximately 50 Spanish centers over 3 years. Patients will be stratified by NST regimen and nodal involvement (isolated tumoral cells or micrometastasis versus macrometastasis) and randomly assigned 1:1 to ART without ALND (study arm) or ALND alone (control arm). Level 3 and supraclavicular radiotherapy will be added in both arms. The primary outcome is the 5-year axillary recurrence determined by clinical and radiological examination. The secondary outcomes include lymphedema or arm dysfunction, quality of life based (EORTC QLQ-C30 and QLQ-BR23 questionnaires), disease-free survival, and overall survival. Discussion: This study aims to provide data to confirm the efficacy and safety of ART over ALND in patients with a positive SLN after NST, together with the impact on morbidity. Ethics and dissemination: The Research Ethics Committee of Bellvitge University Hospital approved this trial (Protocol Record PR148/21, version 3, 1/2/2022) and all patients must provide written informed consent. The involvement of around 50 centers across Spain will facilitate the dissemination of our results. Trial registration: ClinicalTrials.gov, identifier number NCT04889924.

Observational study on fluid therapy management in surgical adult patients.

BACKGROUND: Perioperative fluid therapy management is changing due to the incorporation of different fluids, surgical techniques, and minimally invasive monitoring systems. The objective of this study was to explore fluid therapy management during the perioperative period in our country. METHODS: We designed the Fluid Day study as a cross-sectional, multicentre, observational study. The study was performed in 131 Spanish hospitals in February 2019. We included adult patients undergoing general anaesthesia for either elective or non-elective surgery. Demographic variables were recorded, as well as the type and total volume of fluid administered during the perioperative period and the monitorization used. To perform the analysis, patients were categorized by risk group. RESULTS: We recruited 7291 patients, 6314 of which were included in the analysis; 1541 (24.4%) patients underwent high-risk surgery, 1497 (23. 7%) were high risk patients, and 554 (8.7%) were high-risk patients and underwent high-risk surgery; 98% patients received crystalloids (80% balanced solutions); intraoperative colloids were used in 466 patients (7.51%). The hourly intraoperative volume in mL/kg/h and the median [Q1; Q3] administered volume (mL/kg) were, respectively, 6.67 [3.83; 8.17] ml/Kg/h and 13.9 [9.52;5.20] ml/Kg in low-risk patients undergoing low- or intermediate-risk surgery, 6 [4.04; 9.08] ml/Kg/h and 15.7 [10.4;24.5] ml/Kg in high- risk patients undergoing low or intermediate-risk surgery, 6.41 [4.36; 9.33] ml/Kg/h and 20.2 [13.3;32.4] ml/Kg in low-risk patients undergoing high-risk surgery, and 5.46 [3.83; 8.17] ml/Kg/h and 22.7[14.1;40.9] ml/Kg in high-risk patients undergoing high- risk surgery . We used advanced fluid monitoring strategies in 5% of patients in the intraoperative period and in 10% in the postoperative period. CONCLUSIONS: The most widely used fluid was balanced crystalloids. Colloids were used in a small number of patients. Hourly surgery volume tended to be more restrictive in high-risk patients but confirms a high degree of variation in the perioperatively administered volume. Scarce monitorization was observed in fluid therapy management. TRIAL REGISTRATION: Clinical Trials: NCT03630744.

NECPAL prognostic tool: a palliative medicine retrospective cohort study.

OBJECTIVE: To develop and validate a prognostic model to assess mortality risk at 24 months in patients with advanced chronic conditions. METHODS: Retrospective design based on a previous population cohort study with 789 adults who were identified with the surprise question and NECPAL tool from primary and intermediate care centres, nursing homes and one acute hospital of Spain. A Cox regression model was used to derive a mortality predictive model based on patients' age and six previously selected NECPAL prognostic factors (palliative care need identified by healthcare professionals, functional decline, nutritional decline, multimorbidity, use of resources, disease-specific criteria of severity/progression). Patients were split into derivation/validation cohorts, and four steps were followed: descriptive analysis, predictors' assessment, model estimation and model assessment. RESULTS: All predictive variables were independently associated with increased risk of mortality at 24 months. Performance model including age was good; discrimination power by area under the curve (AUC) was 0.72/0.67 in the derivation/validation cohorts, and correlation between expected and observed (E/O) mortality ratio was 0.74/0.70. The model showed similar performance across settings (AUC 0.65-0.74, E/O 1.00-1.01), the best performance in oncological patients (AUC 0.78, E/O 0.76) and the worst in dementia patients (AUC 0.58, E/O 0.85). Based on the number of factors affected, three prognostic stages with significant differences and a median survival of 38, 17.2 and 3.6 months (p<0.001) were defined. CONCLUSION: The NECPAL prognostic tool is accurate and eventually useful at the clinical practice. Stratification in risk groups may enable early intervention and enhance policy-making and service planning.

Assessment of ovarian reserve and reproductive outcomes in BRCA1 or BRCA2 mutation carriers.

INTRODUCTION: The clinical impact on fertility in carriers of BRCA1 and BRCA2 mutations remains unclear. The aim of this study was to assess ovarian reserve as measured by anti-mullerian hormone levels in BRCA1 or BRCA2 mutation carriers, as well as to investigate the impact of anti-mullerian hormone levels on reproductive outcomes. METHODS: The study involved a cohort of women who tested positive for BRCA1 and BRCA2 screening or were tested for a BRCA1 or BRCA2 family mutation. Blood samples were collected for anti-mullerian hormone analysis and the reproductive outcomes were analyzed after a mean follow-up of 9 years. Participants were classified into BRCA mutation-positive versus BRCA mutation-negative. Controls were healthy relatives who tested negative for the family mutation. All patients were contacted by telephone to collect data on reproductive outcomes. Linear regression was used to predict anti-mullerian hormone levels by BRCA status adjusted for a polynomial form of age. RESULTS: Results of anti-mullerian hormone analysis and reproductive outcomes were available for 135 women (BRCA mutation-negative, n=66; BRCA1 mutation-positive, n=32; BRCA2 mutation-positive, n=37). Anti-mullerian hormone curves according to BRCA status and adjusted by age showed that BRCA2 mutation-positive patients have lower levels of anti-mullerian hormone as compared with BRCA-negative and BRCA1 mutation-positive. Among the women who tried to conceive, infertility was observed in 18.7% of BRCA mutation-negative women, in 22.2% of BRCA1 mutation-positive women, and in 30.8% of BRCA2 mutation-positive women (p=0.499). In the multivariable analysis, there were no factors independently associated with infertility. DISCUSSION: BRCA2 mutation-positive carriers showed more diminished anti-mullerian hormone levels than BRCA1 mutation-positive and BRCA mutation-negative women. However, these differences do not appear to have a negative impact on reproductive outcome. This is important to consider at the time of reproductive counseling in women with BRCA1 or BRCA2 mutations.

Prognostic Factors and Decision Tree for Long-Term Survival in Metastatic Uveal Melanoma.

PURPOSE: The purpose of this study was to demonstrate the existence of a bimodal survival pattern in metastatic uveal melanoma. Secondary aims were to identify the characteristics and prognostic factors associated with long-term survival and to develop a clinical decision tree. MATERIALS AND METHODS: The medical records of 99 metastatic uveal melanoma patients were retrospectively reviewed. Patients were classified as either short (≤ 12 months) or long-term survivors (> 12 months) based on a graphical interpretation of the survival curve after diagnosis of the first metastatic lesion. Ophthalmic and oncological characteristicswere assessed in both groups. RESULTS: Of the 99 patients, 62 (62.6%) were classified as short-term survivors, and 37 (37.4%) as long-term survivors. The multivariate analysis identified the following predictors of long-term survival: age ≤ 65 years (p=0.012) and unaltered serum lactate dehydrogenase levels (p=0.018); additionally, the size (smaller vs. larger) of the largest liver metastasis showed a trend towards significance (p=0.063). Based on the variables significantly associated with long-term survival, we developed a decision tree to facilitate clinical decision-making. CONCLUSION: The findings of this study demonstrate the existence of a bimodal survival pattern in patients with metastatic uveal melanoma. The presence of certain clinical characteristics at diagnosis of distant disease is associated with long-term survival. A decision tree was developed to facilitate clinical decision-making and to counsel patients about the expected course of disease.

Multimarker Strategy for Heart Failure Prognostication. Value of Neurohormonal Biomarkers: Neprilysin vs NT-proBNP.

INTRODUCTION AND OBJECTIVES: Neprilysin breaks down numerous vasoactive peptides. The soluble form of neprilysin, which was recently identified in heart failure, is associated with cardiovascular outcomes. Within a multibiomarker strategy, we directly compared soluble neprilysin and N-terminal pro-B-type natriuretic peptide as risk stratifiers in a real-life cohort of heart failure patients. METHODS: Soluble neprilysin, N-terminal pro-B-type natriuretic peptide, ST2, and high-sensitivity troponin T levels were measured in 797 consecutive ambulatory heart failure patients followed up for 4.7 years. Comprehensive multivariable analyses and soluble neprilysin vs N-terminal pro-B-type natriuretic peptide head-to-head assessments of performance were performed. A primary composite endpoint included cardiovascular death or heart failure hospitalization. A secondary endpoint explored cardiovascular death alone. RESULTS: Median soluble neprilysin and N-terminal pro-B-type natriuretic peptide concentrations were 0.64ng/mL and 1187 ng/L, respectively. Both biomarkers significantly correlated with age (P<.001) and ST2 (P<.001), but only N-terminal pro-B-type natriuretic peptide significantly correlated with estimated glomerular filtration rate (P<.001), body mass index (P<.001), left ventricular ejection fraction (P=.02) and high-sensitivity troponin T (P<.001). In multivariable Cox regression analyses, soluble neprilysin remained independently associated with the composite endpoint (hazard ratio=1.14; 95% confidence interval, 1.02-1.27; P=.03) and cardiovascular death (hazard ratio=1.15; 95% confidence interval, 1.01-1.31; P=.04), but N-terminal pro-B-type natriuretic peptide did not. The head-to-head soluble neprilysin vs N-terminal pro-B-type natriuretic peptide comparison showed good calibration and similar discrimination and reclassification for both neurohormonal biomarkers, but only soluble neprilysin improved overall goodness-of-fit. CONCLUSIONS: When added to a multimarker strategy, soluble neprilysin remained an independent prognosticator, while N-terminal pro-B-type natriuretic peptide lost significance as a risk stratifier in ambulatory patients with heart failure. Both biomarkers performed similarly in head-to-head analyses.

Long-term prognostic value for patients with chronic heart failure of estimated glomerular filtration rate calculated with the new CKD-EPI equations containing cystatin C.

BACKGROUND: Correct estimation of renal function is crucial in assessing prognosis of patients with heart failure (HF). Recently, two new equations have been proposed to calculate estimated glomerular filtration rate (eGFR) with cystatin C alone or both creatinine and cystatin C. We assessed the prognostic value of eGFR estimated by these new equations in outpatients with HF. METHODS: The study included 879 patients with median age, 70.4 years; main etiology of HF ischemic heart disease, 52.7%; and median LVEF, 34%. RESULTS: eGFR estimates by the new equations correlated significantly with eGFR estimates from previous equations, with the best correlation observed between the 2 equations containing cystatin C [intraclass correlation coefficient 0.95 (95% confidence interval 0.94-0.95)]. During a median follow-up of 3.94 years, 371 patients died. The Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations containing cystatin C were found to be best for predicting death [area under the ROC curve 0.685 for CKD-EPI-cystatin C and 0.672 for CKD-EPI-creatinine-cystatin C vs 0.632 for simplified Modification of Diet in Renal Disease Study traceable to isotope dilution mass spectrometry and 0.643 for CKD-EPI (all P < 0.001)]. The CKD-EPI-cystatin C equations also showed significantly better calibration and reclassification measurements for both integrated discrimination improvement and net reclassification improvement in predicting death (P < 0.001). Reclassification with these new equations was particularly better in the subgroup with intermediate eGFR [45-74 mL · min(-1) · (1.73 m(2))(-1)]. CONCLUSIONS: The two new CKD-EPI equations containing cystatin C are useful for HF risk stratification and show better prognostic performance than creatinine-only based eGFR equations, mostly in patients with intermediate eGFR. These equations seem appropriate for assessing prognosis of HF patients with moderate renal insufficiency.