Azienda Ospedaliera San Gerardo

A concerted effort to tackle the global health problem posed by traumatic brain injury (TBI) is long overdue. TBI is a public health challenge of vast, but insufficiently recognised, proportions. Worldwide, more than 50 million people have a TBI each year, and it is estimated that about half the world's population will have one or more TBIs over their lifetime. TBI is the leading cause of mortality in young adults and a major cause of death and disability across all ages in all countries, with a disproportionate burden of disability and death occurring in low-income and middle-income countries (LMICs). It has been estimated that TBI costs the global economy approximately $US400 billion annually. Deficiencies in prevention, care, and research urgently need to be addressed to reduce the huge burden and societal costs of TBI. This Commission highlights priorities and provides expert recommendations for all stakeholders—policy makers, funders, health-care professionals, researchers, and patient representatives—on clinical and research strategies to reduce this growing public health problem and improve the lives of people with TBI.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

BACKGROUND: Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase. METHODS: A total of 532 patients with late--chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated. RESULTS: Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred. CONCLUSIONS: Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.

BACKGROUND: There are limited data from retrospective studies regarding whether survival outcomes after laparoscopic or robot-assisted radical hysterectomy (minimally invasive surgery) are equivalent to those after open abdominal radical hysterectomy (open surgery) among women with early-stage cervical cancer. METHODS: In this trial involving patients with stage IA1 (lymphovascular invasion), IA2, or IB1 cervical cancer and a histologic subtype of squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma, we randomly assigned patients to undergo minimally invasive surgery or open surgery. The primary outcome was the rate of disease-free survival at 4.5 years, with noninferiority claimed if the lower boundary of the two-sided 95% confidence interval of the between-group difference (minimally invasive surgery minus open surgery) was greater than -7.2 percentage points (i.e., closer to zero). RESULTS: A total of 319 patients were assigned to minimally invasive surgery and 312 to open surgery. Of the patients who were assigned to and underwent minimally invasive surgery, 84.4% underwent laparoscopy and 15.6% robot-assisted surgery. Overall, the mean age of the patients was 46.0 years. Most patients (91.9%) had stage IB1 disease. The two groups were similar with respect to histologic subtypes, the rate of lymphovascular invasion, rates of parametrial and lymph-node involvement, tumor size, tumor grade, and the rate of use of adjuvant therapy. The rate of disease-free survival at 4.5 years was 86.0% with minimally invasive surgery and 96.5% with open surgery, a difference of -10.6 percentage points (95% confidence interval [CI], -16.4 to -4.7). Minimally invasive surgery was associated with a lower rate of disease-free survival than open surgery (3-year rate, 91.2% vs. 97.1%; hazard ratio for disease recurrence or death from cervical cancer, 3.74; 95% CI, 1.63 to 8.58), a difference that remained after adjustment for age, body-mass index, stage of disease, lymphovascular invasion, and lymph-node involvement; minimally invasive surgery was also associated with a lower rate of overall survival (3-year rate, 93.8% vs. 99.0%; hazard ratio for death from any cause, 6.00; 95% CI, 1.77 to 20.30). CONCLUSIONS: In this trial, minimally invasive radical hysterectomy was associated with lower rates of disease-free survival and overall survival than open abdominal radical hysterectomy among women with early-stage cervical cancer. (Funded by the University of Texas M.D. Anderson Cancer Center and Medtronic; LACC ClinicalTrials.gov number, NCT00614211 .).

Importance: Many patients with coronavirus disease 2019 (COVID-19) are critically ill and require care in the intensive care unit (ICU). Objective: To evaluate the independent risk factors associated with mortality of patients with COVID-19 requiring treatment in ICUs in the Lombardy region of Italy. Design, Setting, and Participants: This retrospective, observational cohort study included 3988 consecutive critically ill patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinating center (Fondazione IRCCS [Istituto di Ricovero e Cura a Carattere Scientifico] Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network from February 20 to April 22, 2020. Infection with severe acute respiratory syndrome coronavirus 2 was confirmed by real-time reverse transcriptase-polymerase chain reaction assay of nasopharyngeal swabs. Follow-up was completed on May 30, 2020. Exposures: Baseline characteristics, comorbidities, long-term medications, and ventilatory support at ICU admission. Main Outcomes and Measures: Time to death in days from ICU admission to hospital discharge. The independent risk factors associated with mortality were evaluated with a multivariable Cox proportional hazards regression. Results: Of the 3988 patients included in this cohort study, the median age was 63 (interquartile range [IQR] 56-69) years; 3188 (79.9%; 95% CI, 78.7%-81.1%) were men, and 1998 of 3300 (60.5%; 95% CI, 58.9%-62.2%) had at least 1 comorbidity. At ICU admission, 2929 patients (87.3%; 95% CI, 86.1%-88.4%) required invasive mechanical ventilation (IMV). The median follow-up was 44 (95% CI, 40-47; IQR, 11-69; range, 0-100) days; median time from symptoms onset to ICU admission was 10 (95% CI, 9-10; IQR, 6-14) days; median length of ICU stay was 12 (95% CI, 12-13; IQR, 6-21) days; and median length of IMV was 10 (95% CI, 10-11; IQR, 6-17) days. Cumulative observation time was 164 305 patient-days. Hospital and ICU mortality rates were 12 (95% CI, 11-12) and 27 (95% CI, 26-29) per 1000 patients-days, respectively. In the subgroup of the first 1715 patients, as of May 30, 2020, 865 (50.4%) had been discharged from the ICU, 836 (48.7%) had died in the ICU, and 14 (0.8%) were still in the ICU; overall, 915 patients (53.4%) died in the hospital. Independent risk factors associated with mortality included older age (hazard ratio [HR], 1.75; 95% CI, 1.60-1.92), male sex (HR, 1.57; 95% CI, 1.31-1.88), high fraction of inspired oxygen (Fio2) (HR, 1.14; 95% CI, 1.10-1.19), high positive end-expiratory pressure (HR, 1.04; 95% CI, 1.01-1.06) or low Pao2:Fio2 ratio (HR, 0.80; 95% CI, 0.74-0.87) on ICU admission, and history of chronic obstructive pulmonary disease (HR, 1.68; 95% CI, 1.28-2.19), hypercholesterolemia (HR, 1.25; 95% CI, 1.02-1.52), and type 2 diabetes (HR, 1.18; 95% CI, 1.01-1.39). No medication was independently associated with mortality (angiotensin-converting enzyme inhibitors HR, 1.17; 95% CI, 0.97-1.42; angiotensin receptor blockers HR, 1.05; 95% CI, 0.85-1.29). Conclusions and Relevance: In this retrospective cohort study of critically ill patients admitted to ICUs in Lombardy, Italy, with laboratory-confirmed COVID-19, most patients required IMV. The mortality rate and absolute mortality were high.

BACKGROUND: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. METHODS: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. RESULTS: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which four are best practice statements, nine are strong recommendations, and 35 are weak recommendations. No recommendation was provided for six questions. The topics were: 1) infection control, 2) laboratory diagnosis and specimens, 3) hemodynamic support, 4) ventilatory support, and 5) COVID-19 therapy. CONCLUSION: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new evidence in further releases of these guidelines.

BACKGROUND: In the acute respiratory distress syndrome (ARDS), positive end-expiratory pressure (PEEP) may decrease ventilator-induced lung injury by keeping lung regions open that otherwise would be collapsed. Since the effects of PEEP probably depend on the recruitability of lung tissue, we conducted a study to examine the relationship between the percentage of potentially recruitable lung, as indicated by computed tomography (CT), and the clinical and physiological effects of PEEP. METHODS: Sixty-eight patients with acute lung injury or ARDS underwent whole-lung CT during breath-holding sessions at airway pressures of 5, 15, and 45 cm of water. The percentage of potentially recruitable lung was defined as the proportion of lung tissue in which aeration was restored at airway pressures between 5 and 45 cm of water. RESULTS: The percentage of potentially recruitable lung varied widely in the population, accounting for a mean (+/-SD) of 13+/-11 percent of the lung weight, and was highly correlated with the percentage of lung tissue in which aeration was maintained after the application of PEEP (r2=0.72, P<0.001). On average, 24 percent of the lung could not be recruited. Patients with a higher percentage of potentially recruitable lung (greater than the median value of 9 percent) had greater total lung weights (P<0.001), poorer oxygenation (defined as a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen) (P<0.001) and respiratory-system compliance (P=0.002), higher levels of dead space (P=0.002), and higher rates of death (P=0.02) than patients with a lower percentage of potentially recruitable lung. The combined physiological variables predicted, with a sensitivity of 71 percent and a specificity of 59 percent, whether a patient's proportion of potentially recruitable lung was higher or lower than the median. CONCLUSIONS: In ARDS, the percentage of potentially recruitable lung is extremely variable and is strongly associated with the response to PEEP.

BACKGROUND: Pelvic lymph nodes are the most common site of extrauterine tumor spread in early-stage endometrial cancer, but the clinical impact of lymphadenectomy has not been addressed in randomized studies. We conducted a randomized clinical trial to determine whether the addition of pelvic systematic lymphadenectomy to standard hysterectomy with bilateral salpingo-oophorectomy improves overall and disease-free survival. METHODS: From October 1, 1996, through March 31, 2006, 514 eligible patients with preoperative International Federation of Gynecology and Obstetrics stage I endometrial carcinoma were randomly assigned to undergo pelvic systematic lymphadenectomy (n = 264) or no lymphadenectomy (n = 250). Patients' clinical data, pathological tumor characteristics, and operative and early postoperative data were recorded at discharge from hospital. Late postoperative complications, adjuvant therapy, and follow-up data were collected 6 months after surgery. Survival was analyzed by use of the log-rank test and a Cox multivariable regression analysis. All statistical tests were two-sided. RESULTS: The median number of lymph nodes removed was 30 (interquartile range = 22-42) in the pelvic systematic lymphadenectomy arm and 0 (interquartile range = 0-0) in the no-lymphadenectomy arm (P < .001). Both early and late postoperative complications occurred statistically significantly more frequently in patients who had received pelvic systematic lymphadenectomy (81 patients in the lymphadenectomy arm and 34 patients in the no-lymphadenectomy arm, P = .001). Pelvic systematic lymphadenectomy improved surgical staging as statistically significantly more patients with lymph node metastases were found in the lymphadenectomy arm than in the no-lymphadenectomy arm (13.3% vs 3.2%, difference = 10.1%, 95% confidence interval [CI] = 5.3% to 14.9%, P < .001). At a median follow-up of 49 months, 78 events (ie, recurrence or death) had been observed and 53 patients had died. The unadjusted risks for first event and death were similar between the two arms (hazard ratio [HR] for first event = 1.10, 95% CI = 0.70 to 1.71, P = .68, and HR for death = 1.20, 95% CI = 0.70 to 2.07, P = .50). The 5-year disease-free and overall survival rates in an intention-to-treat analysis were similar between arms (81.0% and 85.9% in the lymphadenectomy arm and 81.7% and 90.0% in the no-lymphadenectomy arm, respectively). CONCLUSION: Although systematic pelvic lymphadenectomy statistically significantly improved surgical staging, it did not improve disease-free or overall survival.

BACKGROUND: Hemodynamic therapy to raise the cardiac index and oxygen delivery to supranormal may improve outcomes in critically ill patients. We studied whether increasing the cardiac index to a supranormal level (cardiac-index group) or increasing mixed venous oxygen saturation to a normal level (oxygen-saturation group) would decrease morbidity and mortality among critically ill patients, as compared with a control group in which the target was a normal cardiac index. METHODS: A total of 10,726 patients in 56 intensive care units were screened, among whom 762 patients belonging to predefined diagnostic categories with acute physiology scores of 11 or higher were randomly assigned to the three groups (252 to the control group, 253 to the cardiac-index group, and 257 to the oxygen-saturation group). RESULTS: The hemodynamic targets were reached by 94.3 percent of the control group, 44.9 percent of the cardiac-index group, and 66.7 percent of the oxygen-saturation group (P < 0.001). Mortality was 48.4, 48.6, and 52.1 percent, respectively (P = 0.638), up to the time of discharge from the intensive care unit and 62.3, 61.7, and 63.8 percent (P = 0.875) at six months. Among patients who survived, the number of dysfunctional organs and the length of the stay in the intensive care unit were similar in the three groups. No differences in mortality among the three groups were found for any diagnostic category. A subgroup analysis of the patients in whom hemodynamic targets were reached revealed similar mortality rates: 44.8, 40.4, and 39.0 percent, respectively (P = 0.478). CONCLUSIONS: Hemodynamic therapy aimed at achieving supranormal values for the cardiac index or normal values for mixed venous oxygen saturation does not reduce morbidity or mortality among critically ill patients.

BACKGROUND: Cardiovascular complications are the most important causes of perioperative morbidity and mortality among patients undergoing major vascular surgery. METHODS: We performed a randomized, multicenter trial to assess the effect of perioperative blockade of beta-adrenergic receptors on the incidence of death from cardiac causes and nonfatal myocardial infarction within 30 days after major vascular surgery in patients at high risk for these events. High-risk patients were identified by the presence of both clinical risk factors and positive results on dobutamine echocardiography. Eligible patients were randomly assigned to receive standard perioperative care or standard care plus perioperative beta-blockade with bisoprolol. RESULTS: A total of 1351 patients were screened, and 846 were found to have one or more cardiac risk factors. Of these 846 patients, 173 had positive results on dobutamine echocardiography. Fifty-nine patients were randomly assigned to receive bisoprolol, and 53 to receive standard care. Fifty-three patients were excluded from randomization because they were already taking a beta-blocker, and eight were excluded because they had extensive wall-motion abnormalities either at rest or during stress testing. Two patients in the bisoprolol group died of cardiac causes (3.4 percent), as compared with nine patients in the standard-care group (17 percent, P=0.02). Nonfatal myocardial infarction occurred in nine patients given standard care only (17 percent) and in none of those given standard care plus bisoprolol (P<0.001). Thus, the primary study end point of death from cardiac causes or nonfatal myocardial infarction occurred in 2 patients in the bisoprolol group (3.4 percent) and 18 patients in the standard-care group (34 percent, P<0.001). CONCLUSIONS: Bisoprolol reduces the perioperative incidence of death from cardiac causes and nonfatal myocardial infarction in high-risk patients who are undergoing major vascular surgery.

BACKGROUND: Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established. METHODS: In this multicenter, open-label trial, we randomly assigned 1818 patients with severe sepsis, in 100 intensive care units (ICUs), to receive either 20% albumin and crystalloid solution or crystalloid solution alone. In the albumin group, the target serum albumin concentration was 30 g per liter or more until discharge from the ICU or 28 days after randomization. The primary outcome was death from any cause at 28 days. Secondary outcomes were death from any cause at 90 days, the number of patients with organ dysfunction and the degree of dysfunction, and length of stay in the ICU and the hospital. RESULTS: During the first 7 days, patients in the albumin group, as compared with those in the crystalloid group, had a higher mean arterial pressure (P=0.03) and lower net fluid balance (P<0.001). The total daily amount of administered fluid did not differ significantly between the two groups (P=0.10). At 28 days, 285 of 895 patients (31.8%) in the albumin group and 288 of 900 (32.0%) in the crystalloid group had died (relative risk in the albumin group, 1.00; 95% confidence interval [CI], 0.87 to 1.14; P=0.94). At 90 days, 365 of 888 patients (41.1%) in the albumin group and 389 of 893 (43.6%) in the crystalloid group had died (relative risk, 0.94; 95% CI, 0.85 to 1.05; P=0.29). No significant differences in other secondary outcomes were observed between the two groups. CONCLUSIONS: In patients with severe sepsis, albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve the rate of survival at 28 and 90 days. (Funded by the Italian Medicines Agency; ALBIOS ClinicalTrials.gov number, NCT00707122.).

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

AIMS: The 2019 report from the European Society of Cardiology (ESC) Atlas provides a contemporary analysis of cardiovascular disease (CVD) statistics across 56 member countries, with particular emphasis on international inequalities in disease burden and healthcare delivery together with estimates of progress towards meeting 2025 World Health Organization (WHO) non-communicable disease targets. METHODS AND RESULTS: In this report, contemporary CVD statistics are presented for member countries of the ESC. The statistics are drawn from the ESC Atlas which is a repository of CVD data from a variety of sources including the WHO, the Institute for Health Metrics and Evaluation, and the World Bank. The Atlas also includes novel ESC sponsored data on human and capital infrastructure and cardiovascular healthcare delivery obtained by annual survey of the national societies of ESC member countries. Across ESC member countries, the prevalence of obesity (body mass index ≥30 kg/m2) and diabetes has increased two- to three-fold during the last 30 years making the WHO 2025 target to halt rises in these risk factors unlikely to be achieved. More encouraging have been variable declines in hypertension, smoking, and alcohol consumption but on current trends only the reduction in smoking from 28% to 21% during the last 20 years appears sufficient for the WHO target to be achieved. The median age-standardized prevalence of major risk factors was higher in middle-income compared with high-income ESC member countries for hypertension {23.8% [interquartile range (IQR) 22.5-23.1%] vs. 15.7% (IQR 14.5-21.1%)}, diabetes [7.7% (IQR 7.1-10.1%) vs. 5.6% (IQR 4.8-7.0%)], and among males smoking [43.8% (IQR 37.4-48.0%) vs. 26.0% (IQR 20.9-31.7%)] although among females smoking was less common in middle-income countries [8.7% (IQR 3.0-10.8) vs. 16.7% (IQR 13.9-19.7%)]. There were associated inequalities in disease burden with disability-adjusted life years per 100 000 people due to CVD over three times as high in middle-income [7160 (IQR 5655-8115)] compared with high-income [2235 (IQR 1896-3602)] countries. Cardiovascular disease mortality was also higher in middle-income countries where it accounted for a greater proportion of potential years of life lost compared with high-income countries in both females (43% vs. 28%) and males (39% vs. 28%). Despite the inequalities in disease burden across ESC member countries, survey data from the National Cardiac Societies of the ESC showed that middle-income member countries remain severely under-resourced compared with high-income countries in terms of cardiological person-power and technological infrastructure. Under-resourcing in middle-income countries is associated with a severe procedural deficit compared with high-income countries in terms of coronary intervention, device implantation and cardiac surgical procedures. CONCLUSION: A seemingly inexorable rise in the prevalence of obesity and diabetes currently provides the greatest challenge to achieving further reductions in CVD burden across ESC member countries. Additional challenges are provided by inequalities in disease burden that now require intensification of policy initiatives in order to reduce population risk and prioritize cardiovascular healthcare delivery, particularly in the middle-income countries of the ESC where need is greatest.

OBJECTIVES: Diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP/ES) can be associated with unforeseeable complications, especially when involving postprocedural pancreatitis. The aim of the study was to investigate risk factors for complications of ERCP/ES in a prospective multicentric study. METHODS: One hundred fifty variables were prospectively collected at time of ERCP/ES and before hospital discharge over 2 years, in consecutive patients undergoing the procedure in nine endoscopic units in the Lombardy region of Italy. More than 150 ERCPs were performed in each center per year by a single operator or by a team of no more than three endoscopists. RESULTS: Two thousand four hundred sixty-two procedures were performed; 18 patients were discharged because the papilla of Vater was not reached (duodenal obstruction, previous gastrectomy, etc.). Two thousand four hundred forty-four procedures were considered in 2103 patients. Overall complications occurred in 121 patients (4.95% of cases): pancreatitis in 44 patients (1.8%), hemorrhage in 30 (1.13%), cholangitis in 14 (0.57%), perforation during ES in 14 (0.57%), and others in 14 (0.57%); deaths occurred in three patients (0.12%). In multivariate analysis, the following were significant risk factors: a) for pancreatitis, age (< or = 60 yr), use of precutting technique, and failed clearing of biliary stones, and b) for hemorrhage, precut sphincterotomy and obstruction of the orifice of the papilla of Vater. CONCLUSIONS: The results of our study further contribute to the assessment of risk factors for complications related to ERCP/ES. It is crucial to identify high risk patients to reduce complications of the procedures.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is the most common cause of rapidly progressive glomerulonephritis worldwide, and the renal biopsy is the gold standard for establishing the diagnosis. Although the prognostic value of the renal biopsy in ANCA-associated glomerulonephritis is widely recognized, there is no consensus regarding its pathologic classification. We present here such a pathologic classification developed by an international working group of renal pathologists. Our classification proposes four general categories of lesions: Focal, crescentic, mixed, and sclerotic. To determine whether these lesions have predictive value for renal outcome, we performed a validation study on 100 biopsies from patients with clinically and histologically confirmed ANCA-associated glomerulonephritis. Two independent pathologists, blinded to patient data, scored all biopsies according to a standardized protocol. Results show that the proposed classification system is of prognostic value for 1- and 5-year renal outcomes. We believe this pathologic classification will aid in the prognostication of patients at the time of diagnosis and facilitate uniform reporting between centers. This classification at some point might also provide means to guide therapy.

BACKGROUND: Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical trial. METHODS: We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed. RESULTS: After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events. CONCLUSIONS: In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007-006694-91.).

BACKGROUND: This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. METHODS: We randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. RESULTS: The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P<0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P=0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P=0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively). CONCLUSIONS: Consolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00551928.).

BACKGROUND: Although the value of primary cytoreductive surgery for epithelial ovarian cancer is beyond doubt, the value of debulking surgery after induction chemotherapy has not yet been defined. In this randomized study we investigated the effect on survival of debulking surgery. METHODS: Eligible patients had residual lesions measuring more than 1 cm in diameter after primary surgery. After three cycles of cyclophosphamide and cisplatin, these patients were randomly assigned to undergo either debulking surgery or no surgery, followed by further cycles of cyclophosphamide and cisplatin. The study end points were progression-free and overall survival. At surgery 65 percent of the patients had lesions measuring more than 1 cm. In 45 percent of this group, the lesions were reduced surgically to less than 1 cm. RESULTS: Of the 319 patients who underwent randomization, 278 could be evaluated (140 patients who underwent surgery and 138 patients who did not). Progression-free and overall survival were both significantly longer in the group that underwent surgery (P = 0.01). The difference in median survival was six months. The survival rate at two years was 56 percent for the group that underwent surgery and 46 percent for the group that did not. In the multivariate analysis, debulking surgery was an independent prognostic factor (P = 0.012). Overall, after adjustment for all other prognostic factors, surgery reduced the risk of death by 33 percent (95 percent confidence interval, 10 to 50 percent; P = 0.008). Surgery was not associated with death or severe morbidity. CONCLUSIONS: Debulking surgery significantly lengthened progression-free and overall survival. The risk of death was reduced by one third, after adjustment for a variety of prognostic factors.

Tumor-infiltrating regulatory T lymphocytes (Treg) can suppress effector T cells specific for tumor antigens. Deeper molecular definitions of tumor-infiltrating-lymphocytes could thus offer therapeutic opportunities. Transcriptomes of T helper 1 (Th1), Th17, and Treg cells infiltrating colorectal or non-small-cell lung cancers were compared to transcriptomes of the same subsets from normal tissues and validated at the single-cell level. We found that tumor-infiltrating Treg cells were highly suppressive, upregulated several immune-checkpoints, and expressed on the cell surfaces specific signature molecules such as interleukin-1 receptor 2 (IL1R2), programmed death (PD)-1 Ligand1, PD-1 Ligand2, and CCR8 chemokine, which were not previously described on Treg cells. Remarkably, high expression in whole-tumor samples of Treg cell signature genes, such as LAYN, MAGEH1, or CCR8, correlated with poor prognosis. Our findings provide insights into the molecular identity and functions of human tumor-infiltrating Treg cells and define potential targets for tumor immunotherapy.

PURPOSE Patients with pretreated estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. METHODS This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations. RESULTS Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). CONCLUSION Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.