Breast cancer screening program for risk groups: facts and perspectives

ABSTRACT Objectives: to measure the frequency and compliance of breast cancer screening, according to the risk for this disease. Methods: a cross-sectional study with 950 female users of 38 public Primary Health Care services in São Paulo, between October and December 2013. According to UHS criteria, participants were grouped into high risk and standard risk, and frequency, association (p≤0.05), and screening compliance were measured. Results: 6.7% had high risk and 93.3% standard risk, respectively; in these groups, the frequency and compliance of clinical breast examination were 40.3% and 37.1%, and 43.5% and 43.0% (frequency p=0.631, compliance p=0.290). Mammograms were 67.7% and 35.5% for participants at high risk, and 57.4% and 25.4% for those at standard risk (frequency p=0.090, compliance p=0.000). Conclusions: in the groups, attendance and conformity of the clinical breast exam were similar; for mammography, it was higher in those at high risk, with assertiveness lower than the 70% set in UHS.

Tranexamic Acid for Acute Spontaneous Intracerebral Hemorrhage: A Meta-Analysis of Randomized Controlled Trials

Background: The role of tranexamic acid (TXA) in preventing hematoma expansion (HE) in patients with acute spontaneous intracerebral hemorrhage (ICH) remains unclear. We aim to investigate the efficacy and safety of TXA in acute spontaneous ICH with a particular focus on subgroups.Methods: Randomized controlled trials (RCTs) were retrieved from CENTRAL, Clinicaltrials.gov, EMBASE, PubMed, and WHO ICTRP. The primary outcome measurement was HE. The secondary outcome measurements included 3-month poor functional outcome (PFO), 3-month mortality, and major thromboembolic events (MTE). We conducted subgroup analysis according to the CT markers of HE (standard-risk population and high-risk population) and the time from onset to randomization (>4.5 and ≤4.5 h).Results: We identified seven studies (representing five RCTs) involving 2,650 participants. Compared with placebo, TXA may reduce HE on subsequent imaging (odd ratio [OR] 0.825; 95% confidence interval [CI] 0.692–0.984; p = 0.033; I2 = 0%; GRADE: moderate certainty). TXA and placebo arms did not differ in the rates of 3-month PFO, 3-month mortality, and MTE. Subgroup analysis indicated that TXA reduced the risk of HE in the high-risk population with CT markers of HE (OR 0.646; 95% CI 0.503–0.829; p = 0.001; I2 = 0 %) and in patients who were treated within 4.5 h of symptom onset (OR 0.823; 95% CI 0.690–0.980; p = 0.029; I2 = 0%), but this protective effect was not observed in the standard-risk population and patients who were treated over 4.5 h of symptom onset.Conclusions: Tranexamic acid (TXA) may decrease the risk of HE in patients with acute spontaneous ICH. Importantly, the decreased risk was observed in patients who were treatable within 4.5 h and with a high risk of HE, but not in those who were treatable over 4.5 h and in standard-risk population. However, PFO or mortality at 3 months did not significantly differ between patients who received TXA and those who received placebo. TXA is safe for acute spontaneous ICH without increasing MTE.

Living Donor Kidney Transplantation in Patients With Donor-Specific HLA Antibodies After Desensitization With Immunoadsorption

Due to the current organ shortage, living donor kidney transplantation is increasingly performed across HLA (human leukocyte antigen) or ABO antibody barriers. There is still uncertainty about the risk of antibody-mediated rejection (AMR) episodes, which may limit long-term graft survival. From March 2007 to December 2016, 58 sensitized living donor kidney transplant candidates were identified and 38 patients eventually included in the study: 36 patients (95%) had pre-transplant and pre-desensitization Luminex-detected donor-specific HLA antibodies (DSA), and 17/36 patients (47%) in addition had a positive crossmatch result. Two patients had no detectable DSA but a positive CDC B-cell crossmatch result. Patients were treated with pre- and post-transplant apheresis and powerful immunosuppression including the anti-CD20 antibody rituximab (N = 36) in combination with thymoglobulin (N = 20) or anti-IL2 receptor antibody (N = 18). The results of the 38 successfully desensitized and transplanted patients were retrospectively compared to the results of 76 matched standard-risk recipients. Desensitized patients showed patient and graft survival rates similar to that of standard-risk recipients (P = 0.55 and P = 0.16, respectively). There was a trend toward reduced death-censored graft survival in desensitized patients (P = 0.053) which, however, disappeared when the 34 patients who were transplanted after introduction of sensitive Luminex testing were analyzed (P = 0.43). The incidence of rejection episodes without borderline changes were in desensitized patients with 21% similar to the 18% in standard-risk patients (P = 0.74). Thirty-six patients had pre-transplant HLA class I and/or II DSA that were reduced by 85 and 81%, respectively, during pre-transplant desensitization (P < 0.001 for both). On day 360 after transplantation, 20 of 36 (56%) patients had lost their DSA. The overall AMR rate was 6% in these patients, but as high as 60% in 5 (14%) patients with persistent and de novo DSA during year 1; 2 (40%) of whom lost their graft due to AMR. Eleven (31%) patients with persistent DSA but without de novo DSA had an AMR rate of 18% without graft loss while one patient lost her graft without signs of AMR. Our desensitization protocol for pre-sensitized living donor kidney transplant recipients with DSA resulted in good graft outcomes with side effects and rejection rates similar to that of standard-risk recipients. Adequate patient selection prior to transplantation and frequent immunological monitoring thereafter is critical to minimize rejection episodes and subsequent graft loss.

SIOP PNET5 MB Trial: History and Concept of a Molecularly Stratified Clinical Trial of Risk-Adapted Therapies for Standard-Risk Medulloblastoma

Background. SIOP PNET5 MB was initiated in 2014 as the first European trial using clinical, histological, and molecular parameters to stratify treatments for children and adolescents with standard-risk medulloblastoma. Methods. Stratification by upfront assessment of molecular parameters requires the timely submission of adequate tumour tissue. In the standard-risk phase-III cohort, defined by the absence of high-risk criteria (M0, R0), pathological (non-LCA), and molecular biomarkers (MYCN amplification in SHH–MB or MYC amplification), a randomized intensification by carboplatin concomitant with radiotherapy is investigated. In the LR stratum for localized WNT-activated medulloblastoma and age <16 years, a reduction of craniospinal radiotherapy dose to 18 Gy and a reduced maintenance chemotherapy are investigated. Two additional strata (WNT-HR, SHH-TP53) were implemented during the trial. Results. SIOP PNET5 MB is actively recruiting. The availability of adequate tumour tissue for upfront real-time biological assessments to assess inclusion criteria has proven feasible. Conclusion. SIOP PNET5 MB has demonstrated that implementation of biological parameters for stratification is feasible in a prospective multicentre setting, and may improve risk-adapted treatment. Comprehensive research studies may allow assessment of additional parameters, e.g., novel medulloblastoma subtypes, and identification and validation of biomarkers for the further refinement of risk-adapted treatment in the future.

Radiotherapy in Medulloblastoma—Evolution of Treatment, Current Concepts and Future Perspectives

Medulloblastoma is the most frequent malignant brain tumor in children. During the last decades, the therapeutic landscape has changed significantly with craniospinal irradiation as the backbone of treatment. Survival times have increased and treatments were stratified according to clinical and later molecular risk factors. In this review, current evidence regarding the efficacy and toxicity of radiotherapy in medulloblastoma is summarized and discussed mainly based on data of controlled trials. Current concepts and future perspectives based on current risk classification are outlined. With the introduction of CSI, medulloblastoma has become a curable disease. Due to combination with chemotherapy, survival rates have increased significantly, allowing for a reduction in radiation dose and a decrease of toxicity in low- and standard-risk patients. Furthermore, modern radiotherapy techniques are able to avoid side effects in a fragile patient population. However, high-risk patients remain with relevant mortality and many patients still suffer from treatment related toxicity. Treatment needs to be continually refined with regard to more efficacious combinatorial treatment in the future.

DNA Methylation scores augment 10-year risk prediction of diabetes

Type 2 diabetes mellitus (T2D) is one of the most prevalent diseases in the world and presents a major health and economic burden, a notable proportion of which could be alleviated with improved early prediction and intervention. While standard risk factors including age, obesity, and hypertension have shown good predictive performance, we show that the use of CpG DNA methylation information leads to a significant improvement in the prediction of 10-year T2D incidence risk. Whilst previous studies have been largely constrained by linear assumptions and the use of CpGs one-at-the-time, we have adopted a more flexible approach based on a range of linear and tree-ensemble models for classification and time-to-event prediction. Using the Generation Scotland cohort (n=9,537) our best performing model (Area Under the Curve (AUC)=0.880, Precision Recall AUC (PRAUC)=0.539, McFadden's R2=0.316) used a LASSO Cox proportional-hazards predictor and showed notable improvement in onset prediction, above and beyond standard risk factors (AUC=0.860, PRAUC=0.444 R2=0.261). Replication of the main finding was observed in an external test dataset (the German-based KORA study, p=3.7x10-4). Tree-ensemble methods provided comparable performance and future improvements to these models are discussed. Finally, we introduce MethylPipeR, an R package with accompanying user interface, for systematic and reproducible development of complex trait and incident disease predictors. While MethylPipeR was applied to incident T2D prediction with DNA methylation in our experiments, the package is designed for generalised development of predictive models and is applicable to a wide range of omics data and target traits.

Real World Assessment of Treatment Patterns and Outcomes Among Multiple Myeloma Patients across Different Risk Stratification Criteria in the United States: A Retrospective Cohort Study

Background: Despite the development of highly active novel agents, high risk (HR) multiple myeloma (MM) patients continue to demonstrate relatively poor prognosis. Limited data is published on how treatment patterns with risk stratification systems have changed over time. Moreover, real world studies using electronic health records (EHRs) have not evaluated the performance of risk stratification systems with real world outcomes. This study aims to evaluate the ability to implement three different risk stratification systems - international staging system (ISS), revised ISS (R-ISS), and high-risk chromosomal abnormalities (HRCA, defined as presence of del(17)p, t(4;14) and/or t(4;16)) [Palumbo et al. 2015] - to characterize treatment patterns and associated outcomes [real world overall survival (rwOS) and real world progression free survival (rwPFS)] among newly diagnosed MM (NDMM) patients in the US community practice. Methods: This study used Flatiron Enhanced MM EHR de-identified database (New York, NY). Newly diagnosed MM patients (≥ 18 years) were diagnosed from January 2015 through June 2020 (cohort 1 - for studying treatment distribution) with follow-up through December 2020, and from January 2015 through December 2018 (cohort 2 - for rwOS and rwPFS), with follow-up through December 2020. Patients with malignancies other than MM were excluded. Proportion of rwOS was measured from treatment initiation until death, and median rwPFS was measured from treatment initiation until death, progression, or start of new line of therapy using Kaplan-Meier method. Results: A total of 1,979 and 1,382 patients were eligible in cohorts 1 and 2, respectively. In both the cohorts, approximately 18% (cohort 1: N=367, cohort 2: N=248), 41% (cohort 1: N=805, cohort 2: N=566), and 37% (cohort 1: N=738, cohort 2: N=508) were HR patients according to the R-ISS, ISS, and HRCA criteria, respectively. Approximately half of the HR patients were ≥70 years old (52% for R-ISS III and ISS III, and 47% for HRCA), with chronic kidney disease stage ≥3 by eGFR for 54% R-ISS III and ISS III, and 34% high risk CA, and ECOG score ≥2 for 18% R-ISS III, 19% ISS III, and 14% HRCA patients. Triplets were the most frequent treatment regimens (62% for R-ISS III and II, and 66% for R-ISS I; 59% for ISS III, and 65% for ISS II and I; 65% for HRCA and 61% for standard risk CA(SRCA) with proteasome inhibitors (PIs) / immunomodulatory agents (IMiDs) / dexamethasone being most common regimen across all the risk stratification criteria. Quadruplet agent use was higher in R-ISS III and ISS III categories (6.8% vs. 3.3% for R-ISS III vs. I; 6.3% vs. 2.8% for ISS III vs. I). The median rwPFS in HR patients were shorter than the lower risk subgroups (R-ISS III: 8.8 months [95% CI 7.1 - 11.0], R-ISS II: 12.1 months [95% CI 10.7 - 13.6], R-ISS I: 23.5 months [95% CI 13.8 - .]; ISS III: 10.4 months [95% CI 8.5 - 11.5], ISS II: 12.7 months [95% CI 10.7 - 14.3], ISS I: 16 months [95% CI 12.2 - 19.5]; HRCA: 10.1 months [95% CI 8.8 - 12.1], SRCA: 13.1 months [95% CI 11.3 - 14.8]). The 2-year rwOS was lower in the HR subgroups (R-ISS III: 0.65 [95% CI 0.59 - 0.70], R-ISS II: 0.79 [95% CI 0.76 - 0.81], R-ISS I: 0.91 [95% CI 0.85 - 0.95]; ISS III: 0.68 [95% CI 0.64 - 0.72], ISS II: 0.81 [95% CI 0.77 - 0.84], ISS I: 0.89 [95% CI 0.85 - 0.92]; HRCA: 0.75 [95% CI 0.71 - 0.79], SRCA: 0.79 [95% CI 0.76 - 0.81]). Discussion: This study found that median rwPFS and 2-year rwOS proportions were consistently lower among HR patients compared to the standard risk individuals. The majority of the HR patients were older, with decreased levels of physical functioning and worse indicators of end-organ damage including renal function, anemia, and hypercalcemia. Most patients received triplets with frequent use of PIs likely for aggressive disease control among HR patients. Some HR patients received more quads than lower risk patients suggesting treatment intensification, but HR patients also received stem cell transplants at a lower rate. Although a smaller proportion of patients have all the data collected needed for R-ISS classification, the consistent findings across treatment outcomes suggest that R-ISS is implementable in real world studies and has a greater discriminatory ability than ISS or HRCA alone. Overall, this study suggests that HR patients have relatively poor outcomes which calls for the study of risk-adapted implementation of novel therapies among this patient population in the US community practice settings. Figure 1 Figure 1. Disclosures Rahman: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Kim: Amgen: Current Employment, Current equity holder in publicly-traded company. Mateus: Amgen Inc.: Current Employment, Other: Work at Amgen as a contract employee through DOCS. Keegan: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company.

Replacing the Anthracycline By Gemtuzumab Ozogamicin in Older Patients with De Novo Standard-Risk Acute Myeloid Leukemia Treated Intensively - Results of the Randomized ALFA1401-Mylofrance 4 Study

Introduction Based on the results of the ALFA-0701 trial (Castaigne et al. Lancet 2012), the addition of fractionated doses of the anti-CD33 antibody drug conjugate gemtuzumab ozogamicin (GO, Mylotarg®) to conventional chemotherapy has been approved in 2017 for frontline treatment of adults with CD33-positive acute myeloid leukemia (AML). Prolonged event-free survival (EFS) was observed in patients with AML of favorable or intermediate risk, while not in those with adverse cytogenetics. Nevertheless, more frequent added toxicities could make the addition of GO a questionable option in patients over 60-65 years of age. In this ALFA-1401/Mylofrance 4 trial (NCT02473146), we investigated if the replacement of the anthracycline by GO might also improve EFS in older patients. Methods Between January 2016 and March 2019, 225 patients were randomized 2:1 to receive an experimental GO-cytarabine combination (154 patients) or a standard anthracycline-cytarabine treatment (71 patients). Patients aged 65 to 80 years old (later extended to patients aged 60-64 years old), with previously untreated de novo AML of favorable or intermediate cytogenetics were eligible for the trial. Standard treatment arm consisted in a 7+3 using idarubicin at 12 mg/m 2/d on day 1 to 3 and cytarabine 200 mg/m 2/d on day 1 to 7. Experimental arm (GO arm) consisted of two doses of GO 3 mg/m 2/d on day 1 and 4 and cytarabine 200 mg/m 2/d on day 1 to 7. Post-remission therapy comprised two courses of intermediate-dose cytarabine (IDAC) at 1.5 g/m 2/12h on day 1, 3 and 5. In the GO arm, a third dose of 3mg/m 2/d GO was administered on day 1 of the first IDAC course. The first IDAC course could serve as second induction in patients not responding to the first one. The decision to perform allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first remission was left to the discretion of the physician. The efficacy analysis was conducted in the modified intent-to-treat (mITT) population excluding patients who did not meet the cytogenetic eligibility criteria. The primary study endpoint was EFS. Secondary endpoints were response rate defined by complete remission (CR), CR with incomplete platelets recovery (CRp) and CR with incomplete hematological recovery (CRi), early mortality, relapse incidence, overall survival (OS) and safety. Results Among the 225 randomized patients, 214 (71 standard arm, 143 GO arm) were included in the mITT population. There were 126 men and 88 women. Median age was 70 years (61-80). Cytogenetics was of favorable and intermediate risk in 14 and 200 patients, respectively. One hundred and eighty-one patients reached CR/CRp/CRi, 64 (90%) in standard arm and 117 (82%) in GO arm (p=0.17). Median follow-up time was 38 months. At 2 years, estimated EFS was 38% [95% CI, 28-51] in the standard arm vs. 29% [22-37] in the GO arm (Hazard Ratio (HR), 1.37 [0.98-1.93]; p= 0.067) (Figure 1A). Overall, 118 patients relapsed, 36 (51%) in standard arm and 82 (57%) in GO arm. At 2 years, estimated cumulative incidence of relapse was 48% [36-61] in standard arm vs. 61% [52-70] in GO arm (csHR, 1.32 [0.90-1.93]; p= 0.078). Overall, 122 patients died, 38 (54%) in standard arm, 84 (59%) in GO arm. Sixty-day mortality was 4% in standard arm vs. 10% in GO arm (p=0.13). At 2 years, estimated OS was 65% [55-77] in standard arm vs. 52% [45-61] in GO arm (HR, 1.27 [0.86-1.87]; p= 0.23). In subgroup analysis for EFS (Figure 1B), we found a significant interaction with gender, GO having a detrimental effect in women which persisted after adjustment on known prognostic factors. A total of 33 patients received allo-HSCT in first remission, 19 (30%) in standard arm and 14 (12%) in GO arm (p=0.006). When censoring these patients at transplant time, HR of GO on EFS was 1.27 ([0.88-1.83]; p=0.19). Regarding safety, 76% and 80% of patients had at least one grade 3 to 5 adverse event (p=0.81), including infection in 30% vs. 21% and bleeding in 7% vs. 29% in standard arm and GO arm respectively. Serious adverse events were reported in 34% of patients in standard arm vs. 49% in GO arm (p=0.031). Sinusoidal obstruction syndrome occurred in 2 patients in the GO arm. Conclusion Frontline use of GO instead of idarubicin, when combined to cytarabine, does not benefit older patients with de novo standard-risk AML. At the reduced dose schedule used in this study, GO remains associated with significant toxicities while non-significant higher relapse incidence, shorter EFS and shorter OS were observed. Figure 1 Figure 1. Disclosures Lambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. Pautas: ABBVIE: Consultancy; PFIZER: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Barbieux: ASTRA-ZENECCA: Consultancy. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Castaigne: PFIZER: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; Daiichi Sankyo: Honoraria; BMS-Celgene: Honoraria.