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.

Clostridioides Difficile Carriage Rate Increases during Pediatric ALL Treatment

Background Clostridioides difficile infection (CDI) is frequent in pediatric patients with acute lymphoblastic leukemia (ALL). Studies have shown upwards of 20% positivity rate in CDI testing among pediatric oncology patients, and up to several percent in pediatric ALL patients in the first 180 days of diagnosis. Antibiotic usage has been variably linked to CDI positivity in these populations. As CDI testing is usually done in symptomatic patients, the question of C. difficile carriage versus CDI has not been addressed. We and others have shown that microbiome is altered in pediatric ALL patients and survivors. We conducted a longitudinal stool microbiome study in pediatric ALL patients and tested the hypothesis that alteration of the microbiome during ALL treatment promotes C. difficile carriage. Methods Children with ALL were prospectively recruited on a rolling basis and stool samples were collected at diagnosis (Dx) and at the end of induction (EOI), consolidation (EOC), interim maintenance I (IMI), delayed intensification (DI), interim maintenance II (IMII), as well as approximately 3 months and 6 months into maintenance (M3, M6). Stool samples from healthy siblings were used as controls. TaqMan-based quantitative-PCR (qPCR) was performed on DNA extracted from stool samples to detect C. diff 16S rRNA, tcdA, (Toxin A) and tcdB (Toxin B) genes . Samples positive or either tcdA or tcdB, or both, were designated positive for toxigenic C. difficile. 16S rRNA hypervariable region V4 was sequenced and analyzed for microbiome diversity and relative abundance of microbiota. Results 32 ALL patients age 3 months-19 years were included. The diagnoses were 12 standard risk and 14 high risk pre-B ALL, 5 T-ALL, and 1 relapsed pre-B ALL. Stool samples were collected from 18 healthy siblings. The numbers of samples tested at each treatment phase were: 29 Dx, 24 EOI, 23 EOC, 25 IMI, 21 DI, 6 IMII, 14 M3, 7 M6. No patient had symptoms suggestive of CDI, and no patient was clinically tested or treated for CDI. Total number of stool samples tested was 149, of which 43 (29%) were positive for toxigenic C. difficile (Figure 1). At diagnosis, 2/29 (7%) patients were positive, compared to 2/18 (11%) in healthy siblings. At EOI, positivity rate increased to 17%, then up to 40% - 52% at EOC, IMI, and DI. C. difficile positivity were lower around 30% at M3 and M6, although few patients reached maintenance to contribute samples for analysis. Twenty-five patients (78%) were positive at some phase. Longitudinal analysis of individual patients showed that C. difficile positivity was intermittent through treatment phases; only 3 patients remained persistently positive. Seven patients (22%) were never positive. Multivariate analysis showed that EOC, IMI, and DI treatment phases were significant risk factors for C. difficile carriage. Neither the number of antibiotics nor the number of antibiotic courses administered was significant. Leukemia risk stratification (high risk versus standard risk) also did not correlate with C. difficile positivity. Microbiome analysis showed statistically significant differences in relative abundance of certain taxa between C. diff positive and negative samples at the class, order, and family levels (Figure 2). Examples include depletion of the class Verrucomicrobiae, which contains protective Akkermansia, and depletion of the common taxa Bifidobacteriaceae and Ruminococcaceae. Conclusion Longitudinal PCR testing of toxigenic C. difficile in pediatric ALL patients demonstrated increased C. difficile prevalence further into treatment phases. C. difficile carriage correlated significantly with depletion of several bacterial taxa, as microbiome diversity decreased overall with successive treatment phases. Our data lend support to the hypothesis that altered microbiome in ALL treatment allows permissibility for C. difficile carriage. In addition, no C. difficile positive patient had symptoms of CDI, therefore, caution must be taken in clinical testing, as there is a high asymptomatic carriage rate. Further longitudinal testing during maintenance and off-therapy is needed to see if C. difficile carriage rate returns to baseline and correlates with recovery of gut microbiome. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.