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Background Polytrauma is a major clinical problem due to its impact on morbidity and mortality, especially among the younger population. Its pathophysiology is not completely elucidated, and the study of the involvement of certain cell populations with therapeutic potential, such as mesenchymal stromal cells (MSCs), is an area of growing interest, as mesenchymal cells have anti-inflammatory, immunoregulatory, and osteogenic potential. Methods In the present preliminary work, we have evaluated the characteristics of MSCs in terms of proliferation, immunophenotype, cell cycle, clonogenic capacity, and multilineage differentiation ability in a series of 18 patients with polytrauma and compared them to those from otherwise healthy patients undergoing elective spinal surgery. Results MSCs from polytrauma patients displayed higher proliferative potential with significantly higher cumulative population doublings, increased expression of some important cell adhesion molecules (CD105, CD166), and an early pre-osteogenic differentiation ability compared to those of the control group. Conclusions MSCs could potentially be of help in the repair process of polytrauma patients contribute to both cell-tissue repair and anti-inflammatory response. This potential should be further explored in larger studies.

GOAL The aim of this study was to assess the efficacy of probiotic i3.1 in improving lactose intolerance symptoms compared with placebo after 8 weeks of treatment. BACKGROUND Probiotics are promising strategies to prevent and improve lactose intolerance symptoms, but previous studies have provided conflicting results. MATERIALS AND METHODS This randomized, prospective, placebo-controlled study was conducted at the Hospital Juarez de Mexico. We recruited adult patients with lactose intolerance confirmed by a lactose hydrogen breath test (LHBT) ≥20 parts per million (ppm) and a lactose intolerance symptom score ≥6 both upon lactose challenge. We compared the change from baseline in the scores of a validated symptom questionnaire and the LHBT after 8 weeks of probiotic or placebo treatment. RESULTS We included 48 patients: 33 receiving the probiotic and 15 receiving placebo (2:1 randomization). Demographic characteristics were homogeneous between groups. The reduction in total symptom score after a lactose challenge was significantly higher in the probiotic group versus the placebo group (-5.11 vs. -1.00; P

The genomics of primary prostate cancer differ from those of metastatic castration-resistant prostate cancer (mCRPC). We studied genomic aberrations in primary prostate cancer biopsies from patients who developed mCRPC, also studying matching, same-patient, diagnostic, and mCRPC biopsies following treatment. We profiled 470 treatment-naive prostate cancer diagnostic biopsies and, for 61 cases, mCRPC biopsies, using targeted and low-pass whole-genome sequencing (n = 52). Descriptive statistics were used to summarize mutation and copy number profile. Prevalence was compared using Fisher’s exact test. Survival correlations were studied using log-rank test. TP53 (27%) and PTEN (12%) and DDR gene defects (BRCA2 7%; CDK12 5%; ATM 4%) were commonly detected. TP53, BRCA2, and CDK12 mutations were markedly more common than described in the TCGA cohort. Patients with RB1 loss in the primary tumor had a worse prognosis. Among 61 men with matched hormone-naive and mCRPC biopsies, differences were identified in AR, TP53, RB1, and PI3K/AKT mutational status between same-patient samples. In conclusion, the genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers. RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to mCRPC.

BackgroundBasal cell carcinoma is the most common type of skin cancer with major impact in health-related quality of life. The use of the formulation based on the combination of IFN-alpha 2b and IFN-gamma (HeberFERON) is an effective alternative in the treatment of basal cell carcinoma, immunogenic tumor, potentially responsible to immunotherapies. The aim of this report is to record, retrospectively, the effect of HeberFERON patients with BCC in the Cuban real word condition.MethodsThis is a retrospectively study of the use of HeberFERON in real world conditions. Eligible patients were adults with histologic diagnosis of single or multiple basal cell carcinoma of any skin phototype, lesions of any size, subtype, location, recurrent or not, with or without specific prior treatments. Adult patients, who signed the informed consent to receive the treatment with HeberFERON, were identified from the data bases. The evaluation of clinical effectiveness was carried out according to RECIST 1.1. Ethical committee of participating institutions approved the study.ResultsIn clinical practice evaluated patients the nose was the region of higher frequency of tumors (36.3%) and the nodular clinical subtype was the predominant (45.3%). Clinical response rate differences (p=0. 000) were found, with complete response of 61.9%, and partial response of 32.7%; with an overall response rate of 94.2% The HeberFERON exerted a 100% disease control, with no progression reported in 640 treated patients. The best responder tumor subtypes to HeberFERON were the more aggressive tumors, morpheaform with complete response of 72% (overall response=96%), followed by the infiltrative with complete response of 66.7% (overall response=100%). Tumor with larger size and patients with more than four tumors had lesser response to the anti-tumor effect of HeberFERON.ConclusionsHeberFERON was highly effective in basal cell carcinomas in real world conditions. In the context of resistance of skin tumors to hedgehog and immune check point inhibitors the combination of IFNs alpha 2b and IFN gamma appears as a plausible therapeutic option for a wide number of basal cell carcinomas.

This multicenter phase I trial was designed to evaluate the safety and efficacy of bortezomib (Bz) as part of both the conditioning regimen and the graft-versus-host disease (GvHD) prophylaxis. Patients received fludarabine, melphalan and Bz (days −9 and −2). GVHD prophylaxis consisted of Bz (days +1, +4, and +7), sirolimus (Siro) from day −5 and tacrolimus (Tk) from −3 (except the first five patients that did not receive Tk). Twenty-five patients with poor prognostic multiple myeloma were included. Eleven out of the 19 patients had high-risk features. Out of the 21 patients evaluable at day +100, 14 were in CR (67%) and 7 (33%) in PR. Cumulative incidence (CI) of nonrelapse mortality at 1 year was 24%. CI of grades 2–4 and 3–4 acute GvHD was 35% and 10%, respectively; CI of chronic GvHD was 35% and 55% at 1 and 2 years, respectively. Overall and event free survival at 2 years were 64% and 31%, respectively. Bz as part of the conditioning regimen and in the combination with Siro/tacrolimus for GvHD prophylaxis is safe and effective allowing an optimal disease control early after transplant and reducing the risk of GvHD., This trial was supported by Janssen and Celgene and the Ministerio de Sanidad y Política Social, convocatoria de concesión de ayudas para el fomento de la investigación clínica independiente 2010 (EC10–289); this study was partially supported by two grants from the Ministry of Health CIBER ONC, code CB16/12/00480. TCV was supported by a grant from Ministerio de Sanidad y Política Social (CM10/00161).

CONTEXT: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have rising prostate-specific antigen (PSA) and castrate testosterone levels, with no radiological findings of metastatic disease on computed tomography and bone scan. Given recent drug approvals for nmCRPC, with many other therapeutics and imaging modalities being developed, management of nmCRPC is a rapidly evolving field that merits detailed investigation.OBJECTIVE: To review current nmCRPC management practices and identify opportunities for improving care of nmCRPC patients.EVIDENCE ACQUISITION: A literature search up to July 2018 was conducted, including clinical trials and clinical practice guidelines (National Comprehensive Cancer Network, European Society for Medical Oncology, European Association of Urology, Prostate Cancer Clinical Trials Working Group, Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence). Keywords included prostate cancer, nonmetastatic, castration resistance, rising PSA, and biochemical relapse.EVIDENCE SYNTHESIS: Recommendations regarding indications for, and frequency of, imaging and PSA testing, as well as for initiating systemic therapy in nmCRPC are based on PSA rise kinetics and symptoms. Both enzalutamide and apalutamide have been shown to significantly increase metastasis-free survival in phase III placebo-controlled randomised trials in nmCRPC patients with PSA doubling time (DT) ≤10 mo. The expected impact of new imaging techniques in the assessment of nmCRPC is also reviewed.CONCLUSIONS: nmCRPC is a heterogeneous disease; while observation may be an option for some patients, enzalutamide and apalutamide may be appropriate to treat nmCRPC patients with PSA-DT ≤10 mo. The emergence of more accurate imaging modalities as well as circulating tumour biomarker assays will likely redefine the assessment of nmCRPC in the near future.PATIENT SUMMARY: Herein, we review key literature and clinical practice guidelines to summarise the optimal management of patients with prostate cancer and rising prostate-specific antigen despite castrate testosterone levels, but with no evidence of distant metastasis on traditional imaging. New drugs are being developed for this disease setting; novel imaging and tumour biomarker blood tests are likely to define this disease state more accurately.

What you need to know A previously healthy and fully vaccinated (including 13-valent pneumococcal conjugate vaccine) 22 month old boy is brought to the emergency department because of a 12 hour history of high fever (up to 40°C). He had had low grade fever, runny nose, cough, and decreased oral intake for the past two days. On examination, he did not look severely ill but was febrile (38.3°C). His respiratory rate was 45 breaths/minute (normal range 25-40 breaths/min at 18-24 months old), heart rate was 140 beats/minute (normal range 98-135 beats/min at 18-24 months), and blood oxygen level was 95%. Although breath sounds were not decreased, some bibasilar crackles were noted on chest auscultation. A chest x ray was interpreted as having bilateral peribronchial infiltrates and haziness in the right lower lobe. To aide their decision whether to initiate antibiotic therapy, clinicians requested blood tests, which revealed a white blood cell count of 22.5×109/L (60.0% neutrophils), a CRP of 30 mg/L (normal

Background and importance Tocilizumab is an anti-human IL-6 receptor monoclonal antibody used in the treatment of cytokine release syndrome in patients with pneumonia associated with coronavirus disease. Despite the data from the COVACTA study, tocilizumab continues to be the gold standard for patients in our centre. Aim and objectives To describe the use of tocilizumab in the first peak versus the second peak of the SARS-CoV-2 pandemic, and to describe the results of the use of tocilizumab in both situations. Material and methods All patients treated with tocilizumab were included in the study periods: first peak (March to June 2020) and second peak (August to the present 2020). Demographic and clinical variables were collected. Data were obtained from the electronic medical records and prescription applications. Results 65 patients were included, 36 patients (55.38%) in the first peak versus 29 patients (44.62%) in the second peak. Conclusion and relevance In the first peak, tocilizumab was prescribed to more serious patients: those admitted to the ICU, with a higher FINE score and needing aggressive support therapy. In addition, it was prescribed in patients with a higher D-dimer. Doses and number of administrations were higher in the first peak. New scientific evidence led to the use of different concomitant treatments in the second peak: corticosteroids (second peak dexamethasone versus first peak methylprednisolone) and antiviral therapy (only remdesivir in the second peak). In the second peak, hospital and ICU stays were shorter, probably because tocilizumab was used in less serious patients. Despite this, no differences in mortality were observed. A study limitation was sample size. References and/or acknowledgements Conflict of interest No conflict of interest

Background Enhanced Recovery After Surgery (ERAS) protocols are well-documented logistic programs in elective surgery but it is still uncertain whether ERAS can benefit emergency patients, because of significant challenges facing its application to emergency surgery. The aim of this study was to evaluate the implementation of an ERAS protocol for patients with acute appendicitis (AA), both complicated and uncomplicated. Methods A prospective observational study was performed at two university hospitals in Spain, between January 2012 and December 2019. Inclusion criteria were patients with diagnosis of AA, undergoing appendectomy following an ERAS protocol of perioperative care. The different items of the ERAS protocol were recorded and their implementation was separately evaluated. Analyzed variables also included postoperative complications, hospital stay and readmission rate. Levels of acute phase reactants were assessed as predictors of implementation for the ERAS protocol. Results Eight hundred fifty patients were included; 498 males (58.5%) and 302 females (41.5%), with a mean age of 34.95 +/- 17 years. The implementation of all the items of the protocol was achieved in 770 patients (90.6%), 86.8% of patients with complicated AA and 93.1% of patients with uncomplicated AA (p = 0.02). Higher preoperative C-reactive protein (CRP) levels were significantly associated with the impossibility of implementing all the items of the ERAS protocol (p < 0.001), establishing a cut-off point at CRP = 13.5 mg/dl. Conclusions The implementation of ERAS protocols is safe and feasible in patients with AA. Although the implementation rate of all the items is lower in patients with complicated AA, it can be completed in 86.8% of these patients. CRP levels over 13.5 mg/dl are predictors of difficulties in the implementation of all the items of ERAS protocols.

Peritoneal dialysis (PD)–associated peritonitis constitutes a major complication associated with the procedure. PD-associated peritonitis caused by nontuberculous mycobacteria, usually as a result of an infection related to the PD catheter, has been reported in adults and is associated with significant complications and poor outcome. The management of PD-associated peritonitis caused by Mycobacterium abscessus is particularly challenging because this species is resistant to many antimicrobials commonly used to treat mycobacterial species. We present here the second reported case of PD-associated peritonitis caused by M. abscessus in children. Our patient was a 9-year-old boy with end-stage renal disease (ESRD) who presented with suspected peritonitis, and his PD fluid cultures eventually grew M. abscessus. The patient received a 3-week course of triple therapy with clarithromycin, amikacin, and meropenem in addition to PD catheter removal. The infection completely resolved even though a susceptibility report at the end of treatment revealed that the isolate was resistant to clarithromycin and had decreased susceptibility to carbapenems. Our observations suggest that PD catheter removal is important in PD-associated peritonitis caused by M. abscessus in children and that more studies are needed to define the optimal length of treatment.

We implemented a collaborative diagnostic program in Lahore (Pakistan) aiming to establish the genetic diagnosis, and to asses diagnostic yield and clinical impact in patients with suspected genetic diseases. Local physicians ascertained pediatric patients who had no previous access to genetic testing. More than 1586 genetic tests were performed in 1019 individuals (349 index cases, 670 relatives). Most frequently performed tests were exome/genome sequencing (ES/GS, 284/78 index cases) and specific gene panels (55 index cases). In 61.3% of the patients (n = 214) a genetic diagnosis was established based on pathogenic and likely pathogenic variants. Diagnostic yield was higher in consanguineous families (60.1 vs. 39.5%). In 27 patients, genetic diagnosis relied on additional biochemical testing, allowing rapid assessment of the functional effect of the variants. Remarkably, the genetic diagnosis had a direct impact on clinical management. Most relevant consequences were therapy related such as initiation of the appropriated treatment in a timely manner in 51.9% of the patients (n = 111). Finally, we report 12 candidate genes among 66 cases with no genetic diagnosis. Importantly, three of these genes were validated as ‘diagnostic’ genes given the strong evidence supporting causality derived from our data repository (CAP2-dilated cardiomyopathy, ITFG2-intellectual disability and USP53-liver cholestasis). The high diagnostic yield, clinical impact, and research findings demonstrate the utility of genomic testing, especially when used as first-line genetic test. For patients with suspected genetic diseases from resource-limited regions, ES can be considered as the test of choice to achieve genetic diagnosis.

The etiology of central nervous system (CNS) infections such as meningitis and encephalitis remains unknown in a large proportion of cases partly because the diversity of pathogens that may cause CNS infections greatly outnumber available test methods. We developed a metagenomic next generation sequencing (mNGS)-based approach for broad-range detection of pathogens associated with CNS infections suitable for application in the acute care hospital setting. The analytical sensitivity of mNGS performed on an Illumina MiSeq was assessed using simulated cerebrospinal fluid (CSF) specimens (n = 9). mNGS data were then used as a training dataset to optimize a bioinformatics workflow based on the IDseq pipeline. For clinical validation, residual CSF specimens (n = 74) from patients with suspected CNS infections previously tested by culture and/or PCR, were analyzed by mNGS. In simulated specimens, the NGS reads aligned to pathogen genomes in IDseq were correlated to qPCR CT values for the respective pathogens (R = 0.96; p

Introduction: asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that potently inhibits aberrant kinase activity of the BCR-ABL1 oncoprotein via allosteric binding. asciminib has shown high efficacy profile in heavily pretreated Chronic Myeloid Leukemia (CML) patients with an adequate safety profile in phase I and III clinical trials. However, data from the use of asciminib in real life setting are still scarce. Methods: We gathered real-life retrospective data from 49 patients with BCR-ABL1 positive CML treated with asciminib (mean dose: 40 mg twice daily) between October 2018 and July 2021 at 33 institutions. The indication of asciminib was made according to the criterion of the attending physician and the drug was granted by Novartis under a controlled access program. Molecular biology tests were performed according to ELN guidelines and BCR-ABL/ABL ratios were expressed as % IS in all centers. Treatment responses were calculated with the patients at risk at each specific time points. For the event free survival (EFS), the events were treatment discontinuation due to any reason, progression or death. Data collection followed the local regulations for observational studies. Results: Median time on asciminib was 11,69 months for the entire cohort. Patients' characteristics are displayed on Table 1. Most patients were heavily pretreated with at least 3 prior TKI lines in 45 patients (91,83%), 18 of them receiving prior Ponatinib. Switch to asciminib occurred due to intolerance in 32 patients and due to resistance in the remaining 17. Fifteen patients (30,61%) harbored mutations in BCR-ABL1 (3 with a T315 mutation). Regarding efficacy (Table 2), probability of reaching or maintaining previous responses were 94%, 45% and 21% for complete hematological response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMR), respectively. Considering probabilities of improving previous response, rates were 40%, 42% and 33% for the same parameters. Probabilities to obtain CCyR and MMR in resistant and intolerant patients were 29% (4/14) vs 55% (6/11) and 27% (4/15) vs 52% (11/21), respectively. Amid the patients previously treated with Ponatinib, probabilities of reaching or maintaining previous response were 53% (9/17) and 35% (6/17) for CCyR and MMR respectively, and 30% (3/10), 23% (3/13) displayed improvement of response. Regarding responses in patients with mutations, 39% (5/13) achieved or maintained CCyR and 31% (4/13) MMR; whereas 20% (2/10) and 18% (2/11) improved such responses. Of the three patients with T315I mutation, one discontinued due to progression to advanced stages, and the rest maintained the previous response. With a median follow-up of 11,69 months, the estimated EFS was 80% (figure 1). In terms of safety (Table 3), the most frequent extra-hematological adverse events (AE) were: fatigue (16,2%), joint pain (13,5%) and nausea (8,1%), most of them grade 1-2. Grade 3-4 AE were observed in 10% of patient (fatigue (2), cholestasis enzyme elevation (1), hypertension (1), pancreatitis (1) and pericardial effusion (1)). Thrombocytopenia was shown as the most frequent AE (16,3%), with 6% of patients suffering from grade 3-4. Dose reduction was required in 15 patients (30,6%). After a median follow up of 51 weeks, 73,5% of the patients remained on treatment. Only fourteen patients discontinued treatment due to progression or loss of efficacy, whereas 6% of patients discontinuing treatment due to intolerance. Conclusions: The results presented are in line with the data obtained in clinical trials, positioning asciminib as a potential safe and efficacious treatment for CML patients with failure to several TKI lines. Figure 1 Figure 1. Disclosures Sanchez-Guijo: Novartis: Consultancy, Honoraria, Research Funding; Celgene/Bristol-Myers-Squibb,: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Honoraria, Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Garcia Gutierrez: BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding.

A number of parameters recorded during dobutamine stress echocardiography (DSE) are associated with worse outcome. However, the relative importance of baseline mitral regurgitation (MR) is unknown. The aim of this study was to assess the prevalence and associated implications of functional MR with long-term mortality in a large cohort of patients referred for DSE. 6745 patients (mean age 64.9 ± 12.2 years) were studied. Demographic, baseline and peak DSE data were collected. All-cause mortality was retrospectively analyzed. DSE was successfully completed in all patients with no adverse outcomes. MR was present in 1019 (15.1%) patients. During a mean follow up of 5.1 ± 1.8 years, 1642 (24.3%) patients died and MR was significantly associated with increased all-cause mortality (p

Purpose To determine the correlation between the volume of bone metastasis as assessed with diffusion-weighted (DW) imaging and established prognostic factors in metastatic castration-resistant prostate cancer (mCRPC) and the association with overall survival (OS). Materials and Methods This retrospective study was approved by the institutional review board; informed consent was obtained from all patients. The authors analyzed whole-body DW images obtained between June 2010 and February 2013 in 53 patients with mCRPC at the time of starting a new line of anticancer therapy. Bone metastases were identified and delineated on whole-body DW images in 43 eligible patients. Total tumor diffusion volume (tDV) was correlated with the bone scan index (BSI) and other prognostic factors by using the Pearson correlation coefficient (r). Survival analysis was performed with Kaplan-Meier analysis and Cox regression. Results The median tDV was 503.1 mL (range, 5.6-2242 mL), and the median OS was 12.9 months (95% confidence interval [CI]: 8.7, 16.1 months). There was a significant correlation between tDV and established prognostic factors, including hemoglobin level (r = -0.521, P < .001), prostate-specific antigen level (r = 0.556, P < .001), lactate dehydrogenase level (r = 0.534, P < .001), alkaline phosphatase level (r = 0.572, P < .001), circulating tumor cell count (r = 0.613, P = .004), and BSI (r = 0.565, P = .001). A higher tDV also showed a significant association with poorer OS (hazard ratio, 1.74; 95% CI: 1.02, 2.96; P = .035). Conclusion Metastatic bone disease from mCRPC can be evaluated and quantified with whole-body DW imaging. Whole-body DW imaging-generated tDV showed correlation with established prognostic biomarkers and is associated with OS in mCRPC. (©) RSNA, 2016 Online supplemental material is available for this article.

INTRODUCTION: Infection complications are important cause of morbidity and non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-SCT), even in HLA-identical sibling donors. Although there are many studies associating single nucleotide polymorphisms (SNPs) and allo-SCT evolution, these are mainly related with graft versus host disease (GVHD) and/or transplant related mortality (TRM), with few focused on post-allo-SCT infections. This multicentric study analyzes the potential implication of SNPs with cytomegalovirus (CMV) reactivation and fungal infection (FI) development in allo-SCT with reduced intensity conditioning (RIC). MATERIALS AND METHODS: We included paired recipient-donor samples from 247 RIC allo-SCT for patients diagnosed of AML (35%), NHL (21%), MDS (16%), MM (10%), CLL (7%), HL (6%), or others (5%) in four centers in Spain. Flu-Bu conditioning was used in 55% of the transplants while Flu-Mel in 42%. A total of 52 SNP were analyzed from 44 different gene loci and genotyping was carried out by Sequenom Mass ARRAY platform. Allele frequencies were estimated by direct counting and compared between groups using Fisher's test. P-value RESULTS: Patient's characteristics are shown in Table 1. The median follow up for patients was 28 months (1-175), overall survival at 5 years was 45%, while the event-free survival at 5 years was 57%. Cumulative incidence of CMV reactivation at 3 years was 34% and of FI 11%. Transplant related mortality was 17%, and infection related mortality 14%. In univariate analysis, patients with genotype A/A in rs3093023 (CCR6) showed a lower incidence of CMV reactivation (table 2), along with acute GVHD were the variables associated in multivariate analysis. Regarding to FI, recipient genotype A/A in rs1494555 (IL7R), donor C/C in rs1800795 (FAS), and donor G/G in rs2302217 (MAdCAM-1) were associated with higher FI incidence (table 2), being the only variables related in multivariate analysis. CONCLUSION: This data suggest an association between rs3093023 (CCR6), rs1494555 (IL7R), rs1800795 (FAS) and rs2302217 (MAdCAM-1) polymorphisms with higher incidence of post-allo-SCT opportunist infection. Confirmation in larger series is required. FUNDING: RD12/0036/0069, CB16/12/00233 and 00480, PI12/02361 and ERDF, Innocampus; CEI-2010- 1-0010 Download : Download high-res image (236KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.

3541 Background: So far, no biomarkers of response to anti-angiogenic drugs are available in colorectal cancer (CRC) treatment. Liquid biopsy tracks dynamic mutational changes in CRC patients (pts). RAS mutant allele fraction in plasma (plMAF) is an independent prognostic marker in metastatic CRC (mCRC). We explored the predictive value of plMAF in RAS mutant pts treated in 1st line with chemotherapy +/- bevacizumab (bev). Methods: A multicentric prospective/retrospective analysis was conducted. We collected data from 226 mCRC pts and selected the subset not eligible for metastasis resection with basal plMAF sample evaluable for RAS mutant MAF quantification with digital PCR (BEAMing). Pts were stratified as high (≥ 5.8%) or low ( < 5.8%) plMAF. We investigated associations between clinicopathological variables and progression-free survival (PFS) stratified by plMAF RAS levels using Cox regression models and survival data were calculated by Kaplan-Meier method. Computational analysis of baseline CT scan data extracted 93 radiomics features of all the lesions per patient including 1) 1st class from density histogram distribution and texture analysis by 2) 2nd order and 3) higher order feature classes. The radiomic features distribution between pts with high and low pIMAF was assessed with Student’s t-test analysis. Results: From October 17 to May 19, 63 basal plasma samples were analysed with BEAMing. 42 pts (67.7%) were classified as high and 21 pts (32,3%) as low plMAF. In high plMAF subgroup, a statistically significant longer PFS favouring FOLFOX+bev was observed, compared to FOLFOX alone (10.7 vs 6.9 mts; HR: 0.30; p = 0.002). In low RAS plMAF subgroup, no differences in terms of PFS were observed in either arm (8.9 vs 8.7 mts; HR: 0.7; p = 0.6). Multivariate PFS model showed no association between RAS plMAF and clinicopathological variables, except for high RAS plMAF and treatment benefit with FOLFOX+bev. The CT-radiomics signature, that may translate tumor vascularization, differentiated patients with high vs low pIMAF (p = 0.002). 58 patients (92%) had similar radiomic score; 5 patients with high plMAF (8%) presented very heterogeneous radiomic score distribution. Conclusions: Tumor-borne RAS plMAFs may constitute a potential predictive biomarker of efficacy for anti-angiogenic drugs in mCRC. Next steps will include the identification of -histological, transcriptomic and radiomic- surrogate biomarkers of response that reflect tumor irrigational status.

Purpose: CHD1 deletions and SPOP mutations frequently cooccur in prostate cancer with lower frequencies reported in castration-resistant prostate cancer (CRPC). We monitored CHD1 expression during disease progression and assessed the molecular and clinical characteristics of CHD1-deleted/SPOP-mutated metastatic CRPC (mCRPC). Experimental Design: We identified 89 patients with mCRPC who had hormone-naive and castration-resistant tumor samples available: These were analyzed for CHD1, PTEN, and ERG expression by IHC. SPOP status was determined by targeted next-generation sequencing (NGS). We studied the correlations between these biomarkers and (i) overall survival from diagnosis; (ii) overall survival from CRPC; (iii) duration of abiraterone treatment; and (iv) response to abiraterone. Relationship with outcome was analyzed using Cox regression and log-rank analyses. Results: CHD1 protein loss was detected in 11 (15%) and 13 (17%) of hormone-sensitive prostate cancer (HSPC) and CRPC biopsies, respectively. Comparison of CHD1 expression was feasible in 56 matched, same patient HSPC and CRPC biopsies. CHD1 protein status in HSPC and CRPC correlated in 55 of 56 cases (98%). We identified 22 patients with somatic SPOP mutations, with six of these mutations not reported previously in prostate cancer. SPOP mutations and/or CHD1 loss was associated with a higher response rate to abiraterone (SPOP: OR, 14.50 P = 0.001; CHD1: OR, 7.30, P = 0.08) and a longer time on abiraterone (SPOP: HR, 0.37, P = 0.002, CHD1: HR, 0.50, P = 0.06). Conclusions: SPOP-mutated mCRPCs are strongly enriched for CHD1 loss. These tumors appear highly sensitive to abiraterone treatment. Clin Cancer Res; 24(22); 5585–93. ©2018 AACR.

Purpose: We evaluated whether next-generation sequencing (NGS) of circulating cell-free DNA (cfDNA) could be used for patient selection and as a tumor clone response biomarker in patients with advanced cancers participating in early-phase clinical trials of targeted drugs. Experimental Design: Plasma samples from patients with known tumor mutations who completed at least two courses of investigational targeted therapy were collected monthly, until disease progression. NGS was performed sequentially on the Ion Torrent PGM platform. Results: cfDNA was extracted from 39 patients with various tumor types. Treatments administered targeted mainly the PI3K–AKT–mTOR pathway (n = 28) or MEK (n = 7). Overall, 159 plasma samples were sequenced with a mean sequencing coverage achieved of 1,685X across experiments. At trial initiation (C1D1), 23 of 39 (59%) patients had at least one mutation identified in cfDNA (mean 2, range 1–5). Out of the 44 mutations identified at C1D1, TP53, PIK3CA and KRAS were the top 3 mutated genes identified, with 18 (41%), 9 (20%), 8 (18%) different mutations, respectively. Out of these 23 patients, 13 received a targeted drug matching their tumor profile. For the 23 patients with cfDNA mutation at C1D1, the monitoring of mutation allele frequency (AF) in consecutive plasma samples during treatment with targeted drugs demonstrated potential treatment associated clonal responses. Longitudinal monitoring of cfDNA samples with multiple mutations indicated the presence of separate clones behaving discordantly. Molecular changes at cfDNA mutation level were associated with time to disease progression by RECIST criteria. Conclusions: Targeted NGS of cfDNA has potential clinical utility to monitor the delivery of targeted therapies. Clin Cancer Res; 21(20); 4586–96. ©2015 AACR.

ObjectiveTo assess the availability and source of guidelines for common infections in European paediatric hospitals and determine their content and characteristics.DesignParticipating hospitals completed an online questionnaire on the availability and characteristics of antibiotic prescribing guidelines and on empirical antibiotic treatment including duration of therapy for 5 common infection syndromes: respiratory tract, urinary tract, skin and soft tissue, osteoarticular and sepsis in neonates and children.Results84 hospitals from 19 European countries participated in the survey of which 74 confirmed the existence of guidelines. Complete guidelines (existing guidelines for all requested infection syndromes) were reported by 20% of hospitals and the majority (71%) used a range of different sources. Guidelines most commonly available were those for urinary tract infection (UTI) (74%), neonatal sepsis (71%) and sepsis in children (65%). Penicillin and amoxicillin were the antibiotics most commonly recommended for respiratory tract infections (RTIs) (up to 76%), cephalosporin for UTI (up to 50%) and for skin and soft tissue infection (SSTI) and bone infection (20% and 30%, respectively). Antistaphylococcal penicillins were recommended for SSTIs and bone infections in 43% and 36%, respectively. Recommendations for neonatal sepsis included 20 different antibiotic combinations. Duration of therapy guidelines was mostly available for RTI and UTI (82%). A third of hospitals with guidelines for sepsis provided recommendations for length of therapy.ConclusionsComprehensive antibiotic guideline recommendations are generally lacking from European paediatric hospitals. We documented multiple antibiotics and combinations for most infections. Considerable improvement in the quality of guidelines and their evidence base is required, linking empirical therapy to resistance rates.

Until 2010, docetaxel was the only agent with proven survival benefit for castration-resistant prostate cancer. The development of cabazitaxel, abiraterone acetate, enzalutamide, radium-223, and sipuleucel-T has increased the number of treatment options. Because these agents were developed concurrently within a short period of time, prospective data on their sequential use efficacy are scarce. The challenge now is to reach a consensus on the best way to sequence effective treatments, ideally by the use of an approach specific to patient subgroups. However, the absence of robust surrogates of survival and the lack of predictive biomarkers makes data for the sequential use of these agents difficult to obtain and interpret.

SummaryToward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%–60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.

Background: Microbiologic studies suggest that complicated (CAA) and uncomplicated (UAA) acute appendicitis are different entities. Routine peritoneal fluid cultures continue to be controversially related to a low positive rate, found mainly in UAA; to isolation of typical micro-organisms with expected susceptibilities; and to a community-acquired intra-abdominal infection. The aim of this study was to describe microbiologic isolates in CAA and UAA and the usefulness of peritoneal fluid cultures to determine the susceptibilities to our antibiotic therapy guidelines. Methods: This study was a retrospective review of a prospective database collected at University San Juan Hospital (Spain) between June 2014 and June 2017. Complicated acute appendicitis was defined as gangrenous or perforated, whereas UAA was defined as phegmonous or suppurative. Our antibiotic recommendations are amoxicillin-clavulanic acid and in patients with -lactam allergies, metronidazole plus aztreonam, and an aminoglycoside (gentamicin or tobramycin). Microbiologic cultures were performed in 264 patients, 157 with a CAA and 107 with a UAA. Results: The positive culture rate was significantly higher in CAA (59%) than in UAA (24.3%). Gram-positive cocci (51.6% CAA; 23.1% UAA), including Streptococcus constellatus (29% CAA; 3.8% UAA), and anaerobes (67.7% CAA; 42.3% UAA) were significantly more common in CAA. The rates of antibiotic resistance were amoxicillin-clavulanic acid 14% (17.2% CAA; 3.8% UAA), gentamicin or tobramycin 8.4% (9.7% CAA; 3.8% UAA), ciprofloxacin 5.9% (6.5% CAA; 3.8% UAA), and ertapenem 10.9% (14% CAA; 0 UAA). Conclusions: The culture-positive rate was higher in CAA, with different isolates and susceptibilities than in UAA, identifying a higher frequency of gram-positive cocci (including S. constellatus) and anaerobes. We recommend obtaining peritoneal fluid cultures in CAA, which frequently will lead to a change in the antimicrobial drug therapy guidelines, creating specific recommendations in AA.

Primary malignant brain tumours (PMBT) constitute less than 2% of all malignancies and carry a dismal prognosis. Treatment options at relapse are limited. First-in-human solid tumour studies have historically excluded patients with PMBT due to the poor prognosis, concomitant drug interactions and concerns regarding toxicities. Retrospective data were collected on clinical and tumour characteristics of patients referred for consideration of Ph1 trials in the Royal Marsden Hospital between June 2004 and August 2016. Survival analyses were performed using the Kaplan–Meier method, Cox proportional hazards model. Chi squared test was used to measure bivariate associations between categorical variables. 100pts with advanced PMBT were referred. At initial consultation, patients had a median ECOG PS 1, median age 48 years (range 18–70); 69% were men, 76% had glioblastoma; 68% were on AEDs, 63% required steroid therapy; median number of prior treatments was two. Median OS for patients treated on a Ph1 trials was 9.3 months (95% CI 5.9–12.9) versus 5.3 months (95% CI 4.1–6.1) for patients that did not proceed with a Ph1 trial, p = 0.0094. Steroid use, poor PS, neutrophil-to-lymphocyte ratio and treatment on a Ph1 trial were shown to independently influence OS. We report a survival benefit for patients with PMBT treated on Ph1 trials. Toxicity and efficacy outcomes were comparable to the general Ph1 population. In the absence of an internationally recognized standard second line treatment for patients with recurrent PMBT, more Ph1 trials should allow enrolment of patients with refractory PMBT and Ph1 trial participation should be considered at an earlier stage.

Background: CTEPH is one of the leading causes of severe pulmonary hypertension and can be devastating for those individuals who are affected. The exact incidence of CTEPH after a PE is debated depending on patient selection as well as CTEPH diagnostic criteria. Aim: To determine the incidence for CTEPH at six monyhs of a PE. Methods: A prospective study was conducted in 17 Spanish hospitals. All consecutive PE patients were recruited and followed-up according to a standarized set of clinical questions. Symptomatic patients underwent a structured evaluation with echocardiography and complete work-up for CTEPH. Results: 1065 patients were recruited from April of 2014. 1026 patients completed the follow-up until 6 months, 52% were males. There were significant differences in mean ages between males (63.8±14.7 years) and females (67.2±17.1 years) (p=0.001). Patients were haemodinamically unstable at PE diagnosis in 9%, cancer-associated-PE in 20%, incidental PE in 14% and with previous thromboembolic diseases in 12%. CTEPH with pathological imaging and a mean pulmonary artery pressure (mPAP) ≥25 mmHg at rest was confirmed in seven subjects; accumulated incidence of 6.82‰[CI95%: 2.74-14.0]. Conclusions: Accumulated incidence at 6 months after a PE was infrequent. Only the fourth part of patients who reparted symptons had CTEPH diagnostic criteria. Acknowledgment to Angelica Martin and Tania Jimenez (S-H Medical) for your support, and to Bayer Heathcare for partial funding.

The management of relapsed or refractory Hodgkin’s lymphoma (RR-HL) remains a challenge for hematologists and oncologists. Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard of care for RR-HL. However, one of the most controversial aspects is which the best salvage protocol could be. We retrospectively analyzed 82 consecutive RR-HL who received etoposide, steroids, ara-C, and cisplatin (ESHAP) as salvage therapy followed by ASCT. Fifty percent of patients were refractory and 23 % early relapses. Overall response rate (ORR) was 67 % (50 % complete remission (CR)). Ninety one percent of patients (75/82) were transplanted. With a mean follow-up of 87 ± 53 months, the median progression-free survival (PFS) and time to tumor progression (TTP) for the whole population were 52 and 56 months, respectively, and the 5-year overall survival was 72.6 %. Achieving CR after ESHAP was associated with a longer PFS (78 vs 16 % 5-year PFS, respectively, P < 0.01) and TTP (80 vs 19 % 5-year TTP, respectively, P < 0.01). However, there were no differences for overall survival (OS) when comparing CR and partial response (PR) after ESHAP. Toxicity was low and

Background Strongyloides stercoralis is a nematode endemic to the tropical and subtropical regions. In the United States, it is mostly found at southeastern states. Most infections are asymptomatic but disseminated and fatal infections have been reported in immunocompromised patients. At our institution, universal screening through Strongyloides antibody detection in serum among solid-organ transplant candidates began since 2010 and all seropositive candidates are treated before transplantation. We previously determined our incidence to be about 5%. The aim of this study was to determine demographic characteristics and risk factors that can be used for more cost-effective targeted screening. Methods We performed a retrospective cohort study of patients who underwent transplant evaluation from 2014 to 2016. A total of 228 charts were reviewed for Strongyloides serology status, eosinophilia, demographics and risk factors. Chi-square and Fisher exact tests were used to do a comparative analysis between Strongyloides seropositive and seronegative cohorts. Results We identified 113 seropositive (SP) patients and 115 seronegative (SN) patients. There were more males in the seropositive group (79%) compared with seronegative group (62%) (P = 0.005). Caucasians predominated in both groups (SP 71% vs. SN 57%; P = 0.286). No significant difference was found between both groups with regards to occupation with soil or water contact (SP 38% vs. SN 30%; P = 0.281), birthplace outside USA or travel outside of United States (SP 31% vs. SN 36%; P = 0.732). Eosinophilia occurred less in the seropositive group compared with the seronegative group (SP 16% vs. SN 30%; P = 0.030). Conclusion The study did not find any statistically significant difference in the demographic characteristics or risk factors that can be used for prediction of Strongyloides seropositivity among solid-organ transplant candidates. Hence, our institution will continue universal screening for Strongyloides stercoralis for all our transplant candidates. Our findings further question donor screening for Strongyloides that uses a similar questionnaire which may not be reliable to identify those infected with this parasite. This would put recipients at risk for a donor-transmitted infection. Disclosures All authors: No reported disclosures.

Background So far, no biomarkers of response to anti-angiogenic drugs are available in colorectal cancer (CRC) treatment. Liquid biopsy technique identifies actionable targets in CRC patients (pts), tracking dynamic mutational changes. We and others described RAS mutant allele fraction in plasma (plMAF) as an independent prognostic marker in metastatic CRC (mCRC). Here, we explored the predictive value of plMAF in RAS mutant pts treated in first line with chemotherapy +/- bevacizumab (bev). Methods A multicentric prospective/retrospective analysis was conducted. We collected data from 226 mCRC pts and selected the subset not eligible for metastasis resection that had basal plMAF sample evaluable for RAS mutant MAF quantification using digital PCR (BEAMing). Pts were stratified as high (≥ 5.8%) or low ( Results From October 2017 to May 2019, BEAMing analysis from 62 basal plasma samples was performed. 42 pts (67.7%) were classified as high and 20 pts (32,3%) as low plMAF. Among high RAS plMAF, 24 pts received FOLFOX+bev (57%) and 20 pts FOLFOX alone (43%). In this high plMAF subgroup, a statistically significant longer PFS favouring FOLFOX+bev was observed when compared to FOLFOX alone (10.7 versus 6.9 months, respectively; HR: 0.30; p = 0.002). In the low RAS plMAF subgroup, no differences in terms of PFS were observed in either arm (8.9 versus 8.7 months, respectively; HR: 0.70; p = 0.6). Multivariate PFS model showed no association between RAS plMAF and clinicopathological variables, except for high RAS plMAF and treatment benefit with FOLFOX+bev. Conclusions Our results indicate that tumor-borne RAS plMAFs may constitute a potential predictive biomarker of efficacy for anti-angiogenic agents in mCRC. Confirmatory studies in randomized cohorts will be performed. Legal entity responsible for the study VHIO (Vall d’Hebron Institute of Oncology). Funding AECC (Asociacion Espanola Contra el Cancer). Disclosure G. Martini: Research grant / Funding (self), Research Project supported by ESMO with the aid of a grant from Amgen: ESMO-AMGEN. E. Elez: Honoraria (self): Merck Serono; Honoraria (self): Sanofi; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Servier; Honoraria (self): Amgen; Honoraria (self): Array. G. Argiles Martinez: Honoraria (self), Honoraria (institution), Research grant / Funding (self), Travel / Accommodation / Expenses: Hoffmann-LaRoche, Bristol-Myers Squibb, Bayer, Servier, Amgen, Merck Serono, Menarini; Honoraria (self): Menarini; Honoraria (institution): Boston Pharmaceuticals; Honoraria (institution): Genentech; Honoraria (institution): Boehringer Ingelheim. M.J. Ortiz Morales: Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert Testimony: Sanofi. P.G. Nuciforo: Honoraria (self): BAYER; Honoraria (self): MSD; Honoraria (self): Novartis. R. Dienstmann: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Symphogen, Ipsen, Amgen, Sanofi, MSD, Servier; Research grant / Funding (self): MERCK. J. Tabernero: Advisory / Consultancy: Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Part. E. Aranda Aguilar: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merck; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi. A. Vivancos: Advisory / Consultancy: sysmex; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck; Advisory / Consultancy: Bristol-Meyers Squidd; Advisory / Consultancy: Guardant Health. All other authors have declared no conflicts of interest.

1075 Background: NGS in ctDNA from MBC is feasible and results may be informative for patients’ management, especially in non-luminal tumors (Oliveira et al, ASCO 2018). We aimed to study the determinants of concordance in CRG in a cohort of 60 MBC patients undergoing tBx and ctDNA collection. Methods: MiSeq Amplicon-based NGS (59 cancer-related genes) was performed in one single metastatic lesion per patient and compared with liquid biopsies taken at the same time point at disease progression to prior treatment. The concordance in CRG ( PIK3CA, AKT1, ERBB2, ESR1, PTEN, BRAF, FGFR1, HRAS, KRAS, and PIK3R1) in tBx vs ctDNA was determined at patient and at mutation (mut) level and correlated with mutant allele fraction (MAF), total disease volume (TDV), and clinical characteristics. True positive in plasma (TPP): patient with a mut detected both in ctDNA and tBx. TDV was defined as all metastasis volume assessed by CT scan (excluding sclerotic bone metastasis), and analyzed by an experienced radiologist using the 3DSlicer semiautomatic segmentation tool (TDV = pixel size x number of pixels). Results: Concordance in CRG at patient and mut level was 72% and 55%, respectively. Concordance for ERBB2 (1/1; 100%) and PIK3CA (17/22; 77%) was higher than for ESR1 (8/20; 40%) and AKT1 (2/6; 33%). ctDNA failed to detect 14 mut present in tBx ( ESR1 n = 5, PIK3CA n = 5, AKT1 n = 3, BRAF n = 1). Concordance was 100% for non-luminal and 60% for luminal cases (P = 0.01). In univariate analysis, concordance was not associated with MAF in tBx (P = 0.15), TDV (p = 0.86), number of prior lines of therapy (P = 0.57), number of metastatic sites (P = 0.56) or presence of visceral metastasis (P = 1.0). In patients with PIK3CA mut (N = 22), those with TPP had a numerically higher TDV than those where a PIK3CA mut was not detected in ctDNA (20.9cm3 vs 5.1cm3, P = 0.28). Across all patients, in the multivariate logistic model adjusted for other factors, TDV was a determinant of TPP (OR 1.02, 95%CI 1.0-1.06; P = 0.059). For each increase of 1cm3 in TDV, there was a 2% increase in the probability of detecting a mut in ctDNA. Conclusions: Our results suggest that liquid biopsy testing for the detection of actionable CRG is clinically valid in MBC, although its yield depends on several factors – tumor subtype, analyzed gene, and possibly tumor volume – that reflect both tumor heterogeneity and tumor shedding rate. Due to the potential clinical implications, the observation that mutation detection in ctDNA may correlate with tumor volume merits further study in a larger dataset.

448 Background: Hyperprogressive disease (HPD) is a new pattern of progression in cancer patients (pts) treated with immune checkpoint inhibitors (ICI). The rate and outcome of HDP in pts with metastatic renal carcinoma (RCC) and urothelial carcinoma (UC) are unknown. Here, we report the percentage of HPD in a cohort of pts with GU malignancies treated at our center and explore associations with clinical variables. Methods: Medical records from pts treated in phase I-III clinical trials with ICI alone or in combination between July 2013 and June 2018 were retrospectively reviewed. We defined HPD according to the radiologic VHIO´s criteria (ASCO 2018). Associations between HPD and categorical or continuous variables were evaluated using Fisher exact test and Wilcoxon test respectively. OS were estimated with the Kaplan-Meir method. Statistical analyses were performed using the R statistical software (R version 3.5.0). Results: Overall, 104 pts received therapy with ICI. Of these patients, 16 were not included for the analysis (6 pts with absence of measurable disease, 6 pts did not have CT scan available after the clinical progression and 4 pts treated with ICI plus chemotherapy). Thus, 88 pts were included for the analysis, 29 (33%) with RCC and 59 (67%) with UC. Median follow-up was 7.4 months. Median age was 66.5 years (range 29-91 y).Twenty-three pts (26%) were treated with ICI monotherapy and 65 pts (74%) in combination (anti-CTL4, antiangiogenics, PARP inhibitors, FGFR inhibitors). Forty-seven pts (53%) received ICI as second-line therapy or later. By RECIST v1.1, 26 (30%), 19 (21%) and 43(49%) pts had a best response of progressive disease, stable disease or partial+complete response, respectively. We identified 9 pts (10%) who meet the HPD criteria, 2 pts with RCC and 7 with UC. HPD was associated with anemia at baseline (p = 0.058). Pts with HPD had a trend toward lower overall survival (OS) compared with pts with non-HPD (8.87 vs 4.77 months; p = 0.065). Conclusions: These findings demonstrate that HPD is a phenomenon seen in a significant proportion of pts with RCC and UC and should be taken in account. We found that HPD is associated with poor OS and the anemia at baseline was correlated with HPD.

Bacteremia is the most frequent infectious complication during neutropenia in patients receiving autologous hematopoietic stem cell transplantation (ASCT). The objective of this study was to analyze the incidence, characteristics, risk factors, and outcome of bacteremia during the early period after ASCT. A total of 720 patients undergoing ASCT in two observational prospective consecutive multicenter studies of the Programa Espanol para el Tratamiento de las Hemopatias group were analyzed. Bacteremia occurred in 20 % of patients. Coagulase-negative Staphylococcus was the most frequent (66 %) among the gram-positive agents and Escherichia coli (49 %) among the gram-negative agents. Multivariate analysis showed that the length of neutropenia

We designed a phase II clinical trial including Y-90 ibritumomab-tiuxetan as part of a reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (AlloSCT) in high-risk non-Hodgkin lymphoma (Clinical Trials Identifier: NCT00644371). Eligible patients had high-risk relapsed refractory aggressive lymphoma. The conditioning regimen consisted of rituximab 250 mg (days-21 and -14), Y-90 ibritumomab IV (.4 m Ci/kg, day -14), fludarabine 30 mg/m(2) i.v. (days-3 and -2) plus melphalan 70 mg/m2 i.v. (days-3 and -2) or 1 dose of melphalan and thiotepa 5 mg/kg (day-8). Donors were related. Eighteen patients were evaluable. At the time of transplantation, responses were complete remission (CR) (n = 7, 39%), partial remission (n = 6, 33%) or refractory disease (n = 4, 28%). Y-90-ibritumomab infusions were well tolerated, with no adverse reactions. Nonrelapse mortality at 1 year was 28%. Median follow-up was 46 (range, 39 to 55) months. Estimated 1-year progression-free survival (PFS) was 50%, and 4-year overall survival (OS) and PFS were both 44.4%. CR at the moment of AlloSCT had significant impact on PFS (71% versus 27%, P =.046) and OS (71% versus 27%, P=.047). Our results show that Y-90-ibritumomab-tiuxetan as a component of RIC for AlloSCT is feasible in patients with high-risk B cell lymphoma. Development of phase III clinical trials is needed to clarify the contribution of radioimmunotherapy to RIC AlloSCT. (C) 2017 American Society for Blood and Marrow Transplantation.

762 Table. Age (years) ,50 50-59 60-69 ≥70 Overall N 477 713 873 901 2,968 Peak SBP (mean+SD) 137+25 130+25 131+25 133+23 132+25 Hypertensive cut-point value (mean + 2SD) 187 180 181 179 182 Hypotensive cut-point value (mean -2SD) 87 80 81 87 82 763 Contribution of dobutamine stress echocardiography to the diagnosis and prognosis of low-flow/low-gradient aortic stenosis S. Aguiar Rosa1; G. Portugal1; L. Moura Branco1; A. Galrinho1; M. Afonso Nogueira1; J. Abreu1; D. Cacela1; A. Abreu1; J. Fragata2; R. Cruz Ferreira2 Hospital de Santa Marta, Cardiology, Lisbon, Portugal; Hospital de Santa Marta, Cardiothoracic Surgery , Lisbon, Portugal Purpose: Aortic valve replacement is the treatment of choice in patients (pts) with severe symptomatic aortic stenosis (AS). Pts with depressed left ventricular function and low ejection fraction (LVEF) present as a challenge. Dobutamine Stress Echocardiography (DSE) allows distinguishing fixed Low-Flow/Low-Gradient Aortic Stenosis (LF/LG AS) from pseudo severe AS. Methods: Retrospective analysis of pts who underwent DSE for severe AS investigation, between March 2001 and October 2013. DSE was performed in 3-5 min steps until a maximum dose of 20mcg/kg/min was reached. The baseline echocardiograms, peak DSE, and one year post-op follow-up echocardiograms were analysed. The following parameters were evaluated at basal and peak dose of DSE: left ventricular (LV) end diastolic volume (EDV) and LV end systolic volume (ESV) determined by the Simpson’s biplane method, LVEF, maximum gradient (MaxG), mean gradient (MG) and aortic valve area (AVA) determined by the continuity equation. AS was considered severe if AVA at peak dose was ≤ 1 cm2. The pts were divided into 2 groups according to follow up therapy: aortic valve replacement (GI) or only medical treatment (GII). The average of follow-up period was 26+37 months. Results: 56 pts were analysed, 77% men, with a mean age of 72+7 years. Severe AS was diagnosed in 37 pts (66%). Baseline echocardiographic characteristics were: AVA 0.79+ 0.24cm2, MaxG 45.1+11.6mmHg, MG 27.5+8.5mmHg, LVEF 38.3+13.9%, EDV 155+42 ml, ESV 100+46ml. Peak DSE showed: AVA 0.87+0.36 cm2, MaxG 69.0+ 23.7mmHg, MG 41.5+14.3 mmHg, LVEF 46.2+11.9%, EDV 144.3+35.5 ml, ESV 84.4+32.8 ml. 27 pts (48%) belonged to GI: 2 intervened by transcatheter aortic valve implantation (TAVI) and the remaining 25 by surgery. In GI the mortality was significantly lower than in GII (6pts (22%) VS 20pts (68%); p=0.001). One month after intervention the mortality was null. The survival after one year of follow-up was 91.7% in intervened pts (GI) and 67.9% in non-intervened pts (GII) (p=0.04). In GI with depressed LVEF, there was a significant improvement in LVEF (30.4+5.2% to 42.4+7.0%, p=0.003). On univariate analysis, the predictors of mortality were: age (p=0.023, OR 1.09), peak DSE EDV (p=0.037,OR 1.03), peak DSE ESV (p=0.01, OR 1.07), peak DSE LVEF (p=0.006, OR 0.90) and LVEF improvement , 20% during DSE (p=0.04, OR 1.26). Conclusions: LF/LG AS has a poor prognosis without intervention. DSE permits to establish the lesion severity and define predictors of mortality. In this study age, lack of contractile reserve, peak DSE LVEF,peak DSE EDVandpeak DSE ESVwere predictors ofmortality in follow up. Abstract 760 Figure. ii138 Abstracts Eur Heart J Cardiovasc Imaging Abstracts Supplement, December 2014 by gest on F ebuary 2, 2016 D ow nladed fom 764 The quantitative assessment of the rotation and twist of the left ventricle during dobutamine stress echocardiography A. Mielczarek; JD. Kasprzak; L. Chrzanowski; M. Plewka; P. Lipiec; D. Qawoq; T. Rechcinski; K. Wierzbowska-Drabik Medical University, Lodz, Poland Background: Rotation (R) and twist (T) of the left ventricle (LV) reflects three-layer structure of myocardium and can be assessed quantitatively by speckle tracking echocardiography (STE). Although evaluated in various clinical settings at rest it is poorly validated during stress echocardiography. Aim:Ouraimwas tocalculate and compare rotation atbasalandapical levelsofLVand net twist of LV at rest (0), during peak stage (1) and at recovery (2) of dobutamine stress echocardiography (DSE) in patients without significant lesions in coronary arteries and with negative DSE test. Methods: We analyzed 44 patients with angiographically excluded coronary stenosis ≥50% in left main and ≥70% in other epicardial arteries (27 female, mean age 60+10 years, mean heart rate at baseline 70+12, at the peak 134+17 and at the recovery 92+11, p,0.0001) in whom DSE was performed. Rotation was measured at basal and apical levels of LV. We compared peak systolic rotation (RPS), rotation measured at aortic valve closure (RAVC) and twist (Tcalculated as a difference of basal and apical RAVC) using paired t-test. Results: Neither peak systolic rotation nor rotation measured at endsystole changed significantly during DSE. Similarly twist was practically constant at rest, during peak stage of DSE and at recovery, amounting 6.388, 6.738 and 6.278 respectively, see Table. Conclusions: Peak systolic and end systolic rotation as well as twist of the LV showed distinct independence from heart rate during dobutamine stress echocardiography in patients without significant coronary stenoses. This relationship was observed both at basal and apical level of LV and suggests that rotational parameters are intrinsic features of individual LV mechanics which are constant despite changing inotropic and chronotropic challenge. Abstract 764 Table. Rotation and twist parameters during DSE764 Table. Rotation and twist parameters during DSE Parameter baseline (0) peak DSE (1) recovery (2) p RPS basal segments [8] 23.52+3.17 23.51+4.03 24.15+3.39 ns RPS apical segments [8] 3.93+3.48 3.98+3.75 3.14+2.83 ns RAVC basal segments [8] 22.91+3.33 23.17+3.94 23.87+3.37 ns RAVC apical segments [8] 3.62+3.33 3.71+3.52 2.87+2.73 ns Twist [8] 6.38+4.48 6.73+5.3 6.27+4.01 ns 765 Determinants and prognostic impact of Left Ventricular Contractile Reserve in asymptomatic Aortic Stenosis J. Magne1; E. Donal2; R. Dulgheru3; L. Pierard3; P. Lancellotti3 University Hospital of Limoges, Cardiology, Limoges, France; University Hospital of Rennes Hospital Pontchaillou, Rennes, France; University of Liege Sart Tilman, Liege, Belgium Background: The management of asymptomatic patients with severe aortic stenosis (AS) is extremely controversial. This emphasizes the profound need of new echocardiographic parameters accurate to identify patients at higher risk of poor outcome. There are very few data regarding the assessment, determinants and prognostic value of left ventricular contractile reserve (LVCR) in these patients. We aimed to quantify LVCR and to evaluate its determinants and usefulness for risk stratification in asymptomatic patients with severe AS. Methods and Results: Asymptomatic patients with severe AS (n=150, aortic valve area,1cm, 70+9 years, 64% of male) and preserved left ventricular (LV) systolic function (LV ejection fraction≥55%) were prospectively referred to exercise stress echocardiography. Using 2D speckle tracking analysis, LVCR was defined as an exercise-induced changes in LV global longitudinal strain .2%. LVCR was present in 62 patients (41%) and there was no significant difference between LVCR and no LVCR groups regarding demographic, clinical and exercise data, as well as risk factors. However, patients without LVCR had significantly lower E/Ea ratio and resting LV global longitudinal strain, and higher both resting and exercise indexed left atrial (LA) area. Using multiple linear regression, after adjustment for age, sex and E/Ea ratio, the independent determinant of exercise-induced changes in LV global longitudinal strain were aortic mean pressure gradient (b=0.05+0.02, p=0.005), LV ejection fraction (b=0.06+0.03, p=0.035) and exercise indexed LA area (b=0.20+0.06, p=0.002). During a mean follow-up of 19+12 months, 76 events (51%) occurred. The absence of LVCR was associated with reduced 4-year cardiac event-free survival (26+6 vs. 53+11%, p,0.0001). By opposition, exercise-induced changes in LV ejection fraction did not predict the outcome (p=0.96). In multivariate Cox proportional hazard model, the independent predictors of events were resting brain natriuretic peptide level (p,0.0001), aortic mean pressure gradient (p=0.037), exercise cardiac output (p=0.004) and absence of LVCR (hazard ratio=1.8, 95% of confidence interval: 1.05-3.08, p=0.033). Conclusion: In asymptomatic patients with severe AS, the main determinants of LVCR, as assessed using exercise-induced changes in LV global longitudinal strain, were related to AS severity and exercise LA size. The absence of LVCR is a powerful predictor of reduced cardiac event-free survival. These results strongly support the use of exercise stress echocardiography in asymptomatic AS. Abstracts ii139 Eur Heart J Cardiovasc Imaging Abstracts Supplement, December 2014 by gest on F ebuary 2, 2016 D ow nladed fom

Bone marrow (BM) examination is included in the diagnostic algorithm of fever of unknown origin (FUO), although its role is not clearly determined. The purpose of this study was to assess the role of BM studies in patients with FUO. We retrospectively reviewed 45 consecutive patients (25% human immunodeficiency virus-positive) with FUO who underwent a BM study in the University Hospital of Salamanca from 2000 to 2010. We analysed the diagnostic role of BM smears, multiparameter flow cytometry analysis, histology and microbiological cultures. Five patients (11%) were finally diagnosed by BM study (three had an infectious disease and two were found to have haematological malignancies), all of whom were immunocompetent patients. Histology was the most useful study (diagnosis was obtained in 4/5 patients), while BM cultures did not establish the final diagnosis in any patient. Flow cytometry established the diagnosis in one patient, although this patient was also diagnosed by histology. In conclusion, BM study is useful for establishing the aetiology of FUO. BM biopsy for histological examination should be always mandatory if a BM examination is performed.

Introduction: Over half of patients with chronic myeloid leukemia (CML) in sustained deep molecular remission do not lose the major molecular response (MMR) after stopping treatment with tyrosine kinase inhibitors (TKI). This strategy is safe in controlled clinical trials, but there is scarce information on its applicability in the real-life setting. We aimed to assess if treatment cessation was feasible in clinical practice in a large nationwide series of CML patients from Spain. Methods: This retrospective study comprised a series of 236 patients in chronic-phase CML who discontinued TKI treatment outside of clinical trials between April 2009 and February 2018 in 33 Spanish institutions. Inclusion criteria were: a) TKI treatment duration >3 years; b) sustained MR4.5 in >4 consecutive determinations (one single point in MR4 was acceptable) during >2 years; c) molecular monitoring in a reference laboratory expressing the results on the International Scale (IS). Patients who had undergone allogeneic hematopoietic stem-cell transplantation were excluded. Molecular relapse was defined as consecutively detectable BCR-ABL1 transcripts showing a ≥1 log increase or loss of MMR in any single sample. Treatment-free remission (TFR) was estimated by the method of Kaplan-Meier and defined as the time from TKI discontinuation to the date of restarting therapy for any reason or, if treatment was not restarted, the date of last contact. Incidence of molecular relapse was calculated using the cumulative incidence function with resumption of TKI treatment in the absence of molecular relapse and death in MMR as competing events. Analysis of factors predicting molecular relapse was done by the method of Fine and Gray. Results: Table 1 shows the main characteristics of the series. Median follow-up from treatment discontinuation was 21.5 months, and 5 patients died in MMR due to CML unrelated causes. TKI therapy was reinitiated due to molecular relapse (MMR loss: n=52, increase >1 log in BCR-ABL transcript level at two consecutive assessments without losing MMR: n=12), patient preference (n=2), and severe withdrawal syndrome (n=1). One additional patient lost MMR after 20 months from treatment cessation but decided not to be retreated, with spontaneous recovery of MMR. The probability of TFR at 4 years was 64% (95% Confidence Interval [CI]: 55%-72%)(Figure 1). The cumulative incidence of molecular recurrence was 33% (95% CI: 26%-38%) at 3 years (Figure 2). Forty-nine relapses (75% of total) occurred in the first 6 months. The latest MMR loss was detected 30 months after treatment stop. One patient restarted treatment 44 months after TKI discontinuation due to ≥1 log increase in BCR-ABL1 transcripts in two consecutive samples without losing MMR. In univariate analysis, duration of TKI treatment of less than 5 years (P=0.005) and time in RM4.5 shorter than 4 years before TKI discontinuation (P=0.003) were both significantly associated with a higher incidence of molecular recurrence. No patient progressed to the advanced phases of CML. At the time of restarting treatment, the median BCR-ABL1 IS was 0.3%, with this value being >5% in only 7 instances. Most patients (81%) received the same TKI that they were taking before the trial of treatment cessation. Median follow-up after treatment resumption was 20 months. Among the 64 patients who restarted treatment due to molecular relapse, 46 of 52 cases regained MMR after a median time of 3 months, and 47 of 64 regained MR4.5 after a median time of 5 months. Response status at last control was: MR4.5 (n=196), MR4 (n=15), MMR (n=14), complete cytogenetic response (n=10), and other (n=1). Fifty-one patients (22%) developed musculoskeletal or joint pain after treatment cessation. In patients stopping imatinib, a significant increase in Hb levels, leukocyte counts, total lymphocyte counts, platelet counts, and cholesterol levels was observed. At 6 months, an increase in Hb level >2 g/dL was observed in 47% of patients with anemia. By contrast, nilotinib discontinuation was not followed by any relevant change in laboratory values. Conclusions: Our results confirm that treatment discontinuation is feasible and safe in clinical practice in Spain. Duration of TKI treatment of less than 5 years and a time in RM4.5 shorter than 4 years before TKI discontinuation were significantly associated with a higher incidence of molecular recurrence. Disclosures Hernandez Boluda: Incyte: Consultancy; Novartis: Consultancy. García Gutiérrez:Incyte: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ferrer Marin:Incyte: Consultancy; Novartis: Consultancy, Research Funding. Cervantes:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hospital Clinic Barcelona: Employment.

INTRODUCTION Transplant-associated thrombotic microangiopathy (TMA) is a severe complication after allogeneic stem cell transplantation (ASCT) due to endothelial injury caused by many factors such Calcineurin-inhibitors. In most severe cases, TMA could affect different organs. Intestinal TMA could be fatal and missdiagnosed in many patients. Clinical and pathological criteria to differentiate from intestinal GVHD are needed in order to distinguish both entities with different therapeutical approach. The aim of this study was to review pathological TMA features in patients diagnosed of systemic TMA . PATIENTS AND METHODS We analyzed the incidence of TMA in 527 pts who underwent ASCT in our institution between jan-2010 and apr-2018. Patients were identified if they had TMA according to probable TMA criteria by Ho. We do a pathological review in 96 samples from 18 of 42 patients in whom an endoscopy have been performed after the diagnosis of the TMA; endoscopy have been performed between 30 days before and 60 days after diagnosis of TMA for initial clinical diagnosis of GVHD. Review was performed by a pathologist expert. He examined the biopsies in search of features of GVHD, TMA or viral infection. Diagnosis of GVHD was stablished according to Mcdonald and Sales criteria, intestinal TMA diagnosis was perfomed by the 8 criteria summarized by Warren et al (perivascular mucosal hemorrhage, endothelial cell swelling, endothelial cell separation, intraluminal schistocytes, fibrin or microthrombi, loss of glands and mucosal denudation). RESULTS Baseline/transplant characteristics of patients with TMA are shown in table 1, TMA data in 2 and review hystological features of biopsies in 3. 45 (8.5%) were diagnosed of TMA with a median time from transplant of 75 days. Median age was 49 (19-69). Prophylaxis of GVHD was: Calcineurin inhibitor-MTX in 16 (35.5%), Tacrolimus-Sirolimus in 21 (46.6%), Tacrólimus-MMF and Cyclophosphamide in 8 (17.6%). 42 (93%) had prior or simultaneous acute GVHD, half of them grade III-IV, and 80% with gastrointestinal GVHD. 42% had elevated levels of tacrolimus and 13.6% elevated levels of sirolimus, one week before the diagnosis of TMA. Gastrointestinal MAT have been reported only in 5 patients (28%) at diagnosis whereas when review based on Warren criteria was performed, in 16 patients (89%) the pathologist found at least 1 of the criteria of endothelial damage and 50 % of the patients met 3 or more Warren criteria. The most frequent features were endothelial cell swelling (13 patients, 73 %) and perivascular mucosal hemorrhage (12 patients, 66.7%). In 3 biopsies which we perfomed the inmunochemistry of C4d, an activation of classic way of complement biomarker, it was positive. 4 of the 18 patients (22.2%) presented refractory-hypertension and 3 of them (26.6%) more than 30 mg/d Lof proteinuria, both suggested of poor prognosis. Regarding GVHD, it was founded in 72% at diagnosis and in all patients (18) at pathological review. 13 had grade I, 1 grade II, 1 grade III and 3 histological grade IV). With a median follow-up of 5 months (2-25) 25 of the 45 (56%) are dead. 6 of the deaths (24%) were related to TMA (1 due to TMA, 3 due to TMA+GVHD, 2 due to TMA+infection). Other causes of death were progression (4), GVHD+Infection (7), GVHD (3), infection (2), sinusoidal obstruction síndrome (1) and other causes (2). CONCLUSION TMA is a frequent complication, related with GVHD and underdiagnosed frequently. Only 5 of 18 patients were diagnosed of gastrointestinal TMA. In our study, we found that most of our patients had endotelial damage in the gastrointestinal biopsy pathological reviews. Although histological criteria of GVHD were present at review, in most of them it was only grade I; it contrasts with the severe clinical features. That lack of correlation would suggest that TMA and not GVHD is the main feature. Management of TMA and GVHD are different. To stress an appropiate diagnosis in gastrointestinal TMA is needed in order to offer the patients the best approach. REFERENCES Warren et al. A Complete Histologic Approach to Gastrointestinal Biopsy From Hematopoietic Stem Cell Transplant Patients With Evidence of Transplant-Associated Gastrointestinal Thrombotic Microangiopathy. Arch Pathol Lab Med.2017 Nov;141(11):1558-1566. Jodele S et al. A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015;29(3):191-204. Disclosures No relevant conflicts of interest to declare.

218 Background: CRPC is enriched for germline mutations in DNA damage repair genes (gDDRm). BRCA2 mutations (g BRCA2m) associate with poor prognosis from localized PC, but prognostic and predictive value for standard therapy in CRPC is unclear. We reviewed clinical outcome of 390 patients previously tested for gDDRm. Methods: Patient records were reviewed for 372 patients from 3 institutions (Royal Marsden UK, Weill-Cornell NY, University of Washington, WA) with gDDRm status previously published (Pritchard et al, NEJM 2016) and 18 g BRCA1/2m carriers from KConFab consortium (Australia). Baseline characteristics and survival were annotated. Response (PSA50%/RECIST) and PFS (RECIST/PSA progression or start of a new therapy due to clinical progression) were collected for Abiraterone, Enzalutamide and Docetaxel. To account for potential differences between cohorts, a mixed effect model (Weibull distribution) with random intercept per cohort was pursued. Results: dDDRm status was available for n = 390 (60 gDDRm+, including 37 g BRCA2m, and 330 gDDRm-). Overall, 74% and 69% received Docetaxel and Abiraterone/Enzalutamide respectively; 47% gDDRm+ and 34% gDDRm- received PARPi and/or platinum. Median overall survival from CRPC was 3.0 vs 3.2 years in gDDRm+ vs gDDRm- (p = 0.73; g BRCA2m = 3.0 years, p = 0.72). Age and Gleason score at diagnosis were associated with survival from castration-resistance in multivariate analysis. Median PFS on Docetaxel for gDDRm+ (6.8 months; 6.3 for g BRCA2m) and gDDRm- (5.1 months) were not significantly different (p = 0.2). Similarly, RR to Docetaxel was similar for the two groups (61% vs 54% in gDDRm+ vs gDDRm-; 63% g BRCA2m). Median PFS and RR on first Abiraterone/Enzalutamide were similar across groups (PFS: 8.3 months gDDRm+, 8.3 months for gDDRm-; p = 0.9; RR 46% vs 56% respectively) The Interaction of PARPi/platinum therapy among gDDRm+ patients resulted in an aHR for OS from CRPC of 0.59 (95%CI 0.28-1.25; p = 0.17). Conclusions: In this retrospective analysis, CRPC patients with gDDRm still benefited from standard therapies similarly to non-mutation carriers; interpretation of survival data should consider the high proportion treated with PARPi/platinum.

For PETHEMA Programa para el Estudio de la Terapéutica en Hemopatías Malignas Cooperative Study Group., The clinical utility of minimal residual disease (MRD) analysis in acute myeloid leukaemia (AML) is not yet defined. We analysed the prognostic impact of MRD level at complete remision after induction therapy using multiparameter flow cytometry in 306 non-APL AML patients. First, we validated the prognostic value of MRD-thresholds we have previously proposed (≥0.1%; ≥0.01-0.1%; and, This work was supported in part by Spanish grants from Fondo de Investigación Sanitaria-ISCIII (FIS 00/0023-03, PI12/02321), DGCYT (SAF 94- 0308, SAF2001-1687), Conserjería de Educación de Castilla y León (HUS416A12), and Red Temática de Investigación Cooperativa en Cáncer (RTICC-ISCIII) (RD12/0036/0069).

BACKGROUND Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib. METHODS We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies. RESULTS Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes - including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2 - in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib. CONCLUSIONS Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.)

Previous reports ascribe a modulating capacity of the immune response to Helicobacter pylori (HP). Our hypothesis was to demonstrate in a prospective study that HP infection could have a protective effect against development of gastrointestinal GvHD in patients receiving allogeneic hematopoietic cell transplantation (HCT). Presence of HP before transplant was determined using C(13) urea breath test. Seventy-nine patients receiving an allogeneic HCT were included and 93.7% of them received PBSC; in 51.9%, the donor was unrelated. Acute gastrointestinal GvHD was diagnosed in 51.9% (n=41). In the multivariable analysis, HP infection was associated with a lower frequency of gastrointestinal GvHD (odds ratio (OR)=0.19 (95% confidence interval (CI): 0.05-0.67); in contrast, an unrelated donor was associated with a higher frequency of gastrointestinal GvHD (odds ratio=5.4 (95% confidence interval: 1.6-18.2). One year overall survival (OS) was 74%. In the multivariate Cox proportional-hazards regression analysis, stages 0-II gastrointestinal GvHD (hazards ratio (HR)=0.19), reduced intensity conditioning (HR=0.04) and tacrolimus-sirolimus GvHD prophylaxis (HR=0.06) were all associated with a better OS. In summary, HP infection could have a role in decreasing gastrointestinal GvHD in patients receiving allogeneic HCT from peripheral blood including related and unrelated donors.

After a previous analysis that did not detect clear differences in the results of three conditioning regimens used for autologous stem cell transplantation (ASCT) in patients from the Spanish Registry for Transplant in Multiple Myeloma (MM), we have updated the registry, including a larger number of cases and a fourth conditioning regimen with a longer follow-up. We evaluate 472 MM patients treated with 200 mg/m2 melphalan (MEL200), 135 patients treated with 140 mg/m2 melphalan plus total body irradiation [(MEL140 + TBI)], 186 patients treated with 12 mg/kg busulphan plus 140 mg/m2 melphalan (BUMEL) and 28 patients treated with 14 mg/kg busulphan followed by cyclophosphamide 120 mg/kg (BUCY). There were no significant differences in respect to either transplant related death or haematological recovery, regardless of growth factor use, between the four conditioning programs. Nevertheless, hospitalization time with MEL200 was less than with BUMEL when growth factors were used (19+/-9 vs. 25+/-9 days, P = 0.009) and less than with MEL140 + TBI without growth factors (20+/-8 days vs. 27+/-9 days, P = 0.002). In patients with measurable disease at ASCT (non-complete remission [CR]), BUMEL achieved a 51% CR vs. 43%-31% in the other groups (P = 0.007). The response rate for patients in partial remission (PR) at ASCT was 100% with BUMEL vs. 93%-86% in the other groups (P between 0.02 and 0.0007). The median overall survival (OS) for the BUMEL group was 57 months (95% confidence interval [CI]: 51-78) as compared to 45 (CI: 36-64) months for the MEL200 group and 39 (CI: 28-72) months for the MEL140 + TBI and BUCY groups. The median event free survival (EFS) was longer in the BUMEL group [30 (CI: 22-44) mo] than in the MEL200 [22 (CI: 18-26) mo], BUCY [23 (CI: 11-50) mo] or MEL140 + TBI groups [20 (CI: 15-29) mo]. Nevertheless, the differences in OS and EFS did not reach statistical significance in either the univariate analysis or the multivariate analysis adjusted with other high prognostic weight factors. As in the initial study, differences in regards to the anti-myeloma effect of the conditioning regimens are not conclusive. However, the better response rates associated with the favorable tendency in outcome achieved with BUMEL, continue to justify further prospective studies.

5071 Background: An urgent need exists for new therapies after progression (PD) onAA and enzalutamide (ENZ). Increased PR expression or progesterone-activating AR mutations have been associated with resistance to AR targeting. We aimed to test ONA, a type I PR antagonist with clinical activity in PRpos cancers, in AA/enz-resistant CRPC. In a prospectively defined exploratory analysis, we aimed to report outcome by plasma AR status ( pAR). Methods: This was a multi-institution, open label phase I/II clinical trial in pts progressing after ENZ/AA. Pts were first treated with single agent (SA) ONA using a randomised dose escalation design. ONA at 2 doses was then combined with AA (1000mg od with pred 5mg bid) in pts progressing on AA. The primary end-points were safety, pharmacokinetics (PK) and anti-tumor activity split by p AR. Archival and metastatic biopsies were collected when possible and tested for PR status. p AR was studied using previous methods (Romanel STM 2015). Results: 21 pts received SA ONA (5 = 10mg/ 5 = 20mg/ 4 = 30mg/ 4 = 40mg /3 = 50mg BID) and 15 pts received ONA-AA combination (5 = 30mg ONA BID, 10 = 50mg ONA BID). There were not DLTs or significant LFT abnormalities and no G3/4 adverse events (AE), no treatment discontinuations due to AEs and no SAEs considered related to ONA. PK in SA ONA observed active plasma concentrations and no interaction with AA. Of 32 evaluated pts 15 had a 2105T > A (p.L702H) or 2632A > G (p.T878A) AR mutation detected in plasma pre-treatment and 1 had AR copy number gain. PSA declines were not observed with SA ONA but in 2 pts with combination (-30%, -7%) who were AR normal. The rPFS on SA ONA was 2.8 months for AR normal and 2.6 for AR aberrant (Hazard ratio (HR) 1.41; 95% CI, 0.62-3.72; P 0.48) and on combination was 4.4 months for AR normal (8/15) and 2.2 for AR aberrant (7/15) (HR 6.08; 95%CI, 6.32-221.9; P < 0.001). Conclusions: ONA is safe in CRPC as SA and in combination with AA. There was no difference in rPFS by p AR status for SA ONA but on the combination with AA, pts who were plasma AR normal had a significantly longer rPFS. Clinical trial information: NCT02049190.