Citations

Abstract Background Modern-day penile prostheses use infection retardant coating to decrease rates of postoperative infection, subsequently reducing explantation and revision rates as well. The Coloplast Titan models are dipped into antimicrobial solutions right before implantation, and the components used for dipping can be tailored toward the patient. Aim To compare infection, explantation, and revision rates among different dipping solutions used before implantation for patients with diabetes receiving a Coloplast Titan implant. Methods We systematically reviewed 932 patients with diabetes receiving a primary penile implant across 18 different centers from the period April 2003 to August 2018. Of those patients, 473 received a Coloplast device, whereas 459 received an AMS device. Data regarding the type of antimicrobial solution used before implantation were recorded for 468 patients receiving a Coloplast Titan, including whether or not they suffered a postoperative infection and if they underwent explantation and/or revision. Outcome rates were compared using Fisher’s exact and Pearson’s chi-square tests, and logistic regression modeling was performed to account for covariates. Outcomes The main outcome measures of this study were postoperative infection, explantation, and revision rates. Results Of the total 932 patients reviewed, 33 suffered a postoperative infection. Of 468 patients receiving Coloplast implants, there was a 3.4% infection rate. The most commonly used antibiotic combination before dipping was vancomycin + gentamicin (59.0%). There was a significantly lower rate of postoperative infection, explantation, and revision when vancomycin + gentamicin was used than those associated with the use of all other dipping solutions ([1.4% vs 6.4%; P = .004], [1.1% vs 8.3%; P < .001], and [2.5% vs 12.5; P < .001], respectively). After adjusting for age, body mass index, preoperative blood glucose level, and hemoglobin A1c, the use of other dips was an independent predictor of postoperative infection (odds ratio: 0.191; P = .049). The inclusion of rifampin in the dipping solution trended toward being a significant risk factor for infection (P = .057). Including antifungals in the dipping solution did not affect infection (P = .414), explantation (P = .421), or revision (P = .328) rates. Clinical Implications Vancomycin + gentamicin was the most efficacious combination of antibiotics used for dipping in terms of preventing postoperative infection and subsequent explantation and revision. Strengths and Limitations Data were sampled across multiple institutions providing a large sample that may be more representative of the population of interest. A key limitation of the study was its retrospective nature, which prevented us from controlling certain variables. Conclusion The use of rifampin did not provide the same type of protection, possibly representing a shift in resistance patterns of common bacteria responsible for device infection.

AbstractCWP232291 (CWP291) is a small-molecule inhibitor of Wnt signaling that causes degradation of β-catenin via apoptosis induction through endoplasmic reticulum stress activation. This first-in-human, open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of CWP291 enrolled 69 patients with hematologic malignancies (acute myeloid leukemia [AML], n = 64; myelodysplastic syndrome, n = 5) in 15 dose-escalation cohorts of 4 to 334 mg/m2 using a modified 3+3 design and 1 dose-expansion cohort. CWP291 was administered IV daily for 7 days every 21 days. The most common treatment-emergent adverse events (TEAEs) were nausea (n = 44, 64%), vomiting (n = 32, 46%), diarrhea (n = 25, 36%), and infusion-related reactions (n = 20, 29%). Grade ≥3 TEAEs in >3 patients (5%) were pneumonia (n = 8, 12%); hypophosphatemia (n = 6, 8%); leukocytosis, nausea, cellulitis, sepsis, and hypokalemia (n = 5 each, 7% each); and hypertension (n = 4, 6%). Dose-limiting toxicities included nausea (n = 3) and abdominal pain, anaphylactic reaction, myalgia, and rash (n = 1, each); the MTD was defined at 257 mg/m2. CWP232204, the active metabolite of CWP291, showed pharmacokinetic linearity on both days 1 and 7, and a terminal half-life of ∼12 hours. Among 54 response-evaluable AML patients, there was one complete response at a dose of 153 mg/m2 and one partial response at 198 mg/m2; bone marrow blast percentage reduced from a median of 58.3% to 3.5% and 15.0% to 4.2%, respectively. Future studies will explore CWP291, with a mechanism of action aimed at eradication of earlier progenitors via Wnt pathway blockade, as combination therapy. This trial was registered at www.clinicaltrials.gov as #NCT01398462.

Abstract cIMPACT‐NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT‐NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles—relating to classification categories, approaches to classification, nomenclature, and grading—that the group hopes will also inform the future classification of CNS neoplasms.

Abstract Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs ≥5 years of age at the time of HCT (94% vs 66%; overall P = .0008). OS was excellent regardless of donor type, even in cord blood recipients (90%). Conditioning intensity did not affect OS, but was associated with donor T-cell and myeloid engraftment after HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005, compared with prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution after either myeloablative or busulfan-containing reduced intensity conditioning. (This trial was registered at www.clinicaltrials.gov as #NCT02064933.)

Diabetes is a metabolic disease which affects not only glucose metabolism but also lipid and protein metabolism. It encompasses two major types: type 1 and 2 diabetes. Despite the different etiologies of type 1 and 2 diabetes mellitus (T1DM and T2DM, respectively), the defining features of the two forms are insulin deficiency and resistance, respectively. Stem cell therapy is an efficient method for the treatment of diabetes, which can be achieved by differentiating pancreatic β-like cells. The consistent generation of glucose-responsive insulin releasing cells remains challenging. In this review article, we present basic concepts of pancreatic organogenesis, which intermittently provides a basis for engineering differentiation procedures, mainly based on the use of small molecules. Small molecules are more auspicious than any other growth factors, as they have unique, valuable properties like cell-permeability, as well as a nonimmunogenic nature; furthermore, they offer immense benefits in terms of generating efficient functional beta-like cells. We also summarize advances in the generation of stem cell-derived pancreatic cell lineages, especially endocrine β-like cells or islet organoids. The successful induction of stem cells depends on the quantity and quality of available stem cells and the efficient use of small molecules.

Abstract Background: This Phase 2 study (NCT02383927) is a multi-institutional, open-label trial to determine the efficacy and safety of tipifarnib in patients (pts) with locally advanced/unresectable and/or metastatic solid tumors that carry HRAS missense mutations. HRAS is a proto-oncogene that is overexpressed and mutated in head and neck squamous cell carcinomas (HNSCC) and other SCCs. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase, a critical enzyme for HRAS activity. Methods: Pts received tipifarnib at a starting dose of 600 – 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles. Disease assessments were conducted according to RECIST v1.1 criteria. Null hypothesis and objective response of interest were respectively 10% and 30%. Prior to its completion, this study met its primary objective and, based on preliminary efficacy results (Ho, et. al, ESMO 2018), was amended to continue enrolling only pts with HNSCC (Cohort 2) and other SCC tumors (Cohort 3) carrying HRAS missense mutations at a high variant allele frequency (VAF >35% or ≥20% if baseline serum albumin is >3.5 g/dL). Results: As of May 1, 2019, 23 pts with HNSCC and 10 pts with tumors with other SCC histologies have been treated with tipifarnib. Pts had relapsed/refractory disease with a median of 2 prior regimens. Of note, no objective partial responses were observed on their last therapy prior to study entry, including platinum, immunotherapy and cetuximab +/- chemotherapy. In 15 HNSCC pts meeting the HRAS mutation high VAF inclusion criteria, a 53% overall response rate (ORR) was observed, with 8 confirmed partial responses (PR) and 5 disease stabilizations (SD). Two pts await first on-study tumor response assessment. Overall median progression free survival (PFS) was 5.4 mos (95% CI 4.5 to 19.5 mos, N=15); 19 mos (95% CI 5.3 to 19.5 mos) for pts experiencing a PR and 4.5 mos (95% CI 1.6 to 5.4 mos) for those experiencing SD. Median PFS on last prior therapy was 3.2 mos. All pts had at least 1 treatment-emergent adverse event (TEAE). The most frequently observed drug-related Grade >3 TEAEs occurring in ≥10% pts were blood and lymphatic system disorders, gastrointestinal disorders and renal disorders. Conclusions: Encouraging activity of tipifarnib was observed in HRAS mutant HNSCC. Based on these data, a pivotal study (AIM-HN and SEQ-HN Study, NCT03719690) evaluating the efficacy of this agent in HRAS mutant HNSCC (AIM-HN) and the impact of HRAS mutations on first line therapy of HNSCC (SEQ-HN) has been initiated. Citation Format: Alan Ho, Irene Brana, Robert Haddad, Jessica Bauman, Keith Bible, Laurence Faugeras, Sjoukje Oosting, Deborah J Wong, Myung-Ju Ahn, Valentina Boni, Caroline Even, Jerome Fayette, Maria Jose Flor, Kevin Harrington, Sung-Bae Kim, Lisa Licitra, Ioanna Nixon, Nabil F Saba, Cyrus Sayehli, Pol Specenier, Francis Worden, Binaifer Balsara, Jeanne Britt, Vishnu Mishra, Catherine Scholz, Antonio Gualberto. Preliminary results from a phase 2 trial of tipifarnib in squamous cell carcinomas (SCCs) with HRAS mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR08. doi:10.1158/1535-7163.TARG-19-PR08

Abstract Background: The combination of cyclin dependent 4/6 kinase inhibitors (CDK4/6i) with endocrine therapy (ET) has resulted in clinically significant improvements in progression-free survival (PFS) and overall survival (OS) in hormone-receptor (HR)-positive metastatic breast cancer (MBC). However, most patients’ disease ultimately progresses on CDK4/6i and ET. Therefore, further research is necessary to understand the mechanisms driving primary and secondary resistance. PROMISE is a multicenter prospective cohort study enrolling women with HR-positive MBC commencing treatment with palbociclib + letrozole (1st line) or palbociclib + fulvestrant (2nd Line). The study provides a comprehensive “omic” assessment of blood, tumor, urine and the fecal microbiome to identify molecular or cellular features associated with primary endocrine resistance (e.g. disease progression ≤ 12 months on treatment) and acquired resistance to CDK 4/6i. Additionally, patient derived xenografts and organoids are created to test new drug strategies designed to overcome resistance to CDK 4/6i and ET. Here, we present initial sequencing results from pretreatment biospecimens collected from PROMISE study participants. Methods: On-study tumor biopsies and blood samples were collected for DNA/RNA sequencing (TempusTM). The analyzed biospecimens were all obtained prior to initiation of palbociclib and ET. We correlated patient clinical characteristics (phenotypes) with molecular data and responses to protocol treatment. The data were analyzed using a series of cutting-edge bioinformatics pipelines for somatic and germline mutations in addition to copy number alterations (CNAs). The study database was locked for analysis on 06/20/2019. Results: We analyzed the somatic single nucleotide variants/INDELs (sSNV/INDEL) profiles across the tumor samples to determine the genes that were least likely to occur as a result of background mutation processes. Twenty-six patients had somatic copy number alterations (sCNA) and/or sSNV/INDEL in at least one of 18 genes with the most significant sSNV/INDEL profiles (p < 0.03) which included clinically and biologically relevant genes. The genes with the most statistically significant sSNV/INDEL mutation profiles were GATA3, PIK3CA, CDH1, and ESR1 (p < 0.0009). We observed a high percentage of tumors with somatic alterations in GATA3 (23% sSNV/INDEL, 15% sCNA), PIK3CA (38%, 12%), CDH1 (19%, 50%) and ESR1 (19%, 58%). ESR1 mutations were more frequent in patients receiving 2nd line treatment. Other frequently altered genes included TP53 (15%, 46%), MAP2K4 (8%, 50%), DNAAF1 (8%, 50%), and CDKN1B (8%, 35%). Further, ZNF317 and F3 were altered in 9 and 7 patients, respectively. Twenty-four samples had alterations in at least one of the CDK4/6 pathway genes (RB1, CCNE2, CCND1, CDK6, ESR1, CDKN2A, CCND3, CDK4, CDK2 and CCNE1). Four patients progressed on therapy; three of the four patients had mutations in PIK3CA, and one had a mutation in ESR1. Results of the RNA sequencing data (N=26) will be presented at the SABCS meeting. Conclusions: This is the first report of a prospective study designed to characterize the genomic landscape of ER+/HER2- MBC prior to palbociclib treatment. We observed high frequencies of known targetable alterations in PIK3CA and ESR1, including in patients that progress, which is consistent with previous reports. RNA sequencing data will be presented at the meeting. Citation Format: Ciara C O Sullivan, Krishna R Kalari, Vera J Suman, Peter T Vedell, Ann Moyer, Erin Carlson, Jason Sinnwell, Tejaswi Alaparthi, Xiaojia Tang, Kevin Thompson, Jaeyun Sung, Alvaro Moreno-Aspitia, Donald Northfelt, Minetta C Liu, Tufia C Haddad, Prema Peethambaram, Saranya Chumsri, Kathryn J Ruddy, Karthik V Giridhar, Roberto A Leon-Ferre, Paula Gill, Mohammad Ranginwala, Asad Javed, Sameer Batoo, Brendan P. McMenomy, Richard Weinshilboum, Liewei Wang, Matthew P Goetz. Comprehensive tumor sequencing to identify biomarkers of palbociclib response: First report of the PROMISE study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-07.

OBJECTIVE The nature of the volume-outcome relationship in cases with severe traumatic brain injury (TBI) remains unclear, with considerable interhospital variation in patient outcomes. The objective of this study was to understand the state of the volume-outcome relationship at different levels of trauma centers in the United States. METHODS The authors queried the National Trauma Data Bank for the years 2007–2014 for patients with severe TBI. Case volumes for each level of trauma center organized into quintiles (Q1–Q5) served as the primary predictor. Analyzed outcomes included in-hospital mortality, total hospital length of stay (LOS), and intensive care unit (ICU) stay. Multivariable regression models were performed for in-hospital mortality, overall complications, and total hospital and ICU LOSs to adjust for possible confounders. The analysis was stratified by level designation of the trauma center. Statistical significance was established at p < 0.001 to avoid a type I error due to a large sample size. RESULTS A total of 122,445 patients were included. Adjusted analysis did not demonstrate a significant relationship between increasing hospital volume of severe TBI cases and in-hospital mortality, complications, and nonhome hospital discharge disposition among level I–IV trauma centers. However, among level II trauma centers, hospital LOS was longer for the highest volume quintile (adjusted mean difference [MD] for Q5: 2.83 days, 95% CI 1.40–4.26 days, p < 0.001, reference = Q1). For level III and IV trauma centers, both hospital LOS and ICU LOS were longer for the highest volume quintile (adjusted MD for Q5: LOS 4.6 days, 95% CI 2.3–7.0 days, p < 0.001; ICU LOS 3.2 days, 95% CI 1.6–4.8 days, p < 0.001). CONCLUSIONS Higher volumes of severe TBI cases at a lower level of trauma center may be associated with a longer LOS. These results may assist policymakers with target interventions for resource allocation and point to the need for careful prehospital decision-making in patients with severe TBI.

e19013 Background: Mutation profiling to assess for potentially druggable mutations in NSCLC is being offered at an increasing number of cancer centers throughout North America and internationally. Although data continue to accumulate for the potential value of mutation testing in designing chemotherapeutic regimens, the treatment impact of obtaining information beyond assessment of EGFR and ALK status remains unclear. How best to obtain and clinically utilize these data, including information from exome and whole genome sequencing, also remains unclear. Methods: Patients were reviewed electronically in a multidisciplinary conference regarding indications for testing and results of mutation profiling from various methods, including the mass-spec based LungCarta test, targeted NexGen sequencing, exome, and whole genome sequencing. Outcomes of the multidisciplinary review were communicated back to treating physicians. Results: Mutation testing was performed on 200 patients using a variety of approaches. The majority (>150) were surgically resected stage I and II tumors. Mutations in at least 1 major cancer driver gene, including EGFR, KRAS, MET, BRAF and PIK3CA, were found in 47% of all patients tested. EGFR mutations were present in 14.8% of patients tested, KRAS 21.3%, BRAF 2.6%, PIK3CA 3.2%, and MET 4.5%. A total of 8 patients underwent either exome or whole genome sequencing. A limited number of patients (<10) had mutation results that impacted treatment decisions from this cohort. Conclusions: Mutation profiling can influence treatment decisions in NSCLC, but at a low frequency. The role of exome and or whole genome sequencing for patients with NSCLC is evolving and remains undefined.