In injured and diseased tissues, changes in molecular and cellular compositions, as well as tissue architecture, lead to alterations in both physiological and physical characteristics. Notably, the electrical properties of tissues, which can be characterized as bioelectrical impedance (bioimpedance), are closely linked to the health and pathological conditions of the tissues. This highlights the significant role of quantitatively characterizing these electrical properties in improving the accuracy and speed of diagnosis and prognosis. In this study, we investigate how diseases, injuries, and physical conditions can affect the electrical properties of lung tissues, using both rat and human lung tissue samples. Results showed that rat lung and trachea tissues exhibit a frequency-dependent behavior to alternating current (AC) across the frequency range of 0.1-300 kHz. The bioimpedance of the lung tissue increased with the level of aeration of the lung, which was manipulated by altering alveolar pressure (PALV: 1-15 cmH2O; bioimpedance level: 1.2-2.8 kS2; AC frequency: 2 kHz). This increase is mainly because air is electrically nonconductive. The bioimpedance of rat lungs injured via intratracheal aspiration of hydrochloric acid (HCl; volume: 1 mL; AC frequency: 2 kHz) decreased by at least 82 % compared to that of healthy control lungs due to accumulation of fluids inside the airspace of the injured lungs. Moreover, using decellularized lung tissues, we determined the contributions of cellular components and tissue extracellular matrix (ECM) on the electrical characteristics of the lung tissues. Specifically, we observed a considerable increase in bioimpedance in fibrotic human lung tissues due to excessive ECM deposition (healthy: 70.8 S2 +/- 10.2 S2, fibrotic: 132.1 S2 +/- 15.8 S2, frequency: 2 kHz). Overall, the findings of this study can enhance our understanding of the correlation between electrical properties and pathological lung conditions, thereby improving diagnostic and prognostic capabilities and aiding in the treatment of lung diseases and injuries. Statement of significance: The bioelectrical properties of tissue are closely linked to both its physiological and physical characteristics. This underscores the importance of quantitatively characterizing these properties to improve the accuracy and speed of diagnosis and prognosis. In this study, we investigate how the bioelectrical properties of lung tissues are affected by different physical states and pathological conditions using rat and human lung tissues. As the burden of lung diseases continues to increase, our findings can contribute to improved treatment outcomes by enabling accurate and rapid assessment of lung tissue conditions.

Chronobiology investigations have revealed much about cellular and physiological clockworks but we are far from having a complete mechanistic understanding of the physiological and ecological implications. Here we present some unresolved questions in circadian biology research as posed by the editorial staff and guest contributors to the Journal of Circadian Rhythms. This collection of ideas is not meant to be comprehensive but does reveal the breadth of our observations on emerging trends in chronobiology and circadian biology. It is amazing what could be achieved with various expected innovations in technologies, techniques, and mathematical tools that are being developed. We fully expect strengthening mechanistic work will be linked to health care and environmental understandings of circadian function. Now that most clock genes are known, linking these to physiological, metabolic, and developmental traits requires investigations from the single molecule to the terrestrial ecological scales. Real answers are expected for these questions over the next decade. Where are the circadian clocks at a cellular level? How are clocks coupled cellularly to generate organism level outcomes? How do communities of circadian organisms rhythmically interact with each other? In what way does the natural genetic variation in populations sculpt community behaviors? How will methods development for circadian research be used in disparate academic and commercial endeavors? These and other questions make it a very exciting time to be working as a chronobiologist.

This phase I, dose-escalation trial evaluates the safety of combining interferon-gamma (IFN-γ) and nivolumab in patients with metastatic solid tumors. Twenty-six patients are treated in four cohorts assessing increasing doses of IFN-γ with nivolumab to evaluate the primary endpoint of safety and determine the recommended phase two dose (RP2D). Most common adverse events are low grade and associated with IFN-γ. Three dose limiting toxicities are reported at the highest dose cohorts. We report only one patient with any immune related adverse event (irAE). No irAEs ≥ grade 3 are observed and no patients require corticosteroids. The maximum tolerated dose of IFN-γ is 75 mcg/m 2 , however based on a composite of safety, clinical, and correlative factors the RP2D is 50 mcg/m 2 . Exploratory analyses of efficacy in the phase I cohorts demonstrate one patient with a complete response, and five have achieved stable disease. Pre-planned correlative assessments of circulating immune cells demonstrate intermediate monocytes with increased PD-L1 expression correlating with IFN-γ dose and treatment duration. Interestingly, post-hoc analysis shows that IFN-γ induction increases circulating chemokines and is associated with an observed paucity of irAEs, warranting further evaluation. ClinicalTrials.gov Trial Registration: NCT02614456.

Emergency and trauma physicians typically rely on anatomic landmarks to determine the proper intercostal space for emergent tube thoracostomy. However, physicians using this technique select a potentially dangerous insertion site too inferior in nearly one-third of cases, which have the potential to result in subdiaphragmatic puncture. We investigated a point-of-care ultrasound (POCUS) thoracic “Quick Look” procedure as a technique to allow visualization of underlying structures to avoid tube misplacement. We performed an observational study of adult emergency department patients and their treating physicians. The patient’s emergency physician was asked to rapidly identify and mark a hypothetical tube thoracostomy insertion site on the patient’s chest wall. An ultrasound fellow then performed a POCUS thoracic “Quick Look” exam with a phased-array probe placed directly over the marked site. Over one regular respiratory cycle, the identification of standard lung pattern was considered a negative scan whereas visualization of the diaphragm with underlying liver or spleen was considered a positive scan. Time for completion of the “Quick Look” scan was measured and inter-rater reliability was determined through image review by a single, blinded ultrasound director. Seventy-six thoracic “Quick Look” scans were performed on patient subjects, of which 17

Purpose: Concern for discordance between clinical staging and final pathology drives current management of patients deemed appropriate candidates for radical cystectomy. Therefore, we set out to prospectively investigate reliability and shortcomings of cystoscopic evaluation in radical cystectomy candidates. Materials and Methods: Patients undergoing radical cystectomy for urothelial carcinoma were enrolled in a prospective single-arm study to evaluate reliability of Systematic Endoscopic Evaluation in predicting pT0 urothelial carcinoma (NCT02968732). Systematic Endoscopic Evaluation consisted of cystoscopy and tissue sampling at the time of radical cystectomy. Systematic Endoscopic Evaluation results were compared to radical cystectomy pathology. The primary end point was the negative predictive value of Systematic Endoscopic Evaluation findings in predicting radical cystectomy pathology. Results: A total of 61 patients underwent Systematic Endoscopic Evaluation and radical cystectomy. Indications included muscle invasive bladder cancer in 42 (68.9%) and high risk nonmuscle invasive bladder cancer in 19 (31.1%). In all, 38 (62.3%, 90.5% of patients with muscle invasive bladder cancer) received neoadjuvant chemotherapy. On Systematic Endoscopic Evaluation, 31 (50.8%) patients demonstrated no visual nor biopsy-based evidence of disease (seeT0), yet 16/31 (51.6%) harbored residual disease (>pT0), including 8 (8/31, 25.8%) with residual >= pT2 disease upon radical cystectomy. The negative predictive value of Systematic Endoscopic Evaluation predicting a pT0 bladder was 48.4% (CI 30.2-66.9), which was below our prespecified hypothesis. Therefore, the trial was stopped for futility. Conclusions: Approximately 1 of 4 patients with seeT0 at the time of radical cystectomy harbored residual muscle invasive bladder cancer. These prospective data definitively confirm major limitations of endoscopic assessment for pT0 bladder cancer. Future work should focus on novel imaging and biomarker strategies to optimize evaluations before radical cystectomy for improved decision making regarding bladder preservation.

Background Divergence time estimation is fundamental to understanding many aspects of the evolution of organisms, such as character evolution, diversification, and biogeography. With the development of sequence technology, improved analytical methods, and knowledge of fossils for calibration, it is possible to obtain robust molecular dating results. However, while phylogenomic datasets show great promise in phylogenetic estimation, the best ways to leverage the large amounts of data for divergence time estimation has not been well explored. A potential solution is to focus on a subset of data for divergence time estimation, which can significantly reduce the computational burdens and avoid problems with data heterogeneity that may bias results. Results In this study, we obtained thousands of ultraconserved elements (UCEs) from 130 extant galliform taxa, including representatives of all genera, to determine the divergence times throughout galliform history. We tested the effects of different "gene shopping" schemes on divergence time estimation using a carefully, and previously validated, set of fossils. Our results found commonly used clock-like schemes may not be suitable for UCE dating (or other data types) where some loci have little information. We suggest use of partitioning (e.g., PartitionFinder) and selection of tree-like partitions may be good strategies to select a subset of data for divergence time estimation from UCEs. Our galliform time tree is largely consistent with other molecular clock studies of mitochondrial and nuclear loci. With our increased taxon sampling, a well-resolved topology, carefully vetted fossil calibrations, and suitable molecular dating methods, we obtained a high quality galliform time tree. Conclusions We provide a robust galliform backbone time tree that can be combined with more fossil records to further facilitate our understanding of the evolution of Galliformes and can be used as a resource for comparative and biogeographic studies in this group.

Influenza D viruses (IDV) belong to a new genus in the family Orthomyxoviridae. IDV is the aetiologic agent of acute, mild respiratory disease in ungulate species with agricultural importance (cattle, pigs, sheep, goats, camels, etc.). Despite the initial isolate being of porcine origin, serological data suggest cattle to be the primary host of IDV. The study aims were twofold: elucidating species-specific replication kinetics of IDV in bovine and porcine hosts and defining the interspecies potential with two different IDV strains. Three calves and three pigs were intranasally inoculated with the prototypic strain D/swine/Oklahoma/1334/2017 or a genetically distinct cattle isolate, D/bovine/Texas/72/2017. Two days following infection, three naïve pigs and three naïve calves were co-housed with inoculated calves and pigs, respectively. The species of IDV origin had no effect on virus replication kinetics in the upper respiratory tract of inoculated calves and pigs; similar shedding profiles were observed for each species and virus. However, interspecies transmission was found to be associated with virus origin species; D/bovine/Texas/72/2017 and D/swine/Oklahoma/1334/2017 were directly transmitted only to contact calves or pigs, respectively. Even so, transmission efficiency was higher for calves compared to pigs. Together, these data show that cattle and pigs are permissive for IDV replication, but IDV transmission may be species dependent. Host-specific mutations likely influenced transmission efficiencies between agriculturally important mammalian species.

INTRODUCTION AND OBJECTIVE: Concern for discordance between endoscopic evaluation and final pathology drives current clinical management of patients deemed appropriate candidates for radical cystectomy (RC). Yet, > 30% of patients (pts) who undergo neoadjuvant chemotherapy (NAC) prior to RC do not harbor detectable malignancy within the bladder at the time of extirpative surgery. Our objective was to prospectively assess the reliability of cystoscopic evaluation in RC candidates. METHODS: Pts undergoing RC for urothelial carcinoma (UC) at our institution were enrolled in a prospective single-arm study to evaluate reliability of Systematic Endoscopic Evaluation (SEE) in predicting pT0 UC. SEE consisted of rigid cystoscopy with targeted biopsy (and transurethral resection with loop after protocol amendment) of visible tumor and/or tumor bed/scar, plus two additional random biopsies performed at the time of RC. A standardized bladder map was used to index cystoscopic findings. SEE and biopsy results were compared to RC pathology. Comparisons were considered congruent if both SEE and RC were T0, or if any level of disease seen at both SEE and RC (exception, cT0 with pTis at RC called congruent). This trial design included early stopping rules for futility based on the primary endpoint of a negative predictive value (NPV) less than 70%. RESULTS: In total, 61 pts underwent SEE and RC as part of this trial. The final population included MIBC in 41 pts (67%) and high-risk NMIBC in 20 pts (33%). 38 pts (62%) received platinum-based neoadjuvant chemotherapy. Based on RC final pathology, 16 pts (26%) were pT0 and 28 pts (46%) harbored residual ≥pT2 disease. For detecting any disease, the positive predictive value was 96.7%, but the NPV was 48.4%, necessitating study closure based on pre-specified boundaries for futility. The sensitivity for detecting pT2 at RC disease was 71%. CONCLUSIONS: To our knowledge, this was the first prospective study exploring whether a standardized SEE could sufficiently predict the presence of residual malignancy. The NPV was below the pre-specified threshold, triggering study closure. pT2 or higher disease was missed nearly 30% of the time. This study definitively demonstrates that current cystoscopic techniques are inadequate to guide decisions on bladder preservation.Source of Funding: None

Cisplatin-based neoadjuvant chemotherapy (NAC) has demonstrated an overall survival (OS) benefit in muscle-invasive bladder cancer (MIBC). However, only a subset of patients (25-50%) have a pathologic complete response at cystectomy. Using a cohort of 58 patients from two phase 2 trials, our group previously reported that mutations in the ATM, RB1, and FANCC genes correlate with complete response to cisplatin-based NAC, and consequently improve OS and disease-specific survival (DSS). These trials enrolled patients with T2-4 (N0 or N1) MIBC and treated them with accelerated/dose-dense NAC with methotrexate, vinblastine, adriamycin, and cisplatin, or gemcitabine and cisplatin, with a plan for curative cystectomy. Updated long-term follow-up (median 74 mo) shows that significantly greater OS and DSS was maintained for patients with ATM, RB1, or FANCC mutations. The 5-yr survival rate for patients with at least one mutation was 85%, compared to 45% for patients without a mutation. On the basis of the associations with response and long-term OS and DSS, we propose that these alterations may be useful as predictive biomarkers to allow clinicians to prioritize patients who are most likely to benefit from NAC before radical cystectomy. PATIENT SUMMARY: In this report we looked at outcomes for patients with muscle-invasive bladder cancer treated with cisplatin-based chemotherapy before surgery (neoadjuvant) who had mutations in a set of DNA damage repair genes (ATM, RB1, FANCC) compared to those who did not. We found that patients who had at least one mutation in one of these genes survived longer after receiving cisplatin chemotherapy before surgery than patients who did not.

4536 Background: Although cisplatin-based neoadjuvant chemotherapy (NAC) has demonstrated an overall survival (OS) benefit in MIBC, only a subset of patients have pathologic complete response (pT0) at cystectomy. ATM, RB1 and FANCC mutations have shown correlation with pT0 to cisplatin-based NAC, as previously published. We now report updated OS and disease specific survival (DSS) from two phase II trials using these gene alterations as biomarkers. Methods: Patients with stage T2-T4 (N0 or N1) MIBC were enrolled in phase II trials of dose-dense NAC with MVAC (methotrexate, vinblastine, adriamycin, and cisplatin; NCT01031420) or GC (gemcitabine and cisplatin; NCT01611662). Patients were treated with NAC with plan for curative cystectomy. DNA from pretreatment tumor tissue was sequenced for coding exons of 287 cancer-related genes and analyzed for mutations. Survival in patients with one or more mutations in ATM, RB1, or FANCC genes was compared to those without mutations. Results: Of 58 pts treated, 38% (22/58 pts) had relevant mutations in the combined group of MVAC (13/34 pts) and GC (9/24 pts) trials. At a median follow-up of 56 months and minimum follow up of 16 months, patients with mutations had statistically significantly greater OS (p = 0.0043) and DSS (p = 0.0015). Median OS/DSS was not reached for patients with a mutation in any group. At 5 years post treatment, OS/DSS were greater in mutated vs non-mutated patients in all groups (see table). Conclusions: Long-term follow up reveals that previously reported improved responses to cisplatin-based NAC associated with mutations in ATM, RB1 and FANCC also confer a clinically meaningful and statistically significant survival benefit in these patients. These alterations may be useful as predictive biomarkers to allow clinicians to prioritize patients most likely to benefit from NAC prior to radical cystectomy. [Table: see text]

Seeds are dormant and desiccated structures, filled with storage products to be used after germination. These properties are determined by the maturation program, which starts, in Arabidopsis thaliana, mid-embryogenesis, at about the same time and developmental stage in all the seeds in a fruit. The two factors, chronological and developmental time, are closely entangled during seed development, so their relative contribution to the transition to maturation is not well understood. It is also unclear whether that transition is determined autonomously by each seed or whether it depends on signals from the fruit. The onset of maturation follows the cellularization of the endosperm, and it has been proposed that there exists a causal relationship between both processes. We explored all these issues by analyzing markers for maturation in Arabidopsis mutant seeds that develop at a slower pace, or where endosperm cellularization happens too early, too late, or not at all. Our data show that the developmental stage of the embryo is the key determinant of the initiation of maturation, and that each seed makes that transition autonomously. We also found that, in contrast with previous models, endosperm cellularization is not required for the onset of maturation, suggesting that this transition is independent of the hexose/sucrose ratio in the seed. Our observations indicate that the mechanisms that control endosperm cellularization, embryo growth, and embryo maturation act independently of each other.

Organ recovery techniques are under development to salvage organs that would otherwise be discarded. To allow damaged tissue to recover and enable cell level recovery, lungs must stay viable following procurement for prolonged periods (>24 h). Additionally, little is known about cell energetics, survival, and regenerative potential while lungs are ex-vivo. Cross-circulation enables prolonged normothermic support under conducive homeostatic conditions. In this study we investigate the cellular response to injury and their ability to recover while lungs remain outside the body supported by cross-circulation.

You have accessJournal of UrologyPlenary: Next Frontier1 Apr 2018LBA5 INITIAL RESULTS OF A PROSPECTIVE COHORT STUDY EVALUATING RELIABILITY OF ENDOSCOPIC EVALUATION IN PREDICTING PT0 DISEASE AT THE TIME OF RADICAL CYSTECTOMY: WHERE AND HOW DOES CYSTOSCOPY FALL SHORT? Daniel Parker, Aeen Asghar, John O'Neill, Richard Greenberg, Marc Smaldone, David Chen, Rosalia Viterbo, Robert Uzzo, Joshua Eccles, Daniel Geynisman, Matthew Zibelman, Eric Ross, Philip Abbosh, Elizabeth Plimack, and Alexander Kutikov Daniel ParkerDaniel Parker More articles by this author , Aeen AsgharAeen Asghar More articles by this author , John O'NeillJohn O'Neill More articles by this author , Richard GreenbergRichard Greenberg More articles by this author , Marc SmaldoneMarc Smaldone More articles by this author , David ChenDavid Chen More articles by this author , Rosalia ViterboRosalia Viterbo More articles by this author , Robert UzzoRobert Uzzo More articles by this author , Joshua EcclesJoshua Eccles More articles by this author , Daniel GeynismanDaniel Geynisman More articles by this author , Matthew ZibelmanMatthew Zibelman More articles by this author , Eric RossEric Ross More articles by this author , Philip AbboshPhilip Abbosh More articles by this author , Elizabeth PlimackElizabeth Plimack More articles by this author , and Alexander KutikovAlexander Kutikov More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.03.084AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Concern for discordance between endoscopic evaluation and final pathology drives current clinical management of patients deemed appropriate candidates for radical cystectomy (RC). Yet some 30% of patients who undergo neoadjuvant chemotherapy (NAC) prior to RC do not harbor detectable malignancy within the bladder at the time of surgery. Our objective was to better understand reliability and shortcomings of cystoscopic evaluation in RC candidates utilizing a protocol where all patients undergoing RC at our institution first receive a Systematic Endoscopic Evaluation (SEE). METHODS Patients undergoing RC for urothelial carcinoma (UC) at our institution were enrolled in a prospective, non-randomized, IRB-approved cohort study to evaluate the reliability of SEE in predicting pT0 bladder cancer. Rigid cystoscopy with targeted biopsy of visible tumor and/or tumor bed/scar, plus two additional random biopsies were performed immediately prior to RC. A standardized bladder map diagram was used to index cystoscopic findings. The endoscopic findings and transurethral biopsy results were then compared to the final pathologic cystectomy specimen RESULTS To date, 39 patients consented to the study, and 36 have received RC. 35 had adequate data for analysis. 22 (63%) underwent RC for MIBC, while 13 (37%) had high-risk NMIBC. 21 (60%) received NAC. On SEE, 17 (49%) patients were noted to have detectable cancer. Upon extirpation, pT0, pTis, pTa, pT1, pT2, pT3, and pT4 UC was found in 11 (31%), 7 (20%), 1 (3%), 2 (6%), 2 (6%), 6 (17%), 6 (17%), respectively. The sensitivity of SEE to predict presence of MIBC at RC was 80.0%. Negative predictive value of SEE to rule out any residual cancer at RC was 55%, and to rule out MIBC was 77.8%. Of 18 patients with no residual disease on SEE, 10 had concordant and 8 had discordant findings on final pathology. MIBC was found in 4 of the 8 discordant patients (Table 1), two of whom had prostatic stromal involvement and were known to have cT4a disease prior to NAC. CONCLUSIONS Our assessment of SEE′s test characteristics immediately prior to RC affords a unique understanding of its limitations and provides potential opportunities for identifying patients whose bladders no longer harbor malignancy. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e578-e579 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Daniel Parker More articles by this author Aeen Asghar More articles by this author John O'Neill More articles by this author Richard Greenberg More articles by this author Marc Smaldone More articles by this author David Chen More articles by this author Rosalia Viterbo More articles by this author Robert Uzzo More articles by this author Joshua Eccles More articles by this author Daniel Geynisman More articles by this author Matthew Zibelman More articles by this author Eric Ross More articles by this author Philip Abbosh More articles by this author Elizabeth Plimack More articles by this author Alexander Kutikov More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Katherine E. Reuther, Ph.D., is the Director of Master’s Studies and a Lecturer in Biomedical Engineering at Columbia University and the Co-Director of the Columbia-Coulter Translational Research Partnership. She is is working on developing new instructional tools and programs to enhance graduate education in the Department of Biomedical Engineering. She has spearheaded the development of a graduate-level Biomedical Design program that covers all aspects of the design process, including needs identification, concept generation, and commercialization. Dr. Reuther received her BS in Biomedical Engineering from The College of New Jersey and her Ph.D. in Bioengineering, specializing in Orthopaedic Biomechanics, from the University of Pennsylvania.

Bovine viral diarrhea virus (BVDV) can cause acute and persistent infections. BVDV acute infection results in generalized immunosuppression characterized by lymphocytopenia typically associated with depletion of CD4+ and CD8+ T cells. BVDV persistent infection is the result of immune tolerance and is not associated with lymphocytopenia. The health outcome of persistently infected (PI) calves varies widely; some die of mucosal disease, some succumb to ill thrift and others survive to adulthood. Detection of BVDV at the single lymphoid cell level is important to the study of subsets of PBMC in acute and persistent infections, however there are few methods available for the detection and quantification of BVDV at the single cell level. To circumvent this difficulty, a novel PrimeFlow RNA assay using in-situ detection of BVDV was developed. This assay was used to evaluate differences in viral distribution within subsets of PBMC over time in PI calves carrying one of two different species of BVDV (type 1 and type 2). Calves were sampled at 3 different time points at least one month apart. During the course of the study, a subset of the calves died from ill thrift. Mucosal disease was not indicated in any of the deaths. Using RNA probes specific for the BVDV Npro-Erns coding region for each respective virus, BVDV RNA was detected in all PBMC of PI that appeared clinically healthy. Calves that succumbed to ill thrift were found to have no or little virus in T cells. The clearance of virus from T cells suggests a breakdown in immune tolerance in these calves. This is the first report of an association between viral load in the T cell populations and survival in PI calves.

The current International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) methods for determining the supported shelf life of a drug product, described in ICH guidance documents Q1A and Q1E, are evaluated in this paper. To support this evaluation, an industry data set is used which is comprised of 26 individual stability batches of a common drug product where most batches are measured over a 24 month storage period. Using randomly sampled sets of 3 or 6 batches from the industry data set, the current ICH methods are assessed from three perspectives. First, the distributional properties of the supported shelf lives are summarized and compared to the distributional properties of the true shelf lives associated with the industry data set, assuming the industry data set represents a finite population of drug product batches for discussion purposes. Second, the results of the ICH “poolability” tests for model selection are summarized and the separate shelf life distributions from the possible alternative models are compared. Finally, the ICH methods are evaluated in terms of their ability to manage risk. Shelf life estimates that are too long result in an unacceptable percentage of nonconforming batches at expiry while those that are too short put the manufacturer at risk of possibly having to prematurely discard safe and efficacious drug product. Based on the analysis of the industry data set, the ICH-recommended approach did not produce supported shelf lives that effectively managed risk. Alternative approaches are required.

BACKGROUND:Accelerated (also termed dose-dense, DD) chemotherapy regimens such as accelerated methotrexate, vinblastine, doxorubicin, and cisplatin have shown better efficacy and tolerability in the metastatic setting, and shortened the time to surgery in the neoadjuvant setting compared to standard-schedule regimens. We hypothesized that a DD schedule of gemcitabine and cisplatin (GC) would shorten the time to surgery and yield similar pathologic complete response rates (pT0) in patients with muscle-invasive bladder cancer (MIBC) compared with historical controls with standard GC. OBJECTIVE:To determine the safety and efficacy of neoadjuvant DDGC in MIBC. DESIGN SETTING AND PARTICIPANTS:Patients with cT2-4a, N0-1, M0 MIBC were eligible and received three 14-d cycles of DDGC with pegfilgrastim support followed by radical cystectomy with lymph node dissection. The primary end point was the pT0 rate. Molecular subtypes were assigned and correlated with survival. RESULTS AND LIMITATIONS:Thirty-one patients were evaluable for toxicity and response, of whom 58% had baseline clinical stage >T2N0M0; the median age was 69 yr. Ten patients (32%, 95% confidence interval [CI] 16-49%) achieved ypT0N0 status at cystectomy. Another four patients (13%, 95% CI 1-25%) were downstaged to non-muscle-invasive (<pT2N0) disease. Most patients (54.8%) experienced only grade 1-2 treatment-related toxicities. However, seven patients (23%) had clinically significant vascular events, leading to early closure of the study. Thirty patients (94%) underwent cystectomy. The median time from the start of chemotherapy to cystectomy was 9.3 wk. There was no correlation between molecular subtypes and survival. CONCLUSIONS:DDGC yielded a similar pT0 rate to that noted retrospectively with standard GC. Vascular events precluded, delayed, or increased the risk of surgery for 23% of patients, resulting in early closure of the study. Additional prospective studies with embedded biomarker correlatives of GC in the neoadjuvant setting are critical to accurately define both the activity and toxicity of this combination in MIBC. PATIENT SUMMARY:Neoadjuvant chemotherapy before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC). This prospective phase 2 study tested a dose-dense schedule of gemcitabine and cisplatin in MIBC. The study was closed early because of a higher than expected rate of vascular events. These data suggest that caution is required in using this regimen, particularly when there is better prospective evidence for the safety and efficacy of alternative regimens such as dose-dense or accelerated methotrexate, vinblastine, doxorubicin, and cisplatin.