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PURPOSE Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability. METHODS Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001). CONCLUSION NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Background This article focuses on clinical implementation of smart knee implants for total knee replacement and the future development of smart implant technology. With the number of total knee replacements undertaken growing worldwide, smart implants incorporating embedded sensor technology offer opportunity to improve post-operative recovery, reducing implant failure rates, and increasing overall patient satisfaction. Methods A literature review on smart implants, historical prototypes, current clinically available smart implants, and the future potential for conventional implant instrumentation with embedded sensors and electronics was undertaken. Results The overview of current and future technology describes use cases for various diagnostic and therapeutic treatment solutions. Conclusion Smart knee implants are at an early development stage, with the first generation of smart implants being available to patients and with more novel technologies under development.

INTRODUCTION: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed. RESULTS: One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (

To describe glucose-lowering treatment regimens and glycated haemoglobin (HbA1c) trajectories in individuals with type 2 diabetes (T2D) over 36 months of follow-up from the start of second-line therapy.This data analysis from the 3-year, observational DISCOVER study programme included 14 687 participants from 37 countries with T2D initiating second-line glucose-lowering therapy. Treatment and HbA1c data were collected at baseline (start of second-line therapy) and at 6, 12, 24 and 36 months. Treatment regimen changes over follow-up were analysed using the McNemar test, with carry-forward imputation for intermediate missing values.A total of 11 592 participants had treatment data at baseline and 36 months, and 11 882 had HbA1c data at baseline. At baseline and 36 months, respectively, rates of oral monotherapy use were 12.1% and 12.4% (P = 0.22), rates of dual oral therapy use were 63.4% and 47.6% (P 0.0001), rates of ≥ triple oral therapy use were 17.5% and 25.4% (P 0.0001), and rates of injectable treatment use were 7.0% and 13.7% (P 0.0001). Use of injectable drugs was most common among participants with an HbA1c level ≥64 mmol/mol (≥8.0%). Overall, 42.9% of participants changed treatment during follow-up. Mean HbA1c levels at baseline and 6 months were 67 mmol/mol (8.3%) and 55 mmol/mol (7.2%), respectively, remaining stable thereafter.Dual oral therapy was the most common treatment regimen at the start of second-line treatment, and over half of the participants remained on the same treatment during follow-up.

To analyse the risk of uretero-enteric anastomotic stricture in patients randomised to open (ORC) or robot-assisted radical cystectomy (RARC) with extracorporeal urinary diversion.We included 118 patients randomised to RARC (n = 60) or ORC (n = 58) at a single, high-volume institution from March 2010 to April 2013. Urinary diversion was performed by experienced open surgeons. Stricture was defined as non-malignant obstruction on imaging, corroborated by clinical status, and requiring procedural intervention. The risk of stricture within 1 year was compared between groups using Fisher's exact test.In all, 58 and 60 patients were randomised to RARC and ORC, respectively. We identified five strictures, all in the ORC group. In patients with ≥1 year of follow-up, the increase in risk of stricture from open surgery was 9.3% (95% confidence interval 1.5%, 17%). Of the five strictures, three were managed endoscopically while two required open revision. There was no evidence that perioperative Grade 3-5 complications were associated with development of a stricture (P = 1) and no evidence of a difference in 24-month estimated glomerular filtration rate between arms (P = 0.15).In this study at a high-volume centre, RARC with extracorporeal urinary diversion achieved excellent ureteric anastomotic outcomes. Purported increased risk of stricture is not a reason to avoid RARC. Future research should examine the impact of different surgical techniques and operator experience on the risk of stricture, especially as more intracorporeal diversions are performed.

PURPOSE: Determine the association between biochemically verified post-diagnosis smoking exposure and non-muscle invasive bladder cancer (NMIBC) recurrence risk. MATERIALS AND METHODS: We conducted a prospective study of 354 NMIBC patients with a smoking history undergoing care between 2015 and 2018. Patients contributed at least two biospecimens during follow-up which were tested for cotinine to determine biochemically verified post-diagnosis smoking exposure (yes/no). Our primary endpoint was time to first recurrence after study start date. We examined whether post-diagnosis smoking exposure was associated with recurrence risk in multivariable Cox Proportional Hazards models that accounted for demographics, clinicopathological variables, time since diagnosis, and pack-years. RESULTS: Patients were predominantly white, male and had a median age of 68 years. Most patients had Ta disease (62%) and tumors of high grade (68%). Intravesical BCG was given to 63% of the cohort. Patients were followed for a median of 3.6 years since study start. Post-diagnosis smoking exposure was detected in 22% of patients. 38.7% (n=137) of patients experienced a recurrence during follow up. In multivariable models, only BCG treatment and prior recurrence rate were significantly associated with recurrence. There was no association between post-diagnosis smoking exposure and recurrence risk (Hazard Ratio (HR): 0.73 (95% Confidence Interval (CI): 0.45–1.20)). CONCLUSIONS: In a cohort of patients with predominantly high risk NMIBC, post-diagnosis smoking exposure was not associated with NMIBC recurrence. However, smoking cessation support remains a critical component of cancer care given that the benefits of quitting extend far beyond NMIBC recurrence.

A recent surge of users migrating from Twitter to alternative platforms, such as Mastodon, raised questions regarding what migration patterns are, how different platforms impact user behaviors, and how migrated users settle in the migration process. In this study, we elaborate how we investigate these questions by collecting data over 10,000 users who migrated from Twitter to Mastodon within the first ten weeks following Elon Musk's acquisition of Twitter. Our research is structured in three primary steps. First, we develop algorithms to extract and analyze migration patters. Second, by leveraging behavioral analysis, we examine the distinct architectures of Twitter and Mastodon to learn how different platforms shape user behaviors on each platform. Last, we determine how particular behavioral factors influence users to stay on Mastodon. We share our findings of user migration, insights, and lessons learned from the user behavior study.

Per- and polyfluoroalkyl substances (PFAS) are a diverse group of manmade, fluorinated organic chemicals that gained notoriety for their diverse application, widespread distribution in the environment and toxicity. One of the main sources of PFAS to the environment is through aqueous film forming foam (AFFF), intended for use on fuel fires. AFFF may enter the environment through system testing, training activities, emergency use or accidental release. When AFFF enters the environment PFAS readily adsorb to porous media through hydrophobic and electrostatic interactions. As a result, PFAS impacted porous media may act as a long-term source of contamination to groundwater, potentially influencing water resources and human health. There is a demand for effective treatment of PFAS impacted porous media. Ball milling has emerged as a potential treatment option for PFAS, however, the viability of treating AFFF impacted porous media has been seldom explored. In this work four AFFF formulations were amended onto silica sand and milled without and with the use of potassium hydroxide (KOH) as a co-milling reagent. Six hour milling trials were conducted using a planetary ball mill with stainless steel grinding media. Significant destruction of perfluorosulfonic acids, perfluorocarboxylic acids (PFCAs), fluorotelomer sulfonates, fluorotelomer betaines and fluorotelomer sulfonamido betaines was observed. With the use of KOH as a co-milling reagent the total PFAS destruction percentage in all four AFFFs exceeded 90%. Greater destruction of PFAS was observed in fluorotelomer dominant AFFFs when compared to perfluoroalkyl acid dominant AFFFs. PFCAs and soluble fluoride were identified as destruction byproducts. KOH as a co-milling reagent had the effect of reducing PFCA byproduct formation and increasing fluoride recovery in three of four AFFFs. Fluoride recoveries indicate PFAS molecule defluorination occurs by ball milling. When PFAS in AFFF is compared to PFAS destruction in single analyte trials, less destruction is observed, displaying the necessity of evaluating realistic AFFF contamination events over single or multi analyte mixtures.

PURPOSE Neoadjuvant gemcitabine and cisplatin (GC) followed by radical cystectomy (RC) is standard for patients with muscle-invasive bladder cancer (MIBC). On the basis of the activity of atezolizumab (A) in metastatic BC, we tested neoadjuvant GC plus A for MIBC. METHODS Eligible patients with MIBC (cT2-T4aN0M0) received a dose of A, followed 2 weeks later by GC plus A every 21 days for four cycles followed 3 weeks later by a dose of A before RC. The primary end point was non–muscle-invasive downstaging to < pT2N0. RESULTS Of 44 enrolled patients, 39 were evaluable. The primary end point was met, with 27 of 39 patients (69%) < pT2N0, including 16 (41%) pT0N0. No patient with < pT2N0 relapsed and four (11%) with ≥ pT2N0 relapsed with a median follow-up of 16.5 months (range: 7.0-33.7 months). One patient refused RC and two developed metastatic disease before RC; all were considered nonresponders. The most common grade 3-4 adverse event (AE) was neutropenia (n = 16; 36%). Grade 3 immune-related AEs occurred in five (11%) patients with two (5%) requiring systemic steroids. The median time from last dose of chemotherapy to surgery was 7.8 weeks (range: 5.1-17 weeks), and no patient failed to undergo RC because of AEs. Four of 39 (10%) patients had programmed death-ligand 1 (PD-L1)–positive tumors and were all < pT2N0. Of the patients with PD-L1 low or negative tumors, 23 of 34 (68%) achieved < pT2N0 and 11 of 34 (32%) were ≥ pT2N0 ( P = .3 for association between PD-L1 and < pT2N0). CONCLUSION Neoadjuvant GC plus A is a promising regimen for MIBC and warrants further study. Patients with < pT2N0 experienced improved relapse-free survival. The PD-L1 positivity rate was low compared with published data, which limits conclusions regarding PD-L1 as a predictive biomarker.

Supplementary Figure 1. Mutation rates by cohort. Supplementary Figure 2. ERCC2 mutations. Supplementary Figure 3. ERCC2 mutation status and overall survival. Supplementary Figure 4. ERCC2 mutations occur in highly conserved regions.

Significantly altered genes in clinical subsets. MutSigCV ranked lists for significantly mutated genes in the non-responders only (n = 25), the responders only (n = 25), and the ERCC2WT responders only (n = 16).

All alterations in responders and non-responders. All somatic mutations and short insertion/deletions are listed, with additional annotations regarding genomic coordinates, protein change, allelic fractions, and validation status (if available).

Damaging scores for alterations. This table shows the damaging scores (Methods) for nonsynonymous alterations (missense, nonsense, splice site, frame shift) studied in this cohort. The damaging score was derived as follows: missense mutations were scored using the Polyphen2 score(41) for the amino acid substitution. Nonsense mutations, splice site mutations, and short insertion/deletions were automatically assigned a damaging score of 1. "Unavailable" damaging scores are those that are missense mutations without a PolyPhen2 score.

PDF file - 470KB, All supplementary figures including tumor histology, RAD50 immunohistochemistry, candidate mutations and their clonality, and supporting yeast and MEF experimental data.

PDF file - 2461KB, A complete listing of somatic mutations and rearrangements detected as well as targeted genes, sequences, MRN complex mutation frequency, and strains utilized.

Treatment information and sequencing metrics for all patients The treatment information and raw sequencing metrics, including mean target coverage, for each case is listed here. In addition, the mutation rate data referred to in the Results and represented in Supplementary Figure 1 is listed here by synonymous rate, non-synonymous rate, and total number of mutations per patient. *Cases that were included in the TCGA effort (UC-0296 and UC-0234). (dd = dose dense, GC = gemcitabine/cisplatin, MVAC = methotrexate, vinblastine, doxorubicin, cisplatin). Unavailable cases for Fluidigm Validation (due to inadequate remaining DNA or technical failure) are also denoted (n = 15).

Selective alteration enrichment. This table shows the results of applying Fisher's Exact Test to a tabulated set of predicted damaging somatically altered genes in responders compared to non-responders. A Benjamini-Hochberg/FDR q-value is reported for genes with the minimum number of events necessary to be considered for a theoretically significant p-value of {less than or equal to} 0.01 (n = 6). The results are sorted by p-value (lowest to highest).

PDF file - 321KB, A detailed description of additional methods utilized (and associated references) for sequencing and analysis as well as an explanatory note regarding the TM pathway in yeast.

Supplementary Data from Inherited Germline Cancer Susceptibility Gene Variants in Individuals with Non–Muscle-Invasive Bladder Cancer

Purpose:Identification of inherited germline variants can guide personalized cancer screening, prevention, and treatment. Pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes are frequent among patients with locally advanced or metastatic urothelial carcinoma, but their prevalence and significance in patients with non–muscle-invasive bladder cancer (NMIBC), the most common form of urothelial carcinoma, is understudied.Experimental Design:Germline analysis was conducted on paired tumor/normal sequencing results from two distinct cohorts of patients initially diagnosed with NMIBC. Associations between clinicopathologic features and clinical outcomes with the presence of P/LP germline variants in ≥76 hereditary cancer predisposition genes were analyzed.Results:A similar frequency of P/LP germline variants were seen in our two NMIBC cohorts [12% (12/99) vs. 8.7% (10/115), P = 0.4]. In the combined analysis, P/LP germline variants were found only in patients with high-grade NMIBC (22/163), but none of the 46 patients with low-grade NMIBC (13.5% vs. 0%, P = 0.005). Fifteen (9.2%) patients with high-grade NMIBC had P/LP variants in DNA damage response genes, most within the nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways. Contrary to prior reports in patients with NMIBC not receiving Bacillus Calmette-Guerin (BCG), P/LP germline variants were not associated with worse recurrence-free or progression-free survival in patients treated with BCG or with risk of developing upper tract urothelial carcinoma.Conclusions:Our results support offering germline counseling and testing for all patients with high-grade bladder cancer, regardless of initial tumor stage. Therapeutic strategies that target impaired DNA repair may benefit patients with high-grade NMIBC.

Characteristics of the patients who underwent radical nephroureterectomy for UTUC.

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PDF file - 423KB, Figure S1: Broad copy numbers at the p- and q-arms in the Spanish cohort; Figure S2: Broad copy numbers at the p- and q-arms in the DFCI cohort. (see Figure S1 for an explanation of this plot); Figure S3: These GISTIC output files show the correlation between gene number and frequency of armlevel events in the (a) Spanish cohort and the (b) DFCI cohort; Figure S4: Recurrent copy number gains in the (a) Spanish and (b) DFCI cohort. Figure S5: Recurrent deletions in the (a) Spanish and (b) DFCI cohorts (see Figure S4 for an explanation of this plot); Table S1: Significant (q-value < 0.25) GISTIC broad aberrations and their association with overall survival after start of chemotherapy (Spanish cohort); Table S2: Significant (q-value < 0.25) GISTIC broad aberrations and their association with overall survival after recurrence (DFCI cohort).

Supplementary Figure 2: Enrichment of biallelic RB1 in SCCBs.

Purpose: We aimed to validate and improve prognostic signatures for high-risk urothelial carcinoma of the bladder.Experimental Design: We evaluated microarray data from 93 patients with bladder cancer managed by radical cystectomy to determine gene expression patterns associated with clinical and prognostic variables. We compared our results with published bladder cancer microarray data sets comprising 578 additional patients and with 49 published gene signatures from multiple cancer types. Hierarchical clustering was utilized to identify subtypes associated with differences in survival. We then investigated whether the addition of survival-associated gene expression information to a validated postcystectomy nomogram utilizing clinical and pathologic variables improves prediction of recurrence.Results: Multiple markers for muscle invasive disease with highly significant expression differences in multiple data sets were identified, such as fibronectin 1 (FN1), NNMT, POSTN, and SMAD6. We identified signatures associated with pathologic stage and the likelihood of developing metastasis and death from bladder cancer, as well as with two distinct clustering subtypes of bladder cancer. Our novel signature correlated with overall survival in multiple independent data sets, significantly improving the prediction concordance of standard staging in all data sets [mean ΔC-statistic: 0.14; 95% confidence interval (CI), 0.01–0.27; P < 0.001]. Tested in our patient cohort, it significantly enhanced the performance of a postoperative survival nomogram (ΔC-statistic: 0.08, 95% CI, −0.04–0.20; P < 0.005).Conclusions: Prognostic information obtained from gene expression data can aid in posttreatment prediction of bladder cancer recurrence. Our findings require further validation in external cohorts and prospectively in a clinical trial setting. Clin Cancer Res; 18(5); 1323–33. ©2012 AACR.

Supplementary Figure 3: DNA copy number alterations in SCCB.

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Supplementary Figure 7: Therapeutically actionable lesions.

Oncoprints and Venn diagrams for matched-pair comparisons between UCB and UTUC samples in patients with a history of a prior bladder tumor before resection of the UTUC. The arrows show the time between sample collection in months.

PDF file - 452KB, Independent validation; Validation of 1q23.3 survival association in independent cohorts; Figure S15: Expression of genes on 1q23.3 in an independent cohort 3; S16: Expression of genes on 1q23.3 as in Supplemental Figure S15, but in the Spanish (a-b) and DFCI (c-d) cohorts. Panels (a) and (c) are for samples with 1q23.3 gain or amplification (log2 copy number ratio > 0.15), (b) and (d) for patients without amplification; S17: Panel (a): No association of overall survival after surgery and 1q23.3 amplification in an inde- pendent cohort from DFCI. (b) No significant association of 1q23.3 amplification and OS after recurrence, possibly due to small patient numbers; Table S8: Overall survival (OS) Hazard Ratios (HRs) of genes in the three peaks, available on the Affymetrix HGU133 Plus 2.0 genechip and displaying patterns of gene expression different from background noise as identified by the Sleipnir library 1. The LMX1A gene was flat, i.e., showed minimum expression intensity in all patients. Table S9: Overall survival (OS) Hazard Ratios (HRs) of genes in 1q21.2 as in Supplementary Table S8.

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Univariate and Multivariable Cox regression analysis predicting the risk of bladder recurrence after nephroureterectomy. Each gene mutation was adjusted for sex, prior bladder cancer, location, grade, pT stage.

PDF file - 38KB, Chromosomal Instability. Analysis testing for potential confounding of pathologic stage and tissue type on chromosomal instability. Figure S6: Fraction of genome altered (FGA, 1) in both cohorts.

Supplementary Figure 6: Mixed histology tumors.

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Characteristics of the patients included for the matched-pairs analysis of bladder recurrence after radical nephroureterectomy (RNU).

Purpose: Small-cell carcinoma of the bladder (SCCB) is a rare and aggressive neuroendocrine tumor with a dismal prognosis and limited treatment options. As SCCB is histologically indistinguishable from small-cell lung cancer, a shared pathogenesis and cell of origin has been proposed. The aim of this study is to determine whether SCCBs arise from a preexisting urothelial carcinoma or share a molecular pathogenesis in common with small-cell lung cancer.Experimental Design: We performed an integrative analysis of 61 SCCB tumors to identify histology- and organ-specific similarities and differences.Results: SCCB has a high somatic mutational burden driven predominantly by an APOBEC-mediated mutational process. TP53, RB1, and TERT promoter mutations were present in nearly all samples. Although these events appeared to arise early in all affected tumors and likely reflect an evolutionary branch point that may have driven small-cell lineage differentiation, they were unlikely the founding transforming event, as they were often preceded by diverse and less common driver mutations, many of which are common in bladder urothelial cancers, but not small-cell lung tumors. Most patient tumors (72%) also underwent genome doubling (GD). Although arising at different chronologic points in the evolution of the disease, GD was often preceded by biallelic mutations in TP53 with retention of two intact copies.Conclusions: Our findings indicate that small-cell cancers of the bladder and lung have a convergent but distinct pathogenesis, with SCCBs arising from a cell of origin shared with urothelial bladder cancer. Clin Cancer Res; 24(8); 1965–73. ©2017 AACR.See related commentary by Oser and Jänne, p. 1775