Cost-effectiveness analysis of mosunetuzumab for treatment of relapsed or refractory follicular lymphoma after two or more lines of systemic therapy in the United States.

AIMS: Mosunetuzumab has received accelerated approval by the US Food and Drug Administration for adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) after two or more lines of systemic therapy. We evaluated the cost-effectiveness of mosunetuzumab for the treatment of R/R FL from a US private payer perspective. MATERIALS AND METHODS: A partitioned survival model simulated lifetime costs and outcomes of mosunetuzumab against seven comparators: axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), tazemetostat (taz, EZH2 wild-type only), rituximab plus lenalidomide (R-Len) or bendamustine (R-Benda), obinutuzumab plus bendamustine (O-Benda), and a retrospective real-world cohort (RW) based on current patterns of care derived from US electronic health records (Flatiron Health). Efficacy data for mosunetuzumab were from the pivotal Phase II GO29781 trial (NCT02500407). Relative treatment efficacy was estimated from indirect treatment comparisons (ITCs). Costs included were related to treatment, adverse events, routine care, and terminal care. Except for drug costs (March 2023), all costs were inflated to 2022 US dollars. Costs and quality-adjusted life-years (QALYs) were used to calculate incremental cost-effectiveness ratios (ICERs). Net monetary benefit (NMB) was calculated using a willingness-to-pay (WTP) threshold of $150,000/QALY. RESULTS: Mosunetuzumab dominated taz, tisa-cel, and axi-cel with greater QALYs and lower costs. Mosunetuzumab was projected to be cost-effective against R-Benda, O-Benda, and RW with ICERs of $78,607, $42,731, and $21,434, respectively. Mosunetuzumab incurred lower costs but lower QALYs vs. R-Len. NMBs showed that mosunetuzumab was cost-effective against comparators except R-Len. LIMITATIONS: Without head-to-head comparative data, the model had to rely on ITCs, some of which were affected by residual bias. Model inputs were obtained from multiple sources. Extensive sensitivity analyses assessed the importance of these uncertainties. CONCLUSION: Mosunetuzumab is estimated to be cost-effective compared with approved regimens except R-Len for the treatment of adults with R/R FL.

Budget Impact of Introducing Fixed-Duration Mosunetuzumab for the Treatment of Relapsed or Refractory Follicular Lymphoma After Two or More Lines of Systemic Therapy in the USA.

OBJECTIVE: This study aimed to assess the budget impact of introducing fixed-duration mosunetuzumab as a treatment option for adult patients with relapsed or refractory follicular lymphoma after at least two prior systemic therapies and to estimate the total cumulative costs per patient in the USA. METHODS: A 3-year budget impact model was developed for a hypothetical 1-million-member cohort enrolled in a mixed commercial/Medicare health plan. Comparators were: axicabtagene ciloleucel, tisagenlecleucel, tazemetostat, rituximab plus lenalidomide, copanlisib, and older therapies (rituximab or obinutuzumab ± chemotherapy). Costs per patient comprised treatment-associated costs including the drug, its administration, adverse events, and routine care. Dosing and safety data were ascertained from respective package inserts and clinical trial data. Drug costs (March 2023) were estimated based on the average wholesale acquisition cost reported in AnalySource®, and all other costs were based on published sources and inflated to 2022 US dollars. Market shares were obtained from Genentech internal projections and expert opinion. Budget impact outcomes were presented on a per-member per-month basis. RESULTS: Compared with a scenario without mosunetuzumab, its introduction over 3 years resulted in a budget increase of $69,812 (1% increase) and an average per-member per-month budget impact of $0.0019. Among the newer therapies, mosunetuzumab had the second-lowest cumulative per patient cost (mosunetuzumab = $202,039; axicabtagene ciloleucel = $505,845; tisagenlecleucel = $476,293; rituximab plus lenalidomide = $263,520; tazemetostat = $250,665; copanlisib = $127,293) and drug costs, and its introduction only increased total drug costs by 0.1%. By year 3, the cumulative difference in the per patient cost with mosunetuzumab was -$303,805 versus axicabtagene ciloleucel, -$274,254 versus tisagenlecleucel, -$61,481 versus rituximab plus lenalidomide, -$48,625 versus tazemetostat, and $74,747 versus copanlisib. Older therapies were less costly with 3-year cumulative costs that ranged from $36,512 to $147,885. CONCLUSIONS: Over 3 years, the estimated cumulative per patient cost of mosunetuzumab is lower than most available newer therapies, resulting in a small increase in the budget after its formulary adoption for the treatment of relapsed or refractory follicular lymphoma.

Corrigendum: Molecular markers associated to two non-allelic genic male sterility genes in peppers (Capsicum annuum L.).

[This corrects the article DOI: 10.3389/fpls.2018.01343.].

Rating System for Phytophthora Root Rot Influences Quantitative Trait Locus Detection and Reveals Incomplete Dominance and Duplicative Recessive Epistatic Gene Action in Capsicum annuum.

Phytophthora capsici is one of the most devastating pathogens facing pepper (Capsicum annuum) producers worldwide. Numerous factors, such as the race of the pathogen, the growing environment, and the source of resistance, have resulted in an overall lack of widely applicable molecular markers associated with resistance. Our objective was to determine the effect of the rating system on quantitative trait locus (QTL) detection and understand inheritance patterns of host resistance that can influence selection and molecular marker accuracy. We evaluated an F2:11 recombinant inbred line population screened against the highly virulent strain (Pc134) and scored using two widely used methods, developed by Bosland and Lindsey and by Black. The rating system developed by Bosland and Lindsey resulted in slightly higher logarithm of odds for the QTL on chromosome 5, and we detected a QTL on chromosome 12 uniquely using this rating system. A QTL on chromosome 10 was detected using both rating systems, but Black resulted in considerably higher logarithm of odds for this QTL compared with the Bosland and Lindsey system. Molecular markers developed were nominally better at accurately predicting the phenotype than previously published molecular markers but did not completely explain resistance in our validation populations. The inheritance pattern of resistance in one of our F2 populations did not significantly deviate from a 7:9 segregation ratio, indicating duplicative recessive epistasis. However, these results could be confounded by the presence of incomplete gene action, which was found through the improved selection accuracy when the phenotypes of heterozygous individuals were grouped with those with susceptible alleles.

Patterns and Predictors of First-Line Taxane Use in Patients with Metastatic Triple-Negative Breast Cancer in US Clinical Practice.

We investigated first-line (1L) treatment patterns and predictors of taxane use to better understand the evolving metastatic triple-negative breast cancer (mTNBC) treatment landscape. This retrospective analysis of the Truven Health MarketScan® (Somers, NY, USA) Database included women with mTNBC who received 1L therapy within six months of diagnosis (January 2005-June 2015). Multivariate logistic regression models identified predictors of taxane use, adjusting for prognostic factors. A total of 2,271 women with newly diagnosed mTNBC received 1L treatment during the study period. Half received a 1L taxane (53%), more often in combination than as monotherapy (58% versus 42%), though this varied by specific taxane. Nab-Paclitaxel monotherapy increased substantially after 2010. More recent treatment year (odds ratio, 2.16 (95% CI 1.69-2.76]) and number of metastases (≥3 versus 1: 1.73 (1.25-2.40)) predicted taxane monotherapy versus combination. Having a health maintenance organization versus a preferred provider organization plan predicted less nab-paclitaxel versus paclitaxel (0.32 (0.13-0.80)) or docetaxel (0.30 (0.10-0.89)) use. More recent index year (2011-2015 vs 2005-2010) was the only predictor favoring nab-paclitaxel versus paclitaxel (2.01 (1.26-3.21)) or docetaxel (3.63 (2.11-6.26)). Taxane-containing regimens remained the most common 1L mTNBC treatments. Paclitaxel and nab-paclitaxel use changed substantially over time, with nab-paclitaxel use associated with insurance coverage.

Reproductive compatibility in Capsicum is not necessarily reflected in genetic or phenotypic similarity between species complexes.

Wild relatives of domesticated Capsicum represent substantial genetic diversity and thus sources of traits of potential interest. Furthermore, the hybridization compatibility between members of Capsicum species complexes remains unresolved. Improving our understanding of the relationship between Capsicum species relatedness and their ability to form hybrids is a highly pertinent issue. Through the development of novel interspecific hybrids in this study, we demonstrate interspecies compatibility is not necessarily reflected in relatedness according to established Capsicum genepool complexes. Based on a phylogeny constructed by genotyping using simple sequence repeat (SSR) markers and with a portion of the waxy locus, and through principal component analysis (PCA) of phenotypic data, we clarify the relationships among wild and domesticated Capsicum species. Together, the phylogeny and hybridization studies provide evidence for the misidentification of a number of species from the World Vegetable Center genebank included in this study. The World Vegetable Center holds the largest collection of Capsicum genetic material globally, therefore this may reflect a wider issue in the misidentification of Capsicum wild relatives. The findings presented here provide insight into an apparent disconnect between compatibility and relatedness in the Capsicum genus, which will be valuable in identifying candidates for future breeding programs.

Increased Bacillus Calmette-Guérin Treatment Intensity Associated With Improved Outcomes in Elderly Patients With Non-Muscle-invasive Bladder Cancer in United States Clinical Practice.

OBJECTIVE: To characterize Bacillus Calmette-Guérin (BCG) treatment patterns and associated outcomes in a large cohort of patients with non-muscle-invasive bladder cancer (NMIBC). METHODS: Our retrospective analysis of patients aged ≥66 years with stage 0-1 urothelial bladder carcinoma diagnosed between 2000 and 2012 in the United States Surveillance, Epidemiology, and End Results-Medicare database estimated proxies for recurrence and secondary events and both all-cause and bladder cancer-specific mortality. Proportional hazards models were used in conditional landmark analyses to compare adequate (≥5 induction instillations and ≥2 maintenance instillations) and inadequate BCG, stratified by National Comprehensive Cancer Network risk group. RESULTS: Of 39,532 patients who met the selection criteria, 16,225 (41.0%) received BCG; of them, 4602 (28.4%; 11.6% overall) received adequate treatment. Adequately treated patients were slightly younger and healthier than inadequately treated patients. Half of patients with intermediate- and high-risk NMIBC did not receive BCG; few received adequate treatment. At the 12-month landmark, adequate BCG treatment was associated with decreased risks of recurrence and of cancer-specific and all-cause mortality in patients with intermediate- and high-risk disease. CONCLUSION: We observed lower than expected use of adequate BCG treatment in patients with intermediate- to high-risk NMIBC despite evidence of improved outcomes, which suggested that practice patterns may not be in line with management recommendations in this population.

Cardiac Autonomic Modulation during on-Call Duty under Working Hours Restriction.

Background: Medical residency is a time of high stress and long working hours, which increase the risk of cardiovascular disease. This study aimed to investigate the autonomic modulation of resident physicians throughout the on-call duty cycle. Methods: Spectral analysis of heart rate variability (HRV) was used to compute cardiac parasympathetic modulation (high-frequency power, HF) and cardiac sympathetic modulation (normalized low-frequency power, LF%, and the ratio of LF and HF, LF/HF) of 18 residents for a consecutive 4-day cycle. Results: Male residents show reduced cardiac sympathetic modulation (i.e., higher LF/HF and LF%) than the female interns. Medical residents' cardiac parasympathetic modulation (i.e., HF) significantly increased on the first and the second post-call day compared with the pre-call day. In contrast, LF% was significantly decreased on the first and the second post-call day compared with the pre-call day. Similarly, LF/HF was significantly decreased on the second post-call day compared with the pre-call day. LF/HF significantly decreased on the first post-call day and on the second post-call day from on-call duty. Conclusion: The guideline that limits workweeks to 80 h and shifts to 28 h resulted in reduced sympathetic modulation and increased parasympathetic modulation during the two days following on-call duty.

Real-world practice patterns in veterans with metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is incurable, with most patients surviving less than 3 years. However, many treatments that extend survival have been approved in the past decade. OBJECTIVE: To describe the patient demographics, disease characteristics, treatment patterns, and outcomes in a cohort of Veterans diagnosed with mCRPC in the Veterans Health Administration. DESIGN: We identified 3,637 Veterans diagnosed with prostate cancer between January 2006 and August 2015 with evidence of mCRPC through December 2016. We described the most commonly used systemic mCRPC treatments according to mCRPC diagnosis era: Epoch 1 (2006-2010) or Epoch 2 (2011-2016). Patient demographics, disease characteristics, and treatment patterns were examined using descriptive statistics. An unadjusted Kaplan-Meier method was used to estimate the median time to biochemical progression and overall survival (OS) with 95% confidence intervals. RESULTS: The median age at initial prostate cancer diagnosis was 68 years. Approximately 67% of patients were non-Hispanic white, 29% were black, and 4% were other/unknown. A high-risk Gleason score (8-10) was reported in 748 (67%) of patients in Epoch 1 and 1578 (63%) of patients in Epoch 2, and the median prostate-specific antigen level at initial prostate cancer diagnosis was higher in Epoch 1 patients than in Epoch 2 patients (68 vs. 35 ng/ml). Following mCRPC diagnosis, the most common first-line therapies in Epoch 1 patients were docetaxel (83%) and abiraterone (9%), whereas Epoch 2 patients mainly received abiraterone (47%), docetaxel (36%), and enzalutamide (15%). In Epoch 1 and Epoch 2 patients, the median time to biochemical progression (unadjusted) was 9 and 13 months, respectively, and the median OS (unadjusted) was 15 and 23 months, respectively. CONCLUSIONS: The introduction of new therapies has resulted in increased use of the noncytotoxic agents abiraterone and enzalutamide as first-line treatment in lieu of docetaxel. Our results suggest that more recently diagnosed patients (Epoch 2) have a delayed time to biochemical progression and longer OS (unadjusted) compared with patients diagnosed earlier (Epoch 1).

Yolk sac tumor of endometrium: A case report and literature review.

OBJECTIVE: To report a rare case of endometrial yolk sac tumor (YST) and review published cases of YST of the endometrium. CASE REPORT: A 68-year-old female presented with intermittent vaginal spotting for nine months. An endometrial biopsy showed adenocarcinoma. Complete surgical staging operation was performed and the final pathology revealed stage II endometrial yolk sac tumor. The post-operative α-fetoprotein (AFP) level was 133.4 ng/mL. Post-operative adjuvant chemotherapy with bleomycin, etoposide, and cisplatin (BEP) regimen was prescribed for 6 cycles. AFP levels were normal before the fourth cycle of chemotherapy. She is disease free 6 months after completion of therapy. CONCLUSION: Primary YSTs arising in the endometrium is an extremely rare disease especially in postmenopausal women. Complete surgical staging operation with adjuvant chemotherapy will lead to good outcome in this disease.

Real-world treatment patterns and adverse events in metastatic renal cell carcinoma from a large US claims database.

BACKGROUND: Vascular endothelial growth factor (VEGF), tyrosine kinase (TK) and mechanistic target of rapamycin kinase (mTOR) inhibitors are common first-line (1 L) treatments for metastatic renal cell carcinoma (mRCC). Despite treatment availability, the 5-year survival rate in patients diagnosed at the metastatic stage is only ≈ 10%. To gain contemporary insights into RCC treatment trends that may inform clinical, scientific and payer considerations, treatment patterns and adverse events (AEs) associated with 1 L therapy were examined in a retrospective, longitudinal, population-based, observational study of patients with mRCC. METHODS: US administrative claims data (Truven Health MarketScan Commercial Databases) were used to assess trends in 1 L treatment initiation in mRCC (2006-2015) and characterize patterns of individual 1 L treatments, baseline characteristics, comorbidities and treatment-related AEs from 2011 through 2015. Outcomes were evaluated by drug class and route of administration. RESULTS: Ten-year trend analysis (n = 4270) showed that TK/VEGF-directed therapy rapidly became more common than mTOR-directed therapy, and oral treatments were favored over intravenous (IV) treatments. Overall, 1992 eligible patients initiated 1 L treatment for mRCC from 2011 through 2015: 1752 (88%) received TK/VEGF-directed agents and 233 (12%) received mTOR-directed agents; 1674 (84%) received oral treatments, and 318 (16%) received IV treatments. The most common 1 L treatment was sunitinib (n = 849), followed by pazopanib (n = 631), temsirolimus (n = 157) and bevacizumab (n = 154). Patient characteristics and comorbidities, including age, diabetes and congestive heart failure, were independent predictors of 1 L mRCC treatment choice. The three most common potentially 1 L treatment-related AEs were nausea/vomiting (128.2 per 100 patient-years [PY]), hypertension (69 per 100 PY) and renal insufficiency (44.6 per 100 PY). A wide variety of agents were used as second-line (2 L) therapy. Substantial latency of onset was observed for several potentially treatment-related toxicities in patients treated with TK/VEGF- or mTOR-directed agents. CONCLUSIONS: In the US, 1 L TK/VEGF inhibitor uptake in recent years appears largely in line with national approvals and guidelines, with varied 2 L agent use. Although retrospective evaluation of claims data cannot assess underlying causality, insights from these real-world RCC treatment and AE patterns will be useful in informing medical and payer decisions.

Comparative Effectiveness of Non-cisplatin First-line Therapies for Metastatic Urothelial Carcinoma: Phase 2 IMvigor210 Study Versus US Patients Treated in the Veterans Health Administration.

BACKGROUND: First-line treatments for cisplatin-ineligible patients with metastatic urothelial carcinoma (mUC) include carboplatin-based chemotherapy and checkpoint inhibitors such as atezolizumab (anti-PD-L1). OBJECTIVE: To compare overall survival (OS) among patients with mUC treated in the first-line setting with atezolizumab versus carboplatin-based chemotherapies (any carboplatin-based regimens or carboplatin-gemcitabine). DESIGN, SETTING, AND PARTICIPANTS: Cisplatin-ineligible patients with mUC from the phase 2 trial IMvigor210 (ClinicalTrials.gov NCT02951767) treated with atezolizumab and patients from the Veterans Health Administration (VHA) health care system (2006-2017, with IMvigor210 eligibility criteria applied using proxy measurements) treated according to normal clinical practice. INTERVENTIONS: IMvigor210 cohort 1 patients were treated with atezolizumab, and real-world VHA cohorts were treated with carboplatin-based regimens. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Entropy-balance weighting was applied to balance prespecified baseline patient characteristics. OS was analyzed using weighted Kaplan-Meier and Cox methods. RESULTS AND LIMITATIONS: The median OS was 15.0 mo with atezolizumab (n = 110), 12.1 mo with any carboplatin-based chemotherapy (n = 282), and 8.7 mo with carboplatin-gemcitabine (n = 120). An OS benefit occurred with atezolizumab versus carboplatin-based regimens after 9 mo (hazard ratio [HR] 0.43; p = 0.004) and with atezolizumab versus carboplatin-gemcitabine after 5 mo (HR 0.52; p = 0.005). Study limitations include a predominantly male VHA cohort and ≤24-mo follow-up. Adjustment for confounding, a potential limitation of nonrandomized studies, was limited by the availability of clinical measurements in the VHA data, which allowed for replication of IMvigor210 exclusions in the VHA cohorts. CONCLUSIONS: First-line atezolizumab for cisplatin-ineligible mUC may provide an OS benefit over carboplatin-based treatments after 5-9 mo, depending on the regimen. PATIENT SUMMARY: Many patients with metastatic urothelial carcinoma are ineligible for cisplatin-based chemotherapy. This study compared patients from a clinical trial receiving the immunotherapeutic agent atezolizumab with those in Veterans Health Administration clinical practice receiving carboplatin-based chemotherapy. Atezolizumab provided a survival benefit over chemotherapy after 5-9 mo.

Molecular Markers Associated to Two Non-allelic Genic Male Sterility Genes in Peppers (Capsicum annuum L.).

Male sterility is of high importance in hybrid seed production of hot and sweet peppers. Genic (or nuclear) male sterility (GMS) is a simply inherited (usually monogenic recessive) and highly stable trait. However, one major disadvantage of using GMS is 1:1 segregation of male sterile to male fertile plants in every subsequent generation. Molecular markers tightly linked to genic male sterility (ms) genes would facilitate an efficient and rapid transfer of ms genes into different genetic backgrounds through marker-assisted backcrossing. The two non-allelic genic male sterility genes ms3 and ms w in hot and sweet pepper backgrounds, respectively, are monogenic recessive. Genotyping by sequencing (GBS) in an F2 population segregating for ms3 gene in hot pepper and in an F6 inbred near-isogenic line (NIL) population segregating for ms w gene in sweet pepper yielded 9,713 and 7,453 single nucleotide polymorphism markers, respectively. Four candidate SNPs co-segregating with ms3 gene and one co-segregating with ms w gene were identified by bulk segregant analysis and physically mapped to chromosomes 1 and 5, respectively. In hot pepper, two markers [HPGMS2 (CAPS) and HPGMS3 (dCAPS)] located 3.83 cM away from the ms3 gene and in sweet pepper the dCAPS marker SPGMS1 co-segregated (completely linked) with the ms w gene were developed. These markers will increase the efficacy of the male sterility genes for pepper breeding, as they can be useful in developing the genic male sterile lines in parental inbred lines of commercial hybrids through marker-assisted backcrossing, hybrid seed production, and genetic purity testing of hybrid seeds.

A Real-World Data Study to Evaluate Treatment Patterns, Clinical Characteristics and Survival Outcomes for First- and Second-Line Treatment in Locally Advanced and Metastatic Urothelial Cancer Patients in Germany.

Background: Worldwide, urothelial carcinoma (UC) is a common cause of morbidity and mortality. In particular, the incidence of bladder cancer varies widely across Europe; Germany has the ninth highest international age-standardized incidence. For advanced UC or metastatic UC (mUC), platinum-based combination chemotherapy is the standard first-line (1L) treatment; however, there is wide heterogeneity of second-line (2L) treatments, ranging from vinflunine in parts of Europe to taxanes and other agents elsewhere in Europe, in the United States and globally. Limited data exist on treatment patterns and outcomes in patients with advanced UC or mUC in the routine clinical setting in Germany. The objective of this study was to describe clinical characteristics, treatment patterns and subsequent outcomes in this setting. Methods: This retrospective observational cohort analysis evaluated 1L and 2L treatment patterns and overall survival (OS) in patients aged ≥18 years with advanced UC or mUC (T4b, N2-3 and/or M1) at office-based urology and academic as well as nonacademic urology clinics throughout Germany between 1 November 2009 and 2 June 2016. Data were obtained through the GermanOncology database and additional treatment centers using similar electronic case report forms. Results: Among the 435 patients included in the analysis, 435 received 1L treatment and 125 received 2L treatment. Median age at start of 1L treatment was 69 years, 75% of patients were male, 75% were current or ex-smokers, 15% had hemoglobin <10 g/dL and 44% had creatinine clearance<60 mL/min/1.73; proportions were similar with 2L treatment. Cardiovascular disease was the most frequently reported comorbidity (65%), followed by diabetes (19%). Most patients (77%) received 1L platinum-based combination treatment (most commonly gemcitabine + cisplatin, 83%). Of those treated with 2L treatment, 66% received a single agent (most commonly vinflunine, 71%). Median OS (95% CI) with 1L treatment was 16.1 months (13.7-19.2) overall and 17.7 months (14.4-24.2) with 1L cisplatin + gemcitabine. In the 1L setting, 12-month OS was 61%, 24-month OS was 39% and 36-month OS was 26%. Median (95% CI) OS with 2L treatment was 9.2 months (5.5-11.6) overall and 5.9 months (4.1-12.6) with 2L vinflunine. In the 2L setting, OS rates for the same time periods were 40%, 22% and 8%, respectively. Median (95% CI) progression-free survival was 7 months (6.4-8.1) and 4 months (3.0-4.8), respectively, in the 1L and 2L settings. Objective response rates were 34% in the 1L setting and 14% in the 2L setting. No difference in OS by sex or smoking status was noted. Patients with or without renal impairment had a 12-month OS of 54% or 69%, respectively. OS at 12 months was 63% among patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 vs 53% among patients with an ECOG PS of ≥2. Cox regression analysis found no difference in OS between vinflunine and other 2L treatments (P = 0.69). Conclusions: This study provides a contemporary multicenter assessment of real-world treatment patterns and outcomes among palliatively treated patients with UC in Germany. The findings were generally consistent with the poor treatment outcomes observed globally, underscoring the need for effective 1L and 2L treatment for advanced UC or mUC.

Nomogram to Assess the Survival Benefit of New Salvage Agents for Metastatic Urothelial Carcinoma in the Era of Immunotherapy.

INTRODUCTION: Optimal end points in phase 2 trials evaluating salvage therapy for metastatic urothelial carcinoma are necessary to identify promising drugs, particularly immunotherapeutics, where response and progression-free survival may be unreliable. We developed a nomogram using data from phase 2 trials of historical agents to estimate the 12-month overall survival (OS) for patients to which observed survival of nonrandomized data sets receiving immunotherapies could be compared. PATIENTS AND METHODS: Survival and data for major prognostic factors were obtained from phase 2 trials: hemoglobin, performance status, liver metastasis, treatment-free interval, and albumin. A nomogram was developed to estimate 12-month OS. Patients were randomly allotted to discovery:validation data sets in a 2:1 ratio. Calibration plots were constructed in the validation data set and data bootstrapped to assess performance. The nomogram was tested on external nonrandomized cohorts of patients receiving pemetrexed and atezolizumab. RESULTS: Data were available from 340 patients receiving sunitinib, everolimus, docetaxel + vandetanib, docetaxel + placebo, pazopanib, paclitaxel, or docetaxel. Calibration and prognostic ability were acceptable (c index = 0.634; 95% confidence interval [CI], 0.596-0.652). Observed 12-month survival for patients receiving pemetrexed (n = 127, 23.5%; 95% CI, 16.2-31.7) was similar to nomogram-predicted survival (19%; 95% CI, 16.5-21.5; P > .05), while observed results with atezolizumab (n = 403, 39.0%; 95% CI, 34.1-43.9) exceeded predicted results (24.6%; 95% CI, 23.4-25.8; P < .001). CONCLUSION: This nomogram may be a useful tool to interpret results of nonrandomized phase 2 trials of salvage therapy for metastatic urothelial carcinoma by assessing the OS contributions of drug intervention independent of prognostic variables.

Real-World Effectiveness of Chemotherapy in Elderly Patients With Metastatic Bladder Cancer in the United States.

BACKGROUND: Outcomes for patients with metastatic bladder cancer (mBC) are generally poor and progressively worse following first-line (1L) chemotherapy. OBJECTIVE: To evaluate treatment patterns, survival outcomes, and characteristics of a large, real-world US population of elderly patients with advanced mBC receiving 1L and second-line (2L) treatment retrospectively. METHODS: We identified patients with advanced mBC (aged ≥66 years)-newly diagnosed between January 1, 2004, and December 31, 2011-in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program-Medicare linked database and assessed their palliative systemic chemotherapy treatments and survival outcomes. RESULTS: Of 1703 eligible patients, 42% received 1L chemotherapy; 1L-treated patients tended to be younger and healthier than nontreated patients. Only 27% of 1L-treated patients received cisplatin-based chemotherapy, most commonly cisplatin-gemcitabine. Cisplatin-treated patients were younger and had fewer comorbidities than non-cisplatin-treated patients. Thirty-five percent of 1L-treated patients subsequently received 2L chemotherapy. Patients received a variety of 2L agents as combination chemotherapy (52%) or single-agent chemotherapy (39%). Median overall survival durations in 1L-treated and 2L-treated patients were 8.5 and 7.9 months, respectively. CONCLUSIONS: Results from this retrospective SEER-Medicare database analysis underscore the historical inadequacies of 1L and 2L treatments in elderly patients with advanced mBC. Few patients were treated with 1L chemotherapy, a minority of whom received 1L cisplatin-based chemotherapy, and even fewer received 2L chemotherapy. These findings highlight the disconnect between 1L treatment in clinical trials and treatment in the real-world setting and the lack of standard approaches to 2L treatment in the United States.

Race Characterization of Phytophthora Root Rot on Capsicum in Taiwan as a Basis for Anticipatory Resistance Breeding.

Peppers (Capsicum sp.) are an increasingly important crop because of their use as a vegetable, spice, and food colorant. The oomycete Phytophthora capsici is one of the most devastating pathogens to pepper production worldwide, causing more than $100 million in losses annually. Developing cultivars resistant to P. capsici is challenging because of the many physiological races that exist and new races that are continuously evolving. This problem is confounded by the lack of a universal system of race characterization. As a basis to develop a global anticipatory breeding program, New Mexico recombinant inbred lines (NMRILs) functioned as a host differential for Phytophthora root rot to characterize the race structure of P. capsici populations in Taiwan. Using the NMRILs, 24 new races were identified, illustrating the utility and usefulness of the NMRILs for anticipatory breeding. Virulence of P. capsici was observed to be geographically specific and in two virulence clusters. Interestingly, all but two isolates collected in 2016 were the A2 mating type, which is a shift from the predominantly A1 mating type isolates collected prior to 2008. The NMRILs host differential provides an approach for scientists to work together on a global scale when breeding for resistance as well as on a local level for regional gene deployment. Additionally, we propose that the current race numbering system, which has no biological meaning, be supplemented with the virulence phenotype, based on the susceptible NMRILs to a given isolate. This work provides insights into the population dynamics of P. capsici and interactions within the highly complex Capsicum-Phytophthora pathosystem, and offers a basis for similar research in other crops.

T cell receptor repertoire among women who cleared and failed to clear cervical human papillomavirus infection: An exploratory proof-of-principle study.

BACKGROUND: It is unknown why a minority of women fail to clear human papillomavirus (HPV) and develop precancer/cancer. Differences in T-cell receptor (TCR) repertoires may identify HPV16-infected women at highest-risk for progression to cancer. We conducted a proof-of-principle study nested within the Guanacaste HPV Natural History Study to evaluate the utility of next-generation sequencing for interrogating the TCR repertoires among women who cleared and failed to clear cervical HPV16. METHODS: TCR repertoires of women with HPV16-related intraepithelial neoplasia grade 3 or higher (CIN3+; n = 25) were compared to women who cleared an incident HPV16 infection without developing precancer/cancer (n = 25). TCR diversity (richness and evenness) and relative abundance (RA) of gene segment (V [n = 51], D [n = 2], J [n = 13]) usage was evaluated; receiver operating curve analysis assessed the ability to differentiate case-control status. RESULTS: TCR repertoire richness was associated with CIN3+ status (P = 0.001). Relative abundance (RA) of V-gene segments was enriched for associations between cases and controls. A single V-gene (TRBV6-7) was significantly associated with CIN3+ status (RA = 0.11%, 0.16%, among cases and controls, respectively, Bonferroni P = 0.0008). The estimated area under the curve using richness and V-gene segment RA was 0.83 (95% confidence interval: 0.73-0.90). CONCLUSIONS: Substantial differences in TCR repertoire among women with CIN3+ compared to women who cleared infection were observed. IMPACT: This is the first study to use next-generation sequencing to investigate TCR repertoire in the context of HPV infection. These findings suggest that women with HPV16-associated cervical lesions have significantly different TCR repertoires from disease-free women who cleared HPV16 infection.

Upregulation of microRNA-137 expression by Slug promotes tumor invasion and metastasis of non-small cell lung cancer cells through suppression of TFAP2C.

The epithelial-mesenchymal transition (EMT) regulator, Slug, plays multifaceted roles in controlling lung cancer progression, but its downstream targets and mechanisms in promoting lung cancer progression have not been well defined. In particular, the miRNAs downstream of Slug in non-small cell lung cancer (NSCLC) remain undetermined. Here, we report that miR-137 is downstream of the EMT regulator, Slug, in lung cancer cells. Slug binds directly to the E-box of the miR-137 promoter and up-regulates its expression in lung cancer cells. Knockdown of miR-137 abolished Slug-induced cancer invasion and migration, whereas upregulation of miR-137 was found to trigger lung cancer cell invasion and progression by direct suppressing TFAP2C (transcription factor AP-2 gamma). Clinical data showed that lung adenocarcinoma patients with low-level expression of Slug and miR-137 but high-level expression of TFAP2C experienced significantly better survival. miR-137 is a Slug-induced miRNA that relays the pro-metastatic effects of Slug by targeting TFAP2C. Our findings add new components to the Slug-mediated regulatory network in lung cancer, and suggest that Slug, miR-137, and TFAP2C may be useful prognostic markers in lung adenocarcinoma.

Pathway, in silico and tissue-specific expression quantitative analyses of oesophageal squamous cell carcinoma genome-wide association studies data.

BACKGROUND: Oesophageal cancer is the fourth leading cause of cancer death in China where essentially all cases are histologically oesophageal squamous cell carcinoma (ESCC). Agnostic pathway-based analyses of genome-wide association study (GWAS) data combined with tissue-specific expression quantitative trait loci (eQTL) analysis and publicly available functional data can identify biological pathways and/or genes enriched with functionally-relevant disease-associated variants. METHOD: We used the adaptive multilocus joint test to analyse 1827 pathways containing 6060 genes using GWAS data from 1942 ESCC cases and 2111 controls with Chinese ancestry. We examined the function of risk alleles using in silico and eQTL analyses in oesophageal tissues. RESULTS: Associations with ESCC risk were observed for 36 pathways predominantly involved in apoptosis, cell cycle regulation and DNA repair and containing known GWAS-associated genes. After excluding genes with previous GWAS signals, candidate pathways (and genes) for ESCC risk included taste transduction (KEGG_hsa04742; TAS2R13, TAS2R42, TAS2R14, TAS2R46,TAS2R50), long-patch base excision repair (Reactome_pid; POLD2) and the metabolics pathway (KEGG_hsa01100; MTAP, GAPDH, DCTD, POLD2, AMDHD1). We identified and validated CASP8 rs13016963 and IDH2 rs11630814 as eQTLs, and CASP8 rs3769823 and IDH2 rs4561444 as the potential functional variants in high-linkage disequilibrium with these single nucleotide polymorphisms (SNPs), respectively. Further, IDH2 mRNA levels were down-regulated in ESCC (tumour:normal-fold change = 0.69, P = .75E-14). CONCLUSION: Agnostic pathway-based analyses and integration of multiple types of functional data provide new evidence for the contribution of genes in taste transduction and metabolism to ESCC susceptibility, and for the functionality of both established and new ESCC risk-related SNPs.