bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generation of a prognostic cancer stem-like gene expression signature in men undergoing radical prostatectomy for localized prostate cancer.
Authors: Fairey Adrian Stuart , Yang Dongyun , Groshen Susan G. , Quinn David I. , Kim Philip , Virk Navneet , Wang Lina , Martin Sue Ellen , Stephens Craig , Goldkorn Amir 
Published: March 2020

4563 Background: Novel biomarkers are needed to predict recurrence after radical prostatectomy for localized prostate cancer. Recent data suggest that cancer stem-like cells (CSC) are present in prostate tumors, and the CSC phenotype has been associated with an aggressive cancer phenotype. We investigated whether tumor mRNA levels of genes typically expressed by CSC are associated with disease recurrence. Methods: Clinically annotated prostatectomy specimens (FFPE) were used for this nested case-control study. Samples represented men who underwent radical prostatectomy and either experienced a recurrence (PSA or clinical; n=152) or no recurrence (controls; n=124) with minimum 5-year follow-up. Men were excluded if they received neoadjuvant hormone therapy. Cases and controls were frequency matched based on D’Amico risk group. Laser capture microdissection with mRNA extraction and quantitative RT-PCR were used to quantify the expression of 12 candidate CSC-associated genes (ALDH1A1, Axin2, Bmi1, CD133, CD44a, CTNNB1/β-catenin, ITGA2/integrin α2, NANOG, Nkx3-1, Notch1, OCT 4, TACSTD2/Trop2). Univariable and multivariable analyses were conducted to measure associations with recurrence. Results: mRNA data were evaluable for 241 of 276 patients. Univariate Wilcoxon analysis showed that 4 genes (Axin2, p<0.001; CD44a, p=0.036; OCT 4, p=0.017; TACSTD2, p=0.008) were expressed at low levels in tumors of patients whose disease recurred. Recursive partitioning analysis identified 3 genes significantly predictive of disease recurrence (Axin2, NANOG, CTNNB1), with cutpoints yielding odds ratios (OR) of 8.5 (Axin2low/NANOGhigh; n=94, 95%CI 3.7-19.2) and 5.1 (Axin2low/NANOGvery high/CTNNB1low; n=26, 95%CI 1.7-14.8). Conclusions: We identified a novel CSC-associated 3 gene expression signature with the potential to predict recurrence after radical prostatectomy. Axin2 is known to interact with CTNNB1/β-catenin in the Wnt signaling pathway, which in turn has been shown to regulate expression of NANOG, a key protein that mediates pluripotency. In vitro experiments and an independent cohort validation study are planned based on these novel findings.
Investigator-sponsored trial of efficacy and tolerability of cabozantinib (cabo) at lower dose: A dose-finding study in men with castration-resistant prostate cancer (CRPC) and bone metastases.
Authors: Lee Richard J. , Michaelson M. Dror , Saylor Philip James , Gurski Carol Ann , Rothenberg Stephen M. , Miyamoto David Tomoaki , Maheswaran Shyamala , Haber Daniel A. , Goldin Jonathan G. , Smith Matthew Raymond 
Published: March 2020

4566 Background: Cabo (XL184) is an oral inhibitor of MET and VEGFR2. In a randomized discontinuation trial of cabo 100mg daily, 76% of men with CRPC and bone metastases had partial or complete resolution of bone scan lesions as early as week (wk) 6. However, treatment was limited by adverse events (AEs), with dose reductions in 51% of patients (pts), and discontinuations in 10%. The current study was designed to determine the efficacy and tolerability of cabo at lower starting doses. Methods: An adaptive response scheme was used to determine the lowest active daily cabo dose among dose levels +1 (60mg), 0 (40mg), and -1 (20mg). The primary endpoint was wk 6 bone scan response (BSR) assessed with an automated FDA 510(k) approved computer-aided detection system. A ≥30% decrease in total bone scan lesion area (BSLA) was defined as a response. The first cohort was treated at dose level 0. The number of responses (≥8 vs. <8 among 11 evaluable pts) was used to select the dose level (-1 vs. +1) for the second cohort. Based on the observed BSR rate in the second cohort of 11 pts, a dose was selected for expansion to treat 13 more pts. Results: The study completed planned enrollment of 36 pts. Median age was 66; 44% were docetaxel-pretreated. Among 12 pts enrolled at dose level 0, there were 10 BSRs at wk 6 including 1 complete response (CR), and 1 pt with stable disease (SD). The median decrease in BSLA was 62%. Ten pts evaluated at wk 12 included 9 BSRs (3 CRs), and 1 sustained SD. Among 11 pts then treated at dose level -1, 10 pts were evaluable at wk 6: 1 BSR, 5 SD, and 4 had progressive disease. No pts in the 2 cohorts required dose reduction or treatment interruption at 12 wks; 1 pt discontinued due to grade 3 AEs (anorexia, fatigue). 6/12 pts with ≥6 months follow-up remain on study. 5/5 pts enrolled at 40mg with CTCs ≥5 per 7.5mL converted to <5. Thirteen pts accrued to the expansion cohort at 40mg daily had confirmed high BSR rate. Conclusions: Cabo 40mg daily achieves a high BSR rate in men with CRPC and bone metastases, and is associated with better tolerability than previously reported for cabo 100mg daily.
A multinational phase III adjuvant study of immediate (I) versus deferred (D) chemotherapy (C)/hormone therapy (HT) after radical prostatectomy (RP): TAX-3501.
Authors: Eisenberger Mario A. , Kattan Michael W. , Sternberg Cora N. , De Wit Ronald , Epstein Jonathan I , Ecstein-Fraïssé Evelyne B , Kibel Adam Stuart 
Published: March 2020

4570 Background: TAX 3501 was designed to test I or D C/HT after RP. No adequately designed prospectively randomized surgical systemic adjuvant studies have ever been successfully completed. Methods: TAX-3501 was a randomized phase III study. Eligibility included post-operative predicted probability of 5-year freedom from progression of <60% (Kattan et al) after central pathology review, no prior C/HT, undetectable PSA, M0, normal hematology/chemistries, signed consent. Pts were randomized within 120 days after RP to I or D (at 1st progression) Rx with HT (leuprolide acetate 22.5mg S.C. q.3 months x 6 ) +/- C (docetaxel 75mg/m2 q.3wks x 6). F/U included a physical exam, PSA, CBC/chemical profile, serum T, scans yearly or at progression (PSA≥ 0.4ng/ml, clinical or radiographic and death). Main objectives comparing PFS and 5-year progression-free rates after systemic treatment (2 × 2 factorial design, 4 arms). 1,696 subjects would provide 90% power to detect the targeted treatment effect at a 5% 2-sided type I error level. Results: From 12/2005-9/2007399 pts were registered, 228 randomized after central path review ICHT=55, IHT=55, DCHT=56, DHT=62, median age 62 (41-76), pre-op PSA (ng/ml) 9.38 (2.2 - 90.0), Gleason score- 8,T3a (19.6%),R+(65%),S.V.+(50%),N+(19.7%%), all had undetectable post op PSA. Predicted probability of no progression was 21% on 228pts. Study was terminated by sponsor (9/2007) due to poor accrual F/U continued from 2007-2010. Small sample size precludes reliable analyzes 37/118 (31.3%) on the D arms received CHT/HT (all PSA progressions); ICHT 10/55, IHT 14/55, DCHT 9/56, DHT 8/62 met progression endpoint after I/D Rx (1/31 bone). AEs were characteristic and reversible (no grade 5). Leading causes of accrual impediment were inadequate site selection, no consensus regarding patient and treatment selection for this pt population, physician and patient bias re: treatment and evolving changes in the adjuvant treatment landscape during follow-up time (adjuvant RT). Conclusions: The role of adjuvant systemic treatment after RP remains undefined. Clinical trials in this pt population are challenging. Supported by Sanofi NCT000283062.
Multidimensional investigation of HER2 in advanced urothelial carcinoma (UC).
Authors: Park Rachel S. , Werner Lillian , Greulich Heidi , de Muga Silvia , Salido Marta , Stack Edward C. , Lis Rosina , Schutz Fabio A. B. , Lloreta Trull Josep , Gallardo Enrique , Rojo Federico , Berman David M. , Molins Joaquim Bellmunt , Rosenberg Jonathan E. 
Published: March 2020

4580 Background: Incidence of Her2 positivity and association with overall survival (OS) are controversial in advanced UC. Activating Her2 mutations have been identified in other cancers, but they have not been previously reported in UC. We determined Her2 status by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and copy number gain (CNG) via array CGH of primary UC tumors from patients (pts) with metastatic disease. Targeted Her2 sequencing was performed at known mutation hotspots, and mutation effect was investigated in vitro. Methods: Tissue microarrays of formalin fixed paraffin-embedded tumor from 98 UC pts treated with platinum-based combination chemotherapy for metastatic disease were evaluated for Her2 protein and for Her2 gene amplification by using standard clinical protocols. Positive staining was defined as an IHC score of 3+ or a FISH ratio of ≥2 using scoring criteria established for evaluation of breast cancer. Her2 CNG was evaluated by aCGH with cutoff log base 2 ratio > 0.9. Mutation status was validated by hME sequencing. OS was measured from start of treatment for metastatic disease. Association of OS and Her2 status was assessed by a Cox regression model. NIH-3T3 cells with Her2 V777L were assessed for growth, invasion, and Her2 kinase activation. Results: 22% of pts had 3+ Her2 staining by IHC. 21% of pts had FISH amplification. These were concordant in 78% of pts. CNG was identified in 16% and was concordant with FISH and IHC 85% and 88% of the time, respectively. Her2 status by any modality showed no significant association with OS in either univariate [HR=0.94, 95% CI: (0.52, 1.70), p=0.83] or multivariate [HR=1.12, 95% CI: (0.61, 2.06), p=0.72] analysis. Her2 mutations (V777L and L755S) were identified in 2 pts (2%). In vitro analysis of V777L results in transformation of NIH-3T3 cells, leading to increased growth, invasion on soft agar, and Her2 kinase constitutive activation. Conclusions: Her2 overexpression or amplification in the primary tumor does not predict OS in pts with metastatic UC. Other research has suggested that V777L sensitizes cells to lapatinib, while L755S leads to lapatinib resistance. These rare oncogenic Her2 mutations occur and may be therapeutic targets in selected pts.
Mortality from other malignancies in bladder cancer survivors.
Authors: Ahmadi Hamed , Skinner Eila C. , Miranda Gus , Cai Jie , Djaladat Hooman , Leslie Scott , Daneshmand Siamak 
Published: March 2020

4589 Background: Other-cause mortality represents a considerable proportion of overall long-term mortality in bladder cancer (BC) patients who underwent curative radical cystectomy (RC). Other malignancies besides BC are reportedly among the most common etiologies of other-cause mortality. We report on mortality from other malignancies in BC survivors who have undergone prior RC. Methods: Data on BC patients who died of other malignancies were derived from a cohort of 1964 patients with pathologic diagnosis of urothelial carcinoma of bladder who underwent RC with intent to cure due to BC at University of Southern California between 1971 and 2008. For subsequently developed malignancies, the time interval between RC and occurrence of malignancy was calculated. Other malignancies mortality was evaluated with respect to gender, pathological stage of BC, and type of malignancy. Results: Other malignancies were diagnosed in 463 (23.5%) patients. They were the cause of death in 122 (6.21%) patients (109 male) who had a median age of 68.6 (range 43.4 – 88.7) at time of RC. Of all 122 patients with other malignancies, 22(18%) patients were diagnosed prior to RC, 5 (4%) concurrently with BC diagnosis, and 94 (77%) subsequent to RC. At the time of cystectomy, 87/122 (71.3%) patients had lymph node-negative organ-confined disease, compared to 56.3% in the whole cohort; and 18 (14.7%) patients had nodal disease, compared to 23.2% in the whole cohort. 116/122 (95%) of these patients had no evidence of BC recurrence at time of death. Secondary cancers occurred at a median of 7.7 years (Range 3 months – 29.9 years) after RC. Most common sites and types of malignancies that led to death were lung in 43/122 (35.2%), predominantly non-small cell carcinoma in 17/43(39.5%); hematologic in 15/122 (12.3%), largely lymphoma in 6/15 (40%); and colon in 11/122 (9%), primarily adenocarcinoma in 8/11 (72.7%) patients. Conclusions: Lung, hematologic, and colon cancers are the most common causes of death due to other malignancies in BC survivors and more commonly found in male patients with lymph node-negative organ-confined tumor. Continued screening for other cancers in the follow-up of BC survivors may be warranted.
External validation of prognostic models for overall survival (OS) in patients (pts) with advanced cancer (UC) treated with cisplatin-based chemotherapy.
Authors: Apolo Andrea Borghese , Philips George , Ostrovnaya Irina , Rosenberg Jonathan E. , Milowsky Matthew I. , Small Eric Jay , Bajorin Dean F. , Halabi Susan 
Published: March 2020

4592 Background: The most commonly used model predicting OS for UC pts treated with cisplatin-based chemotherapy is based on 2-variables (visceral metastases and performance status), developed at MSKCC in 1999, and validated in a phase III study (DeSantis JCO 2011). A prognostic model of OS for advanced UC pts based on 4 variables (visceral metastases, albumin, performance status, and hemoglobin) was developed using 308 pts from MSKCC (ASCO 2007 abstr 5055). We report the discriminative ability of the 4- and 2- variable models for advanced UC pts using an independent dataset from CALGB 90102. Methods: The analysis was performed using an external multi-institutional dataset from CALGB 90102. The primary measurement of predictive discrimination was Harrell’s c-index which was computed with 95% confidence interval (CI). To assess whether there was a statistically significant difference in discrimination between the two models, the U statistic was used to test whether the predictions of the 4-variable model in all possible pairs were more concordant with actual observations than the 2-variable model in the same pairs. Results: CALGB 90102 included 74 UC pts (58 males, 16 females), median age 64 years, treated with cisplatin, gemcitabine and gefitinib, enrolled from 7/02 to 4/05 with a median follow-up of 72.5 months. Visceral metastases were present in 64% (bone, 18%, liver, 31%, lung, 43%), median KPS 90%. The MSKCC 2-variable risk group distribution was 30% =0, 65%= 1 and 5%=2. The median OS =12.7 months (95% CI=10.4-20.5) with 68 deaths observed. When applied to the CALGB cohort, the predictive accuracy for the 4- and 2-variable models were 0.63 (95 CI= 0.56- 0.69) and 0.58 (95% CI= 0.52-0.65), respectively. There was a statistically significant difference in discrimination between the two models (p =0.019), with superiority of the 4-variable model compared to the 2-variable model. Conclusions: A 4-variable prognostic nomogram for survival in pts with advanced UC was superior to a 2-variable risk-group model. The 4-variable prognostic model may replace the widely used 2-variable model and can be used in the design and conduct of future phase II and III trials in advanced UC.
Late gastrointestinal (GI) complications in patients with stage I-II testicular seminoma treated with radiotherapy (RT).
Authors: Hallemeier Christopher Leigh , Davis Brian , Pisansky Thomas Michael , Choo Richard 
Published: March 2020

4595 Background: For stage I-II testicular seminoma, RT is highly effective at eradicating disease in the abdominopelvic lymph nodes, but results in unnecessary exposure to normal tissues including the GI tract. The purpose of this study was to define the incidence and risk factors for late GI complications in this patient population. Methods: A retrospective review was performed of 251 patients with stage I-II testicular seminoma treated with curative intent RT at our institution from 1974-2009. All patients underwent orchiectomy and postoperative external beam RT to the involved and/or at-risk nodal basins. Potential late GI complications that were assessed included endoscopically-confirmed gastric or duodenal ulceration, small bowel obstruction (SBO), and biopsy-confirmed malignancy of the GI tract. Risks were estimated using the Kaplan-Meier (KM) technique and univariate/multivariate analyses were performed using the Cox proportional hazards model. Results: Median age at diagnosis was 36 years (range 18 – 80). Clinical stage was I (n=199) or II (n=52). Median abdominopelvic RT dose was 26 Gy (interquartile range 25 – 30). Median follow-up was 15 years (range 0.1 – 38). KM estimates for any GI complication (ulcer, SBO, or GI malignancy) at 10, 20, and 30 years were 7, 10 and 24%, respectively. Four patients died as result of a GI complication. KM estimates for ulcer at 10, 20, and 30 years were 4, 7, and 9%, respectively. Age at RT (Hazard Ratio [HR] 1.05, 95% Confidence Interval [CI] 1.00 – 1.10, p=0.03) and RT total dose (per Gy, HR 1.20, 95% CI 1.09 – 1.31, p<0.01) were associated with risk of ulcer. KM estimates for SBO at 10, 20, and 30 years were 2%, 2%, and 3%, respectively. History of inflammatory bowel disease was associated with risk of SBO (HR 43, 95% CI 7-325, p<0.01). KM estimates for GI malignancy at 10, 20, and 30 years were 0.5, 3 and 16%, respectively. Age at RT was associated with risk of GI malignancy (HR 1.07, 95% CI 1.02-1.14, p=0.01). Conclusions: In patients with stage I-II testicular seminoma treated with RT, late GI complications were a relatively uncommon, but clinically significant source of late morbidity. Use of low dose, limited field, and/or proton RT may reduce these risks.
Clinical relevance of specialist pathologic testicular tumor review.
Authors: Church David N. , Protheroe Andrew , Roberts Ian SD , Crane Gemma Louise , Turner Gareth D , Verrill Clare 
Published: March 2020

4599 Background: Therapeutic options in stage IA/B testicular cancer include surveillance, retroperitoneal lymph node dissection, and adjuvant chemotherapy/radiotherapy; clinician and patient choice is guided by recurrence risk. Specialist pathologic review is important in informing this decision as it may alter diagnosis and staging. Methods: Analysis of a prospective supraregional database of 627 testicular tumors diagnosed in Oxford or referred for central review between 2004 and 2012. Tumor histology, stage (AJCC 7th ed.), and other factors predictive of relapse were compared between referring and final pathology reports. Results: Of 402 cases referred from 11 hospitals during the study period, 370 primary testicular tumors with an informative initial pathology report were analysed. There was a discrepancy between referring and final reports in 116 cases (31.4%), with significant variation between referring units in the frequency of discordance (20.0-89.9%, p<0.0001, x2). Changes to histological diagnosis in 34 cases (9.2%) were minor alterations in type and proportion of non-seminomatous germ cell tumor (NSGCT) elements of no clinical significance, with exception of one classical seminoma reclassified as spermatocytic seminoma. For seminomas (n=201) the commonest discrepancies were in identification of rete testis invasion (RTI) (15.9%); lymphovascular invasion (LVI) (9.5%); and spermatic cord invasion (SCI) (5.0%). RTI was more frequently under-reported (14.4%), and LVI over-reported (8.0%) on initial assessment. Disparity of tumor size in 2 cases (1.0%) was of no clinical significance. For NSGCT (n=150) the commonest discrepancies were in RTI (9.3%), LVI (7.3%) and SCI (6.7%), with LVI typically over-reported (4.0%) and RTI and SCI under-reported (6.7%, 5.3% respectively) on primary analysis. Central review resulted in change of primary tumor stage in 45 cases (12.1%). 12 (6.0%) and 16 (8.0%) seminomas, and 12 (8.0%) and 5 (3.3%) NSGCTs were upstaged and downstaged respectively. Conclusions: Central pathology review results in frequent alteration of factors predictive of relapse in stage IA/B testicular cancer. Particular attention should be directed to review of RTI, LVI and SCI to ensure accurate prognostication.
Post-axitinib systemic therapy in metastatic renal cell carcinoma (mRCC).
Authors: Haddad Housam , Rini Brian I. , Jonasch Eric , Tannir Nizar M. , Dreicer Robert , Garcia Jorge A. , Wood Laura S. , Elson Paul 
Published: March 2020

4609 Background: Axitinib is a potent and selective inhibitor of the VEGF receptor family with efficacy as a second-line therapy in mRCC. Evaluation of further systemic therapy following axitinib has not been previously reported. Methods: The medical records ofmRCCpatients (pts) treated at The Cleveland Clinic or MD Anderson Cancer Center who received axitinib were retrospectively reviewed. Patient characteristics including best response and duration of treatment on axitinib and each subsequent line of therapy were recorded. Results: Eighty-one patients were initially identified; 29 patients received at least one approved targeted agent following axitinib and are included in this analysis. The remainder of pts were excluded due to ongoing axitinib (n=16), lack of subsequent therapy (n=13), lost to follow up (n=11), received experimental agents post-axitinib (n=7) or were inevaluable (n=2). Three pts were excluded due to ≤ 21 days on axitinib. Pt characteristics at start of axitinib included 76% male, median age 59 (range, 44-78); 97% clear cell; 93% prior nephrectomy; 64% previously-treated. Pts were favorable (39%) or intermediate (60%) risk based on Heng criteria. Overall response rate to axitinib was 52% and median duration of treatment of 11.2 months (range, 1.1-90). Thirty eight percent of patients had new brain, bone, and/or liver metastases at disease progression on axitinib. For the first subsequent therapy post axitinib (n=25), pts were treated with tyrosine kinase inhibitors (72%) or mTOR inhibitors (28%). Overall 8% of pts achieved partial responses (one pt each to sunitinib and pazopanib) and 52% had a best response of stable disease. Estimated median duration of therapy was 4.4 months (range, 0.2-27.5+). Fifteen pts received a second post-axitinib targeted therapy with mTOR inhibitors (60%) or TKIs (40%). One patient (7%) achieved a partial response to pazopanib and 8 patients (53%) had a best response of SD. Estimated median treatment duration was 4.8 months (range, 0.7-19.1+). Conclusions: There are objective responses and stable disease to post-axitinib targeted therapies, consistent with previous series and trials in refractory RCC patients.