bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of therapy with sunitinib and treatment-related hyperparathyroidism in renal cell carcinoma
Authors: Gruenwald V. , Fenner M. , Varvenne M. , Reuter C. , Ganser A. , Ivanyi P. 
Published: August 2020

e16023 Background: Targeted therapies have been thought to combine high potency with high specifity. With increasing experience with multitargeted tyrosine kinase inhibitors (MTKI) recent findings suggest various interactions with physiological organ functions. Here, we report on abnormalities of the mineral metabolism in patients with renal cell carcinoma (RCC) treated with MTKI. Methods: We identified a total of 61 patients with metastatic RCC and evaluable markers of bone metabolism, which were either treated at our institution (N=53) or followed (N=8) during March 2005 and December 2008. Chemistry and parathyroid hormone (PTH) tests were assessed retrospectively. Patients received either sunitinib (4 weeks on/2 weeks off schedule) or sorafenib (continuous dosing) for metastatic disease. PTH, calcium and phosphate were either determined prior to, during and in some cases after completion of therapy with MTKI. Statistical analyses included either student's t-test or one-way ANOVA. Results: Of 61 evaluable patients, 47 received sunitinib, 6 sorafenib, and 8 patients follow-up only. Mean phosphate levels significantly decreased during treatment from 1.151 (CI 1.077–1.224) to 0.9264 (CI 0.844–1.008) (P<0.0001), whereas mean calcium levels remained unchanged (2.37; CI 2.30–2.44 and 2.36; CI 2.28–2.43 mmol/l, respectively). Treatment with MTKI resulted in increased mean levels of PTH (118.3; CI 91.37–145.2), when compared to baseline 43.52 (CI 30.94–56.10) (P<0.0001). In 4 patients additional values after end of therapy were evaluable, which showed reversible PTH increase (42.7; CI 7.473–77.93). Increase of PTH remained significant for treatment with either sorafenib or sunitinib (P0.05). Conclusions: Treatment with MTKI is associated with dysregulated parathyroid axis, which may have clinical implications in a number of patients and therefore should be monitored throughout the treatment. The mechanism for hormone disturbances remains elusive, but may involve the PDGFR, which plays a major role in transmitting signaling of the bone metabolism. [Table: see text]
The significance of urine NMP22 in the screening of urothelial cancer (comparison of ELISA and immunochromatography method)
Authors: Ikeda H. , Ishida Y. , Dejima T. , Nomura M. , Sanefuji H. 
Published: August 2020

e16024 Background: The early diagnosis of urothelial cancer allows for effective local treatment and optimizes the success of surgical therapy. Urine nuclear matrix protein 22 (NMP22) was introduced for the detection of transitional cell carcinoma. Add to old NMP22 (ELISA), new NMP22 (immunochromotography method : BladderChek) can be available from 2004. The objective of this study is to determine whether there are any correlation between urine NMP22 (two methods) and the grade or stage of urothelial cancer, and whether it can serve as a biochemical marker of urothelial cancer. Methods: A total of 246 patients with hematuria or followed up after TUR-BT, from March 2007 to December 2007,visited our hospital and subsequently underwent cystoscopy. The 246 patients provided voided urine samples. We immediately examined urine cytology and NMP22 (two methods). We set the cut off value on 12.0U/ml for NMP22 (ELISA). NMP22 (BladderChek) was judged by qualitative analysis. We decided that in urine cytology, classI,II,III were negative, while IV,V were positive by Papanicolaou classification. Results: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) were 66.7 %, 98.3 %, 81.8 %, 96.3 % in urine cytology, 40.7 %, 75.9 %, 16.2 %, 91.8 % in NMP22 (ELISA), 59.3 %, 79.3 %, 24.6 %, 94.5 % in NMP22 (BladderChek). In 9 cases with false negative of urine cytology, 4 cases were picked up by NMP22 (ELISA), and 5 cases by NMP22 (BladderChek). Sensitivity of grade 1 was 33.3 % in urine cytology, while 66.7 % in NMP22 (BladderChek). By adding NMP22 (BladderChek) to urine cytology, sensitivity rose about 18 %. Conclusions: The sensitivity of urine cytology was unexpectedly high. NMP22 (BladderChek) is more useful than NMP22 (ELISA) because of higher sensitivity, specificity and advantage of simplicity, rapidity. It seems that the addition of NMP22 (BladderChek) to urine cytology is beneficial. No significant financial relationships to disclose.
Phase II study of aflibercept (VEGF-Trap) in patients (pts) with recurrent or metastatic transitional cell carcinoma (TCC) of the urothelium: A California Cancer Consortium trial
Authors: Twardowski P. , Stadler W. M. , Frankel P. , Lara P. N. , Ruel C. , Chatta G. , Heath E. I. , Quinn D. I. , Gandara D. R. 
Published: August 2020

e16030 Background: The role and efficacy of subsequent systemic therapies for advanced TCC following failure of frontline platinum-based chemotherapy is unclear. There is evidence that vascular endothelial growth factor (VEGF) is important in the pathophysiology of TCC. Aflibercept is a recombinant fusion protein that binds and neutralizes multiple VEGF isoforms. Methods: Pts with measurable, metastatic or locally advanced urothelial TCC previously treated with one platinum-containing regimen were entered. Aflibercept was given at 4 mg/kg IV q 2 weeks. Response rate (RR) and progression free survival (PFS) were assessed in a 2-stage accrual design (22+18). A maximum of 40 pts were to be accrued to rule out a null hypothesized RR of 4% and PFS of 3 months versus alternative of 15% RR and 5.4 months PFS with α=0.12 and β=0.19. Results: 22 pts were accrued between 11/06–2/08. Pt characteristics: M/F 15/7; Median age 67 years (45–79); 18 had bladder primary. One partial response (4.5% RR) was seen in a pt with nodal metastasis. Median PFS was 3.5 months (95% CI: 1.8–4.1). Attributable grade 3 toxicities included: hypertension (2), proteinuria (1), pulmonary hemorrhage (1), back pain (1), upper GI bleed (1), hyponatremia (1), anorexia (1) and fatigue (1). There were no attributable grade 4+ toxicities Conclusions: Aflibercept was well tolerated with toxicities similar to those seen with other VEGF pathway inhibitors, however it has limited single agent activity in platinum-pretreated TCC pts. [Table: see text]
Erlotinib with sirolimus for advanced renal cell carcinoma: Preliminary efficacy results
Authors: Flaig T. W. , Costa L. , Breaker K. , Schultz M. , Crighton F. , Kim F. J. , Drabkin H. A. 
Published: August 2020

e16037 Background: The mammalian target of rapamycin (mTOR) is an important therapeutic target in the treatment of renal cell carcinoma (RCC). Temsirolimus, an analog of rapamycin, prolongs survival when used to treat high-risk RCC patients and is approved for the treatment of advanced RCC. Oral rapamycin (sirolimus/Rapamune) is less expensive than temsirolimus and plasma levels can be routinely monitored. Pre-clinical data indicate that the combined inhibition of the epidermal growth factor receptor (EGFR) and mTOR results in enhanced anti-cancer activity, especially in cell lines with wt-VHL. Methods: All patients on this study had metastatic or unresectable renal cell carcinoma with progression despite sunitinib and/or sorafenib. Treatment was started with erlotinib (Tarceva) 150 mg po daily. On day 8, sirolimus was begun with a single 6 mg loading dose and then given as 2 mg daily. Radiographic assessments were performed every 8 weeks. Results: The current data set was obtained through July of 2008. Enrollment started in July of 2006 with the last patient accrued in March 2008; 25 patients have been treated. The median subject age was 60 years with an average of 2.6 previous medical treatments. The unconfirmed median progression free survival (PFS) was 12 weeks (range 2–52) with 4 patients remaining on active treatment and included in this analysis. No confirmed complete or partial responses were observed, but meaningful stable disease (SD) (e.g., > 6 months) was noted in a small group of patients. The most common adverse events were rash and diarrhea with the majority of these observed as a grade 1 event. Grade 3 and 4 toxicities included rash, mucositis, neurological motor weakness, dehydration, worsening cardiac function, non-ST elevation MI, and anemia. Additional efficacy, toxicity and pharmacokinetic data will be presented. Conclusions: The combination of erlotinib and sirolimus produces a median PFS of 12 weeks in a significantly pretreated RCC population, which is not dissimilar to recent results with other mTOR inhibitors in this setting. The toxicity profile of this combination is consistent with the expectations of this pre-treated patient population with advanced RCC. [Table: see text]
Predictors of renal function in nephron sparing surgery for renal cell carcinoma in solitary kidneys
Authors: Wosnitzer M. , Lee D. J. , Hirsch A. J. , McKiernan J. M. 
Published: August 2020

e16045 Background: Partial nephrectomy (PN) is an effective option for the treatment of renal cell carcinoma (RCC) in patients who need to preserve renal function. However, the oncologic safety and functional outcome after PN in solitary kidneys have not been fully examined. We assessed the outcomes after PN, and evaluated predictors of post-operative renal function. Methods: A retrospective analysis of the Columbia Urologic Oncology database found 1327 patients were treated for RCC from 1988 - 2008, of whom 38 consecutive patients underwent PN on a solitary kidney. Glomerular filtration rate (GFR) was estimated with the Modification of Diet in Renal Disease (MDRD) equation. Severe chronic kidney disease (CKD) and renal failure were defined as GFR of 15–30 cc/min/1.73m2 and GFR<15, respectively. Cox proportional hazards regression methods were used. Results: The study group included 30 men and 8 women with unilateral RCC. The mean age was 63.2 years (range 35–83). The mean estimated blood loss was 465cc, the mean tumor diameter was 3.9cm, and 6 (17%) of the patients had a positive surgical margin. 9 patients (30%) had recurrence of RCC at a mean of 23 months postoperatively. Recurrence occurred in the kidneys of 4 patients, lung in 3 patients, bone in 3 patients, and the ipsilateral adrenal gland in one patient. The mean preoperative GFR was 55.6, and the GFR decreased postoperatively by an average of 14.2%. No patients required postoperative hemodialysis. Preoperative GFR (HR=1.01, p<0.01) and the volume of kidney removed (HR=0.93, p=0.01) were associated with severe CKD and renal failure on a univariate Cox regression analysis, but were not independent predictors after adjusting for age, race, tumor stage and grade. Preoperative GFR, volume removed, age, tumor stage or grade were not independent predictors of RCC recurrence. Conclusions: PN in solitary kidneys pose difficult challenges for surgical and clinical management. Nephron sparing surgery for the treatment of RCC is feasible with acceptable morbidity and renal function outcome. The volume of renal parenchyma removed and the preoperative GFR are associated with renal function loss several months after surgery, and may be useful in predicting long-term renal function. No significant financial relationships to disclose.
Aberrant promoter methylation in serum of prostate cancer patients and controls
Authors: Singal R. , Navarro L. , Gordian E. , Ramachandran K. , Reis I. , Manoharan M. , Soloway M. 
Published: August 2020

e16046 Background: The current screening method for prostate cancer (PC), which is based on prostate specific antigen (PSA) level lacks specificity and sensitivity. Previous studies have reported that increased levels of free circulating DNA (fcDNA) and hypermethylation of genes are associated with several cancers. In this study we evaluated the use of fcDNA level and aberrant promoter methylation of 4 genes in serum as biomarkers for PC. Methods: 89 PC patients, 59 with prostatitis (PT) and 104 with benign prostatic hyperplasia (BPH) were enrolled. Serum DNA was analyzed for methylation of GSTPi, RARB, RASSF1A and ECAD by methylation-specific PCR. FcDNA level was analyzed by quantitative PCR. We examined the effect of methylation and fcDNA on PC risk by fitting two logistic regression models, one comparing PC vs BPH and PT vs BPH and the other comparing PC vs PT+BPH. Models were adjusted for age, race, and log2PSA, and tested for variation in effect of methylation by race. Similar analyses assessed the effect of fcDNA as continuous variable, after log2 transformation, and as dichotomous variable with cutpoint near the upper quartile for BPH controls. Results: When adjusted for age and log2PSA, positive GSTPi methylation was associated with increased risk of PC in whites (OR = 6.11, p < 0.001, PC vs BPH; OR = 3.93, p = 0.001, PC vs BPH + PT). Methylation of RARB was associated with PT independent of race (OR = 2.85, p = 0.032, PT vs BPH). Patients with fcDNA ≥180ng/ml were at twice the risk of PC compared to those with levels <180ng/ml, and this result did not vary by race. Models including both GSTPi and fcDNA confirmed the independent effect of these two factors in whites (high fcDNA OR = 3.77, p = 0.002, positive GSTPi methylation OR = 5.41, p < 0.001, PC v. BPH + PT). Although high fcDNA also increased risk of PC in blacks, the effect was not statistically significant (OR = 1.91, p = 0.189, PC vs BPH + PT). Conclusions: Our results suggest that aberrant promoter methylation of GSTPi in serum is a potential biomarker for prostate cancer in whites. Level of fcDNA in serum also appears to be an independent diagnostic marker in whites. No significant financial relationships to disclose.
A phase I study of intravesical Ad-IFN in superficial bladder cancer patients
Authors: Dinney C. P. , Benedict W. F. , Cutler D. L. , Fisher M. F. , O'Donnell M. A. 
Published: August 2020

e16048 Background: Intravesical BCG (Bacillus Calmette-Guérin) is the gold standard for treatment of superficial bladder cancer. Recurrence is a significant problem. Intravesical interferon α (IFN) demonstrated complete response (CR) in ∼40% patients with most relapsing <1 year. Intravesical Ad-IFN takes advantage of the bladder to allow prolonged exposure to high concentrations of IFN; this is expected to potentiate durable therapeutic responses. Syn3 is an excipient used to increase adenoviral vector (Ad) transfection. Methods: The phase I study is a nonrandomized, open-label, rising-dose, multi-center study of Ad-IFN in patients with papillary bladder cancer, or carcinoma in situ refractory to BCG. Patients with T1 were not enrolled unless they refused cystectomy. A minimum of 3 subjects were enrolled at each dose level. Adverse events and lab abnormalities were graded according to CTC version 3 criteria. The occurrence of treatment-related Grade 3 or Grade 4 toxicity is considered dose-limiting toxicity (DLT). The maximum tolerated dose is defined as the dose which results in DLT in ≤1/6 subjects. Urine from pre-treatment, posttreatment days 0–7, 10, 14, and 28 were tested for IFN, Syn3, Ad-IFN DNA, and research biomarkers. Blood was assayed for IFN, Syn3, Ad-IFN DNA, anti- adenovirus and anti-IFN antibodies. Results: Intravesical administration of 3×109, 1×1010, 3x1010, 1×1011, or 3×1011 particles/ml of Ad-IFN (75ml) in 1mg/ml Syn3 is safe with only minor initial urgency controlled with anticholinergic medication. Of the 13 evaluable patients, 6 are CR, defined as a negative cytology and biopsy at 3 months. CR patients were offered a second dose. Response duration is variable with longest >1 year. Urinary IFN was seen for all patients in a dose-dependent fashion. TRAIL, IP-10, M65, and M30 were also seen. Conclusions: Initial safety and response activity justify further clinical development. [Table: see text]
Impact of age at diagnosis on survival of hormone-refractory prostate cancer (HRPC) patients
Authors: Humphreys M. R. , Ma C. , Sridhar S. S. 
Published: August 2020

e16050 Background: Conflicting data exist for age as a determinant of overall survival (OS) in pts with HRPC. We hypothesize that young (<55) HRPC pts represent a more aggressive biological phenotype and therefore have a decreased OS. Methods: A retrospective chart review was conducted on 334 consective HRPC pts treated between 1995–2005. Summary statistics for demographic and clinical factors were generated, and Kaplan-Meier (KM) OS curves were created. Bivariate Cox Proportional-Hazards regression was used to test the association of age at diagnosis while adjusting for a covariate, with significant covariates entered into multivariate models. Results: Overall median survivals in the age stratified categories (<55, ≥55–65, ≥65–75, ≥75) were 5.5, 6.9, 7.9, and 4.3 yrs, with 5 yr survivals 51.9%, 67.4%, 67.0%, and 34.9%, respectively. KM curves showed divergence with an overall significant log-rank test (p < 0.0001). Compared to pts ≥65–75, the hazard ratios (HR) for HRPC pts <55 and ≥75 were 1.40 (95% CI 0.90–2.60) and 2.52 (95% CI 1.67–3.82), respectively. However, following multivariate analysis HRs for HRPC pts <55 and ≥75 were 1.60 (95% CI 0.98–2.62) and 1.25 (95% CI 0.71–2.20). Pts <55 and ≥75 presented with advanced stage at diagnosis and progressed to bone metastasis earlier. Pts ≥75 had decreased performance status, more comorbidities, higher PSA at diagnosis, shorter duration of hormone sensitive disease, and were less likely to receive chemotherapy than pts <75. The percentage of rapid PSA doubling times was highest in the <55 cohort. In multivariate analysis with age as a categorical variate, ECOG 3–4 (HR 2.65), time from diagnosis to both HRPC (HR 0.78) and bone metastasis (HR 0.80), and duration of response to androgen ablation (HR 0.86) remained highly predictive. Conclusions: Age at diagnosis influences OS in HRPC with a bimodal survival curve. Pts <55 and ≥75 present with more aggressive disease, translating into reduced median and 5 yr survivals. Other covariates, especially ECOG status, likely account for the decreased OS in the ≥75 cohort. Conversely, pts <55 had an adjusted HR of 1.60 (p = 0.06). Our study supports a growing body evidence that suggests a poor prognosis in younger men; correlating these differences at the molecular level could lead to better targeted therapies. No significant financial relationships to disclose.
Phase II study of sorafenib and docetaxel in men with metastatic castration resistant prostate cancer (mCRPC)
Authors: Cetnar J. P. , Rosen M. A. , Vaughn D. J. , Haas N. B. , Troxel A. B. , Song H. , Adluru G. , Flaherty K. T. , O'Dwyer P. J. , Amaravadi R. K. 
Published: August 2020

e16055 Background: Previous trials of the antiangiogenic kinase inhibitor sorafenib in mCRPC have reported PSA elevation accompanying radiographic response, and evidence that sorafenib may potentiate docetaxel (dxl) myelosuppression. To assess the safety, antivascular effects, and activity of sorafenib and dxl in mCRPC, a phase II trial with dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) was conducted. Methods: Eligible men had mCRPC and no prior chemotherapy. Treatment consisted of dxl 75 mg/m2(day 1) and sorafenib (days 2–19) of a 21 day cycle. Patients received 7 days of sorafenib before cycle 1. Six patients received sorafenib 200mg BID and remaining patients received sorafenib 400 mg BID if <4/6 patients had grade 4 neutropenia. DCE-MRI was performed at baseline, days 8 and 28. The primary endpoint was PSA response rate (>50% PSA decline). Secondary endpoints were vascular response rate (>20% decline in area under the gadolinium curve [AUC60]), toxicity rates, and time to progression (TTP). PSA-only progression (2 consecutive PSA rises) was confirmed by a third PSA rise or radiographic progression after a 21-day drug holiday. Sample size of 69 patients in 1 stage was designed to maximize detection of significant correlations between DCE-MRI and clinical outcomes. Results: Six of 13 enrolled patients (46%) had a PSA response. A median PSA increase of 37% was observed in 73% of patients after 1 week of sorafenib. The median TTP was 8+ months. Two patients had complete disappearance of bone lesions. Grade 3 adverse events were neutropenia (77%), hand-foot syndrome (23%), anemia (15%), nausea (8%), and rash (8%). A median AUC60 decline of 40% from baseline was observed after 7 days of sorafenib, and only a 6% decline on day 28 during a scheduled sorafenib holiday. Conclusions: Sorafenib 400 mg po bid and dxl 75 mg/m2 are tolerable in men with mCRPC. Elevated PSA values in men treated with sorafenib and dxl does not always reflect disease progression. DCE-MRI can capture sorafenib's impairment of tumor vasculature in osseous metastases and rebound angiogenesis during drug holidays. Bone responses and TTP data provide evidence of encouraging activity. No significant financial relationships to disclose.
CT response assessment combining reduction in size and arterial enhancement correlates with time to progression in metastatic renal cancer patients treated with TKIs
Authors: Nathan P. D. , Vinayan A. , Stott D. , Goh V. 
Published: August 2020

e16062 Background: Targeted therapy is now the standard of care in advanced Renal Carcinoma (RCC). Response assessment by RECIST criteria is insensitive as treated tumours often have only a modest change in size despite the induction of significant necrosis and does not correlate with time to progression (TTP). The Choi criteria (10% size reduction or 15% contrast enhancement reduction) are routinely used in the assessment of GIST tumours treated with targeted agents. We report the use of combined size and density assessment in RCC metastases treated with either sunitinib or cediranib. Methods: CT scans from 32 patients with metastatic RCC treated with either sunitinib (18) or cediranib (14) were assessed. Scans from 10 patients were not evaluable as non-contrast enhanced scans were performed due to impaired renal function. Scans from a further 2 patients were excluded as they ceased treatment due to toxicity rather than progression. Scans from 20 evaluable patients at baseline and 12 weeks on treatment were assessed using RECIST, Choi, and modified criteria in which both a 10% decrease in size and 15% decrease in enhancement in the arterial phase were required to define a response (PR). A total of 60 lesions were assessed. Response assessment was performed using each of the three methods and correlated with time to disease progression (itself RECIST defined). Statistical analysis was performed using the Mann-Whitney U test. Results: There was no difference in TTP between RECIST defined PR (346.8 days) and SD (328.5 days) (P=0.965). TTP in Choi defined PR (358.4 days) and SD (189.6 days) groups showed improved but non-significant separation of TTP duration (P=0.266). TTP in PR (421.5 days) and SD (200.3 days) groups defined by a combined assessment of reduction in size and enhancement showed greatly improved separation (P=0.064). Conclusions: A combined reduction in both size and arterial phase enhancement of RCC metastases treated with TKIs correlates with time to progression. RECIST and standard Choi criteria appear inferior. No significant financial relationships to disclose.