bluuebunny/crossref_metadata_2025_split huggingface dataset:
Soluble iC3b as an early marker for pancreatic adenocarcinoma compared to CA 19.9 and radiology
Authors: Marten A. , Büchler M. W. , Wente M. N. , Schmidt J. 
Published: August 2020

4626 Background: Pancreatic adenocarcinoma as an aggressive tumor still lacks specific markers. Resection offers the only potential cure, and earlier diagnosis could benefit many patients. Here, we analyzed siC3b as a potential diagnostic marker.siC3b is generated in the fluid phase after binding of auto-antibodies to tumor cells and subsequent inactivation of the complement cascade by interaction with complement regulatory proteins. Methods: 232 plasma samples from subjects with adjuvant treatment after resection, from healthy volunteers and from vulnerable patients were collected prospectively and analyzed for siC3b. Every three months, patients underwent imaging and the results from siC3b ELISA were categorized according to radiological-defined recurrence within four months after blood withdrawal. Furthermore, regulatory factors of the complement system were analyzed on tumor cells and in urine. Results: The most important finding was that up to four months prior to radiological defined recurrence, siC3b plasma level is increased with a sensitivity and specificity resulting in an AUC of 0.85 which could be further increased by combining it with CA 19.9 (AUC = 0.92). Complement regulatory proteins are highly expressed on pancreatic carcinoma cells and detectable in patient's urine. Conclusions: In summary, screening for siC3b in subjects with an increased risk for PDAC (patients with chronic pancreatitis, hereditary pancreatitis, after curative resection and patients with a variety of familial cancer syndromes) allows for early detection with high sensitivity, as siC3b plasma levels are increased up to four months prior to radiological evidence. Sensitivity could be further increased by combining this approach with CA 19.9. No significant financial relationships to disclose.
Gene expression signatures to predict the response of gastric cancer to cisplatin and fluorouracil
Authors: Kim H. K. , Choi I. J. , Kim C. G. , Oshima A. , Green J. E. 
Published: August 2020

4628 Background: A prospective high-throughput gene expression study was conducted to identify transcriptional profiles predictive of a clinical response to cisplatin and fluorouracil (CF) combination chemotherapy and to identify dysregulated genes associated with acquired resistance to CF. Methods: Endoscopic biopsy samples were collected from CF-treated metastatic gastric cancer (MGC) patients (pts) prior to CF (n = 123) and following the development of resistance (n = 22) at the National Cancer Center of Korea from 2001 to 2006, and analyzed using CGH and expression microarrays. We developed 2 survival risk predictors. The first predictor was constructed using genes in DNA amplicons and identified in the expression signature that correlates with survival (intrinsic resistance signature). The second predictor was based on the acquired resistance signature, which was identified by comparing matched expression array data from initially responsive patients prior to treatment with profiles obtained at progressive disease. Results: Array CGH revealed the gene amplification of MYC, EGFR, and FGFR2 whose Affymetrix U133A signals significantly correlated with a poor prognosis (P values, 0.0154, 0.0096, and 0.0057) of training set pts (n = 96). Three-gene-predicted high-risk group of the validation cohort (n = 10) demonstrated a shorter median survival than low-risk (n = 17) group (7.4 vs 16.8 months; p = 0.047). The 3-gene signature, as a continuous variable, was the independent predictor for overall survival (OS) and time to progression (TTP) (adjusted P, 0.021, and 0.012). Importantly, the acquired resistance signature strongly overlapped the intrinsic resistance signature (LS P<10-5), and was highly enriched for MYC target genes (LS p = 2x10-5). A predictor based on MYC target genes within the acquired resistance signature was the independent predictor for OS and TTP of 101 separate pts (adjusted p, 0.015, and 0.011). Conclusions: Combined overexpression of MYC, EGFR, and FGFR2 predicts a poor response of MGC pts to CF. There is significant overlap between intrinsic and acquired resistance signatures of MGC, where the MYC gene network plays a central role. This is the first demonstration that the acquired resistance signature predicts the initial response to chemotherapy. No significant financial relationships to disclose.
Correlation of multidrug-resistance gene (MDR1) expression levels and outcome to adjuvant cisplatin/MTX based chemotherapy in patients enrolled in the AUO-AB 05/95 phase III trial
Authors: Hoffman A. C. , Wild P. , Gauler T. , Leicht C. , Bertz S. , Danenberg K. D. , Danenberg P. V. , Stöhr R. , Stöckle M. , Lehmann J. , Hartmann A. 
Published: August 2020

5026 Background: The human MDR1 gene encodes an integral membrane protein, P glycoprotein (Pgp), whose function is the energy dependent export of substances from the inside of cells, and from membranes, to the outside. MDR1 mRNA levels have been shown to influence metabolism of cancer drugs. We tested whether MDR1 gene expression is associated with outcome in patients with locally advanced bladder cancer. Methods: 221 formalin fixed paraffin embedded (FFPE) tumor samples from patients with locally advanced and/or lymph node-positive bladder cancer enrolled for adjuvant therapy in the AUO-AB 05/95 phase III trial (Lehmann et al, J Clin Oncol. 2005;23:4963–4974) were analyzed (110 pts treated with cisplatin/MTX, 101 pts treated with MTX, vinblastine, epirubicin, and cisplatin, M-VEC).FFPE tissues were dissected using laser-captured microdissection and analyzed for MDR1 and ERCC1 mRNA expression using a quantitative real-time RT-PCR method. Gene expression values (relative mRNA levels) are expressed as ratios between the target gene and internal reference gene (beta-actin). Results: MDR1 was significantly correlated to progression free and overall survival. We included tumor stage (pT), lymph node status (pN) and the blood vessel invasion along with the measured gene expression in a stepwise multivariate Cox proportional hazards regression model. The overall model fit had a significance level of p = 0.0001 (<0.05). The relative risk for shorter survival in patients with High MDR1 expression was 2.8. Regarding survival MDR1 was strongly associated to ERCC1 expression in patients with M-VEC treatment. Conclusions: These results suggest that MDR1 gene expression levels predict response and overall survival in patients with locally advanced urothelial cancer enrolled in AUO-AB 05/95. MDR1 gene expression levels may allow the selection of patients who benefit likely from adjuvant cisplatin/MTX based chemotherapy. Further studies are warranted to study this association. [Table: see text]
Investigation of human mammary stem and progenitor subpopulations from BRCA1 mutation carriers and noncarriers
Authors: Lim E. , Vaillant F. , Wu D. , Forrest N. , Pal B. , Gyorki D. , Smyth G. K. , Visvader J. , Lindeman G. 
Published: August 2020

504 Background: We have previously isolated discrete populations of mouse mammary epithelial cells (MECs) and defined a population that expresses ‘basal’ markers and is highly enriched for mammary stem cells. This subset was ‘triple negative’ for ER, PR and ErbB2 expression and is reminiscent of the basal subtype of breast cancer, suggesting that the mammary stem cell may be the ‘cell of origin’ for this poor prognosis group. Since tumors arising in BRCA1 mutation carriers often exhibit a ‘basal’ phenotype, we hypothesized that the mammary stem cell pool is aberrant in these women. Our objective was to define the human MEC hierarchy and evaluate the functional characteristics of MECs from BRCA1± and normal breast tissue. Methods: Single cell suspensions prepared from fresh human BRCA1± and normal breast tissue were sorted by flow cytometry. Hematopoietic (CD45+, CD235a+) and endothelial (CD31+) cells were removed, and the remaining viable ‘lineage minus’ (Lin-) MECs fractionated based on cell surface markers. These subpopulations were evaluated by immunostaining, RNA profiling, in vitro culture in Matrigel and in vivo xenotransplantation into ‘humanised’ mammary fat pads of immunocompromised mice. Results: Lin- cells fractionated with α6-integrin (CD49f) and epithelial cell adhesion molecule (EpCAM) revealed three discrete MEC subpopulations. A stem/progenitor population that preferentially yields breast outgrowths in vivo has been identified. These subpopulations gave rise in vitro to colonies that were either large and heterogenous or small and homogenous. Only the latter differentiated into milk-producing cells when exposed to lactogenic stimuli. Immunostaining confirmed their origins from myoepithelial and luminal progenitor cells respectively. Intriguingly, BRCA1± MECs exhibited perturbed in vitro growth properties when compared to normal controls. Conclusions: Our studies provide evidence for a human MEC hierarchy, a model to interrogate the perturbation noted in pre-neoplastic tissue derived from BRCA1 mutation carriers and the identification of the cell of transformation in BRCA1 associated breast cancer. These findings may have implications on developing prevention strategies for hereditary breast cancer. No significant financial relationships to disclose.
Association of tumor burden characteristics with outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib
Authors: Golshayan A. R. , Elson P. , Wood L. S. , Garcia J. A. , Dreicer R. , Rini B. I. 
Published: August 2020

5043 Background: An important goal of non-curative therapy for mRCC is tumor burden (TB) control. However, the impact of tumor burden characteristics on clinical outcome has not been studied in mRCC pts treated with VEGF-targeted therapy. Methods: Pts with clear-cell mRCC treated with sunitinib from June 1, 2004, to October 5, 2007, were retrospectively identified. CT scan images were re-reviewed from baseline, at the time of maximal tumor burden shrinkage (TS), at time of disease progression and at time of last assessment prior to death. TB and percent TS were measured per RECIST criteria. Results: Sixty-nine pts were identified. The majority (54%) were favorable risk based on CCF TKI risk group classification. All pts underwent prior nephrectomy and 77% had received prior systemic therapy. Sites of metastases included: lung (87%), mediastinal lymph nodes (52%), retroperitoneal lymph nodes (36%), adrenal (29%), bone (38%), liver (22%), pancreas (14%), kidney (7%), and brain (6%). There were a median of 8 metastatic deposits across all organs (range, 1–20). Median TB at start of therapy was 14.0 cm (range, 3.0–42.2 cm). Overall response rate was 52% and 87% had some degree of TS. Median progression-free survival (PFS) and overall survival (OS) were 13.5 months and 30.9 months, respectively. In multivariable analysis, disease confined to above the diaphragm (p = 0.03) and total TB <13cm (p = 0.09) prior to sunitinib were independent positive predictors of PFS. Total number of metastases <10 (p < 0.001) and tumor volume above the diaphragm <6.5 cm (p = 0.05) were independent positive predictors of OS. Increased TS while on sunitinib was also prognostic for OS (p < 0.001). Fifty-nine pts (86%) have progressed. At time of disease progression (PD), tumor location and pattern of progression were not associated with OS. However, total TB (p = 0.003) and total number of metastatic deposits (≤12 vs. >12, p < 0.001) were significant predictors of OS from PD. At the time of last assessment prior to death, median TB was 23.9 cm, significantly higher (p < 0.001) than in pts still alive (median TB 14.4 cm). Conclusions: Tumor burden shrinkage and tumor burden at time of disease progression are associated with overall survival in pts with mRCC treated with sunitinib. [Table: see text]
Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: A phase I/II study (CA180086)
Authors: Araujo J. , Armstrong A. J. , Braud E. L. , Posadas E. , Lonberg M. , Gallick G. E. , Trudel G. C. , Paliwal P. , Agrawal S. , Logothetis C. J. 
Published: August 2020

5061 Background: Dasatinib, a potent inhibitor of SRC family kinases, inhibits in vitro prostate cancer cell proliferation and migration. Consistent with those findings are the clinical observations that osteoclast activity and bone turnover are downregulated in patients treated with dasatinib. We report promising preliminary results of dasatinib in combination with docetaxel (D) for treatment of metastatic castration-resistant prostate cancer (CRPC). Methods: Male pts with progressive CRPC and castrate levels of testosterone (≤50 ng/dL) requiring chemotherapy were enrolled. Escalating doses of dasatinib (50–120 mg QD) and D (60–75 mg/m2 Q 21 days) were evaluated (n = 16) followed by enrollment of 30 pts at the phase 2-selected dose (100 mg dasatinib QD + D at 75 mg/m2 Q 21 days). Continuation of bisphosphonates was permitted; anti-androgens were discontinued. Primary endpoint (Ph. 2) was to determine drug-drug interactions. Secondary endpoints were: changes in PSA, bone scans and tumor size, bone metabolism [urinary N-telopeptide (uNTX) and bone alkaline phosphatase (BAP)] and PK. Results: 46 pts were treated with 28 pts still on therapy. Median treatment duration (n = 18, pts off study) was 4.2 months (0.13–9.63). Preliminary analysis showed no interaction between dasatinib and D. PSA response was seen in 13/32 (41%) pts, clinical benefit (PR + SD) for RECIST-evaluable pts was 21/21, [7 PR, 5 uPR and 4 SD (at ≥21 wks) and 5 SD at ≥6 wk)]. Of 31 pts with bone scans, 30 patients had a best response of either improved (32%) or stable (65%) at ≥6 weeks. For pts with measurable bone markers levels, 12/26 (46%) had a ≥35% decrease in uNTX and 17/24 (71%) had a decrease in BAP from baseline. 6 of 42 pts experienced ≥ grade 3 adverse events (AEs), including fatigue, myelosuppression and pleural effusion (n = 1). Most common grade 1/2 AEs were fatigue, dysgeusia, GI, and skin disorders. Conclusions: Dasatinib and D at doses up to 120 mg QD and 75 mg/m2 are safe with manageable toxicities and no drug-drug interactions. These data confirm the antitumor and antiosteoclast activity of dasatinib in combination with D and serve as the basis for the ongoing phase III study of this combination. [Table: see text]
A single institution experience with induction and maintenance intravesical docetaxel in the management of non-muscle-invasive bladder cancer refractory to BCG therapy
Authors: Benson M. C. , Barlow L. , McKiernan J. 
Published: August 2020

5080 Background: Our initial phase I trial showed docetaxel to be a safe agent for intravesical therapy with no systemic absorption and minimal toxicity after 6 weekly instillations. In that trial, docetaxel appeared to show a 56% complete response (CR) but the durability was only 22% (no additional therapy) to 39% (CR with additional TURBT). Owing to this excellent initial response rate, a second group of patients were treated with a 6 week induction and then given monthly maintenance therapy with intravesical docetaxel for BCG refractory high-grade, non-muscle invasive bladder cancer (NMIBC). Methods: 13 patients with recurrent Ta (n=1), T1 (n=6), and Tis (n=6) TCC who failed at least one prior BCG treatment were treated. Induction therapy was administered to all 13 patients as 6 weekly instillations of 75mg intravesical docetaxel followed by single-dose monthly maintenance therapy for 9 additional instillations in 9 of the patients who experienced complete initial response. Initial response at 12 weeks from the start of induction therapy was evaluated by cystoscopy with biopsy and urine cytology. Follow-up consisted of quarterly cystoscopy with biopsy and cytology and periodic CT scans. Results: The median follow-up was 14.4 months for the entire cohort. Median duration of maintenance treatment was 9 months. 10/13 patients (77%) from the entire cohort had a complete initial response after induction, and 6/13 patients (46%) have remained disease-free in follow-up. Of those who failed, 6 patients underwent TURBT and one underwent cystectomy. 9/10 initial responders completed at least 3 doses of maintenance therapy to date, of whom 6/9 (67%) have remained recurrence-free. Conclusions: Monthly maintenance therapy with intravesical docetaxel appears to extend the durability of response to induction treatment for a select group of patients with BCG refractory high risk NMIBC and may decrease overall risk of recurrence in NMIBC. No significant financial relationships to disclose.
Malignant transformation of teratoma to primitive neuroectodermal tumor (PNET): Outcome analysis with retroperitoneal lymph node dissection and PNET specific chemotherapy
Authors: Foster R. , Ehrlich Y. , Ulbright T. M. , Cheng L. , Bihrle R. , Beck S. D. , Andreoiu M. , Brames M. J. , Einhorn L. H. 
Published: August 2020

5081 Background: Malignant transformation of teratoma to PNET is a rare entity. Surgical resection has been the mainstay of therapy because these tumors are not curable with cisplatin based chemotherapy. We report long-term survival and potential cure with retroperitoneal lymph node dissection (RPLND) and PNET specific chemotherapy. Methods: Retrospective review of 75 patients (pts) with PNET in the testis or at distant metastasis treated from Jan 1988 to Dec 2007. 74 had RPLND as part of initial treatment or at relapse. PNET specific chemotherapy consisted of cyclophosphamide, doxorubicin, vincristine alternating with ifosfamide and etoposide. Available PNET specimens were tested for the Ewing's sarcoma (EWS) translocation using a FISH-based method. Results: The median follow-up was 40 months (range 2 to 235). 27 pts presented with clinical stage I disease. 18 underwent primary RPLND with PNET in the retroperitoneum in 5. 4 are dead of disease (DOD). 9 elected surveillance or adjuvant chemotherapy. 8 relapsed with PNET. 4 are DOD. 48 pts presented with metastatic disease. 20 are DOD, 24 have no evidence of disease (NED) and 4 are alive with disease. 50 of 75 pts had PNET documented metastasis with an estimated 5 years disease specific survival of 47%. 10 of these were treated with PNET specific chemotherapy for unresectable disease. 8 of the 10 achieved objective response with the duration of response ranging from 4 to 73 months. 2 pts are NED. 2 additional pts were treated with PNET specific chemotherapy as adjuvant to RPLND. Both are continuously NED. Specimens from 14 pts were tested for the EWS translocation, 2 were positive. Conclusions: Malignant transformation of teratoma to PNET carries an adverse prognosis. RPLND is an integral part of the therapeutic strategy. PNET specific chemotherapy, adjuvant to RPLND or for treatment of unresectable disease followed by surgery, may result in long-term survival and potential cure. No significant financial relationships to disclose.
Sunitinib in patients (pts) with unresectable primary renal cell carcinoma (RCC)
Authors: Wood L. , Garcia J. A. , Elson P. , Salas R. N. , Lane B. R. , Klein E. , Stephenson A. , Dreicer R. , Campbell S. C. , Rini B. I. 
Published: August 2020

5096 Background: Sunitinib inhibits VEGF and related receptors, with high tumor shrinkage rates in metastatic (met) RCC. Shrinkage of primary tumors has been observed, although prospective investigation is lacking. The ability of sunitinib to convert primary RCC tumors from unresectable to resectable is of high clinical interest. Methods: Pts with histologically-confirmed RCC with an unresectable primary tumor with or without met disease were enrolled on a single-arm phase II trial. Primary tumors were unresectable due to ≥ 1 of the following: large tumor size, bulky lymphadenopathy, encasement of renal vessels, IVC thrombosis or proximity to vital structures. Pts received 50 mg sunitinib continuous dosing in repeated 6-week cycles. Staging by CT scans or MRI was done at baseline and every 2 cycles. A Simon 2-stage design was employed to test the alternative hypothesis of a conversion to resectability rate of 20% versus the null hypothesis of 5%; β = 0.8, α = 0.05 (n = 31). Results: 18 pts have been enrolled; 1 excluded due to a non-RCC diagnosis. Pts were unresectable due to bulky lymphadenopathy (6), IVC thrombosis (4), proximity to vital structures (4) or tumor size (3), although most pts had multiple factors. Median age among 14 evaluable pts was 61 years (range, 37–80), 59% male, 76% ECOG PS 0; 79% had distant met disease. The 14 evaluable pts have received a median of 3 cycles of therapy (range, 1–10+). Three pts (21%) have undergone primary tumor resection; viable RCC was identified in all specimens with no unexpected surgical morbidity. Nine pts (53%) had primary tumor reduction (median 19%; range, -64% to -1%). Overall, median best % change in tumor burden was 4.9% reduction for primary tumors (range, -43.1% to +8.5%) and 10.7% reduction for met sites (range, -89.5% to +28.6%). Median PFS is 4.9 months. Eleven pts (79%) discontinued therapy; 8 for PD, 1 for adverse events and 2 following surgery which removed all visible disease. Eight pts (57%) experienced grade 3 toxicity including thrombocytopenia, fatigue, hypertension, anemia, hemoptysis, and hand-foot syndrome; 1 pt had grade 4 neutropenia. Conclusions: Sunitinib has activity in unresectable primary RCC tumors, permitting resection in some pts. Continued prospective investigation is required to optimize patient selection and timing of surgery. [Table: see text]
An open-label extension study to evaluate safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC)
Authors: Hawkins R. E. , Hong S. J. , Ulys A. , Rolski J. , Hong B. , Sternberg C. 
Published: August 2020

5110 Background: The efficacy and safety of pazopanib (paz), a multikinase angiogenesis inhibitor, was evaluated in a randomized, double-blind placebo-controlled phase III study (VEG105192), in treatment-naïve and cytokine-pretreated patients (pts) with advanced RCC. Pts with progressive disease (PD) on placebo had the option to receive paz 800 mg QD via an extension study (VEG107769). Methods: Pts with ECOG PS ≤ 2, adequate organ function and no other systemic anticancer treatment since PD on VEG105192 were eligible. The primary endpoint was safety. Secondary endpoints included response rate (RR) per RECIST and progression-free survival (PFS). RR was described along with 95% confidence intervals (CIs). PFS was summarized descriptively using Kaplan-Meier estimates for the median, quartiles and PFS rates at 6, 12, and 18 mo along with approximate 95% CIs. Results: 70 placebo pts were enrolled (+ 1 paz pt as an exemption due to symptom improvement). 34 pts (48%) were treatment-naïve and 37 (52%) were cytokine pretreated (at baseline in VEG105192). Median age was 59 y (25–80); baseline ECOG PS 0 (32%), 1 (52%), and 2 (14%). Median time from randomization to placebo in VEG105192 to start of paz treatment on VEG107769 was 6.4 mo (1–18 mo). At VEG107769 clinical cut-off (May 08), 21 (30%) pts had died, 40 (56%) pts had discontinued paz, and 31 (44%) pts were still on paz. Median exposure to paz was 5.7 mo. Most pts died or discontinued paz due to PD. The majority of adverse events (AEs) were Gr 1/2. Gr 3/4 AEs were experienced by 21%/7% of pts. The most common AEs were hypertension (46%; 4% Gr 3/4), hair color changes (39%; 0% Gr 3/4), diarrhea (38%; 1% Gr 3/4), anorexia (24%; 1% Gr 3/4), and nausea (24%; 0% Gr 3/4). Two pts had fatal AEs: sudden death and gastrointestinal hemorrhage. The most common Gr 3 chemistry laboratory abnormalities were hyponatremia (7%) and elevated ALT (7%) and AST (6%); no Gr 4. RR was 32.4% (95% CI: 21.5, 43.3); median PFS was 8.3 mo (95% CI: 6.1, 11.4 mo). Conclusions: Patients with advanced RCC who developed PD on placebo in a phase III study subsequently achieved clinical benefit from paz treatment in this extension study. These findings support the continued evaluation of paz in advanced RCC. [Table: see text]