bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary results of a phase I study: A chimeric monoclonal anti IL-6 antibody CNTO 328 in combination with docetaxel in patients with hormone refractory prostate cancer
Authors: Hudes G. R. , Nanus D. , Qi M. , Prabhakar U. , Corringham R. , Jiao Q. , Eisenberger M. 
Published: March 2020

15521 Background: High serum levels of pro-inflammatory cytokine IL-6 may impact the progression and survival of metastatic hormone refractory prostate cancer (HRPC). CNTO328, an anti IL-6 monoclonal antibody, inhibited prostate tumor growth in several preclinical xenograft mouse models. Methods: This Phase 1, open label study evaluates the safety, pharmacokinetics (PK), and pharmacodynamics of CNTO328 at three dose levels (6mg/kg q2 weeks, 9mg/kg q3 weeks and 12mg/kg q3 weeks) in combination with docetaxel (75mg/m2 q3 weeks) in men with metastatic HPRC. C-reactive protein (CRP), a surrogate biomarker of serum IL-6, and circulating tumor cells (CTC) are evaluated. Results: Eight patients with a median baseline PSA value of 56.8 ng/ml (range 13.6- 436.9 ng/ml) were treated in the first cohort (6 mg/kg CNTO328 q2 weeks in combination with docetaxel 75 mg/m2 q3 weeks). At baseline, 6 patients (75%) had detectable CRP and 6 patients had detectable CTCs. The median number of CNTO328 doses and docetaxel cycles administered was 6 (CNTO328: range 3 to 11 doses; docetaxel: range 3 to 13 cycles). No first-cycle DLT was observed for this combination. Three patients discontinued treatment due to docetaxel-related grade 3 adverse events (deep vein thrombosis, hyperbilirubinemia, and nail changes) after 6, 11, and 13 cycles of docetaxel, respectively. Serum CRP decreased to below detectable levels 7 days after the first dose of CNTO328 in all patients with measurable values at baseline and remained undetectable throughout treatment. Two patients with post-treatment CTC values showed CTC reduction from 82 to1, and 127 to1, respectively. Six of 8 patients had = 50% PSA reductions and all had stable or improved bone scans and/or CT scans. PK of CNTO328 and docetaxel, alone and in combination, will be presented. Conclusions: Thus far, anti-IL6 therapy with CNTO328 at 6mg/kg q2 weeks in combination with docetaxel 75mg/m2 q3 week has been feasible and tolerable. Complete suppression of CRP and PSA reduction provide evidence of biological and anti-tumor activity of this approach and support further testing. [Table: see text]
Prognostic role of chromogranin A expression for docetaxel response in hormone-refractory metastatic prostate cancer
Authors: Gernone A. , Trabucco S. , Troccoli G. , Pagliarulo V. , Pagliarulo A. 
Published: March 2020

15528 Background: The neuroendocrine (NE) cells in prostate cancer are indistinguishable from non-NE cancer cells morphologically and are usually detected by immunohistochemical study for NE markers. We analyzed the expression of Chromogranin A (Chr A) in malignant prostate tissue as prognostic factor for docetaxel response in metastatic HRPC. Methods: From January 2003 to December 2006, 40 patients with metastatic HRPC received a median of 12 cycles (range 2–18) of Docetaxel 75 mg/mq every 21 days and 5 mg of prednisone twice daily as initial therapy. Tissue blocks from primary prostate cancer tissues were obtained and immunostaining for Chr A was performed. The median age was 70 years (range 46–82); median baseline PSA: 310 ng/ml (range 0.15–700); median ECOG Performance Status: 1 (range 0- 2). PSA level was measured every 4 weeks and the treatment was considered effective if a rate of PSA-decline > 50% from baseline was found. TTP was the preliminary end point. Results: Response to Docetaxel was assessed at every 3 cycles of treatment. The Chr A expression was found in 19/40 patients with Gleason = 7, PSA < 20, bone and soft tissue metastasis; 10 of them showed PR (decrease in PSA < 50%), 4 SD and TTP was 9.2 months. Moreover they received second line chemotherapy without significant efficacy. 5/19 patients with Chr A expression showed PD, the PSA level was not correlated with clinical outcome, TTP was 5 months and were chemoresistant to different line treatment. Besides, Chr A was not detected in 21/40 patients with Gleason = 7, PSA > 20 and bone metastasis; 10 of them showed CR (PSA normalized) and 11 PR, TTP was 20 months. Conclusions: NE differentiation do not constituite a different histopathological category of prostate cancer but the NE phenotype can be correlated with poorly differentiated adenocarcinoma. NE differentiation can be considered a factor that influences prognosis and treatment in advanced prostate cancer; cases with Chr A expression did not benefit from Docetaxel and had poor prognosis. These preliminary data indicate that initial therapeutic approach should be different according to Chr A expression. No significant financial relationships to disclose.
Prostate cancer distribution in patients diagnosed by transperineal template-guided saturation biopsy: Implications for brachytherapy treatment planning
Authors: Merrick G. S. , Gutman S. , Adamovich E. , Anderson R. , Allen Z. , Butler W. , Wallner K. 
Published: March 2020

15533 Background: Prostate cancer remains undetected in approximately one-third of patients following standard transrectal ultrasound-guided biopsy. In this study, we evaluated prostate cancer incidence, anatomic distribution, Gleason score profile and tumor burden in patients diagnosed by transperineal template-guided saturation biopsy (TTSB). Methods: One hundred and seventeen patients underwent TTSB. TTSB was performed under general anesthesia. All but one patient had undergone at least one prior negative TRUS biopsy. Criteria for inclusion included an elevated PSA and/or the diagnosis of ASAP or high-grade PIN on prior biopsy. The prostate gland was divided into 24 regional biopsy locations with 1–3 biopsies per region. The median number of biopsy cores was 50. Multiple clinical parameters were evaluated as predictors for prostate cancer diagnosis. Results: The mean patient age was 64.8 years with a mean PSA of 9.1 ng/mL and a prostate volume of 78.6 cm3. On average, patients had undergone 2.1 prior negative TRUS biopsies with a mean of 22.4 core biopsies. Prostate cancer was diagnosed in 49 patients (41.9%) with a Gleason score distribution of 6–9. Patients with a prostate volume of = 60 cm3 had a higher rate of cancer diagnosis compared to patients with larger glands (66% vs. 30%). Although no anatomic region of the prostate gland was spared of cancer, there was a preponderance of anterior-based malignancies. In patients with prostate cancer, an average of 9.9 cores were involved. In multivariate analysis, pre-saturation biopsy diagnosis and prostate volume were the best predictors for prostate cancer diagnosis. Conclusions: Transperineal template-guided saturation biopsy diagnosed prostate cancer in 41.9% of previously biopsied patients. Considerable anatomic variability in prostate cancer distribution was documented. Based on this and other reports, cancer eradication will be dependent on treatment of the entire prostate gland. No significant financial relationships to disclose.
Radiation morbidity and micronuclei in lymphocytes of prostate cancer patients
Authors: Lee T. , Allison R. R. , O’Brien K. F. , Wiley A. L. , Johnke R. M. , Wang W. 
Published: March 2020

15540 Background: Since formation of micronuclei (MN) in interphase cells is a reflection of DNA damage, it has been postulated that enhanced peripheral blood lymphocytes (PBL) radiosensitivity might correlate with the development of radiation morbidity. Methods: We conducted the cytokinesis-block (CB) MN assay of PBL in 54 prostate cancer (PC) patients ( mean age ± SEM: 68 ± 1.6 yrs) who had no previous exposure to cytotoxic agents. Patients received standardized pelvic radiotherapy (RT) (41.4 -50.4 Gy) with mean follow-up of 29.1± 3.3 mos. Blood samples were drawn before RT and at designated intervals after RT initiation. Gastrointestinal (GI) and genitourinary (GU) morbidity were determined using RTOG criteria. Results: Average reactors (AR, n = 14) were defined as patients who did not develop morbidity. Grade 1 (G1R, n = 19) and Grade 2 reactors (G2R, n = 21) were defined as those who developed Grade 1 or Grade 2 GI or GU morbidity, respectively. Results of the MN yield in PBL before RT indicated that (1) at baseline level (0 Gy), differences in MN yield for AR, G1R, and G2R patients were insignificant; (2) after ex vivo irradiation (1 - 4 Gy), MN yield followed a linear-quadratic polynomial trend in AR, G1R, and G2R patients; and (3) differences in MN yield in AR vs. G1R or AR vs. G2R patients were significant (P = 0.0001). After the initiation of RT, MN yields in PBL at 24 h, one week, and six weeks, the ratio of relative increment (RI) of RT-induced MN yield, i.e. MNRI = MN (RT-induced) - MN (pre-RT)/ MN (pre-RT) in both G1R and G2R patients was significantly higher than that in AR patients. Our results suggest that prediction of GI or GU morbidity in patients is potentially possible through the evaluation of both ex vivo radiation dose-response relationship of MN in PBL before the initiation of RT and the in vivo MNRI after RT. No significant financial relationships to disclose.
Dystroglycan expression correlates with tumor grade and with outcome in renal cell carcinoma patients
Authors: Sgambato A. , Camerini A. , De Luca F. , Genovese G. , Valsuani C. , Tartarelli G. , Garrone O. , Cecchi M. , Cittadini A. , Amoroso D. 
Published: March 2020

15554 Background: The dystroglycan (DG) complex is a transmembrane glycoprotein that forms a continuous link from the extracellular matrix to the actin cytoskeleton. Deregulated expression of DG has been reported in a variety of human malignancies and related to tumor differentiation and aggressiveness. Methods: In this study, the expression of the a-subunit of DG was evaluated by immunostaining in a series of 125 renal cell carcinomas (RCCs) and its relation with disease progression and cancer-specific survival was evaluated. Results: to date, median follow-up is 19 months (range 1–96). We found that a-DG expression was lost in a significant fraction of tumors (66%) with 18% being the mean percentage of positive cells (median = 0; range = 0–80%). Loss of DG staining correlated with higher tumor grade (p=0.039) but not with tumor stage or size. Recurrence (p=0.014) and death (p=0.041) from RCCs were significantly more frequent in patients whose tumors displayed reduced staining for DG compared with patients whose tumors were positive for a-DG expression. Kaplan-Meier analysis showed a significant separation between high vs low a-DG expression for both disease-free (p=0.0094) and overall (p=0.0023) survival. In a multivariate analysis, loss of a-DG expression was the only independent risk predictor for recurrence (HR=6.509, p=0.0012) and death (HR=4.701, p=0.012) from RCCs when tumor size as well as tumor grade and stage were included in the model. Conclusions: These findings demonstrate that loss of a-DG expression, which correspond to loss a functional DG complex, is a frequent event in human renal tumorigenesis and is associated with an aggressive phenotype of the disease. They also suggest that evaluation of DG expression has the potential to offer important prognostic information and warrant further studies to better understand the role(s) of this molecule in term of renal cancer development and as a new prognostic marker for RCC patients. No significant financial relationships to disclose.
Adjuvant multimodality treatment in patients with high-risk prostate cancer following radical prostatectomy: Results of a prospective clinical phase-II trial
Authors: Thüer D. , Ohlmann C. , Pfister D. , Engelmann U. , Heidenreich A. 
Published: March 2020

15557 Background: High risk prostate cancer (PCA) is associated with a high frequency of PSA relapse. Even with adjuvant androgen deprivation therapy about 50% of patients experience systemic recurrences within 5 years. Docetaxel has demonstrated significant activity in men with metastatic androgen independent PCA, zoledronic acid has been shown to significantly inhibit the development of osseous metastases. It was the aim of the current prospective clinical phase-II trial to evaluate safety and clinical efficacy of early multimodality treatment in high risk PCA after radical prostatectomy (RPE). Methods: Between 3/2004 and 12/2005 25 patients with high risk PCA following RPE were recruited. High risk PCA was defined by a risk of biochemical progression > 70% according to the postoperative Kattan nomograms. Adjuvant therapy consisted of androgen deprivation with LHRH analogues for 12 months, zoledronic acid at 4mg every 3 months and docetaxel at 75 mg/qm for six consecutive cycles. Adjuvant treatment was initiated 4 to 6 weeks after surgery. Follow-up examination were undertaken every 3 months with PSA serum determinations; in case of PSA increase 2 consecutive measurements at 4 weeks intervals were performed. Time to progression defined the time interval between initiation of therapy and first PSA relapse. Results: The mean follow-up is 20.5 (6–31) months. Adjuvant multimodality treatment was well tolerated in all patients with grade 3/4 hematotoxicity in 3 (12%) and gastrointestinal toxicity in 5 (16%) patients; 2 (8%) developed significant oncolysis with surgical intervention. In none of the patients the dosage of docetaxel or the number of cycles had to be reduced. Currently, 4 (16%) patients have developed PSA relapse with 2 exhibiting osseous metastases and 2 having died. Median time to progression was 14.5 (10–16) months. Conclusions: The clinical efficacy appears to be lower than expected with a 16% progression rate and a 8% mortality rate after only 20 months of follow-up. Adjuvant multimodality treatment of high risk PCA after RPE can be applied without significant treatment-associated side effects. Currently ongoing clinical phase-III trials have to further validate the concept of adjuvant chemotherapy. No significant financial relationships to disclose.
Phase II trial of the anti-prostate specific membrane antigen (PSMA) monoclonal antibody (mAb) J591 plus low-dose interleukin-2 (IL-2) in patients (pts) with recurrent prostate cancer (PC)
Authors: Jeske S. J. , Milowsky M. I. , Smith C. R. , Smith K. A. , Bander N. H. , Nanus D. M. 
Published: March 2020

15558 Background: The de-immunized mAb J591 recognizes the extracellular domain of PSMA and was engineered to induce antibody-dependent cellular cytotoxicity (ADCC). Low-dose IL-2 results in the clonal expansion of NK cells and may enhance ADCC. We conducted a phase 2 trial to determine the efficacy and toxicity of mAb J591 plus low-dose subcutaneous (SC) IL-2 in pts with recurrent PC. Methods: 17 pts with recurrent PC (2 groups: 11 with PSA relapse only; and 6 with progressive castrate metastatic disease) received continuous low-dose SC IL-2 (1.2 x 106 IU/m2/day) daily for 8 weeks with mAb J591 (25 mg/m2 IV) weekly on weeks 4, 5 and 6 (1 cycle). Pts could receive a maximum of 3 cycles. Results: 16 evaluable pts received up to 3 cycles of therapy (16 pts, one cycle, 9 two cycles and 2 three cycles). Toxicity was mild and limited to fatigue and injection site reactions. At the end of cycle 1, PSA was stable (-50%<change in PSA<25%) in 9 of 16 patients, with PSA declines up to 34%. No PSA decline >50% was observed. A post-hoc analysis of PSA kinetics showed 5 patients had a reduction in their PSA slope of =25%; 8 of the remaining 11 patients demonstrated PSA stabilization (- 25%<change in PSA slope<25%). PSA response was most commonly observed during weeks 4–6 of the cycle correlating with mAb administration. Flow cytometric analysis of peripheral blood mononuclear cells revealed an average increase in absolute NK cell count of 107% at week 4 and 117% at the end of cycle 1. Conclusions: The combination of mAb J591 with low-dose IL-2 was well tolerated and inhibited PSA kinetics in some patients, however no responses were seen. Repetitive dosed mAb J591 is a viable strategy for use in combination with immune modulatory or other therapies in recurrent prostate cancer. No significant financial relationships to disclose.
A phase II study of IV gemcitabine (G) and oral capecitabine (C) in patients (pts) with advanced renal cell cancer (RCC): Results of Southwest Oncology Group study 0312
Authors: Van Veldhuizen P. J. , Hussey M. , Lara P. N. , Gumerlock P. H. , Clark J. , Lange M. K. , Crawford E. D. 
Published: March 2020

15562 Background: Previous reports have suggested benefit of GC in a modest number of patients with RCC but with concerns regarding toxicity. We subsequently evaluated an adjusted dose regimen in pts with advanced unresectable or metastatic RCC. Methods: Pts who had not received prior chemotherapy where treated with G at 900mg/m2 days 1,8,15 and C at 625mg/m2 BID day 1- 21 of a 28 day cycle. Pts must have had adequate performance status, organ function and may have received prior immunotherapy. The primary endpoint was probability of response, confirmed and unconfirmed complete (CR) and partial responses (PR). A one-stage design for accrual was used and regimen would not be considered of interest if the true probability of response was <=5%. Results: 43 patients were enrolled of which 1 was ineligible and 2 were not analyzable. Median follow-up was 11.2 months (range: 1.3 to 18.5). One confirmed complete response (CR) and three unconfirmed partial responses (PR) were observed, for an overall response probability of 10% (95% CI: 3% to 24%). Four of the eligible patients had inadequate disease assessment and were assumed to be non-responders. 19 pts (48%) had stable disease (SD). The 6-month probability of being free from treatment failure was 20% (95% CI: 8% to 32%). The probability of survival at 6 months was estimated to be 75% (95% CI: 62% to 88%). Median survival was estimated to be 13 months (lower limit of 95% CI is 7 months, upper limit not estimable). One patient each experienced Grade 4 neutropenia, fatigue, thrombocytopenia and hemolysis/renal failure. Most common Grade 3 toxicities were neutropenia (12 pts), fatigue (5 pts), and leucopenia (4 pts). Conclusions: GC at this dose and schedule benefits a small percentage of pts with RCC with an acceptable toxicity profile. Given the RR and SD, GC may serve as a base regimen for combination therapy with targeted agents. No significant financial relationships to disclose.
Global proteome analysis of germ cell tumor (GCT) cell lines under treatment with cisplatin (CDDP)
Authors: Honecker F. U. , Glaesener S. , Venz S. , Walther R. , Brummendorf T. H. , Balabanov S. , Bokemeyer C. 
Published: March 2020

15567 Background: GCTs are the most common malignancy in young Caucasian males aged 20–40. With CDDP-based chemotherapy, highly effective treatment has been developed for the majority of patients with GCT. However, the molecular mechanisms underlying treatment response remain elusive. Therefore, we used a global proteomics approach to screen for changes induced in GCT cell lines by CDDP. Material and Methods: Global protein expression analysis of three GCT cell lines, NTERA2, 2102EP, and NCCIT, both untreated and treated with CDDP for 48 hours at the IC50, was performed using 2-dimensional gel electrophoresis. Differentially expressed proteins were analyzed using matrix-assisted laser desorption/ionization - time of flight (MALDI TOF) and Fourier transform ion cyclotron resonance (FTICR) mass spectrometry. Identification of proteins was performed using peptide mass-fingerprinting and NCBI/SwissProt and The Global Proteome Machine database search. Results: In total, 66 proteins were found to be differentially expressed comparing untreated and treated cells. Numbers of proteins showing upregulation under CDDP were 18 in NTERA2, 10 in NCCIT, and 9 in 2102EP, whereas 17 proteins were downregulated in NTERA2, 5 in NCCIT, and 7 in 2102EP. Identification of corresponding proteins was successful in 44 out of 66 spots (67%). Differential expression of 5 proteins was found in more than one cell line. One protein (Enolase 1) was consistently up-regulated in all three cell lines under CDDP. The identified proteins can be grouped into different categories: 15 are involved in DNA-binding/transcription, 8 in metabolism, 8 in protein folding/binding/chaperone, 6 in cell signaling/differentiation, 4 in apoptosis, and 3 in cytoskeleton/cell movement. Conclusion: The results of this screening approach identify factors differentially regulated during response to CDDP in GCTs, and reveal a specific response pattern for each cell line. This knowledge can help to identify therapeutic targets and factors potentially involved in treatment sensitivity and resistance. No significant financial relationships to disclose.
A population-based study evaluating metastatic renal cell cancer (mRCC) patients treated with interferon (IFN) alone, first-line IFN then second-line sunitinib, or sunitinib alone
Authors: Kollmannsberger C. K. , Heng D. Y. , Murray N. , Chi K. N. 
Published: March 2020

15572 Background: Previously, immunotherapy agents such as IFN were the only treatments available for mRCC. Sunitinib has demonstrated prolonged progression free survival in a phase III trial but overall survival benefit has yet to be determined and few patients (pts) with poor MSKCC prognostic profiles were included. Methods: The province-wide BC Cancer Agency Registry was cross-referenced to the central pharmacy database to identify all pts with the diagnosis of mRCC who were treated with IFN and/or sunitinib. Sunitinib became available after October 2005 under an expanded access program or as standard treatment. Three groups of pts were identified: Group A consisted of pts who received IFN alone between January 2003 to October 2005, Group B was all pts who progressed on first-line IFN after October 2005 and subsequently were treated with second-line sunitinib and Group C was all pts treated with first-line sunitinib. Baseline characteristics and overall survival were collected on all patients. Results: A total of 75 patients were identified with 36 patients in Group A, 23 patients in Group B, and 16 patients in Group C. Data are reported from the initiation of IFN in Group A and the initiation of sunitinib in Groups B and C. Median follow-up was 6.0 months in group A, 7.6 months in group B, and 6.2 months in group C. Median age of treatment initiation (62y vs. 60y vs. 62y), number of metastatic sites (>1 site in 63% vs. 61% vs. 56%), and Karnofsky performance status (79 vs. 86 vs. 81) were similar between groups A, B and C, respectively. The MSKCC prognostic profiles were favorable, intermediate and poor in 26%, 51% and 23% in group A, 17%, 65% and 17% in group B and 31%, 38% and 31% in group C, respectively. The estimated 6-month overall survival in groups A, B and C was 56%, 72% and 100%, respectively (log rank A vs C p=0.009; log rank B vs C p=0.042). Conclusion: With the limitations of retrospective analysis and preliminary follow-up, the introduction of sunitinib as standard treatment into the general population of patients with mRCC appears to be associated with a longer overall survival compared to patients treated with IFN alone. Population-based analysis on the impact of the introduction of sunitinib therapy is ongoing. No significant financial relationships to disclose.