bluuebunny/crossref_metadata_2025 huggingface dataset:
Bidirectional immune tolerance in nonmyeloablative MHC-mismatched BMT for murine β-thalassemia
Authors: E Shuyu , Seth Aman , Vogel Peter , Sommers Matt , Ong Taren , Pillai Asha B.
Published: March 2017

Key Points

TLI/ATS/alkylator conditioning allows engraftment without GVHD after curative MHC-mismatched BMT for murine β-thalassemia. Recipient MDSCs generated in TLI/ATS/alkylator nonmyeloablative conditioning facilitate donor Treg recovery and graft-versus-host tolerance.
Hydrating softwood and hardwood samples using pure and modified supercritical carbon dioxide
Authors: Hammond Georgina , Cox Phil
Published: March 2017

This article describes an in-progress research project that looks to investigate the use of supercritical carbon dioxide (scCO2) for the addition of water to historic and modern, softwood and hardwood samples. The experiments were carried out at 20 MPa and 50 °C, the effects of co-solvent addition, methanol (MeOH), were examined. A three point bend test provided mechanical data for the wood samples treated with both pure and modified scCO2. All the wood samples, with only one exception, saw an increase in Modulus of Rupture (MOR) after being treated with scCO2. Thereby indicating an increased resistance to force in the treated samples. Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy was performed to help deduce if any trends in the OH/CH and OH/Cellulose peak area ratios could be established with the nature of the treatment and the type of wood used. The development of this technique seeks to be relevant and safe for applications within modern conservation practices, where dry and fragile materials are prevalent.
Leukocyte immunoglobulin-like receptors in human diseases: an overview of their distribution, function, and potential application for immunotherapies
Authors: Zhang Jilu , Mai Sunny , Chen Hui-Ming , Kang Kyeongah , Li Xian Chang , Chen Shu-Hsia , Pan Ping-Ying
Published: March 2017

Myeloid-derived suppressor cells (MDSCs), a population of immature myeloid cells expanded and accumulated in tumor-bearing mice and in patients with cancer, have been shown to mediate immune suppression and to promote tumor progression, thereby, posing a major hurdle to the success of immune-activating cancer therapies. MDSCs, like their healthy counterparts, such as monocytes/macrophages and granulocytes, express an array of costimulatory and coinhibitory molecules as well as myeloid activators and inhibitory receptors, such as leukocyte immunoglobulin-like receptors (LILR) A and B. This review summarizes current findings on the LILR family members in various diseases, their potential roles in the pathogenesis, and possible strategies to revert or enhance the suppressive function of MDSCs for the benefit of patients by targeting LILRs.
OTC boasts more than 40 technical sessions for 2017
Authors: Martinez Alex , Brookshire Brian , Cole Lance
Published: March 2017

Held annually since 1969, the Offshore Technology Conference (OTC) in Houston, Texas, is the largest global offshore-focused conference in the world, often drawing more than 100,000 attendees. The conference technical-session development and coordination is a collaborative effort among many professional societies, including SEG, that represent a broad spectrum of engineering and geoscience disciplines. This year's OTC is scheduled for 1–4 May at NRG Park in Houston.
Seismic interpretation below tuning with multiattribute analysis
Authors: Roden Rocky , Smith Thomas A. , Santogrossi Patricia , Sacrey Deborah , Jones Gary
Published: March 2017

The tuning-bed thickness or vertical resolution of seismic data traditionally is based on the frequency content of the data and the associated wavelet. Seismic interpretation of thin beds routinely involves estimation of tuning thickness and the subsequent scaling of amplitude or inversion information below tuning. These traditional below-tuning-thickness estimation approaches have limitations and require assumptions that limit accuracy. The below-tuning effects are a result of the interference of wavelets, which are a function of the geology as it changes vertically and laterally. However, numerous instantaneous attributes exhibit effects at and below tuning, but these are seldom incorporated in thin-bed analyses. A seismic multiattribute approach employs self-organizing maps to identify natural clusters from combinations of attributes that exhibit below-tuning effects. These results may exhibit changes as thin as a single sample interval in thickness. Self-organizing maps employed in this fashion analyze associated seismic attributes on a sample-by-sample basis and identify the natural patterns or clusters produced by thin beds. This thin-bed analysis utilizing self-organizing maps has been corroborated with extensive well control to verify consistent results. Therefore, thin beds identified with this methodology enable more accurate mapping of facies below tuning and are not restricted by traditional frequency limitations.
Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy
Authors: Zucca Emanuele , Conconi Annarita , Martinelli Giovanni , Bouabdallah Reda , Tucci Alessandra , Vitolo Umberto , Martelli Maurizio , Pettengell Ruth , Salles Gilles , Sebban Catherine , Guillermo Armando Lopez , Pinotti Graziella , Devizzi Liliana , Morschhauser Franck , Tilly Hervé , Torri Valter , Hohaus Stefan , Ferreri Andrés J.M. , Zachée Pierre , Bosly André , Haioun Corinne , Stelitano Caterina , Bellei Monica , Ponzoni Maurilio , Moreau Anne , Jack Andrew , Campo Elias , Mazzucchelli Luca , Cavalli Franco , Johnson Peter , Thieblemont Catherine
Published: March 2017

Purpose

There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG-19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial.

Patients and Methods

Eligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m2/d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) or a combination of chlorambucil (same schedule as above) and rituximab (375 mg/m2 intravenously on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 21). After the planned enrollment of 252 patients, the protocol was amended to continue with a three-arm design (1:1:6 ratio), with a new arm that included rituximab alone (same schedule as the combination arm) and with a final sample size of 454 patients. The main end point was event-free survival (EFS). Analysis of chlorambucil versus the combination arm was performed and reported separately before any analysis of the third arm.

Results

At a median follow-up of 7.4 years, addition of rituximab to chlorambucil led to significantly better EFS (hazard ratio, 0.54; 95% CI, 0.38 to 0.77). EFS at 5 years was 51% (95% CI, 42 to 60) with chlorambucil alone, 50% (95% CI, 42 to 59) with rituximab alone, and 68% (95% CI, 60 to 76) with the combination ( P = .0009). Progression-free survival was also significantly better with the combination ( P = .0119). Five-year overall survival was approximately 90% in each arm. All treatments were well tolerated. No unexpected toxicities were recorded.

Conclusion

Rituximab in combination with chlorambucil demonstrated superior efficacy in mucosa-associated lymphoid tissue lymphoma; however, improvements in EFS and progression-free survival did not translate into longer overall survival.
The effect of prostatectomy technique on genitourinary toxicity.
Authors: Ciezki Jay P. , Reddy Chandana A. , Haber Georges-Pascal , Kaouk Jihad , Stephenson Andrew J. , Berglund Ryan Kent , Klein Eric A.
Published: March 2017

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Background: Recent clinical trials have examined the toxicity associated with various treatment modalities available for prostate cancer. None have examined genitourinary (GU) toxicity using CTCAE v4.02 among prostatectomy (RP) techniques. Methods: An IRB-approved inception cohort study was used to assess the association of GU toxicity by prostatectomy technique: open RP, pure laparoscopic (lap RP) RP, and robotic-assisted laparoscopic (robotic) RP. The primary end point was grade 3 or greater GU toxicity. The cumulative incidence method was used to calculate the rates of grade 3 or higher GU toxicity, and Gray’s test was used to compare the rates of toxicity among the three treatment modalities. Results: There were 1308 patients in the study with a median follow-up of 55.6 months. The patients were segregated into the three cohorts as follows: 732 open RP, 103 lap RP, and 473 robotic RP. The cumulative incidence rates of the primary end point is shown in table 1. There was no significant difference among the three modalities (p = 0.6028). The most common toxicities were urinary obstruction (54.8 % of all toxicities) and urinary incontinence (33.3 % of all toxicities). Eighty-five percent of all toxicities were grade 3. Conclusions: Overall toxicities were mild and were not different among the three RP techniques. [Table: see text]
Clinical significance of AR mRNA quantification from circulating tumor cells (CTCs) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone (Abi) or enzalutamide (Enza).
Authors: Silberstein John , Luber Brandon , Wang Hao , Lu Changxue , Chen Yan , Zhu Yezi , Taylor Maritza N. , Carducci Michael Anthony , Eisenberger Mario A. , Luo Jun , Antonarakis Emmanuel S.
Published: March 2017

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Background: AR-targeting agents remain the backbone of mCRPC therapy. We previously reported an association between AR-V7 mRNA detection in CTCs and resistance to Abi/Enza (NEJM 2014). Here, we report the prognostic significance of full-length androgen receptor (AR-FL) mRNA quantification from CTCs in pts starting Abi or Enza. Methods: We prospectively enrolled mCRPC pts starting Abi or Enza, and examined the prognostic value of AR-FL detection using a CTC-based mRNA assay (modified AdnaTest, Qiagen). We examined PSA50 responses, PSA progression free survival (PSA-PFS), clinical/radiologic PFS (PFS), and overall survival (OS). We constructed multivariable (MVA) Cox regression models adjusting for AR-V7 status, PSA level, Gleason sum, number of prior therapies, prior Abi/Enza use, prior taxane use, presence of visceral disease, and ECOG score. Results: We enrolled 202 pts (median f/u 12.9 mo). AR-FL status was negative in 97/202 pts (48%), < median in 52/202 (26%) and > median in 53/202 (26%). Higher AR-FL levels correlated with positive AR-V7 detection (35.5 copies [range: 2.5–1209] in AR-V7+ vs 1.4 copies [range: 0–172.5] in AR-V7–, P< .001), as well as lower PSA50 responses (55.4 copies in nonresponders vs 6.7 copies in responders, P< .001). In Kaplan-Meier analysis, PSA-PFS, PFS and OS differed significantly between AR-FL negative, AR-FL < median, and AR-FL > median (Table). In MVA models, AR-FL level (as a continuous variable) was prognostic for PSA-PFS (HR 1.06, 95%CI 1.00–1.12, P= .04) and trended with prognosis for PFS (HR 1.04, 95%CI 0.99–1.11, P= .13) and OS (HR 1.07, 95%CI 1.00–1.15, P= .06). AR-V7 status was also independently prognostic for all outcomes in MVA analyses. Conclusions: This study demonstrates CTC-derived AR-FL copy number is prognostic for clinical outcomes in Abi/Enza-treated mCRPC pts. In addition to AR-V7 status, AR-FL quantification could serve as another molecular biomarker of Abi/Enza sensitivity after analytical validation/standardization. [Table: see text]
Burden of metastatic hormone-sensitive prostate cancer to identify men more likely to benefit from early docetaxel.
Authors: Gravis Gwenaelle , Boher Jean-Marie , Chen Yu-Hui , Liu Glenn , Fizazi Karim , Carducci Michael Anthony , Oudard Stephane , Joly Florence , Jarrard David Frazier , Soulie Michel , Eisenberger Mario A. , Habibian Muriel , Dreicer Robert , Garcia Jorge A. , Hussain Maha , Kohli Manish , Vogelzang Nicholas J. , Picus Joel , DiPaola Robert S. , Sweeney Christopher
Published: March 2017

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Background: Patients with a low burden of metastatic disease and who relapse after localized therapy with curative intent have a longer overall survival. It is unclear whether these patients benefit from early docetaxel (D). Methods: Patients in GETUG-AFU15 (N = 385, median follow-up 84 mo) and CHAARTED (N = 790, median follow up 54 mo) were randomized to ADT alone or ADT + D and outcomes described using the same definition of high volume (HV) and low volume (LV) disease. (HV: visceral metastases and/or 4 or more bone metastases with at least one outside the axis) and whether the patients had prior local therapy or not. Results: Table 1 details across both studies that de novo HV group treated with ADT alone has the shortest overall survival and D has a consistent effect in improving OS. In contrast, in both studies patients with LV disease had a much longer OS with no evidence that D improved OS. Conclusions: There was no apparent survival benefit in CHAARTED and GETUG-15 studies with D for LV whether patients had prior local treatment or not. Across both studies, early D had a consistent effect and improved OS in HV pts especially those with no prior local therapy. Partial Support and drug supply by Sanofi. Clinical trial information: NCT00104715, NCT00309985. [Table: see text]
Lower PSA at 7 months is prognostic for improved overall survival (OS) in metastatic hormone sensitive prostate cancer (mHSPC) treated with ADT with and without docetaxel (D).
Authors: Harshman Lauren Christine , Chen Yu-Hui , Liu Glenn , Carducci Michael Anthony , Jarrard David Frazier , Dreicer Robert , Hahn Noah M. , Garcia Jorge A. , Hussain Maha , Shevrin Daniel H. , Eisenberger Mario A. , Kohli Manish , Wong Yu-Ning , Cooney Matthew M. , Vogelzang Nicholas J. , Picus Joel , DiPaola Robert S. , Sweeney Christopher
Published: March 2017

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Background: Prior work from SWOG 9346 revealed that PSA ≤ 0.2 ng/dL at 7 months (mo) is prognostic for longer OS with ADT alone. We sought to evaluate if this optimal decline remained predictive of better OS when D was added to ADT for initial mHSPC treatment. Methods: We performed a landmark survival analysis at 7 mo using the E3805 database (NCT00309985). Inclusion required at least 7 mo of followup and PSA levels at 7 mo from ADT initiation. Survival was defined from ADT start or randomization to death. SWOG 9346 PSA nadirs of ≤ 0.2, > 0.2-4 and > 4 were used as classifiers. Results: 719 patients were eligible for analysis: 358 treated with ADT plus D and 361 with ADT alone. Median follow-up was 23.1 mo. On multivariable analysis (MVA), achieving a PSA ≤ 0.2 at 7 mo was more likely if the patient received D and had lower volume disease, prior local therapy, and lower baseline PSAs (all p ≤ 0.01). Across all patients, median OS was significantly longer if PSA at 7 mo reached ≤ 0.2 compared to > 4 (p < 0.0001) (Table). On MVA, PSA ≤ 0.2 at 7 mo and low volume disease were prognostic of longer OS (all p < 0.01). On ADT, 28.8% achieved a PSA ≤ 0.2 at 7 mo vs. 45.3% on ADT+D. Patients on ADT alone who achieved a PSA nadir ≤ 0.2 had the best survival. These patients were more likely to have low volume disease (56.7%) compared to the ADT + D pts (46.3%). Conclusions: Achieving PSA ≤ 0.2 at 7 mo remains prognostic for longer OS with ADT for mHSPC, whether administered alone or with D. Adding D to ADT increased the likelihood of a lower PSA and improved survival. Partial support and drug supply by Sanofi. Clinical trial information: NCT00309985. [Table: see text]
Adverse effects of ADT on cognitive function and dementia for men with prostate cancer: A meta-analysis and systematic review.
Authors: Sun Maxine , Cole Alexander , Hanna Nawar , Kibel Adam S. , Choueiri Toni K. , Nguyen Paul L. , Trinh Quoc-Dien
Published: March 2017

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Background: Nearly 50% of men diagnosed with prostate cancer may receive treatment with some form of androgen deprivation therapy (ADT). While some side effects of ADT are well acknowledged, the specific impact of ADT on cognitive function is uncertain. Our objective was to perform a systematic review and meta-analysis assessing the impact of ADT on overall cognitive decline, and the risks of Alzheimers, Parkinson’s disease. Methods: Relevant studies were identified through search of English language articles indexed in PubMed Medline, PsycINFO, Cochrane Library and Web of Knowledge/Science. First, we assessed rates of cognitive decline in five cohorts from three studies. Second, we assessed rates of Alzheimer’s or Parkinson disease using three large retrospective studies. A pooled-analysis was conducted using a meta-analysis. Weighted averages were reported as odds ratios (OR) with 95% confidence intervals (CI) using RevMan and a DerSimonian and Laird random-effects model. The heterogeneity test was measured using the Q-Mantel-Haenszel ( P< 0.10 was considered of significant heterogeneity). Results: With respect to overall cognitive decline (defined as scoring 1.5 standard deviations [SD] in two or more objective cognitive tests), patients receiving ADT had higher odds of overall cognitive decline than patients with prostate cancer not treated with ADT or health controls (OR: 2.03, 95% CI: 1.42–2.90). Furthermore, men with a history of ADT for prostate cancer had higher odds of developing Alzheimer’s and Parkinson dementia compared to men with prostate cancer not treated with ADT (OR: 1.32, 95% CI: 1.27–1.37). Conclusions: Men receiving ADT for prostate cancer performed significantly worse on measures of overall cognitive function. Additionally, results from the three large observational trials included suggest men exposed to ADT for prostate cancer have higher rates of Parkinson/Alzheimer’s compared to men without ADT.
A randomized phase II trial of docetaxel plus carboplatin versus docetaxel in patients with castration-resistant prostate cancer who have progressed after response to prior docetaxel chemotherapy: The RECARDO trial.
Authors: Bouman-Wammes Esther W. , de Munck Linda , van den Berg H Pieter , Beeker Aart , Smorenburg Carolien H. , Verheul Henk M.W. , Gerritsen Winald R. , van den Eertwegh Alfonsus Johannes Maria
Published: March 2017

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Background: Docetaxel is the standard first-line chemotherapy for patients with castration resistant prostate carcinoma (CRPC). Docetaxel re-challenge has never been tested in a prospective randomized clinical trial. As some studies supported the addition of carboplatin to docetaxel in this setting, we performed a phase II trial investigating the combination of docetaxel plus carboplatin versus docetaxel monotherapy in docetaxel pre-treated CRPC patients. Methods: Patients with CRPC with a progression-free interval (PFI) of at least 3 months after initial treatment with docetaxel were randomized between docetaxel 75mg/m2 or docetaxel 60mg/m2 plus carboplatin AUC 4, both plus prednisone in a 3-weekly schedule. Treatment was continued until progressive disease, unacceptable toxicity or completion of 10 cycles. The primary endpoint is progression-free survival (PFS) (PSA and/or RECIST). Secondary objectives are overall survival, toxicity, PSA response and quality of life. Results: As a result of insufficient recruitment, the study was discontinued early after inclusion of 75 patients, instead of the targeted 150 patients. The median PFS was comparable between both groups (docetaxel 12.7 months versus combination therapy 11.7 months p = 0.99), and no difference in OS was found (median OS 18.5 months versus 18.9 months, p = 0.88). Rates of PSA response were comparable (response/stable PSA in 42.1%/39.4% of the patients in the monotherapy arm versus 35.1%/48.6% in the combination arm, NS). The incidence of grade 3-4 infections and gastro-intestinal (GI) side effects was higher in the docetaxel plus carboplatin arm (GI side effects 0% versus 13.9% p = 0.03; infection 2.7% versus 16.7% p = 0.056). The difference in febrile neutropenia (0% versus 11.1%) is not significant. Conclusions: For patients with CRPC and an initial good response to docetaxel, re-treatment with docetaxel monotherapy is a feasible, save and effective treatment. Addition of carboplatin resulted in more toxicity. Docetaxel re-challenge is a viable therapeutic option for selected patients. Clinical trial information: NTR3070.
Phase Ib study of apalutamide (APA) with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Update on safety and efficacy.
Authors: Posadas Edwin M. , Chi Kim N. , De Wit Ronald , De Jonge Maja J. , Attard Gerhardt , Friedlander Terence W. , Yu Margaret K. , Hellemans Peter , Chien Caly , Abrams Charlene Connelly , Gonzalez Martha , Trudel Geralyn Carol , Chauhan Vijay , Jiao Juhui James , Saad Fred
Published: March 2017

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Background: APA and AA target the androgenreceptor (AR) axis via different mechanisms and may have complementary activity in mCRPC. APA is an advanced AR antagonist that targets the AR ligand-binding domain with high affinity (Clegg. Cancer Res. 2012). APA prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. This phase 1b study evaluates potential PK interactions between APA and AA + P. Here we report antitumor activity and safety of APA in combination with AA + P from 57 pts versus 29 pts presented at ASCO 2015 (NCT02123758). Methods: Pts with progressive mCRPC and ECOG PS ≤ 2 received AA (1000 mg/d) + P (5 mg BID) on Cycle 1 Day 1 (C1D1) with addition of APA (240 mg/d) on C1D8 in 28-day treatment (tmt) cycles. Efficacy assessment was based on RECIST 1.1 and PCWG2 criteria. Results: 57 pts started tmt on study; median tmt duration was 17 weeks. Median age was 70 years (range, 49-89) and median baseline PSA was 111 µg/L (range, 4-2597). Bone, nodal, and visceral disease were present in 50 (88%), 31 (54%), and 17 (30%) pts, respectively. 29 (51%), 29 (51%), and 23 (40%) pts were previously treated with a taxane, AA, or enzalutamide (ENZ), respectively. 47 pts discontinued tmt: disease progression (n = 39), consent withdrawal (n = 3), physician decision (n = 1), death (n = 1), and other (n = 3). In AA- and ENZ-naïve pts (n = 18), 67% had PSA decline ≥ 50%. In AA- or ENZ-treated pts (n = 39), 15% had PSA decline ≥ 50%. Most commonly reported ( > 10% of pts) drug-related AEs: fatigue (42%), diarrhea (21%), vomiting (21%), nausea (19%), hypokalemia (19%), decreased appetite (16%), hot flush (12%), abdominal pain (12%), and dysgeusia (11%). Grade ≥ 3 drug-related AEs reported in > 1 pt: fatigue (7%), hypokalemia (3.5%), hyponatremia (3.5%), and hypertension (3.5%). 1 pt discontinued study drug for grade 3 fatigue. Conclusions: Interim data indicate that 240 mg/d of APA with 1000 mg/d of AA + P has antitumor activity and an acceptable safety profile in mCRPC. Clinical trial information: NCT02123758. [Table: see text]
Circulating tumor DNA (ctDNA) and correlations with clinical prognostic factors in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Khalaf Daniel , Annala Matti , Beja Kevin , Vandekerkhove Gillian , Zulfiqar Muhammad , Finch Daygen L. , Oja Conrad D. , Vergidis Joanna , Gleave Martin , Wyatt Alexander William , Chi Kim N.
Published: March 2017

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Background: Sequencing of ctDNA is a minimally invasive method to study somatic DNA alterations. Quantitation and characterization of ctDNA may correlate with tumor burden and poor risk clinical features, but this is unproven in mCRPC. Methods: We performed deep targeted sequencing of 73 mCRPC-related genes in plasma ctDNA from 136 treatment naïve mCRPC patients. Fraction of ctDNA was determined by quantifying somatic mutant allele frequency and the deviation from heterozygosity for germline single nucleotide polymorphisms at regions of somatic copy number alterations. Baseline clinical factors were correlated with ctDNA fraction and genomic aberrations. Results: ctDNA could be quantified in 86/136 (63%) patients. Increasing fraction correlated with elevated ALP (chi2, p < 0.001), LDH (p < 0.001) and presence of liver metastasis (p = 0.01). Patients with any one of these factors were more likely to have a ctDNA fraction ≥ 40% (67% vs 36% of patients with neither factor, p = 0.001) and less likely to have unquantifiable ctDNA (26% vs 49%, p = 0.006). A decreased ctDNA fraction was associated with metastases only to lymph nodes (p = 0.012). Among the most frequently aberrant genes were Androgen Receptor (AR), p53, RB1, and PTEN, present in 38%, 30%, 23% and 22% of patients, respectively. Aberrations were associated with poor prognosis factors, including: AR and p53 alterations, which both correlated with presence of liver metastasis (p = 0.020 and p = 0.004 respectively), elevated LDH (p = 0.001, p < 0.001), and presence of ≥ 10 bone metastasis (p = 0.018, p = 0.017); PTEN deletion which correlated with elevated ALP (p < 0.001), elevated LDH (p = 0.001), ≥ 10 bone metastasis (p = 0.009) and time to CPRC of < 12 months (p = 0.021); and RB1 correlated with ≥ 10 bone metastasis (p = 0.009). Conclusions: We found an association between poor prognostic factors and increasing ctDNA fraction in patients with mCRPC. Genomic aberrations, particularly alteration in AR, p53 and PTEN, correlated with poor prognostic factors. These data show that clinical factors may help predict ctDNA yield in patients with mCRPC, and also provide insight into the role of deleterious genetic alterations.
Effect of enzalutamide on sensitivity in prostate cancer cells to radiation by inhibition of DNA double strand break repair.
Authors: Ghashghaei Maryam , Muanza Thierry , Paliouras Miltiadis , Niazi Tamim
Published: March 2017

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Background: Prostate cancer is the second leading cause of cancer-related deaths amongst men in North America. Data suggests that, following radiation therapy (XRT), androgen receptor (AR) enhances DNA damage repair and contributes to resistance of prostate cancer (PCa) cells to XRT. At present AR-pathway inhibition is the mainstay treatment of metastatic castration resistance prostate cancer (mCRPC). Enzalutamide (ENZA), a potent AR inhibitor is one of the approved drugs in this setting. The purpose of this study was to assess the potential radiosensitization of ENZA and its mechanism of action in hormone resistant PCa cells. Methods: The effect of ENZA alone or in combination with XRT was assessed on hormone-sensitive, (HS: LNCaP, PC3-T877A) and insensitive PCa cells (HI: PC3, PC3-AR V7, C4-2) using viability and clonogenic assays, cell cycle arrest and DNA damage analysis. Results: MTT assay demonstrates that ENZA significantly inhibits the proliferation of HS PCa cells in a dose dependent manner whereas CRPC required ENZA in combination with ADT (androgen deprivation therapy). Additionally, clonogenic assay proves that concurrent administration of ENZA or ADT+ENZA and XRT led to a supra-additive antitumor effect with the dose enhancement factor of 1.76±0.008 in LNCaP, 1.65±0.01 in PC3-T877A and 1.35±0.003 in C4-2 respectively at surviving fraction of 0.1. This effect was not observed in PC3 and PC3-AR V7 cells pre-treated with ENZA (in all cases DEF = 1 at SF = 0.1). Additionally, the level of γH2AX increased in HS cells and CRPC cells treated with ENZA/ADT+ENZA and XRT when compared to XRT alone. The enhanced H2AX activity remained unchanged up to 24 hours after combination treatment. Furthermore, there is an initial inhibition of DNA-PKcs in HS and CRPC cells treated with ENZA/ADT+ENZA administered before XRT. Conclusions: Our data suggest that the higher efficacy of ENZA/ENZA+ADT and XRT could be partially due to inhibition of DNA damage repair. Our results demonstrated a significant enhancement of XRT efficacy and confirms the rational for the ongoing combination clinical trials with XRT.
A phase II trial of zoptarelin doxorubicin in castration- and taxane-resistant prostate cancer.
Authors: Yu Steven , Athreya Kanthi , Liu Stephen V. , Schally Andrew V. , Groshen Susan G. , Tsao-Wei Denice D , Quinn David I. , Dorff Tanya B. , Xiong Shigang , Pinski Jacek , Engel Jurgen
Published: March 2017

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Background: Luteinizing hormone-releasing hormone receptors (LHRH-R) are expressed in ~86% of prostate cancers, with sustained expression despite prolonged exposure to LHRH agonists. Limited expression of LHRH-R on normal cells suggests LHRH-R may be a therapeutic target for prostate cancer. Zoptarelin doxorubicin is a cytotoxic hybrid molecule linking doxorubicin to an LHRH analog that selectively targets doxorubicin to cancer cells expressing LHRH-R. Methods: This Phase 2 trial evaluated the clinical benefit of zoptarelin doxorubicin for metastatic castration-resistant prostate cancer (mCRPC) following androgen deprivation therapy and ≥1 taxane-based regimen. The primary endpoint was clinical benefit (CB) defined as progression-free survival (PFS) per RECIST v1.1 at 12 weeks with no dose-limiting toxicities (DLT) or other toxicities resulting in treatment cessation. Secondary endpoints were time to overall progression, response rate, pain response, overall survival (OS), and PSA response. Results: Of 25 patients enrolled, 20 had ≥1 measurable lesion at baseline with PFS ≥12 weeks achieved in 56% and PSA response of PR (4%) and SD (84%). Median PFS and OS were 3.8 and 6.0 months, respectively. Reduced pain was reported by 59%. Treatment was well tolerated, with no cardiotoxicity and neutropenia (all grades) the most common hematologic adverse event. Conclusions: This phase 2 trial demonstrated clinical benefit in 56% of patients with no DLT or other toxicity requiring treatment termination. These results suggest a role for zoptarelin doxorubicin for mCRPC following progression on second- and third-line hormonal therapy. Clinical trial information: NCT01240629. [Table: see text]
Investigating RUNX1 and RUNX2 in prostate cancer.
Authors: McKillop Anne Jane , Edwards Joanne , Johnson Emma , Mason Susan , Cameron Ewan R , Blyth Karen
Published: March 2017

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Background: Prostate cancer is the most commonly diagnosed cancer in men and is increasing in incidence. Current treatment for metastatic disease is initially hormone treatment and chemotherapy. While this produces a response in the vast majority of patients, it is not curative. Novel therapeutic agents could provide a further treatment strategy and it is therefore important to understand the molecular pathways which contribute to this disease. The RUNX family of genes have been implicated as both oncogenes and tumor suppressors, with their role being context dependent. It has been reported that RUNX2 may have a tumor suppressor role in early stage prostate cancer but that this may switch to an oncogenic role in later stage disease. Methods: This project examines the expression of both RUNX1 and RUNX2 in a tissue microarray (TMA) of human prostate cancers. In parallel to the human studies both RUNX1 and RUNX2 were investigated in murine models of prostate cancer. Results: Analysis of the TMA showed that increasing levels of RUNX2 were associated with increasing Gleason grade, shorter time to relapse and poorer survival; the opposite effect was seen in RUNX1, where low levels of protein expression correlated with shorter survival. In concordance with the human results, reducing levels of RUNX2 in mouse models was associated with delayed tumor initiation, and smaller, less cystic tumors at endpoint. The opposite effect was seen with Runx1 where low levels resulted in more aggressive and invasive disease. Finally, when loss of both genes was combined in a model with loss of Pten and stimulation of WNT, survival was significantly reduced compared to controls. Conclusions: This study suggests that RUNX2 expression may correlate with a poorer prognosis in prostate cancer, while expression of RUNX1 is likely to be associated with an improved outcome.
Histone demethylase KDM7a to control androgen receptor activity in hormone-sensitive prostate cancer.
Authors: Kang Minyong , Jeong Chang Wook , Lee Kyoung-Hwa , Ku Ja Hyeon , Kim Hyeon Hoe , Kwak Cheol
Published: March 2017

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Background: Prostate cancer can be controlled by androgen-hormone treatment until the cancer becomes refractory. It is believed that hormone sensitivity is largely dependent on androgen receptor (AR) activity. Here, we investigated the molecular mechanism whereby androgen receptor activity is regulated by histone demethylase KDM7a, which demethylates histone H3K9 and H3K27. Methods: The LNCaP, PC3, and DU145 cell lines were cultured at 37 °C in 5% CO2 in Minimum Essential Medium alpha, which was supplemented with 10% fetal bovine serum. We engineered AR-positive LNCaP cells to stably express a short-hairpin RNA against KDM7a mRNA from a lentiviral vector. To examine the mechanisms of AR regulation by KDM7a, we used various techniques of molecular biology, such as real-time PCR, western blot, and chromatin immunoprecipitation assay. Also, we performed immunohistochemical staining by using prostate cancer tissue microarray. Results: By measuring AR downstream gene expression following androgen stimulation, we found that a KDM7a-deficient cell line showed lower AR downstream gene expression compared to a control cells. KDM7a knock-down in LNCaP cell line caused decreased cell proliferation, compared to control cell line. Silencing KMD7a in AR insensitive cell lines did not cause differences in cell proliferation. Western blot analysis with modified-histone antibody revealed that the KDM7a-knock-down LNCaP cell line had increased H3K27 dimethylation. We confirmed KDM7a binding on AR target-gene promoters after hormone stimulation in chromatin-immunoprecipitation experiments. And increased H3K27 di-methylation was observed in KDM7a knock-down LNCaP stable cell. Finally, we observed that the KDM7a protein was significantly upregulated in prostate cancer tissue (compared to control tissue), and that this difference correlated with the Gleason score. Conclusions: These data suggested that KDM7a is potentially a good therapeutic target for prostate cancer drugs and can be used as potentially a good prognostic indicator for prostate cancer and related treatment strategies.
Abiraterone acetate with prednisone and cabazitaxel as subsequent treatment after first-line docetaxel in metastatic castrate-resistant prostate cancer (mCRPC): Final efficacy and safety analysis of the CAPRO study.
Authors: Gonzalez del Alba Arancha , Puente Javier , Sala Nuria , Mendez Maria Jose , Pinto Alvaro , Rodriguez Sanchez Angel , Cuevas Sanz Jose Miguel , Muñoz del Toro Jacobo , Ruiz Pedro , Garcia Angela , Vazquez-Estevez Sergio
Published: March 2017

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Background: Abiraterone acetate + prednisone (AA) and cabazitaxel (CB) have shown an improvement in overall survival after Docetaxel (DOC) in (mCRPC)1,2. There is little evidence about the optimal sequencing treatment in prospective trials. In this final analysis we now compare the efficacy of AA and CB as second line (2L) treatment in mCRPC patients (pts) in routine clinical practice (RCP) in Spain. Methods: The CAPRO study is a prospective multicenter national observational descriptive study. The primary endpoint was to describe the management in 2L mCRPC pts after DOC in RCP. bPFS (biochemical progression free survival) and PFS (clinical or radiological progression free survival) were assessed by the Kaplan-Meier method. Results: 150 patients were recruited (Jul 2013-Jan 2015). At median follow-up of 7.8 mo (IQR 4.2-12.8) 67% (n = 100) of the pts received AA, 29% (n = 44) CB, and 4% (n = 6) other treatments as 2L. PSA response > 50% was 47.3% and 32.3% for AA group and CB group respectively (p = 0.146). Median bPFS was similar between the AA and the CB group (9.19 mo [95% CI 6.84-11.55] vs 9.92 mo [95% CI 6.08-13.76]; hazard ratio 0.779 [95% CI 0·49–1.24]; p = 0·29), whereas median PFS was significantly longer in the AA group than in the CB group (8.74 mo [95% CI 6.54-10.94] vs 6.41 mo [95% CI 4.99-7.82]; hazard ratio 0·56 [95% CI 0·38–0·85]; p = 0·005). A difference was observed in bPFS and PFS depending on the time of progression to first line (during treatment, < 3 or more than 3 mo) for both AA and CB. The most common toxicities of special interest (all grades/grade 3–4 as % of pts) were fatigue (31/1% in the AA group vs 54/4% in the CB group), oedema (15/0% AA group vs 13/4% CB group), hypertension 7/1% AA group, diarrhea (8/0% AA group vs 31/4% CB group), vomits (9/2% AA group vs 11/0 CB group) and neutropenia 7/4% CB group. Conclusions: In this final analysis AA was the 2L treatment of choice in routine clinical practice in Spain during the period of time in which the study was conducted. PSA response and bPFS were similar between AA and CB, whereas PFS was significantly longer in the AA group. There were no new safety signals observed.
Quality of life (QL) of patients (pts) treated for muscle invasive bladder cancer (MIBC) with radiotherapy (RT) +/- chemotherapy (CT) in the BC2001 trial (CRUK/01/004): Analysis of impact of treatment at an individual level.
Authors: Huddart Robert Anthony , Hall Emma , Miranda Miguel , Crundwell Malcolm , Jenkins Peter , Rawlings Christine Lisa , Tremlett Jean , Hendron Carey , Lewis Rebecca , Porta Nuria , Hussain Syed A. , James Nicholas D. ,   on behalf of the BC2001 Investigators
Published: March 2017

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Background: BC2001 showed that adding 5FU+MMC CT (cRT) to RT significantly improved locoregional disease free survival [James 2012] & using reduced high dose volume RT (RHDVRT) rather than standard RT (stRT) did not reduce late side effects [Huddart 2013]. Here we report the impact of treatment on QL at the individual level. Methods: 458 (pts) were randomised to RT (178) vs. cRT (182) (CT comparison) &/or to stRT (108) vs. RHDVRT (111) (RT comparison). Pts completed Functional Assessment of Cancer Therapy-Bladder (FACT-BL) questionnaires at baseline (bl), end of treatment (EoT), 6, 12, 24, 36, 48 & 60 months (m). Mean changes from bl were compared between randomised groups. A minimal clinically relevant change from bl score was defined as 3 points in bladder cancer subscale (BLCS) & 7 points in total FACT-BL (TOTAL). The proportion of pts with an improvement, no difference & worsening at 12m were compared by Chi squared/Fishers exact test (1% significance). Results: Data were available for 331 (92%) & 204 (93%) pts at bl & 181 (50%) & 107 (49%) at 12m for the CT & RT comparison respectively. QL scores were significantly reduced at EoT but recovered to bl levels by 12m with no significant difference in TOTAL or BLCS mean change scores between randomised groups. By EoT ~60% pts reported worsening of QL. At 12m & beyond, whilst mean change scores were not different to bl, ~30-40% reported worsening of QL (-) with a similar proportion reporting an improvement (+) (Table 1). No statistically significant differences were found between randomised groups. Conclusions: Following (c)RT a significant proportion of pts have a decline in QL at EoT but after 12m overall QL is, on average, similar to bl. At an individual level approximately equal proportions of pts report an improvement in QL as report a worsening. There is no evidence of additional impairment in QL by the addition of CT to RT. Clinical trial information: ISRCTN6832433. [Table: see text]
A phase I study of cabozantinib plus nivolumab (CaboNivo) and ipilimumab (CaboNivoIpi) in patients (pts) with refractory metastatic urothelial carcinoma (mUC) and other genitourinary (GU) tumors.
Authors: Apolo Andrea B. , Mortazavi Amir , Stein Mark N. , Pal Sumanta K. , Davarpanah Nicole N. , Parnes Howard L. , Ning Yangmin M. , Francis Deneise C , Cordes Lisa M , Monk Paul , Lancaster Tiffany , Costello Rene , Nanda Swati , Bottaro Donald P. , Wright John Joseph , Streicher Howard , Steinberg Seth M. , Berninger Marilise , Lindenberg Liza , Dahut William L.
Published: March 2017

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Background: We report the safety and clinical activity of CaboNivo and CaboNivoIpi in pts with mUC and other GU tumors. Methods: Part I included 4 dose levels (DLs) (Cabo PO daily and Nivo IV q2wk): DL1 Cabo40/Nivo1, DL2 Cabo40/Nivo3, DL3 Cabo60/Nivo1, DL4 Cabo 60/Nivo3. Part II included 3 DLs (Cabo PO daily, plus NivoIpi IV q3 wk x 4 doses then Nivo q2wk): DL5 Cabo 40/Nivo1/Ipi1, DL6 Cabo40/Nivo3/Ipi1, DL7 Cabo 60/Nivo3/Ipi 1. Tumors were assessed for overall response rate (ORR) by RECIST 1.1. Adverse events (AEs) were graded (G) by NCI-CTCAE v4.0. Results: From 7/22/15-10/14/16, 40pts [mUC N=14/(plasmacytoid N=1); bladder urachal N=4; bladder squamous cell carcinoma (bSCC) N=2; germ cell tumor (GCT) N=4; castrate-resistant prostate cancer (CRPC) N=9/(neuroendocrine prostate N=1); sarcomatoid renal cell carcinoma (sRCC) N=1; trophoblastic tumor N=1); sertoli cell tumor N=1; and penile SCC N=4] were treated. Median age was 58 (range 31-77); 36 (90%) were male. AEs related to study drugs with [1] CaboNivo included G3 hyponatremia 4/24 (17%), hypophosphatemia 4/24 (17%), lipase increase 3/24 (13%), dehydration 2/24 (8%), diarrhea 2/24 (8%), fatigue 2/24 (8%), HTN 2/24 (8%), thromboembolic event 1/24 (4%), rash 1/24 (4%), chest pain 1/24 (4%), amylase increase 1/24 (4%), hyperthyroid 1/24 (4%), proteinuria 1/24 (4%), thrombocytopenia 1/24 (4%); and G4 pyelonephritis 1/24 (4%); [2] CaboNivoIpi included G3 hypophosphatemia 2/16 (13%), lipase increase 2/16 (13%), fatigue 1/16 (6%), ALT increase 1/16 (6%), and HTN 1/16 (6%). There were 2/40 (5%) G3 immune-related AEs: 1 aseptic meningitis/CaboNivo; and 1 colitis/CaboNivoIpi. There were no G5 toxicities, or DLTs. 38 pts were evaluable for response. ORR was 12/38 (32%): 1 CR (bSCC); 11 PRs (5 mUC, 1 sRCC, 1 urachal, 1 bSCC, 1 CRPC, 2 penile). SD 20/38 (53%); 9/11 responses were ongoing and 26/39 (67%) pts remain on study. Conclusions: CaboNivo and CaboNivoIpi were well tolerated with no DLTs. Responses were seen at all DLs. The recommended dose for Part I is Cabo40/Nivo3 and for Part II is Cabo40/Nivo3/Ipi1. Rare tumors such as bSCC, urachal, and penile cancer demonstrated responses. Clinical trial information: NCT02496208.
Resection margins after radical cystectomy at academic versus community cancer centers.
Authors: Scarberry Kyle , Scarberry Kelly , Agrawal Shree , Kim Simon P.
Published: March 2017

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Background: Positive surgical margins are reported in 1-5% of specimens following radical cystectomy (RC) for urothelial carcinoma of the bladder (UC). Negative margin (R0) resection correlates with improved overall survival (OS) following RC in individual institutional analyses compared to microscopic (R1) or grossly (R2) positive margins. The present study hypothesized that RC surgical resection margins vary between treating centers. Methods: Patients with UC undergoing RC were identified from the National Cancer Database (2004-2013). Treating centers were categorized as Academic Cancer Centers (ACC) and Community Cancer Centers (CCC). Rates of R0 vs. R1/2 resection were examined and logistic regression was performed to determine predictive factors for margin status. Results: A total of 40,187 patients were identified with a median age of presentation of 68 years. RC was performed equally at ACC (52%) compared to CCC (48%). Neoadjuvant chemotherapy was utilized more often at ACC (21%) compared to CCC (14%). RC at ACC was associated with higher rates of R0 resections (90%) compared to CCC (88%) (p < 0.001). On logistic regression, after adjusting for age, sex, ethnicity, comorbidities, disease stage, tumor grade, tumor size, and use of neoadjuvant chemotherapy, RC at ACC were associated with decreased risk of experiencing positive margins (OR = 0.79, 95% CI 0.74-0.85). Following multivariate regression, RC performed at ACC were associated with a significant hazard ratio (HR) for survival (HR = 0.88, 95% CI 0.85-0.91). Compared to all variables, R1/2 resection status was the next most significant predictor for poor survival in RC patients (HR = 1.83, 95% CI 1.75-1.91) after cancer stage. Conclusions: Surgical margin is an important, independent risk factor for mortality in patients undergoing RC for UC. RC at ACCs is associated with a higher rate of negative resection margins, suggesting that site of care may impact bladder cancer patient’s oncologic outcomes.
A chemically-modified miR-21 inhibitor (ADM-21) as a novel potential therapy in bladder cancer.
Authors: Drakaki Alexandra , Koutsioumpa Marina , O'Brien Neil A. , Vorvis Christina , Iliopoulos Dimitrios , Slamon Dennis J.
Published: March 2017

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Background: MicroRNAs are key regulators of cancer signaling pathways.Targeting their expression has therapeutic potential. MicroRNA-21 (miR-21) acts as an oncogene in several cancers. Here we describe its functional significance in bladder oncogenesis and the therapeutic properties of a novel chemically-modified miR-21 inhibitor (ADM-21). Methods: MiR-21 expression was assessed by RT-PCR in a panel of human bladder cancer tissues and cell lines. Transcriptomic profiling of 28 bladder cancer cell lines performed to identify miR-21-dependent gene signatures. ADM-21 is a chemically-modified (phosphorothioate backbone and locked-nuclei-acid) antisense oligo against miR-21 with high potency and stability.The efficacy of ADM-21 treatment was evaluated in vitro and in vivo. Results: MiR-21 was up-regulated by 5-fold in bladder tumors relatively to normal tissue and by 3-fold in advanced compared to early stage bladder cancers. The 28 cancer cell lines were stratified in 3 groups (high, intermediate, low) according to miR-21 levels. Transcriptomic analysis revealed a 15-gene signature that negatively correlated with miR-21 levels. Protein Phosphatase 2 Regulatory Subunit B Isoform A (PPP2R2A) displayed tumor suppressive properties in bladder cancer. Moreover, PPP2R2A represents a novel miR-21 direct target gene and a negative regulator of the AKT/mTOR pathway. ADM-21 (10uM) treatment suppressed 43.5% the growth and 90% the invasiveness of 5367 bladder cancer cells. Also, intravenous (I.V.) administration of ADM-21 was proven more effective than intraperitoneal (I.P.) administration in mouse xenografts. Specifically, 15mg/kg of ADM-21 (I.V.) every 5 days for 3 cycles reduced 37% and 47% (day 16) the growth rate of tumors originating from injections of 5367 and RT-112 cells, respectively. Conclusions: Integrative analysis of human bladder tumors and cell lines revealed a novel 15-gene signature that correlates with miR-21 levels. PPP2R2A is a miR-21 direct target and regulator of the AKT/mTOR pathway. ADM-21effectively reduces bladder cancer growth in vitro and in vivo. Upon completion of ADM-21 toxicology studies and confirm safety we will design phase I clinical trial for advanced bladder cancer.