tbuckley/cabot-search huggingface dataset:
Cabazitaxel in patients with metastatic castrate-resistant prostate cancer previously treated with a docetaxel-containing regimen: A single U.K. cancer center's experience using Early Access Programme and Cancer Drugs Fund.
Authors: Claire L. S. Kelly, Christina J. Hague, Stephanie A. Cornthwaite, Alison J. Birtle
Journal: Journal of Clinical Oncology (2013)

224 Background: The TROPIC Trial demonstrated improved overall survival in patients with mCRPC who progressed during or after treatment with docetaxel. The trial established cabazitaxel as a tolerable and viable second line treatment option in these patients. We report our experience with cabazitaxel in patients receiving treatment within the Early Access Programme (EAP) and via the Cancer Drugs Fund (CDF). Methods: Retrospective review of patients receiving cabazitaxel chemotherapy from 1st January 2011 to 1st January 2012. Chemotherapy administration was corroborated via the electronic prescribing system. Patient records provided documentation regarding disease response and treatment toxicities. For patients within the EAP, data was confirmed and supplemented via the Trials Office. Results: 22 patients were identified, of which 20 received cabazitaxel. 12 were treated within the EAP and 8 via the CDF. Median age was 68.5 years (59-83) within the EAP group and 70 years (52-78) within the CDF group, whilst median number of cycles was 6 (1-10) and 5.5 (1-8) respectively. 83.3% of EAP patients received full dose throughout, compared with 62.5% of the CDF patients. Primary GCSF was used in 91.6% of EAP patients and 75% of CDF patients, with secondary GCSF in 8.3% and 12.5% respectively. 3/20 patients had treatment discontinued due to progressive disease (after a minimum of 3 cycles). 13/20 patients had a positive biochemical and/or clinical response. 15/20 patients (Gleason score ≥ 8, 7 of 15) remain alive with a mean survival of 12.1 months (3.4-19.4). There were no treatment related deaths. Treatment related adverse events are shown in the Table. Conclusions: Our results are comparable with the TROPIC data, suggesting cabazitaxel offers demonstrable response rates and meaningful survival with an acceptable toxicity profile. [Table: see text]
Inhibition of tumor growth in a VEGFR TKI-resistant model of renal cell carcinoma using dalantercept combined with sunitinib.
Authors: Rupal Satish Bhatt, Xiaoen Wang, Nicolas Solban, Lin Wei, Sabina Signoretti, David Alsop, Marat Alimzhanov, Scott Pearsall, Michael B. Atkins, Ravi Kumar, Matthew L. Sherman, James Walter Mier
Journal: Journal of Clinical Oncology (2013)

370 Background: Antagonists of VEGF/VEGFR pathway have demonstrated clinical utility in patients with metastatic renal cell carcinoma (RCC); however, the therapeutic responses tend to be short-lived. Thus, there is a need for new treatments to overcome the acquired resistance to the current standards of care. Methods: We have used a murine xenograft model of RCC to study the relationship of the bone morphogenetic protein (BMP)/transforming growth factor-β (TGF-β) superfamily pathways and the VEGF pathways. Additionally, we have studied the effects of BMP9/10 inhibition on RCC tumor growth and performed MRI based tumor blood flow analyses to study antiangiogenic activity of the treatments. To explore the role of BMP9/10/ALK1 signaling in resistance to VEGFR inhibition, we used dalantercept (human ALK1-Fc fusion protein) as a ligand trap for BMP9 and 10. Results: We have found evidence of upregulation of BMP10 in A498 RCC xenograft tumors that have developed resistance to sunitinib. In tumors that had developed resistance to sunitinib, addition of ALK1-Fc to sunitinib led to prolonged tumor stabilization compared to either agent alone. Imaging of tumors revealed that addition of ALK1-Fc to sunitinib prevented the resumption in blood flow that is generally seen with continued sunitinib. Conclusions: These murine xenograft model data demonstrate that inhibition of ALK1 receptor pathway in combination with inhibition of VEGFR pathway may be a useful strategy for the treatment of RCC. A phase II randomized study of dalantercept in combination with axitinib in patients with metastatic RCC after progression on VEGFR/TKI therapy is ongoing.
Costs and trends in pancreatic cancer treatment: A population-based analysis.
Authors: C. B. O'Neill, C. L. Atoria, E. M. O'Reilly, J. LaFemina, E. B. Elkin
Journal: Journal of Clinical Oncology (2011)

6015 Background: Pancreatic cancer is the fourth leading cause of cancer-related death in the United States; information on the economic impacts of this disease, particularly in the elderly population, is limited. Methods: We retrospectively identified patients 66 years of age and older diagnosed with pancreatic adenocarcinoma in 1999-2005, in the linked SEER-Medicare dataset. Six-month and lifetime costs of medical care were estimated from Medicare payments. We examined the relative contributions of specific types of care and trends in these costs over time. Cancer-related costs were calculated as the difference between total payments for patients with pancreatic cancer and for a sample of cancer-free Medicare beneficiaries matched by age, sex, race, and SEER registry. Payments were adjusted for inflation and geographic variability and reported in 2006 U.S. dollars. Results: The cohort included 11,914 older adults with pancreatic cancer. Median survival was 4.1 months, and 97% of patients died within the study period. Total Medicare payments were largest for those with regional disease, and cancer-directed procedures were the most costly component of their care (Table). Mean costs overall and by cancer stage were stable over time, and there was little variation in the contribution of each category to the total cost of care. Mean cancer-related 6-month and lifetime costs were $40,100 and $53,000. Six-month cancer-related costs for local, regional and distant disease accounted for 70%, 70%, and 82% of lifetime cancer-related costs, respectively. Conclusions: Despite its short survival, pancreatic cancer is associated with substantial costs that have not changed markedly over time. Emerging technologies, including molecularly targeted therapies and other novel anticancer agents, may affect the economic impact of pancreatic cancer in the future. All stages Localized Regional Distant (N = 11,914) (N = 1,048) (N = 3,887) (N = 6,979) Mean $ % Total Mean $ % Cost Mean $ % Cost Mean $ % Cost Total 59,300 100 73,900 100 80,800 100 45,100 100 Procedures 14,100 24 20,000 27 25,400 32 6,900 15 Chemo/RT 8,200 14 8,500 12 10,200 13 7,100 16 Inpatient 19,500 33 22,900 31 22,100 27 17,600 39 Hospice 4,000 7 5,100 7 5,100 6 3,300 7 Other 13,400 23 17,400 24 17,900 22 10,300 23
Prevalence and adverse impact of extended antibiotic prophylaxis in urologic oncology surgery.
Authors: Matthew Mossanen, Josh Calvert, Sarah Holt, Andrew Callaway James, Jonathan L. Wright, Michael P. Porter, John L. Gore
Journal: Journal of Clinical Oncology (2014)

294 Background: Providers exhibit variation in the selection of the class, dose, and duration of prescribed antibiotic prophylaxis (ABP) to prevent postsurgical infections. We sought to evaluate ABP practice patterns for common inpatient urologic oncology surgeries and ascertain the association between extended ABP and hospital-acquired Clostridium difficile (C. diff) infections. Methods: From the PREMIER database for 2007–2012, we identified patients who underwent radical prostatectomy (RP), radical or partial nephrectomy (Nephx), or radical cystectomy (RC). We defined extended ABP from charges for antibiotics ≥ 2 days after surgery; exclusive of patients with a switch in antibiotic class within 2 postoperative days for presumption of infection. We identified postoperative C. diff infections using ICD-9 diagnosis codes. Hierarchical linear regression models were constructed by procedure to identify patient and provider factors associated with extended ABP. Logistic regression models evaluated the association between extended ABP and postoperative C. diff infection, adjusting for patient and provider characteristics. Results: We identified 59,184 RP patients, 27,921 Nephx patients, and 5,425 RC patients. RC patients were more likely to receive extended ABP (56%) than RP (18%) or Nephx (29%) patients (p&lt;0.001). Other factors associated with extended ABP included prolonged postoperative length of stay (OR ≥ 1.69, p&lt;0.001 for all procedures), and surgical volume (p&lt;0.001 for highest vs. lowest volume quartiles). Hospital identity explained 35% of the variability in ABP after RP, 23% after Nephx, and 20% after RC. Among Nephx and RC patients, extended ABP was associated with significantly higher odds of postoperative C. diff infection (OR 3.79, 95% CI 2.46–5.84, and OR 1.64, 95% CI 1.12–2.39, respectively). Conclusions: We identified marked hospital-level variability in extended ABP following RP, Nephx, and RC, which was associated with significantly increased odds of hospital-acquired C. diff infections. Efforts to increase provider compliance with national ABP guidelines may decrease preventable hospital-acquired infections after urologic cancer surgery.
Can pelvic lymph node dissection be omitted in intermediate-risk prostate cancer patients? A SEER-based comparative study using inverse-probability-of-treatment weighting.
Authors: Yu-Wei Chen, Brandon Arvin Virgil Mahal, David R. Ziehr, Michelle Daniel Nezolosky, Vidya Bhavani Viswanathan, Toni K. Choueiri, Quoc-Dien Trinh, Paul Linh Nguyen
Journal: Journal of Clinical Oncology (2015)

95 Background: To investigate whether pelvic lymph node dissection (PLND) reduces prostate cancer specific mortality (PCSM) in surgically-treated men with intermediate-risk prostate cancer (Pca). Methods: We identified 44,112 men diagnosed with intermediate-risk Pca from 2004-2009 in Surveillance, Epidemiology and End Results Program (SEER). We used inverse-probability-of-treatment weighting (IPTW) to adjust for baseline characteristics between PLND + radical prostatectomy (RP, N=26,571), versus RP alone (N=17,541) groups; Cox competing-risk model and propensity score-adjusted analyses were used for validation. Gleason scores were based on prostatectomy since biopsy scores were not available for RP-treated patients in SEER from 2004-2009. Results: After a median follow-up of 54 months, there was no survival benefit associated with PLND + RP compared to RP alone (Gray's test, P=0.30). After IPTW adjustment for baseline characteristics, PLND was still not associated with PCSM (AHR: 0.93, 95% CI: 0.65-1.33). This result was consistent with propensity score-adjusted model (AHR=1.05, 95% CI: 0.71-1.55) and the Cox competing-risk model (AHR=1.06, 95% CI: 0.71-1.57). Of men who received RP with PLND, 502 men (1.9%) had pathologically positive lymph nodes, which were associated with a higher risk for PCSM (AHR: 4.02, 95%CI: 1.83-8.84). Conclusions: PLND with RP was not associated with reduced PCSM compared with RP alone in men with intermediate-risk disease, suggesting that PLND is diagnostic but not therapeutic in this patient population. However, a caveat of this study is that risk group was defined by pathologic Gleason score; the 5% of clinically intermediate risk patients who are typically found to have Gleason 8-10 disease at prostatectomy could not be included in this analysis. [Table: see text]
Clinical characteristics of an incident cohort of patients with resected squamous cell carcinoma of the head and neck (SCCHN) in the United Kingdom.
Authors: K. Kim, M. Amonkar, D. Högberg, F. Kasteng
Journal: Journal of Clinical Oncology (2011)

5540 Background: SCCHN is the sixth most common cancer worldwide with about 600,000 cases diagnosed annually. Locally advanced SCCHN continues to be a therapeutic challenge with high rates of morbidity and mortality and a low cure rate, despite the fact that most lesions are localized or have spread only to regional lymph nodes. Methods: This retrospective analysis was based on inpatient and outpatient records extracted from UK’s Hospital Episode Statistic (HES) database and linked to mortality data from the Office for National Statistics. SCCHN patients with cancers of the lip, tongue, oral cavity, pharynx or larynx who underwent surgical resection (identified with OPCS-4.5 codes) between July 1, 2003 and March 31, 2008 were followed for at least one year (max. of 5 years) from the surgery date. Results: The HES dataset identified 38,460 SCCHN patients of which 11,403 patients met the study inclusion criteria. Mean age of the patient cohort was 63.2 (+12.6) years and 69.8% were male. Larynx and pharynx cancer patients accounted for 29% and 20% of the patient cohort, respectively. Oral cavity, tongue and lip cancer patients accounted for 21%, 19% and 11%, respectively. The larynx cancer subgroup had the largest percentage of males (85%). 58.1% of patients with lip cancer were male. Lip cancer patients were the oldest (mean 69.6 years) compared to the other four cancer sites. Mean length of follow-up for the patient cohort was 31.0 (+18.4) months. 32.3% of the patients died in the follow-up period and the mean time to death from surgery was 16.9 months. The highest percentage of deaths occurred among larynx cancer patients (37.3%), followed by pharynx (35.4%), oral cavity (32.7%), tongue (30.3%) and lip cancer patients (16.2%). The average time to death from the surgery date was longest for lip cancer patients (22.4 months) and shortest for patients with cancers of the tongue, pharynx and larynx (16.4 months). Conclusions: In the cohort, 30% of the SCCHN patients underwent surgical resection and the resected SCCHN patients showed high mortality rate. The high mortality rate among these patients suggests the need for new therapies that could improve outcomes and reduce the disease burden.
Correlation of galeterone-induced degradation of the androgen receptor with inhibition of a deubiquitinating enzyme.
Authors: Daniel T. Dransfield, Nivedita Namdev, Douglas B Jacoby, Karen Ferrante
Journal: Journal of Clinical Oncology (2016)

345 Background: Galeterone is a highly selective oral small molecule drug candidate that disrupts androgen receptor (AR) signaling. It degrades the AR (IC50 ~1µM), is a potent CYP17 lyase inhibitor ( &lt; 50nM), and possesses AR antagonist activity (~600nM). Galeterone-induced AR degradation was observed in models having either full-length AR or known constitutively active truncated forms of the AR receptor that lack the ligand binding domain (LBD), AR-V7 and AR567es. The LBD of the AR is not required for galeterone-dependent AR degradation. Galeterone-induced degradation activity is blocked by co-administration of the proteasome inhibitor MG132. Furthermore, galeterone-induced degradation of AR can be blocked by selective knock-down of the E3 ligases, Mdm2 and CHIP. Methods: We utilized a series of biochemical and cell-based in vitro studies to further elucidate and characterize additional signaling molecules in the proteasomal dependent mechanism of galeterone-induced AR degradation. Results: We screened a panel of 22 deubiquitinating enzymes (DUBs) in vitro and demonstrated that galeterone inhibited enzymatic activity of the DUB, USP12 with IC 50 in the single digit micromolar range. In addition, we used surface plasmon resonance to demonstrate that dose-dependent inhibition of USP12 activity involves direct binding of galeterone to USP12 and USP12/UAF1 complexes with a K D of ≤ 10µM. Conclusions: Interestingly, USP12 is a co-activator of AR and selective knock-down of this DUB has been shown to increase AR degradation. USP12 has been linked to regulation of the phosphatases PHLPPs through ubiquitination. PHLPPs dephosphorylate AKT, providing an important regulatory mechanism for controlling the PI3K/AKT pathway. Since it is known that galeterone induces an increase in pAKT and pMdm2, the latter being a substrate of activated AKT, this suggests that inhibition of USP12 regulates pAKT levels through enhanced degradation of PHLPPs via increased ubiquitination. These data suggest that a differentiating mechanism of galeterone from other AR targeting agents is through inhibition of USP12, leading to enhanced AR degradation.
Patterns of care according to treatment intent for metastatic colorectal cancer (mCRC): A 2.5-year review of routine practice.
Authors: Kathryn Maree Field, Jayesh Desai, Jeanne Tie, Suzanne Kosmider, Susie Bae, Joseph James McKendrick, Michael Harold, Peter Gibbs
Journal: Journal of Clinical Oncology (2012)

e16516 Background: Cure is potentially achievable in select patients with mCRC with limited metastatic disease to liver and/or lung. To date the peri-operative strategies undertaken by oncologists in routine practice for such pts have not been well documented. Methods: A clinical database recording information on all pts diagnosed with mCRC since July 2009 from 5 hospitals was analysed. Management strategies where a curative-intent resection had occurred; was planned; or was a potential option were compared with those managed with palliative intent. Results: Status at the time of first review regarding systemic chemotherapy (CT) was documented for 354 pts. 15 (4.2%) had undergone curative-intent resection; 37 (10.5%) had a resection planned; 36 (10.2%) were considered potentially resectable if response to treatment was good; and 266 (75.1%) were treated with palliative intent. Only one patient (1.9%) already resected or planned for resection was &gt;ECOG1, compared with 8% (3/36) potentially resectable and 20% (53/266) palliative pts. CT was delivered in 12 (80%) already-resected, 29 (78%) planned for resection, 33 (92%) potentially-resectable and 202 (76%) palliative-intent pts. Combination CT was the dominant strategy, although 5 of 12 (42%) resected pts received single agent treatment. 17% (n=2) resected pts received bevacizumab with CT, compared with 29% (n=18) of planned or potentially-curative pts and 55% (n=112) of those treated with palliative intent. At the time of analysis 17 pts (46%) with a planned resection and 7 (20%) considered potentially curative have had surgery, while 6 (2.3%) where treatment was initially considered palliative have had curative-intent surgery. Conclusions: Treatment strategies for pts with mCRC differ significantly based on the treatment intent, and may be affected by surgical preference and referral pattern. Bevacizumab was less likely to be used for already-resected pts and the use of single agent therapy in this group was also not uncommon. Many pts initially considered resectable do not ultimately undergo resection, whereas occasional ‘palliative’ pts may become resectable, confirming the importance of continued consideration of this option.
Efficacy and safety of single-agent sunitinib in treating patients with advanced hepatocelluar carcinoma after sorafenib failure: A prospective, open-label, phase II study.
Authors: T. Yau, R. C. Leung, H. Wong, J. Chiu, P. Chan, R. Pang, S. T. Fan, R. T. P. Poon
Journal: Journal of Clinical Oncology (2011)

4082 Background: This is an open label and single arm phase II study to assess the efficacy and tolerability of sunitinib for the treatment of sorafenib-refractory advanced hepatocellular carcinoma (HCC) patients. Methods: Between October, 2008 and October, 2010, eligible patients with advanced HCC and documented disease progression after sorafenib treatment received sunitinib 37.5 mg continuously at Queen Mary Hospital, Hong Kong. Response assessment was performed after every 8 weeks. The primary endpoint was time-to-progression (TTP) and the secondary endpoints were tumor response rate (RR), overall survival (OS) and safety. Results: At the time of analysis, 38 patients were recruited in the trial. The median age was 56 years (range, 27-80) and all patients were in ECOG Performance Status 0-1. Ninety-five percent of patients were chronic hepatitis B carriers with underlying Child-Pugh A and B cirrhosis in 70% and 30% of the enrolled patients, respectively. Ten (25%) patients had tumor vascular invasion and 32 (80%) patients had extra-hepatic metastasis. Among 35 evaluable patients, RR was 6% with 2 patients achieved partial response and another 12 (34%) patients achieved stable disease. Overall, 40% of patients derived clinical benefits from sunitinib treatment for at least 8 weeks. The median TTP was 2.9 months (0.5-15) and OS was 5.2 months (1-22.5). Malaise (60%), neutropenia (45%) and diarrhea (36%) were the most commonly encountered adverse events, with nearly 30% of patients experienced grade 3 or 4 toxicity. No treatment-related death was reported. Conclusions: Sunitinib has substantial anti-tumour activity with manageable toxicity profile in treating sorafenib-refractory advanced HCC population. These data may imply sunitinib inhibits signaling pathways involved in sorafenib resistance and support the hypothesis of sequential use of antiangiogenic tyrosine kinase inhibitors in treating advanced HCC patients.
The role of epidermal growth factor receptor (EGFR)-directed recombinant dimeric IgA antibodies in tumor cell killing.
Authors: T. Valerius, S. Lohse, S. Derer, T. Beyer, K. Klausz, M. Peipp, J. H. W. Leusen, J. G. J. van de Winkel, M. Dechant, M. Gramatzki
Journal: Journal of Clinical Oncology (2011)

e13014 Background: The epidermal growth factor receptor (EGFR) is a validated target for personalized cancer therapy with IgG antibodies. IgA antibodies contribute to the humoral part of the mucosal immune system, but their immunotherapeutic potential has hardly been explored. Here, we describe the production, purification and functional evaluation of recombinant dimeric IgA antibodies against EGFR. Methods: Human J-chain-containing IgA was produced under serum-free conditions by transfecting non-adherent CHO-K1 cells expressing EGFR-specific monomeric 225-IgA (mIgA) with a vector coding for His-tagged human J-chain. Dimeric IgA (dIgA) was purified by two different affinity (anti-human-κ and anti-His-tag) and one size exclusion chromatography. The resulting homogenous preparation of highly pure IgA dimers was biochemically and functionally characterized. Results: Functional studies demonstrated dIgA to be at least as effective as mIgA in triggering antibody-dependent cellular cytotoxicity of A431 tumor cells by isolated monocytes (EC50 1.9/0.8 nM for mIgA/dIgA), by isolated PMN (EC50 5.6/3.7 nM for mIgA/dIgA) and in human whole blood 51chromium-release-assays (EC50 1.8/1.4 nM for mIgA/dIgA). Importantly, dimeric IgA was more effective in F(ab)-mediated mechanisms: inhibition of binding of FITC-labelled EGF to A431 cells and furthermore downmodulation of EGFR by dIgA was achieved at significantly lower concentrations than by mIgA (EC50 14.9/124.5 nM, 76.2/335.2 nM, respectively). In addition, growth of EGFR-expressing DiFi cells was inhibited more effectively by dimeric than by monomeric IgA (EC50 6.2/49.7 nM). Furthermore, only dimeric but not monomeric IgA or IgG was directionally transported via the pIgR through an epithelial cell monolayer in a transcytosis assay with polarized MDCK cells stably transfected with human polymeric immunoglobulin receptor (pIgR). Conclusions: These studies demonstrate that recombinant dimeric IgA antibodies against EGFR trigger a distinct repertoire of effector functions compared to monomeric IgA or IgG1 antibodies - suggesting that dimeric IgA antibodies may constitute an interesting antibody format for tumor therapy.