tbuckley/cabot-search huggingface dataset:
Early assessment of PSA response in CRPC patients treated with enzalutamide (Enza) or abiraterone (Abi).
Authors: Jeffrey R. Guccione, Elisa M. Ledet, Michael D. Stolten, Allie E. Steinberger, Lydia D. Chow, Patrick Cotogno, Brian E. Lewis, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2016)

249 Background: Abi and Enza are used in treating metastatic CRPC. Primary resistance is well described but little data exists for early treatment responders. Further characterization of patients with early PSA declines was the goal of this study. Methods: Single institution, retrospective reviews were performed on 84 CRPC patients (pts) treated with Abi or Enza. PSAs were recorded for the duration of treatment. The primary end point was to describe receiver operating characteristics (ROC) of early PSA changes, including sensitivities and specificities, as a predictor of later treatment response (defined as ≥ 50% decrease in PSA from baseline). 12 additional clinical covariates were also evaluated as treatment response predictors. Results: 30/63 pts in the Abi treatment group and 12/44 pts in the Enza treated group had a PSA treatment response at some point. Among the “eventual” Abi responders, some achieved a response early; 16/30 at 4 weeks and 22/30 at 8 weeks. Of Enza “eventual” responders, 7/12 achieved response at 4 weeks. For early responders (either 4 or 8 weeks), Abi pts median treatment time was 336 days. Enza early responders median treatment was time 303 days. For ROC analysis of PSA changes at 4 &amp; 8 weeks, in terms of predicting ‘eventual’ responders, the Abi group had an area under the curve (AUC) of 0.86 ± 0.07 and 0.93 ± 0.08, respectively. Enza ROC analysis of PSA change at 4 weeks had an AUC of 0.97 ± 0.03. Sensitivities and specificities were also described for various PSA change thresholds in each group. Ideal cut-off points for Abi at 4 weeks was a 37% decrease in PSA (sensitivity: 0.74, specificity: 0.97) and at 8 weeks was a 33% decrease (0.82, 0.97). For Enza ideal cut-off at 4 weeks was a 31% PSA decrease (0.82, 0.93). Covariate analysis of the Abi pts indicated that metastasis at diagnosis (P = 0.048) and prior taxanes predicted resistance to treatment (P = 0.019), as measured by &lt; 50% decline in PSA. All covariates in the Enza pts failed to reach significance. Conclusions: Results suggest that early PSA changes for both Enza and Abi may be a reliable way for clinicians to predict long-term PSA response. This may allow for earlier modifications to be made in patient management for those not achieving an early PSA response.
Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects
Authors: Elena Bekerman, Gregory Neveu, Ana Shulla, Jennifer Brannan, Szu-Yuan Pu, Stanley Wang, Fei Xiao, Rina Barouch-Bentov, Russell R. Bakken, Roberto Mateo, Jennifer Govero, Claude M. Nagamine, Michael S. Diamond, Steven De Jonghe, Piet Herdewijn, John M. Dye, Glenn Randall, Shirit Einav
Journal: Journal of Clinical Investigation (2017)

Global health is threatened by emerging viral infections, which largely lack effective vaccines or therapies. Targeting host pathways that are exploited by multiple viruses could offer broad-spectrum solutions. We previously reported that AAK1 and GAK, kinase regulators of the host adaptor proteins AP1 and AP2, are essential for hepatitis C virus (HCV) infection, but the underlying mechanism and relevance to other viruses or in vivo infections remained unknown. Here, we have discovered that AP1 and AP2 cotraffic with HCV particles in live cells. Moreover, we found that multiple viruses, including dengue and Ebola, exploit AAK1 and GAK during entry and infectious virus production. In cultured cells, treatment with sunitinib and erlotinib, approved anticancer drugs that inhibit AAK1 or GAK activity, or with more selective compounds inhibited intracellular trafficking of HCV and multiple unrelated RNA viruses with a high barrier to resistance. In murine models of dengue and Ebola infection, sunitinib/erlotinib combination protected against morbidity and mortality. We validated sunitinib- and erlotinib-mediated inhibition of AAK1 and GAK activity as an important mechanism of antiviral action. Additionally, we revealed potential roles for additional kinase targets. These findings advance our understanding of virus-host interactions and establish a proof of principle for a repurposed, host-targeted approach to combat emerging viruses.
Results of a phase II trial of docetaxel (DOC), bevacizumab (BEV), and androgen deprivation therapy (ADT) for biochemical relapse (BCR) after definitive local therapy for prostate cancer (PC).
Authors: Rana R. McKay, Kathryn P. Gray, Julia H. Hayes, Glenn J. Bubley, Jonathan E. Rosenberg, Philip W. Kantoff, Mary-Ellen Taplin
Journal: Journal of Clinical Oncology (2014)

54 Background: Despite primary treatment for localized PC, 20-30% of men experience a BCR, detected by a rise in prostate-specific antigen (PSA). Though 30% of these patients develop metastatic disease, the optimal treatment of men with BCR has yet to be determined. In this trial, we evaluate the efficacy of DOC, BEV, and ADT for men with BCR after local therapy for PC. Methods: 41 men with a BCR and PSA doubling time of ≤10 months (mos) were enrolled. Patients received 4 cycles of DOC (75 mg/m 2 ) every 3 weeks, 8 cycles of BEV (15 mg/kg) every 3 weeks, 18 mos of a luteinizing-hormone releasing hormone (LHRH) agonist, and 15 mos of bicalutamide (50 mg daily) beginning after completion of DOC. The primary endpoint was the proportion of patients free from PSA-progression 1 year after completion of ADT. Secondary endpoints included PSA response, testosterone recovery, and toxicity. Results: Median follow-up was 27.6 mos. Median age at diagnosis was 58 years. Median PSA at diagnosis was 6.7 ng/mL, with the majority of patients (59%) having Gleason 7 disease. Most patients underwent radical prostatectomy +/- radiation therapy (n=36). At baseline, 33 men (81%) had a normal testosterone (&gt; 240 ng/dL). The table describes the PSA responses for the entire cohort. 10 men (28%) had a normal testosterone 6 mos after completing ADT. 17 men (47%) had a normal testosterone 12 mos after completing ADT, of whom 5 (29%) had a PSA &lt;0.2 ng/mL at that time. There were 15% grade 1, 34% grade 2, 39% grade 3, and 12% grade 4 adverse events (AEs). The most frequent grade 3-4 AEs included neutropenia (24%), febrile neutropenia (11%), and hypertension (9%). Conclusions: DOC, BEV, and ADT for BCR resulted in complete responses in 16 men (44%) 1 year after completion of therapy. Longer follow-up is needed to determine the efficacy of this regimen. Clinical trial information: NCT00658697. [Table: see text]
Balloon Kyphoplasty Improves Both Roland-Morris Disability Scores and Bone Pain among Cancer Patients with Vertebral Compression Fractures: Interim Analysis of Results from a Phase IV Random Trial
Authors: James R. Berenson, John B Tillman, Mohamad A. Hussein, Robert Pflugmacher, Peter Jarzem, Sami Elmoufti, Frank D Vrionis
Journal: Blood (2008)
High-dose chemotherapy with autologous peripheral blood stem cell transplantation in patients with poor- and intermediate-prognosis metastatic germ cell tumors: A retrospective monocenter analysis of 44 cases.
Authors: M. Mohr, I. Hartig, T. Kessler, C. Hamisch, S. Kliesch, U. Krug, T. Spieker, M. Semik, K. Wiebe, G. Puehse, L. Hertle, C. Mueller-Tidow, R. M. Mesters, W. E. Berdel
Journal: Journal of Clinical Oncology (2011)

e15043 Background: Metastatic germ cell tumors (GCT) are curable. The International Germ Cell Cancer Collaborative Group (IGCCCG) reports a poor prognosis subgroup with a 5-year survival rate of 48%. High-dose chemotherapy with autologous peripheral blood stem cell transplantation (HD-PBSCT) in these patients showed promising results in phase II trials, but failed to show significant advantage in randomized trials. We report on our series of patients with poor and intermediate prognosis GCT treated with individually tailored multiple-course HD-PBSCT and secondary surgery of remaining tissue. Methods: We performed a retrospective analysis of our complete single center series of 44 patients (40 poor prognosis; 4 intermediate prognosis) treated with HD-PBSCT. All patients received 1 up to 6 cycles of standard-dose cisplatin-etoposide-ifosfamide (PEI) chemotherapy followed by granulocyte colony-stimulating factor and stem cell mobilisation. Subsequent high-dose chemotherapy regimen HD-PEI was adapted from a phase I/II trial of the German Testicular Cancer Study Group (GTCSG). In 14 patients we added paclitaxel according to another phase I/II study by the GTCSG. Up to 4 cycles of HD-chemotherapy were administered according to individual patient’s response and tolerability. Patients with residual disease in computed tomography (CT) or positron-emission tomography (PET)-CT underwent secondary surgery. Results: In this retrospective analysis the CR rate after up to 4 cycles of HD-PBSCT and resection was 73%. Three patients showing a marker-negative PR did not undergo surgery, because they were PET negative and/or fine needle aspiration did not show viable tumor. The 3-year survival rate was 80%, with a median follow up of 43 months (range: 3-130 months). Disease-related death rate was 16%. Treatment-related death after HD-PBSCT did not occur. One patient died postoperatively. Conclusions: In our single center experience multiple courses of individually tailored HD-PBSCT is a safe and effective treatment option in poor and intermediate prognosis metastatic germ cell cancer.
Treatment patterns and costs in second-line (2L) metastatic colorectal cancer (mCRC).
Authors: April H. Teitelbaum, Dana Evans, Elaine Yu, Robert Morlock, Stacey DaCosta Byfield
Journal: Journal of Clinical Oncology (2013)

544 Background: Administrative claims databases are an important data source to examine treatment (tx) patterns, costs and outcomes, but are subject to limitations. This study included a chart review to assess a claims-based algorithm for identifying 2L mCRC patients (pts). Tx patterns and costs were compared between mCRC pts treated with bevacizumab (BEV) or cetuximab (CET). Methods: 2LmCRC pts were identified from a US commercial insurance claims database (1/2008-6/2011). Initial identification required pts to have ≥2 claims ≥30 d apart for colon or rectal cancer and metastatic (met) disease. Continuous enrollment for ≥6 mo before and after the date of 1 st met claim, ≥2 lines of therapy (LOT), and 2L tx with BEV or anti-EGFR was required. 2L was defined as addition of any new agent ≥28 d after start of 1st LOT. Charts from 92 pts were abstracted and used to refine and corroborate the algorithm. Generalized Linear Models (GLM) were used to assess differences in healthcare costs between patients on BEV or CET during 2L. Results: The match rate of claims identified mCRC pts treated with multiple lines of therapy confirmed by chart abstraction ranged from 85% to 97%. Applying the final algorithm to the overall claims data resulted in the identification of 569 pts: 450 pts receiving BEV and 119 pts receiving CET. A total of 38 panitumumab patients were excluded from analysis due to small sample size. Pt characteristics were similar; mean age was 61 years and 58% were males. In 2L, BEV was commonly used with 5FU or capecitabine-based regimens (81%) and CET with irinotecan-based regimens (73%). BEV pts had significantly lower all-cause healthcare costs (adjusted difference: –$12,239, p=0.02), and medical costs (–$13,672, p=0.01) during 2L. While on second-line therapy, BEV pts also had lower average monthly all-cause and medical costs than CET pts. Sensitivity analysis using variations of the case finding algorithm yield similar results. Conclusions: The use of BEV during second line treatment of mCRC was found to be associated with significantly lower healthcare costs relative to the use of CET from a large US healthcare claims database.
Phase I pharmacokinetic study of temsirolimus (CCI-779) in patients with advanced malignancies and normal and impaired liver function: An NCI Organ Dysfunction Working Group (ODWG) study.
Authors: J. Sarantopoulos, H. Lenz, P. LoRusso, S. Shibata, S. Kummar, D. Mulkerin, R. K. Ramanathan, M. M. Mita, P. O'Rourke, S. C. Remick, S. Goel, M. Gutierrez, S. S. Ramalingam, A. Murgo, A. M. Davies, S. Mani, J. Boni, M. Shapiro, S. P. Ivy, C. H. Takimoto
Journal: Journal of Clinical Oncology (2011)

3072 Background: Temsirolimus (T) is a first in class mTOR inhibitor FDA approved for advanced renal cell cancer. It is a water soluble rapamycin ester given IV weekly, rapidly metabolized to sirolimus, and extensive metabolism by CYP3A. We conducted a phase I study to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of T in patients (pts) with hepatic dysfunction (HD). Methods: Pts with advanced solid tumors or lymphoma, ECOG ≤2, adequate renal and bone marrow function, received IV T over 30 minutes weekly. Cycles q28 days. Pts stratified into 5 HD cohorts: normal, mild, moderate, severe, transplant, using NCI ODWG Criteria. Data also collected for Child-Pugh classification (CPC). T dose was escalated in sequential cohorts of pts within each HD category. Whole blood analysis for T and sirolimus concentrations were determined during cycle 1 using a validated LC-MC/MS assay. Study objectives included characterizing safety, tolerability, PK, identifying the MTD and obtaining preliminary evidence of efficacy. Results: 110 pts received 333 cycles of T at doses starting at 25 mg in mild HD (5-175 mg). Median age 60, male 58%, ECOG 1 62%. CRC 44% Cohorts: normal-25, mild-39, moderate-20, severe-24, liver transplant 2 pts. Related AEs include thrombocytopenia 40%, fatigue 29%, nausea 28%, anemia 27%, stomatitis 27%, hypophosphotemia 27%, rash 24%. Thrombocytopenia was the most common dose limiting toxicity (DLT) (n=7). Nonlinear PK disposition, and no accumulation. Sirolimus formed rapidly. Apparent increased Cmax and AUC, decreased CL with worsening HD. Cycle 1 Day 1 T 25mg Normal Cohort: Cmax 613 ng/mL, AUC 2230 ng·h/mL, T1/2 19.8 h, CL 11.6 L/h. Severe Cohort 10 mg: Cmax 455 ng/mL, AUC 3200 ng·h/mL, T1/2 28.1 h, CL 3.3 L/h. Correlates of PK exposure to the CPC were fairly consistent with the NCI ODWG categorization and support dose adjustment only in patients with severe HD. Disease stabilization was noted in 33 pts, 1 CR (NHL), and 1 PR (breast cancer). Conclusions: Recommended dose for temsirolimus for pts with mild, moderate, or severe HD are 25 mg, 25 mg, 10 mg respectively, given IV weekly for pts with baseline platelets ≥ 100 109/L
Outcomes following immediate versus delayed radical prostatectomy among men on active surveillance for prostate cancer.
Authors: Christopher James Welty, Pauline Fillipou, Janet E. Cowan, Peter Carroll
Journal: Journal of Clinical Oncology (2015)

40 Background: Little is known about the risk of delaying radical prostatectomy (RP) until biopsy progression following active surveillance (AS) for prostate cancer. This study examines the pathological outcomes associated with surgery following AS compared to immediate treatment of prostate cancer with similar grades. Methods: Men who underwent RP between 1997-2013 at University of California San Francisco were included. The first comparison consisted of men who met strict AS inclusion criteria (Gleason Score ≤ 6, PSA ≤ 10, clinical stage &lt;T3, ≤ 33% biopsy cores positive, and &lt;= 50% of any single core positive) at diagnosis and underwent AS prior to RP (AS+RP) compared to men who met strict AS criteria and underwent RP within 6 monts (immediate RP). The second comparison consisted of men who met strict AS criteria and were upgraded on follow-up biopsy compared to a cohort of men matched on the basis pre-treatment biopsy pathology. Logistic regression was used to determine associations of RP group with adverse pathology (stage ≥pT3/N1, positive margins, and/or upgrade to Gleason &gt;=4+3), adjusting for clinical and demographic factors. Results: We identified 241 men who underwent RP after a period of AS, 157 of whom initially met strict AS criteria. The median time to RP was 20 months (IQR 14-36). Men who met strict criteria and underwent immediate RP were less likely to have unfavorable pathology than those who underwent AS+RP (OR 0.39, 95% CI 0.24-0.62). Fifty-four of the men who underwent AS+RP did so have upgrading to Gleason 3+4 disease. These patients were matched with 154 men based on their pre-treatment biopsy features. After appropriate matching, the timing of RP was not associated with adverse pathology (OR 1.27, 9% CI 0.65-2.49). Conclusions: Men who undergo surgery following AS are a selected subset of men with low risk prostate cancer. The surgical pathology features of these patients are more similar to men undergo surgery after diagnosis with intermediate risk prostate cancer than those diagnosed with very low risk disease. Additional follow-up of this and other cohorts is needed to assess long term clinical outcomes following delayed RP.
Grade 3 or higher morbidity requiring urologic surgical management following curative-intent radiotherapy of localized prostate cancer: Patient characteristics.
Authors: Cameron S. Thorpe, Jeremy B. Myers, Dennis C. Shrieve, Jonathan D. Tward
Journal: Journal of Clinical Oncology (2015)

116 Background: Although there are prospective data reporting the incidence of grade 3 morbidity after treatment of prostate cancer (PCA), little has been reported on the specific morbidities, latency period and surgical management of these patients. We retrospectively evaluated the characteristics of patients treated for grade 3 or higher complications at the University of Utah. Methods: We identified patients with PCA from our institutional database who were treated with definitive or postoperative radiation between the years 1995 and 2012 with at least 1 CTCAE defined Grade 3 or higher adverse event (AE). We evaluated the details of surgery and/or radiation, time course to development of AE’s, and procedures performed to manage the AE’s. Descriptive statistics were performed. GI toxicities were not evaluated. Results: There were 208 Grade 3 events reported in 44 patients. Five had a single event, 8 had 2 events, and 31 patients had 3 or more. Following radiotherapy, 21 patients initially presented with a grade 3 toxicity, whereas 12 presented with a grade 1 and 11 presented with a grade 2 that progressed to grade 3. One subject had a grade 4 toxicity. There were 9 subjects who reported baseline grade 1 to 3 toxicity prior to curative-intent treatment. The most common Grade 3 events were: obstruction (100 events), incontinence (40 events) and fistula (21 events). Fourteen patients had surgery and EBRT, and at least 16 patients had HDR brachytherapy. The average latency period to the first grade 3 event was 76.8 months (range 0 to 195 months). Between 2005 and 2010 an average of 531 and 92 patients with PCA were treated with radiation in the state of Utah (SEER) and the University of Utah annually, respectively. Conclusions: Grade 3 or higher urologic morbidity is uncommon following prostate cancer radiation treatment. Combinations of radiation therapies and HDR brachytherapy appear to increase the risk of an adverse event. Outcome studies reporting late toxicity with median follow up of less than 5 years may significantly under-report the incidence.
Inhibition of XIAP Renders Newly CD40-Activated Chronic Lymphocytic Leukemia Cells Sensitive to Fas (CD95) Mediated Apoptosis.
Authors: Arnon P. Kater, Frank Dicker, Massimo Mangiola, Kate Welsh, John Ostresh, Richard Houghten, John C. Reed, Thomas J. Kipps, Clemencia Pinilla
Journal: Blood (2004)
Utilization of local salvage therapy after primary radiotherapy for prostate cancer.
Authors: Henry Tran, Jaime Kwok, Tom Pickles, Scott Tyldesley, Peter C. Black
Journal: Journal of Clinical Oncology (2013)

231 Background: Early biochemical detection and subsequent slow progression of recurrent prostate cancer after primary radiotherapy permit the delivery of potentially curative local salvage therapy (LST). Several LST options are available, including cryotherapy, brachytherapy (BT), and radical prostatectomy (RP). We studied the rates at which patients are offered, and receive LST after failure of primary radiotherapy. Methods: Patients with localized prostate cancer who received primary radiotherapy with curative intent between 1999-2000 were identified in the British Columbia radiotherapy database. Data on clinicopathologic features, primary therapy, PSA kinetics, and salvage therapy were collected retrospectively. We excluded patients with T4 tumors, PSA &gt;40, or age &gt;72 years at time of primary therapy. Biochemical recurrence (BCR) was defined by the Phoenix criteria. Patients were also deemed radiation failures if salvage therapy was started without meeting criteria for BCR. Results: Out of 1785 patients treated with radiation, 1067 met the inclusion criteria. Of these, 257 experienced BCR. Five patients received LST (3 RP, 2 BT). LST was considered in 11 other patients, but 2 were not referred for urologic opinion, and 9 declined intervention. 60 patients were considered ineligible for LST: 43 due to suspected metastasis and 17 due to other comorbidities. LST was unlikely to be offered to 80 patients due to age &gt;75 at time of BCR. 59 additional patients appeared to be eligible for LST but there was no evidence that it was considered in the medical record. ADT was started within 12 months of BCR in 118 patients, and after at least one year of observation in another 66. Conclusions: Few patients were considered for LST in the study period, and only 5 received it. This review of practice patterns reveals a lack of uniform monitoring and treatment strategies in this challenging patient population, and indicates a need for more collaboration between all treating physicians, as well as with tertiary care centers.
A phase II multicenter study of metastasectomy for intra- and extra-hepatic metastases from colorectal cancer.
Authors: Alice Chia-chi Wei, Natalie G. Coburn, Carol-anne Moulton, Sean P Cleary, Calvin Law, Paul David Greig, Steven Gallinger
Journal: Journal of Clinical Oncology (2013)

482 Background: Metastasectomy for liver limited metastases from colorectal cancer (CRC) provides excellent 5-year overall survival (OS) rates. The presence of extra-hepatic metastases (EHM) has traditionally been a contraindication to surgery. On this basis, as many as 80% of patients are deemed ineligible for liver resection. Due to the improved safety of hepatic surgery, there is a growing interest in multi-site metastasectomy for patients with intra-hepatic and extra-hepatic metastases (IHM, and EHM). The objective of this study was to evaluate the results of complete metastasectomy for patients with IHM and EHM from CRC. Methods: A phase II study of metastasectomy for both IHM and EHM from CRC was conducted at 2 high volume hepato-pancreato-biliary (HPB) centers. Eligible patients with any number resectable IHM and up to 3 foci of EHM, resectable with RO intent were offered metastasectomy. Clinical and survival data was analyzed using standard statistical methods. Results: Twenty-five patients were enrolled with a median age of 57 (32-84) years; 14/25 (56%) patients presented with synchronous disease. The median number of IHM, EHM and combined sites were 2, 1 and 3, respectively. The lung was the most common site of EHM (12/25, 48%). Protocol surgery was completed in 18/25 (72%) including 11/25 (44%) planned sequential resections. Perioperative morbidity and mortality was 11/25 (44%) and 1/25 (4%), respectively. The median disease free survival was 6 months. The median OS from the time of CRC diagnosis, first metastasectomy and completion metastasectomy was 47, 27 and 23 months, respectively. Conclusions: Complete metastasectomy of multi-site CRC is feasible and safe. However, disease will recur in the majority of patients. The impact to aggressive multi-site metastasectomy is modest but may provide OS benefit in selected patients.