tbuckley/cabot-search huggingface dataset:
Optimal testosterone suppression on medical ADT should strive to suppress free testosterone levels to levels similar to orchiectomy: What is that value?
Authors: Evan Y. Yu, Robert H. Getzenberg, Jordan Smith, Michael L. Hancock, Matthew Raymond Smith, S. Bruce Malkowicz, Paul Sieber, James T. Dalton, Mitchell S. Steiner
Journal: Journal of Clinical Oncology (2014)

144 Background: The goal of medical androgen deprivation therapy (ADT) for advanced prostate cancer is to provide an equivalency to orchiectomy based upon older assays for serum testosterone (T). Literature shows that based on more modern assays, medical ADT does not always provide optimal total T suppression equivalent to orchiectomy. With the understanding that free, or unbound, T is the biologically and clinically relevant component, the therapeutic goal of ADT should be to decrease free T to levels similar to orchiectomy. Free T has not been well studied in a substantial number of orchiectomized men. The purpose of this study was to examine a subpopulation of orchiectomized men in a clinical trial to determine the level of serum-free T in advanced prostate cancer. Methods: Baseline data was utilized from a double blind, randomized, placebo controlled trial (G300203) to determine the capacity of toremifene 80 mg to prevent bone fractures in men on ADT. This study included 1,389 men from 150 sites in the U.S. and Mexico. Baseline characteristics, including whether men were on medical ADT or status post orchiectomy, were available. Free T levels were assayed at baseline by radioimmunoassay (RIA) (Diagnostic Products Corporation) and are reported for men who underwent orchiectomy. Results: A subpopulation of 114 men underwent orchiectomy. Median age was 76 (range 51 to 90). Median serum free T level was 0.92 pg/ml (min. 0.35 pg/ml and max. 33.95 pg/ml) with a mean level of 1.71 pg/ml ± 2.77. Conclusions: This study is believed to be the largest cohort in which free T levels have been reported in men who underwent orchiectomy. In this cohort, median serum free T is approximately 0.9 pg/ml. This value could be considered to be the optimal testosterone suppression of free T with orchiectomy and represents the goal of medical ADT. At the time this study was performed, RIA was considered to be the standard but has since been shown to underestimate free T levels by 20 to 60%. Currently, equilibrium dialysis coupled with LC-MS/MS is the gold standard, but the results from this analysis provide us with increased understanding of the optimal level of free T in treating advanced prostate cancer. Clinical trial information: NCT00129142.
Randomized, open-label trial of gemcitabine/nab-paclitaxel (G/NP) ± pamrevlumab (P) as neoadjuvant chemotherapy in locally advanced, unresectable pancreatic cancer (LAPC).
Authors: Vincent J. Picozzi, Flavio G. Rocha, Scott Helton, Michael J. Pishvaian, Patrick G Jackson, Kabir Mody, Horacio Asbun, Mairead Carney, Tina Etheridge, Thomas B Neff, Seth Porter, Ming Zhong, Frank Valone, Elias Kouchakji, Joanne C. Imperial, Ewa Carrier
Journal: Journal of Clinical Oncology (2017)

365 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stroma and connective tissue growth factor (CTGF) overexpression. Although prolonged overall survival (OS) can be achieved through resection, only approximately 15% to 20% of patients are treated with surgery. Previously, pamrevlumab (P), a fully human monoclonal antibody blocking CTGF, was combined with gemcitabine/erlotinib (G/E) in a study of advanced PDAC. P plasma levels of &gt; 150 μg/mL and low baseline CTGF levels resulted in prolonged OS. We hypothesize that neoadjuvant (NA) treatment of LAPC with P + G/nab-paclitaxel (NP) may alter LAPC’s stroma, increase R0 resectability, and improve OS similar to that of patients resectable at presentation. Methods: LAPC subjects, confirmed by NCCN criteria and staging laparoscopy, were randomized 2:1 to G/NP ± P for 6-cycle/24-week treatment. Safety and efficacy (resection rate, OS, progression-free survival, tumor response) were assessed. Resection was performed in subjects who met protocol-defined criteria with no contraindications. Results: As of 26 Sep 2016, 25 subjects were enrolled. Of 14 subjects in Arm A (G/NP + P), 7 completed, 2 discontinued. Of 11 subjects in Arm B (G/NP), 4 completed, 4 discontinued. 6 subjects (43%) in Arm A and 4 (36%) in Arm B experienced SAEs; no P-related SAEs were reported. Out of 7 eligible Arm A subjects, 3 were not resected. Successful resection was achieved in 4 Arm A subjects (3 R0, 1 R1) and 1 Arm B subject (R0) (Table). Conclusions: The combination of G/NP + P is feasible and well-tolerated with no incremental safety signals in this study. The addition of P suggests a trend toward increased resectability among LAPC subjects. Clinical trial information: NCT02210559. [Table: see text]
The role of serum osteopontin (OPN) as a prognostic and predictive marker in patients with advanced gastric cancer.
Authors: O. Yazici, H. Akbulut, N. Akgun, G. Utkan, B. Yalcin, F. Icli
Journal: Journal of Clinical Oncology (2011)

e14627 Background: Osteopontin (OPN), a phosphorylated sialoprotein, is overexpressed in a variety of cancers including gastric cancer. OPN has been reported to be related with lymphatic metastases and prognosis. In this study, we aimed to study the predictive and prognostic role of OPN as a tumor marker in patients with advanced gastric cancer. Methods: A total of 42 consecutive chemonaive patients with advanced gastric cancer (ECOG performance status < 3) and 29 healthy controls were included in the study. All the patients were treated with a modified DCF (docetaxel 60 mg/m2 d1, cisplatin 60 mg/m2 d1 and 5-florouracil 600 mg/m2 d1-4 CI, q3w) chemotherapy regimen. The blood samples were obtained before each chemotherapy cycle from the patients and once from the healthy controls. The serum OPN measured by ELISA. Results: The overall response rate and disease stabilization rate were 25% and 72%, respectively. The median overall survival time was 7.0 ± 1.1 (95% CI: 4.9–9.2) months. The serum OPN was found to be a better tumor marker than either CEA or CA 72-4 in patients with advanced gastric cancer (ROC analysis: AUCOPN= 0.992; p<0.00001; AUCCEA=0.735, p=0.085; AUCCA72-4=0.600, p=0.745). The performance status and serum OPN levels were found to be significant factors for overall survival in the multivariate analysis (p=0.001 and 0.009, respectively). The serum OPN was a significant predictor of DCF response (OPNlow (≤310 ug/dL): 47% vs OPNhigh (>310ug/dL): 0%, p=0.026). Conclusions: The serum OPN seems to be a prognostic factor in patients with advanced gastric cancer. The predictive role of OPN in advanced gastric cancer patients on DCF chemotherapy regimen is needed to be supported with further clinical trials.
Evaluating the safety of abiraterone acetate (AA) and docetaxel (D) administered in combination in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Scott T. Tagawa, David M. Nanus, Edwin M. Posadas, Daniel Peter Petrylak, Justine Yang Bruce, Emerson A. Lim, Weimin Peng, Raymond Scott Maul, Martha Gonzalez, Namphuong Tran
Journal: Journal of Clinical Oncology (2014)

205 Background: D and AA may have complementary mechanisms of action; coadministration may be beneficial. A phase Ib study assesses the safety of escalating doses of D + AA. Methods: Up to4 cohorts (C) of chemo-naïve mCRPC pts would receive D + AA. Data for C1 and C2 are presented. Primary end point: proportion of pts with dose-limiting toxicity (DLT) between Wks 2 and 7, defined as grade (Gr) ≥ 3 non-heme toxicity, Gr 4 neutropenia (absolute neutrophil count &lt; 500/mm 3 ) &gt; 7 days (or febrile neutropenia), Gr 4 thrombocytopenia, or other intolerable toxicity. D + AA was deemed safe if ≤ 33% of pts experienced DLT. Pharmacokinetic (PK) parameters were evaluated for D and AA alone and in combination. Results: 15 pts were treated and 6 pts/C were evaluable for DLT assessment. 2 DLTs were observed in C1, and 1 in C2. 73% and 87% of pts had confirmed ≥ 90% and ≥ 50% prostate-specific antigen (PSA) decline, respectively. Median time to PSA progression has not yet been reached. Systemic exposure, based on maximum plasma concentration (C max ) and area under the concentration–time curve [(AUC) ∞ for D, AUC 24 for abiraterone (ABI)], was comparable for both D and AA alone and for D + AA. 3 pts in C3 (D 75 mg/m 2 + AA 1000 mg) have been treated past Wk 7 without DLT. Conclusions: D + AA was well tolerated in the cohorts tested. Preliminary results justify further evaluation of safety and efficacy in additional Cs. Clinical trial information: NCT01400555. [Table: see text]
Salvage brachytherapy for prostate bed recurrence following radical prostatectomy.
Authors: Kristin Smith, Jay P. Ciezki, Kevin L. Stephans, Chandana A. Reddy, Eric A. Klein
Journal: Journal of Clinical Oncology (2013)

218 Background: Approximately 10% of patients who undergo a radical prostatectomy (RP) for localized prostate cancer subsequently experience a local recurrence. A small percentage of these patients present with prostate bed nodules (PBN). We present here, a case series of 12 patients treated with low dose rate brachytherapy (BT) for a PBN post RP. Methods: All 12 patients had biopsy confirmed cases of recurrent adenocarcinoma in the prostatic bed. At the time of PBN diagnosis, 2 patients had received EBRT, 2 patients had received ADT, and 1 patient had undergone HIFU. Patients were confirmed to have a negative CT and bone scan prior to salvage BT. All patients received salvage BT with I-125 prescribed to 144 Gray. Results: The median interval between RP and BT was 8 years (range 0.5- 17.9), median PSA prior to BT was 4.53 ng/ml (range 0.55-15.2), and the median age was 69 (range 59-86). Forty-two percent of patients had a PBN Gleason score of 8, 33% had a score of 7, and a score was not reported for 25% of patients due to prior EBRT or ADT use. The median follow up for this series is 26.5 months (range 1-69). At the time of this analysis, 10 patients were evaluable for biochemical failure (bF) (nadir+2) and distant metastases (DM). The one and two year rates of bF were 0% and 52%. There was no association between pre-BT PSA and bF, nor between pre-BT Gleason score and bF. Two patients subsequently developed DM at 17 months and 55 months after BT. The pelvic lymph nodes were the site of DM for both patients. The median PSA velocity post BT was -0.120 ng/ml/yr (range -1.404- 9.096). Five patients had a negative PSA velocity at last follow-up, while 4 had an increasing PSA velocity. Velocity could not be defined for 3 patients (insufficient PSA n=2, ADT n=1). To date, no gastrointestinal or urinary toxicities have been noted. Conclusions: Brachytherapy as a salvage treatment for a PBN appears to be well tolerated. The rates of bF and DM following salvage BT are comparable to those of salvage EBRT for this patient population. Intermediate-term biochemical control was attained in a sub-set of patients with declining PSA at last follow-up.
Impact of a best practice alert on transfusion practices for solid tumor oncology patients.
Authors: Ryan Buck, Kelley Wachsberg, Charlotta Weaver, Lyndsey Dombrowski, Madeleine Ma, Jungwha Lee, Kevin O'Leary
Journal: Journal of Clinical Oncology (2016)

57 Background: Recent evidence supports a restrictive transfusion strategy in the majority of hospitalized patients, though transfusion practices for oncology patients remain highly variable. We evaluated whether use of a best practice alert for solid tumor oncology inpatients would result in more restrictive transfusion practices and impact patient outcomes. Methods: We conducted a retrospective, historical control analysis at a large academic hospital in Chicago, IL. We compared transfusion utilization among solid tumor oncology patients before and after implementation of a transfusion alert. Patients with active bleeding, hematologic malignancies and those undergoing surgical procedures were excluded. A best practice alert with clinical decision support encouraging use of a restrictive transfusion strategy (Hgb &lt; 7 g/dL) was implemented 6/14 with phase-in completed by 9/14. We abstracted PRE intervention medical records of patients hospitalized from 5/1/13 to 4/30/14 and POST intervention records from 9/1/14 to 8/31/15. Readmission rates, incidence of ICU transfer and inpatient mortality were also compared using multiple linear regression. Outcomes were adjusted for age, gender, race, BMI, smoking status and Charlson comorbidity index. Results: 1296 total patients were included in the analysis (PRE, n = 685; POST, n = 611). There were no differences in age, gender, BMI or Charlson comorbidity index among cohorts, although the PRE cohort included more Caucasians (60.2% vs. 46.8%, p &lt; 0.0001) and smokers (6.0% vs. 2.5%, p = 0.002). Packed red blood cells transfused per 100 patient-days were significantly lower in the POST-intervention cohort (3.8 vs. 6.4, p = 0.01). The POST-intervention cohort also had fewer 30-day emergency department visits (3.3% vs. 5.1%, p = 0.03). There were no significant differences in rates of 30-day readmission (34.6 % vs. 37.3%, p = 0.19), ICU transfer (0.5% vs. 1.1%, p = 0.08) or inpatient mortality (1.7% vs. 1.8%, p = 0.96). Conclusions: Implementation of a best practice alert among solid tumor oncology patients effectively reduced utilization of packed red blood cells without affecting patient outcomes.
Oncotype Dx in PR-negative tumors in light of the prognostic value of PR expression.
Authors: A. Shai, A. Rivkin, M. Leviov, M. Steiner
Journal: Journal of Clinical Oncology (2011)

e11092 Background: It was suggested that breast tumors that are ER positive / PR negative carry a worse prognosis than ER /PR positive tumors if treated only by adjuvant hormonal therapy. Most studies did not account for HER 2 expression. PR was assessed by methods that measure protein content. Oncotype Dx measures mRNA expression. In clinical trials the discrepancy between IHC and RT PCR for the expression of PR was about 20%, but this was not assessed in a community setting. The meaning of a high level of mRNA without detectable PR protein is unclear and might be due to technical issues or a biological mechanism such as translational inhibition by miRNA's. We sought to verify the prognostic value of the expression of the progesterone receptor by IHC in women with early stage HER 2 negative, ER positive BC treated with systemic hormonal therapy only and to characterize the results of Oncotype Dx in ER positive, PR negative HER 2 negative tumors. Methods: An historical prospective analysis of patients files. Results: Initial cohort: Files of 286 consecutive patients with ER positive HER 2 negative tumors that were treated by adjuvant hormonal treatment during 2000-2006 were reviewed. 82% of tumors were node negative. 80 were PR negative and 209 were PR positive. There were no significant differences between the groups with respect to nodal status or grade. After a median follow up of 7.24 years (0.78 to 9.5) 8 women with PR negative and 9 women with PR positive tumors experienced disease recurrence (10% vs 4.3%, RR 2.32, p 0.014). Second cohort: 58 PR negative tumors were testes by Oncotype Dx during 2007-2010. 24 (47%) were PR positive by RT PCR. Most (47.3%) were intermediate risk by the test, 36.9 were low risk and 15.8 were high risk. Of note, grade 3 tumors were more likely to be RT PCR negative for progesterone receptor (91% vs 40.5%) and high risk (35% vs 7.5%). Conclusions: In our hands ER positive PR negative HER 2 negative tumors carry a worse prognosis when treated by hormonal adjuvant treatment compared with ER/PR positive tumors. We found a high rate of discrepancy between IHC and RT PCR concerning PR expression. Most PR negative tumors are labeled intermediate risk. The value of the test in this setting is unclear.
Characterization of abiraterone responses in African American castrate-resistant prostate cancer.
Authors: Michael Stolten, Elisa M. Ledet, Allison H. Feibus, Brian E. Lewis, Jonathan L. Silberstein, Oliver Sartor
Journal: Journal of Clinical Oncology (2015)

203 Background: African American (AA) men have a higher incidence and mortality from prostate cancer (PCa) compared to other racial groups. Abiraterone acetate (Abi) is approved for treatment of mCRPC. While some AA patients were included in Abi trials, the majority of patients have been Caucasian (CA). To date, there have been no reports of Abi responses exclusively in AA men. This study evaluated Abi responses in AA men with mCRPC. Methods: PSA values during Abi treatment as well as baseline hemoglobin (Hgb), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were tabulated. Prior therapy with docetaxel (Doc) or enzalutamide (Enza) was recorded. PSA response, progression and duration were assessed and compared between racial groups. PSA response, duration of response, and progression were defined by PCWG2 criteria. PSA half-life (PSAHL) based on time to nadir was calculated to assess rate of PSA decline. Results: A total of 74 Abi patients with mCRPC (n = 20 AA; n = 54 CA) were assessed from a single institution. Median AA baseline Hgb, ALP, LDH, and PSA were 11.8 (r = 6.4-15.4), 220 (r = 88-713), 209 (r = 157-401), and 48.41 (r = 4.8-1460) respectively. Median CA baseline Hgb, ALP, LDH, and PSA were 12.35 (r = 7.6-15), 165.5 (r = 70-1699), 218 (r = 133-528), and 44.84 (r = 1.71-2890) respectively. There were no significant differences in baseline labs between AA and CA. Prior use of Doc or Enza was 30% and 5% for AA; 31% and 4% for CA. PSA response was not significant for PSA decline of &gt;30% (&gt;30%: AA = 40%; CA = 44%), &gt;50% (&gt;50%: AA = 35%; CA = 30%), or &gt;90% (&gt;90%: AA = 20%; CA = 9%). In addition, no significant differences between the time to nadir (AA median = 209 days; CA median = 218 days), rate of PSA decline (AA PSAHL median = 72.4 days; CA PSAHL median = 80.1 days), or time to progression was observed. The median treatment length was 278 days and median time to progression was 66 days for AA men; 264 days and 88 days for CA men. Conclusions: Abi response rates, duration of response, and time to progression were not statistically different in AA men compared to CA men in patients with mCRPC. Larger studies are needed to fully evaluate this observation.
Contribution of the epithelial-mesenchymal (EMT) phenotype to the sensitivity of colorectal cancer cell lines to the p21-activated kinase inhibitor, PF-3758309.
Authors: E. Im, T. M. Pitts, G. Kulikowski, A. Tan, J. J. Tentler, B. Murray, W. Carley, T. Smeal, C. Guo, S. G. Eckhardt
Journal: Journal of Clinical Oncology (2011)

438 Background: Increased expression of p21–activated kinase (PAK) family proteins has been observed in a range of malignancies including those of breast, ovarian, colorectal (CRC), and pancreatic origin. PAK (PAK 1-6) proteins are critical mediators of cell proliferation, motility, transcription, and translation. In initial studies, we demonstrated that the PAK4 inhibitor, PF-3758309, exhibited robust single agent efficacy against selected CRC cell lines, with IC 50 s of less than 0.015 uM, whereas some cell lines were relatively resistant to the agent, with IC 50 s of greater than 1 uM. In subsequent gene array analyses, CRC cell lines sensitive or resistant to PF-3758309 exhibited overexpression of core genes associated with a mesenchymal or epithelial phenotype, respectively. Thus, the goal of this study was to assess the functional consequences of altering the expression of EMT-associated genes and to seek rational combination partners in CRC. Methods: CRC cell lines that were sensitive to PF-3758309 (IC 50 =0.015 uM) were transfected with selected short hairpin- (sh)RNAs or micro-(mi)RNAs that are known to regulate EMT. Semi-quantitative RT-PCR and immunoblotting were performed to confirm target knockdown. The transfected cell lines were then exposed to increasing concentrations of PF-3758309 to determine the functional role of these genes in conferring responsiveness to PF-3758309. Results: Sensitive CRC cell lines were transfected with shRNAs to Zeb1, vimentin, and caldesmon, genes that are associated with a mesenchymal phenotype. Interestingly, when the cell lines were exposed to increasing concentrations of PF- 3758309 they demonstrated a ′right shift′ towards a more resistant phenotype. Likewise, transfection with miRNA 200c, a known suppressor of Zeb1, resulted in a similar shift towards resistance. Conclusions: These data suggest that the EMT phenotype may play a functional role in determining CRC sensitivity to the PAK4 inhibitor PF-3758309, and in addition, a rational combination targeting the epithelial phenotype with epidermal growth factor receptor inhibitors, may be warranted. [Table: see text]
Can protocol development improve breast cancer and breast surgery quality measures?
Authors: Laila Samiian, Ricardo Rivera-Fernandez, Katherine Puckett, Jilma Patrick, David Chesire
Journal: Journal of Clinical Oncology (2014)

119 Background: Since 2009, UF Health Jacksonville has made significant changes in the Breast Cancer Program. These changes spanned across multiple specialties and have focused on creating protocols, guidelines, checklists, and policies for the management of breast cancer. This study evaluated the effect of standardized institutional protocols on breast cancer quality measures. Methods: Tumor registry was used to identify 350 patients who were diagnosed and treated at UF Health Jacksonville for breast cancer from 2006-2012 (Stage 0-III excluding LCIS). A retrospective review of electronic health records was performed to compare the achievement of quality measures 2 years before program development (6/2006 – 6/2008) to that of 2 years after program development (6/2010 -6/2012). Results: There were significant improvements in breast cancer diagnosis and surgical treatment quality measures after establishment of standardized protocols. Performance of pre-surgical needle biopsies regardless of diagnostic outcome (90% vs. 96%, p=0.02), and diagnosis of carcinoma via needle biopsy (50% vs. 87%, p=0.04) both showed significant improvement. More patients underwent sentinel lymph node biopsy post-protocol (43% vs. 68%, p&lt;0.001). There was improvement in surgical specimen orientation (58% vs. 88%, p&lt;0.001), and image confirmation of the specimen post-protocol (86% vs. 97%, p=0.01). There was a reduction of second or additional operations (44% vs. 26%, p=0.004), which included a significant reduction in lumpectomy re-excisions for margins (30% vs. 14%, p=0.003). There was a non-significant improvement in attempted (64% vs. 71%, p=0.17), and successful breast conservation surgery (57% vs. 65%, p=0.10). There were no significant changes in the rates of recommendation for adjuvant radiation, endocrine, or chemotherapy. There was no improvement in patient adherence to the recommended adjuvant therapy based on protocol implementation. Conclusions: Implementation of standardized institutional protocols can significantly increase achievement of quality measures in breast cancer diagnosis and surgery. However, these protocols did not have a significant effect on systemic therapy or radiation therapy quality measures.