tbuckley/cabot-search huggingface dataset:
Pharmacodynamic and pharmacokinetic characterization of tumor proliferation during acute sunitinib (SU) withdrawal.
Authors: B. H. Chao, M. R. Harrison, J. Kolesar, M. Vanderhoek, S. Perlman, J. C. Eickhoff, L. Carmichael, D. B. Alberti, G. Wilding, R. Jeraj, G. Liu
Journal: Journal of Clinical Oncology (2011)

e13556 Background: We have shown that nearly all patients with solid tumors have an increase in tumor proliferation during acute withdrawal of SU as quantified by FLT PET/CT imaging. We hypothesize that this results from compensatory increases in proangiogenic factors such as VEGF and HIF1-α during SU exposure. We conducted this study to understand the contribution of plasma VEGF, HIF1-α, and PKs to withdrawal flare. Methods: Pts with advanced solid cancers and no prior anti-VEGF therapy were enrolled. SU was given at 50 mg QD using standard 4:2 (Part A) or alternative 2:1 (Part B) schedule. SUVmean from FLT PET/CT scans, plasma SU, SU metabolite, VEGF, and HIF1-α were measured at baseline, peak SU exposure, and after SU withdrawal (A: baseline, wk 4, wk 6; B: baseline, wk 2, wk 3). Changes in parameters over time were evaluated using a paired t-test and nonparametric Wilcoxon signed rank test. Multivariate regression analysis was conducted to evaluate the association between changes in PK and PD parameters. Results: Of 25 pts enrolled (A: 14, B: 11), complete data were available for 8 in Part A and 5 in Part B. During SU exposure: plasma SU, SU metabolite, and VEGF increased, while SUVmean decreased. Likewise, during SU withdrawal: plasma SU, SU metabolite, and VEGF decreased, while SUVmean increased (Table). No significant difference in HIF1-α was observed. Change in VEGF during SU exposure was identified as a statistically significant independent predictor for change in SUVmean after SU withdrawal (r=0.90; p=0.002) from change in HIF1-α and change in SU concentration. Conclusions: Upregulation of plasma VEGF during SU exposure independently predicts tumor proliferation after withdrawal as evidenced by an increase in SUVmean. An ongoing study (NCT01243359) sequences SU with the VEGF mAb bevacizumab in an attempt to block the withdrawal flare. SU exposure SU withdrawal A B A B Median D Range Median D Range Median D Range Median D Range SU (ng/mL) 63* 37–184 62* 32–162 -59* -181–32 -51* -104–23 SU metabolite (ng/mL) 20* 14–39 21* 4.8–52 -18* -29–5.3 -16* -26–0.76 VEGF (pg/mL) 168* 51–461 100* 18–361 -184* -448–22 -96* -253–26 SUVmean (% difference) -16* -100–0 -18* -64–6.3 15* -14–277 19* -5.3–200 * p <0.05
Quality of life and adverse drug reaction measured in patients undergoing cancer chemotherapy.
Authors: Harminder Singh, Raja Banipal, Ritu Bala
Journal: Journal of Clinical Oncology (2014)

214 Background: Cancer prevalence in India is estimated around 2.0-2.5 million, 0.7- 0.8 million new cases identified every year, and cancer deaths reported per year is 0.4-0.5 Million. The objective of this study was to analyze and compare patient-reported QoL (quality of life), and their physical/psychosocial symptom and adverse drug reaction in cancer patients. Methods: Study done by questionnaire EORTC QLQ-C30. Comparison among 3 distinctive groups (G) (varied number of Chemotherapy cycles) was done. ADR measured appropriately Results: 131 patients were recruited and QoL scoring GHS (global health status) and 4 items of symptom scale i.e. insomnia, pain, appetite loss, constipation, and financial difficulties attained a significance difference. GHS significantly improved in G3 as compared to G1, indicating that the patient overall health improved as the chemotherapy sessions progressed. Female patients had more ADR (mean 3.2/person) and G3 had more ADR (mean 3.96). Conclusions: QoL score didn’t show significant improvement in all areas (except insomnia, pain, appetite loss, constipation &amp; financial difficulties), a judicious diagnosis with an appropriate treatment including chemotherapy may lessen the negative perception of cancer. [Table: see text]
The Adverse Impact of Age and Central Nervous System Involvement on Survival in Adult T-ALL, an Analysis of 92 Consecutive Patients
Authors: Hassan B Alkhateeb, Moussab Damlaj, Tasha Lin, Mehrdad Hefazi, Aref Al-Kali, Naseema Gangat, William J. Hogan, Michelle Elliott, Grzegorz S. Nowakowski, Carrie Thompson, Thomas E. Witzig, Stephen M Ansell, Mark R Litzow, Mrinal M Patnaik
Journal: Blood (2015)
Characterization of patients who present with de novo metastatic prostate cancer: Single-institution database analysis.
Authors: Jessica Strock, Kathryn P. Gray, Mari Nakabayashi, Carolyn Evan, Elizabeth O'Donnell, Mark Pomerantz, Philip W. Kantoff, Christopher Sweeney
Journal: Journal of Clinical Oncology (2013)

33 Background: Less than 5% of men in a PSA screened population present with denovo metastatic prostate cancer. We sought to characterize the clinical characteristics and survival of this unique group of men. Methods: Retrospective analysis of an institutional data-base – Dana Farber Cancer Institute - Prostate Clinical Research Information Systems (CRIS). All men with metastatic disease as their first presentation of prostate cancer were identified. Patient and disease characteristics were summarized descriptively. The distributions of the study endpoints were estimated using the Kaplan-Meier method with median and 95%CI reported. Results: The analytic cohort has 185 patients with a median follow-up of 7.8 years (95% CI:7.5,11.1) and 94% diagnosed after 1998. Median age at diagnosis is 62 years (Range: 42-86); PSA at diagnosis: Median (Q1-Q3) - 100.2 (23.0, 346.0). Metastases: 97% bone, 2% liver, 2% lung, 8% lymph node. The median time from metastasis diagnosis to start of androgen deprivation therapy (ADT) was 26 days, 139 of those who started ADT had subsequently started treatment for castration resistant prostate cancer (CRPC) - 2 nd line hormonal therapy and/or chemotherapy. The median time from ADT to subsequent therapy for CRPC is 14 months with 95% (CI:12,16). 128 patients have died and the median overall survival is 48 months (95% CI:40, 51). Conclusions: This unique cohort of patients at a referral institution tend to be younger and have an overall survival comparable to outcomes in modern day randomized hormone sensitive prostate cancer studies. Assessment of similar group in a multivariate analysis of a prospective trial is needed to confirm this observation. If confirmed, the data would suggest the responsiveness to therapy drives outcome rather than development of metastasis with or without a previously treated primary.
Imaging characteristics and response after intraarterial administration of the oncolytic herpes virus NV1020 to treat hepatic colorectal metastases
Authors: D. Y. Sze, S. S. Gambhir, R. S. Chari, D. A. Geller, A. Iagaru, A. Mescheder, J. J. Nemunaitis, T. R. Reid, K. Tanabe
Journal: Journal of Clinical Oncology (2008)

15121 Background: Tumor response to oncolytic viruses may show atypical imaging characteristics compared with other agents. Methods: NV1020, a replication-competent attenuated herpes simplex virus, was administered in an open-label Phase I/II study. Patients had liver-dominant metastatic colorectal carcinoma, failed multiple FDA-approved chemotherapies, and were seropositive for HSV1. Dose-escalation phase was followed by cohort expansion at the highest dose (1×10e8 pfu). Four weekly doses of NV1020 were administered by hepatic arterial infusion without chemotherapy, followed by at least two cycles of systemic chemotherapy alone. CT and FDG-PET were performed at screening, after completion of 4 viral infusions, after second cycle of chemotherapy, and every 3 months thereafter. Images were reviewed by independent radiology and nuclear medicine readers, and response was graded by WHO, RECIST, and EORTC criteria. Results: 13 patients were enrolled in the dose escalation phase and 19 more in the high-dose expansion. 7 of 10 patients who received lower doses showed progressive disease (PD) by size criteria at the conclusion of viral infusions, but 3 of these showed subsequent regression after 2 cycles of chemotherapy. 11 of 21 high-dose patients also reached PD after viral infusions, but of these 11, 5 of 8 evaluable patients subsequently showed regression. After viral infusion, some tumors exhibited altered rim enhancement, and magnitude of CT changes exceeded increase in SUV measured by PET in half of the patients after viral infusions, suggesting a complex mechanism other than simple tumor growth. Using the post-viral infusion CT scan as an adjusted baseline, of 14 evaluable high-dose patients, 2 (14%) have shown PR, 9 (65%) SD, and 3 (21%) PD. Conclusions: NV1020 appears to exhibit biological activity when administered intraarterially to hepatic metastases from colorectal carcinoma. Biological activity of oncolytic viruses may manifest as changes in contrast enhancement and paradoxical increase in tumor size. Initial size increase is not necessarily indicative of progressive disease and treatment failure, and traditional WHO and RECIST criteria may be inadequate metrics for assessment of response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration MediGene MediGene, AG
Evaluating the confluence of oncology market trends and key levers to drive payment and delivery reform for treatment of multiple myeloma.
Authors: Jenna Waltersdorf, Lauren G. Barnes, Fauzea Hussain, Kristi Mitchell
Journal: Journal of Clinical Oncology (2014)

45 Background: A multi-factorial focus on treatment costs and the incremental improvement in outcomes has accelerated interest in payment and delivery reform in oncology, specifically a shift from fee-for-service to fee-for-value. As the landscape continues to evolve, there are key levers that will accelerate reform for specific cancer types. Our objective was to examine how broad oncology market trends and key levers for multiple myeloma (MM) intersect to drive payment and delivery reform. Methods: We evaluated 18 oncology market trends, classified the pervasiveness of each as nascent, emerging, or widespread, and assessed trends for specificity to MM compared to other cancers. We then evaluated six key levers that, within the context of each trend, may ripen MM for payment and delivery reform. Levers included 1) national guidelines; 2) quality measures; 3) prevalence/incidence relative to other cancer types; 4) advanced imaging or other high-cost treatment expenditures; 5) drug/biologic contribution toward treatment costs; and 6) approved companion diagnostic(s). Results: While some guidelines exist to address treatment of MM, there are gaps in recommendations that do not address the full continuum of care to guide physician decision making, giving this lever low influence to drive reform. One measure for quality improvement has been used at a broad national level, giving this lever moderate influence on reform. Today, characteristics of MM that trigger key levers make MM an unlikely focus for widespread reform initiatives. Conclusions: Most oncology market trends are cancer-type agnostic, but trend pervasiveness and their confluence with key levers will dictate the shape of alternative payment models for changes to treatment delivery and reimbursement. By developing additional quality measures and addressing guideline gaps, stakeholders may further trigger two key levers to ripen MM for payment and delivery reform. Reform initiatives may be expedited as additional treatment options are introduced to the market, and as stakeholders work to influence key levers and evaluate the feasibility for and implementation new payment and delivery models for MM.
Functional analysis of PARP inhibitors AZD 2281 and BSI-201 in human tumor primary cultures: A comparison of activity and examination of synergy with cytotoxic drugs.
Authors: R. A. Nagourney, K. R. Kenyon, F. R. Francisco, P. J. Bernard, S. S. Evans
Journal: Journal of Clinical Oncology (2011)

e13599 Background: Poly(ADP-ribose) polymerases (PARP) are activated in response to cellular injury. DNA damage from radiation and cytotoxic drugs results in the up-regulation of PARP 1/2, leading to base excision repair. PARP inhibition enhances chemotherapy and induces cell death by synthetic lethality in patients with deficient homologous repair (BRCA1/2 and ATM). PARP inhibitors in development include benzamides, phthalazinones and benzimidazoles. Our work with 3-aminobenzamide (3-AB) led to the study of BSI-201 and AZD 2281, in human tumor micro-spheroids, isolated from surgical specimens and cytologically (+) fluids. Methods: Delayed loss of membrane integrity, morphologic and metabolic measures of drug-induced programmed cell death (EVA/PCD) were applied in 45 human tumor specimens exposed to PARP inhibitors, alone and in combination with cytotoxics. Lethal concentrations (LC50) were interpolated from 5-point dose response curves. Synergy was assessed by median effect. Drug activity comparisons were performed by modified Z-score. Results: PARP inhibitors are active in human tumor micro-spheroids. Activities for AZD 2281 and BSI-201 are superior to 3AB favoring BRCA1/2 and triple-negative (TN) breast over wild type and ER/PR (+); (AZD avg LC50 12 vs. 60 ug/mL; BSI avg LC50 19 vs. 30 ug/mL). AZD2281 and BSI-201 reveal synergy with CDDP, CDDP and gemcitabine, and alkylators. Of interest, BSI-201 and AZD-2281 activity did not correlate in parallel analyses (Pearson Moment, r = 0.07, P > 0.5). A comparison of BSI-201 and AZD 2281 activity with CDDP or taxol, suggested correlation with CCDP but not with taxol. Conclusions: 1) PARP inhibitors are active in human tumors favoring BRCA1/2 and TN breast. 2) Favorable interactions with DNA damaging agents are observed. 3) Activity profiles correlate more strongly with CDDP than taxol. 4) Direct comparisons suggest somewhat different activity profiles for BSI-201 vs. AZD-2281. 5) Individual activity/synergy profiles may provide opportunities for patient selection in the development of novel PARP combinations. Analyses in BRCA 1/2 and TN breast cancers are ongoing. Supported by The Vanguard Cancer Foundation and The Nagourney Institute.
Comparison of MammaPrint and TargetPrint with clinical parameters in patients with breast cancer: Findings from a prospective U.S. cohort.
Authors: K. B. Deck, R. Sinha, D. Kerlin, J. Barone, E. Rivera, A. A. Garcia, K. Yao, L. Stork-Sloots, R. A. Bender, B. Nguyen
Journal: Journal of Clinical Oncology (2011)

e11094 Background: The MammaPrint 70-gene expression profile (MP) is a powerful predictor of disease outcome in early stage breast cancer. In addition, TargetPrint (TP), a microarray-based test that measures the mRNA expression level of ER, PR and HER2 was developed. In the present study, MP was measured in a prospective U.S. breast cancer patient cohort to determine how MP compares to treatment advice according to NCCN consensus guidelines and how TargetPrint results compare to IHC/FISH. Methods: MP results were evaluated in fresh tumor samples from 111 breast cancer patients (T1-4N0-2; median age 62 [39 -97 yr]) collected by core needle biopsy or from a surgical specimen between July 2008 and November 2010. We compared treatment advice as recommended by NCCN guidelines and classification according to MP. A direct comparison was also made between MP and the Oncotype DX (ODX) assay in a small subset of patients. In addition, we compared IHC/FISH ER, PR and HER2 assessments with TP. Results: According to NCCN treatment recommendations, 6 patients should receive adjuvant endocrine therapy: 5 of these patients were classified as High Risk and 1 as Low Risk by MP. For another 5 patients, NCCN recommendations could not be determined due to a missing clinical parameter (all high risk by MP). For the remaining 100 patients, NCCN guidelines recommends (n=46) or suggests to consider (n=54) adjuvant chemotherapy (CT): 24 of these patients were classified as MP Low Risk and the remaining as MP High Risk. Comparison of TP with IHC/FISH indicated a concordance of 98% for ER, 90% for PR, and 93% for HER2. For 19 patients the ODX assay was also performed, resulting in 4 patients classified as low risk ODX: 3 are MP High Risk and 1 is MP Low Risk. Fifteen patients classified as intermediate risk ODX; 14 were High Risk MP and 1 was Low Risk MP. Conclusions: For the 100 (94%) out of 111 patients from 7 US hospitals, NCCN guidelines either recommended or suggested considering adjuvant CT. In contrast, MP indicated a Low Risk of recurrence in 24 of these cases. Integration of MP into clinical risk assessment could improve the management of early-stage breast cancer and avoid unnecessary CT for Low Risk patients.
Racial variation of leptin levels in women with breast cancer.
Authors: T. P. Avery, K. R. Sexton, A. Brewster, R. El-Zein, M. Bondy
Journal: Journal of Clinical Oncology (2011)

1590 Background: Incidence of breast cancer is lower in African-American women than White women, but African-American women have worse survival and represent a greater proportion of young women. Obesity is a factor in disparities. Leptin and adiponectin, hormones produced by adipose tissue, are active in breast cancer cell lines and correlate with tumor characteristics. Leptin has mitogenic effects in vitro and increases with obesity; adiponectin has inhibitory effects and decreases with obesity. Studies suggest that adipocytokine levels differ by race, adjusted for body mass index (BMI). In a small study of adipocytokine levels by race in women with breast cancer, we found that African-American women had higher levels of adipocytokines, adjusted for BMI. There was also a correlation between tumor grade and adipocytokine levels. In this study, we examined a larger number of women to replicate these findings. We measured adipocytokine levels in African-American and White women with breast cancer and correlated tumor characteristics with adipocytokine levels. Methods: We performed a retrospective case-case study of 164 African-American and 172 White breast cancer patients. Adiponectin and leptin levels were measured in serum by ELISA. Records were abstracted for BMI, age, stage, grade, ER/PR, and Her-2 neu status. Adipocytokine levels were compared between races by Chi-square analysis and adjusted for BMI. Results: Mean leptin levels were higher in African-American women, adjusted for BMI (p<0.001). There was a trend toward triple negative tumors with higher leptin levels (p==0.06). There was a correlation between younger age and premenopausal status with lower adiponectin levels, adjusted for BMI. Women aged 60 had higher adiponectin levels than women aged 40-49, (p==0.002). Premenopausal women had lower adiponectin levels (p==0.01). Conclusions: Our findings suggest that leptin levels may differ by race in women with breast cancer, adjusted for BMI. Higher levels of leptin may correlate with triple negative tumors. We found that younger women have lower levels of adiponectin, which may play a role in breast cancer in young women. With further study, differences in leptin may prove to be a biologic cause of some of the observed disparities in breast cancer.
Effect of early detection of asymptomatic visceral recurrence after radical cystectomy on prognosis in patients with muscle invasive bladder cancer.
Authors: Shingo Hatakeyama, Hayato Yamamoto, Atsushi Imai, Takahiro Yoneyama, Yasuhiro Hashimoto, Takuya Koie, Ayumu Kusaka, Chikara Ohyama
Journal: Journal of Clinical Oncology (2015)

361 Background: It is unknown whether routine follow-up with computed tomography (CT) to detect asymptomatic visceral recurrence after radical cystectomy improves patient survival. We accessed the impact of symptoms at recurrence on patient survival after radical cystectomy and survival after recurrence. Methods: A total 348 radical cystectomy for muscle invasive bladder cancer (MIBC) were performed at our institution between January 1996 and December 2013. All patients had regular followup examinations with urine cytology every 3 months, blood biochemical test, and CT of the chest and abdomen every 6 months. Additional examinations were required for symptomatic recurrence. We investigated the first site and date of tumor recurrence. Overall survival in patients with recurrence stratified by the mode of diagnosis (asymptomatic vs. symptomatic) was estimated using the Kaplan-Meier methods and compared with the log rank test. Cox proportional hazard regression models were used to evaluate the impact of the mode of diagnosing recurrence on survival. Results: A total 91 patients (20%) experienced recurrence after surgery. Seven patients (8%) were excluded due to missing data. Finally, 84 patients were enrolled in this retrospective study. Of those, 46 (55%) were asymptomatic and 38 (45%) were symptomatic. Recurrence sites included lymph nodes in 46 patients (55%), local recurrence in 23 (27%), bone in 14 (17%) and visceral organs in 21 (25%). The most common symptoms at recurrence were pain in 20 patients (53%). Overall survival after radical cystectomy and recurrence were significantly shorter in patients with asymptomatic recurrence. The median survival after surgery and after tumor recurrence in patients with asymptomatic vs. symptomatic recurrence were 33 and 14 vs. 13 and 5 months, respectively (P=0.0142 and P=0.0001). Multivariate analysis showed that a symptomatic recurrence was one of the independent factors for overall survival after surgery and recurrence. Conclusions: Routine CT followup after radical cystectomy for early detection of asymptomatic recurrence may contribute better prognosis in patients with MIBC.
Identifying men at greatest risk of weight gain from androgen deprivation therapy.
Authors: Daniel Martin Seible, Xiangmei Gu, Andrew Hyatt, Clair Beard, Jason Alexander Efstathiou, David Tomoaki Miyamoto, Timur Mitin, Neil E. Martin, Joshua Beckman, Shehzad Basaria, Paul Linh Nguyen
Journal: Journal of Clinical Oncology (2014)

80 Background: Androgen deprivation therapy (ADT) is a mainstay of prostate cancer therapy. Weight gain is among the adverse metabolic changes associated with ADT, and may contribute to cardiovascular comorbidity. A better understanding of the risk factors for weight gain on ADT is important for optimal management of ADT-associated morbidity. Methods: A retrospective review assessed weight change among 118 men with nonmetastatic prostate cancer treated with ADT. The primary endpoint was weight change at one year from ADT initiation, with the secondary aim to stratify risk of weight gain by baseline patient characteristics. Statistical analyses were performed using two-tailed t-tests and linear regression. Results: Men in our cohort exhibited a significant increase in weight (p=0.0005) in the one year following ADT initiation. Three risk factors for weight gain on ADT were identified: younger than age 65 (5.98 pounds gained, p=0.001 vs. 1.63 pounds, p= 0.09 for age 65+), body mass index (BMI) less than 30 (4.36 pounds gained, p=0.00002 vs. 0.22 pounds, p=0.87 for BMI 30+), and non-diabetic status (3.43 pounds gained, p=0.0003 vs. 0.57 pounds, p=0.74 for diabetics). An aggregate risk scoring system was contrived to allow for weight change prediction by total number of risk factors present: scores of 0, 1, 2, and 3 risk factors corresponded to weight changes of -2.42 (p=0.43), +0.9 (p=0.56), +2.9 (p=0.01) and +8.3 pounds (p= 0.0001) respectively. Weight gain increased significantly with increasing risk score (p-trend= 0.0005), decreasing baseline age (p-trend= 0.004) and decreasing baseline BMI (p-trend= 0.01). Conclusions: Younger than age 65, BMI less than 30, and non-diabetic status were each significantly associated with weight gain one year after starting ADT. Increasing weight gain was strongly associated with increasing number of baseline risk factors. Although metabolic consequences were previously considered most significant for patients with preexisting comorbidity, these data suggest younger, slimmer, and non-diabetic patients may be at higher risk for gaining weight on ADT. As these three categories of men generally have higher endogenous testosterone (T) levels prior to ADT compared to older, obese, and diabetic men, the magnitude of T decline following ADT might explain these findings.