tbuckley/cabot-search huggingface dataset:
Poor prognostic features in angiosarcoma: A single institution retrospective study of 324 patients.
Authors: Sandra P. D'Angelo, Nicole H. Moraco, Li-Xuan Qin, Deborah Kuk, Richard D. Carvajal, Mark Andrew Dickson, Mrinal M. Gounder, Mary Louise Keohan, Cristina R. Antonescu, Samuel Singer, Gary K. Schwartz, William D. Tap
Journal: Journal of Clinical Oncology (2013)

10580 Background: Angiosarcoma (AS) is a rare, malignant endothelial cell tumor of vascular origin with a five year overall survival (OS) of approximately 35%. It is a heterogenous disease whose natural history is poorly defined. We sought to identify clinical and treatment outcomes to better define this disease. Methods: In a retrospective study using an institutional sarcoma database, we identified all patients(pts) with AS treated at Memorial Sloan-Kettering Cancer Center between 1992-2011 and collected their correlative clinical information.Kaplan-Meier method and Cox’s proportional-hazard models were used to determine OS and prognostic factors. Hazard ratios (HR) are listed with their 95%confidence intervals (CI). Results: We identified 324 pts, median age was 63 (range 15-94), 127(39%) were men. At presentation, 188 (58%), 19 (6%) and 117(36%) had localized disease (L), local recurrences (LR) or distant metastases (M), respectively. L sites included: RT breast 43 (23%,) head&amp;neck 33 (18%,) scalp 30 (16%,) breast 26 (14%,) extremity 23 (12%,) abdomen/pelvis 14 (7%,) thorax 10 (5%) and trunk 9 (5%). The median OS is 3.3 years (2.44-4.33) for pts w L disease and 0.89 years (0.74-1.11) for pts with M disease. Among pts that presented with L disease, 29% had a LR and the median local relapse free survival (RFS) time was not reached (8.71-NA); 31% had distant recurrences with a median distant RFS of 12.8 yrs (4.13-NA.) Among L disease patients, older age (HR 1.04, 1.03-1.06, p &lt;0.0001) and site were independent predictors of decreased OS. Visceral tumors arising in the abdominal/pelvis (AP) (HR 2.89, 1.27-6.61, p = 0.012) had worse OS compared to those arising the breast. Conclusions: AS remains an aggressive, heterogenous malignancy with poor OS and high rates of local and distant recurrences. Patients with M disease do poorly. Adverse prognostic factors include AP visceral tumors and older age. These factors could be helpful for stratification in future clinical trials. The identification of genomic differences is necessary to define therapeutic targets in AS.
Targeting hyaluronan (HA) in tumor stroma: A phase I study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of pegylated hyaluronidase (PEGPH20) in patients with solid tumors.
Authors: Mitesh J. Borad, Ramesh K. Ramanathan, Alberto Bessudo, Patricia LoRusso, Harold Michael Shepard, Daniel C. Maneval, Ping Jiang, Joy Zhu, Gregory I Frost, Jeffrey R. Infante
Journal: Journal of Clinical Oncology (2012)

2579 Background: HA, a glycosaminoglycan, accumulates in ~25% of solid tumors and is associated with poor prognosis. Tumors that accumulate HA develop high interstitial fluid pressure (IFP) and become resistant to chemotherapy. In animal models, PEGPH20 reduced tumor-associated HA and increased efficacy of chemotherapy. Methods: This ongoing phase 1 study was designed to assess safety, tolerability, PK, PD, and the maximum tolerated dose (MTD) of PEGPH20 as a single agent in patients with treatment-refractory solid tumors. IV PEGPH20 was administered in a twice weekly or a once weekly dosing schedule with oral dexamethasone (dex) pre-and post dose. Biomarkers included tumor histochemistry to detect HA depletion, plasma HA catabolites, and DCE-MRI or FDG-PET. Results: Fifteen patients have been enrolled into the study. Dose administration ranged from 0.5 µg/kg to 5 µg/kg. Musculoskeletal events (MSEs) were the most common and dose limiting toxicities. To date, up to 3 µg/kg twice weekly IV infusions of PEGPH20 were well tolerated with manageable Grade 1 MSEs in most patients. MTD has not been reached. Plasma concentrations of PEGPH20 showed dose proportional exposure with a terminal half life of ~2 days. Enzymatic activity of PEGPH20 was reflected by dose-dependent HA catabolites in plasma. Pre- and post-dose tumor biopsies from 2 colon patients demonstrated 23-60% reduction in tumor HA after 4 weeks of dosing. Serial DCE-MRI and FDG-PET demonstrated increased tumor perfusion (K trans ) and decreased metabolic activity 8 and 24hrs post-PEGPH20 in one patient each. Doses of ≤3 µg/kg were tolerated with intermittent Grade 1-2 MSE. Enrollment at dose levels &gt; 3 µg/kg is ongoing. Conclusions: Repeated IV PEGPH20 infusion resulted in dose-dependent systemic exposure and is tolerated with concomitant dex treatment. HA catabolites in plasma demonstrated the in vivo enzymatic activity of PEGPH20. Reduced HA in tumor biopsies and serial DCE-MRI and FDG-PET images confirmed PD activity. Increased tumor perfusion by PEGPH20 may enhance drug delivery to tumor. Combination studies of PEGPH20 with cytotoxic chemotherapy are planned.
Final results of a phase 2 study of ramucirumab (RAM) plus eribulin (E) versus E in advanced metastatic breast cancer (MBC).
Authors: Denise A. Yardley, Paul D. Richards, James Andrew Reeves, Elizabeth Claire Dees, Cynthia R. C. Osborne, Hatem Hussein Soliman, Devchand Paul, Foluso Olabisi Ademuyiwa, Troy H. Guthrie, Jane L. Bromund, Yihuan Xu, Ayman B. Ibrahim
Journal: Journal of Clinical Oncology (2014)

1035 Background: RAM, a recombinant human IgG1 monoclonal antibody, targets VEGFR-2 and blocks the interaction of VEGF ligands and VEGFR-2. E is a microtubule inhibitor active in MBC. The primary goal of this multicenter US study was to identify if the addition of RAM to E would increase progression-free survival (PFS) in comparison to E alone as third- to fifth-line therapy in patients (pts) with MBC. Methods: Pts with locally recurrent or MBC and 2-4 prior chemotherapy regimens in the advanced setting were randomized 1:1 to receive RAM+E or E (E 1.4 mg/m2 days 1 and 8; RAM 10 mg/kg day 1; q21 days). Stratifications included prior antiangiogenic therapy and triple negative status. Prior anthracycline and taxane treatment, normal LVEF, and ECOG PS 0-1 were required. Treated, stable brain metastases were allowed. Results: 141 pts with a median age of 56 yrs were in the ITT population (RAM+E, n=71; E, n=70). Median PFS was 4.4 mo in RAM+E and 4.1 mo in E (HR=0.8: 95% CI 0.6-1.2; p=0.4) with a median overall survival (OS) of 13.5 mo and 11.5 mo in the RAM+E and E arm (HR=0.8: 95%CI 0.5-1.3; p=0.4), respectively. Objective response rate was 20% for RAM+E and 24% for E. Median duration of response in RAM+E was 5.5 mo and 3.0 mo in E. Relative mean dose intensity was 95.3% for RAM and 80.7% for E in RAM+E, and 79.0% in E. All-cause treatment emergent adverse events (TEAEs) ≥20% and grade 3 ≥5% are shown (Table). Any grade TEAEs of special interest in RAM+E vs. E included bleeding (18.8% vs. 4.6%), hypertension (HTN) (13% vs. 1.5%), and congestive heart failure (1.4% vs. 0%). RAM+E bleeding included 7 events of epistaxis and 1 grade 3 GI hemorrhage. 3 RAM+E pts and 1 E pt had grade 3 HTN. Conclusions: Addition of RAM to E did not improve PFS. Higher rates of fatigue, headache, hypertension, diarrhea, and bleeding were observed in the RAM+E arm. Clinical trial information: NCT01427933. TEAE, n (%) RAM+E (n=69) E (n=65) Any grade (≥20%) Grade ≥3 (≥5%) Any grade (≥20%) Grade ≥3 (≥5%) Fatigue 44 (64) 11 (16) 37 (57) 4 (6) Neutropenia 29 (42) 27 (39) 29 (45) 24 (37) Nausea 28 (41) 27 (42) Headache 27 (39) 10 (15) Constipation 20 (29) 19 (29) Vomiting 19 (28) 17 (26) Diarrhea 17 (25) 10 (15) Dyspnea 15 (22) 14 (22) Peripheral neuropathy 15 (22) 4 (6) 16 (25) 3 (5) Anemia 14 (20) 16 (25) 3 (5) Leukopenia 4 (6) 8 (12) 7 (11)
Standard chemotherapy versus capcitabine for older women with early stage breast cancer: An update of CALGB/CTSU/Alliance 49907.
Authors: Hyman B. Muss, Donald A. Berry, Constance T. Cirrincione, Maria Theodoulou, Arti Hurria, Harvey Jay Cohen, Ann Partridge, Larry Norton, Clifford A. Hudis, Eric P. Winer
Journal: Journal of Clinical Oncology (2015)

1022 Background: CALGB 49907 compared capecitabine (X) with standard (S) chemotherapy in BC patients (pts) 65 yrs and older. Initial results: inferiority of X for both RFS and OS at 2.4 yrs median follow-up (NEJM 2009;360:2055). Current median 9 yrs. Methods: Pts ≥ 65 years with Stage I-IIIB BC. Randomization: Xx6 vs S (physician choice: CMFx6 or ACx4 (q3wk)). Endocrine therapy recommended for hormone receptor (HmR) positive. Endpoints: relapse-free (RFS) and overall survival (OS). We now include recurrence-free interval (RFI) and BC-specific survival (BCSS) to separate competing risk from other-cause mortality. All endpoints defined by the STEEP. Primary analysis: Bayesian probability of X inferiority in RFS for early stopping and final. Results: At first interim analysis, after 633 pts (9/2001–12/2006), met the criterion for early stopping. Final Bayesian probability of inferiority of X to S was > 99% for both RFS and OS. Accrual closed (2006) and results published (2009). At 7-yrs for S vs X: RFS 60% vs 52%; RFI 83% vs 75%; OS 79% vs 68%; BCSS 91% vs 83% - all p < .05. Table shows hazard ratios (HR) of X:S and 95% confidence intervals (CI). The magnitude of S effect and its interaction with HmR status has decreased; its benefit in HmR-neg tumors remains. There are 45 new primary cancers (S: 29; X: 16): breast 13 (S:5, X:8), AML/MDS 6 (CMF: 2; AC: 3; X:1). Conclusions: Long-term follow-up shows X inferior to S. Competing risks are important contributors to mortality in this population. Clinical trial information: NCT00024102. HR of X:S (95% CI) by time of analysis and HmR status. Endpt (events) NEJM2009 Current RFS(95) OS(62) RFI(66) BCSS(29) RFS(243) OS(208) RFI(130) BCSS(78) All 2.09* 1.38-3.17 1.85* 1.11-3.08 2.54* 1.51-4.27 2.49* 1.13-5.50 1.35* 1.05-1.74 1.37* 1.04-1.80 1.62* 1.14-2.30 1.67* 1.06-2.62 HmR-neg 3.13* 1.68-5.84 2.90* 1.33-6.31 2.68* 1.39-5.17 2.18 0.87-5.42 1.71* 1.13-2.59 1.61* 1.03-2.51 1.88* 1.12-3.16 1.71 0.88-3.33 HmR-pos 1.43 0.80-2.54 1.23 0.61-2.48 2.32 0.99-5.42 3.63 0.73-18.1 1.18 0.85-1.62 1.24 0.88-1.75 1.42 0.88-2.30 1.63 0.88-3.02 *Significant at P < .05.
Research on Skin Cancer–Related Behaviors and Outcomes in the NIH Grant Portfolio, 2000-2014
Authors: Frank M. Perna, Laura A. Dwyer, Gina Tesauro, Jennifer M. Taber, Wynne E. Norton, Anne M. Hartman, Alan C. Geller
Journal: JAMA Dermatology (2017)

The Surgeon General's Call to Action to Prevent Skin Cancer broadly identified research gaps, but specific objectives are needed to further behavioral intervention research.
Impact of locoregional therapy among women 70 years or older with early stage hormone receptor positive breast cancer: A population based study.
Authors: Shaheenah S. Dawood, Xiudong Lei, Paul N. Mainwaring, Sudeep Gupta, Bhawna Sirohi, Javier Cortes, Rebecca Alexandra Dent
Journal: Journal of Clinical Oncology (2015)

573 Background: In 2004 the CALGB 9343 trial determined that omission of radiation therapy after lumpectomy in women ≥ 70 years with ER+ T1N0 breast cancer did not significantly impact outcome. This retrospective study aimed to determine trends in locoregional therapy practice in this cohort and to determine its impact on outcome. Methods: Using SEER registry we identified 27852 pts who were ≥ 70 years with pT1N0M0 ER+ breast cancer diagnosed between 1990 and 2005. A cutoff of 2005 was chosen to ensure a minimum of 5 years of follow up. Pts were divided into 3 groups based on locoregional therapy received: a) mastectomy, b) lumpectomy plus radiation, c) lumpectomy without radiation. Breast cancer specific survival (BCSS) was computed and Cox models were then fitted to evaluate the association between type of locoregional therapy and BCSS, adjusted for various pt and tumor characteristics. We expanded the cohort to include pts diagnosed until 2010 to look at practice trends in locoregional therapy. Results: 11533 (41.4%) pts had mastectomy, 13035 (56.8%) pts had lumpectomy plus radiation therapy and 3284 (11.8%) pts had lumpectomy alone. At a median follow-up of 92 months, 5- year BCSS was 97%, 98% and 97% among pts who had undergone mastectomy, lumpectomy plus radiation and lumpectomy alone, respectively (p < 0.0001). Compared to those who underwent mastectomy, there was no significant difference in breast cancer deaths among those who underwent lumpectomy plus radiation (HR 0.89, 95% CI 0.7-1.003, p = 0.056) or lumpectomy alone (HR 1.13, 95% CI 0.94-1.36, p = 0.18). Comparing 1990, 2005 and 2010, the proportion of pts undergoing mastectomy steadily decreased (74.2%, 27.4% and 25% respectively) while proportion undergoing lumpectomy plus radiation steadily increased (21.1%, 51.5% and 52.7% respectively) as did proportion undergoing lumpectomy alone (4.7%, 21.1% and 22.4% respectively). Conclusions: Omission of radiation therapy after lumpectomy in older women did not seem to significantly impact BCSS in this population based analysis. Although the use of lumpectomy without radiation increased over time, post-lumpectomy radiation is still the more favored treatment practice.
Early obesity and risk of cholangiocarcinoma in the United States.
Authors: Akram Shalaby, Milind M. Javle, Rachna T. Shroff, Ahmed OS Abousamra, Reham Abdel-Wahab, Vijayashri Rallapalli, Donghui Li, Manal Hassan
Journal: Journal of Clinical Oncology (2017)

239 Background: In the United States, the incidence of intrahepatic cholangiocarcinoma (ICC) has been increasing over the last few decades. Despite the public health problem of obesity and the increasing incidence of ICC, the relationship between early adulthood obesity and ICC has never been examined in the American population. Methods: At the University of Texas MD Anderson Cancer Center we conducted a case-control study aimed at examining relationship between ICC and history of obesity after controlling for the potential confounding of several risk factors. Cases were patients with pathologically confirmed diagnosis of ICC. Controls were healthy subjects recruited from spouses of patients at MD Anderson who had cancers other than liver or gastrointestinal. Each case was frequency matched to 4 controls by age (± 5 years), sex, and race. Case patients and controls were interviewed for risk factors of liver cancer. A self-reported weight and body size pictogram at ages 20, 30, 40, 50, 60 was obtained from each participant. In 2016 we recruited 63 newly diagnosed patients with ICC who were compared to 252 healthy controls. Obesity was defined as body mass index (BMI) ≥ 30.0. Results: There was a significant 3 fold increase in ICC risk for obese individuals compared to those with normal weight. The estimated odds ratio (OR), 95%; confidence interval (CI) was 3.3 (1.3-9.1); P = .02. Obesity at the mid-20s, mid-30s, and mid- 40s was significantly associated with ICC risk; the estimated OR (95% CI) was 7.3 (2.8-19.7), 7 (2.4-20.9), and 4.8 (2-11.4), respectively. In addition, viral hepatitis, heavy alcohol use ( &gt; 40 ml ethanol/day), and family history of cancer were significantly associated with ICC. Underlying radiological, pathological, or clinical evidence of steatosis, fibrosis, and cirrhosis was significantly observed in 25% ICC patients with early obesity. Conclusions: We concluded that early adulthood obesity is a significant risk factor for ICC in USA where underlying fatty liver diseases can be a significant factor for ICC progression. Integration of obesity with other ICC risk factors into a risk model may lead to identify high-risk individuals. Future collaboration with other US institutions is highly warranted to highlight the mechanism of obesity-induced ICC.
Magnitude of progression-free survival (PFS) improvement and treatment (Tx) duration in metastatic colorectal cancer (mCRC) for bevacizumab (BV) in combination with oxaliplatin-containing regimens: An analysis of two phase III studies
Authors: B. J. Giantonio, N. J. Meropol, P. J. Catalano, V. Ng, R. Oliver, F. Sirzen, S. Leonard, J. Cassidy, A. B. Benson
Journal: Journal of Clinical Oncology (2007)

4073 Background: In trials of BV with FOLFOX (fluorouracil, leucovorin, oxaliplatin) for mCRC, variability in the magnitude of PFS improvement has been reported [HR=0.61 in E3200 vs HR= 0.83 (FOLFOX or CAPOX (capecitabine and oxaliplatin)) in NO16966]. We propose that differences in rates of treatment discontinuation (D/C) for adverse events (AE) between these studies may have resulted in differences in the observed benefits associated with BV. We explored Tx duration (proportion of patients on Tx) and Tx D/C data at median PFS for the BV containing arms of each study. Methods: ECOG study E3200 randomized previously treated patients with mCRC to FOLFOX ± BV (10 mg/kg). NO16966 employed a 2x2 design that randomized previously untreated patients with mCRC to CAPOX vs FOLFOX and to BV (5 mg/kg) or placebo. In both trials, study Tx was defined as any component of the prescribed regimen. PFS was estimated from Kaplan-Meier curves, and hazard ratios (HR) for PFS were estimated by Cox regression. Results: Median PFS for the BV containing arm of the study: 30 weeks for E3200; 42 weeks for NO16966 Conclusion: These data suggest possible differences between the two studies in Tx duration and Tx D/C patterns with a greater proportion of patients on NO16966 discontinuing Tx for any AE. Duration of study Tx might have affected both the incidence of AEs and the magnitude of PFS benefit observed for the addition of bevacizumab to oxaliplatin-based chemotherapy in these studies. Attention to Tx duration and Non-PD Tx D/C in future clinical trials will be important when considering PFS as a primary efficacy endpoint. [Table: see text] No significant financial relationships to disclose.
Cabozantinib (C) exposure-response (ER) modeling of safety endpoints in patients (pts) with renal cell carcinoma (RCC) in the phase III METEOR study.
Authors: Steven Lacy, Matthew M Hutmacher, Bei Yang, Robert J. Motzer, Bernard J. Escudier, Thomas Powles, Toni K. Choueiri, Jace Nielsen
Journal: Journal of Clinical Oncology (2017)

447 Background: ER models were previously developed to characterize the relationship between C exposure and efficacy endpoints in RCC pts in the phase III METEOR study (J Clin Oncol 34, 2016 [suppl; abstr 2565]). Higher C exposure correlated with decreased tumor size and improved progression-free survival and objective response rate. Model-based predictions showed that C would be effective at the 60 mg starting dose evaluated in METEOR as well as dose levels of 40 and 20 mg resulting from dose reduction. In the current study, ER models were developed to characterize the relationship between C exposure and safety endpoints in RCC pts. Methods: The ER analysis included 318 RCC pts who had received at least one C dose and had at least one measurable C concentration. Time-to-event Cox proportional hazard ER models were developed to characterize the relationship between various individual predicted C exposure measures and the likelihood of dose modification and 6 specific adverse events (AEs): fatigue/asthenia, palmar-plantar erythrodysesthesia (PPE), nausea/vomiting, diarrhea, hypertension, and stomatitis. Results: A statistically significant relationship was identified between individual predicted C clearance (CL/F) and the rate of dose modification (p &lt;0.0001), with the risk of dose modification decreasing with increasing CL/F. An increase in average C concentration was associated with increased risk of fatigue/asthenia (Grade ≥3), PPE (Grade ≥1), hypertension (systolic blood pressure [BP] &gt;160 mmHg or diastolic BP &gt;100 mmHg), and diarrhea (Grade ≥3). The predicted hazard ratios for these AEs were 2.01, 2.21, 1.85, and 1.78, respectively, based on the predicted steady-stage average C concentration for a 60 mg dose relative to a 20 mg dose. Statistically significant ER relationships were not identified for nausea/vomiting (Grade ≥3) or stomatitis (Grade ≥3). Conclusions: Based on the ER analysis, higher C exposures resulting from lower C CL/F are predicted to increase the dose modification rate. Reduced C exposures resulting from dose reduction are predicted to decrease the risk of fatigue/asthenia, PPE, hypertension, and diarrhea while maintaining clinical benefit. Clinical trial information: NCT01865747.
Abstract 118: PP2A/HSP70 Dynamically Regulates HDAC2 Phosphorylation and its Activity in Cardiac Hypertrophy
Authors: Gwang Hyeon Eom, Somy Yoon, Hyun-Ki Min, Yoon Seok Nam, Duk-Hwa Kwon, Hyun Kook
Journal: Circulation Research (2015)

Rationale: Cardiac hypertrophy is an adaptation for increased hemodynamic demands by underlying diseases and histone deacetylase (HDAC) 2 phosphorylation and following its activation are closely associated with those of process. Recently, we have demonstrated that the acetylation of HDAC2 K75 could induce S394 phosphorylation; however, specific mechanism for inter-modifications regulation in the single protein largely remains unclear. Objective: We aimed to delineate the regulation mechanism how K75 acetylation modulates S394 phosphorylation and which phosphatase regulates HDAC2 phosphorylation in the cardiac hypertrophy. Methods and Results: We found that the catalytic subunit of protein phosphatase (PP) 2A bound to HDAC2 in the H9c2 cell. PP2A kept HDAC2 unphosphorylated in the absence of hypertrophic stresses. Hypertrophic stresses-induced activation of pCAF, however, induced HDAC2 K75 acetylation, which then allowed PP2A to dissociate from HDAC2. This dissociation leads CK2α1 to bind to and phosphorylate HDAC2. Hypertrophic stresses induced HSP70 which then preferentially bound to phosphorylated HDAC2 rather than to unphosphorylated one. Forced expression of PP2CA not only reduced enzyme activity of HDAC2 but inhibited hypertrophic response in the cardiomyocytes. On the other hand, HSP70 bound to phosphorylated HDAC2 in order to mask the phosphor-HDAC2 from PP2CA. HDAC2 phosphorylation and following activation of intrinsic activity were regulated by binding of PP2CA to HDAC2. PP2A functioned as a negative regulator for cardiac hypertrophy by targeting of HDAC2 S394 phosphorylation. Conclusion: Taken together, HDAC2 forms a complex with PP2A in the absence of hypertrophic stresses and remains inactivated. HDAC2 acetylation results in both detachment of PP2A and binding of CK2α1 for phosphorylation, which is maintained by the association with HSP70 during development of cardiac hypertrophy.