tbuckley/cabot-search huggingface dataset:
Obesity, diabetes, and race in Type 1 and Type 2 endometrial cancers.
Authors: E. M. Ko, J. Franasiak, K. Sink, W. R. Brewster, P. A. Gehrig, V. L. Bae-Jump
Journal: Journal of Clinical Oncology (2011)

5111 Background: Type1 endometrial cancers (EC) classically occur in obese, Caucasian women and arise in a hyper-estrogenic milieu. In contrast, Type2 EC (i.e. serous and clear cell) behave more aggressively and occur more frequently in African-American (AA) women. Obesity has not been conclusively demonstrated to be a risk factor for Type2 EC, but recent studies are lacking. Given the obesity and diabetes (DM) epidemic and the poorer outcomes in AA with EC, we sought to re-assess whether obesity and DM are associated with both types of EC. Methods: An institutional review board approved cross-sectional analysis of all Type1 and Type2 EC diagnosed in a single institution from Jan 2005-Sept 2010 to assess obesity, race and other prognostic factors. Statistical analyses using student t-test, Χ2 test, and multiple logistic regression were performed in STATA 11. Statistical significance was set at p=0.05, with confidence levels of 95%. Results: Of 881 (691 Type1 and 190 Type2) EC cases, 16.6% of Type1 and 30.2% of Type2 were AA. Of Type1 and Type2 EC, 84.4% and 78.1% were overweight-obese (OvOb) (p=NS); 61.9% and 50.8% were obese (p=0.007). 94.7% of AA patients were OvOb compared to 79.8% of Caucasian patients (p<0.001). AA had a higher mean BMI than Caucasians for Type1 (37.0 v 33.9, p<0.005) and Type2 (34.9 v 30.2, p<0.001) cancers. For Type2 EC, AA had 6.62 times the odds of being OvOB (95CI 1.93, 22.6) as Caucasians. AA race was associated with 2.36 times the odds (95CI 1.58, 3.54) of having Type2 EC compared to Caucasian race after adjusting for OvOb. Overall, 21.6% of EC patients had DM, of which 95.3% were non-insulin dependent. The proportion of DM did not differ between Type1 and Type2 EC (23.1 v 20.5%, p=0.456). More AA patients had DM than Caucasian patients (34.8 v 19.9%, p<0.001). Within Type2 EC, AA had 3.48 times the odds (95CI 1.63, 7.42) of having DM than Caucasians. Stage, lymphovascular and myometrial invasion did not differ between normal and OvOB, or DM and non-DM patients. Conclusions: Despite traditional dogma, the vast majority of both Type I and 2 endometrial cancer patients are overweight and obese and many have diabetes. Thus, strategies to impact obesity may be just as critical for women faced with Type 2 as Type 1 disease.
Histologic subtyping and tumor stromal responses in advanced-stage lung adenocarcinoma and their relationship to survival.
Authors: M. D. Pool, M. J. Fidler, K. A. Kaiser-Walters, S. Basu, E. Braun, L. Buckingham, T. A. Hensing, P. D. Bonomi
Journal: Journal of Clinical Oncology (2011)

e21135 Background: Lung adenocarcinoma (ADC) has variegated histology and diverse clinical behavior. The 2011 IASLC classification of lung ADC recognizes distinctive architectural types but cytological features and tumor stromal responses may also be useful for prognosis. The predictive value of these features in relation to erlotinib treatment is unknown. The objectives were to develop a tool for detailed morphologic profiling of lung ADC and to identify potential features related to outcome in a cohort of patients (pts) with advanced NSCLC treated with erlotinib. Methods: This was a retrospective study of resected lung ADC from pts with advanced NSCLC treated with erlotinib (N=51). Subtyping of resected ADC was adapted from morphometric profiling using hierarchical clustering (Okudela 2008). Tumor-associated fibrotic (TAFR) and lymphoid responses (TALR) were graded on H&E sections as prominent vs mild/none. The log-rank test was used to compare selected morphologic parameters for their effects on overall (OS) and progression-free survival (PFS). Results: 51 pts included 29 females, 8 never smokers, and 8 with EGFR activating gene mutations. ADC with prominent TAFR (N=33) showed a significant difference for improved PFS (p=0.002) vs with those without (N=5), but no difference in OS. No significant differences in survival were found between mixed vs pure ADC types, mixed type with solid pattern vs without, mixed subtype with high columnar cell type vs without, and prominent TALR vs none. Conclusions: This is a small, retrospective study but our data show that prominent TAFR is related to improved PFS in advanced ADC pts treated with erlotinib. This suggests that altered tumor microenvironment may be an important effect of erlotinib therapy. Our data suggest that tumor cytologic changes and TALR are not important for survival in advanced stage pts. Detailed morphologic subtyping of ADC and tumor stromal responses will be validated in early stage ADC for prognostic markers and may be useful in predicting improved PFS in EGFR mutation-negative ADC patients receiving erlotinib.
A phase II study of estramustine (E), docetaxel (D) and exisulind in hormone-refractory prostate cancer (HRPC): Initial results of CALGB 90004
Authors: N. A. Dawson, S. Halabi, D. D. Biggs, S.-S. Ou, W. K. Kelly, E. J. Small
Journal: Journal of Clinical Oncology (2005)

4649 Background: D/E is a known active regimen in HRPC with an associated prolongation of survival. Exisulind induces apoptosis and in a double blind trial in men failing prostatectomy (RP) suppressed the increase in prostate specific antigen (PSA). Methods: Eighty men with chemotherapy-naïve HRPC were enrolled in a multi-institutional trial from December 2002 to January 2004. Treatment consisted of E-280 mg po TID for days 1–5, D 70 mg/m2 on day 2, exisulind 250 mg po BID daily. Dexamethasone 8 mg po BID for days 1–3, and warfarin 2 mg po daily. The primary endpoints were time to objective progression (TTOP) and response rate (objective and post-therapy PSA). An increase in expected TTOP of 11 to 13.5 months would warrant further study. Results: The median age was 69.5, with a median number of years since diagnosis of 4 years. ECOG PS was 0 in 46%, 1 in 48%and 2 in 6%. The median baseline PSA was 152 ng/mL. The Gleason Score of the primary tumor was 8–10 in 59% and 5–7 in 41%. Sites of disease were visceral 24%, bone 83%, soft tissue 11% and lymph nodes 50%. Measurable disease (MD) was present in 54%. The median cycles of chemotherapy was 6 (inter-quartile range 3–10). A ≥ 50% decline in PSA was seen in 60% (95% CI= 48–71%). Objective response (CR+PR) was documented in 21% (95% CI=10–36%) for a median duration of 6.2 months. Median objective progression free survival (PFS) is 10.9 months (95%CI=9.6-NR). Median survival is 16.9 months (95%CI=13.0-NR) and the median time to progression is 5.8 months, (95%CI=4.73–7.67). Toxicity was significant. The maximum grade 3 toxicity was observed in 26% of patients, grade 4 in 64% and grade 5 in 3%. The primary grade 4 toxicity was neutrophils/granulocytes in 46 pts (58%). One patient died with febrile neutropenia and one patient had an unobserved death at home on day 14 on study. Non fatal venous thrombosis/pulmonary embolism occurred in 8 pts (10%). Conclusions: The combination of estramustine, docetaxel and exisulind was associated with significant thromboembolic toxicity despite prophylactic warfarin. The contribution of exisulind to toxicity is uncertain. PSA response rate, overall survival and PFS are similar to that reported with estramustine and docetaxel alone. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis
The pharmacokinetic (PK) effect of AMG 706 on CYP3A activity evaluated by use of oral midazolam as probe in patients with advanced solid tumors
Authors: L. Yan, S. Wong, L. Wathen, D. Chang, L. Ni, M. Ingram, M. Parson, L. Rosen
Journal: Journal of Clinical Oncology (2005)

3178 Background: AMG 706 is a potent and selective oral inhibitor of multiple kinases, including vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor (PDGF) receptor, Ret, and kit. In vitro, AMG 706 inhibits CYP3A4, 2D6, 2C9, and 2C19 with IC50 values of 2.0, 2.8, 2.1, and 11.7 μM, respectively. We report the results of a PK substudy of the AMG 706 phase 1, first-in-human (FIH) trial. The objective was to evaluate the in vivo effect of AMG 706 on CYP3A activity, using oral midazolam as a probe, in 12 patients (pts) with advanced solid tumors. Methods: This was an open-label, fixed-dose, sequential substudy to accommodate the dosing regimen used in the trial. Pts received a single, 2-mg, oral dose of midazolam alone, and then a second, 2-mg, oral dose of midazolam after daily administration of AMG 706 125 mg for at least 14 days. AMG 706 125 mg/day was the maximum tolerated dose determined in the dose escalation phase of the FIH study. Pts fasted at least 8 hrs before and 2 hrs after each midazolam dose. PK samples were collected at the following time points: 0 (just before midazolam administration), 15 min, 30 min, and 1, 2, 3, 4, 6, 8, 12, and 24 hrs after midazolam administration for concentration determination. AUC, Cmax, Tmax, C24, and half-life were calculated based on the serum level of midazolam over a 0–24 hr period in the absence and presence of concomitant AMG 706 administration. Results: The mean age (range) of this cohort of pts was 61.3 yrs (36 - 90 yrs). Maximum plasma concentrations of midazolam were typically observed 0.25 to 1 hr after the dose. Based on the mean AUC values, there was a slightly increased systemic exposure to the second dose of oral midazolam (given after pts had been treated with AMG 706 125 mg). The point estimate (90% confidence interval) for the geometric mean ratio of midazolam serum AUC for pts receiving AMG 706 125 mg prior to midazolam vs midazolam alone was 1.82 (1.50 - 2.22). Conclusions: AMG 706 is a weak inhibitor of CYP3A in humans. In general, clinically significant interactions of AMG 706 with drugs that are CYP3A substrates are not anticipated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen
A phase I study of oral panobinostat (LBH589) alone and in combination with docetaxel (Doc) and prednisone in castration-resistant prostate cancer (CRPC)
Authors: D. E. Rathkopf, B. Y. Wong, R. W. Ross, D. J. George, J. Picus, E. Tanaka, Y. Chen, P. Atadja, W. Yang, K. W. Culver, H. I. Scher
Journal: Journal of Clinical Oncology (2008)

5152 Background: Deacetylases are enzymes that remove acetyl groups from proteins and thereby regulate transcription and other cellular processes involved in oncogenesis. Panobinostat is a deacetylase inhibitor with potent activity against prostate cancer at low nanomolar concentrations. Methods: Eligible patients had CRPC and adequate organ function. The study was designed to determine the MTD of oral panobinostat alone and with Doc, and to characterize the safety, tolerability, activity and pharmacokinetics of panobinostat. Arm I: oral panobinostat (20mg) on days 1, 3, and 5 for 2 weeks on/1 week off. Arm II: oral panobinostat (15mg) on days 1, 3, and 5 for 2 weeks on/1 week off with Doc 75mg/m2 i.v. every 21 days and oral prednisone 5mg twice daily. Results: The study enrolled 16 patients, 8 patients in each arm. There was a single DLT in both arm I (grade 3 dyspnea) and in arm II (grade 3 neutropenia x >7 days). In arm I, all patients developed progressive disease while on study. In arm II, 3 patients remain on study at a median of 7 cycles (range 7–13); Three patients achieved a PR as best response, of those, two elected to hold treatment due to fatigue. All evaluable patients at the 20 mg single agent dose (7/7), versus 1 at the 15 mg combination dose (1/6), demonstrated accumulation of acetylated histones in monocytes. Exposure to oral panobinostat was similar with and without Doc. Conclusions: Oral panobinostat with and without Doc is feasible and a drug-drug interaction is not apparent. Since preclinical studies suggest a biphasic, dose-dependent effect of panobinostat on PSA expression, and other phase I data demonstrate that i.v. panobinostat produces higher peak concentrations (>20–30 fold) and AUC (3.5–5x) with a comparable toxicity profile, this study is now closed to enrollment in order to focus on development of the i.v. formulation of panobinostat in CRPC. Sponsor: Novartis; under DOD PCCTC. Mean PK parameters of oral panobinostat Day Dose (mg) Tmax (hr) Cmax (ng/mL) AUC (0–24) (hr*ng/mL) AUC (0-inf) (hr*ng/mL) T 1/2 (hr) Arm I: LBH589 1 20 1.8 ± 1 14.3 ± 7.4 83 ± 35.6 116.9 ± 60.4 16.5 ± 8.9 Arm II: LBH589 + Doc 1 15 1.6 ± 1.6 10.2 ± 6.6 55.2 ± 22.8 121.7 ± 87.9 19.7 ± 16.8 Arm II: LBH589 + Doc 8 15 3 ± 2.6 7.9 ± 3.5 77.7 ± 18 98.1 ± 18.7 10.9 ± 1.7 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis
Closing the gap between cancer clinical trials participation and those willing to participate
Authors: L. Tis, R. Comis, T. Gansler, K. Sharpe, R. Nickens
Journal: Journal of Clinical Oncology (2008)

6581 Background: Adult enrollment in cancer clinical trials is 3–5%, even though two thirds of cancer patients are receptive to enrolling in a study. Closing this gap requires convenient delivery of comprehensive information on relevant trials and nearby sites to patients. Methods: The American Cancer Society (ACS) and the Coalition of Cancer Cooperative Groups (Coalition) joined forces to provide information from TrialCheck, the Coalition's caBIG bronze level certified cancer clinical trial database and matching/eligibility tool via the ACS 24–7-365 national call center (800-ACS-2345) and website (www.Cancer.org). Trial search parameters included demographic, clinical and geographic information. The ACS conducts person-to-person interaction and follow up with the individuals to assess enrollment status and barriers to trial participation. Results: In the first four months of operation the service provided 5,183 TrialCheck screenings for 2,557 individuals, leading to 727 fulfillment orders. The top 5 cancers screened were breast (661 screenings), lung (397), bone/soft tissue (338), prostate (337) and head & neck (246); 203 screenings for cancer prevention/control trials were also conducted. The fulfillment orders yielded 7,198 protocol matches, with an average number of 9.9 matches of interest (based on orders of trial protocol and site location information) in the state where the patient resides. 25.8% of matches of interest were for phase I trials, 8.1% for phase I/II, 42.0% for phase II, 8.4% for phase II/III and 15.7% for phase III. Conclusions: Of those patients and caregivers who conducted a clinical trials search, 28.4% completed the process through to requesting the trial matches be sent to them for them to consider participation and discuss with their physician. The impact of this service on clinical trial enrollment will be monitored as data mature. No significant financial relationships to disclose.
Phase I study of chemoradiation therapy (nab-paclitaxel/Gemcitabine) in 15 patients with unresectable locally advanced pancreatic cancer (UR-LAPC).
Authors: Hironari Sueyoshi, Tatsuya Ioka, Takeshi Tamura, Ryoji Takada, Nobuyasu Fukutake, Reiko Ashida, Kazuyoshi Ohkawa, Hidenori Takahashi, Teruki Teshima, Kazuhiro Katayama
Journal: Journal of Clinical Oncology (2015)

475 Background: Pancreatic cancer (PC) is one of the most difficult cancers to treat. Over 90% of cases, they are UR-LAPC or metastatic PC (mPC) at the first time of diagnosis. To prolong survival time, radiation therapy is considered to be promising with strong local control. Some papers reported that RT with 5-FU is effective to LAPC, but they are far from standard regimen. Gemcitabine (Gem) has enhancing effect of sensibility to RT. Gem and nab-paclitaxel (G+NP) showed priority compared with Gem monotherapy in mPC patients with Phase III study. So, we performed Phase I study to decide recommended dose of G+NP when we administer for concurrent CRT in URPC patients. Methods: From Aug 2013, we have registered patients who were examined as UR-LAPC because of cancer invasion to major artery. Dose of G+NP are classified by each level. At Level 1, Gem 600mg/m 2 and NP 50mg/m 2 . At Level 2, Gem 600mg/m 2 and NP 75mg/m 2 . At Level 3, Gem 600mg/m 2 and NP 100mg/m 2 . At each level, patients accepted RT (50.4Gy/28fr). During performing RT period, we prescribed G + NP weekly. So, G+NP are prescribed 4-5 times if pts accomplish the study.We evaluate effectiveness and side effect of the regimen, and try to decide maximum tolerated dose. Results: Until July 2014, 14 pts (11 males and 3 females) have been registered in this trial. 6 cases were performed at Level 1, 7cases at Level 2, 1 cases at Level 3. 13 cases accomplish the prescription. 1 case at Level 1 dropped out because the patient suffered liver abscess. Effectiveness of the regimen is as follows; 4cases are PD (progressive disease), 6cases are SD (stable disease), and 2cases are PR (partial response). Conclusions: Now we prescribe the regimen at Level 3. We have not yet decided MDT. But, CRT with G + NP may be promising regimen for LAPC. When we accumulate more cases, and decide MDT, we will report later. Clinical trial information: UMIN000012254.
Bioluminescence image-guided irradiation and tumor monitoring in a preclinical pancreatic cancer mouse model.
Authors: R. Tuli, A. Surmak, E. C. Ford, E. Tryggestad, J. Wong, T. L. DeWeese, J. M. Herman
Journal: Journal of Clinical Oncology (2011)

192 Background: Preclinical pancreatic cancer animal models for radiation research are far from optimal because they utilize nonlocalized, single-beam irradiation of large fields due to lack of accurate targeting and delivery. We report on a novel preclinical pancreatic cancer research model that utilizes bioluminescence imaging (BLI)-guided irradiation (RT) of orthotopic xenograft tumors, sparing of surrounding normal tissues and quantitative, noninvasive longitudinal assessment of treatment response. Methods: In accordance with institutional guidelines, luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were used to generate orthotopic pancreatic tumors in nude mice. BLI of tumors were correlated to PET/CT and necropsy specimens using Pearson correlation. BLI was compared to cone-beam CT (CBCT) to determine the location of the tumor centroid and estimate an appropriate margin for radiation planning. Off-line fusion of BLI with CBCT was performed to guide radiation delivery to tumors using our small animal radiation research platform (SARRP). RT-induced DNA damage was assessed by γ-H2Ax and p-ATM foci. BLI was used to longitudinally monitor radiation treatment response and was correlated to necropsy specimen. Results: BLI accurately predicted tumor volume (R 2 = 0.9961) and correlated well with PET/CT imaging of tumors (R 2 = 0.97). BLI centroid accuracy was 3.5 mm relative to that of the CBCT. Irradiated pancreatic tumors stained positively for γ-H2Ax and p-ATM, while surrounding organs were spared. Longitudinal assessment of irradiated (5 Gy) tumors with BLI revealed a significant tumor growth delay of 20 days relative to untreated controls. This was also confirmed pathologically as mean tumor volume of irradiated mice was 30.2% that of unirradiated mice (p &lt; 0.05). Conclusions: We have developed a bioluminescent, orthotopic preclinical pancreas cancer model that allows noninvasive 1) normalizing of pretreatment tumor burden; 2) treatment planning and image-guided focal RT therapy; and 3) longitudinal assessment of treatment response. This unique translational model offers a means to investigate targeted and systemic agents with focused RT for pancreatic cancer. No significant financial relationships to disclose.
Severe psychopathology: An unusual manifestation of carcinoid disease—Case reports.
Authors: T. Philip, S. H. Jacoby, S. Nissel-Horowitz, M. Russ, B. Mehrotra
Journal: Journal of Clinical Oncology (2011)

e14624 Background: Carcinoid tumors are known to secrete neurohumoral substances resulting in the manifestation of carcinoid syndrome. There are only rare reports of severe psychiatric symptoms associated with carcinoid disease. We report our institutional experience of two pts with advanced carcinoid disease who developed significant psychiatric symptoms during their disease course. Methods: A retrospective chart review was performed of two cases that met the criteria for carcinoid disease and serious psychopathology. Results: Case 1 was a 57 year old man who was found to have carcinoid tumors six years prior during an exp. laparotomy for an abdominal injury. At presentation to our institution, he was noted to have a history of psychiatric illness that had required hospitalization. Exam was notable for features of acromegaly. Liver biopsy confirmed metastatic carcinoid. His serum chromogranin (chr) levels varied between 2,300-65,000 ng/mL. He had spinal metastases and manifestations of carcinoid heart disease; and was treated with long acting octreotide and zoledronic acid. He required treatment for severe depression during the course of his disease. Progressive liver disease required hepatic embolization which caused a flare in chr levels to 158,000 ng/mL and coincided with the development of transient catatonia. Six months later he succumbed to cardiac and GI complications of carcinoid. Case 2 is a 47 year old man with a history of pituitary adenoma and acromegaly who was initially diagnosed with advanced small bowel carcinoid during an exp. laparotomy for symptoms of bowel obstruction. He was treated with doxorubicin, streptozocin and long acting octreotide. His serum chr levels ranged from 12-470 ng/mL. Seven years after initial diagnosis, he reported new onset suicidal ideation in the context of depression. He was placed on antidepressants and remains stable at this time. Conclusions: These two cases illustrate the rare association of serious psychiatric disorders and advanced carcinoid disease. We present these cases to increase awareness among treating oncologists who follow these patients with typically indolent disease. The pathophysiologic basis for this association remains to be elucidated.