tbuckley/cabot-search huggingface dataset:
How do social factors explain outcomes in non-small cell lung cancer among Hispanics/Latinos in California?
Authors: Manali I. Patel, Ellen T. Chang, Scarlett Lin Gomez, Clayton Schupp, Heather A. Wakelee
Journal: Journal of Clinical Oncology (2012)

6050 Background: Hispanics in the United States have a lower age-adjusted incidence and mortality rate from non-small cell lung cancer compared with non-Hispanic whites. Previous studies have demonstrated the influence of nativity on survival among Hispanic patients but no studies have evaluated the interplay of nativity, clinical factors, social factors, and neighborhood factors on survival among Hispanic patients with non-small cell lung cancer. Methods: All Hispanic patients with non-small cell lung cancer between the years of 1988-2008 were identified in the California Cancer Registry (CCR). Kaplan Meier curves depict survival by nativity status among Hispanics with non-small cell lung cancer. Cox proportional hazard models estimate the hazard of mortality by race with adjustment for individual covariates (age, gender, marital status), clinical factors (histologic grade, surgery, radiation, and chemotherapy), and social and neighborhood factors (neighborhood and ethnic enclave status). Results: A total of 4,062 Hispanic patients with non small cell lung cancer were included. Overall, there was a 7% decreased risk of disease-specific mortality for foreign-born patients as compared with US-born patients (HR 0.93, p=0.08, 95% CI 0.87-1.00) although not-statistically significant. Adjustment for individual patient factors and clinical factors conferred a statistically significant 16% decreased risk of disease-specific mortality compared with US-born patients (HR 0.84, p&lt;0.0001, 95% CI 0.78-0.91). Adjustment for socioeconomic status and neighborhood socioeconomic and ethnic enclave status did not explain the differences in survival (HR 0.84, p &lt;0.001, 95% CI 0.78-0.91). Conclusions: Overall, foreign-born Hispanics with non-small cell lung cancer have a decreased risk of disease-specific mortality compared with US-born Hispanics with non-small cell lung cancer but social factors do not explain this survival advantage. Further investigation is needed to understand the drivers of the survival advantage outcomes in foreign-born populations.
Pharmacodynamic study of neoadjuvant vemurafenib (VEM) in patients (pts) with BRAF mutated, locally advanced papillary thyroid cancer (PTC).
Authors: Maria E. Cabanillas, F. Christopher Holsinger, Erich M. Sturgis, Mouhammed Amir Habra, Michael A. Davies, Mark F. Munsell, Jena French, Naifa Busaidy, Mimi I-Nan Hu, Steven I. Sherman
Journal: Journal of Clinical Oncology (2013)

TPS6100 Background: BRAF mutations are found in 40% of pts with newly diagnosed PTC but much more prevalent in recurrent PTC, ranging from 78-86%, suggesting they play an active role in tumor progression. Activating mutations in BRAF result in constitutive activation of MEK and subsequently ERK. ERK mediates activation of nuclear transcription factors coordinating expression of genes involved in proliferation and survival of malignant cells. PTC usually has an excellent prognosis, especially in younger pts and in pts who respond to the only effective treatment: surgery followed by radioactive iodine (RAI). However, more advanced stage disease at diagnosis, older age, and lack of RAI avidity are associated with a high rate of recurrence and distant metastasis, imparting a worse overall survival. Long-term outcomes depend highly on initial surgery outcome. Pts at highest risk of recurrence and death are those with gross residual disease after surgery and macroscopic tumor invasion. VEM is an inhibitor of the activated form of the BRAF serine-threonine kinase enzyme. The drug is FDA approved for the treatment of advanced melanoma and is currently being studied in a phase 2 trial in metastatic BRAF-mutated PTC. This is a neoadjuvant trial to determine if pharmacodynamic changes in the tumor correlate with response to drug. Methods: Pts with primary or recurrent BRAF mutated PTC who are planned for surgical resection are eligible. Pts will undergo baseline core biopsy prior to starting VEM 960mg bid. After 56 days of treatment they will undergo surgery and post-treatment specimen will be collected. Pts with widely metastatic PTC may continue VEM. The primary endpoint is to determine whether changes in ERK phosphorylation responses after treatment with VEM correlate with clinical response at day 56 in pts with locally advanced, BRAF mutated PTC. Secondary endpoints include assessments of safety of neoadjuvant VEM, response by RECIST, rate of surgical complications, persistent disease at the surgical site at 1 year, and mechanisms of resistance to VEM. The trial began enrolling pts in December 2012, with a total of 22 pts planned. This trial has no sponsor. Clinical trial information: NCT01709292.
Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer (LACC) and negative positron emission tomography with computerized tomography (PET-CT) in the para-aortic area undergoing laparoscopic para-aortic (PA) lymphadenectomy before chemoradiation therapy.
Authors: Sebastien Gouy, Philippe Morice, Fabrice Narducci, Catherine Uzan, Annie Rey, Alejandra Martinez, Patricia Pautier, Desiree Deandreis, Denis Querleu, Christine Haie-Meder, Eric Leblanc
Journal: Journal of Clinical Oncology (2012)

5083 Background: In three comprehensive cancer centers, patients with LACC were systematically staged using conventional and PET-CT imaging before chemoradiotherapy. If patients had no uptake in the PA area, laparoscopic extraperitoneal PA surgery was then performed to define radiation field limits more accurately. The aim of this study was to evaluate the therapeutic impact of this management. Methods: A prospective multicenter series of 237 patients treated from 2004 to 2011 for LACC with a negative PET-CT of the PA area and undergoing laparoscopic PA lymphadenectomy. Radiation fields were extended to PA area when PA nodes were involved. Chemoradiotherapy modalities were homogeneous between Institutions. Patients with a poor prognosis histologic subtype, peritoneal carcinomatosis or ovarian metastasis were excluded. Results: Clinical stages were IB2 (n=79), IIA (n=10), IIB (n=120), III (n=23), IVA (n=5). The histologic types were squamous carcinoma (n=197), adenocarcinoma (n=34) and others (n=6). Twenty-nine (11%) patients had nodal involvement (false negative PET-CT results): 16 with PA nodal metastasis measuring &gt; 5 mm and 13 &lt; 5 mm. With a median follow-up of 18 (range, 0-67) months, disease-free survival (DFS) at 2 years in patients without and with PA involvement was respectively 76% (68%-83%) and 61% (37%-80%)(p=.007). DFS at 2 years in patients without PA involvement or with PA metastasis measuring &lt; or &gt; 5 mm was respectively 76% (68%-83%), 89% (57%-98%) and 38% (14%-68%)(p=.0006). Conclusions: This is the largest series of patients reported undergoing such strategy. We obtained a similar survival rate for patients with PA nodal metastasis &lt; 5 mm and patients without PA lymph node involvement suggesting that this strategy is highly efficient in such patients. Conversely, the survival of patients with PA nodal involvement &gt; 5 mm remained poor, despite no extrapelvic disease at PET-CT imaging in this subgroup. Other treatment modalities should be evaluated for these patients.
Development of a small molecule drug for EBV-associated gastric cancers.
Authors: Troy E Messick, Samantha S Soldan, Julianna Deakyne, Paul M Lieberman
Journal: Journal of Clinical Oncology (2017)

63 Background: Worldwide, EBV is associated with ~10% of gastric cancer. Currently, no pharmaceutical-based therapies exist that selectively target EBV associated gastric cancers. EBV, in its latent oncogenic form, is dependent on the continuous expression of Epstein-Barr Nuclear Antigen 1 (EBNA1), a multifunctional dimeric protein critical for viral replication, genome maintenance and viral gene expression. Methods: The aim of this program is to advance the development of a New Chemical Entity (NCE) for latent infection of Epstein-Barr Virus (EBV) to treat EBV-associated gastric cancer. We have used structure-based drug design and medicinal chemistry methods to identify and develop a small molecule clinical candidate that selectively inhibits the DNA-binding activity of EBNA1. Results: The clinical candidate inhibits EBNA1 function with nanomolar potency in biochemical assays and low micromolecular activity in several cell-based assays. We demonstrate that our clinical candidate provides protection in 4 different xenograft models of EBV-driven tumor growth, including patient-derived xenografts. Furthermore, RNA analysis experiments confirm in vivo target engagement by the elimination of EBV in treated tumor tissue. The clinical candidate is selective, showing no activity in an EBV-negative xenograft experiments. The clinical candidate has met industry-accepted criteria for drug suitability, safety and toxicology including physicochemical properties, metabolic stability, selectivity in broad-based screens and bioavailability, and lack in vivoliabilities, including genotoxicity and 14-day toxicity studies. Conclusions: IND-enabling studies including safety pharmacology and toxicology and GMP manufacturing have begun with a projected First-In-Human clinical trial in Q4 2017. These data establish proof-of-concept for targeting EBNA1—a protein previously thought to be undruggable.
A prospective database of 100 patients with locally soft tissue sarcoma (STS) treated by isolated limb perfusion with melphalan and TNFα 1mg
Authors: V. Bedard, A. Vataire, C. Desouche, C. Le Péchoux, J. Muret, D. Vanel, P. Terrier, A. Le Cesne, S. Bonvalot
Journal: Journal of Clinical Oncology (2007)

10010 Background: In a prior randomized phase II trial comparing hyperthermic isolated limb perfusion (HILP) with melphalan and 4 different doses of TNFa (0.5 mg; 1 mg; 2mg, 3 mg/4mg superior/ inferior limb), there was no dose effect detected for the tumour response but systemic toxicity was significantly lower with low doses TNF-a (Bonvalot S et al. 2005). The objective of the present study was to confirm these datas on a larger population of locally advanced or recurrent STS of the extremity using low dose TNFa. Methods: Prospective database including 100 HILP (38–40°) with melphalan (10 mg/L) and TNFa 1 mg. Resection of the remnant tumour was performed 2 months after ILP. The main endpoint was complete response on MRI. Secondary endpoints were histological response, rate of amputation and toxicity. Results: Sex ratio was and median age was 43 years. Location/ median size were 30/48 mm and 70/72 mm for upper and lower limbs respectively. There were 26 multifocal tumors, 52 recurrences of which 18 arising in a pre irradiated field. Grade (FNCLCC) were 1 (23 pts), 2 (34 pts), 3 (43 pts). Fifty one pts had pre ILP systemic chemotherapy. A complete radiological response was obtained in 30% of pts while 48%, 9% and 13% of pts exhibited a partial, no change and disease progression. There was no mortality and no systemic toxicity. Local toxicity were (Wieberdink) grade 2 (16 pts), 3 (5 pts) and 4 (1 pt). A limb salvage surgery was achieved in 88% pts. With a median follow-up of 27 months, 3 years overall survival and local recurrence rate were 89% and 15% respectively. Age, gender, tumor size, recurrence, uni/multifocality, grade, pre op chemotherapy, pre irradiated field, were not predictive of the responses rates. Conclusions: This study confirm that 1mg TNFa is as effective as the standard dose without its systemic toxicity. A wide population of pts may benefit from this approach. No significant financial relationships to disclose.
Time and chemotherapy treatments trends in the elderly (age&gt;70) with lung cancer in a single UK cancer centre
Authors: T. Yau, S. Asley, I. Smith, M. O'Brien
Journal: Journal of Clinical Oncology (2004)

7128 Background: There are few data on the outcome in elderly populations (> 70) with lung cancer over the past 20 years. Equally there is little known about long term outcomes when treated with chemotherapy. This study focuses on elderly lung cancer patients (age>70) in a single UK cancer centre over the past 20 years. Methods: We retrospectively reviewed 960 patients who received treatment for lung cancer (NSCLC, SCLC and mesothelioma) in Royal Marsden Hospital (RMH) between 1982 and 2003. Patient characteristics, type of tumors, stage, performance status (PS), year of presentation, treatment and cause of death were analyzed. Survival analysis was done by the Kaplan Meier method. Comparison of all cause survival was done between patients presenting in 1982–1994 and 1995–2003 by the log rank test. Comparison of survival between different treatment regime used the proportional hazards model. Results: There has been an improvement in all cause survival (adjusted for sex, stage and PS) in all age groups. Between 1982 and 2003, there were 960 elderly patients with 519 aged 70–74, 328 aged 75–79 and 113 were aged ≥ 80 treated in the RMH. Of these, 55% of patients had NSCLC, 38% SCLC and 7% patients had mesothelioma which was either locally advanced or metastatic. Over 85% patients were had performance status 0–2. In early cohort, there were 270 patients and 690 patients in the recent cohort. The later group of patients has better survival and the difference is more pronounced in patients >80( p<0.001). As treatment, 41% patients received cisplatin combination, 18% carboplatin combination, 4% non-platinum combination, 17% single agent treatment and 30% no chemotherapy. Carboplatin combinations were significantly better than others after adjusting for PS, stage and sex(p =0.007) in all 3 groups of elderly patients. Cisplatin combinations were found to do marginally better (p=0.06). Conclusions: This analysis demonstrated that there has been a significant improvement in survival for elderly patients with lung cancer in the past 20 years. Carboplatin combination seems to have greater impact on survival than other combinations and single agent treatment. No significant financial relationships to disclose.
CYP3A inhibitors and adverse outcomes in patients treated with docetaxel chemotherapy.
Authors: Paul L. Swiecicki, Pamela J. Atherton, Heidi D. Finnes, Suneetha Puttabasavaiah, Matthew P. Goetz
Journal: Journal of Clinical Oncology (2013)

2596 Background: Docetaxel (D) is an anti-mitotic drug metabolized by the cytochrome P450 (CYP) 3A4 enzyme. While case reports have demonstrated a potential association of CYP3A inhibitor use with severe toxicity in D treated patients (pts), there are no data whether co-administration of CYP3A inhibitors with D increases the rate of hospitalization and/or death. Methods: A retrospective cohort of pts treated with D at the Mayo Clinic Rochester from 1/1/09-10/1/11 was identified. Information regarding D and concomitant chemotherapy (starting dose and dose reductions), type of CYP3A inhibitor, growth factor use, hospitalizations and deaths was abstracted. Time to event analyses (either hospitalization or death) were conducted using Kaplan-Meier estimates and proportional hazards modeling. Results: 384 pts (median age 63, range 20-93) received D as monotherapy (48%) or as multi-agent chemotherapy (52%) for a median of 4 cycles. 56 pts were co-administered CYP3A inhibitors (45 moderate, 11 strong). 90 pts were hospitalized during D chemotherapy and 15 died. The mean time to hospitalization was significantly shorter in pts treated with a mod/strong CYP3A inhibitor (186 days) vs not treated (408 days) (p=0.02) . While time to death was not significantly different based on inhibitor use (111 vs. 177 days, p=0.49), time to first event (hospitalization or death) varied significantly according to those on inhibitors (187 days) versus not (397 days) (HR: 1.78, p=0.02). Time dependent analyses indicated that use of multiage chemotherapy (combination vs D monotherapy; HR 1.96, p= 0.002) and chemotherapy dose reduction of either D (HR 0.54, p&lt;0.01) or other chemotherapy (HR 0.61, p=0.02) were significantly associated with the risk of an event. In a multivariate analysis, moderate/strong CYP3A inhibitor use was associated with a higher risk of any event (HR 1.79, p&lt;0.02), independent of the use or dose of either multi-agent chemotherapy or D dose. Conclusions: These are the first data to demonstrate that co-administration of CYP3A inhibitors with D increases the risk of hospitalization and/or death. Oncologists should reconcile medications prior to D administration and mod/strong CYP3A inhibitors should be avoided or used with caution.
Clinical research on radiotherapy at different time for unresectable cervical cancer.
Authors: Wenhui Li, Li Chang, Yunhe Ju, Meiping Jiang, Lang Li, Li Wang, Yanyou Liu, Yuhui Wang, Zhou Jiang, Jing Xiao, Zhengrong Wang
Journal: Journal of Clinical Oncology (2013)

e16516 Background: Radiotherapy is one of the mainstay treatments for cervical cancer. Circadian rhythm can be associated with cancers. In this study, we focused on the therapeutic effects, acute radiation damages and expressions of circadian genes in unresectable cervical cancer irradiated at different time. Methods: A total of 67 patients of unresectable cervical cancer (stage IIB-IIIB) were randomized to morning (9:00-11:00am) and evening (9:00-11:00pm) irradiation groups. Patients were treated with external beam radiotherapy to the whole pelvis (50 Gy in 25 fractions) and brachytherapy (36-42 Gy in 6-7 fractions). Therapeutic effects and acute radiation toxicities were evaluated after radiotherapy. Samples analyzed by flow cytometry were obtained from cervix at 9:00-11:00am and 9:00-11:00pm before and after radiotherapy. Results: Of 65 patients, the overall and higher grade of diarrhea (III-IV) induced by radiation in patients after morning vs evening radiotherapy were 75.0% vs 57.6% (p = 0.138), 12.5% vs 6.1% (P=0.427). Higher grade of hematologica toxicity in evening group was significantly increased as compared with morning group (54.5% vs 21.9%. p = 0.007). But patients’ response to radiation in two groups was similar (p = 0.708). Increased cell apoptosis and decreased G2/M phase fraction were observed significantly both in two groups after radiotherapy, but the increased/decreased values between two groups were found not to differ significantly. Expressions of circadian genes Per1, Per2 and Clock also increased after radiotherapy, and the increased levels between two groups were similar. Moreover, there were significant negative correlations between expressions of circadian genes Per1, Per2, Clock and G2/M phase fraction. But their expressions were positively correlated with cell apoptosis. Conclusions: Circadian genes may be associated with the similar radiation response and different toxicity in cervical cancer irradiated at different time by influencing cell cycle and apoptosis. The knowledge may provide a possibility of treating the patients with increased effect and decreased toxicity. Clinical trial information: ChiCTR-TRC-10001228.
A phase I/II clinical trial of veliparib (ABT-888) and radiation followed by maintenance therapy with veliparib and temozolomide in patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG): A Pediatric Brain Tumor Consortium Interim Report of Phase I Study.
Authors: Patricia Ann Baxter, Jack M. Su, Xiao-Nan Li, Arzu Onar-Thomas, Catherine A Billups, Patrick A. Thompson, Stewart Goldman, Sridharan Gururangan, Tina Young-Poussaint, Evelyn Mary McKeegan, Xia Wan, Vincent L. Giranda, Arnold Paulino, Edward Smith, Susan Blaney, James M. Boyett, Maryam Fouladi
Journal: Journal of Clinical Oncology (2015)

10053 Background: We report the results of the dose escalation component of a phase 1/2 trial in children with newly diagnosed DIPG designed to determine the maximum tolerated dose (MTD) and toxicities of veliparib in combination with radiation therapy (XRT) as well as the optimal dose for veliparib and TMZ post-XRT. We also evaluated the pharmacokinetics (PK) of veliparib and its impact on poly(ADP-ribose) (PAR) levels in PBMCs. Methods: Veliparib was given daily x 5, BID, during XRT (6-7 wks) followed by maintenance therapy with daily TMZ and twice daily veliparib for 5 days, every 28 days for up to 10 cycles. The veliparib starting dose during XRT was 50 mg/m2/dose BID. Maintenance therapy began at week 10 with veliparib 25 mg/m2/dose BID and 135 mg/m2/day TMZ. Blood for PK studies was obtained pre- and post veliparib days 1 and 4 of XRT. PAR levels, as measured using an ELISA assay, were assessed on days 1 and 3 to 5 of XRT. Results: 18 patients were enrolled in the phase 1 portion of the trial. Dose-limiting toxicities (DLT) during the XRT phase were a grade 2 intra-tumoral hemorrhage (n = 1), grade 3 maculo-papular rash (n = 2), and grade 3 nervous system disorder (generalized neurologic deterioration) (n = 1). The RP2D for veliparib was 65 mg/m2/dose BID during radiation therapy. After completion of veliparib and radiation, patients received veliparib at 25 mg/m2/dose BID and TMZ at 135 mg/m2/day for 5 days every 28 days, which was the RP2D from preceding PBTC027, a phase I trial in children with recurrent CNS tumors. Intra-patient escalation of TMZ during maintenance was attempted but was not feasible due to hematologic DLT. Conclusions: Veliparib, 65 mg/m2/dose BID, plus radiation therapy, followed by veliparib plus TMZ was reasonably well tolerated in children with newly diagnosed DIPG. A phase 2 trial is ongoing to study the efficacy of this treatment in children with newly diagnosed brainstem gliomas. Clinical trial information: NCT01514201.
Tasisulam-sodium in combination with liposomal doxorubicin in patients with ovarian cancer.
Authors: D. Scott McMeekin, Lee S. Rosen, Alberto Bessudo, Datchen Fritz Tai, Robert L. Ilaria, Jian Chen, P. Kellie Turner, Sandia Krueger, Michael S. Gordon
Journal: Journal of Clinical Oncology (2013)

5551 Background: Tasisulam-sodium (TASI) is a novel, highly albumin-bound small molecule that induces tumor cell apoptosis and has antiangiogenic activity. This phase 1b study was designed as a dose-finding study for TASI in combination with liposomal doxorubicin (DX) in patients (pts) with advanced solid tumors, followed by a dose-confirmation phase in platinum-resistant DX-naïve ovarian cancer (OvCa) pts. However, the study was stopped early for business reasons. Nonetheless, the dataset allowed partial characterization of the safety and antitumor activity of TASI + DX among OvCa pts who achieved an albumin-corrected exposure (AUC alb ) within a hypothesized therapeutic range identified in phase II monotherapy trials. Methods: In the dose-escalation phase (3+3 schema), pts received TASI (escalating C max targets of 300-380 μg/mL, 2-h IV) plus DX (40 mg/m 2 , 1-h IV) every 28 days. Pharmacokinetic and safety analyses identified an AUC alb target of 3500 h*μg/mL for the dose-confirmation phase. We analyzed data for OvCa pts from both phases who achieved TASI AUC alb of 1200-6400 h*μg/mL in cycle 1. Results: Of the 13 OvCa pts who completed the dose-escalation phase and 6 OvCa pts who completed the dose-confirmation phase, 10 had AUC alb of 1200-6400 h*μg/mL in cycle 1. For these pts, the most common possibly drug-related Grade 3-4 adverse event was neutropenia (see table). Although no pt achieved complete response, 2 pts achieved partial response. Data from the other OvCa pts will also be presented. Conclusions: The early closure of the study did not allow complete assessment of TASI in combination with DX; however, acceptable tolerability and some antitumor activity were observed for OvCa pts with TASI AUC alb within the hypothesized therapeutic range. Clinical trial information: NCT01214668. [Table: see text]