tbuckley/cabot-search huggingface dataset:
The free hormone hypothesis: Correlation of decreases in PSA with free testosterone rather than total testosterone in men with advanced prostate cancer treated with GTx-758.
Authors: Alvin M. Matsumoto, Robert H. Getzenberg, Christopher Coss, Michael L. Hancock, Xuemei Si, James T. Dalton, Mitchell S. Steiner
Journal: Journal of Clinical Oncology (2013)

e16015 Background: Androgen deprivation therapy (ADT) improves disease-free survival but disease progression is related, in part, to ineffective castration. The free hormone hypothesis states that the biological activity of steroid hormones is affected by its unbound (free) rather than its protein-bound concentration. Serum total testosterone (T) concentrations predominantly reflect the T bound to plasma proteins and do not accurately predict prostatic levels of T. Methods: In a Phase II study (G200705), men with advanced prostate cancer (n=159) were randomized to receive 1000 mg or 2000 mg GTx-758 daily or leuprolide as their initial ADT. Serum total T (mass spectrometry), free T (equilibrium dialysis), SHBG and PSA concentrations were measured. A second Phase II study (G20007) was performed in men (n=9) with CRPC who then received GTx-758 2000 mg daily. Results: Although both treatments reduced serum total T levels to &lt; 50 ng/dL, leuprolide decreased them to a greater extent. However, GTx-758 caused greater reductions in serum PSA, suggesting that total T concentrations did not accurately reflect the suppression of androgen activity. Both dosages of GTx-758 reduced free T levels to a greater extent (mean of 0.7 and 0.4 pg/ml at day 60, and 0.4 and 0.4 pg/ml on day 90, respectively) than leuprolide (mean of 1.4 pg/ml on day 60 and 1.4 pg/ml on day 90; p values &lt;0.03). Similar clinical results were observed in CRPC patients where GTx-758 daily resulted in a 71% decrease in %free T and clinically relevant PSA reductions in men maintained on ADT with LHRH agonists. As a result of adverse events at higher doses of GTx-758, the trial was stopped early. Conclusions: The ERα agonist, GTx-758, reduced the biologically active form of T, free T, to significantly lower levels than leuprolide. Reductions in PSA appeared to be more highly associated with changes in free T. These data provide compelling evidence to support the free hormone hypothesis and suggest that serum free T concentrations would provide a better measure of therapeutic efficacy in ADT than total T. A Phase II clinical trial utilizing lower doses of GTx-758 (G200712) is currently being performed. Clinical trial information: NCT01326312.
Computed tomography (CT) imaging features in early-stage lung adenocarcinoma differentiating exon 19 and exon 21 epidermal growth factor receptor (EGFR) mutated tumors.
Authors: Benjamin F. Chu, Efe Ozkan, Selnur B Erdal, Weiqiang Zhao, Konstantin Shilo, Gregory Alan Otterson
Journal: Journal of Clinical Oncology (2014)

7548 Background: Imaging studies provide essential clinical information for lung cancer diagnosis, treatment and management. Features such as ground glass opacity (GGO), while commonly seen in early stage lung cancer, have minimal clinical implication. We previously described a correlation between GGO and exon 21 mutation in a subset of our current cohort. Here, we report our analysis in a single institution confirming GGO component as an imaging characteristic differentiating exon 19 and exon 21 EGFR-mutated (MT) tumors. Methods: Since 2009, our institution has prospectively characterized the EGFR status of all non-squamous lung carcinomas. Our inclusion criteria included tumor size < 3 cm and positive EGFR mutation. We randomly selected wild type (WT) patients matched by age and tumor size. The CT imaging of these patients was evaluated by a single radiologist (EO). Results: Imaging features were extracted from 20 WT and 45 EGFR-MT tumors. Of the EGFR-MT tumors, 21 had the exon 21 point mutation and 24 had in-frame exon 19 deletion. There were 69% (31) solid nodules in EGFR-MT and 90% (18) in WT tumors. While solid nodule was the primary feature seen in both WT and EGFR-MT tumors, exon 21-MT tumors were associated with GGO component (p = 0.006). This tendency, however, is not present in the exon 19-MT tumors. Lack of pleural attachment is seen more frequently with exon 19-MT tumor as compared to WT tumors. Other imaging features such as internal air bronchogram, and spiculated/lobulated border did not differentiate between groups. Conclusions: Among these treatment-naive lung adenocarcinomas, we discovered a propensity for exon 21-MT tumor to develop GGO on CT imaging. While both exon 21 point mutation and exon 19 deletion are predictive of response to EGFR tyrosine kinase inhibition, they exhibited distinct radiological phenotypes suggesting a different underlying biology. Exon 19 n=24 (%) Exon 21 n=21 (%) Exon 19 and 21 n=45 (%) Wild type n=20 (%) GGO 3(12) 11(52) 14 (31) 2(10) Solid 21(88) 10(48 ) 31(69) 18(90) p values 1.000* 0.009≠ 0.006# 0.107& * p value comparing WT and Exon 19. ≠ Exon 19 and Exon 21. # WT and Exon 21. & WT and Exon 19 and 21.
Metastatic basal cell carcinoma: Differences in survival by site of spread.
Authors: Margaret Elizabeth McCusker, Jeannie Hou, Lisa Wang, Huibin Yue, Axel Hauschild
Journal: Journal of Clinical Oncology (2012)

8585 Background: Basal cell carcinoma (BCC), the most common skin cancer, rarely metastasizes. Consequently, the epidemiology of metastatic BCC (mBCC) is poorly characterized. The largest published mBCC review includes 170 cases reported from 1894–1980 (von Domarus H, Stevens P. J Am Acad Dermatol 1984;10:1043-60). Targeted therapies with hedgehog signaling pathway inhibitors, such as vismodegib, are currently being developed to treat this rare disease. The objective of the current analysis was to provide an updated description of the epidemiology and survival outcomes for mBCC. Methods: A PubMed literature search was conducted for mBCC case reports published in English during 1981–2011. mBCC cases that met the following criteria were evaluated: primary BCC located on skin; primary tumor and metastasis confirmed by pathology, and metastasis was not the result of direct tumor spread. Only cases with survival data giving dates (month and year) or durations were included in the analysis. Differences between groups were assessed with t tests and χ 2 tests as appropriate. Survival was assessed with Kaplan–Meier (K-M) methods. Results: We identified 101 mBCC cases that met the selection criteria; 38 patients (38%) had lymph node-only disease (LD) and 63 (62%) had distant metastases (DM). In both groups, males predominated. DM patients were younger at mBCC diagnosis (mean 59 vs 66 y for LD). Among 96 cases with treatment data for metastatic disease, more DM patients received chemotherapy (25% vs 9% for LD), but more LD patients underwent surgery (85% vs 52% for DM). Survival duration ranged from 0 to 120+ months in all patients. The overall 1-y probability of survival after mBCC diagnosis was 75.7% (95% CI 67.2–84.2%), with lower survival in DM patients (69.1%; 95% CI 57.5–80.7%) vs LD patients (86.5%; 95% CI 75.5–97.5%). Conclusions: Patients with LD and DM mBCC may have different clinical courses and outcomes. Based on published case reports, DM patients were younger at mBCC diagnosis and had a lower 1-y survival probability vs LD patients. To our knowledge, these are the first K-M survival estimates reported for an mBCC case series of this size. These data help to provide a historical context for novel mBCC therapies under development, such as vismodegib.
Cetuximab in combination with concurrent chemoradiotherapy (CRT) in locally advanced non-small cell lung carcinoma (NSCLC): A feasibility study
Authors: M. M. van den Heuvel, J. Belderbos, O. Dalesio, M. van der Pol, L. Uitterhoeve, P. van de Vaart, M. Verheij, N. van Zandwijk
Journal: Journal of Clinical Oncology (2009)

7540 Background: Despite modest benefits from CRT regimens in patients with locally advanced NSCLC, more efficacious treatment options are needed. Cetuximab, a monoclonal antibody that selectively binds to the epidermal growth factor receptor, has demonstrated activity in patients with metastatic NSCLC. This trial was initiated to assess the feasibility of combining cetuximab with concurrent CRT. Methods: Patients with non-operable locally advanced NSCLC received cetuximab (400 mg/m 2 on day 1, 250 mg/m 2 q1w from weeks 2–6) in combination with cisplatin (6 mg/m 2 q1d from weeks 2–6), and RT (66 Gy in 24 fractions from weeks 2–6). Results: Between April and July 2008, 12 consecutive, eligible patients entered the study. The mean age was 61 years (range: 43–77) and 50% were male. Baseline NSCLC staging was: IIb (1 patient), IIIa (5 patients), and IIIb (6 patients). Treatment was generally well tolerated. Acne-like rash and radiation esophagitis were the most common side effects (grade ≤3 according to CTCAE v 3.0) (see table). No unexpected toxicities were observed. Early-response monitoring using PET-CT scans was performed 4 weeks after the last fraction of RT in 10/12 patients. A metabolic response was seen in 50% (complete: 3 patients; partial: 2 patients) of patients. One patient showed progressive disease. Conclusions: Cetuximab added to CRT in patients with NSCLC was generally well tolerated and produced promising early clinical responses. A randomized phase II study comparing CRT with CRT and cetuximab is ongoing. [Table: see text] [Table: see text]
An open label safety and efficacy phase 2a study of the N-cadherin (N-cad) antagonist ADH-1 in subjects with N-cadherin expressing solid tumors
Authors: Q. S. Chu, J. Knox, G. Batist, P. Venner, K. N. Chi, L. Woods, H. A. Burris, R. K. Malik, W. P. Peters, D. J. Jonker
Journal: Journal of Clinical Oncology (2007)

3567 Background: Malignant transformation and invasive capacity is highly correlated with N-cad, a cell adhesion molecule expressed on tumor cells and vascular endothelium. ADH-1, a cyclic pentapeptide (CHAVC), is a functional inhibitor of N-cad, and produces apoptosis and tumor vascular disruption in preclinical models. We report results from a Phase 2a study of intravenous (IV) ADH-1 (q 3 W, modified to qW) in subjects with N-cad+ solid tumors. Methods: Subjects with the following N-cad+ refractory tumors with measurable disease were eligible: renal cell (RCC); hepatocellular (HCC); adrenocortical (ACC); gastroesophageal (GE); NSCLC; HNSCC; and breast (HSNCC and breast subjects were only eligible for q3W schedule). ADH-1 was administered at 500 mg/m 2 q 3 W, or 600 mg/m 2 in the qW schedule. Intra-subject dose escalation was permitted at cycle 3 to 600 mg/m 2 (900 mg/m 2 with the qW schedule) in the absence of significant toxicity, tumor response or progression. Results: Tumor samples from 159 subjects were tested for N-cad, and 90 were N-cad+ (N-cad+/number tested: GE 13/48, HCC 29/35; NSCLC 16/33; RCC 27/28; ACC 3/8; HNSCC 2/6; Breast 0/1). Forty subjects, 10 on the q3W and 30 on the qW schedule (19 HCC; 7 RCC; 6 NSCLC; 6 GE; 1 ACC; 1 HNSCC) received 121 cycles of ADH-1. The drug was well tolerated, with commonly reported adverse events being Grade 1 or 2 in severity. One subject with HCC had pre-existing renal insufficiency, developed Grade 2 nausea and vomiting 11 days after the 3 rd cycle of ADH-1 administered q 3W, leading to non-oliguric renal failure. Following an initial period of recovery, she developed sepsis and died; these events were considered to not be related to study drug. A second subject with HCC developed a hemiparesis due to a Grade 3 intracranial hemorrhage from a previously unknown metastatic brain lesion, 5 days after the 1 st dose of ADH-1. There were no complete or partial responses; 32 subjects had SD for =2 cycles, 8 had SD for =4 cycles (4 HCC, ACC, GE, RCC, HNSCC), 6 had SD for =6 cycles (3 HCC, GE, RCC, HNSCC). The longest duration on study was 12 cycles (RCC). Conclusions: ADH-1 was well tolerated and prolonged SD was noted in several subjects. No significant financial relationships to disclose.
Effective complementary ASCO policy and day to day decision support strategies optimize anti-emetic choices.
Authors: Anmol Baranwal, Dinah Faith Q. Huff, Kevin B. Knopf, Charles L. Bennett, William S. Shimp, Marc L. Fishman, William J. Hrushesky
Journal: Journal of Clinical Oncology (2015)

9630 Background: Emetogenicity is a common reason for patients forgoing effective chemotherapy. ASCO, in its 2013 Top Five list, recommends against overuse of antiemetics and for the use of cost-effective agents. Oncology Analytics (OA) is a cancer care decision-support entity comprised of oncologists, PharmDs and oncology RNs, interacting with some 5000 oncologists and promoting high quality cost-effective cancer treatment based on level I data and national guidelines. We hypothesize that on-patent antiemetics are overused in comparison to equally effective generics; that this misuse/overuse induces financial toxicity; and that these ill effects can be offset by ASCO policy initiatives and OA decision support activities. Methods: We analyzed antiemetic requests in 2013 & 2014 in Georgia and Florida. Linear regression and chi-squared were utilized to determine time trends for the ratio of palonosetron vs. generic antiemetic regimens (ondansetron and granisetron) across these 7 quarters. We contrasted prescribing behavior concurrent with ongoing OA interaction, before and after the release of ASCO recommendations against unnecessary expensive anti-emetics. Results: 12,116 antiemetic requests were assessed in a pre-approval setting. After the 2013 ASCO policy recommendation, there was an immediate increase in the likelihood of requests for cost-effective regimens compared to more expensive “on -patent” choices (chi-squared p = 0.004). Over a thousand (1164/5341, 22%) of the requests for branded medications were inappropriate according to ASCO and/or NCCN guidelines, and discouraged by OA. Over this time span, there is a clear trend toward cost-effective generic choices, decreasing extrapolated costs by about $300,000 annually. Conclusions: The ASCO-defined overuse of expensive antiemetics in Florida and Georgia is substantial. ASCO national Policy, supported by daily OA interventions, diminishes the unnecessary use of expensive anti-emetics, increases the use of cost-effective antiemetic alternatives, and diminishes financial toxicity while enhancing cancer care quality. ASCO guidelines, when supported by a decision support program, result in significant cost savings.
Vorinostat as a radiosensitizer for CNS malignancies: Preclinical results and phase I trial in brain metastasis.
Authors: Wenyin Shi, Yaacov Richard Lawrence, Hak Choy, Phyllis R. Wachsberger, David W. Andrews, Maria Werner-Wasik, Adam Dicker
Journal: Journal of Clinical Oncology (2013)

2100 Background: To evaluate the effect of vorinostat as radiosensitizer in human Glioblastoma cell lines in preclinical study, as well as a phase I study to evaluate the safety, and tolerability of vorinostat, an HDAC inhibitor, when combined with whole brain radiation treatment (WBRT) for patients with brain metastasis. Methods: Preclinical studies evaluated the effect of vorinostat on DNA repair enzyme expression, repair of radiation induced DNA damage, and cell survival to radiation treatment as a proof of concept. Further phase I clinical trial included patients with histological diagnosis of malignancy and radiographic evidence of brain metastasis. WBRT was 37.5 Gy in 2.5 Gy fractions delivered over 3 weeks. Vorinostat was administrated by mouth, once daily, Monday through Friday, concurrently with radiation treatment. The vorinostat dose was escalated from 200 mg to 400 mg daily using a 3+3 trial design. Results: Preclinical studies showed with increasing doses of vorinostat more profoundly decrease expression of key genes involved in DNA repair, inhibiting the repair of DNA damage induced by ionizing radiation and leading to decreased clonogenic survival. It enhanced the radiation effect in vitro. In the phase I trial, 17 patients were enrolled, 4 patients were excluded from the analysis due to either incorrect radiation dose (n=1), or early treatment termination due to disease progression (n = 3). There were no treatment related grade 3 or higher toxicities in the 200 mg and 300 mg dose levels. In the 400mg cohort there was a grade 3 pulmonary embolus and one death within 30 days of treatment. Although both events were most likely related to disease progression rather than treatment. However, to be more conservative, we defined the death as a dose limiting toxicity. Conclusions: Preclinical studies demonostrated that vorinostat profoundly decrease expression of key genes involved in DNA repair, inhibiting the repair of DNA damage induced by ionizing radiation and leading to decreased clonogenic survival. Vorinostat administered orally once daily with concurrent whole brain radiation treatment is well tolerated to the dose of 300 mg. This is the recommended dose for phase II study. Clinical trial information: NCT00838929.
A Prospective Multicenter Single-Arm Study of Low-Dose Decitabine in Adult Patients with Immune Thrombocytopenia
Authors: Hai Zhou, Ping Qin, Chenglu Yuan, Haiyan Zhang, Zhencheng Wang, Xuehong Ran, Xiaoxia Chu, Yunliang Hao, Wenzheng Yu, Xin Wang, Jun Peng, Ming Hou
Journal: Blood (2016)
Clinical and biological significance of CD157 in malignant pleural mesothelioma
Authors: S. Morone, E. Ortolan, A. Giacomino, R. Parrotta, N. Lo Buono, I. Rapa, L. Righi, M. Volante, E. Ruffini, S. Demichelis, G. Rovere, S. Novello, F. Malavasi, A. . Funaro
Journal: Journal of Thoracic Oncology (2011)
Skin, nail, and staphylococcal infections associated with the addition of pertuzumab to trastuzumab-based chemotherapy.
Authors: Joanne E. Mortimer, Jae J Jung, Yuan Yuan, Laura Kruper, Daphne Stewart, Samuel Chung, Mary Mendelsohn, Massimo D'Apuzzo, Bernie Tegtmeier, Sanjeet Dadwal
Journal: Journal of Clinical Oncology (2015)

e11610 Background: The addition of pertuzumab, to trastuzumab-based chemotherapy is currently considered first-line therapy for locally advanced and metastatic disease HER2 positive breast cancer and has also been suggested for use in the adjuvant setting. Over the past 18 months, we have observed an increase in infectious complications in patients receiving the combination of pertuzumab and trastuzumab with and without chemotherapy. We expand a series of prospectively identified patients who developed infections while on these regimens. Methods: We became concerned about an increased incidence of infections shortly after the FDA approval of pertuzumab, and created an IRB approved registry of these patients. Results: Twenty-five women were identified to have 29 separate infections (often > one site); 7 after cycle 1; 6 after cycle 2, 8 after cycle 3 and 8 after > 4 cycles. The median age was 51 (Range 33-67); 12 received pertuzumab, trastuzumab, carboplatin, and docetaxel, 5 pertuzumab, trastuzumab, and docetaxel,6 pertuzumab, trastuzumab, and nab-paclitaxel, and 2 pertuzumab and trastuzumab. Folliculitis of the scalp, abdomen, and/or buttocks was observed in 17 patients, abscesses in 8 patients (4 of whom required incision and drainage) and cellulitis in 2. Severe paronychial infections involving one to 16 digits were observed in 3; 1 pt required surgical removal of 2 nails. Quantitative immunoglobulins were found to be low in 8 of 15 women tested; 2 patient had low total protein but did not have an assessment of quantitative immunoglobulins. All patients were initially treated with oral antibiotics, and 5 required hospitalization. Cultures were obtained in 8 patients; Staph aureus was identified in 3 and methicillin resistant Staph in 5. A 57 year old pt receiving neoadjuvant PTCH died on cycle 2 day 7. Autopsy was consistent with sepsis and gram positive cocci were identified. Skin biopsies were performed in 3 patients and pathologic findings are consistent with EGFR changes. Conclusions: We continue to observe an increased incidence of infections in women treated with pertuzumab and trastuzumab regimens. We have initiated patient education to ensure awareness of this potential complication.
Breast cancer risk among women following lifestyle recommendations: A case-control study in Spain.
Authors: Marina Pollán, Adela Castello, Amparo Ruiz, Ana Casas, Jose Manuel Baena-Cañada, Virginia Lope, Silvia Antolín, Manuel Ramos Vazquez, Montserrat Munoz-Mateu, Ana Lluch, Ana De Juan, Carlos Jara-Sanchez, M. Angeles Jimeno, Petra Rosado, Elena Diaz Pena, Vicente Guillem, Eva Maria Carrasco, Beatriz Perez-Gomez, Jesus Vioque, Miguel Martin
Journal: Journal of Clinical Oncology (2014)

1602 Background: In 2007, the World Cancer Research Fund (WCRF) and the American Institute of Cancer Research (AICR) issued 8 general and 2 special recommendations for cancer prevention based on available evidence. The objective of this study was to explore the association between the WCRF/AICR recommendations and breast cancer risk. Methods: Epi-GEICAM is a nation-wide case-control study, 1019 cases from 23 hospitals were matched to 1019 controls by age and municipality of residence. The cases were sub classified by tumor subtype: 1) Estrogen Receptor(ER)+ or Progesterone Receptor(PR)+ with Human Epidermal Growth Factor Receptor 2(HER2)-; 2) HER2+; and 3) ER-,PR-&HER2- tumors. We constructed a score (0-9) based on 9 of the 10 WCRF/ AICR recommendations. The score was grouped in 4 categories (0 to <4, 4 to <5, 5 to <6 and ≥6) and its association with BC risk was evaluated using conditional logistic regression models adjusted by total calorie intake, smoking habit, age at first delivery, education, history of breast problems, family history of BC and menopausal status. Multinomial logistic regression models were used to evaluate the association of the WCRF/AICR score with each of the intrinsic BC subtypes. These models were adjusted by age, hospital, and the same set of potential confounders described above. Results: The women with higher score showed a decreased risk of BC (OR[6-9]vs[0-4] =0.51; 95%CI=0.36-0.73 and ORunit-increase=0.82; 95%CI =0.74-0.91; p-trend<0.001). This preventive effect was slightly more pronounced in postmenopausal women (OR[6-9]vs[0-4] =0.43; 95%CI=0.26-0.70 and ORunit-increase=0.81; 95%CI=0.71-0.93, p-trend=0.001) and in women with ER+/PR+&HER2- tumors (OR[6-9]vs[0-4] =0.43; 95%CI =0.30-0.62 and ORunit-increase=0.78; 95%CI=0.70-0.87; p-trend<0.001). However, none of the differences in the magnitude of risk by menopausal status and intrinsic tumor subtypes was statistically significant. Conclusions: Adherence to the WCRF/AICR recommendations for cancer prevention might reduce breast cancer risk in both pre and postmenopausal women and all cancer subtypes.