tbuckley/cabot-search huggingface dataset:
Randomized phase 2 study of abiraterone acetate (AA) with or without exemestane (E) in postmenopausal patients (pts) with estrogen receptor–positive (ER+) metastatic breast cancer (MBC).
Authors: Joyce O'Shaughnessy, Mario Campone, Etienne Brain, Patrick Neven, Daniel F. Hayes, Igor Bondarenko, Thomas W. Griffin, Jason L. Martin, Peter De Porre, Thian San Kheoh, Margaret K. Yu, Weimin Peng, Stephen R. D. Johnston
Journal: Journal of Clinical Oncology (2014)

519 Background: Androgen receptor (AR) signaling and/or incomplete inhibition of agonistic estrogen synthesis may contribute to MBC resistance to a nonsteroidal aromatase inhibitor (NSAI). Combined inhibition of the AR with AA and the ER with E may be of clinical benefit. We assessed the safety and efficacy of AA + prednisone (P) in postmenopausal pts with NSAI-pretreated ER+ MBC. Methods: 297 pts were randomized to receive 1000 mg AA + 5 mg P (AA + P) vs AA + P with 25 mg E (AA + P + E) vs 25 mg E alone (E); 293 pts were treated. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and clinical benefit rate (CBR). Results: The median age was 63 (37-87); 64% (AA + P + E), 64% (AA + P), and 65% (E) of pts had prior NSAI for MBC while 70% (AA + P + E), 66% (AA + P), and 65% (E) had prior chemotherapy. AA + P enrollment was discontinued (n = 89) after the planned interim analysis. 181 pts had measurable disease at baseline by RECIST. There was no significant difference in PFS or CBR with AA + P or AA + P + E compared with E (Table). Median OS was not reached. Increased serum progesterone concentrations were observed in both AA arms but not with E. The grade 3 or 4 toxicities associated with AA included (AA + P + E vs E) hypokalemia (5.8% vs 2.0%), hypertension (5.8% vs 2.9%), AST increase (4.8% vs 3.9%), and ALT increase (2.9% vs 2.9%). Treatment discontinuation for treatment-emergent adverse events was uncommon and only included 6 (5.9%) in E and 10 (9.6%) pts in AA + P + E. Conclusions: Adding AA to E in NSAI-pretreated MBC pts did not improve PFS or CBR. Administration of 5 mg of P adequately suppressed AA-associated mineralocorticoid excess effects. AA-induced CYP17 inhibition may not suppress steroid hormone receptor signaling in ER+ MBC potentially due to AA-induced increased progesterone synthesis. Clinical trial information: NCT01381874. Outcome E AA + P AA + P + E n = 102 n = 89 n = 106 PFS, median (months) HR (95% CI) p value 3.7 3.7 1.1 (0.82-1.60) 0.437 4.5 0.96 (0.70-1.32) 0.794 n = 63 n = 52 n = 66 CBR, n (%) RR (95% CI) p value 8 (13) 5 (10) 0.76 (0.26-2.18) 0.603 15 (23) 1.79 (0.82-3.93) 0.137 Abbreviations: HR, hazard ratio; HR < 1 favors AA + P or AA + P + E. RR, relative risk; RR > 1 favors AA + P or AA + P + E.
Effect of celastrol on temozolomide cytotoxicity in melanoma cells and inhibition of NF-kB signaling
Authors: M. Chen, I. Osman, S. J. Orlow
Journal: Journal of Clinical Oncology (2009)

9076 Background: Temozolomide (TMZ) exhibits clinical activity in the treatment of melanoma and glioblastoma, but response rates are low. Identification of agents that improve TMZ's efficacy and overcome resistance is of great interest. In this study, we have identified celastrol as a natural product that significantly enhances TMZ-induced cytotoxicity by testing a library of drugs and natural products for cytotoxic activity against glioma and melanoma cell lines and have examined its mechanism of action in melanoma cells. Methods: A preliminary screening of a library of 2000 drugs and natural products was performed and a short list of drugs was identified as able to enhance TMZ-induced cell killing in TMZ-resistant cancer cell lines. The effects of these compounds were further confirmed in five melanoma cell lines. A cell proliferation assay was used to compare growth inhibitory effects of single agent TMZ versus combination treatments. Synergy in inhibiting cell proliferation was assessed using combination-index methods. The expression of NF-kB, IkB, MAPK, and PARP were examined using Western blot analysis. The effect of treatments on the cell cycle was examined by flow cytometry. The localization of NF-kB in melanoma cells was evaluated through immunofluorescence microscopy. Results: Combining celastrol and TMZ synergistically inhibited cell proliferation, enhanced cell cycle arrest, and increased apoptosis in a series of melanoma cell lines, compared to treatment with TMZ alone. We further found that celastrol inhibited proteasome activity, TNF-α induced IkB phosphorylation and NF-kB translocation to the nucleus. Inhibition of NF-kB with siRNA mimicked the ability of celastrol to sensitize melanoma cells to TMZ-induced cell killing, suggesting inhibition of NF-kB was indeed involved in TMZ/celastrol-induced cytotoxicity. Furthermore, combination treatment induced phosphorylation of JNK. Conclusions: Our data suggest that combined use of TMZ with celastrol, a natural product derived from a vine extract that has been used orally in Chinese medicine for over a thousand years, may enhance the chemotherapeutic efficacy of TMZ in melanoma. No significant financial relationships to disclose.
Adherence to chemotherapy guidelines for non-metastatic (NM) and metastatic (M) colorectal cancer (CRC).
Authors: Brian S. Seal, Kenneth Shermock, Carl V Asche, Jane Chang, Muralikrishna Tangirala, Jonathan K Kish, Erin Zagadailov, Michael Eaddy
Journal: Journal of Clinical Oncology (2015)

e14690 Background: Evaluate concordance to NCCN-recommended treatment guidelines across lines of care for patient diagnosed and treated for NM and MCRC. Methods: Patients age ≥ 18 diagnosed and treated for CRC from 01/2008–12/2013 in a database were identified. Patients were required to be continuously enrolled ≥ 6 months pre- and ≥ 3 months post-diagnosis and were subsequently stratified into cohorts based on the occurrence and diagnostic timing of M disease: no metastases (NM); ≤ 90 days (M1), ≥ 90 days (M2) from initial diagnosis. NCCN guideline-adherent care (GAC) was assessed for patients treated with chemotherapy. GAC regimens included monotherapy or combination treatment with 5-FU (+LV), capecitabine (C), irinotecan (I), oxaliplatin (O), bevacizumab (B), panitumumab, cetuximab (C), and regorafenib. Partial adherent care (PAC) included the GAC regimens with a non-guideline regimen. Non-guideline (NG) care did not include any recommended agents. Results: Of 17,793 patients, 13,859 (77.9%) were NM, 2,051 (11.5%) M1, and 1,883 (10.6%) M2. Overall, 23.9% of patients received chemotherapy, with 11.1% receiving second- and 3.8% third-line therapy. Treatment rates from first to third line declined across all groups: NM, 11.7–0.4%; M1, 70.0–14.2%; M2, 63.5–17.6%. Over 90% of patients receiving chemotherapy received GAC, with NM patients being less likely to receive GAC across all lines compared to M patients. In first and second line, 5-FU/LV ± O and C were the most frequently used therapies for both NM and M patients. In third line, 5-FU/LV/I/B was most frequently used among M patients. Conclusions: Chemotherapy treatment rates declined for NM and M patients from first through third lines of care. Guideline adherence was similar across both groups in first and second line; however, for the small number of NM patients receiving third line, the rate of NG care more than doubled. 5-FU-based regimens were the most frequently used across all groups and lines. First Line Second Line Third Line NM M1 M2 NM M1 M2 NM M1 M2 % Treated 11.7% 70.0% 63.5% 3.3% 37.4% 39.7% 0.4% 14.2% 17.6% GAC 85.2% 95.6% 90.6% 88.5% 94.8% 91.2% 75.4% 94.2% 93.7% PAC 0.2% 0.8% 1.0% 0.2% 2.7% 2.7% 0.0% 4.1% 2.4% NG 12.7% 2.6% 7.2% 11.0% 2.6% 6.1% 24.6% 2.1% 4.2%
Dose-finding and safety study of an oncolytic polio/rhinovirus recombinant against recurrent glioblastoma.
Authors: Annick Desjardins, John Howard Sampson, Katherine B. Peters, Tulika Ranjan, Gordana Vlahovic, Stevie Threatt, James Emmett Herndon, Allan H. Friedman, Henry S. Friedman, Darell D. Bigner, Matthias Gromeier
Journal: Journal of Clinical Oncology (2013)

2094 Background: Current therapies for glioblastoma are limited by ineffective delivery beyond the blood-brain barrier, limited diffusion of macromolecules, and lack of tumor specificity. Sustained direct intracerebral infusion at slow flow rates [convection-enhanced delivery (CED)] can overcome delivery barriers. PVSRIPO is the live attenuated, oral (SABIN) serotype 1 poliovirus vaccine containing a heterologous internal ribosomal entry site stemming from human rhinovirus type 2. PVSRIPO recognizes nectin-like molecule-5, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We report the results of an ongoing phase I study evaluating PVSRIPO when delivered by CED. Methods: Eligible on study are adult patients with: 1-5 cm of measurable supratentorial recurrent glioblastoma ≥1cm away from the ventricles; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS ≥70%; and positive anti-poliovirus titer. PVSRIPO is delivered intratumorally by CED over 6.5 hours. PVSRIPO dose escalation is accomplished by increasing agent concentration, allowing flow-rate and infusion volume to remain constant. Two-step continual reassessment method is used for dose escalation, with one patient each treated on dose levels 1-4, and a possibility of up to 13 patients on dose level 5. Results: Thus far, a total of five patients have been treated on study. No related or unrelated grade 3 or higher adverse events have been observed. Grade 1 adverse events possibly related to the study drug or procedure include one each of fever, cough, nasal congestion, vomiting, headache, hemiparesis, and lethargy. Grade 2 adverse events include one each of diarrhea and seizure. Patient #1 had failed bevacizumab prior to enrollment and remains disease free more than 9 months post PVSRIPO. Two more patients are disease free 8+ and 2+ months post treatment, respectively. One patient had pathology confirmed disease recurrence two months post treatment and one patient came off study due to clinical decline four months post treatment. Conclusions: Infusion of PVSRIPO via CED is safe thus far and encouraging efficacy results are observed. Updated results will be presented. Clinical trial information: NCT 01491893.
Prospective Evaluation of 18F-FDG PET/CT As Predictor of Prognosis in Newly Diagnosed Transplant Eligible Multiple Myeloma (MM) Patients: Results from the Imaging Sus-Study of the EMN02/HO95 MM Randomized Phase III Trial
Authors: Elena Zamagni, Cristina Nanni, Paola Tacchetti, Annibale Versari, Stephane Chauvie, Lucia Pantani, Andrea Bianchi, Marco Rensi, Marilena Bellò, Ilaria Rambaldi, Andrea Gallamini, Francesca Patriarca, Carolina Terragna, Elisa Bertone, Francesca Gay, Barbara Gamberi, Alessandra Larocca, Beatrice A Zannetti, Mario Boccadoro, Katia Mancuso, Stefano Fanti, Pieter Sonneveld, Michele Cavo
Journal: Blood (2016)
Neurotoxicity after high-dose melphalan.
Authors: Jose Eugenio Najera, Tummala Sudhakar, Qaiser Bashir, Nina Shah, Richard E. Champlin, Muzaffar H. Qazilbash, Sergio Giralt, Chitra Hosing, Uday R. Popat, Stefan O. Ciurea
Journal: Journal of Clinical Oncology (2012)

6546 Background: High dose melphalan (HDM) at 200 mg/m 2 is the standard preparative regimen for patients with multiple myeloma (MM) and light-chain amyloidosis (AL) undergoing autologous hematopoietic stem cell transplantation (auto-HCT). Neurotoxicity has been seen with HDM. In this report we describe the incidence, clinical manifestations and outcome of HDM- associated neurotoxicity. Methods: We performed a chart review of all patients who received HDM and auto-HCT for MM or AL between January 2007 to December 2009 at the University of Texas MD Anderson Cancer Center (MDACC). HDM- associated encephalopathy was defined as altered mental status, seizure or unexplained loss of consciousness within 30 days of auto-HCT. Patients with documented hemorrhagic or embolic stroke, or metabolic abnormalities were excluded. Results: 451 patients were included. Median age at auto-HCT was 59 years (range: 35-80). Thirty patients (6.6%) had AL and 61 patients (13.5%) had a pre-transplant serum creatinine of &gt; 1.5 mg/dl. Nine patients (2.0%) developed HDM-associated encephalopathy with a median of 13 days (range 4-22) from auto-HCT. Among patients with encephalopathy, 8 (89%) developed changes in mental status ranging from drowsiness and confusion to loss of consciousness, while one patient had tonic-clonic seizures (11%). Of the affected patients there were 6 (66%) females, 8 patients (89%) &gt; 59 years of age and only 2 patients (22%) had a creatinine clearance of &lt; 60 ml/min. One patient was dialysis-dependent. A CT scan or MRI was obtained in all 9 patients. Only one patient had imaging abnormalities reported as posterior reversible encephalopathy syndrome (PRES). Electroencephalogram (EEG) was performed on 6 patients. Epileptiform activity was seen in one patient with clinical seizures. Mild generalized slowing was noted in 2 other patients with mental status changes. Cerebrospinal fluid was obtained in 2 patients and did not show any abnormalities. Complete resolution of neurologic symptoms was seen in all patients prior to hospital discharge, and there were no deaths. Conclusions: HDM-induced encephalopathy was seen in only 2% patients, and it is associated with complete neurologic recovery without any increase in transplant-related mortality.
Weekly topotecan as a salvage therapy in heavily pre-treated patients with recurrent platinum-resistant epithelial ovarian cancer
Authors: M. Marinaccio, E. De Marino, E. Mele, R. Catacchio, D. Meo, C. Iezzoni, C. Conversano
Journal: Journal of Clinical Oncology (2007)

16076 Background: The prognosis of patients with recurrent epithelial ovarian cancer is extremely poor after several lines of chemotherapy; this situation becomes more and more difficult to manage in the presence of a platinum-resistance condition. Topotecan 1.5mg/m2 on days 1 through 5 of a 21-day cycle is often employed as a second-line chemotherapy also for platinum-resistant epithelial ovarian cancer. In this phase II study we investigated the safety as well response rate of weekly topotecan as a salvage therapy in heavily pretreated patients with recurrent platinum-resistant epithelial ovarian cancer (RprEOC). Methods: To be elegible for the study patients had to be considered resistant to platinum and paclitaxel pretreated. Eleven patients (median age 51 yrs, range 45 - 70) with performance status 0–2 affected by RprEOC with measurable disease, were planned to receive weekly topotecan. They had received at least 3 prior lines of chemotherapy. Topotecan was administered at the dose of 2.0 mg/m2 via a 30-minute i.v. infusion once every week until disease progression or unacceptable toxicity. Results: All patients were evaluable for toxicity and clinical response. All the 11 pts enrolled had stage III-IV disease. Median number of chemotherapy cycles was 5 (range 3 - 8). A total of 62 cycles were administered. Dose reduction was necessary for 12% of the cycles. Main toxicities included anemia (12%), leucopenia (18%), thrombocytopenia (15%) and asthenia (20%). No deaths were attributable to therapy. No one showed complete response, while two partial response (18.2%) and four stable disease (36.4%) were observed. Five pts (45.4%) progressed on therapy. The median progression-free interval was 13 weeks. Conclusion: Salvage therapy for patients with ovarian cancer who failed several platinum and paclitaxel treatments remains a therapeutic challenge. Topotecan administered at low weekly dosage (2.0 mg/m2) is an active option in the subset of heavily RprEOC and it seems also to be a more tolerable regimen compared to the classical 5-day schedule. No significant financial relationships to disclose.
Development and Validation of a Prognostic Score for Intrahepatic Cholangiocarcinoma
Authors: Mustafa Raoof, Sinziana Dumitra, Philip H. G. Ituarte, Laleh Melstrom, Susanne G. Warner, Yuman Fong, Gagandeep Singh
Journal: JAMA Surgery (2017)

In patients with intrahepatic cholangiocarcinoma (ICC), the oncologic benefit of surgery and perioperative outcomes for large multifocal tumors or tumors with contiguous organ involvement remain to be defined.To develop and externally validate a simplified prognostic score for ICC and to determine perioperative outcomes for large multifocal ICCs or tumors with contiguous organ involvement.This study of a contemporary cohort merged data from the California Cancer Registry (January 1, 2004, through December 31, 2011) and the Office of Statewide Health Planning and Development inpatient database. Clinicopathologic variables were compared between tumors that were intrahepatic, small (<7 cm), and solitary (ISS) and those that had extrahepatic extension and were large (≥7 cm) and multifocal (ELM). External validation of the prognostic model was performed using an independent data set from the National Cancer Institute's Surveillance, Epidemiology, and End Results database from January 1, 2004, through December 31, 2013.Patient overall survival after hepatectomy.A total of 275 patients (123 men [44.7%] and 152 women [55.3%]; median [interquartile range] age, 65 [55-72] years) met the inclusion criteria. No significant differences in overall complication rate (ISS, 48 [34.5%]; ELM, 37 [27.2%]; P = .19) and mortality rate (ISS, 10 [7.2%]; ELM, 6 [4.4%]; P = .32) were found. A multivariate Cox proportional hazards model demonstrated that multifocality, extrahepatic extension, grade, node positivity, and age greater than 60 years are independently associated with worse overall survival. These variables were used to develop the MEGNA prognostic score. The prognostic separation/discrimination index was improved with the MEGNA prognostic score (0.21; 95% CI, 0.11-0.33) compared with the staging systems of the American Joint Committee on Cancer sixth (0.17; 95% CI, 0.09-0.29) and seventh (0.18; 95% CI, 0.08-0.30) editions.The MEGNA prognostic score allows more accurate and superior estimation of patient survival after hepatectomy compared with current staging systems.
Predictive factors associated with achievement of major cytogenetic response (MCyR) to omacetaxine mepesuccinate among patients with chronic phase chronic myeloid leukemia (CML-CP).
Authors: Meir Wetzler, Hagop M. Kantarjian, Franck E. Nicolini, Jeffrey Howard Lipton, Luke Paul Akard, Michele Baccarani, Hanna Jean Khoury, Adam Craig, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2013)

7088 Background: Omacetaxine mepesuccinate (OMA), a first-in-class cephalotaxine, is a protein synthesis inhibitor not dependent on Bcr-Abl signaling. OMA has shown clinical activity in CML patients resistant/intolerant to tyrosine kinase inhibitors (TKIs). This subanalysis of 2 phase 2 studies examines predictors of MCyR to OMA in patients failing ≥2 TKIs. Methods: OMA 1.25 mg/m 2 BID was given in 28-day cycles: ≤14 days for induction, ≤7 days for maintenance. MCyR was defined as ≤35% Ph+ metaphases in bone marrow. A full logistic regression model with 11 baseline parameters was examined by Hosmer and Lemeshow Goodness-of-Fit test. Results: Of 81 patients (median age 59 y; range 26-83), 16 (20%) achieved MCyR. Mean (SD) baseline body surface area (BSA) was 1.90 kg/m 2 (0.240). Median time since last TKI to start of study was 1.3 mo (range 0.2-28.0) and median time from diagnosis was 75.4 mo (range 7.9-234.3). The final model had 8 baseline predictors (goodness of fit of p=0.1473; Table). (Sex, 2 vs 3 TKIs, or status of any mutation were not in the final model.) Logistic regression analysis showed a significant association between MCyR and no hydroxyurea (HU) use at baseline (p=0.0118). Numerically higher MCyR rates occurred in patients with baseline CHR and BSA ≥1.94 kg/m 2 . Conclusions: This small sample suggests that omacetaxine may be an important option for a range of patients, regardless of Bcr-Abl T315I mutation status. Prior HU may indicate more proliferative disease. Support: Teva BPP R&amp;D, Inc. Clinical trial information: NCT00375219, NCT00462943. [Table: see text]
A circulating miRNA signature to help prognosticate at prostate cancer diagnosis.
Authors: Ailsa Roberg Sita-Lumsden, Damien Leach, Andrea Zivi, Jonathan Waxman, Mathias Winkler, Charlotte Bevan
Journal: Journal of Clinical Oncology (2017)

108 Background: Prostate cancer (PCa) is the most commonly diagnosed cancer in men. Around 80% of PCas are diagnosed as early, localised stage yet a subset of these will metastasise and eventually prove fatal. Management decisions are based on risk stratification systems. However, these systems are not able to clearly distinguish indolent from aggressive PCa’s and as a result many patients with indolent cancers may be over treated. Circulating microRNAs (miRNA) may be an easily accessible, suitable biomarker to distinguish true indolent from clinically significant early prostate cancers (PCa) thus reducing overtreatments. Methods: Blood samples from 24 men with benign prostatic hypertrophy (BPH, n = 8), localised PCa (n = 8) or metastatic PCa (n = 8) were collected at time of diagnosis. All men had intact prostates and were naïve to any endocrine or other cancer therapy. A platform of circulating miRNAs were analysed in serum using Abcam Firefly technology. Data collected were independently verified using real-time qPCR (Exiqon). The miRNAs identified as being significantly different between groups were then analysed in a published dataset. Results: Serum levels of seven of the miRs examined were significantly different in patients with prostate cancer compared to control across both platforms (miR-10b, miR-125b, miR-210, miR-21, miR-378a, miR-483 and miR93 all with P values &lt; 0.005). A further four miRNAs could differentiate between the benign and metastatic cohorts (miR-126 P = 0.008, miR-150 P = 0.05, miR375 P = 0.007). Kaplein-Meier analysis further identified that the serum levels of four miRNAs showed significant association with survival rates (miR-21 P = 0.032, miR-126 P = 0.032, miR-150 P = 0.032, miR-93 P = 0.019). On examination in a cohort of 280 men from The Cancer Genome Atlas (TCGA), four miRs from the cohort had significantly different expression in patients who eventually relapsed (miR-21 P = 0.048, miR-375 P = 0.021, miR-210 P = 0.0003, miR-93 P = 0.008) Conclusions: Our circulating miRNA based signature could be used to stratify men at prostate cancer diagnosis and help identify those who are likely to harbour micro metastases and would benefit more from an early radical treatment. The data is being validated in larger cohorts.