tbuckley/cabot-search huggingface dataset:
Phase III, placebo-controlled trial (SUCCEED) evaluating ridaforolimus as maintenance therapy in advanced sarcoma patients following clinical benefit from prior standard cytotoxic chemotherapy: Long-term (≥ 24 months) overall survival results.
Authors: Jean-Yves Blay, Sant P. Chawla, Isabelle Ray-Coquard, Axel Le Cesne, Arthur P. Staddon, Mohammed M. Milhem, Nicolas Penel, Richard F. Riedel, Binh Bui Nguyen, Lee D. Cranmer, Peter Reichardt, Emmanuelle Bompas, Thierry Alcindor, Daniel A. Rushing, Yang Song, Scot Ebbinghaus, Frank G. Haluska, Pierre F. Dodion, George D. Demetri
Journal: Journal of Clinical Oncology (2012)

10010 Background: The mammalian target of rapamycin (mTOR) regulates cell growth and proliferation and is abnormally activated in many sarcomas. Ridaforolimus, an oral mTOR inhibitor, demonstrated clinical activity in previous nonrandomized trials in advanced sarcomas following failure of prior chemotherapy. Methods: An international, multicenter, placebo-controlled, phase 3 trial was conducted to evaluate maintenance therapy with ridaforolimus in patients with metastatic soft-tissue or bone sarcomas who achieved disease control from prior chemotherapy. Patients were randomized (1:1) to receive oral ridaforolimus (40 mg) or placebo once daily for 5 days each week. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety and tolerability. For OS, patients were to be followed at 3-month intervals for at least 24 months and up to 60 months after randomization. Results: 702 of 711 randomized patients received treatment. At the time of the data cutoff for OS (386 deaths), patients in the study population had been followed for at least 15 months. Median OS was 93.3 weeks with ridaforolimus vs 83.4 weeks with placebo (hazard ratio [HR]=0.88; 95% confidence interval [CI]: 0.72, 1.08; P=0.23). Ridaforolimus significantly improved PFS vs placebo (HR=0.72; 95% CI: 0.61, 0.85; P=0.0001; median PFS: 17.7 weeks vs 14.6 weeks); PFS improved across all prespecified baseline characteristics. As expected from the class of mTOR inhibitors, the most common adverse events with ridaforolimus were stomatitis, thrombocytopenia, noninfectious pneumonitis, hypertriglyceridemia, hyperglycemia, infections, and rash. Conclusions: Oral ridaforolimus was generally well-tolerated and significantly improved PFS in metastatic sarcoma patients with benefit from prior chemotherapy, offering an effective treatment alternative to surveillance alone. Results of a long-term OS analysis (prespecified to occur at 67% mortality, 24 months minimum follow-up) in the intent-to-treat population will be available in early 2012.
ACRIN 6695 perfusion CT as prognostic imaging biomarker in ovarian cancer.
Authors: Chaan S. Ng, Ting Yim Lee, Robert L. Coleman, Zheng Zhang, Bernadine Dunning, Darryl L'Heureux, Robert S. Mannel, Susanna Lee
Journal: Journal of Clinical Oncology (2012)

TPS5114 Background: Tumor size and the cell surface glycoprotein CA125 levels have been traditional biomarkers for ovarian carcinoma, but remain suboptimal for assessing patients receiving chemotherapy. Current morphological criteria do not adequately evaluate lesion necrosis from anti-angiogenic therapy when no tumor volume change is measured. The evaluation of functional biomarkers rather than tumor volume may better distinguish responders from non-responders early in treatment with anti-angiogenic therapy. Perfusion CT can evaluate changes in tumor vascularity including blood flow (BF), blood volume (BV), mean transit time (MTT) and capillary permeability surface product (PS) before and after anti-angiogenic therapy with/out decrease in tumor volume. Objectives: The aims of the study are to evaluate the relationship between changes in tumor perfusion parameters and clinical outcomes of progression free survival, overall survival, and standard RECIST anatomic response criteria. A test-retest perfusion CT scan will also be performed to evaluate reproducibility of perfusion parameters in a subset of participants. Methods: In this collaborative trial, participants will be co-enrolled in the GOG-262 treatment trial. Participants will receive doublet chemotherapy of paclitaxel and carboplatin, followed by anti-angiogenic monoclonal therapy at cycle two. Perfusion CT will be performed at three time points: at baseline prior to therapy (T0), between days 18 and 21 of cycle one chemotherapy (T1), and at 8-10 days (T2) in anti-angiogenic monoclonal therapy. Participants with primary epithelial ovarian, peritoneal or fallopian tube cancer with optimally or suboptimally debulked FIGO Stage II, III or IV disease are eligible for the trial. Lesion eligibility will be evaluated by size and attenuation criteria. Accrual: ACRIN 6695 is activated at 12 GOG sites; 4/78 participants have accrued Discussion: Perfusion CT has been readily incorporated into the pre-existing clinical CT protocols and during scheduled RECIST scans. These perfusion CT functional maps of BF, BV, MTT and PS have been generated using vendor provided software without issue. Contact: Please contact Chaan Ng, MD cng@mdanderson.org for additional information.
Interpathologists discrepancies in Ki67 assessment in the PACS01 trial: An independent prognosis factor.
Authors: Frederique Madeleine Penault-Llorca, Aicha Goubar, Ines Raoelfils, Christine Sagan, Magali Lacroix-Triki, Yves Denoux, Veronique Verrielle, Jocelyne Jacquemier, Anne-Laure Martin, Henri Roche, Fabrice Andre
Journal: Journal of Clinical Oncology (2012)

543 Background: Several reports suggest an inter-observer variability in Ki67 assessment. Nevertheless, there is no large study that evaluates the rate of discrepancies, together with their impact. Methods: Ki67 expression was assessed on 663 samples from patients with ER-positive breast cancers included in the PACS01 trial (Roche, J Clin Oncol, 2006). Ki67 staining was done using MiB1 antibody (Dako, Copenhagen, Denmark, Dilution 1:250). Prognostic and predictive values have been reported previously (Penault-Llorca, J Clin Oncol, 2009). A second central review was done by a senior breast pathologist from a French Cancer center. A discrepancy was defined as either a false positive or false negative result. Cut-off for positivity was defined at 15% according to data from Cheang et al (JNCI, 2009). Results: The rate of discrepancy was correlated with the percentage of stained tumor cells. A 10% discrepancy rate between the 2 pathologists was observed when the first pathologist reported &lt;10% tumor cells stained. Same low rate of discrepancy (10%) was observed if more than 30% cancer cells were stained according to the first assessment. At the opposite, discrepancy rates were 47%, 45%, 22%, 34% when the first pathologist reported 10-15%, 15-20%, 20-25% and 25-30% tumor cells stained. Overall, 36% of the patients presented a grade II tumor together with Ki67 &lt;10% or &gt;30%. We then evaluated the impact of discrepancy in terms of prognosis. Patients presenting a concordant result between the two pathologists showed a better outcome as compared to patients presenting a discrepancy, independently to the percentage of tumor stained (p=0.05, patients with concordant Ki67 ranged between 10-30% versus those with one reader &lt;10% and the other one &gt;10%-&lt;30%). Conclusions: Discrepancy rates between pathologists are acceptable when Ki67 is either &lt;10% or &gt;30%. A Ki67 ranged between 10 and 30% could define a grey zone in which Ki67 should be reported with caution or be double checked by another pathologist. Survival analysis suggested that inter-observer discrepancies could act a prognostic factor. Such finding could reflect underlying intra-tumor heterogeneity.
BK Virus (BKV) Associated Haemorrhagic Cystitis Is Associated with Graft Versus Host Disease (GVHD) and Significant Morbidity Post Haematopoietic Stem Cell Transplant (HSCT).
Authors: Alesia Abigael Hunt, Anjum Bashir Khan, Donal McLornan, Majid A Kazmi, Matthew Streetly, Victor Noriega, Eithne MacMahon, Kavita Raj
Journal: Blood (2012)
Survival for patients with colorectal cancer is influenced by insurance status.
Authors: Dianne Pulte, Lina Jansen, Hermann Brenner
Journal: Journal of Clinical Oncology (2015)

e17611 Background: Colorectal cancer (CRC) is a common cancer which is treatable in early stages but generally fatal when metastatic. Thus, prompt diagnosis and treatment is vital to a good outcome. Patients with no insurance or suboptimal insurance may be vulnerable to delays in treatment leading to poorer outcomes. Here, we evaluate survival of patients with CRC by insurance type. Methods: Data were extracted from the Survival, Epidemiology, and End Results (SEER)-17 database. Patients with a CRC diagnosis in 2007-2011 were included. Complete analysis was used to determine 3-year relative survival for patients overall and by insurance type (none, Medicaid, and other insurance). The association between survival and insurance status was estimated with Cox regression models with adjustment for age (15-44, 45-54, and 55-64 years at diagnosis), gender, cancer stage, and race. Results: After adjustment for age, race, and gender, mortality was higher for patients with no insurance and with Medicaid only as compared to patients with other insurance, with hazard ratios for mortality of 1.96 (95% CI 1.85-2.07) for patients without insurance and 2.24 (2.15-2.33) for patients with Medicaid only as compared to patients with other insurance. When adjustment for stage was included in the model, the hazard ratios were 1.63 (1.54-1.72) and 1.72 (1.65-1.80), respectively, for uninsured and Medicaid only compared to other insurance. The hazard ratio for mortality was higher for patients at each stage, with the highest ratio for patients with stage I disease at 2.26 for no insurance and 3.42 for Medicaid. Age standardized 3-year relative survival estimates were 73.7% overall, 61.7% for uninsured patients, 57.2% for Medicaid patients, and 77.3% for patients with non-Medicaid insurance. Conclusions: Survival is lower for patients with CRC who have no insurance or Medicaid only as compared to patients with non-Medicaid insurance. At least part of the difference appears to be attributable to differences in stage at diagnosis, but mortality was higher at all stages and the greatest differential was seen for stage I patients, especially for Medicaid patients. Survival was slightly higher in patients without insurance than in patients with Medicaid.
Hyperdiploidy in AML: Outcomes of acute myelogenous leukemia (AML) patients (pts) with a hyperdiploid karyotype.
Authors: Aditya Shetty, Jorge E. Cortes, Farhad Ravandi, Tapan M. Kadia, Guillermo Garcia-Manero, Naveen Pemmaraju, Sherry Pierce, Hagop M. Kantarjian, Gautam Borthakur
Journal: Journal of Clinical Oncology (2014)

7088 Background: Hyperdiploidy with greater than 49 chromosomes is an infrequent phenomenon in AML, with a reported incidence of less than 2%. While autosomal loss is known to have poor prognosis, the outcome of patients with hyperdiploid karyotype (HK) is unclear. Methods: We reviewed data of 1313 pts with AML treated at our institution between 2003 and 2013. Results: Hyperdiploidy was identified in 41 pts (3%). Baseline characteristics in pts with HK at initial diagnosis included: a median age of 68 years (range, 18-81) and a median white blood cell count of 2.1 (range, 0.4-22.4). Median chromosome number in the HK group was 55 (range, 49-104). The most common chromosomes gained included trisomy 8 in 22 pts (54%), trisomy 22 in 16 pts (40%) and trisomy 21 in 13 pts (33%). A monosomal karyotype (MK) was noted in 23 pts (56%) in the HK group. Structural abnormalities defined as intermediate risk by European LeukemiaNet classification were noted in 11 pts (27%). Hyperdiploidy as the only chromosomal aberrations was noted in 6 pts (15%). Thirteen pts (32%) received high-dose ara-C-based induction and 9 pts (22%) received a clofarabine- based induction. 20 pts (49%) achieved a complete remission. The median CR duration was 5 months (range, 0-81 months). 35 pts (85%) had died, with a median overall survival of 7 months (range, 1-84 months) compared with 10 months (range, 0-120 months) for a control group of all AML pts (non-M3, non-cbf) (p=0.16), 6 months (range, 0-115 months) for AML pts with complex, non-hyperdiploid cytogenetics (p=.100) and 15 months (range, 0-120 months) for AML pts with diploid cytogenetics (p=.001). In subgroup analysis limited by small pt numbers, pts with hyperdiploidy alone had median overall survival of 12 months (range, 1-43 months), compared with 6 months (range, 1-51 months) and 9 months (range, 1-84 months) in the structural abnormalities subgroup and the monosomal subgroup, respectively (p=.237). Conclusions: Hyperdiploidy is a rare abnormality in AML with trisomy 8, 22 and 21 being the most commonly gained chromosomes. HK pts had a significantly worse outcome compared to a diploid cohort and a minor trend towards better outcomes compared to AML pts with complex cytogenetics.
Phase II study with Wee1 inhibitor AZD1775 plus carboplatin in patients with p53 mutated ovarian cancer refractory or resistant (&lt;3 months) to standard first line therapy.
Authors: Suzanne Leijen, Robin van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik D. van Werkhoven, Shelonitda Rose, Mark Anthony Lee, Jos H. Beijnen, Jan H. M. Schellens
Journal: Journal of Clinical Oncology (2015)

2507 Background: AZD1775 (formerly MK-1775) is a potent and selective inhibitor of Wee1, a kinase that phosphorylates CDC2. Phosphorylation of CDC2 inactivates the CDC2/cyclin B complex and is therefore essential for normal G2 checkpoint function. As most p53-deficient tumors lack a functional G1 checkpoint, they rely on the G2 checkpoint for cell cycle arrest in response to DNA damage. G2 checkpoint abrogation, using a Wee1 inhibitor may therefore sensitize p53 deficient tumor cells to DNA-damaging anti-cancer agents. In a phase I study the maximum tolerated dose (MTD) of AZD1775 in combination with carboplatin demonstrated target engagement (NCT00648648). Methods: Patients (pts) with p53 mutated ovarian cancer refractory or resistant ( < 3 months) to standard first line therapy (carboplatin plus paclitaxel) were re-exposed to carboplatin (AUC 5), plus 5 bi-daily doses of 225 mg AZD1775 in a 21 day cycle (MTD) (NCT01164995). p53 mutation status was analyzed by both sequencing analysis (TP53 exons 2-10) and AmpliChip TP53 array (TP53 exons 2-11). Response evaluation was performed according to RECIST 1.0, volumetric tumor measurement (enhanced RECIST) and CA-125 blood levels. Results: Bone marrow toxicity, fatigue, diarrhea, nausea and vomiting were the most common adverse events. Out of 24 pts enrolled, 22 pts were evaluable for study endpoints. As best response (RECIST 1.0), 6 pts (27%) showed confirmed partial response (PR) with a median progression-free survival (PFS) of 10.9 months. Nine pts (41%) had stable disease and 7 pts (32%) had progressive disease as best response, with a median PFS of 5.3 and 1.3 months, respectively. Conclusions: AZD1775 is a first in class Wee1 inhibitor that in combination with carboplatin is well tolerated and shows promising anti-tumor activity in p53 mutated ovarian cancer refractory or resistant ( < 3 months) to standard first line therapy. Clinical trial information: NCT01164995.
Sipuleucel-T immunotherapy in clinical practice: Patient characteristics, tolerability, and survival.
Authors: Matthew O'Shaughnessy, Christopher Warlick, Matthew Ziegelmann, Badrinath Konety, Gautam Gopalji Jha
Journal: Journal of Clinical Oncology (2012)

e15211 Background: Sipuleucel-T has been shown to provide survival benefit to men with minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). In the 18 months following FDA approval of sipuleucel-T, we sought to characterize patients referred for consideration of sipuleucel-T, determine the tolerability of therapy, and evaluate survival outcomes in clinical practice. Methods: We reviewed the records of patients referred to our institution for consideration of sipuleucel-T. Clinical characteristics, disease characteristics, and previous treatments were identified. Tolerability and adverse events were characterized. Results: Patients with minimally symptomatic mCRPC were offered sipuleucel-T (n=90), whereas patients with ECOG&gt;1, progressive disease, or lack of metastases were not (n=11). Post chemotherapy patients started sipuleucel-T if their CD4 count was &gt;400 at least 3 weeks following chemotherapy. Treatments were well tolerated, with 96% completing an entire series. Three patients did not complete treatment due to disease progression. The biggest challenge with sipuleucel-T therapy was disease control immediately before, during and post therapy. Androgen receptor blockade with nilutamide or high dose bicalutamide was used to control the disease during this time. Mean patient age was 69.8±9.7 years and all had ECOG status of 0-1. 40% of patients had minimal metastases, while 36% and 19% had moderate or extensive metastases. Median survival time (MST) for men &gt;65 years who received sipuleucel-T was 17.6 months, whereas MST for men ≤65 years was not reached. There was no significant difference in overall survival (OS) between these groups (p=0.27). When stratified by disease burden, we found that OS of patients with extensive disease was shorter than men with mild or moderate disease burden (p=0.002 and p=0.04), with MST of 6.0 months. MST was not reached for men with mild and moderate disease burden. Conclusions: Sipuleucel-T is well tolerated in clinical practice for well-selected patients with asymptomatic or minimally symptomatic mCRPC. Patients with extensive metastatic disease, even when minimally symptomatic, did not appear to benefit from sipuleucel-T.
Transdermal Protein Delivery Using Choline and Geranate (CAGE) Deep Eutectic Solvent
Authors: Amrita Banerjee, Kelly Ibsen, Yasunori Iwao, Michael Zakrewsky, Samir Mitragotri
Journal: Advanced Healthcare Materials (2017)

Transdermal delivery of peptides and other biological macromolecules is limited due to skin's inherent low permeability. Here, the authors report the use of a deep eutectic solvent, choline and geranate (CAGE), to enhance topical delivery of proteins such as bovine serum albumin (BSA, molecular weight: ≈66 kDa), ovalbumin (OVA, molecular weight: ≈45 kDa) and insulin (INS, molecular weight: 5.8 kDa). CAGE enhances permeation of BSA, OVA, and insulin into porcine skin ex vivo, penetrating deep into the epidermis and dermis. Studies using tritium-labeled BSA and fluorescein isothiocyanate labeled insulin show significantly enhanced delivery of proteins into and across porcine skin, penetrating the skin in a time-dependent manner. Fourier transform IR spectra of porcine stratum corneum (SC) samples before and after incubation in CAGE show a reduction in peak area attributed to SC lipid content, suggesting lipid extraction from the SC. Circular dichroism confirms that CAGE does not affect insulin's secondary conformation. In vivo studies in rats show that topical application of 10 U insulin dispersed in CAGE (25 U kg-1 insulin dose) leads to a highly significant 40% drop in blood glucose levels in 4 h that is relatively sustained for 12 h. Taken together, these studies demonstrate that CAGE is a promising vehicle for transdermal delivery of therapeutic proteins; specifically, as a noninvasive delivery alternative to injectable insulin for the treatment of diabetes.
Early Pseudomonas aeruginosa colonisation in cystic fibrosis patients [4] (multiple letters)
Authors: Giovanni Taccetti, Teresa Repetto, Elena Procopio, Silvia Farina, Silvia Campana, G. Döring, F. Ratjen, W. H. Nikolaizik, Federico Marchetti, Manila Candusso, Dino Faraguna, Barouk M. Assael
Journal: The Lancet (2002)
Safety and tolerability of increasing doses of CB-839, a first-in-class, orally administered small molecule inhibitor of glutaminase, in solid tumors.
Authors: James J. Harding, Melinda L. Telli, Pamela N. Munster, Mai H. Le, Christopher Molineaux, Mark K. Bennett, Erik Mittra, Howard A. Burris, Amy Sanders Clark, Mark Dunphy, Funda Meric-Bernstam, Manish R. Patel, Angela DeMichele, Jeffrey R. Infante
Journal: Journal of Clinical Oncology (2015)

2512 Background: Glutamine is required for the growth and survival of multiple tumor types. CB-839 is a highly selective, reversible, allosteric inhibitor of glutaminase, a choke point in the utilization of glutamine. CB-839 has broad in vitro and in vivo anti-tumor activity in solid and heme malignancies. Methods: CX-839-001 is an ongoing Phase 1 study of escalating doses of CB-839 in advanced and/or treatment-refractory solid tumor patients (pts) to evaluate safety and tolerability, and to identify the recommended Phase 2 dose (R2PD). CB-839 was administered orally continuously in 21-day cycles. Pharmacokinetics (PK) was monitored on Days 1, 15, and 22; pharmacodynamic (PD) assessment of glutaminase activity was measured ex vivo in platelets and tumor biopsies. Additional pts will be enrolled at the RP2D with triple negative breast cancer (TNBC), non-small cell lung adenocarcinoma (NSCLC), renal cell carcinoma (RCC), mesothelioma, and tumors with mutations in enzymes of the TCA cycle. Results: 35 pts were enrolled in dose escalation receiving CB-839 doses from 100 to 800 mg TID and 600 mg BID. Exposure increased less than dose proportionally but there was a clear PK/PD relationship with > 90% glutaminase inhibition in platelets when CB-839 exceeded 450 nM; target inhibition was confirmed in tumors. Radiographic stable disease (SD) was observed in 7 (28%) of 25 efficacy-evaluable pts (average duration 107 days; range 59-209) across all diseases and dose levels including TNBC (2/9 evaluable pts), NSCLC (2/4), mesothelioma (2/4) and RCC (1/3). Grade ≥ 3 treatment-related AEs occurred in 7 (20%) of pts, including ALT/AST (4 pts), creatinine, alkaline phosphatase, and GGT increases, lymphopenia, and hypoglycemia (1 pt each). A Grade 3 increase in creatinine considered unlikely related to CB-839 was a DLT at 250 mg TID. CB-839 was absorbed rapidly (Tmax 1-2 hr fasted and 2-4 hr fed) and cleared with a half-life of about 4 hr. Plasma Cminwas > 450 nM at steady state at the RP2D of 600 mg BID. Conclusions: Continuous CB-839 administration showed an acceptable safety profile, significant glutaminase inhibition and preliminary signs of clinical activity in multiple tumor types. Clinical trial information: NCT02071862.