tbuckley/cabot-search huggingface dataset:
The role of IL-17/IL-6 axis in the development of chronic lymphocytic leukemia.
Authors: Fang Zhu, David Spaner, Haoran Li, Reginald M. Gorczynski
Journal: Journal of Clinical Oncology (2015)

e22119 Background: The tumor microenvironment (TME) is critical to the survival of tumor B cells in chronic lymphocytic leukemia (CLL). Bone marrow mesenchymal stem cells (BMMSCs) and the cytokines they produced are important components of TME. Methods: 49 Patients with various stages of CLL were included. BMMSCs were co-cultured with human CLL cells with or without the presence of IL-17. Peripheral blood mononuclear cells from CLL patients were injected into NSG mice and IL-6/IL-17 were delivered daily. Student t test and Pearson product-moment correlation were used in statistical analysis. Results: CLL cells survived better when co-cultured with BMMSCs. ELISA array revealed a high concentration of IL-6 in co-culture system. Inhibition of IL-6 by Actemra decreased CLL cell survival in the co-culture. IL-6 production can be induced by IL-17 in both BMMSCs and CLL cells. In a xenograft animal model, BMMSCs and its culture supernatant promoted the engraftment of CLL cells via inducing IL-6. Human recombinant IL-17 administration also increased CLL engraftment through inducing IL-6. The plasma of CLL patients had elevated levels of IL-6 (16.3 ± 8.1 vs. 2.6 ± 2.1 pg/mL, p < 0.001) and IL-17 (9.2 ± 8.0 vs. 1.4 ± 1.1 pg/mL, p < 0.001), compared to healthy controls. There was a linear correlation between the levels of IL-6 and IL-17 in CLL patients (p < 0.0001), but not in the healthy controls. The patients who received Fludarabine based chemotherapy (n = 18) had higher concentration of IL-6 (21.77 ± 12.25 vs. 10.33 ± 11.51 pg/mL, p < 0.001) and IL-17 (12.78 ± 8.20 vs. 4.42 ± 5.59 pg/mL, p < 0.001) compared to those untreated (n = 13). Patients with low levels IgA or IgM (n = 14) had elevated IL-6 concentration in their plasma compared to the controls (n = 33) (22.51 ± 13.00 vs. 10.20 ± 9.10 pg/mL, p = 0.001). IL-6 and IL-17 levels were not associated with tumor cell load, CD38 expression or β2-microglobulin in our cohort of patients. Conclusions: Our study suggests an important role of IL-6 in survival of CLL cells. High levels of IL-17 in CLL patients may be responsible for the elevation of IL-6. CLL patients with higher IL-6 or IL-17 levels tend to have more aggressive diseases. IL-17/IL-6 axis could be a therapeutic target in CLL treatment.
Evaluation of safety and efficacy of somatuline autogel in combination with molecular targeted therapies (MTT) in patients with neuroendocrine tumors (NETs): Data from one Spanish cohort.
Authors: Jaume Capdevila, Isabel Sevilla, Vicente Alonso, Luis Anton Aparicio, Paula Jimenez, Enrique Grande, Juan J Reina, Jose Luis Manzano, Juan Domingo Alonso-Guadalajara, Pilar Garcia Alfonso
Journal: Journal of Clinical Oncology (2012)

e14671 Background: Analysis of the mechanisms of action of somatostatin analogs (SSAs) and mTOR inhibitors or tyrosine kinase inhibitors suggest that they may provide synergistic effects when used in combination for the treatment of pts with NETs. Methods: This is a Spanish multicenter cohort of pts with NETs treated with the SSAs lanreotide (LAN) and MTTs at 35 Spanish referral centers. Data of 159 combined treatments (133 pts) was retrospectively collected in order to evaluate the efficacy and safety of such combinations. Results: 133 pts (52,6% M) with a median age of 59,9 years; ECOG 0/1/2/3: 34%/49%/16%/1%; Lung/Pancreas/Gastrointestinal//Unknown(UK) origin: 9%/48% /32%/11%; G1/G2/G3/UK: 41%/32%/1%/26%; Non Functioning/ Functioning (69%/31%) received treatment with MTT + LAN for synergistic antiproliferative purpose in 85% of the cases, hormonal control (13,5%) or both objectives (1,5%). 115 pts received one combination treatment and 18 pts received between 2 (12 pts) and 5 (1 pt). LAN was administrated in combination with sunitinib (61), everolimus (73), bevazucimab (9), sorafenib (8) and pazopanib (8). The reported toxicity was determined by the MTT profile with no significant additional severe adverse events related to the combination with LAN. The probability of progression-free survival (PFS) at 6, 12 and 18months was 89%, 73% and 67% respectively for those pts who received LAN and sunitinib (n=50) and 78%, 69% and 57%, respectively for those pts who received LAN and everolimus (n=56). Median PFS was not reached at the time of analysis. Conclusions: The combination of LAN and MTT, mainly everolimus and sunitinib, is widely used in clinical practice without unexpected toxicities. Median PFS will be higher than data observed in phase III studies with sunitinib and everolimus, raising the hypothesis of enhanced efficacy combining SSAs and MTT that should be confirmed in randomized prospective clinical trials. [Table: see text]
Targeting reciprocal feedback inhibition: Apalutamide and everolimus in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Dana E. Rathkopf, Susan F. Slovin, Michael J. Morris, Daniel Costin Danila, Anthony Delacruz, Gregory Shelkey, Mia DeNunzio, Brigit McLaughlin, Howard I. Scher
Journal: Journal of Clinical Oncology (2017)

204 Background: Studies in xenograft CRPC and PTEN-deficient prostate cancer models have shown synergistic anti-tumor activity of next-generation anti-androgens such as apalutamide when combined with PI3K/mTOR inhibitors such as everolimus. (Carver B et al., Cancer Cell 2011) The primary hypothesis of this study was that the combination of apalutamide with everolimus would overcome resistance to prior hormonal therapy with abiraterone acetate and prednisone (AAP). Methods: The primary endpoint in mCRPC patients with prior AAP was to evaluate the safety, pharmacokinetics (PK), and recommended phase 2 dose (RP2D) of fixed dose apalutamide 240 mg po qd when combined with everolimus 5 mg po qd (cohort 1, n = 3) and everolimus 10 mg po qd (cohort 2, n = 6). The plan was to expand to treat 40 patients at the RP2D. Results: Nine patients were enrolled in phase 1. The PK for the combination was consistent with historical data of either drug given as monotherapy. The most common treatment related adverse events were &lt; = grade 2 fatigue (67%), diarrhea (56%), and anorexia (56%). In cohort 2, 1 patient had a DLT of grade 3 rash. The median time on treatment was 17 weeks (range 7-51+). The best response was SD in all 9 patients. Patients came off study for: progression (n = 3), investigator choice (n = 3) and toxicity unrelated to treatment (n = 2). Seven patients had detectable CTCs at baseline (EPIC Sciences). One patient had a rise in CTC number that then converted to undetectable and remained on study 37 weeks. One out of 6 evaluable patients had PTEN loss in tissue at baseline (MSK IMPACT) and remained on study 12 weeks. One patient with prior AAP and enzalutamide exposure has remained on study 51+ weeks with a &gt; 50% decline in PSA (PTEN pending). Conclusions: Although the combination of apalutamide and everolimus was safe and well tolerated, the treatment response was similar to historical data of AAP followed by apalutamide alone. (Rathkopf D et al., ASCO 2014) We elected to close this study before expansion in favor of evaluating novel AR/PI3K pathway combinations in patients who have not yet been exposed to AAP. Drug provided by Janssen and Novartis. Trial support: PCF and MSK Experimental Therapeutics Center. Clinical trial information: NCT02106507.
ECOG multiple myeloma (MM) clinical trial (CT) accrual performance evaluation utilizing the NCITrial Complexity and Elements Scoring (NCI-TCES) and the NCI Myeloma Steering Committee Accrual Working Group (NCI MYSC AWG) scoring models.
Authors: Matthias Weiss, Susanna J. Jacobus, Morie A. Gertz, Nikhil C. Munshi, Sagar Lonial, Shaji Kumar, Rafael Fonseca, Angela Dispenzieri, Martha Lacy, A. Keith Stewart, William R. Friedenberg, Robert A. Kyle, Philip R. Greipp, Vincent Rajkumar
Journal: Journal of Clinical Oncology (2014)

8600 Background: Accrual to NCI CTs is often slower than planned and at times mandating premature closure resulting in loss of valuable resources and delay of scientific progress. The NCI MYSC AWG identified 10 barriers to accrual (BtA) to MM CTs (reimbursement, competing treatment options, treatment at NCI designated sites only, etc.). The NCI-TCES was created to objectively assess CT complexity (study arms, registration/randomization steps, treatment and follow-up complexity and duration, etc.). We evaluated the accrual performance of all previously conducted and currently ongoing (as of 12-31-2013) therapeutic ECOG MM CTs (excluding transplant) utilizing these tools. Methods: The planned and actual accrual, duration of open enrollment and accrual per month of each selected CT was determined. The NCI-TCES model was applied to each CT and a total score calculated (range 0-18). The 10 NCI MYSC AWG BtA were reviewed as it concerns their relevance for each selected CT and described as unlikely (0), possibly (1) or definitely (2) impacting accrual adversely. A total score was calculated (range 0-20). Results: 11 ECOG MM CTs were evaluated. 6 of 11 achieved planned accrual goals and 5 of 11 did not due to premature closure due to lack of accrual, less than half of planned accrual per month or more than twice the planned enrollment period. CTs achieving planned accrual performance had a NCI MYSC AWG score average of 4.83 versus 8.0 for those CTs failing accrual goals. The NCI-TCES score was 4.83 versus 4.2, respectively. None of the 6 CTs, which successfully enrolled were identified to have BtA, which definitely impacted accrual adversely versus 3 out of 5 of the CTs which failed planned accrual performance. Conclusions: In this retrospective analysis of ECOG MM CT accrual performance, the NCI MYSC AWG scoring model correlated well with actual accrual performance. Given its general applicability to therapeutic CTs evaluating any malignant disease, this tool may be useful for prospective accrual performance assessment of planned therapeutic clinical trials.
An analysis of phase II and III therapeutic cancer vaccine trials and review of the successes and failures behind 10 different vaccine modalities.
Authors: Holbrook Edwin Kohrt, Amabel CL Tan, Anne Goubier
Journal: Journal of Clinical Oncology (2015)

3078 Background: Between 1996-2014, the FDA approved 175 drugs for the treatment of various indications of oncology and despite the progress that has been made in other forms of cancer therapy, Provenge (Sipuleucel-T) is the only therapeutic vaccine that has received FDA approval for the treatment of cancer. To understand the current landscape of therapeutic oncology vaccines, an analysis of cancer vaccines under in phase 2 and phase 3 investigation was performed. Methods: A search of the terms “vaccine” and “cancer” or “oncology was performed on the clinicaltrials.gov. registry and medtrack. A literature review was also performed to identify factors that have impacted the perceived success or failure of 10 different vaccines. Results: Database analysis of 451 phase 2 and phase 3 therapeutic cancer vaccine trials identified the most targeted indications, vaccine modalities, adjuvant and vaccine-treatment combinations and highlighted the shift in trends between studies completed prior to 2014 and those with completion scheduled after 2014. Despite the lower number of phase 3 compared to phase 2 trials, the registration of phase 3 trials between 2010 and 2014 appeared stable indicating continued investment in the development of immunotherapeutic vaccines at this stage. The review of vaccine trials revealed that patient characteristics (disease stage, HLA-type, MGMT status, antigen signature) and combination treatments had an impact on on vaccine success while the detection of immune responses was found to be important, provided parameters such as tumour antigen expression, breadth and magnitude of the response and correspondence to intra-tumour responses were considered. Conclusions: Identification of factors that can impact on vaccine success and their implementation into study design could ensure vaccine trials are best matched to patients most likely to benefit from the selected mode of vaccination, improving the outlook for both the patient and the development of therapeutic cancer vaccines.
Dose-Intensified Combined Modality Treatment with 2 Cycles of BEACOPP Escalated Followed by 2 Cycles of ABVD and Involved Field Radiotherapy (IF-RT) Is Superior to 4 Cycles of ABVD and IFRT in Patients with Early Unfavourable Hodgkin Lymphoma (HL): An Analysis of the German Hodgkin Study Group (GHSG) HD14 Trial
Authors: Peter Borchmann, Andreas Engert, Annette Pluetschow, Michael Fuchs, Jana Markova, Andreas Lohri, Zdenek Kral, Richard Greil, Max Topp, Matthias Villalobos, Jose Zijlstra, Martin Soekler, Harald Stein, Hans Theodor Eich, Rolf Peter Mueller, Volker Diehl
Journal: Blood (2008)
Multivariate analysis of PFS from the AETHERA trial: A phase III study of brentuximab vedotin consolidation after autologous stem cell transplant for HL.
Authors: Jan Andrzej Walewski, Auayporn Nademanee, Tamás Masszi, Jerzy Holowiecki, Muneer Abidi, Andy I. Chen, Patrick J. Stiff, Simonetta Viviani, Veronika Bachanova, John W. Sweetenham, Shih-Yuan Lee, Dirk Huebner, Emily K. Larsen, Naomi N. H. Hunder, Craig H. Moskowitz
Journal: Journal of Clinical Oncology (2015)

8519 Background: In the phase III, randomized, placebo-controlled AETHERA trial, PFS was significantly improved with brentuximab vedotin (BV) vs placebo (HR=0·57, P=0·001) in HL pts at risk of progression post-autologous stem cell transplant (ASCT). A multivariate analysis was performed to determine which factors significantly influence PFS by investigator assessment. Methods: After ASCT, 329 pts were randomized to receive BV 1.8 mg/kg q3wk (n=165) or placebo (n=164) for up to 16 cycles. The primary endpoint was PFS per independent review. Multivariate analysis using a Cox-proportional hazards model was developed on the following factors: treatment, age, sex, weight, geographical region, initial disease stage, time from diagnosis, no. of treatments pre-ASCT, chemosensitivity, response to frontline (FL) and salvage, type of FL therapy, prior radiotherapy, extranodal disease pre-ASCT, ASCT conditioning regimen, B symptoms at pre-ASCT relapse, no. of risk factors, baseline ECOG, baseline lesions, and pre-existing peripheral neuropathy. Significant factors (p<0.05) were determined after a stepwise addition and elimination of nonsignificant factors from the model. Results: Multivariate modeling indicated that factors significantly associated with PFS by investigator assessment included: treatment (BV vs. placebo), salvage response, gender, no. of treatments pre-ASCT, type of FL therapy, B symptoms pre-ASCT, and weight. Conclusions: After adjustment for significant clinical factors in a multivariate regression analysis, consolidation treatment with BV significantly reduced the risk of treatment failure compared to placebo with a HR of 0.44. These results support the primary analysis. Clinical trial information: NCT01100502.Multivariate analyses of PFS by investigator assessment. Effect Hazard Ratio (95% CI) P value Treatment (BV vs Placebo) 0.44 (0.31, 0.62) <0.001 Salvage response (CR vs PR/SD) 0.44 (0.30, 0.64) <0.001 Gender (F vs M) 0.60 (0.43, 0.85) 0.004 No. treatments pre-ASCT (2 vs >2) 0.65 (0.47, 0.90) 0.010 FL therapy (ABVD vs BEACOPP/Other) 0.63 (0.44, 0.91) 0.013 B symptoms pre-ASCT (No vs Yes) 0.64 (0.45, 0.92) 0.015 Baseline weight (≤100 vs >100 kg) 0.58 (0.36, 0.94) 0.026
Imaging techniques in pancreatic cancer screening: Preliminary results from the PanGen-FAM registry.
Authors: Carmen Guillen-Ponce, Evelina Mocci, Julie Earl, Mirari Marquez, Roger Milne, MJ Molina-Garrido, Carmen T Guerrero, Francisco X Real, Nuria Malats, Alfredo Carrato
Journal: Journal of Clinical Oncology (2013)

1529 Background: The incidence of pancreatic cancer (PC) is low, thus screening is recommended for individuals considered to be at high risk. These include members of families with ≥ 2 relatives with PC (FPC), Peutz Jegher syndrome, hereditary breast/ovarian cancer (HBOC), familial atypical multiple mole melanoma and Lynch syndrome. Previous studies have shown that non-invasive precursor lesions, such as intraductal papillary mucinous neoplasm (IPMN) and pancreatic intraepithelial neoplasia (PanIN) are more common and of a higher invasive grade in patients with a family history of PC. Methods: Baseline screening consisted of endoscopic ultrasound (EUS) and computed tomography (CT) and magnetic resonance imaging (MRI). FNA-EUS was performed when mass lesions or cysts ≥1 cm in size were encountered. The possibility of surgical intervention or ongoing clinical observation was discussed by a multidisciplinary team in the case of abnormal findings. Furthermore Circulating Tumor Cells (CTC) in peripheral blood as a diagnostic marker was assessed. Thirty-five individuals from FPC and HBOC families were screened between October 2011and December 2012. Results: The most frequent abnormal findings by EUS were parenchymal changes found in chronic pancreatitis (hyperechoic foci, echogenic strands, lobularity, cysts). Overall 13 (41%) patients showed at least 1 of these changes; of note, 7 patients were from the same FPC family. Four patients were diagnosed with cystic lesions by EUS; two lesions were confirmed by MRI but not by CT, one lesion was confirmed by both MRI and CT and was compatible with a mucinous tumor &lt; 1cm in diameter and one lesion was detected only by EUS. One patient with cystic lesion &gt;1 cm in size underwent EUS-FNA and the cytology showed benign celularity. One patient has a solid lesion, and it was a neuroendocrine tumor. The remaining patients with cystic lesions were proposed for ongoing close clinical observation. CTC have not been detected in 54 patients tested. Conclusions: A high prevalence of pancreatic abnormalities was found in patients from FPC families. Preliminary data suggest that EUS is the most sensitive method to detect small tumors and premalignant lesions.
Identification of putative molecular targets in Merkel cell carcinoma.
Authors: Sherif S. Morgan, Rebecca Feldman, Lee D. Cranmer
Journal: Journal of Clinical Oncology (2014)

e20052 Background: Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine tumor. MCC is attributed to Merkel Cell Polyoma virus infection in up to 80% of patients, but is of unknown molecular pathogenesis in the remainder. Advanced disease has been managed by analogy, using regimens for small-cell lung cancer (SCLC). No targeted agents have been identified for treatment. We profiled molecular changes in MCC to provide insight into new therapeutic strategies. Methods: 64 MCC cases referred to Caris Life Sciences between 2009 and 2013 were evaluated. Diagnoses were collected from referring physicians and classified at intake based on pathology and clinical history. Specific testing was performed per physician request and included a combination of sequencing (Sanger, NGS), protein expression (IHC), and gene amplification (CISH or FISH). Results: Positive expression of biomarkers occurring in more than half of specimens included MRP1 and TOP2A (94%), TUBB3 (90%), RRM1 (79%), PTEN (66%), and TS (63%). Low expression of biomarkers occurring in more than half of specimens included PGP and SPARC (84%), ERCC1 and TLE3 (80%), PDGFRA (75%), and BCRP, cKIT, and MGMT (~60%). TOPO1 and PR were overexpressed in approximately 40% of patients. Gene amplification was not observed in cMET, EGFR, HER2, or TOP2A. Sanger sequencing did not reveal mutations in BRAF, cKIT, EGFR, KRAS, NRAS, or PIK3CA. NGS detected variant genes in 6 of 11 (55%) patients: alterations occurred in APC (n=1), ERBB4 (n=1), HRAS (n=1), RB1 (n=1), and TP53 (n=5). Two patients exhibited multiple mutations. Conclusions: Our data support the utility of cytotoxic therapies for MCC by analogy to SCLC, including platinum agents, anthracyclines, and topotecan. MRP1 was however expressed in 94%, suggesting etoposide resistance. A novel finding was overexpression of PR in 37% (22/60) of patients; anti-hormonal therapies merit further investigation in light of the disease’s male predominance. Sporadic mutations of cancer-related genes were identified by NGS. The only mutational pattern observed was the presence of TP53 mutations in 5/11 (45%), potentially targeted by Wee1 and ChK1 inhibitors. Further evaluation is necessary to identify key changes in MCC that might be exploited.
The effects of resident participation on patient morbidity and mortality in major gastrointestinal oncologic surgery.
Authors: Geoffrey Bellini, Annabelle Teng, David Y Lee, Keith Rose
Journal: Journal of Clinical Oncology (2017)

437 Background: While the effects of resident participation have been documented in various studies, there has yet to be a comprehensive study analyzing resident participation in overall gastrointestinal (GI) oncologic surgery. The aim of this study was to compare outcomes in major GI oncologic cases performed by an attending alone and those performed by an attending and resident. Methods: The ACS-NSQIP database from 2005-12 was utilized to study major (GI) operations (esophagectomy, gastrectomy, pancreatectomy, enterectomy, hepatectomy, and colectomy/proctectomy) in patients with an ICD-9 cancer diagnosis. Major complications and 30-day mortality were then compared in those patients who underwent surgery with an attending alone (AA) to those patients who underwent surgery with an attending and resident (AR). Results: A total of 64,637 patients met criteria for the study; AR n = 48,022 and AA n = 16,615. In 76.6% of AR cases, the resident assistance was classified as senior level PGY-4 or higher. On average, operative time was significantly increased in AR cases compared to AA cases (228 ± 130 vs 163 ± 104 min, p &lt; 0.001). On multivariate analysis, AR cases were more likely to develop superficial incisional infection (OR 1.3, CI 95% 1.2-1.4, p &lt; 0.001) and urinary tract infection (OR 1.2, CI 95%, 1.1-1.4, p &lt; 0.001) compared to AA cases. However, on multivariate analysis, resident participation was associated with less likelihood of returning to the operating room (OR 0.9, 95% CI 0.8-0.9, p &lt; 0.001) and lower mortality (OR 0.7, CI 95% 0.6-0.8, p &lt; 0.001). Conclusions: The majority of major GI oncologic operations in the NSQIP database are performed by an attending with the assistance of a senior level resident. This may be due to the complex nature of GI oncologic operation. Potentially, operative time in cases with resident participation may be increased by teaching or by the complex nature of the operation due to the referral bias to teaching centers. However, even with potentially more complex operations, there was less mortality in cases performed by a resident and an attending.