tbuckley/cabot-search huggingface dataset:
Impact of language on distress screening in cancer patients at an NCI-Designated Comprehensive Cancer Center.
Authors: Veronica Jones, Karen L. Clark, Susanne Warner, Jenny Rodriguez, Joanne E. Mortimer, Betty R. Ferrell, Victoria Louise Seewaldt, Laura Kruper, Matthew J. Loscalzo
Journal: Journal of Clinical Oncology (2017)

e18070 Background: Psychological distress has been linked to poor outcomes among cancer patients. In 2007, the Institute of Medicine reported that distress is often unrecognized. While much is known about distress screening in English speaking populations, little is known about the provision of screening in Spanish. Methods: From 2009-2016, over 9000 solid tumor and lymphoma patients treated at an NCI CCC were prospectively administered a validated biopsychosocial distress questionnaire in their preferred language. The data was retrospectively stratified by language and Chi-square and ANOVA tests were performed to detect differences. Results: Spanish-speaking patients had the highest levels of reported distress in every category when compared to any other group. Of the 629 patients that reported Spanish as their preferred language, 400 (63.6%) took the questionnaire in Spanish (SS) with the rest taking it in English (SE). There was no difference in reported gender, marital status, education level or income between the two groups. The SS patients were younger (mean age 56 vs 60.5, P = 0.00) and reported significantly higher distress than the SE patients in every biopsychosocial domain except functional. The greatest difference was seen in “understanding treatment options” (40.1% SS vs 19% SE, p = 0.00) with a significant difference seen also in “fear of medical procedures” (38.2% SS vs 29.9% SE, p = 0.037), “finances” (66.5% SS vs 55.4% SE, p = 0.01), “finding community resources” (34.8% SS vs 26% SE, p = 0.03), “managing emotions” (40.3% SS vs 31.5% SE, p = 0.032), “needing help to coordinate care” (41% SS vs 23.4% SE, p = 0.00) and “transportation” (35.2% SS vs 21.9% SE, p = 0.001). The distress of the SE patients was more similar to that seen in the English-English patients, but was still significantly higher. Conclusions: These provocative data demonstrate distress levels are stratified by preferred language among cancer patients. Spanish speaking patients had the highest levels of reported distress but this difference was more pronounced when they were administered the questionnaire in Spanish. More studies are needed to determine culturally effective ways to identify distress in Spanish speaking populations.
The evolving landscape of oncolytic virotherapy (OV) clinical trials (CT): Meta-analysis.
Authors: Wungki Park, Sandra Algaze, Simon Abi Aad, Deukwoo Kwon, Roy Elias, Nicolas Acquavella, Jaime R. Merchan
Journal: Journal of Clinical Oncology (2017)

e14636 Background: The number of new OV CT have been increasing along with the evolution of cancer immunotherapy. The OVs induce direct oncolysis and enhances the host innate and adaptive immunity. There are ongoing efforts to improve the anticancer efficacy of OVs with combinational strategies. However, there has been no direct comparison of OV CTs to evaluate their different dose levels, administration routes, frequencies, and the types of OVs and combinations. Methods: A random-effect meta-analysis was performed to evaluate pooled best ORR of all the existing OV phase II and III trials from publications and presented abstracts from ASCO, AACR, and ASGCT from 1/1/2016 to 12/4/2016. MeSH term “oncolytic” was used in PubMed. The inclusion criteria were: phase II or III, solid tumor, reported ORR. We evaluated the best ORR among different viruses, DNA vs. RNA, intratumoral (IT) vs. intravenous (IV) / intra-arterial (IA), and single vs. combination. Results: From 79 publications and 176 presented abstracts identified, 6 published studies and 12 presented abstracts were selected and pooled (n=875). The best ORRs were: DNA OV 23% (15 ~ 34%) vs. RNA OV 31% (13 ~ 58%), IT 36% (23 ~ 51%) vs. IV/IA 16% (10 ~ 25%), and single agent 22% (16 ~ 31%) vs. combinations 35% (17 ~ 58%). The combination OV CTs were either with chemotherapy (n= 144), chemoradiation (n= 23), or immunotherapy (n= 69). Each OV’s ORR is summarized in the table below. Direct comparison of the secondary endpoints: clinical outcome and adverse events will be presented with the poster. In general, the OV CTs had good overall safety profile and most adverse events were less than grade 3. Conclusions: The antitumor effect of OVs against solid tumors is evident and consistent in many trials. The largest data currently available is with herpes virus and coxsackie virus appears to have the best ORR possibly due to the combination with immunotherapy. The above results confirm the promising clinical activity of novel oncolytic viral vectors both alone and in combination. [Table: see text]
Improving versatility of generating recombinant adenovirus.
Authors: Jason Hirshberg
Journal: Journal of Clinical Oncology (2018)

e24321 Background: Adenovirus is a non-integrating DNA virus that inhibits tumor-suppressors and stabilizes oncogenes. Despite these interactions, infection causes mild illness. Recent studies using recombinant adenovirus expanded our understanding of p53 as a central mediator of innate immunity. Studies like these demonstrate the continued value of adenoviruses to cancer research. Current methods of generating recombinant adenovirus are limited. The AdEasy system restricts insertion of a transgene into a region defined by a shuttle vector and does not permit modification of endogenous genes. To overcome this, we developed a synthetic method to enhance the versatility of generating recombinant adenovirus. Methods: Using PCR, we synthesized seven overlapping amplicons forming a contig across the genome. Two assembly strategies were tested. First, HEK293s were nucleofected with equimolar concentrations of amplicons. Assembly via homologous recombination (HR) utilized intracellular machinery to join amplicons at sites of terminal overlap. Our second assembly strategy utilized an in-vitro pre-assembly method based on the Gibson reaction which uses an exonuclease, polymerase, and ligase to assemble fragments at sites of overlap. This strategy sought to maximize assembly efficiency. Nucleofected cells were cultured and monitored for cytopathic effects indicative of adenoviral replication. Amplicons were ligated into plasmids for site-directed mutagenesis. If amplicons can successfully yield virus after nucleofection, recombinants may be generated with the flexibility of primer-design. Results: HR alone failed to assemble overlapping amplicons in-vivo. However, in-vitro pre-assembly prior to nucleofection sufficiently generated adenovirus from seven amplicons representing the complete adenovirus genome. Conclusions: Successful production of virus from overlapping amplicons enables greater freedom in generating recombinant adenoviruses. This method may also work for other DNA viruses such as cytomegalovirus. Engineered viruses hold continued potential for cancer research and gene therapy. Improved versatility of generating recombinant viruses enables researchers to study a wider repertoire of responses to infection.
First-in-human study of KHK2455, a long-acting, potent and selective indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor, in combination with mogamulizumab (Moga), an anti-CCR4 monoclonal antibody, in patients (pts) with advanced solid tumors.
Authors: Timothy Anthony Yap, Solmaz Sahebjam, David S. Hong, Vi Kien Chiu, Emrullah Yilmaz, Sergey Efuni, Dmitri O. Grebennik, Agron Collaku, Eniola Ogunmefun, Yi Liu, Tomonori Tayama, Robert Raymond Latek, Olivier Rixe
Journal: Journal of Clinical Oncology (2018)

3040 Background: IDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. Unlike other inhibitors, KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Moga is a monoclonal antibody with enhanced ADCC activity that has shown synergy with KHK2455 in preclinical models. Methods: Pts with advanced solid tumors received escalating doses of KHK2455 alone (0.3, 1, 3, and 10 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV Moga for 4 weeks (Cycle 1) and then on Days 1 and 15 (from Cycle 2) in a standard 3+3 Phase I design. Dose escalation was based on safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production). Results: 21 pts were enrolled in cohorts that received KHK2455 at 0.3, 1, 3, and 10 mg dose levels. No DLTs were observed. The most frequent adverse events (≥5%) included maculopapular rash, thrush, dysphagia, thrombotic event, and tachycardia, none of which were considered related to KHK2455. One case of rash (Gr 3) was considered related to Moga but not a DLT. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated in plasma samples (67% and 66% inhibition in Kyn concentrations and Kyn:Trp ratio, respectively, compared to baseline) and ex vivo stimulation assays ( > 95% inhibition in Kyn production) at 10 mg KHK2455, confirming target modulation. Four patients (n = 3 head and neck; n = 1 ovarian) from all dosing groups have achieved durable RECIST disease stabilization for more than 6 months, and one (salivary gland carcinoma) for more than 14 months. Conclusions: KHK2455 in combination with Moga is safe and well tolerated at all doses tested, suppresses Kyn production in a dose-dependent and sustained manner, and demonstrates early signals of antitumor activity. These data support the continued development of this promising combination. Clinical trial information: NCT02867007.
The trough levels of bevacizumab significantly affect the outcome of the treatment in patients with metastatic colorectal cancer: A Turkish Oncology Group study.
Authors: Hakan Akbulut, Muge Ocal, Fatma Gizem Sonugur, Samira Abdi Abgarmi, Cansu Babahan, Busra Akay, Ülkü Yalçintas Arslan, Mehmet Artac, Mehmet Ali Nahit Sendur, Ahmet Demirkazik
Journal: Journal of Clinical Oncology (2018)

e15553 Background: We aimed to investigate the role of angiogenic factors and bevacizumab (Beva) trough levels on the efficacy of Beva plus chemotherapy combination in metastatic colorectal cancer patients (mCRC). Methods: Eighty-eight patients with mCRC treated with Beva plus either irinotecan or oxaliplatin-based regimens were prospectively included. The serum levels of angiogenic factors including hepatocyte growth factor (HGF), PlGF, VEGF, PDGF, bFGF, Annexin-1, Angiopoietin-2, Endothelin-1 and MMP9 were measured before the onset of the Beva. The through levels of Beva on the 14th day of the first cycle and following the eighth cycle and anti-Beva Ab levels in the 3rd month of the treatment were assayed by ELISA. Results: Beva (5mg/kg, q2w) has been implemented to the chemo backbone either at the first line (in 35% of the patients) or second line (65%) setting. The chemo backbone was irinotecan-based in 51% of the patients. The median number of treatment cycles was 6. The objective response and disease stabilization rates were 35% and 77%, respectively. The median overall survival (OS) time was 15 months. Though not significant, only the patients with lower HGF levels ( < 1750 pg/ml) had favorable OS time when compared to the higher group (22 mos vs 15 mos). The levels of the other factors including VEGF had no impact on OS. The median trough levels of bevacizumab after the first and eighth cycles were 27,6 and 76,5 ug/ml, respectively. No correlation was found between the serum VEGF levels and trough levels of Beva. The patients with lower trough levels (≤25 ug/ml) at the first cycle had significantly lower OS times when compared to the patients with higher levels ( > 25 ug/ml) (12 mos vs 24 mos, p = 0.0198). The presence of anti-Beva Abs (in 15% of the patients) had no impact on treatment outcomes. Conclusions: In conclusion, our results show that the pretreatment angiogenic factor levels are not predictors of outcomes for Beva plus chemotherapy in mCRC patients. The development of anti-Beva Abs seems has no effect on the efficacy of the Beva treatment. The trough levels of Beva at the first cycle could be a good predictor of survival for Beva treatment in patients with mCRC.
Effects of the multikinase inhibitor regorafenib in neuroblastoma.
Authors: Peter E. Zage, Divya Subramonian, Qianxing Mo, Shixia Huang
Journal: Journal of Clinical Oncology (2017)

10553 Background: Neuroblastoma (NB) is the most common extracranial solid pediatric tumor, and children with high-risk NB have poor survival rates and need novel treatment strategies. Regorafenib, a multi-receptor tyrosine kinase (RTK) inhibitor approved for treating adult solid tumors such as advanced metastatic colorectal cancer and gastrointestinal stromal tumors, inhibits many RTKs, including PDGFR-β, VEGFR1-3, RET, c-Kit and FGFR family members. Based on the potential roles for these targets in neuroblastoma pathogenesis, we explored the therapeutic potential of Regorafenib alone and in combination with 13-cis-retinoic acid against neuroblastoma cells. Methods: We treated NB cell lines with increasing concentrations of Regorafenib and measured cell viability using MTT assays. We further measured the occupied percent confluence over time using continuous live cell imaging. We performed Western blots for caspase cleavage to measure apoptosis and flow cytometry to determine cell cycle expression. We performed Reverse Phase Protein Array (RPPA) analysis of neuroblastoma cells before and after treatment with regorafenib combined with 13- cis-retinoic acid. Results: IC 50 values for the tested cell lines ranged between 2.5mcM and 12.5mcM after 72 hours of exposure to Regorafenib, and decreased viability was due to a combination of apoptosis and cell cycle arrest. RPPA analysis identified alterations in multiple proteins and pathways after Regorafenib with retinoic acid treatment, including the PI3K/Akt/mTOR and Jak/Stat pathways. Phosphorylation of Erk1/2, S6, Akt, and c-Jun were decreased, while protein expression of GATA3 was increased in a dose-dependent manner. Conclusions: Regorafenib treatment results in reduced neuroblastoma cell viability and increased apoptosis via effects on several signaling pathways. Effects on intracellular signaling pathways associated with responses to the combination of regorafenib plus retinoic acid represent opportunities to develop novel combination therapies, representing potential new therapeutic strategies for children with neuroblastoma.
Sorafenib (Soraf) and irinotecan (Iri) combination for pretreated RAS-mutated metastatic colorectal cancer (mCRC) patients: A multicentre randomized phase II trial (NEXIRI 2-PRODIGE 27).
Authors: Emmanuelle Samalin, Christelle De La Fouchardiere, Simon Thezenas, Valerie Boige, Helene Senellart, Rosine Guimbaud, Julien Taïeb, Eric Francois, Marie-Pierre Galais, Antoine Adenis, Astrid Lievre, Jean-François Seitz, Jean-Philippe Metges, Frédéric Di Fiore, Florence Boissiere, Evelyne Lopez-Crapez, Frederic Bibeau, Alexandre Ho-Pun-Cheung, Thibault Mazard, Marc Ychou
Journal: Journal of Clinical Oncology (2016)

3545 Background: Sorafenib and irinotecan combination (NEXIRI) showed promising efficacy with a 65% disease control rate (DCR) in pretreated mutated (mt) KRAS mCRC. In this single arm study, CCND1 rs9344 A/A polymorphism had a predictive value (Samalin et al. 2014).This multicentre randomized phase II trial aimed to determine the 2-month progression-free survival rate (2-PFS) of NEXIRI vsIri or Soraf monotherapies in these patients (pts) after failure of all approved active drugs at the time of the study. Methods: Pts PS≤1 with progressive non-resectable mtKRAS (then RAS) mCRC pretreated with irinotecan, oxaliplatin, fluoropyrimidines and bevacizumab (none with regorafenib), were randomized in 3 arms: NEXIRI (biweekly Iri IV 120, 150, 180mg/m² at C3 combined with a fixed dose of Soraf 400mg twice daily) vs Iri (180mg/m²) alone vs Soraf alone, until progression or toxicity, with cross-over to NEXIRI at progression. Primary endpoint was the 2-PFS (RECIST v1.1). Pharmacokinetic, pharmacogenetics and pathologic translational studies were undertaken. Results: We included 173 pts (age 62 [31-82]; PS 0/1: 38/61%) between 2012 and 2014 in 17 French centres. Main results were (median follow-up 17.5 months): See table. Conclusions: We confirmed the NEXIRI regimen efficacy in a randomized study for refractory mtRAS mCRC pts. CCND1 rs9344 may identify patients who benefit from this combination. These results justify comparing NEXIRI to Regorafenib or TAS 102 monotherapies in CCND1 rs9344 A/A pts subgroup. Other results from ancillary studies will be presented at the meeting. Clinical trial information: NCT01715441. NEXIRI (n=57) Iri (n=56) Soraf (n=57) Median treatment duration (months)* 3 2 2.5 Grade 3/4 toxicities (%)* Neutropenia (febrile) 16/2 (5) 6/0 (0) 0/0 (0) Diarrhea 26/0 7/0 7/0 Hand-foot syndrome 17/0 0/0 16/0 Hypertension 10/0 2/0 10/0 2-PFS (%)$ 59 [39-66] 23 [10-33] 22 [8-30] DCR/PR (%)$ 59/4 25/0 22/0 Cross-over to NEXIRI n(%) - 42(75) 27(47) Median PFS (months) 3.7 [2.2-4.9] 1.9 [1.7-2.1] 2.1 [1.9-2.5] Median OS (months) 7.0 [5.8-9.4] 6.3 [4.8-8] 5.1 [3.7-7.7] CCND1 rs9344 genotype response SD PD SD PD SD PD A/A 11 1 0 8 0 9 A/G or G/G 15 14 9 23 6 22 *170 pts $18 (6/4/8) non-evaluable pts
Chemosensitivity of patient derived human tumor xenograft models against 5FU, Capecitabin, CPT-11 and Oxaliplatin
Authors: Heinz Fiebig, Thomas Greiner, Sandra Kissel, Andre Korrat, Julia Schuler
Journal: Cancer Research (2007)

2219  Patient derived tumor models established sc in nude mice have been shown to predict well the response of standard and novel agents compared with clinic activity. In 80 comparisons we have treated the same tumor in the patient and in the nude mouse. In 21 cases the tumor went into remission in the patient and the same response were seen in 19 cases in the nude mouse (90%). When no response was seen in 59 patients the same result was observed in the nude mouse in 57 tumors giving a correct prediction of the xenograft model of 97%. The combination of cytotoxic agents with novel signal transduction inhibitors improved the time to progression and survival time in patients with colorectal (chemo plus Avastin or Cetuximab), non-small cell lung (Avastin) and breast cancers (combo with Herceptin or Avastin). In order to identify suitable xenograft models for such combination studies we investigated the effect of 5FU, Capecitabin, CPT-11 and Oxaliplatin. Treatment started when the sc implanted tumors reached tumor volumes around 5 - 7 mm (about 100 mm³). The compounds where given at their MTD (around LD20 after 2 cycles): 5FU at 100 mg/kg/d ip day 1, 8, 15, Capecitabin 300 mg/kg/d po day 1 to 10 - 14, CPT11 75 mg/kg/d iv day 1 and 8 as well as Oxaliplatin 8 mg/kg day 1,15 ip.  All 4 compounds showed high activity mainly in colorectal, mammary and in non-small lung cancer. Capecitabin effected inhibition   Overall the activity pattern in the engraft system resembles the activity in the clinic. Suitable models with a moderate sensitivity against the single agent therapy are being selected for combining two-drug cytostatic combinations with Avastin, Cetuximab, and other new signal transduction inhibitors.
A phase IV, randomized, double-blind, placebo (PBO)-controlled study of continued enzalutamide (ENZA) post prostate-specific antigen (PSA) progression in men with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC).
Authors: Gerhardt Attard, Michael Borre, Howard Gurney, Yohann Loriot, Corina Andresen, Ranjith Kalleda, Trinh Pham, Mary-Ellen Taplin
Journal: Journal of Clinical Oncology (2017)

5004 Background: We hypothesized resistance to the androgen receptor inhibitor ENZA is due to increases in androgens and can be overcome by combination with the androgen synthesis inhibitor abiraterone (abi). The phase 4 PLATO trial (NCT01995513) is evaluating the safety and efficacy of continued ENZA + abi/prednisone (abi/P) vs PBO + abi/P after PSA progression on ENZA. Methods: In Period (P) 1, men with chemotherapy-naïve mCRPC received ENZA (160 mg); men with no PSA increase from baseline at wk 13 and 21 continued treatment until PSA progression (≥ 25% increase and ≥ 2 ng/mL above nadir). Eligible men were then randomized 1:1 in P2 to ENZA + abi/P (1000 mg/10 mg) or PBO + abi/P. The primary endpoint (EP) was progression-free survival (PFS; radiographic or unequivocal clinical progression, or death on study) in P2, with a prespecified sensitivity analysis of radiographic PFS (rPFS); protected secondary EPs were time to PSA progression (TTPP) and PSA response ≥ 50% in P2. Results: 509 men enrolled in P1. At data cutoff (Oct 7, 2016), 84 were active, 174 discontinued, and 251 were randomized in P2 (ENZA + abi/P, n = 126; PBO + abi/P, n = 125). Median treatment duration in P2 was 5.6 mo for both arms. PFS event by radiographic/clinical/death was 38%/25%/2% for ENZA + abi/P and 55%/18%/1% for PBO + abi/P. Median PFS was 5.7 mo for ENZA + abi/P and 5.6 mo for PBO + abi/P (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.61, 1.12; P = 0.22). Median TTPP was 2.8 mo for both arms (HR, 0.87; 95% CI, 0.62, 1.24; P = 0.45). PSA response rate was 0.8% for ENZA + abi/P and 2.5% for PBO + abi/P ( P = 0.31). Median rPFS was 10.0 mo for ENZA + abi/P and 7.0 mo for PBO + abi/P (HR, 0.67; 95% CI, 0.47, 0.94; P = 0.02). The most common (≥ 15%) adverse events for ENZA + abi/P vs PBO + abi/P were back pain (21% vs 23%), hypertension (20% vs 7%), nausea (17% vs 9%), and fatigue (14% vs 15%). Conclusions: ENZA + abi/P post PSA progression on ENZA was associated with increased hypertension and nausea and did not result in a statistically significant improvement in composite PFS. The signal seen in rPFS needs further evaluation. Clinical trial information: NCT01995513.
Abstract 18967: Inhibition of Circulating Exosome Improved Ischemic Hindlimb Repair in Type Diabetic db/db Mice
Authors: Zhongjian Cheng, Venkata Naga Srikanth Garikipati, Maria Cimini, Yan Tang, Chunlin Wang, May Trungcao, Yujia Yue, Cindy Benedict, David Goukassian, Suresh K Verma, Raj Kishore
Journal: Circulation (2017)

Background: Recent studies have demonstrated that exosomes from diabetic animals/cells have detrimental effects on the post-injury vascular repair. Here, we tested the hypothesis that systemic exosome inhibition in vivo improves blood flow recovery in ischemic hindlimbs of diabetic db/db following surgical ischemia. Methods and Results: Exosomes were isolated from plasma of non-diabetic db/+ and diabetic db/db mice by standard ultracentrifugation method. Unilateral hindlimb ischemia surgery was conducted by ligation of left femoral artery in 12-week old, male db/+ and db/db mice. Exosome inhibitor GW-4869 (GW, 2 μg/g body weight) was administrated by intraperitoneal injection every other day for 4 weeks starting from one week before the hindlimb ischemia (HLI) surgery. HLI mice injected with vehicle served as controls. Mice were divided into four groups: 1) db/+ + vehicle; 2) db/db+ vehicle; 3) db/+ GW; 4) db/db + GW. We found that systemic administration of GW decreased necrosis and loss of toe/toenail, ...