tbuckley/cabot-search huggingface dataset:
Inhibition of autophagy sensitizes gastrointestinal stromal tumor cells to TKI/Bcl-2 inhibitors-induced apoptosis.
Authors: Shuchao Zhang, Guozhi HU, Ana Cristina Paz-Mejia, Luyuan Li, Jonathan C. Trent
Journal: Journal of Clinical Oncology (2017)

11036 Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the GI tract. Most GISTs are driven by mutations in KIT or platelet-derived growth factor receptor-α (PDGFRA), which responds well to imatinib, a tyrosine kinase inhibitor (TKI) that blocks KIT and PDGFR-α signaling. Bcl-2 family plays a critical role in the regulation of cell apoptosis in GISTs. ABT-737 as an inhibitor of Bcl-2/Bcl-xL can result in a time and dose-dependent activation of apoptosis. Autophagy is a key mechanism to promote tumor cells survival, inhibition of which can induce the cell death in GISTs. Chloroquine, an antimalarial drug, has been also identified as an autophagy inhibitor. In this study, we assessed the combinational effects of imatinib, ABT-737 and chloroquine in GIST cells. Methods: Human GIST cell lines, GIST-T1 and GIST-882, were employed in our study. Cells were treated with imatinib, ABT-737 and chloroquine either separately or in different combinations. Cell viability was tested by means of MTS and synergistic effects were analyzed by isobologram software. The levels of related proteins of apoptosis (PARP, Caspase-3) and autophagy (LC3-II, beclin-1) were measured by western blot. Cell apoptosis and cell cycle were tested by flow cytometry. Results: Cell viability assay indicated cell survival percentage of double or triple drug combinations ( &lt; 5%) dramatically decreased compared to single drug treatments (42%, 36% or 12%) ( P&lt; 0.05). Isobologram analysis revealed triple drugs combination had stronger synergistic effects than double drugs combinations (CI = 0.204 vs 0.309 or 0.356, P&lt; 0.05). Cell apoptosis percentage of double (32.9% or 36.6%) or triple drugs combinations (66.5%) significantly increased compared to single treatments (6.1%, 6.1% or 13.1%) ( P&lt; 0.05). Western blot showed drugs combinations increased cleavage of PARP and Caspase-3 levels, but inhibited autophagy. Conclusions: The combination of imatinib, ABT-737 and chloroquine has collaborative effects on the treatment of GISTs in vitro. The combined strategy may enhance the clinical efficacy, which provides a rationale for the clinical evaluation of these drug combinations in GISTs treatment.
Leveraging transcriptomic data to pinpoint mechanisms of gemcitabine resistance and potential combination therapies for pancreatic cancer.
Authors: Rebecca L. Kusko, Yoonjeong Cha, Joseph Perez-Rogers, Nacho Caballero, Gregory Koytiger, Jyoti Shankar, Andrew Lysaght, Brian Weiner, Sarah Kolitz, Fadi Towfic, Kevin Fowler, Badri Vardarajan, Maxim Artyomov, Benjamin Zeskind
Journal: Journal of Clinical Oncology (2016)

e15730 Background: Pancreatic cancer has an estimated 5-year survival rate of only 5-6% and is often diagnosed after metastasis has occurred. Gemcitabine or gemcitabine combination therapies are frequently utilized, although existing gemcitabine combination therapies are highly toxic. The minimal effectiveness of current treatment options for pancreatic cancer precipitates the urgent unmet clinical need for promising novel combination therapies to enhance the efficacy of gemcitabine. Methods: In order to interrogate targetable mechanisms which orchestrate gemcitabine resistance, we analyzed transcriptomic data from three pancreatic cancer cell line datasets: (Klijn et al(N = 14), Collisson et al(N = 11), and CCLE(N = 12). After data processing and filtering low quality samples, a t-test was leveraged to identify genes differentially expressed (DE) between cell lines that are sensitive to gemcitabine vs resistant to gemcitabine as dictated by IC50 values reported in Collisson et al. Results: The overlap of DE genes between all three studies revealed 41 genes upregulated and 29 genes downregulated in gemcitabine resistant cell lines. Enrichment of genes upregulated in resistant cell lines includes WikiPathways ErbB signaling pathway (p = 0.006), Reactome G1 Phase (p = 0.002), and GO negative regulation of protein serine/threonine kinase activity (p = 0.004). Enrichment of genes downregulated in resistant cell lines includes WikiPathways Wnt signaling pathway (p = 0.02), and GO cell morphogenesis involved in differentiation (p = 9E-5). DE of putative drivers of resistance was validated using qRT-PCR, and expression changes after gemcitabine treatment was evaluated with FACS. Conclusions: Analysis to identify drugs which may reverse this signature of gemcitabine resistance is ongoing, and additional experimental studies are underway to substantiate key targets. By elucidating a robust and consistent signature distinguishing gemcitabine resistant from gemcitabine sensitive pancreatic cancer cell lines, we have pinpointed numerous genes and pathways which could be targeted by a potential combination therapy.
Characterizing social worker and chaplain interactions with parents of critically ill children with cancer.
Authors: Nicole Lentini, Elizabeth Martinez, Kelly Michelson
Journal: Journal of Clinical Oncology (2017)

e22024 Background: Parents of children with cancer admitted to the pediatric intensive care unit (PICU) often obtain support from social workers and/or chaplains (SWs/Cs). Yet, empirical work describing the roles and activities of SWs/Cs caring for patients in the PICU is lacking. This study examined the roles of SWs/Cs caring for critically ill children with cancer and their families. Methods: Parents of patients with cancer expected to have a PICU stay &gt; 72 hours, ongoing involvement with palliative care, or a pediatric index of mortality score &gt; 4 were invited to participate. These criteria were meant to identify patients with more complicated PICU admissions. The SWs/Cs caring for these families in the PICU were also invited to participate. SWs/Cs audio recorded information about their encounters with parents and patients, specifically, who was present, the kinds of supports provided, and the discussion topics. These recordings were analyzed using content analysis resulting in broad categories describing support provided to the families by SWs/Cs. Results: In total, 3 SWs and 3 Cs submitted recordings about 34 encounters with families of 9 patients. Categories of activities and supports identified from these recordings included: discussing the child’s condition, assessing parent or child coping, assessing the role of faith, discussing communication between parents and the medical team or advocating for the family with the medical team, providing emotional support to patients and families, discussing concerns outside of the hospital (family, financial, work), and providing legal and/or logistical support. SWs/Cs, in general, provided very similar services to families. Conclusions: SWs and Cs caring for PICU patients with cancer and their families have overlapping roles in providing emotional, communication, and logistical support. Future work will identify barriers and facilitators to SWs and Cs providing support to critically ill children with cancer.
A curative approach to central nervous system metastases of neuroblastoma.
Authors: Kim Kramer, Brian H. Kushner, Shakeel Modak, Neeta Pandit-Taskar, Ursula Tomlinson, Suzanne L. Wolden, Pat Zanzonico, Humm L. John, Sofia Haque, Mark M. Souweidane, Jeffrey Greenfield, Ellen M. Basu, Stephen S. Roberts, Jorge A. Carrasquillo, Jason Stuart Lewis, Serge K. Lyashchenko, Steven M. Larson, Nai-Kong V. Cheung
Journal: Journal of Clinical Oncology (2017)

10545 Background: Neuroblastoma metastatic to the central nervous system (CNS NB) is associated with significant mortality (median survival &lt; 6 months, &lt; 10% survival at 36 months). Intraventricular compartmental radioimmunotherapy (cRIT) with radio-iodinated murine IgG1 monoclonal antibody 131 I-8H9 targeting tumor cell-surface glycoprotein B7-H3 offers a therapeutic strategy. We analyzed overall survival of patients with CNS NB treated with intraventricular 131 I-8H9 cRIT at Memorial Sloan Kettering Cancer Center (MSK) since 2003. Methods: After radiographic and/or pathologic confirmation of CNS NB, and assessment of adequate CSF flow, cRIT eligible patients underwent treatment on an IRB-approved protocol with either temozolomide/irinotecan-based CNS salvage regimen incorporating craniospinal radiation therapy, 131 I-8H9 cRIT plus systemic immunotherapy (group 1), or non-regimen therapies with 131 I-8H9 cRIT (group 2). cRIT administration involved a 2mCi tracer of 124 I- or 131 I-8H9 with nuclear imaging and CSF sampling for dosimetry followed by 1 or 2 therapeutic injections up to 70 mCi 131 I-8H9. Disease surveillance included serial MR brain/spine, MIBG, CT, and bone marrow evaluation. Data are presented as overall survival after detection of CNS metastasis. Results: 105 patients with CNS NB were evaluated;80 patients (76%) were treated (57 group 1, 23 group 2). Of the 25 patients who were not eligible for cRIT, survival averaged 8.6 months. Of 19 patients with radiographic evidence of disease at the time of cRIT, 7 (36%) demonstrated post cRIT radiographic improvement. At analysis, 45/80 (56%) patients were alive 4.8–152 months (median 58 months) after CNS metastasis, including 36 (45%) at 36 months and 23 (29%) &gt; 60 months. Subgroup analyses of 131 I-8H9–treated patients identified age at NB diagnosis (≤18 months), relapse restricted to CNS and group 1 status as factors positively correlated with survival. Conclusions: 76% of patients with CNS NB treated at MSK received 131 I-8H9 cRIT, and approximately half completed multimodality CNS salvage regimen with 131 I-8H9 cRIT. Despite advanced CNS involvement, over 50% of patients treated with 131 I-8H9 cRIT are still alive and nearly 50% have survived at least 36 months. Clinical trial information: NCT00089245.
A phase I pharmacokinetic and safety study of polatuzumab vedotin in Japanese patients with relapsed/refractory b-cell non-Hodgkin lymphoma: A comparison with non-Japanese DCS4968g study.
Authors: Kiyohiko Hatake, Tomohiro Kinoshita, Yasuhito Terui, Masahiro Yokoyama, Dai Maruyama, Shinichi Makita, Kazuhito Yamamoto, Yusuke Higuchi, Satsuki Murakami, Akiko Uechi, Yoshimasa Ishida, Jamie H. Hirata, Kensei Tobinai
Journal: Journal of Clinical Oncology (2016)

e19070 Background: Polatuzumab vedotin (PoV) is an antibody-drug conjugate (ADC) that contains a humanized anti-CD79b monoclonal antibody and a potent anti-mitotic agent, monomethyl auristatin E (MMAE). DCS4968g, a phase I study of PoV in patients (pts) with relapsed or refractory (r/r) B-cell NHL (Palanca-Wessels MC, et al. Lancet Oncol. 2015), showed that both monotherapy and combination with rituximab were effective with acceptable safety profiles in these pts. We conducted a phase I study (JO29138) to assess the safety, pharmacokinetics (PK), and efficacy of single agent PoV in Japanese pts, and compared results with those of DCS4968g. Methods: JO29138 was an open-label, multicenter 3+3 dose escalation study to assess the safety, tolerability, and PK of PoV in Japanese pts with r/r B-cell NHL. In JO29138, single agent PoV was administered intravenously at 1.0 or 1.8 mg/kg every 3 wks until disease progression. Results: As of 1 Oct 2015, 7 pts were enrolled (1.0 mg/kg cohort, 4 pts; 1.8 mg/kg cohort, 3 pts). Pt demographics were: 4 pts with FL and 3 pts with DLBCL; median age, 62 yrs; 6/7 female; median weight, 58 kg; median no. of prior therapies, 3. No dose-limiting toxicity was observed in either cohort. The only grade ≥ 3 AE was one grade 4 neutropenia in the 1.0 mg/kg cohort. The most common AE was peripheral sensory neuropathy, observed in 4 pts. Overall safety profile seems comparable with that of DCS4968g. PK profile of PoV showed long serum half-life, and the systemic exposure of unconjugated MMAE was limited. No distinct difference in PK profile between the 2 studies was observed. Preliminary response rate in JO29138 at 1.0 and 1.8 mg/kg was 43% (3/7) overall, comparable to the 43% (3/7) in DCS4968g. In JO29138, tumor lesions in 2 pts completely disappeared on CT. Four pts have received over 15 cycles of treatment without disease progression. Conclusions: The safety, PK, and efficacy of PoV monotherapy were reasonably comparable between Japanese and non-Japanese, and 1.8 mg/kg was tolerable as the recommended phase 2 dose. These results support further clinical studies of PoV, including combination with other antitumor agents. Clinical trial information: JapicCTI-142580.
Phase II trial of ribociclib and everolimus in p16 low anaplastic thyroid cancer (ATC).
Authors: Bernard Tawfik, David E. Gerber, Barbara Burtness, Randall S. Hughes, Larry L. Myers, Baran D. Sumer, John Truelson, Tobin Joel Strom, Pamela Kurian, Sehresh Saleem, Jean Pearson, Hong Zhu, Saad A. Khan
Journal: Journal of Clinical Oncology (2017)

TPS6098 Background: ATC is a rare thyroid cancer with a highly aggressive clinical course. Median OS is 3-4 months and 90% of patients die within 1 year of the diagnosis. There are no effective treatment options in metastatic disease. Targeted therapies to ALK and BRAF are occasionally associated with dramatic responses. Retinoblastoma (Rb) inhibits cell cycle progression and is inactivated by CDK 4/6, which is the target for ribociclib. Nearly all differentiated thyroid cancers are Rb negative, conversely nearly 100% of ATC expresses intact Rb which may be crucial for rapid cell cycle progression. Ribociclib is a CDK 4/6 inhibitors that slows cell cycle progression and DNA replication in tumors with functional Rb. The p16 protein similarly inhibits CDK4/6; if p16 levels are high Rb is phosphorylated and thus inactive. p16 is low in ATC, and from our comprehensive genomic analysis 30% of ATC lacks the p16 gene CDKN2a. Most ATC demonstrates PI3K/Akt/mTOR abnormalities, this pathway represents an attractive target in ATC. The mTOR inhibitor everolimus has shown promising efficacy in ATC cell lines, especially in those with TSC2 mutation whose wild type negatively regulates mTOR. Methods: The combination of everolimus and ribociclib targets mutations/abnormalities that are frequently seen in ATC, and is tolerable based on Phase I/II trial results in the latest arm of the biomarker/oncogene driven ATC Master Protocol . This open-label trial treats metastatic Rb+ ATC patients with p16-/ CDKN2a-. Treatment is ribociclib 400 mg + everolimus 5 mg QD. The primary endpoint is the overall response rate; secondary endpoints are PFS, OS, safety and toxicity. Exploratory objectives include if tissue biomarkers or mutations noted on Next Generation Sequencing correlate for enhanced/impaired response to combination therapy. Simon's two-stage design will be used with the null hypothesis that the true response rate is 5%, this will be tested against a one-sided alternative. In the first stage, 9 patients will be accrued. If no response in these 9 patients, the study will be stopped. Otherwise, 21 additional patients will be accrued for a total of 30. Clinical trial information: NCT02289144.
Estimated Resting Metabolic Rate and Body Composition Measures Are Strongly Associated With Diabetic Retinopathy in Indonesian Adults With Type 2 Diabetes
Authors: Muhammad B. Sasongko, Felicia Widyaputri, Dian C. Sulistyoningrum, Firman S. Wardhana, Tri Wahyu Widayanti, Supanji Supanji, Rifa Widyaningrum, Sarah R. Indrayanti, Idhayu A. Widhasari, Angela N. Agni
Journal: Diabetes Care (2018)

OBJECTIVE To investigate the associations of estimated resting metabolic rate (RMR), body fat (BF), subcutaneous fat (SCF), visceral fat (VF), fat-free mass (FFM) percentage, BMI, and waist circumference (WC) with diabetic retinopathy (DR) in Indonesian adults with type 2 diabetes. RESEARCH DESIGN AND METHODS This was a community-based cross-sectional study of 1,184 subjects with type 2 diabetes. DR was assessed from fundus photography and categorized as mild, moderate nonproliferative DR (NPDR), and vision-threatening DR (VTDR). RMR and body composition parameters were measured using automated body composition scan. Logistic regression with semipartial correlation analysis was used. RESULTS DR and VTDR were present in 43.1 and 26.3% of participants, respectively. After adjustment for age, sex, diabetes duration, fasting glucose, systolic blood pressure, smoking, diabetic ulcer, and use of combined diabetes treatment, per SD increase in RMR (odds ratio [OR] 2.60 [95% CI 2.19–3.07]; P &amp;lt; 0.001) was associated with DR, while per SD increases in BF (0.66 [95% CI 0.56–0.78]; P &amp;lt; 0.001), FFM (0.69 [0.57–0.84]; P &amp;lt; 0.001), VF (0.77 [0.67–0.88]; P &amp;lt; 0.001), BMI (0.83 [0.73–0.94]; P = 0.004), and WC (0.81 [0.73–0.91]; P &amp;lt; 0.001) were inversely associated with presence of DR. Similar associations were found for VTDR. Among all variables, RMR had the largest contribution to the variance in the DR model (39%). CONCLUSIONS In this study, RMR and body composition measures were strongly associated with and contributed considerably to the presence and severity of DR. These findings, if confirmed, suggest that RMR and body composition may be strong markers that represent actual metabolic state in the pathophysiology of DR.
Pulmonary function testing is safe in patients with thoracic aortic aneurysms
Authors: Freddy Frost, Rob Peat, Joan McWean, Matt Shaw, Mark Field, Dilip Nazareth, Martin Walshaw
Journal: European Respiratory Journal (2018)

Thoracic aortic aneurysms (TAA) occur in up to 16 patients per 100 000 of the population and are increasingly amenable to surgical correction [1]. However, low lung function is associated with poor post-operative outcomes, and a pre-operative assessment of pulmonary function is therefore important for prognostication [2]. Spirometry is safe as part of pre-operative work-up in patients with thoracic aortic aneurysms <http://ow.ly/uwSe30lJ6Qn>
Phase I study of personalized peptide vaccination combined with radiotherapy for advanced hepatocellular carcinoma patients.
Authors: Jie Shen, Lifeng Wang, Zhengyun Zou, Jia Wei, Baorui Liu
Journal: Journal of Clinical Oncology (2017)

e15628 Background: Advanced hepatocellular carcinoma is a challenging disease to treat because of its late stage, rapid progression. We conducted a new treatment modality, meaning a cellular immune therapy based on personalized peptide vaccination (PPV-DC-CTL) combined with radiotherapy, to treat advanced hepatocellular carcinoma. It integrates personalized peptide vaccination in tumor immunotherapy, takes full advantages of the immune modulation of radiotherapy, promotes tumor cells releasing antigens and results in more effective therapeutic strategy in local control and system treatment. Methods: A total of 9 patients with advanced hepatocellular carcinoma were admitted. Multidisciplinary consultation confirmed that all the patients were clearly no surgical opportunity. 4 patients with multiple liver metastases (liver lesions &gt; 3 pieces), 1 patient with liver metastases and portal vein tumor thrombosis, 1 patient with lung and bone metastasis, 2 patients with liver and lung metastasis, and 1 patients with liver metastases and peritoneal metastasis. Patients with metastasis were treated with precise radiotherapy combined with PPV-DC-CTL. Results: After radiotherapy and 1-3 cycles of PPV-DC-CTL treatment, AFP levels were significantly decreased in 6 patients, of which, imaging assessment of lesions researched PR for 3 patients and SD for another 3 patients. Response rate (RR) was 33%, and disease control rate (DCR) was 66%. This scheme is safe and well tolerated. None of the patients had side effects on liver and kidney function. Only one patient had Grade2 of bone marrow suppression, and the rest had no significant side effects on hemogram. Conclusions: Radiotherapy combined with PPV-DC-CTL provides a new therapeutic strategy for patients with advanced hepatocellular carcinoma, which is well tolerated, safe, feasible, and effective. Clinical trial information: ChiCTR-OIC-16010025.
Incidence of pneumonitis in patients with solid tumors treated with everolimus: A systematic review and meta- analysis of randomized controlled trials.
Authors: Kyaw Zin Thein, Anita Sultan, Sriman Swarup, Fred L. Hardwicke, Catherine Jones, Lukman Aderoju Tijani, Sanjay Awasthi, Nicholas C. D'Cunha
Journal: Journal of Clinical Oncology (2018)

e22220 Background: Aberrant signaling through the PI3K/AKT/mTOR signaling pathway has been implicated in the pathogenesis of multiple cancers. Everolimus (E), an mTOR inhibitor, has been employed in different tumors with success. Yet, the risk of pneumonitis, a major cause of morbidity and mortality (M&M), is substantial. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the incidence of pneumonitis. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2018 were queried. Trials that mention pneumonitis as adverse effect were incorporated in the analysis. The primary meta- analytic approach was a random effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Results: Twelve phase 3 RCTs with a total of 6298 patients with solid tumors were eligible for analysis. Studies compared E+ paclitaxel(P) + herceptin(H) vs P+H, E+ exemestane(Ex) vs Ex, E+ vinorelbine(V)+ H vs V+H, E vs cabozantinib, E vs nivolumab, or E vs placebo. The I2 statistic for heterogeneity was 62.98, and the heterogeneity X2 (Cochran's Q) was 24.31 (P = 0.004), suggesting some heterogeneity among RCT. The incidence of all-grade pneumonitis was 329 (10.80%) in E group vs 36 (1.75%) in control group and of high-grade pneumonitis was 77 (2.23%) in E arm vs 12 (0.51%) in control arm. The pooled RR for all-grade pneumonitis was significant at 6.57 (95% CI: 3.07–14.07, P < 0.001) and the absolute RD was 0.08 (95% CI: 0.05 – 0.12, P < 0.001). The pooled RR for high-grade pneumonitis was noted at 3.25 (95% CI: 1.44–7.33, P = 0.004) and the absolute RD was 0.01 (95% CI: 0.007–0.025, P = 0.001). Conclusions: Our meta-analysis demonstrated that patients on everolimus based regimen experienced a significant increase in all grades of pneumonitis. Pneumonitis has significant impact on M&M, patients' quality of life and financial burden among patients undergoing chemotherapy. Timely recognition may aide physicians in delivering good supportive care and enhance patients' quality of life.