tbuckley/cabot-search huggingface dataset:
Abstract 1321: IT-147: A stabilized polymer micelle formulation of epothilone D for treatment of solid tumors
Authors: Adam Carie, Taylor Buley, Bradford Sullivan, J.Edward Semple, Tyler Ellis, Tara Lee Costich, Jyothi Sethuraman, Rick Crouse, Kevin Sill, Suzanne Bakewell
Journal: Cancer Research (2016)

Abstract IT-147 is a formulation of epothilone D encapsulated in a stabilized polymer micelle. Epothilones are a class of cytotoxic chemotherapeutics that induce apoptosis via microtubule stabilization. Epothilone D is a poor substrate for P-glycoprotein efflux pumps and has demonstrated equivalent activity against drug-sensitive and multidrug-resistant human cancer cell lines. This offers a distinct advantage over other microtubule stabilizing agents such as taxanes, however clinical utility is limited by a narrow therapeutic window due to dose limiting toxicities such as peripheral sensory neuropathy, GI toxicities, and cognitive abnormalities. We have optimized a lead formulation comprising 2% epothilone D (w/w) encapsulated in a polymer micelle that is crosslinked with iron to provide micelle stability upon dilution. IT-147 has an average diameter of 70 nm. The iron-mediated crosslinking provides pH-dependent release of epothilone D such that drug can be released in the tumor microenvironment as well as in the endosome/lysosome upon cellular entry. In addition, the geometrical arrangement of iron molecules around the core of the micelle imparts superparamagnetic properties that allow for imaging of intact nanoparticles by MRI. IT-147 demonstrates a low nanomolar IC50 against a panel of human cancer cell lines in vitro. In vivo, IT-147 demonstrates a 4-fold increase in maximum tolerated dose in a mouse model compared to epothilone D free drug. Pharmacokinetics (PK) in a cannulated rat model for a 20 mg/kg epothilone D dose demonstrates a 6.5-fold increase in area under the time versus concentration curve (AUC), and a 14.3-fold increase in the terminal half-life compared to free drug. Dose escalation of IT-147 to 30 and 40 mg/kg epothilone D in the rat PK model results in linear increases in AUC from 53.5 h*μg/mL at 20 mg/kg to 82.9 and 110.8 h*μg/mL at 30 and 40 mg/kg, respectively. Treatment with IT-147 at the MTD in an HCT116 tumor xenograft model led to tumor stasis during the course of treatment, and MRI imaging of mice treated with IT-147 demonstrates tumor accumulation over 24 and 48 hours post administration. Taken together, data for IT-147 demonstrates successful encapsulation of epothilone D leading to a safer, more effective formulation with the potential for MRI imaging as a predictor for response. Citation Format: Adam Carie, Taylor Buley, Bradford Sullivan, J.Edward Semple, Tyler Ellis, Tara Lee Costich, Jyothi Sethuraman, Rick Crouse, Kevin Sill, Suzanne Bakewell. IT-147: A stabilized polymer micelle formulation of epothilone D for treatment of solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1321.
Cyclosporine Treatment of Drug-Induced Hypersensitivity Syndrome
Authors: Mark G. Kirchhof, Aaron Wong, Jan P. Dutz
Journal: JAMA Dermatology (2016)

Drug-induced hypersensitivity syndrome (DIHS), also known as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, is a potentially life-threatening reaction to medications with a mortality rate up to 10%. Standard therapy involves the use of systemic corticosteroids with tapering doses extending up to 9 months after the initial reaction. Alternative treatments for DIHS are needed, especially for patients for whom systemic corticosteroids are contraindicated.To assess a short course of cyclosporine as first-line therapy for DIHS.In this case series, 2 patients referred to the dermatology service of an academic tertiary care hospital and subsequently diagnosed as having DIHS were studied from December 1, 2013, through July 31, 2014.Short course (3-7 days) of cyclosporine.Clinical and laboratory indicators were examined to determine the timing and efficacy of cyclosporine treatment.Two cases are reported of drug hypersensitivity reaction that were treated with cyclosporine, resulting in rapid and significant clinical improvement. The first case involved a woman in her 40s who developed DIHS after treatment with carbamazepine. A 7-day course of cyclosporine resulted in clinical resolution of the DIHS. The second case was that of a man in his 30s with minocycline-induced DIHS. A 3-day course of cyclosporine resulted in rapid and sustained clinical improvement.A short course of cyclosporine was of therapeutic benefit in the treatment of 2 patients with DIHS. Short courses of cyclosporine in the acute care setting may be an alternative to longer courses of systemic corticosteroids in the treatment of DIHS.
Brentuximab Vedotin (BV) an Effective Treatment for Autologous (ASCT) and/or Allogeneic (alloSCT) Transplant naïve Patients with Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL) : A retrospective Single-Institution Study
Authors: Simonetta Viviani, Serena Dalto, Paola Matteucci, Massimo Di Nicola, Anna Guidetti, Liliana Devizzi, Michele Magni, Anna Dodero, Lucia Farina, Francesco Spina, Alessandro M. Gianni, Paolo Corradini
Journal: Blood (2014)
Case 23-1991
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Peter McL. Black, David N. Louis
Journal: New England Journal of Medicine (1991)

Presentation of CaseA 27-year-old man was admitted to the hospital because of ataxia and a cerebellar mass. The patient was well until the age of 14 years, when he began to have episodes of abnormal sensation and clumsiness of the right hand and foot. Evaluation elsewhere revealed a left parietal mass; a craniotomy was performed, with resection of the mass. Microscopical examination of the excised specimen was reported to show a cystic Grade 2/4 astrocytoma. Postoperative radiation therapy was administered in a dose of 50 Gy to the whole brain and 20 Gy to the area of the tumor . . .
Role of MEK inhibition in improving anti-tumor responses in xenograft models of BRAF-mutated metastatic colorectal cancer.
Authors: Van Karlyle Morris, Ji Wu, Liana Adam, Feng Tian, Mihai Gagea, David S. Hong, David Menter, Scott Kopetz
Journal: Journal of Clinical Oncology (2016)

265 Background: BRAF V600E mutations occur in fewer than 10% of all patients with metastatic colorectal cancer (mCRC) and are associated with poor survival outcomes. Addition of anti-EGFR therapy improves responses when combined with BRAF inhibition, yet acquired resistance to targeted therapies invariably develops. Novel therapeutic approaches to deepen anti-tumor activity are warranted for patients with this subset of mCRC. Methods: Patient-derived xenograft (PDX) models of BRAF V600E mCRC were established and treated with vemurafenib (V) +/- cetuximab (C) until acquired resistance. DNA from resistant tumors was sequenced and compared to that of untreated controls. BRAF V600E mCRC tumors from PDX mice with acquired mutations in MAPK signaling were reimplanted into another generation of nude mice and treated with V +C or trametinib (T) + cetuximab. Results: Twelve resistant models were developed in BRAF V600E mCRC PDX models treated with V +/- C, with nine models demonstrating acquired mutations resulting in MAPK pathway re-activation, including codons 12 or 13 KRAS mutations. While sensitivity to V + C was observed in BRAF V600E /KRAS wild-type mCRC tumors, this combination demonstrated no anti-tumor response in BRAF V600E models with acquired KRAS G12R or KRAS G12D mutations. In these PDX models harboring dual BRAF/KRAS mutations, the combination of T + C generated sustained tumor regression not observed with V+C (P &lt;.001 for both BRAF V600E / KRAS G12R and BRAF V600E /KRAS G12D models). Addition of T following resistance to V+C restored sensitivity in both models. Conclusions: Dual blockade of BRAF + EGFR has shown promise in early-phase clinical trials for patients with BRAF V600E mCRC, and MAPK pathway reactivation appears to be a critical mechanism of resistance. These results suggest that use of a MEK inhibition may reverse such acquired resistance. While MEK + EGFR targeting has been associated with excessive skin toxicity in humans, these data provide rationale for the pursuit of triple BRAF + MEK + EGFR inhibition in patients with BRAF V600E mCRC.
Glucose metabolism enzymes gene expression analysis and selective metabolic advantage in the progression of colorectal cancer (CRC).
Authors: Francesco Graziano, Annamaria Ruzzo, Elisa Giacomini, Teresa Ricciardi, Giuseppe Aprile, Fotios Loupakis, Paola Lorenzini, Elena Ongaro, Federica Zoratto, Vincenzo Catalano, Chiara Cremolini, Donatella Sarti, Eliana Rulli, Michele De Nictolis, Giovanna De Maglio, Alfredo Falcone, Giammaria Fiorentini, Mauro Magnani
Journal: Journal of Clinical Oncology (2015)

e14519 Background: Cancer cells reprogram their metabolism to meet specific bioenergetic/biosynthetic needs. Abnormal expression of energy metabolism enzymes may sustain aggressive phenotypes, therapeutic resistance and it may disclose novel therapeutic targets. We analyzed mRNA expression of glucose metabolism, key-enzyme genes in normal mucosa (NM), primary tumor (PT) and liver metastasis (LM) of CRC patients (pts) who underwent surgery and systemic therapy for advanced disease. Methods: Tissues of chemotherapy-naive, non-diabetic CRC pts were retrospectively studied by RT-qPCR for mRNA expression of the following genes: hexokinase-1 (HK1) and 2 (HK2), embryonic pyruvate kinase (PKM2), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (SLC2A), voltage-dependent anion-selective channel protein-1 (VDAC1). The RT-qPCR ΔCt values (Cttarget–Ctreference) were used for calculating the expression level of each target gene with B2M and GUSB adopted as reference genes. A preliminary assessment was planned in a random sample of 24/72 enrolled pts (33%) to verify whether differences were detectable. T-test (Tt) and Wilcoxon test (Wt) were used for comparing ΔCt values between tissues (PT versus NM, LM versus NM, PT versus LM). Results: In the 24 pts, assays repeated with B2M and GUSB showed higher PT mRNA expression than NM for HK1 (Tt p = 0.0001; Wt p = 0.0004), LDH-A (Tt p < 0.0001, Wt p < 0.0001), PKM2 (Tt p < 0.0001, Wt p < 0.0001), SCL2A (Tt p < 0.0001, Wt p < 0.0001), VDAC1(Tt p = 0.0002, Wt p = 0.0004). The same significant associations were found when comparing LM versus NM tissues. There was a trend for higher mRNA expression of these genes in LM than in PT, but at this stage differences did not reach statistical significance. Conclusions: These results indicate enhanced glucose uptake (SCL2A, HK), glycolysis (LDH, PKM2) and mithocondrial trafficking (VDAC1) in CRC. Final analysis will include correlations with RAS/RAF mutational status and survival outcomes.
Evaluation of preventive factors for postoperative pulmonary complications following esophagectomy for T1bN0M0 cancer using data from JCOG0502.
Authors: Isao Nozaki, Junki Mizusawa, Ken Kato, Hiroyasu Igaki, Yoshinori Ito, Hiroyuki Daiko, Masahiko Yano, Harushi Udagawa, Satoru Nakagawa, Masakazu Takagi, Shigeru Tsunoda, Tetsuya Abe, Tetsu Nakamura, Jun Hihara, Yasushi Toh, Yasunori Akutsu, Yuichi Shibuya, Hiroshi Katayama, Kenichi Nakamura, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2016)

98 Background: Postoperative pulmonary complications (PPCs) are the most common cause of serious morbidity following esophageal cancer resection and are associated with a poorer prognosis in esophagectomized patients (pts). We have recently reported that thoracoscopic esophagectomy (TSE) decreases PPC frequency. However, it remains unclear whether the frequency is further decreased by the combination with laparoscopic esophagectomy (LSE). This study aimed to clarify the combined effect of TSE with LSE on the prevention of PPCs and to determine the preventive factors for PPCs following esophagectomy using data from JCOG0502. Methods: JCOG0502 is a four-arm prospective study comparing esophagectomy with definitive chemoradiotherapy for T1bN0M0 cancer, with randomized and patient preference arms. The primary endpoint is overall survival, which will be analyzed in 2018. PPCs were defined as one or more of the following ≥ grade 2 postoperative morbidities per CTCAE v3.0: pneumonia, atelectasis, and acute respiratory distress syndrome. The use of TSE and/or LSE was decided at the surgeon’s discretion. Results: Totally, 379 pts (11 in the randomized and 368 in the patient preference arm) were enrolled between 2006 and 2013 from 37 institutions. Of the 210 pts who underwent esophagectomy, TSE was performed in 101 pts (TSE with laparotomy in 43 pts and TSE with LSE in 58 pts), while esophagectomy via thoracotomy was performed in 109 pts. PPCs occurred less often in pts who underwent TSE than esophagectomy via thoracotomy (15.8% vs 30.3%, p = 0.01); however, there was no difference in the frequency of PPCs between those who underwent TSE with laparotomy and TSE with LSE (16.3% vs 15.5%). In univariate analysis, both TSE (shown above) and less blood loss ( &lt; 350 mL) were associated with the prevention of PPCs (16.3% vs 30.2%, p = 0.02). Multivariate analysis showed that TSE was associated with the prevention of PPCs [Odds ratio, 0.33; 95% confidence interval (0.12-0.88); p = 0.03]. Conclusions: This study indicated that TSE was the only independent preventive factor for PPCs following esophagectomy, and LSE had limited effectiveness in the prevention of PPCs when it is combined with TSE. Clinical trial information: UMIN000000551.
Abstract 710: Epidermal growth factor-induced pyruvate dehydrogenase kinase 1 enhances head and neck squamous cell carcinoma metastasis through fibronectin up-regulation
Authors: Ben-Kuen Chen, Jinn-Yuan Hsu, Wen-Chang Chang
Journal: Cancer Research (2016)

Abstract Epidermal growth factor receptor (EGFR) activation is a major cause of metastasis in many cancers, such as head and neck squamous cell carcinoma (HNSCC). However, whether the induction of pyruvate dehydrogenase kinase 1 (PDK1) mediates EGF-enhanced HNSCC metastasis remains unclear. Interestingly, we found that EGF induced PDK1 expression in HNSCC. The tumor cell transformation induced by EGF was repressed by the depletion of PDK1. The down-regulation of PDK1 expression or inhibition of its activity significantly blocked EGF-enhanced cell migration and invasion. In addition, depletion of PDK1 impeded EGF-enhanced binding of HNSCC cells to endothelial cells and tumor cells metastastic seeding of the lungs. Knockdown of PDK1 also inhibited EGF-induced matrix metalloproteinase-1 (MMP-1), MMP-2, MMP-3, MMP-9, and fibronectin expression and Rac1/cdc42 activation. These results demonstrate that EGF-induced PDK1 expression enhances HNSCC metastasis via activation of the fibronectin signaling pathway. The inhibition of PDK1 may be a potential strategy for the treatment of EGFR-mediated HNSCC metastasis. Citation Format: Ben-Kuen Chen, Jinn-Yuan Hsu, Wen-Chang Chang. Epidermal growth factor-induced pyruvate dehydrogenase kinase 1 enhances head and neck squamous cell carcinoma metastasis through fibronectin up-regulation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 710.
Patient-reported outcomes (PROs) comparison of 5-FU and capecitabine (cape) with concurrent radiotherapy (RT) for neoadjuvant treatment of rectal cancer: Results of NSABP R-04.
Authors: Greg Yothers, Patricia A. Ganz, Samia H. Lopa, Clifford Y. Ko, D. Lawrence Wickerham, Norman Wolmark
Journal: Journal of Clinical Oncology (2012)

391 Background: Preliminary results of NSABP R-04 indicated that 5-FU and cape have similar pathologic complete response (pCR) outcomes and that the addition of oxaliplatin did not improve pCR. We present PROs comparing 5-FU and cape treatments on quality of life (QoL), convenience of care (CoC), and symptoms. Methods: Clinical stage II or III rectal cancer patients were randomized to receive 5-FU (225mg/m 2 5 days/wk) or cape (825 mg/m 2 5 days/wk) along with RT (4,500cGy in 25 fractions over 5 wk + boost of 540-1080cGy in 3-6 daily fractions). About half of these patients were also randomized to receive oxaliplatin (50 mg/m 2 /wk). QoL was assessed by the functional assessment of cancer therapy–colorectal (FACT-C) trial outcome index (TOI) and symptoms were assessed by the fluoropyrimidine specific symptom checklist (SCL) collected at baseline, after chemoradiation before surgery (post therapy), and at 1 year. CoC was assessed by the modified ECOG CoC scale post therapy. Primary hypotheses were to compare 5-FU and cape on the endpoints of change in TOI and SCL baseline to post therapy and CoC at post therapy. P-values, means, and confidence intervals (CI) are adjusted for clinical stage, sex, and intent for sphincter-saving surgery. Results: 625 5-FU and 650 cape patients completed baseline and post therapy data forms. Patient characteristics were similar by treatment. Change in TOI was similar by treatment post therapy (p = .21). Change in SCL post therapy was greater for cape patients than for 5-FU patients (mean difference 1.02, 95% CI 0-2.04, p = .05). CoC was superior with cape compared to 5-FU post therapy (mean difference 3.07, 95% CI 1.31-6.01, p = .002). The change from baseline to post therapy for all FACT-C subscales was similar by treatment. Change in TOI, SCL, and all FACT-C subscales were similar by treatment at the 1-year assessment. Conclusions: PROs indicate that patients treated with 5-FU and cape have similar QoL. Cape provides significantly greater convenience of care but slightly increased symptoms compared to 5-FU. NCI PHS grants U10CA37377, U10CA69974, U10CA12027, and U10CA69651, support from sanofi-aventis and Hoffmann La-Roche.
Rhinovirus‐specific antibody responses in preschool children with acute wheeze reflect severity of respiratory symptoms
Authors: K. Stenberg‐Hammar, K. Niespodziana, C. Söderhäll, A. James, C.R. Cabauatan, J. R. Konradsen, E. Melén, M. van Hage, R. Valenta, G. Hedlin
Journal: Allergy (2016)

Abstract Background Some children with rhinovirus ( RV ) infections wheeze, but it is unknown whether this is due to more virulent strains of virus or differences in host immune responses. The aim of this study was to investigate the RV species‐specific antibody responses measured at a follow‐up visit in preschool children in relation to reported time with respiratory symptoms and the presence of different RV species during an acute episode of wheeze. Method Nasopharyngeal swabs and blood samples were taken among 120 preschool children (&lt;4 years of age) at an acute episode of wheeze and at a follow‐up visit (median 11 weeks later). Nested PCR was used to detect different RV strains, and serum levels of IgG 1 against purified recombinant VP 1 proteins from representatives of the three RV species ( RV ‐A, RV ‐B, and RV ‐C) were measured by ELISA . Results Rhinovirus was detected in 74% ( n = 80/108) of the children at the acute visit, and RV ‐C was the most common subtype ( n = 59/80, 74%). An increase in RV ‐specific IgG 1 was seen in 61% ( n = 73) of the children at follow‐up, most frequently against RV ‐A ( n = 61/73, 86%) irrespective of the RV strains detected by PCR . Increases in RV ‐specific IgG 1 against RV ‐A or against RV ‐A and RV ‐C were significantly associated with more respiratory symptoms (p = 0.03, p = 0.007). Conclusion Antibody response to recombinant RV VP 1 proteins was associated with longer time with respiratory symptoms.
Abstract 1667: A novel method to identify radiosensitizers targeting hypoxic cancer cells by high-throughput screening
Authors: Keisuke Tamari, Yuji Seo, Yutaka Takahashi, Osamu Suzuki, Fumiaki Isohashi, Yasuo Yoshioka, Kazuhiko Ogawa
Journal: Cancer Research (2016)

Abstract Tumor hypoxia correlates radioresistance and poor clinical outcomes after radiotherapy. Radiosensitizers have been studied for a long time especially to overcome the problem of hypoxic tumor cells. Until now, however, radiosensitizers for hypoxic tumors have had only limited success in clinic. High throughput screening is popular method to identify candidate compounds from a large number of compounds for drug discovery, but have not been established method to study new radiosensitizers. The aim of this study was to identify radiosensitizers targeting hypoxic cancer cells by high throughput screening and validate the efficacy of this method. We performed cell-based high throughput screening by using 384 well plates and 1280 compounds. After exposing compounds to HeLa cells, gamma-irradiation was delivered under hypoxic condition and incubated for 4 days. To identify candidate compounds, cell counting was performed by MTS assay. Then, radiosensitizing effect of these compounds was validated by clonogenic survival assay. We performed high throughput screening and identified 22 compounds as candidates. We selected Ro90-7501 and dicyclomine hydrochloride which were not reported as radiosensitizers. Clonogenic survival assay showed their significant radiosensitizing effect in hypoxic condition. In conclusion, we identified novel radiosensitizers by high throughput screening. This method may be useful for identifying radiosensitizers targeting hypoxic cancer cells. Citation Format: Keisuke Tamari, Yuji Seo, Yutaka Takahashi, Osamu Suzuki, Fumiaki Isohashi, Yasuo Yoshioka, Kazuhiko Ogawa. A novel method to identify radiosensitizers targeting hypoxic cancer cells by high-throughput screening. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1667.