tbuckley/cabot-search huggingface dataset:
Abstract 16479: Remote Ischemic Preconditioning: Do Exosomes Play a Requisite Role in Evoking Cardioprotection?
Authors: Joseph Wider, Andrew R Kulek, Vishnu V Undyala, Karin Przyklenk
Journal: Circulation (2015)

Remote ischemic preconditioning (RIPC) is the phenomenon whereby brief episodes of ischemia-reperfusion applied in distant tissues or organs render the heart resistant to a subsequent sustained ischemic insult. The hallmark of RIPC is inter-organ communication, with recent evidence suggesting that exosomes may serve as the vector for the transport of protective factor(s) from the site of the distant trigger to the cardiomyocytes. To test this hypothesis, rats underwent a standard RIPC stimulus: i.e., 4 5-min episodes of bilateral femoral artery occlusion. Serum (~3 mL per rat) was harvested immediately after RIPC; 1 mL was stored at -80°C, and 2 mL was processed for exosome isolation by prolonged ultracentrifugation (12 hours at 300,000 xg ). Aliquots of the pellet and supernatant were probed (by immunoblotting) for expression of exosome markers including HSP60 and flotillin. Most importantly, the cardioprotective efficacy of: 1) RIPC serum, 2) the pellet, reconstituted in buffer, 3) supernatant-bottom layer, 4) supernatant-top layer and 5) buffer alone was assessed by transfer of volume-matched aliquots to cultured HL-1 cardiomyocytes. After 1 hour of pretreatment, cells were subjected to 2.5 hours simulated ischemia + 24 hours reoxygenation and % cell death was quantified by Trypan blue staining. As expected, RIPC serum was protective: mean cell death was 34 + 5%* vs 48 + 5% in buffer-controls (*p&lt;0.05). As further expected, the exosome-depleted top layer of supernatant failed to confer protection. However, in contrast to the ‘exosome hypothesis’, RIPC with exosome-rich aliquots did not yield consistent cardioprotection: both the pellet and the supernatant-bottom layer had robust expression of HSP60 and flotillin, yet only the supernatant-bottom attenuated cell death (32 + 3%*; Figure). Thus, while transport of protective factor(s) via exosomes may play a role in RIPC, our results reveal that exosomes per se are not sufficient to evoke remote cardioprotection.
Final analysis of quality-of-life assessment in lymphoma patients who underwent high-dose chemotherapy and autologous stem cell transplant (HDC ASCT) using first validated, translated Arabic form of FACT-BMT version (4): Single-institution experience.
Authors: Hussein Soudy, Tusneem Elhassan, Eman M Abdullah, Ahmad Al Zahrani, Irfan Maghfoor, Saad Akhtar
Journal: Journal of Clinical Oncology (2014)

e20612 Background: Quality of life (QOL) is growing in importance as an assessment measure following HDC ASCT. Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) from English has been translated into several languages. We report our translated and validated first Arabic FACT-BMT. Methods: Study was approved by the Institutional Research Advisory Council. The Arabic translation followed the standard Functional Assessment of Chronic Illness Therapy (FACIT.org) translation methodology (permission was obtained). Provisional Arabic FACT-BMT was pre-tested and then statistically validated. Results: 108 relapsed /refractory lymphoma patients underwent HDC ASCT. Salvage protocol was (ESHAP) +/- rituximab and BEAM protocol as HDC. Diagnosis was Hodgkin lymphoma 69%; non-Hodgkin lymphoma 31%.Males 63% and females 37%. Reliability coefficients Cronbach’s alpha for internal consistency was 0.90, Intraclass correlation coefficient for internal consistency 0.89, agreements 0.86 all were excellent. 31 (30%), 25 (24.5%), 30 (29.4%) and 16 (15%) patients were interviewed 3-12 , 12-24,24-60 or > 60 months respectively from HDC ASCT. 93% were educated. Patients have high scores in all domains of quality of life including physical, social, emotional and functional well-being, indicating that most patients were leading a normal life. Twenty-six percent of patients were concerned about their ability to have children post-transplant. We found no difference in physical wellbeing, social wellbeing, functional wellbeing, and BMT domain in patients < 30 or > 30 years or male vs female. The score of emotional wellbeing domain for patients < 30 years was significantly lower than the score achieved by > 30 years patients (p-value=0.02). Conclusions: Our data reports the first translated and validated Arabic version of FACT-BMT. This is likely to help large number of Arabic speaking patients, not only in the Middle East and Arab countries, but also in Europe and North America. Most of our patients enjoyed a good quality of life post HDC-ASCT.
PET/CT assessment of tumor perfusion in metastatic renal cell carcinoma (RCC) before and during sunitinib: A comparison of <sup>15</sup>O-water with <sup>62</sup>Cu-ETS.
Authors: Theodore F. Logan, James W. Fletcher, Mark A. Green, Jacob Aaron Eitel, Gary Hutchins
Journal: Journal of Clinical Oncology (2014)

11110 Background: RCC is a vascular cancer treated with antiangiogenic agents. Tumor perfusion (TP) can be measured by PET using 15O-water (H215O), but its short physical half-life limits use to PET centers with a cyclotron. We studied a new “microsphere-like” perfusion agent with 9.7 min half-life, 62Cu-ETS, in RCC patients before and during sunitinib. As a generator-based agent, the kit-formulated 62Cu-ETS can be made available to virtually any PET camera from a central manufacturing site. And, since the 62Cu label is trapped after perfusion-rate-limited delivery, PET/CT whole-body imaging is possible, allowing evaluation of both primary tumor and distant metastases. Methods: Consented RCC patients were entered on this IRB approved protocol. PET/CT imaging was performed in 14 RCC patients with H215O and 62Cu-ETS, both before and during week 3-4 of Sunitinib (50mg/day X 4 wks on/2 wks off). PET/CT was performed after i.v. H215O (10-minute list mode), followed 10-minutes later by i.v. 62Cu-ETS, with the heart and at least one tumor in the PET field-of-view (6-min list mode). Whole body scan (WBS) of the 62Cu-ETS was then carried out from 6-20 min using 2-3 min/bed. Proportional Technologies, Inc. provided the 62Zn/62Cu-generators, and kits for 62Cu-ETS preparation (IND #75,018). Blood flow (k1) was quantified for both normal and malignant tissues in a 21.7 cm dynamic FOV. Arterial input functions were derived from the left atrium. Results: Paired k1 data were available for 14 metastatic lesions before and post Rx. The average pre-Rx TP was similar with both H215O and 62Cu-ETS, (0.97 ± 0.51 and 0.97 ± 0.40 ml/min/g, respectively). The average TP for the two agents dropped significantly during Rx to 0.51 ± 0.35 and 0.56 ± 0.32 ml/min/g, p=0.010 and 0.0002 by paired T-tests. The correlation (r2) between the k1 values of both agents for normal and tumor tissues was 0.87 (y=0.88x+0.13). Conclusions: TP (k1) measured by H215O and 62Cu-ETS using PET/CT in RCC was highly correlated. Sunitinib significantly decreases TP in metastatic RCC. 62Cu-ETS appears to be an excellent agent for the assessment in TP in RCC patients. Clinical trial information: NCI-2012-00051.
Prognostic value of novel combined scoring system in patients with high-grade soft tissue sarcoma.
Authors: Akihiko Takeuchi, Norio Yamamoto, Toshiharu Shirai, Hideji Nishida, Katsuhiro Hayashi, Yoshikazu Tanzawa, Hiroaki Kimura, Shinji Miwa, Kentaro Igarashi, Shingo Shimozaki, Takashi Kato, Takashi Higuchi, Hiroyuki Tsuchiya
Journal: Journal of Clinical Oncology (2014)

e21523 Background: Prognostic factors of high-grade soft tissue sarcoma have been reported as the response to preoperative chemotherapy, tumor size, age, location or surgical margin. In this study, we generated the combined scoring system of the treatment–related factors and assessed the prognostic value of this scoring system on overall survival (OS) and event-free survival (EFS). Methods: Seventy-nine patients with high-grade soft tissue sarcoma (64 patients in UICC/AJCC stage III and 15 in stage IV) were included in this study. They were treated by doxorubicin or ifosfamide-based caffeine-potentiated chemotherapy and surgery. Caffeine was combined due to the cytocidal effects of anticancer drugs We developed the combined scoring system using radiological response to chemotherapy (MRI and 201Tl or 99mTc-MIBI scintigraphy), histological response, and the oncological status after surgery (a: no residual tumor, b: microscopic residual tumor, c: macroscopic residual tumor, d: residual metastatic tumor; Table). The score of each factor was determined from the correlation with OS and EFS using univariate and multivariate analysis. The patients with a total score ≥ 4 points were classified as good group. Results: The response rate of preoperative chemotherapy was 59.5% in MRI, 55.7% in radioisotope scan and 35.4% in pathology. Oncological status was 62 cases in a, 4 in b, 1 in c, and 12 in d. Average score was 3.8 points and 48 cases (60.8%)were classified as good group. In univariate analysis, the patients of good group showed significantly better OS and EFS (p<0.001). In multivariate analysis, the patients of poor group (< 4 points) showed significantly poor EFS (HR 6.24, p=0.014) and marginally poor OS (HR 5.20, p=0.060). Conclusions: This newly developed combined scoring system could be considered as prognostic factors in high-grade soft tissue sarcoma. Combined scoring system. Definition of the responders Point MRI Reduction rate ≥ 30% 2 201Tl or 99mTc-MIBI ΔUR ≥ 30% 2 Pathology Tumor necrosis ≥ 90% 2 Oncological status a: no residual tumor 2 b: microscopic residual tumor -1 c: macroscopic residual tumor -2 d: residual metastatic tumor -4 ΔUR: the percentage reduction in uptake ratio.
External validation of the neoadjuvant rectal (NAR) score and Valentini prediction nomogram (VPN): A multicenter study.
Authors: Soundouss Raissouni, Jamison Mercer, Gillian Gresham, Aalok Kumar, Rachel Anne Goodwin, Maria Jiang, Alexander Leung, Daniel Yick Chin Heng, Patricia A. Tang, Corinne M. Doll, Anthony MacLean, Erin Diana Powell, Julie A. Price Hiller, Jose Gerard Monzon, Winson Y. Cheung, Michael M. Vickers
Journal: Journal of Clinical Oncology (2014)

3532 Background: The VPN [JCO 2011;29(23)] is a tool used for individualized prognostication in rectal cancer, and the recently described NAR score [Yothers et al. JCO 32, 2014 abst: 38] has been suggested as a surrogate endpoint for overall survival (OS) in clinical trials. However, these tools have not been validated outside of the clinical trial setting. We assessed these models in a retrospective multi-institution database, to determine their predictive ability for outcome in patients with rectal cancer treated with neoadjuvant chemoradiation (nCRT). Methods: Data from patients with locally advanced rectal cancer who received nCRT and had curative intent surgery from 2005 to 2012 were collected from Tom Baker Cancer Center, Cross Cancer Institute, BC Cancer Agency, Ottawa Hospital Cancer Centre and Dr. H. Bliss Murphy Cancer Centre. The NAR score was compared with pathologic complete response (pCR) status for OS and with the VPN for local control (LC), distant control (DC) and OS using Akaike’s information criterion (AIC – a tool for comparing models in a dataset). C-index was evaluated for VPN and NAR for OS. Results: 1,172 patients were included; pCR was achieved in 16.6%.The median NAR score was 17.36; NAR risk groups included low (22.6%), intermediate (42.6%), and high (34.9%). The 5-year OS in the NAR risk groups were 88.1% (low), 82% (intermediate – HR 1.89, 95% CI 1.13 – 3.1), 59.5% (high – HR 5.05, 95% CI 3.1 – 8.2), and 89.9% for pCR (HR 0.25, 95% CI 0.14 – 0.45) versus 73.1 % for no pCR (log rank p-value <0.0001 for both). AIC favoured NAR compared with pCR for OS (2,549.6 v 2,824.0).VPN as a continuous variable predicted LC (HR 0.97, 95% CI 0.95-0.99, p=0.015), DC (HR 0.98, 95% CI 0.98-0.99, p<0.0001) and OS (HR 0.96, 95% CI 0.95-0.96, p<0.0001). The AIC favoured VPN over NAR for LC (851.2 v 856.5), DC (2,154.5 v 2,160.6) and OS (2,455.3 v 2,549.6). C-index also favoured VPN over NAR for OS (0.697 v 0.66). Conclusions: Similar to recent clinical trial data, NAR outperformed pCR in predicting OS, and the VPN was significantly associated with LC, DC and OS in the non-clinical trial setting. VPN appeared to better predict LC, DC, and OS compared with the NAR score and is favoured for individual patient prognostication.
A phase 1 study of LJM716 in patients with esophageal squamous cell carcinoma, head and neck cancer, or HER2-overexpressing metastatic breast or gastric cancer.
Authors: Kerry Lynn Reynolds, Dejan Juric, Jose Baselga, Maria Alsina, Josep Tabernero, Philippe L. Bedard, Donna M. Graham, Ana M. Gonzalez-Angulo, Ignacio Garrido-Laguna, Sunil Sharma, Chia-Chi Lin, Ezra E.W. Cohen, Se-Hoon Lee, Mauro Zucchetto, Xianbin Tian, Lily Delgado, Jian Li, Alex Morozov, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2014)

2517 Background: The HER3 receptor is important for maintenance of EGFR- and HER2-driven cancers and targeted therapy resistance. LJM716 is a fully human HER3 monoclonal antibody active in ligand-dependent and -independent preclinical models. Methods: This phase 1, first-in-human study is evaluating LJM716 in patients (pts) with squamous cell carcinoma of the head and neck (SCCHN) or esophagus (ESCC) and HER2-overexpressing metastatic breast cancer (MBC) or gastric/gastroesophageal junction cancer (MGC) for which no effective treatment exists. The objective for the dose-escalation part of the study, guided by a Bayesian model with overdose control, was to identify the maximum tolerated dose (MTD), recommended dose for expansion (RDE), and preferred dosing schedule. MTD was based on cycle 1 dose-limiting toxicity (DLT). Results: As of October 4, 2013, 54 pts (escalation, n = 24; expansion, n = 30) were enrolled (SCCHN, n = 21; ESCC, n = 15; MBC, n = 10; MGC, n = 8) and treated intravenously for 2 hr at dose levels (DLs) 3, 10, 20, or 40 mg/kg once weekly (QW, n = 48) or 20 mg/kg every 2 wk (n = 6) in 28-day cycles. Twenty-nine pts (54%) had ≥ 3 prior anticancer regimens. LJM716 exposure was approximately dose proportional, with an effective half-life of 10 ± 2 days in 5 evaluable pts, supporting QW dosing. Treatment-related toxicities (≥ 20%, all grades) were diarrhea (39%), chills (24%), infusion-related reactions (24%), and reduced appetite (22%). At ≥ 20 mg/kg QW (n = 48), grade 3/4 events occurred (gastrointestinal disorders [n = 3], hypokalaemia [n =2], asthenia [n = 1], and elevated lipase [n = 1]). One DLT was reported (grade 3 diarrhea and hypokalemia), which resolved after discontinuing LJM716. The MTD/RDE of LJM716 was 40 mg/kg QW. One pt with HER2+ MGC achieved an unconfirmed partial response. pHER3 reduction was seen in 4 of 5 paired tumor biopsies. Minor responses were observed in pts with SCCHN, ESCC, and MBC. Stable disease (SD) was observed in 17 pts (31%), including 1 SCCHN pt with SD > 40 wk. Five pts were on the study > 16 wk. Conclusions: LJM716 was well tolerated at DLs up to the RDE of 40 mg/kg QW and demonstrated preliminary evidence of antitumor activity. The study is ongoing. Clinical trial information: NCT01598077.
Prostate embryonal rhabdomyosarcoma in an adult patient with Crohn’s disease.
Authors: Omar Atef Behery, Jiahua Li, Suja Mathew
Journal: Journal of Clinical Oncology (2014)

e16111 Background: Embryonal rhabdomyosarcoma of the prostate (ERP) is an extremely rare malignant tumor, primarily presenting in children with obstructive urinary symptoms and frequent metastases. Methods: In this case report, we present an atypical case of ERP, presenting as pelvic mass and rectal pain without urinary symptoms or metastases. Results: (Case Description) A 36-year old man with a history of Crohn’s disease with anorectal fistulas and urethral strictures treated with supra-pubic catheter, presented with a 2-week history of rectal pain and purulent discharge from the fistulas, associated with constipation, low-grade fevers, and significant unintentional weight loss. Lab results showed mild leukocytosis with left shift. An MRI of the abdomen and pelvis revealed a large (11.8 x 8.1 x 16.1cm) solid heterogeneous mass in the pelvis, encasing the distal wall of the rectum and the coccyx. Tumor-staging workup showed no distant metastasis. The patient underwent an excisional biopsy of the mass and a diverting colostomy. The biopsy revealed a microscopic pattern of a high-grade sarcoma with myogenic differentiation. Immunohistochemical staining was strongly positive for WT-1, CD10, desmin, and myogenin; absence of FOXO1 gene rearrangement; and negative for endothelial, epithelial, hematopoietic, neurogenic, and smooth muscle markers. The final diagnosis was embryonal rhabdomyosarcoma. Conclusions: ERP is an extremely rare neoplasm with less than 30 adult cases reported in the literature (Bisceglia et al. 2011). To our knowledge, this is the first case of ERP identified in a patient with Crohn’s disease. In Crohn’s disease, pelvic tumors are most likely colorectal carcinomas, posing a diagnostic challenge in our case. Additionally, Crohn’s associated urethral strictures and the pre-existing supra-pubic tube obscured any urinary symptoms. Also, our patient did not have metastases at the time of presentation, which is very atypical for this tumor, particularly given the large size of the pelvic mass. Although surgery is the mainstay of treatment, there are no clear guidelines formanagement, and adults seem to have worse response to multi-modal therapy than children.
Heat shock protein 27 is involved in acquisition of 5-FU resistance in human colon cancer
Authors: Masashi Tsuruta, Hideki Nishibori, Hirotoshi Hasegawa, Yoshiyuki Ishii, Takashi Endo, Nobuhiro Nitori, Koji Okabayashi, Fumitaka Asahara, Tetsuro Kubota, Masaki Kitajima
Journal: Cancer Research (2006)

3753  [Introduction]5-Fluorouracil (5-FU) is widely used in the treatment of solid tumors, particularly of colon cancer. However the intrinsic or acquired resistance to 5-FU is one of the most critical issues, of which cause is not always interpreted as the known molecules, such as thymidylate synthase, dihydropyrimidine dehydrogenase and uridine phosphate. Other molecules are possibly involved in 5-FU resistance. Heat shock protein 27 (HSP27) mRNA expression has been recently shown to be correlated with 5-FU resistance in 5-FU-resistant cell lines. Our aim was to elucidate the functional mechanism of HSP27 on 5-FU resistance in colon cancer cells. [Materials and methods]HSP27 protein levels in some human colon cancer cell lines (LoVo, HCT15, WiDr, HCT116, HT-29 and SW480) were determined by immunoblot and densitometry analysis. The in vitro growth inhibition rates (IR) of the cell lines by various concentrations of 5-FU were assessed by MTT assay. The degree of 5-FU resistance was estimated as the drug concentrations inducing 50% of IR (IC50). The correlation between the HSP27 protein level and IC50 was evaluated by regression analysis. Moreover, the effect of HSP27 suppression by RNA interference on the IC50 was determined. [Results] In LoVo, HCT15, WiDr, HCT116, HT-29 and SW480, respectively HSP27 protein levels normalized by β-actin were 0.05, 2.78, 0.28, 2.52, 0.15 and 2.43 and IC50 were 0.31, 3.93, 1.49, 2.24, 0.47 and 3.01 μg/ml. HSP27 protein levels were significantly correlated with 5-FU resistance in human colon cancer cell lines (p=0.010). In these cell lines HCT-15 exhibited the most abundant HSP27 protein level and the highest 5-FU resistance. In HCT15, HSP27 siRNA suppressed HSP27 protein levels and also reduced IC50 in a dose-dependent manner. [Conclusions] These data indicated that HSP27 was involved in acquisition 5-FU resistance and that its down-regulation restored 5-FU chemosensitivity in human colon cancer cell lines. HSP27 is potentially a novel determinant of 5-FU resistance in colon cancer and may be one of the therapeutic targets for 5-FU-resistant colon cancer.
Trends in hospitalization outcomes of elderly patients undergoing allogeneic stem cell transplantation for acute myeloid leukemia/myelodysplastic syndrome (AML/MDS).
Authors: Guru Subramanian Guru Murthy, Paulette Mehta, Yogesh Jethava, Ishwori Dhakal, Issam Makhoul
Journal: Journal of Clinical Oncology (2014)

7044 Background: Allogeneic stem cell transplant (AlloSCT) is increasingly used for treatment of elderly patients with AML/MDS. This study aims to explore the US national trends in hospital stay, inpatient cost, and outcomes associated with AlloSCT in elderly patients with AML/MDS. Methods: Using Nationwide Inpatient Sample database, we identified all hospitalizations for AlloSCT in patients age ≥ 60 years with AML/MDS from 2007 through 2011. ICD 9 codes were used to identify diagnoses and procedure related information. Data on patient demographics, source of stem cell, length of stay (LOS), complications and deaths were obtained. Outcomes were analyzed using Kruskal Wallis test for comparing means and Chi -square test for categorical variables. Multivariate logistic regression method was used to determine factors associated with prolonged hospital stay and death. Results: Based on sample weights, an estimated 4242 AlloSCT procedures for AML/MDS in elderly patients were identified nationwide between 2007-2011. Patients had a median age of 64 years (range – 60-78). Inpatient AlloSCT was more common in males (60.1%) and whites (76.7%). There was a significant reduction in the LOS for AlloSCT from 2007 to 2011. Mean LOS in 2007 was 28.70± 0.69 days, and mean LOS in 2011 was 23.69 ± 0.46 days (p<0.01). Inpatient cost showed an increase till 2009 followed by a decline (mean cost - USD 257,291 in 2007, USD 344,454 in 2009 and USD 259301 in 2011, p<0.01). In-hospital mortality has decreased from 9.4% in 2007 to 5% in 2011 (p=0.02). Complications causing prolonged LOS included acute GVHD (4.2%), septicemia (20.0%), acute renal failure (12.9%), parenteral nutrition (12.8%). On multivariate analysis, stem cell source from bone marrow compared to peripheral blood was associated with higher complications, prolonged LOS (OR 1.88, CI 1.55-2.28, p <0.01) and higher mortality (OR 2.45, CI 1.87-3.220, p<0.01). Conclusions: Our study demonstrates an improvement in the hospitalization outcome of elderly AML/MDS patients undergoing AlloSCT in US. Further focus of research in this risk group to reduce complications would improve mortality and cost benefits.