tbuckley/cabot-search huggingface dataset:
Erythropoietin (EPO) has no direct effect on tumor growth or angiogenesis in animal models
Authors: M. E. Hardee, J. P. Kirkpatrick, S. Snyder, S. Shan, Z. Vujaskovic, Z. N. Rabbani, M. W. Dewhirst, K. L. Blackwell
Journal: Journal of Clinical Oncology (2004)

9530 Background: Erythropoietin (EPO) increases tumor oxygenation in several pre-clinical models. This improvement in oxygenation should lead to enhanced treatment responses. However, EPO has failed to show improved treatment outcomes in 2 recent, randomized clinical trials involving non-anemic patients with head and neck and metastatic breast cancer. In this study we characterize the direct effects of EPO on tumor growth and angiogenesis in both breast and colorectal carcinoma. Methods: Effects of EPO (Ortho Biotech, Raritan, NJ) on murine tumor growth (CT-26 and R3230) in over 200 non-anemic rodents randomized to either EPO or control was measured. EPO receptor expression was determined using standard IHC in both tumor types before and after treatment. Tumor proliferation, assessed by Ki-67 IHC staining, was also determined. In vivo angiogenesis was measured by vascular length density (VLD) and was calculated from intravital microscopy images of R3230 tumors grown in mammary window chambers. Results: EPO increased the hematocrit significantly in all treated animals. Measured bidimensionally over the entire growth period, EPO had no effect on CT-26 or R3230 tumor growth at any time point. Both tumors expressed the EPO receptor. Ki-67 staining revealed no differences in proliferation between EPO-treated and control animals. In addition, angiogenesis was unaffected by systemic treatment with EPO. Conclusions: This study suggests that although EPO improves tumor oxygenation, this physiologic change is not attributable to either direct effects on tumor growth or angiogenesis. The cause for improvement in oxygenation remains under investigation. It is likely due to subtle changes in perfusion or tumor consumption that are not detected by simple vascular length density measurements. Besides its known effects on tumor oxygenation, other direct effects of EPO on tumor biology need to be examined. No significant financial relationships to disclose.
Is uterine serous carcinoma a part of hereditary breast cancer syndrome?
Authors: Saeed Rafii, Philip Dawson, Sarah Williams, Jennifer S. Pascoe, James E. Nevin, Sudha Sundar
Journal: Journal of Clinical Oncology (2013)

5587 Background: Whilst the association between breast cancer and uterine serous carcinoma (USC) is attributed to tamoxifen treatment, few studies have reported that this increased risk is independent of tamoxifen. Methods: To further investigate the relationship between breast cancer and USC, we retrospectively studied 216 patients from 5 hospital trusts in Birmingham, UK who were diagnosed with USC between 1993 and 2012. We collected personal history of cancer in these cases before or after USC diagnosis. In addition FIGO staging, clinical and survival data were collected from our local cancer registry and patients’ clinical records. Results: In this case series, 56 patients (25.9%) had personal history of at least one cancer before and 18 patients (8.3%) had history of at least one cancer after the diagnosis of USC. Within the group of patients with the history of cancer before the USC, 38 patients (68%, 17.5% of all cases) had personal history of breast cancer prior to the development of USC, higher than the UK expected age standardised relative incidence of breast cancer (350 in 100,000, CRUK 2006-2008). Although 27/38 cases (71%) had endocrine treatment for their primary breast cancer, 11/38 patients (29%) did not have any tamoxifen treatment due to hormone receptor negative breast cancer. Additionally the median age of breast cancer diagnosis for the hormone receptor negative group was significantly lower than those patients who had hormonal treatment for their breast cancer (56 vs. 64 years, p :0.036) compatible with the younger age at diagnosis expected of the familial (BRCA mutated) or triple negative breast cancer. Of 18 patients with a second cancer after diagnosis of USC, 6 patients (33%) were diagnosed with breast/ovarian cancer. This group also had no treatment with tamoxifen. Conclusions: Lack of exposure to tamoxifen and younger age at diagnosis in this subgroup suggest that other factors such as a common underlying genetic predisposition may be responsible for the development of both malignancies. We propose that at least a subgroup of USC may be a part of hereditary breast cancer syndrome. This may have implications in prevention (prophylactic hysterectomy) or trials of targeted treatments (PARP inhibitors) for a subgroup of USC patients.
Trends in the content and format of main and optional consent forms in oncology clinical trials.
Authors: Sonja Rummell, Leo Chen, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2017)

153 Background: Informed consent forms (ICFs) should provide prospective subjects with an opportunity to balance the risks and benefits of study participation. However, there are growing concerns about the quality of ICFs. Optional ICFs are also increasingly used as the number of companion studies and biomarker evaluations requiring additional tests become more frequent. We examined trends in the content and format of main and optional ICFs. Methods: ICFs from clinical trials at a tertiary cancer center in British Columbia from 2000 to 2015 were reviewed. We focused on breast or gastrointestinal (GI) cancer studies. Readability was evaluated with the Flesch Reading Ease Score (FRES) and Flesch Kincaid Grade Level (FKGL) where a higher FRES (maximum 100) and a lower FKGL (maximum 12) indicated easier readability. We applied t-tests and linear regressions to examine variations among clinical trials and changes over time. Results: We identified 133 main ICFs of which 70% had optional ICFs and where 57% and 43% were breast and GI cancer studies. Phase III trials (44%), industry funded investigations (70%), and studies involving palliative therapies (72%) were most common. Trials from recent years were more likely to have optional ICFs than those from earlier years (p &lt; 0.001). The median length and median word count in main and optional ICFs were 16 and 6 pages and 6183 and 1862 words, respectively. These changed significantly over time whereby main ICFs increased approximately by 1 page and 364 words per year over the 15 year period (p &lt; 0.001). Industry funded trials also had longer ICFs (p = 0.006). Study methods, risks, and confidentiality occupied 29%, 20%, and 11% of the content on ICFs, respectively. Sections pertaining to eligibility (p &lt; 0.001) and screening procedures (p = 0.007) also increased with time, particularly for industry funded studies (p = 0.006). In terms of readability, optional ICFs were generally more difficult to read than main ICFs (FRES 48.3 vs 50.0, p = 0.024; FKGL 11.8 vs 11.1, p &lt; 0.001), especially in recent years (p &lt; 0.001). Conclusions: This is one of the first analyses to include optional ICFs. Length of ICFs is increasing and readability is discordant with the average reading level of potential trial participants.
Clinical and pharmacokinetic study of gemcitabine (GEM) - oxaliplatin (OXA) association in metastatic or locally advanced pancreatic adenocarcinoma
Authors: M. Airoldi, L. Cattel, R. Passera, C. Micari, E. Ferrarato, C. Zanon
Journal: Journal of Clinical Oncology (2004)

2059 Background: Combination of gemcitabine (GEM) with oxaliplatin (OXA) is among the most active chemotherapy for advanced and metastatic pancreatic adenocarcinoma. Based on preclinical data, a supra-additive effect was observed when tumor cells were exposed to GEM first and to OXA 24 h later. Study aim was to evaluate clinical benefits and tolerability of GEM-OXA association in MTS/LA pancreatic carcinoma. By administering sequence-dependent combinations of the two drugs (GEM d1-OXA d2 or OXA d1-GEM d2), pharmacokinetic (PK) interactions were also evaluated. Methods: 30 patients (median age 60.7 yr; ECOG PS = 1) affected by MTS (67%) or LA pancreatic carcinoma (33%) were enrolled. Pts received GEM 1,000 mg/m2 as 10 mg/m2/min infusion and OXA 100 mg/m2 as 2 h infusion q 2 wks (median cycles/patient = 10). For PK study, 15 patients (28 cycles) were enrolled following two alternated protocols: A (GEM-OXA) (9 pts, 16 cycles) received 1st-3rd-5th cicle GEM on day 1 and OXA on day 2; B (OXA-GEM) (6 pts, 12 cycles) received OXA in 2nd-4th-6th cycle on day 1 and GEM on day 2. Results: 30 pts were evaluable for response and toxicity. Response rate was 30%, superimposable in LA and MTS pts; 50% of patients had clinical benefit. Median PFS and OS were 5.5 and 9.5 months, with 40% of pts alive at 1 year. Grade 3/4 toxicity per patient: 10% neutropenia and thrombocytopenia, 13% nausea/vomiting, 7% diarrhea and 10% peripheral neuropathy. By evaluating GEM and OXA PK parameters in arms A and B, no statistically significant difference was revealed between two protocols (Mann-Whitney test). GEM AUC and Cl (A vs B, p 0.84 and 0.87); OXA tot AUC and Cl (p 0.87 and 0.80); OXA ultr AUC and Cl (p 0.91 and 0.84). Pt though level progressively accumulated, from 1st to 6th cycle (Cmin 74.7–321.35 ng/ml). Conclusions: This phase II study showed that biweekly GEM-OXA as a first line chemotherapy in MTS/LA pancreatic carcinoma is well tolerated and has a excellent clinical activity. PK profile of both drugs does not show statistically significant differences between GEM-OXA and OXA-GEM alternate schedules. No significant financial relationships to disclose.
Myeloproliferative leukemia protein activation directly induces fibrocyte differentiation to cause myelofibrosis
Authors: T Maekawa, Y Osawa, T Izumi, S Nagao, K Takano, Y Okada, N Tachi, M Teramoto, T Kawamura, T Horiuchi, R Saga, S Kato, T Yamamura, J Watanabe, A Kobayashi, S Kobayashi, K Sato, M Hashimoto, S Suzu, F Kimura
Journal: Leukemia (2017)
A virtual tumor board-driven synaptic knowledge network.
Authors: Laurence J. Heifetz, Ahrin B. Koppel, Elaine Melissa Kaime, Daphne Palmer, Thomas John Semrad, Cathey Bervid, Christina Potter, Janet Goodall, Ann Truscott, Scott Christensen
Journal: Journal of Clinical Oncology (2017)

89 Background: In 2006, Tahoe Forest Hospital District—a 25-bed hospital in Truckee, CA, a mountain resort community one hour from regional and two hours from academic cancer services—designed and implemented an oncology program utilizing effective telecommunications with a committed academic partner, the UC Davis Comprehensive Cancer Center in Sacramento. Methods: The UC Davis Cancer Care Network was established with four remote cancer programs, enabling participation in daily virtual tumor boards, clinical trial enrollment, and quality assurance assistance. (Richard J. Bold, et. al., Virtual tumor boards: community-university collaboration to improve quality of care. Community Oncol 10(11):310-315, November 2013.; Laurence J. Heifetz, MD, et. al., A Model for Rural Oncology. J Oncol Pract, 7:168-171, May 2011.). An increasing number of patients were observed to in-migrate to Truckee from even more remote rural areas in the mountains. In 2013, the now Gene Upshaw Memorial Tahoe Forest Cancer Center developed four remote telemedicine clinics to allow even more physically distant patients the capacity to be followed locally. Results: Since we opened the remote telemedicine clinics, our Sullivan-Luallin patient satisfaction scores have averaged 4.82/5.00 for “overall satisfaction with the practice” and 4.90/5.00 for “recommending your provider to others”; our in-migration rate of patients from outside our primary catchment area increased from 43% to 52%: and clinical trial accrual rate averaged 10%. Conclusions: Reducing cancer health disparities is an ASCO mission. (cover, ASCO Connection, July 2014; Laurence J. Heifetz, MD. Country Docs with City Technology Can Address Rural Cancer Care Disparities. Oncol, 29(9):641-644, September 2015.). We believe this synaptic knowledge network effectively addresses that mission for rural communities. This model can be scaled in many configurations to address the inherent degradation of quality care as a function of physical distance to an academic center that rural doctors and patients deal with on a daily basis. The key is to insist on a cultural shift – Do something smart at lunch every day. Attend a virtual tumor board.
The long term outcome of clinical trial-based treatment comparing standard treatment for metastatic breast cancer.
Authors: Gun Min Kim, Joohyuk Sohn, Seho Park, Hyung Seok Park, Seung Il Kim
Journal: Journal of Clinical Oncology (2015)

11106 Background: All NCCN guidelines have black box recommendations as “NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is es...
The role of pazopanib in various histologic subtypes of metastatic soft tissue sarcomas.
Authors: Kwai Han Yoo, Seung Tae Kim, Jeeyun Lee, Se Hoon Park, Sung Joo Kim, Hyo Song Kim
Journal: Journal of Clinical Oncology (2014)

10586 Background: Soft tissue sarcomas (STS) are a rare and heterogeneous group of tumors, and known to have limited treatment options.We investigated the treatment outcome of pazopanib, an oral multi-tyrosine kinase angiogenesis inhibitor, in patients with advanced STS. Methods: A total of forty-four patients with relapsed or refractory STS with metastatic disease received pazopanib for salvage chemotherapy after one or more cytotoxic regimens. All patients were analyzed by histologic subtype, FNCLCC grade and existence of liver involvement and locoregional disease. Results: The majority of patients were male (n=26, 59%) and one (n=9, 20.5%) or two (n=15, 34.1%) previous chemotherapy was introduced. Common histologic subtypes were as follows; leiomyosarcoma (n=9), angiosarcoma (n=6), malignant perpheral nerve sheath tumor (n=5) and liposarcoma (n=2). 9 patients (20.5%) achieved confirmed partial response and 16 patients (.36.5%) revealed stable disease, resulting in disease control rate (DCR) of 56.8% (95% CI, 41.8-71.8). The median progression free survival (PFS) and overall survival (OS) were 100 and 199 days, respectively. The non-liposarcoma group (such as leiomyosarcomas, angiosarcomas and osteosarcomas, n=38) demonstrated significantly prolonged PFS than pediatric type and liposarcoma group (including rhabdomyosarcomas and small round cell sarcomas, n=6) (P<0.001). The median PFS were 132 and 115 days for angiosarcomas (n=6) and leiomyosarcomas (n=9), while rhabdomyosarcomas (n=3) and liposarcomas (n=2) patients demonstrated 27 and 39 days, respectively. Conclusions: Pazopanib demonstrated better antitumor activity for the patients with angiosarcoma and leiomyosarcoma compare to liposarcoma and pediatric type sarcoma.
ACCEPT: Afatinib as cancer therapy for exocrine pancreatic tumors–An explorative randomized phase II trial.
Authors: Michael Haas, Stefan Hubert Boeck, Dirk Waldschmidt, Anke Reinacher-Schick, Jens Freiberg-Richter, Thomas Seufferlein, Stephan Kanzler, Rolf Mahlberg, Jens T. Siveke, Volker Heinemann
Journal: Journal of Clinical Oncology (2015)

TPS4150 Background: Metastatic pancreatic cancer still remains a disease difficult to treat. Since gemcitabine was established as a standard of care in the 1990s, the only targeted therapy which showed a moderate improvement in overall survival (OS) when applied along with gemcitabine was the tyrosine-kinase inhibitor erlotinib. Afatinib, a novel, oral irreversible ErbB family blocker has been approved for first-line-treatment in patients with non-small-cell lung cancer (NSCLC) bearing driver mutations of the epidermal-growth-factor-receptor (EGFR). Afatinib has shown superior progression-free survival and overall survival (in the prespecified subpopulation of Del 19 mutations) compared to standard of care chemotherapy. The combination of gemcitabine and afatinib was well tolerated with manageable adverse events (AEs) in patients with relapsed or refractory solid tumors in a phase I trial. Methods: ACCEPT is an open-label, controlled, randomized phase II trial for patients with histologically proven pancreatic adenocarcinoma previously untreated for metastatic disease. Patients are randomized in a 2:1 ratio to receive either gemcitabine 1000mg/m2 intravenously over 30 minutes on days 1, 8 and 15 of a 28 day cycle in combination with oral afatinib, flat dose of 40mg daily, continuously (Arm A, experimental arm) vs. gemcitabine alone (Arm B). The study is designed to demonstrate a benefit in OS for the combination of gemcitabine and afatinib vs. gemcitabine alone. Estimating a hazard ratio (HR) of 0.60 for OS in favor of the experimental arm and expecting a drop-out rate of 15%, a total number of 117 patients to be recruited was calculated. The first patient was included in April 2013 and currently thirty high-volume centers are open for recruitment in Germany. The current recruitment status is 49/117 patients. The study has an explorative endpoint: tumor samples and peripheral blood are prospectively collected and centrally stored from all study participants. As part of this translational program analyses regarding tumor- and blood samples will focus on potential prognostic and predictive biomarkers associated with the EGFR pathway.Clinical trial information: NCT01728818 Clinical trial information: NCT01728818.
Engineered Exosomes as Vehicles for Biologically Active Proteins
Authors: Ulrich Sterzenbach, Ulrich Putz, Ley-Hian Low, John Silke, Seong-Seng Tan, Jason Howitt
Journal: Molecular Therapy (2017)

Exosomes represent an attractive vehicle for the delivery of biomolecules. However, mechanisms for loading functional molecules into exosomes are relatively unexplored. Here we report the use of the evolutionarily conserved late-domain (L-domain) pathway as a mechanism for loading exogenous proteins into exosomes. We demonstrate that labeling of a target protein, Cre recombinase, with a WW tag leads to recognition by the L-domain-containing protein Ndfip1, resulting in ubiquitination and loading into exosomes. Our results show that Ndfip1 expression acts as a molecular switch for exosomal packaging of WW-Cre that can be suppressed using the exosome inhibitor GW4869. When taken up by floxed reporter cells, exosomes containing WW-Cre were capable of inducing DNA recombination, indicating functional delivery of the protein to recipient cells. Engineered exosomes were administered to the brain of transgenic reporter mice using the nasal route to test for intracellular protein delivery in vivo. This resulted in the transport of engineered exosomes predominantly to recipient neurons in a number of brain regions, including the olfactory bulb, cortex, striatum, hippocampus, and cerebellum. The ability to engineer exosomes to deliver biologically active proteins across the blood-brain barrier represents an important step for the development of therapeutics to treat brain diseases.
Effect of physician-level performance feedback on pattern of structured cancer stage entry.
Authors: Chintan Pandya, Alex Alongi, David W. Dougherty
Journal: Journal of Clinical Oncology (2017)

141 Background: In contrast to unstructured free text, structured entry of cancer type and stage facilitates easy utilization of this clinically important data to accurately identify patient population, measure and report performance on outcomes and quality of care as well as for various clinical decision support systems. There is significant variation in physician utilization of Electronic Medical Record based staging modules which capture the data in structured form. The aim of study is to increase structured cancer staging by providing performance feedback to individual physicians. Methods: An EPIC based physician performance feedback report was developed consisting of staging tool utilization performance captured by percentage of staged patients out of all the patients seen by the provider as well as the MRN link (to act upon) of the un-staged patients with stageable cancer diagnosis using criteria: 1) un-staged cancer on the problem list 2) active treatment plan and 3) seen by provider in last one year. Reports were sent monthly to the providers starting 11/1/2015. Pre-intervention structured staging rates were compared with 6- and 12-month post-intervention rates. Results: EPIC patient data was used to determine the number of patients eligible for staging. In 12 months prior to the intervention, 36% (n = 414/1164) of patients eligible for staging were staged in the structured staging module. After the intervention, the 6- and 12-month staging rates were 60% (n = 836/1387) and 68% (n = 1084/1585), respectively, suggesting an absolute improvement of 89% in structured stage entry. Conclusions: Performance feedback to oncology providers resulted in behavior change and dramatically improved rates of structured cancer staging. Availability of such structured data is essential for development, implementation and evaluation of various quality improvement interventions and strategies such as quality reporting, outcomes analysis, practice patterns, and other population health initiatives. Incremental and large-scale improvement in care processes and outcomes may be achieved through such individual-level feedback mechanisms and contribute to learning health care systems.
ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity
Authors: Xinyun Bi, Fanghong Li, Shanshan Liu, Yan Jin, Xin Zhang, Tao Yang, Yifan Dai, Xiaoxi Li, Allan Zijian Zhao
Journal: Journal of Clinical Investigation (2017)

Despite the benefit of insulin, blockade of autoimmune attack and regeneration of pancreatic islets are ultimate goals for the complete cure of type 1 diabetes (T1D). Long-term consumption of ω-3 polyunsaturated fatty acids (PUFAs) is known to suppress inflammatory processes, making these fatty acids candidates for the prevention and amelioration of autoimmune diseases. Here, we explored the preventative and therapeutic effects of ω-3 PUFAs on T1D. In NOD mice, dietary intervention with ω-3 PUFAs sharply reduced the incidence of T1D, modulated the differentiation of Th cells and Tregs, and decreased the levels of IFN-γ, IL-17, IL-6, and TNF-α. ω-3 PUFAs exerted similar effects on the differentiation of CD4+ T cells isolated from human peripheral blood mononuclear cells. The regulation of CD4+ T cell differentiation was mediated at least in part through ω-3 PUFA eicosanoid derivatives and by mTOR complex 1 (mTORC1) inhibition. Importantly, therapeutic intervention in NOD mice through nutritional supplementation or lentivirus-mediated expression of an ω-3 fatty acid desaturase, mfat-1, normalized blood glucose and insulin levels for at least 182 days, blocked the development of autoimmunity, prevented lymphocyte infiltration into regenerated islets, and sharply elevated the expression of the β cell markers pancreatic and duodenal homeobox 1 (Pdx1) and paired box 4 (Pax4). The findings suggest that ω-3 PUFAs could potentially serve as a therapeutic modality for T1D.