tbuckley/cabot-search huggingface dataset:
Effect of trametinib in combination with panitumumab and trastuzumab on tumor growth in an orthotopic xenograft model of human pancreatic cancer.
Authors: James M. Lindberg, Sara J Adair, Timothy E. Newhook, Alison Kim, J Thomas Parsons, Todd W. Bauer
Journal: Journal of Clinical Oncology (2013)

190 Background: Aberrant MAPK and EGFR family signaling are key drivers of pancreatic ductal adenocarcinoma(PDAC). We hypothesized that combination trametinib(MEK1/2 inhibitor), panitumumab(EGFR inhibitor) and trastuzumab(Her2 inhibitor) would more effectively suppress tumor growth than any of these monotherapies. Methods: Patient-derived PDAC cell line MAD09-366 was exposed to trametinib, panitumumab, trastuzumab, and combination therapies in vitro. Western blot analysis was performed on treated cell lysates. Athymic, nude mice were orthotopically implanted with patient-derived PDAC xenografts(MAD09-366, 08-608, and 08-738). Established murine tumors were treated with control, trametinib (0.3mg/kg, qDay), panitumumab (500ug, BIW), trastuzumab (200ug, BIW) or in combination. MRI was used to assess tumor response. Results: Two of 3 PDACs were Kras mutant, 2 of 3 demonstrated increased Her2 activity, and all 3 showed increased EGFR activity. In vitro studies showed increased growth inhibition of triple-therapy-treated cells relative to control or each inhibitor alone. Western blot analysis revealed that EGF stimulation increased Ras pathway signaling in this Kras-mutant cell line. With EGF stimulation, the greatest Ras pathway signaling inhibition was seen in triple-therapy-treated cells. In vivo studies in all PDAC xenografts revealed that triple therapy significantly decreased tumor growth rate relative to control, trametinib alone, panitumumab alone, or panitumumab plus trastuzumab. In 2 of 3 PDACs assessed, triple therapy was superior to trametinib plus panitumumab. Average tumor size in MAD08-738 triple-therapy-treated mice decreased by 9.3%. Conclusions: Triple therapy with trametinib, panitumumab, and trastuzumab demonstrated the greatest in vitro Ras signaling blockade. In vivo, this combination produced significant tumor growth inhibition or regression in all PDAC tumors studied. This regimen should be considered for a future clinical trial in pancreatic cancer patients.
Breast cancer treatment delays in a majority minority community: Is there a difference?
Authors: Kate Ida Lathrop, Helen M. Parsons, Anand B. Karnad
Journal: Journal of Clinical Oncology (2013)

83 Background: Recent studies based from large nationwide cancer databases have consistently shown that Hispanic women with breast cancer have delays in treatment compared to non-Hispanic whites. However, time to treatment has not been studied in a community where Hispanics are the majority population. We hypothesized that Hispanic women in greater San Antonio will have no significant treatment delays compared to Non-Hispanic whites in the same community. Methods: We conducted a retrospective, observational study in 362 female breast cancer patients treated at a NCI designated cancer center with a largely Hispanic population. Using Kaplan-Meier analyses and multivariate Cox proportional hazards models, we examined the relationship between race/ethnicity and treatment delays including: 1) time from mammogram to biopsy and 2) time from biopsy to treatment, adjusting for patient demographics and cancer characteristics. Results: In our study, the majority of patients were Hispanic (50.0%, n=181). Hispanic patients were more likely to be obese, have estrogen receptor positive and higher grade tumors than non-Hispanic Whites (p ≤ 0.05 for all). After adjusting for a comprehensive set of socio-demographic and cancer characteristics, we continued to find no significant differences between race/ethnicity and time from mammogram to biopsy or time from biopsy to treatment (Table). Conclusions: Hispanic and non-Hispanic White women with breast cancer treated at our NCI designated cancer center have similar times to treatment. These findings suggest that minority status, as opposed to racial status, is an important risk factor for delays in breast cancer care. Future research should be focused on barriers imposed on minority groups within their community regardless of race. [Table: see text]
Image guidance for post-prostatectomy radiotherapy: Are we missing the mark?
Authors: Noah S. Kalman, Lionel L. Banez, Leah Gerber, Judd W. Moul, Mitchell Steven Anscher, W. Robert Lee, Bridget F. Koontz
Journal: Journal of Clinical Oncology (2013)

56 Background: Image-guided radiation therapy (IGRT) has been widely adopted for both definitive and post-operative prostate radiotherapy. In the postoperative setting, numerous studies of prostate bed motion have recommended tight planning margins (&lt;10mm) if IGRT is used daily. The purpose of this analysis is to determine the effect of IGRT on the efficacy and toxicity of post-operative prostate radiotherapy. Methods: Between 1998 and 2010, 286 patients received radiation therapy after prostatectomy at Duke. Recurrent disease following radiation therapy was defined as PSA &gt;0.2 ng/ml and rising or initiation of salvage ADT. CTCAE v 4.0 and the RTOG/LENT late morbidity scores were used to grade acute and late toxicities. Risk for biochemical failure and late Grade 2+ GI toxicity were compared between IGRT (N = 113) and non-IGRT (N = 173) patients using multivariable adjusted Cox regression controlling for age, treatment technique (3D vs IMRT), radiation dose, androgen suppression, pathologic Gleason Score, margin status, pathologic stage, and pre-radiotherapy PSA level. Results: The median margin size for patients with IGRT was 7mm (IQR 6-10mm) and 15mm (IQR 7-15mm) for those without IGRT (p &lt; 0.001). Median follow up was 21 months (IQR 15-33 mo) for patients with IGRT and 49 months (IQR 30-73 mo) for those without IGRT (p &lt; 0.001). On multivariate analysis, patients treated with IGRT had a greater risk of progression versus non-daily imaging (HR = 2.51, p &lt; 0.001), as did patients who received salvage versus adjuvant radiotherapy (HR = 2.41, p = 0.005). Higher pathologic Gleason Score (HR = 1.96, p = 0.026) and pathologic stage (HR = 1.93, p = 0.003) conferred increased risk of progression, while positive margin status was protective (HR = 0.53, p = 0.002). Age, radiation dose, androgen suppression, and treatment technique did not affect biochemical outcome (p &gt; 0.1). There were no differences in acute or late GI toxicity according to treatment technique or use of IGRT (both p &gt; 0.1). Conclusions: The use of IGRT was associated with increased biochemical recurrence for patients receiving post-operative prostate radiotherapy. For these patients, we recommend using treatment margins of at least 10mm to address subclinical disease and organ motion.
Kinetics and Apoptotic Profile of Circulating Endothelial Cells In Patients Undergoing Autologous Stem Cell Transplantation
Authors: Anna Szmigielska-Kaplon, Krawczynska Anna, Czemerska Magdalena, Agnieszka Pluta, Barbara Cebula-Obrzut, Anna Wolska, Olga Grzybowska-Izydorczyk, Piotr Smolewski, Tadeusz Robak, Agnieszka Wierzbowska
Journal: Blood (2011)
Assessment of knowledge of vincristine toxicities in outpatient pediatric hematology/oncology nurses: An educational intervention.
Authors: David Tishler, Leidy Isenalumhe, Sajad Khazal, Sujata Mushrif, Teresa Rushing
Journal: Journal of Clinical Oncology (2013)

231 Background: Vincristine (VCR) is a chemotherapeutic agent with a unique neurological side effect profile and is integral to the treatment of many pediatric hematological and solid malignancies. Side effects requiring VCR dose modification include peripheral neuropathies, intestinal ileus, cranial nerve abnormalities, hyponatremia and seizures. In our institution, orders for weekly VCR are written in advance by oncologists and administered by outpatient nurses independent of a provider physical examination. We sought to increase knowledge of VCR toxicities and improve pre-chemotherapy evaluation skills among outpatient Hematology/Oncology (Hem/Onc) nurses. Methods: A 23-question written quiz was given as a pre-test to 14 outpatient Hem/Onc nurses to assess their fund of knowledge regarding VCR toxicities. An educational intervention was then provided to the cohort as a lecture by a Hem/Onc fellow physician. The lecture was followed by the same quiz given as post-test to the nurses. Individual participant and group scores were tabulated comparing pre and post-test responses to assess improvement in identification and recognition of VCR toxicities. Results: 12/14 nurses demonstrated improvement in their fund of knowledge regarding VCR side effects (mean change in individual scores + 4.7). As a group, mean scores increased from 15.2 to 18/23 (the two-sample paired t-test was significant with a two-tailed p&lt;0.005). Conclusions: An educational intervention significantly improved outpatient Hem/Onc nurses fund of knowledge regarding identification and evaluation of VCR toxicities. Future objectives include follow-up evaluation of retention of knowledge of VCR side effects and incorporating a VCR toxicity checklist into the electronic medical record outpatient nursing note.
Phase I trial of FOLFIRI in combination with sorafenib and bevacizumab in patients with advanced gastrointestinal malignancies.
Authors: Joleen Marie Hubbard, George P. Kim, Mitesh J. Borad, Rui Qin, Janet Lensing, John Joseph Wright, Charles Erlichman, Axel Grothey
Journal: Journal of Clinical Oncology (2014)

551 Background: Sorafenib inhibits various pro-angiogenesis pathways including PDGFR-B, a factor associated with resistance to anti-VEGF therapy. A previous phase II trial in patients with chemorefractory metastatic CRC demonstrated a 63% disease control rate with a combination of bevacizumab (BEV) and sorafenib. This phase I trial sought to determine the MTD of BEV and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers. Methods: Patients with advanced GI malignancies appropriate for irinotecan-based therapy were enrolled (14 with CRC, 3 gastroesophageal). A standard 3 + 3 design was used with 3 escalating sorafenib dose levels (DL): (1) 200 mg po daily, days 3-7, 10-14; (2) 200 mg po twice daily, days 3-6, 10-13; and (3) 200 mg po twice daily, days 3-7, 10-14. FOLFIRI: irinotecan 180 mg/m 2 d1, leucovorin 400 mg/m2 d1, 5-fluorouracil (FU) bolus 400 mg/m 2 d1, 5-FU infusion 2400 mg/m 2 d1-2 and BEV 5 mg/kg d1. 1 cycle = 14 days. Results: Seventeen pts were enrolled, median age of 56 (range 32 and 81). Two pts were replaced, as they did not complete DLT evaluation, leaving 15 evaluable pts. Four evaluable pts at DL1 and 6 pts at DL2 had no DLTs. At DL 3, the first cohort of 3 pts did not experience any DLTs. In the second cohort of 3 pts, 2 pts experienced DLTs (asymptomatic G3 hypophosphatemia, G3 dehydration and diarrhea). MTD was determined to be DL2: sorafenib 200 mg PO twice daily, days 3-6, 10-13 combined with FOLFIRI and BEV at standard doses. Of the 15 evaluable pts, 4 pts had PR, 8 pts had SD as best response, 1 pt had PD, and 2 pts discontinued treatment prior to first tumor assessment. The median number of cycles was 10 (range 1-37). Three pts with CRC had disease control &gt; 12 months. Conclusions: The MTD of this regimen is sorafenib 200 mg PO twice daily, days 3-6,10-13 combined with standard doses of FOLFIRI and BEV. Dual VEGF inhibition combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies. Supported by CA69912 and CA15083. Clinical trial information: NCT01383343.
Early identification of high-risk neutropenia in the ambulatory setting.
Authors: Anitha S. Nallari, Neeta K. Venepalli, Lawrence Eric Feldman, Rozina A. Chowdhery, Janet Golick
Journal: Journal of Clinical Oncology (2014)

87 Background: The University of Illinois Cancer Center (UICC) utilizes nurse (RN) visits for laboratory review and toxicity evaluations for patients (pts) receiving chemotherapy. Upon review of nursing visits, we observed that RN visit documentation for neutropenia was variable without standard language, communication with physicians (MD), or requirement for MD evaluation. We sought to implement an early intervention strategy to prevent morbidity and mortality from high risk neutropenia (HRN). Methods: A multidisciplinary task force of oncology RNs and MDs created actual and ideal process maps, from identification of neutropenia to patient disposition. We developed a Standard Operating Protocol (SOP) involving a HRN checklist (created based on NCCN and ISDA guidelines) and new process for triage of HRN pts. RNs were required to complete the HRN checklist within the electronic health record for all pts with ANC &lt; 1,000. If high risk features were identified, MD evaluation was required within 1 hour of RN call, with SOAP note and attending notification. Results: Over an 8 week period, 17 HRN templates were generated. The process and checklist were adjusted after the first 4 weeks with clinic wide feedback. Within the first 4 weeks, 8 templates were generated (5 MD, 3 RN); no patients met high risk neutropenia criteria and all were discharged home. Within the second 4 weeks, 9 templates were generated (3 MD, 6 RN); 3 HRN pts were identified with two direct admissions and one home discharge with favorable outcomes. Clinic staff reported greater understanding of HRN, increased satisfaction with multidisciplinary interactions, and more comfort with calling MDs for prompt patient evaluation. Conclusions: UICC successfully piloted the creation and implementation of an early identification and intervention strategy for HRN with strong multidisciplinary support. Compared to the prior 6 month period, we found that use of the SOP and checklist resulted in improvement in evaluation of quality and timeliness of HRN pts and prevented morbidity and mortality. Additionally, the checklist provoked critical thinking from end users with more thorough patient evaluations and improved documentation, resulting in aggressive intervention and better outcomes.
Effect of inflammation-associated cytokines of biliary tract cancer on chemoresistance and therapeutic implications.
Authors: Shogo Kobayashi, Hiroaki Nagano, Daisaku Yamada, Hideshi Ishii, Yoshito Tomimaru, Naoki Hama, Hiroshi Wada, Koichi Kawamoto, Hidetoshi Eguchi, Yuichiro Doki, Masaki Mori
Journal: Journal of Clinical Oncology (2014)

247 Background: Biliary tract cancer (BTC) is well-known to be commonly suffered from inflammations; cholangitis and/or liver abscess. The author previously showed interleukin-6 (IL-6) worked on anti-apoptotic process in BTC. Herein, we focused on inflammation-associated cytokines including not only IL-6 but also transforming growth factor-beta 1 (TGF-β1), and investigated the working processes, their relationship to chemoresistance, and therapeutic implications. Methods: We employed resected specimens and BTC cell lines. We evaluated IL-6/TGF-β1 expression, invasion, endothelial-mesenchymal transition (EMT), and chemoresistance to gemcitabine, with or without silencing of PI3K/Akt, MAPK, STAT, and Smad pathways. Results: Resected specimens expressed IL6 and TGF-β1 staining at the invasion front by immunohistochemical staining. In BTC cell lines, spontaneous expression of IL-6/TGF-β1 was related to malignant potencies such as EMT and chemoresistance. Rh IL-6/TGF-β1 induced invasion, EMT, and chemoresistance. Smad4 among cell signaling pathways functioned in a dominant manner; inhibition of Smad4 pathway reduced invasion, and reversed EMT and chemoresistance, in both rh IL-6/TGF-β1-treated cells, and we confirmed these results using SMAD4 siRNA. And, our established gemcitabine-resistant cells expressed high level of IL-6/TGF-β1, and promoted EMT. Inhibition of Smad4 also reversed chemoresistance in gemcitabine-resistant cells. We confirmed N-cadherin and Smad4 expression at the invasion front by immunohistochemistry. Conclusions: IL-6 and TGF-β1 resulted in chemoresistance, and inhibition of Smad4 would reverse chemoresistance in BTC.
Trump’s mental health, gun laws, and health insurance
Authors: Michael McCarthy
Journal: BMJ (2017)

In the first of an occasional series, Michael McCarthy rounds up the latest health related developments under the US president’s administration

In a letter to the New York Times on 13 February, 35 mental health professionals said that “too much was at stake” for them to remain silent any longer about Donald Trump’s mental health.1 The US president had shown that he was unable to tolerate views different from his own, they said, adding, “We believe …
Immune cell changes in the peripheral blood of metastatic renal cell carcinoma (mRCC) patients (pts) treated with sunitinib or temsirolimus
Authors: R. N. Salas, J. L. Ireland, J. S. Ko, P. Elson, J. A. Garcia, L. Wood, R. M. Bukowski, B. I. Rini, J. H. Finke
Journal: Journal of Clinical Oncology (2008)

5099 Background: Sunitinib is an oral tyrosine kinase inhibitor of VEGFR-2, PDGFR, KIT, and FLT3 and a first line standard of care for mRCC. Temsirolimus, also approved for mRCC, is an analog of the immunosuppressant sirolimus and a mTOR inhibitor. There is little known on how these agents may affect immune cell populations in RCC. Methods: Peripheral blood mononuclear cells (PBMCs) from mRCC pts treated with sunitinib (n=7) or temsirolimus (n=7) were collected at cycle 1 day 1 (C1D1), C1D28, C2D28, and C4D28 as available, and from age-matched normals (AMNs; n=20). PBMCs were stained for the following cell populations (pop): myeloid derived suppresser cells (MDSC) [CD15+/CD14- or CD33+/HLA-Dr-]; T regulatory cells (Treg) including FoxP3 [CD3+CD4+CD25hiFoxP3+], Tr1 [Lymphocyte gate/CD4+/IL- 10+/IL-4-], and Th3 [Lymphocyte gate/CD4+/TGF-β+]; dendritic cells (DC) including mDC1 [BDCA1+CD19-], mDC2 [BDCA3hi CD14-BDCA1-], and pDC [BDCA2+CD14-BDCA1-]; and, after 72 hour stimulation with anti-CD3/anti-CD28 beads, Th1 [CD3+CD4+IFN-γ+] and Th2 [CD3+CD4+IL-4+] responses. Samples were acquired by flow cytometry and analyzed with FlowJo software. Statistical analysis was performed using the Wilcoxon rank sum and signed rank tests. Results: Compared to AMNs, mRCC pts had increased MDSCs (CD15+ pop: p=0.005; CD33+ pop: p=0.05) and Tregs (FoxP3: p=0.009; Tr1: p=0.03; Th3: p=0.02), decreased Th1 responses (p=0.01), but similar numbers of all DC pops. Sunitinib pts had significant decreases from C1D1 to C2D28 in the following: MDSCs (n=5, p = 0.06), mDC1s (n=7, p=0.03), mDC2s (n=7, p=0.06), and pDCs (n=7, p=0.05). Temsirolimus pts had significant increases in pDCs from C1D28 to C2D28 (n=5, p=0.06), increases in % FoxP3 within CD4+CD25hi from C1D1 to C2D28 (n=5, p=0.06), and an increase in Th1 (n=7, p=0.08) with a decrease in Th2 (n=7, p = 0.08) from C1D1 to C1D28. Conclusions: mRCC pts have increased MDSCs and Tr1/Th3 Tregs in addition to previously reported increased FoxP3 Tregs and decreased Th1 responses. Sunitinib not only decreases the suppressive MDSCs but also all DC subsets. Temsirolimus was found to increase Th1 and decrease Th2 responses, as previously shown with sunitinib, while its affects on other cell pops is still unclear. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology, Wyeth Pfizer Oncology, Wyeth Pfizer Oncology, Wyeth
Lack of Association between Single Nucleotide Polymorphism rs3811647 in the TF Gene and Iron Status in Patients with Iron Deficiency and Control Subjects
Authors: Gordon D. McLaren, Catherine A. McCarty, Marylyn Ritchie, Stephen Turner, Victor R. Gordeuk, Chad P. Garner, Chris D. Vulpe, Stela McLachlan, Paul C. Adams, Christine E. McLaren
Journal: Blood (2010)
Influence of pre-diagnosis statin use on survival among patients with pancreatic cancer.
Authors: Brian Z Huang, Jonathan I Chang, Bechien U Wu
Journal: Journal of Clinical Oncology (2016)

427 Background: Recent studies have suggested associations between statin use and enhanced survival among patients with pancreatic ductal adenocarcinoma (PDAC). We aimed to explore the impact of pre-diagnosis statin treatment on survival across different agents and exposure levels. Methods: We conducted a retrospective cohort study on 2,142 pancreatic cancer patients diagnosed from 2006-2014 in an integrated healthcare system. Patients were identified from an internal cancer registry and followed until censored at death, date of last contact, or end of study. We used electronic pharmacy records to abstract information on the type, length and dosage of all statin exposures in the year prior to diagnosis. The overall influence of statins as well as the individual effects of simvastatin, lovastatin, atorvastatin, pravastatin and rosuvastatin were assessed using Cox proportional hazards regression. All analyses were adjusted for age, race, stage, receipt of surgery, receipt of chemotherapy and Charlson comorbidity index. We further adjusted for cholesterol control to determine whether statins acted through a lipid-mediated pathway. Results: Overall statin use was associated with a 13% decrease in the risk of mortality (HR 0.87, CI 0.79-0.97). Specifically, those who had used statins for 9-12 months (HR 0.85, CI 0.75-0.95), received higher doses (40+ mg/day) (HR 0.86, CI 0.76-0.98) or were active users at diagnosis (HR 0.86, CI 0.78-0.96) all had better survival compared to non-statin users. When assessing the individual statins, we found similar improvements in survival only among simvastatin users. Further stratified analyses revealed that simvastatin decreased the risk of death by 26% in stage IV patients (HR 0.74, CI 0.64-0.85), but had no effect for stage I-III patients (p interaction = 0.03). Cholesterol control did not impact any of the associations between statin use and survival. Conclusions: We found that pre-diagnosis statin use, specifically simvastatin, was associated with improved survival in pancreatic cancer patients.