tbuckley/cabot-search huggingface dataset:
A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma
Authors: Todd Crocenzi, Benjamin Cottam, Pippa Newell, Ronald F. Wolf, Paul D. Hansen, Chet Hammill, Matthew C. Solhjem, Yue-Yun To, Amy Greathouse, Garth Tormoen, Zeljka Jutric, Kristina Young, Keith S. Bahjat, Michael J. Gough, Marka R. Crittenden
Journal: Journal for ImmunoTherapy of Cancer (2016)

Preclinical studies have shown synergy between radiation therapy and immunotherapy. However, in almost all preclinical models, radiation is delivered in single doses or short courses of high doses (hypofractionated radiation). By contrast in most clinical settings, radiation is delivered as standard small daily fractions of 1.8-2 Gy to achieve total doses of 50-54 Gy (fractionated radiation). We do not yet know the optimal dose and scheduling of radiation for combination with chemotherapy and immunotherapy.To address this, we analyzed the effect of neoadjuvant standard fractionated and hypofractionated chemoradiation on immune cells in patients with locally advanced and borderline resectable pancreatic adenocarcinoma.We found that standard fractionated chemoradiation resulted in a significant and extended loss of lymphocytes that was not explained by a lack of homeostatic cytokines or response to cytokines. By contrast, treatment with hypofractionated radiation therapy avoided the loss of lymphocytes associated with conventional fractionation.Hypofractionated neoadjuvant chemoradiation is associated with reduced systemic loss of T cells.ClinicalTrials.gov NCT01342224, April 21, 2011; NCT01903083, July 2, 2013.
Early T-Lymphocyte Chimerism Kinetics Is Influenced By Conditioning Regimen in Reduced Intensity Allogeneic Stem Cell Transplantation
Authors: Nosha Farhadfar, Damlaj Moussab, Ajoy L. Dias, Hassan B Alkhateeb, Mark R Litzow, Shahrukh K. Hashmi, Mrinal M Patnaik, William J Hogan
Journal: Blood (2015)
Abstract B23: Elucidating metastatic signaling networks in TNBC by investigating RKIP-regulated kinome
Authors: Ali E. Yesilkanal, Casey Frankenberger, Daniel C. Rabe, Gary L. Johnson, Marsha R. Rosner
Journal: Cancer Research (2016)

Abstract Metastatic progression of tumors is the major cause of death in patients with triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer. However, since metastasis is a multi-step process, unraveling its complexity is a major challenge. One effective way of tackling this question is to study natural blockers of the metastatic process, metastasis suppressors, and identify the mechanisms by which they regulate metastasis. Raf kinase inhibitory protein (RKIP), a protein that regulates kinase activity, is a suppressor of TNBC metastasis. Although RKIP inhibits the activity of key kinases such as Raf-1, GRK2, NIK/IKK in cultured cells, the kinase targets of RKIP in tumors are not known. To address this question, we used a mass spectrometry approach involving inhibitor-conjugated beads to identify kinases that are down-regulated by RKIP in human TNBC xenograft tumors. Our results identified novel targets of RKIP whose kinase activity is either down-regulated or up-regulated by RKIP. We used bioinformatics analysis to build RKIP-regulated signaling networks based upon RKIP-induced changes in kinase activity and related gene expression. Elucidating RKIP function at a systems level reveals the interplay between key metastatic signaling cascades, particularly in relation to cell migration and invasion, and can potentially identify novel anti-metastatic target combinations in TNBCs. Citation Format: Ali E. Yesilkanal, Casey Frankenberger, Daniel C. Rabe, Gary L. Johnson, Marsha R. Rosner. Elucidating metastatic signaling networks in TNBC by investigating RKIP-regulated kinome. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B23.
Abstract 310: Mechanism of sorafenib resistance in acute myeloid leukemia
Authors: Oscar Lindblad, Eugenia Cordero, Alexandre Puissant, Lucy Macaulay, Nuzhat N. Kabir, Jianmin Sun, Karin Haraldsson, Åke Borg, Fredrik Levander, Kimberly Stegmaier, Kristian Pietras, Lars Rönnstrand, Julhash U. Kazi
Journal: Cancer Research (2016)

Abstract Activating mutations in FLT3 occur in up to 35% of patients with AML and correlate with poor prognosis. Therapy directed against FLT3 has been shown to induce response in patients with AML, but these responses are almost always transient. Dual PI3K/mTOR inhibitors have displayed promising results in the treatment of solid tumors, and of hematological cancers. In this report we describe that a dual PI3K/mTOR inhibitor is effective against sorafenib-responsive, and -resistant, AML cell lines both in vitro and in vivo. We generated two cell lines by sustained treatment with sorafenib. Parental cell lines carry the FLT3-ITD mutation and are highly responsive to FLT3 inhibitors, while sorafenib-resistant cell lines display resistance to multiple FLT3 inhibitors. Next generation sequencing did not show any significant difference in the mutational burden in between responsive and resistant cell lines. While next generation sequencing identified FLT3-D835Y with an allele-depth of 67:37 in a resistant cell line, Sanger sequencing and protein mass-spectroscopy did not identify any acquired mutations in the kinase domain of FLT3 in the resistant cells. Moreover, sorafenib treatment effectively blocked FLT3 activation in resistant cells, while it was unable to block colony formation or cell survival, suggesting that the resistant cells are no longer dependent on FLT3. Gene expression analysis of sorafenib-sensitive and -resistant cell lines, as well as of blasts from patients with sorafenib-resistant AML, suggested an enrichment of the PI3K/mTOR pathway that correlated with the resistant phenotype, which was further supported by phospho-specific-antibody array analysis. The selective PI3K/mTOR inhibitor, gedatolisib, efficiently blocked proliferation, colony and tumor formation of resistant cell lines as well as induces apoptosis. Taken together, our data suggest that aberrant activation of the PI3K/mTOR pathway results in FLT3-inhibitors-resistance and a dual specific PI3K/mTOR inhibitor is an effective treatment in both tyrosine kinase inhibitor sensitive and resistant AML. Citation Format: Oscar Lindblad, Eugenia Cordero, Alexandre Puissant, Lucy Macaulay, Nuzhat N. Kabir, Jianmin Sun, Karin Haraldsson, Åke Borg, Fredrik Levander, Kimberly Stegmaier, Kristian Pietras, Lars Rönnstrand, Julhash U. Kazi. Mechanism of sorafenib resistance in acute myeloid leukemia. [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 310.
Canada’s scientists win overhaul of federal research grant system
Authors: Owen Dyer
Journal: BMJ (2016)

The Canadian Institutes of Health Research (CIHR), which fund most biomedical research in Canada, have agreed to scrap the system of reviewing grant applications, in place since 2012, and return to previous methods after numerous complaints culminated in an open letter to the health minister signed by 1309 researchers.

Until 2012 the institutes conducted peer review of funding applications by creating panels in 53 disciplines. Experts would then be flown in at considerable expense for face to face …
Therapy Related MDS/AML In Multiple Myeloma Patients In The Era Of Novel Agents
Authors: Morie A Gertz, Suzanne R Hayman, David Dingli, Angela Dispenzieri, Prashant Kapoor, Shaji K Kumar, Martha Q Lacy, Nelson Leung, Yi Lin, John A Lust, Joseph R. Mikhael, S. Vincent Rajkumar, Stephen J. Russell, Steven R Zeldenrust, Robert Kyle, Francis K Buadi
Journal: Blood (2013)
Abstract LB-378: Ankyrin repeat domain 30A as a novel molecular marker of columnar alterations in benign breast disease and subsequent breast cancer in African American women
Authors: Andreana N. Holowatyj, Rouba Ali-Fehmi, Julie J. Ruterbusch, Eman Abdulfatah, Vishakha Pardeshi, Woodlyne Roquiz, Baraa Alosh, Sudeshna Bandyopadhyay, Derek Radisky, Michele L. Cote
Journal: Cancer Research (2016)

Abstract An estimated 1.6 million breast biopsies are performed annually in the United States, and the vast majority are benign. Benign breast disease is an established breast cancer risk factor for both Caucasian and African American women. Yet little is still known about benign breast tissue from African American women, who suffer from disproportionately high-grade tumors and poorer breast cancer survival. To better characterize the risk of breast cancer among African American women with benign breast disease, we assessed benign breast disease pathology of African American women in our metropolitan Detroit cohort (n = 3,737). We classified benign breast lesions for pathological characteristics and used logistic regression to estimate subsequent breast cancer risk with histological characteristics. We observed that women whose biopsies showed columnar alterations, columnar cell lesions of the breast, were 1.78-fold more likely to develop an invasive breast cancer [odds ratio (OR) 1.78, 95% confidence interval (CI) 1.19-2.65] after adjusting for age at biopsy, biopsy year, and overall impression. Columnar alterations were not found to be significantly associated with risk of developing ductal carcinoma in situ (DCIS) among African American women [OR 1.53, 95% CI 0.83-2.82]. Next, to identify molecular markers associated with columnar alterations in benign breast lesions, we performed gene expression analyses on biopsy tissues from 27 African American women that subsequently developed an invasive breast cancer. Transcriptional profiling of these lesions identified differentially expressed genes significantly associated with columnar alterations, including ankyrin repeat domain 30A (ANKRD30A). ANKRD30A, also known as NY-BR-1, is a mammary tissue-specific differentiation antigen that is overexpressed in breast cancers. Increased expression of ANKRD30A in benign breast lesions with columnar alterations may be indicative of subsequent breast cancer development. Taken together, novel molecular markers, including ANKRD30A, and ethnicity can lead to better risk assessment and earlier diagnosis of breast cancer. Citation Format: Andreana N. Holowatyj, Rouba Ali-Fehmi, Julie J. Ruterbusch, Eman Abdulfatah, Vishakha Pardeshi, Woodlyne Roquiz, Baraa Alosh, Sudeshna Bandyopadhyay, Derek Radisky, Michele L. Cote. Ankyrin repeat domain 30A as a novel molecular marker of columnar alterations in benign breast disease and subsequent breast cancer in African American women. [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 LB-378.
Cover Image: Acquired generalized lipodystrophy in a patient with systemic lupus erythematosus
Authors: M.J. Diaz Navarro, N. Lozano‐Rivas, C. Marras Fernández‐Cid, M.R. Oliva Ruiz, P. Sanchez‐Pedreño, I. Pagan Muñoz, G. Garcia Buendia
Journal: British Journal of Dermatology (2016)
Another piece in the ‘research mosaic’ that describes the role of the lung microbiome in COPD
Authors: Gary B Huffnagle
Journal: Thorax (2016)

Bacterial colonisation/infection is ubiquitous in patients with COPD and is likely a biologically relevant facet of disease progression. Correlations have been reported between the identification of bacteria and increases in the intensity of the inflammatory/immune response, cough, sputum production and rates of acute exacerbations of COPD.1–5 The inflammatory/immune response in COPD also persists despite smoking cessation and there is a particularly enhanced inflammatory response in chronic bronchitis and acute exacerbations of COPD, all of which is consistent with a microbial mechanism underlying chronicity and exacerbations. Chronic bacterial colonisation in COPD subjects had been traditionally evaluated by cultivation-based methods of sputum and bronchoalveolar lavage (BAL), with the magnitude and types of organisms varying widely. Culture-independent analyses, such as those used in the study by Einarsson et al ,6 are providing new insights into the pulmonary microbiome of patients with COPD. This current study underscores the concept that the COPD lung harbours a microbiome distinct from that in healthy non-smokers and smokers, which is not captured completely by standard culture techniques. Overall, this study, together with complementary studies from other labs,6–13 is building a ‘research mosaic’ that is identifying the changes in the microbiome that occur during COPD and delineating their importance in the pathogenesis of the disease.

In the paper by Einarsson et al ,6 the objective was to determine whether there are …
Impact of Drug Transporters ABCB1 and ABCG2 and Regulators of Xenobiotic Transport and Metabolism Pxr and CAR Gene Polymorphisms on Clinical Efficacy of Imatinib in Chronic Myeloid Leukemia (CML)
Authors: Anna Stepien, Alessandro Martino, Federico Canzian, Daniele Campa, Angelika Stein, Joanna Gora-Tybor, Tomasz Sacha, Dorota Link-Lenczowska, Izabela Florek, Witold Prejzner, Zofia Specht-Szwoch, Malgorzata Calbecka, Marcin Rymko, Marek Dudzinski, Pawel Gaj, Tadeusz Robak, Krzysztof Warzocha, Krzysztof Jamroziak
Journal: Blood (2014)
Abstract 2862: The balance of divergent IRE1α signaling regulates pancreatic neuroendocrine tumor growth
Authors: Jenny Y. Qi, Paul C. Moore, Maike Thamsen, Rajarshi Ghosh, Micah J. Gliedt, Dustin J. Maly, Bradley J. Backes, Feroz R. Papa, Scott A. Oakes
Journal: Cancer Research (2016)

Abstract The Unfolded Protein Response (UPR) is an intracellular signaling pathway that communicates the protein folding status of the endoplasmic reticulum (ER) to the nucleus to maintain ER homeostasis. Hypoxia, nutrient deprivation, proteasome dysfunction, or sustained demands on the secretory pathway–conditions often encountered by solid tumor cells–lead to the accumulation of misfolded proteins in the ER and cause “ER stress.” However, the precise role of UPR signaling in the development and maintenance of cancer remains controversial. We reasoned that pancreatic neuroendocrine tumors (PanNETs) might be one class of solid tumor that may be particularly sensitive to protein folding stress due to their high secretory activity. The Master UPR regulator IRE1α is an ER transmembrane kinase/endoribonuclease (RNase) that acts as a critical life-death switch depending on the level of ER stress. We analyzed primary human PanNET samples for activation of UPR components and found strong evidence of ER stress and IRE1α hyperactivation in this tumor type. We used a variety of chemical-genetic tools to selectively manipulate IRE1α's homeostatic and apoptotic outputs in a PanNET xenograft model and found that the precise balance of IRE1α signaling is critical for tumor growth in vivo. Disrupting this balance by pushing the pathway in either direction is detrimental to PanNET survival. Moreover, targeting IRE1α with highly selective small molecules in a preclinical mouse model phenocopied the results of genetic manipulation. Our results indicate that IRE1α is an important regulator of PanNET cell survival and growth, and provide a strong rationale for therapeutically targeting this kinase in PanNETs and other cancers that experience high levels of ER stress. Citation Format: Jenny Y. Qi, Paul C. Moore, Maike Thamsen, Rajarshi Ghosh, Micah J. Gliedt, Dustin J. Maly, Bradley J. Backes, Feroz R. Papa, Scott A. Oakes. The balance of divergent IRE1α signaling regulates pancreatic neuroendocrine tumor growth. [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 2862.
Abstract CT077: PRECISION (Profiling Early Breast Cancer for Radiotherapy Omission): a phase II study of breast-conserving surgery without adjuvant radiotherapy for favorable-risk breast cancer
Authors: Lior Z. Braunstein, Alphonse G. Taghian, Jay R. Harris
Journal: Cancer Research (2016)

Abstract Background: Radiation therapy (RT) following breast conserving surgery (BCS) is well-known to improve outcomes for patients with invasive breast cancer. However, RT poses an inconvenience to patients and confers a small, yet real, risk of long-term adverse effects. In addition, reports have suggested that not all patients stand to benefit equally from RT, with certain disease features portending an excellent prognosis regardless of the adjuvant treatment approach. Specifically, favorable luminal A cancers exhibit a 10-year locoregional recurrence (LRR) rate of 2% following BCS and RT, suggesting very low putative risk in the absence of RT. While luminal A breast cancers are the most favorable among subtypes, robustly distinguishing them from luminal B tumors is a challenge. This trial seeks to employ a molecular profiling approach to identify favorable-risk, early-stage breast cancer patients who may feasibly omit RT following BCS. Methods: To identify a low-risk, luminal A cohort of breast cancer patients, we will employ well-characterized clinicopathologic parameters in addition to molecular profiling. Eligible patients will be 50-75 years of age and must have invasive breast cancer ?2 cm (T1), that is estrogen receptor positive, low- or intermediate-grade, without HER2 amplification, and with negative margins (no ink on tumor) following BCS. Following resection, tumor samples will undergo prediction analysis of microarray 50 (PAM50) profiling via the NanoString Prosigna assay to characterize intrinsic biologic subtype. Patients with tumors classified as luminal A (low-risk score) will be eligible for the omission of RT. The trial is a single-arm prospective cohort study designed to assess the viability of RT omission in this favorable population. The primary endpoint will be LRR at 5 years and a rate of &amp;lt;5% will be considered of interest. Projected accrual will be 345 patients to be enrolled over 4 years. Using this design, the study has 90% power to distinguish a 5-year LRR rate of 1% from 5% using a one-sample exponential test with one-sided type I error of 0.025. Secondary endpoints include 5- and 10-year recurrence rates of any type (local, regional and/or distant), disease-free survival, invasive-disease-free survival and overall survival, in addition to rates of salvage mastectomy and radiotherapy. (ClinicalTrials.gov: NCT02653755) Citation Format: Lior Z. Braunstein, Alphonse G. Taghian, Jay R. Harris. PRECISION (Profiling Early Breast Cancer for Radiotherapy Omission): a phase II study of breast-conserving surgery without adjuvant radiotherapy for favorable-risk breast cancer. [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 CT077.
Female cystectomy with orthotopic urinary diversion: Is fear of urethral recurrence justified?
Authors: Cory Michael Hugen, Gus Miranda, Jie Cai, Anne K. Schuckman, Hooman Djaladat, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2016)

e16006 Background: Orthotopic urinary diversion (OUD) following radical cystectomy (RC) is performed significantly less frequently in females compared with males. Reasons for this disparity are likely related to functional outcomes as well as fear of local urethral recurrences. We present our long-term oncologic outcomes in women with OUD. Methods: We reviewed our institutional cystectomy database to identify females who underwent RC with OUD for primary bladder cancer with curative intent from 1990-2011 with minimum of 3 year follow-up. Demographic, pathologic, complication, and outcome data were compiled and statistical analyses were performed. Results: From 1990-2011, 191 women underwent RC with orthotopic neobladder for bladder cancer with curative intent. Demographic data are shown in Table 1. The 30 and 90-day complication rates were 37.2 and 44.0%, respectively. The 30-day operative mortality rate was 1.6%. On multivariate logistic regression, only age was associated with 30-day (p<0.028) and 90-day(p<0.020) complication rates. There were 5 patients (2.6%) with positive urethral margins on final pathology of which 1 was also positive on frozen section. There was one single case of urethral recurrence in a patient who did not have a positive urethral margin. There was no association between primary tumor location (trigone, bladder neck, urethra) and the location of recurrence (distant vs local). The 5-year recurrence free and overall survival rates were 62.3 and 60.7%, respectively. Median overall survival was 9.4 years. Conclusions: RC with OUD can be performed safely with pathologic, survival, and recurrence rates similar to those in large published series of predominantly male patients. Urethral recurrence remains rare with long-term follow-up. Female patients with negative intraoperative urethral margin are candidates for orthotopic diversion. Demographic data. Mean(SD) Median Range Age 64(10) 65 33-84 Total(%) <60 52(27.2) 60-69 79 (41.4) 70-79 51 (26.7) 80-89 9 (4.7) BMI 27(6) 26 16-54 Race African American 5 (2.6) Black 7 (3.7) Caucasian 167(87.5) Hispanic 8 (4.2) Middle Eastern 3 (1.5) Other 1 (0.5) ASA Score 1-2 51 (33.6) 3-4 101(66.4) Chemotherapy Neoadjuvant 19 (10) Adjuvant 48(25.1)
Sentinel-node biopsy before or after neoadjuvant systemic treatment: The German SENTINA trial.
Authors: T. Kühn, I. Bauerfeind, T. N. Fehm, B. Fleige, G. Helms, C. Liedtke, M. Mai, G. Von Minckwitz, A. Staebler, M. Untch
Journal: Journal of Clinical Oncology (2010)

TPS114 Background: For patients with breast cancer undergoing neoadjuvant systemic treatment (NST) the optimal timing of sentinel-node biopsy (SLNB) is unclear. While adequate axillary staging prior to NST could allow for a priori tailoring of systemic treatment, SLNB after NST could spare those patients from complete axillary dissection (AD), who are free of metastases in the axilla or convert from a positive (Npos) to a negative (Nneg) axillary status following NST. For these patients, however, the reliability of SLNB to predict the axillary status remains yet to be prospectively confirmed. Methods: The German SENTINA protocol, as a substudy of the German Geparquinto neoadjuvant trial of the AGO and the German Breast Group (GBG), is a 4-arm prospective multicenter case control study designed to examine the role of SLN in patients undergoing NST. Study objectives are: 1) to compare the detection rate of SLNB before and after NST; 2) to evaluate the number of patients with involved nodes despite being clinically Nneg before NST; 3) to determine the number of patients who convert from clinically Npos to histologically Nneg after NST; 4) to evaluate the false-negative rate of SNB for patients who convert from clinically Npos to histologically SNneg after NST; 5) to determine lymphatic pathway configuration, detection rate and false-negative rate of SLNB after prior SLNB; 6) to determine the false negative rate of intraoperative frozen section before and after NST. TransSENTINA program: The SENTINA study allows for the development of prediction models that may be employed in the setting of sentinel lymph node biopsy among patients undergoing PST. For instance, the TransSentina program will enable us to develop statistical models that may predict the probability of positive non-sentinel lymph nodes following PST. Study design Arm A Before NST: clinically Nneg + negative SLN No additional axillary surgery Arm B Before NST: clinically Nneg + positive SLN Sentinel-node-guided AD Arm C Before NST: clinically Npos After NST: clinically Nneg Arm D Before NST: clinically Npos After NST: clinically Npos AD No significant financial relationships to disclose.