tbuckley/cabot-search huggingface dataset:
Management of dermatologic toxicities associated with epidermal growth factor inhibitors (EGFRIs) and multikinase inhibitors (MKIs).
Authors: D. Chen, J. Gordon, O. Ibrahim, Y. Balagula, A. Rademaker, D. P. West, M. E. Lacouture
Journal: Journal of Clinical Oncology (2011)

e19624 Background: EGFRIs and MKIs are targeted agents used to treat a variety of malignancies. Their specificity reduces side effect profiles, however they lead to well-recognized dermatological toxicities (dTs). These dTs include papulopustular rash (PPR), xerosis, pruritus, hand-foot skin reaction and paronychia. Current management strategies of these dTs are based largely on anecdotal evidence. We use experience from our SERIES clinic, a referral center for anticancer therapy dTs, to help develop evidence-based treatment recommendations. Methods: A retrospective chart review was conducted for patients receiving the following: cetuximab, panitumumab, erlotinib, lapatinib, sorafenib, or sunitinib between July 2005 and June 2008. Response to treatment was defined as the best recorded response during the study period. Response rate was defined as percentage of patients receiving treatment that had either a partial or full response. Treatments for these dTs were categorized into: topical antibiotics/antifungals (TAA), topical corticosteroids/immunomodulators (TCI), topical moisturizers (TM), oral antibiotics/antifungals (OAA), systemic corticosteroids/immunomodulators (SCI), retinoids or oral doxycycline. Results: A total of 217 patients received targeted therapy and were treated for an associated dT. Patients who developed PPR were analyzed (n=169). The best response rate was seen with retinoids (100%, n=7), versus a 75% response rate in patients who received other management (n=162). Two other treatments had ≥80% response rate: TAA (85%, n=48) and TM (80%, n=59). Patients receiving doxycycline and TCI still had a higher response rate compared to those receiving other therapies (77%, n=125, p=0.84 and 78%, n=162, respectively). Patients who received OAA (n=145) and SCI (n=25) had a lower response rate than patients receiving other therapies (63% and 74% versus 79% and 88%, respectively). Conclusions: Although SCI and OAA had an inverse response rate compared to other treatments, the majority of treatments utilized for dT management showed response rates ≥77%.
216. TLR9-Targeted STAT3 Silencing Abrogates Immunosuppressive Activity of Myeloid-Derived Suppressor Cells from Prostate Cancer Patients
Authors: Dewan Md S. Hossain, Dayson Moreira, Jeremy Jones, Sumanta K. Pal, Marcin Kortylewski
Journal: Molecular Therapy (2015)

Recent advances in immunotherapy of advanced human cancers underscored the need to eliminate tumor-induced immunosuppression. The myeloid-derived suppressor cells (MDSCs) are important negative regulators of T cell responses in advanced solid tumors, such as prostate cancers. Targeting MDSCs proved challenging due to heterogeneity and phenotypic similarities between myeloid cell lineages. Here, we identify a population of Lin–CD15HICD33LO granulocytic MDSCs that accumulate in patients' blood during prostate cancer progression from localized to metastatic disease. The prostate cancer-associated MDSCs potently inhibit autologous CD8+ T cell proliferation, IFNg and Granzyme-B production. The circulating MDSCs have high levels of activated STAT3, a central immune checkpoint regulator. As shown by immunofluorescent microscopy, the CD15+/pSTAT3+ cells are also important component of immune infiltrate in primary tumor and tumor-draining lymph node tissues in these patients. We previously generated an original strategy to silence genes specifically in TLR9+ cells using naked CpG-siRNA conjugates. Here, we demonstrate that the CpG-STAT3siRNA is quickly internalized by human MDSCs effectively reducing STAT3 expression. The TLR9-dependent STAT3 blocking abrogates immunosuppressive effects of patients-derived MDSCs on CD8+ T cells. Our further studies demonstrated that these effects resulted from reduced expression and enzymatic activity of Arginase-1, a downstream STAT3 target gene and T cell inhibitor. Overall, we demonstrate the feasibility of using targeted STAT3 blockade to alleviate MDSC-mediated immunosuppression without depletion of myeloid cells in prostate cancer patients. We anticipate that further development of this oligonucleotide strategy will generate safer and more effective immunotherapy for advanced prostate cancers and potentially other solid tumors.
An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Richard B Warren, Ulrich Mrowietz, Ralph von Kiedrowski, Johannes Niesmann, Dagmar Wilsmann-Theis, Kamran Ghoreschi, Ina Zschocke, Thomas M Falk, Norbert Blödorn-Schlicht, Kristian Reich
Journal: The Lancet (2016)
Abstract 3848: Subtype-specific DNA damage dependent and independent functions of damage repair proteins confer chemo-resistance to leukemia
Authors: Sameer Salunkhe, Ekjot Kaur, Ashwin Ramaswamy, Ketaki Patkar, Shilpee Dutt
Journal: Cancer Research (2015)

Abstract Resistance to chemotherapy is a major challenge in the field of leukemia. Since, cancer cells can acquire resistance to DNA damage based therapy by modulating DNA Damage Repair (DDR) pathways, an in-depth understanding of DDR is important for novel drug discoveries. Hence, to understand relation between DDR and resistance we used doxorubicin resistant sub-line (K562-R) of K562 and Mitoxantrone resistant sub-line (HL60/MX) of HL60 as a model system. We show that lethal doses of Mitoxantrone to HL60 and HL60/MX do not induce DNA DSBs (double strand breaks) and accordingly there is no activation of Chk2, although there is equal uptake of drug in both, sensitive and resistant cell types. Since Mitoxantrone produce DSBs by targeting TOP2B, we checked the expression of TOPB2 and found significant decrease in the levels of topoisomerase 2 B (TOP2B). Moreover, negative regulator of TOPB2, mir 21-5P is upregulation in untreated HL60/MX explaining the absence of DSBs in HL-60/MX with Mitoxantrone treatment. Surprisingly, although there are no DSBs induced, we find high levels of DNA-PKcs, MRE11 and Rad50 in HL-60/MX. Furthermore, inhibition of DNA-PKcs re-sensitizes HL-60/MX cells to Mitoxantrone, suggesting a DNA damage independent role for DNA-PK in HL-60/MX cells. Recently DNA-PKcs is shown to play key role in fat metabolism. Indeed we find significant differences in the metabolism of HL60 and HL-60/MX where HL-60 cells use glucose but HL-60/MX cells show reduced glucose and glutamine metabolism and an over expression of fatty acid synthase. However link between DNA-PKcs over expression and differential metabolism in these cells still need to be explored. Interestingly, in contrast to HL60 model, Doxorubicin does induce equal DSBs in K562 and K562-R cells. However K562-R cells hyperactivate ATM and Chk2 to repair their DNA and survive. Importantly, we show that K562 start to show elevated activation of ATM and Chk-2 as early as two rounds of drug treatment. Accordingly, ATM inhibition leads to induction of apoptosis in resistant K562 cells. In conclusion, we show that K562 and HL60 cells use the DNA double strand break repair proteins in DNA damage dependent and independent pathways to acquire resistance to DSB inducing chemo therapeutics. Our data also highlight the importance of considering subtype specific therapeutics in leukemia. Note: This abstract was not presented at the meeting. Citation Format: Sameer Salunkhe, Ekjot Kaur, Ashwin Ramaswamy, Ketaki Patkar, Shilpee Dutt. Subtype-specific DNA damage dependent and independent functions of damage repair proteins confer chemo-resistance to leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3848. doi:10.1158/1538-7445.AM2015-3848
Lenalidomide Plus Dexamethasone Versus Lenalidomide Plus Melphalan and Prednisone: A Case-Control Study in Newly Diagnosed Elderly Myeloma Patients.
Authors: Francesca Gay, S. Vincent Rajkumar, Patrizia Falco, Shaji Kumar, Angela Dispenzieri, Morie Gertz, Francesco Di Raimondo, Martha Q. Lacy, Claudia Crippa, Francis Buadi, Antonietta Falcone, Suzanne R Hayman, Nicola Giuliani, Kristen E Detweiler Short, Pellegrino Musto, Vivek Roy, Paolo Corradini, Rafael Fonseca, Maria Teresa Petrucci, Philip R Greipp, Mario Boccadoro, A. Keith Stewart, Antonio Palumbo
Journal: Blood (2009)
OP37THREE-DIMENSIONAL MRI ASSESSMENT OF DIFFUSION AND PERFUSION STRATIFIES OVERALL SURVIVAL IN PATIENTS WITH GLIOBLASTOMA
Authors: Natalie R. Boonzaier, Jiun-Lin Yan, Tomasz Matys, Timothy J. Larkin, Stephen J. Price
Journal: Neuro-Oncology (2015)

INTRODUCTION: Imaging assessment of glioblastoma (GBM) currently involves 2-dimensional analysis of conventional T1- and T2-weighted images. This study used advanced imaging to assess 3-dimentional (3-D) patterns of diffusion and perfusion spread in GBM. METHOD: 25 patients with retrospectively-confirmed GBM underwent pre-operative MRI. Maps of apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) were processed and regions of interest (ROIs) were developed using thresholds of low ADC with overlapping high rCBV. ROIs were visually assessed using interactive 3-D images. Patterns of spread within the T1- and T2-weighted abnormality (entire lesion) were qualitatively categorised and the presence or absence of ‘ROI clusters' within different tumour components was also observed. Overall survival (OS) was assessed using Kaplan-Meier statistics with significance accepted at p = 0.05 with statistical power > 95%. RESULTS: Four 3-D phenotypes were identified based on ROI pattern of spread: localised (4/25 patients, 16%), showing minimal and confined ROI spread; diffuse (19/25, 76%), shapeless ROI spread throughout the ‘entire lesion'; massive (2/25, 8%), ROI composing most of the ‘entire lesion'; and encapsulated (5/25, 20%), ROI diffusely spreading around a spherical component. The presence of ‘ROI clusters' was observed in CE (12/25, 48%) and necrotic (6/25, 24%) regions. Kaplan-Meier statistics found that an encapsulated ROI shape was associated with poor OS (p < 0.001). The presence of ‘ROI clusters' within CE was associated with improved survival patterns (p < 0.001). CONCLUSION: Qualitatively assessing 3-D patterns of ADC and rCBV spread stratifies overall survival in patients with GBM.
Acute Leukemia and Myelodysplastic Syndrome: Outcomes in Patients with Chronic Lymphocytic Leukemia (CLL) At MD Anderson Cancer Center (MDACC)
Authors: Francesco Paolo Tambaro, Guillermo Garcia-Manero, Stefan Faderl, Susan O'Brien, Alessandra Ferrajoli, Jan A. Burger, Long Xuan Trinh, Susan Lerner, Hagop M. Kantarjian, Michael J Keating, William G. Wierda
Journal: Blood (2011)
PTU-004 Incidental findings in the UK Bowel Cancer Screening Programme
Authors: G Chakrabarty, G Sadler, M Bouwer, R Pollok, C Groves, D Forton, R Leicester, A Poullis
Journal: Gut (2010)

<h3>Introduction</h3> The UK National Bowel Cancer Screening (BCS) Programme aims to identify individuals between the ages of 60 and 70 years at risk for bowel cancer. Those with a positive faecal occult blood test (FOBT) are offered screening colonoscopy. We aimed to quantify and characterise the incidental findings in individuals attending for colonoscopy. <h3>Methods</h3> We audited the St George9s Hospital BCS database from Nov 2006 to Sep 2009. We determined the various incidental findings and symptoms in this cohort. Case notes of patients under local follow-up were reviewed. <h3>Results</h3> 1286 patients have been screened (744 male, 542 female). Colorectal cancer was diagnosed in 128 cases (9.95%). 61 patients had findings other than colonic adenoma or colorectal cancer. 31 individuals (50.8%) were found to have inflammatory bowel disease (IBD) (21 Male, 10 Female). Out of them nine had ulcerative colitis (29%), 11 Crohn9s disease (35.4%) and in 11 cases IBD was of indeterminate subtype (35.4%). Colitis was a pre-existing diagnosis in eight (25.8%) patients, none of who were receiving treatment at the time of colonoscopy. 11 cases of radiation proctitis and one radiation enterocolitis was found (19.6%). All radiation proctitis was due to radiotherapy for prostate cancer and the enterocolitis due to radiotherapy for lymphoma. We identified three cases of neuroendocrine tumours (4.9%) and one granular cell tumour. Three neuroendocrine tumours were found in the rectum and the granular cell tumour in the caecum. We found seven cases of angiodysplasia (11.5%), and their distribution was 2 in rectum, 2 in caecum, 2 in right colon and 1 in transverse colon. Other incidental findings were: 3 solitary rectal ulcer syndrome, 1 Peutz-Jeghers syndrome, 1 threadworm infection, 1 lipoma and 1 case of lymphoid polyp. None of the cases had coexisting colorectal cancer. <h3>Conclusion</h3> The relative risk of having IBD in the BCS cohort is approximately nine times greater than in the background population. The majority of IBD patients seemingly had not been investigated previously. These findings suggest that a small but significant group of patients with IBD remain undiagnosed into the seventh decade of life. Radiation colitis and angiodysplasia are also significant cause of positive FOBT. The risk of neuroendocrine tumour (0.23%) in the BCS cohort is hundred times more than the background population. Our findings suggest there has been, prior to the BCS programme, a significant proportion of Colonic tumours other than colorectal cancer that were not identified.
Abstract 1500: Syndecan-1 targeted mesoporous silica-coated gold nanorods act as theranostic agents for <i>in vivo</i> detection of orthotopic pancreatic tumors using multispectral optoacoustic tomography
Authors: Anil Khanal, Charles W. Kimbrough, Nichola C. Garbett, Joseph A. Burlison, William E. Grizzle, Lacey R. McNally
Journal: Cancer Research (2015)

Abstract Detection of pancreatic cancer is especially challenging in comparison to many cancers due to severe limitations of both contrast agent delivery to pancreatic tumors and limitations of traditional imaging techniques such as poor resolution and low depth penetration. Theranostic nanoparticles encompassing both therapeutic and diagnostic capabilities can overcome limitations associated with conventional cancer diagnosis and therapy. In this study, we compared mesoporous silica coated gold nanorods (MS-GNR) and polyacrylic acid coated gold nanorods (PAA-GNR) targeted to tumor cells via Syndecan-1 ligand for detection of orthotopic pancreatic cancer in vivo. Because one of the major difficulties for translation of theranostic nanoparticles to the clinic is an inability track performance of nanoparticles in vivo, especially at depths required of orthotopic tumors, we will overcome this impediment by utilizing multispectral optoacoustic tomography (MSOT). Multispectral optoacoustic tomography provides high optical contrast images at a microscale resolution and reasonable penetration depth by combining the advantages of optical (high sensitivity) and ultrasound (increased depth of penetration). Our results indicate that the Syndecan-1 MS-GNR were superior to Syndecan-1 PAA-GNR, untargeted MS-GNR, or untargeted PAA-GNR as contrast agents to identify pancreatic cancer in vivo via MSOT. The Syndecan-1 MS-GNR particles also resulted in reduced off-target accumulation compared to Syndecan-1 PAA-GNR. This study is among the first to evaluate biodistribution of ligand-targeted nanoparticles in the context of orthotopic pancreatic cancer using multispectral optoacoustic tomography. The MS GNR can be utilized as theranostic platform due to ability of mesoporous silica to encapsulate drug and easy surface modification with cancer recognizing motif peptide. Citation Format: Anil Khanal, Charles W. Kimbrough, Nichola C. Garbett, Joseph A. Burlison, William E. Grizzle, Lacey R. McNally. Syndecan-1 targeted mesoporous silica-coated gold nanorods act as theranostic agents for in vivo detection of orthotopic pancreatic tumors using multispectral optoacoustic tomography. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1500. doi:10.1158/1538-7445.AM2015-1500
Abstract 2035: Targeting the hyperactive polyisoprenylated monomeric G-proteins functions in pancreatic cancer
Authors: Augustine T. Nkembo, Olufisayo Salako, Rosemary Poku, Tryphon Mazu, Byron Aguilar, Hernan Flores-Rozas, Nazarius S. Lamango
Journal: Cancer Research (2015)

Abstract Pancreatic cancer (PC) incidence is a major healthcare problem as the five-year survival rate remains below 5%. Over 90% of PC cases harbor the hyperactive K-Ras mutant protein. Polyisoprenylation processes facilitate the proper localization and signaling of K-Ras whose gain-in-function mutations drive uncontrolled cell survival, differentiation and proliferation. Efforts to target and disrupt this pathway and signaling for cancer therapy have been unsuccessful. The purpose of this study was to determine the effects of polyisoprenylated cysteinyl amide inhibitors (PCAIs) as a potential novel class of small molecules for PC therapy. The effects of the PCAIs on cell viability, proliferation, survival, apoptosis, migration, colony formation and cytoskeletal F-actin organization in four human PC cell lines representing wild type K-Ras (BxPC-3), Mutant K-Ras (MIAPaCa-2 and Panc10.05) and mucins (HPAF-II) were examined. PCAIs induced apoptosis with EC50 values ranging from 2.4 to 5.1, 2.0 to 7.3, 1.8 to 3.3 and 7.0 to 33 μM in MIAPaCa-2, BxPC-3, Panc10.05 and HPAF-II cells, respectively. At 0.2 μM, PCAIs arrested MIAPaCa-2 cells at the G0/G1 phase and significantly inhibited cell migration in the wound-healing assay. MIAPaCa-2 cells transfected with a plasmid expressing a protein that fluoresces red when interacting with F-actin were used to determine the PCAIs effects on F-actin organization. Treatment with PCAIs disrupted the F-actin structures causing the cells to shrink and become rounded upon treatment with PCAIs concentrations as low as 0.2 μM. The ability of PCAIs to disrupt these biological phenomena in pancreatic cancer cells shows that PCAIs may halt progression in tumors with the hyperactive K-Ras mutations. Citation Format: Augustine T. Nkembo, Olufisayo Salako, Rosemary Poku, Tryphon Mazu, Byron Aguilar, Hernan Flores-Rozas, Nazarius S. Lamango. Targeting the hyperactive polyisoprenylated monomeric G-proteins functions in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2035. doi:10.1158/1538-7445.AM2015-2035
A national prospective survey of breakthrough cancer pain characteristics and treatments in France 10 years after the preliminary study (ASCO 2000).
Authors: J. F. Morere, P. Poulain, M. Filbet, I. Krakowski, A. Serrie, C. Delorme, D. Ammar, F. Scotte, V. Grange
Journal: Journal of Clinical Oncology (2011)

e19661 Background: Breakthrough cancer pain (BTcP) is frequent in cancer patients (75%) and is still underrecognized and undertreated. This survey was aimed to evaluate BTcP prevalence and treatment 10 years after the initial survey published by Di Palma and coll (Di Palma M., Poulain P., Filbet M. and coll. ASCO 2000 [abstract 2406] and Douleurs, 2005; [6, 2]: 75-80.). Methods: This prospective, national, multicenter survey was conducted from march to september 2010 in 45 centers treating painful cancer patients: Oncology, palliative care and pain centers, public or private. Practitioners evaluated during 1 week all patients with severe cancer pain requiring opioids, using patient and observer-rated measures. Results: 512 patients, aged 62.1±13.3 (mean ± SD) were evaluated. Patients were male (52.2%), hospitalized (48.2%), in day care (18.1%) or ambulatory (33.7%). Primary cancer was lung (26.9%), digestive (17.5%) and breast (16.5%). Cancer was metastatic for 83.3% of patients. Around the clock medication was morphine (26.2%), fentanyl (38.7%) or oxycodone (33.0%), and pain was adequately controlled for 64.3% of patients. Over a period of 7 days, BTcP were observed in 85.3% of patients. 77.7% presented 1 to 4 BTcP per day and 22.3% more than 4 BTcP per day. Pain duration was less than 15 min (24.3%), from 15 to 30 minutes (40.5%), and more than 30 min (35.1%). Mean (SD) intensity of BTcP episodes was 7.1±1.7 (VAS). Only 24.5% of patients treated BTcP with transmucosal opioids. Other BTcP treatments were oxycodone (35.0%) and morphine (37.3%). Adequate and quick pain relief was achieved within 15 min for 60.8% (fentanyl 68.9%, oxycodone 57.2%, morphine 59.6%). 63.6% of patients reported important impairment in daily life, the mean number of days with BTcP occurrence during the week was 4.8±2.8. Conclusions: This study confirm the impact of BTcP not only due to the pain characteristics but also in terms of the interference with the activities of daily living. The management of BTcP remains inadequate and pain relief is still not achieved after 15 min for 40% of patients. Use of Rapid Onset Opioïds (ROO) and both patient and practitioners education are needed.
Potent Alloreactive Effector T Cells Cause Limited Damage to Non-Hematopoietic Tissues Under Non-Inflammatory Conditions, Despite Proper Expression of the Relevant Target Antigens.
Authors: Boris van der Zouwen, Alwine B. Kruisselbrink, Peter A. Von Dem Borne, Roelof Willemze, J.H. Frederik Falkenburg, Inge Jedema
Journal: Blood (2009)
BMET-27CEREBRAL METASTASIS OF BREAST CANCER IS FACILITATED BY THE T CELL RESPONSE INVOLVING GBP1
Authors: Dana Mustafa, Anieta Sieuwerts, Marcel Smid, Theo Luider, Reno Debets, John Martens, John Foekens, Johan Kros
Journal: Neuro-Oncology (2015)

INTRODUCTION: Cerebral metastasis usually defines the terminal stage of disease for women suffering from disseminated breast cancer. Understanding the molecular basis of the tumor cells crossing the blood-brain barrier is crucial to prevent metastasis to the brain. THE AIM: To identify pathways involved in the development of cerebral metastasis in breast cancer patients. MATERIAL AND METHOD: The expressional profiles of FFPE primary breast cancer samples of patients who suffered from estrogen receptor negative breast cancer with cerebral metastases were compared to the profiles of women with metastases to other sites. Illumina WG-DASL RNA platform was used. The most prominent emerging pathway was validated by immunohistochemistry. Functional studies using human breast cancer cell lines in an in vitro BBB model were carried out, and by using mass spectrometry proteins responsible for crossing of tumor cells through the BBB were identified. The identified proteins were validated in the original samples used for discovery. RESULTS: The T cell response pathway was the most significant for the formation of cerebral metastasis of breast cancers. Immunohistochemistry confirmed the presence of higher numbers of T cells in the tumor samples of women who developed cerebral metastases. Following co-culturing with T cells, the ability of tumor cells to cross the BBB significantly increased. Proteomics comparison identified 18 candidate proteins expressed in the tumor cells which are associated with the ability of crossing the BBB. Searching for these proteins in the original gene expression profiles of the primary breast cancer samples highlighted the involvement of GBP1 protein in brain metastasis, and the expression of the GBP1 protein was confirmed to be exclusively expressed in samples of patients who developed brain metastases. CONCLUSION: T cell response mediates ER- breast cancer metastasis to the brain. This discovery may open new therapeutic opportunities based on the immune therapy field.