tbuckley/cabot-search huggingface dataset:
Differential clinical associations of <i>BRAF</i> and <i>NRAS</i> mutations among histologic types of cutaneous melanomas.
Authors: David Stockman, Michael T. Tetzlaff, Tariq Al-Zaid, Carlos A. Torres-Cabala, Amanda Dawn Bucheit, Alexander J. F. Lazar, Dawen Sui, John Andrew Jakob, Roland Bassett, Victor G. Prieto, Michael A. Davies, Jonathan L. Curry
Journal: Journal of Clinical Oncology (2013)

e20034 Background: Previous studies have investigated whether BRAF and NRAS mutation status in melanoma correlate with histologic parameters and overall survival (OS), but evaluation of mutation groups irrespective of specific mutation among histologic types of melanoma has led to variability in the reproducibility of results. We tested the hypothesis that different histologic types of melanoma (nodular [NM] and superficial spreading [SSM]) have distinct clinical associations with specific BRAF and NRAS mutations. Methods: Primary tumor histology, BRAF/NRAS mutation status, and clinical outcomes were collected for 195 patients (pts) with stage III or IV disease. Clinical associations with specific mutations were determined separately for patients with NM (n=105) and SSM (n=90) histologic types of primary cutaneous melanomas. Results: Mutational status in NM: 69 BRAF (66%), 19 NRAS (18%), &amp; 17 wild-type (WT;16%). Specific BRAF mutations in NM: V600E 50 (75%), V600K 13 (19%), V600R 4 (6%). Specific NRAS mutations in NM: Q61K 6 (32%), Q61L 2 (11%), Q61R 8 (42%); other 3 (16%). Mutation status in SSM: 45 BRAF (50%), 24 NRAS (27%), 21 WT (23%). Specific BRAF mutations in SSM: V600E 32 (71%), V600K 12 (24%), V600R 0. Specific NRAS mutations in SSM: Q61K 2 (8%), Q61L 5 (21%), Q61R 12 (50%). The distribution of specific BRAF (p=0.21) and NRAS (p=0.29) mutations between NM and SSM was not significantly different. Among NM pts, pts with activating NRAS mutations had shorter OS from the diagnosis of Stage IV melanoma than WT (HR 3.42, p=0.02) and BRAF (HR 2.40, p=0.009). There was no significant difference for BRAF pts vs WT (HR 1.43, p=0.47). Among SSM patients, neither NRAS (HR 1.3, p=0.53) nor BRAF(HR 0.54, p=0.16) were significantly associated with OS compared to WT. Comparison of patients with BRAF V600E vs V600K showed significant association for OS from stage 4 in SSM pts (HR 0.24, p=0.01), but not in NM pts (HR 0.64, p=0.36). Conclusions: The prognostic significance of BRAF and NRAS mutations on OS from stage IV differed for pts with NM and SSM primaries. Further investigation of the histologic types of melanoma with specific BRAF and NRAS mutations in a larger series is necessary to validate these apparent impacts on patient outcomes.
Nonalcoholic fatty liver disease after adjuvant therapy in nonmetastatic breast cancer.
Authors: Berna Bozkurt Duman, Meral Gunaldi, Burcak Evren Tasdogan, Cigdem Usul Afsar, Semra Paydas, Yuksel Gumurdulu
Journal: Journal of Clinical Oncology (2013)

9587 Background: Nonalcholic fatty liver disease (NAFLD) is an important health problem in the general population. Also NAFLD developing after treatment is very important in cases with cancer especially having long term life expectancy like breast cancer. The aim of this this study is to explore the rate and risk factors of NAFLD in cases with breast cancer receiving adjuvant therapy. Methods: In this prospective study, 201 cases with breast cancer treated by chemo and/or anti-hormonal treatment were included between years 2010-2012. Patients who had ductal carcinoma insitu and metastatic disease and also chronic HBV and HCV infections, chronic liver diseases with other reasons and liver cirrhosis were excluded. Body mass index (BMI) was calculated based on the following formula: weight in kilograms divided by height in meters squared. Diabetes mellitus, hypetension and hyperlipidemia, if there is in past medical history, were documented. NAFLD was deteced by abdominal ultrasound imaging and there was no history of alcohol consumption. Biopsy was performed in 2 patients who had refractory high transaminasis. Results: The patients were divided into three groups. Group I: Patients without NAFLD, Group II: Patients with NAFLD before cancer treatment, Group III: Patients with NAFLD after cancer treatment. There was no difference for age and menopousal status between three groups. Diabetes mellitus, hypetension and hyperlipidemiawere not important risk factors for the development of NAFLD after cancer treatment. (p values 0,085, 0,525, 0,207, respectively). BMI was found to be higher in cases with NAFLD and the occurrence of NAFLD was detected more frequently in obese patients (BMI&gt;30 kg/m2) (p=0,001). Tamoxifen, LHRH analougs and aromatase inhibitors were not found to be asociated with NAFLD (p=0,7, 0,8, 0,5, respectively) while the combination of fluorouracil, antharcycline and cyclophospamide was found to be a risk factor in the development of NAFLD (p=0,02). Conclusions: High BMI (both before and after treatment), obesity and fluorouracil, antharcycline and cyclophospamide combinationin were found to be important risk factors for the occurrence of NAFLD.
A phase II study of doxorubicin plus paclitaxel followed by weekly paclitaxel as neoadjuvant chemotherapy for breast cancer (SBCCSG-07)
Authors: K. Inoue, H. Takei, M. Kurozumi, K. Futsuhara, T. Kai, T. Kuroda, S. Ueda, H. Miyake, Y. Hakamada, K. Suemasu, T. Tabei
Journal: Journal of Clinical Oncology (2007)

11103 Background: The primary aim of this study was to estimate the rate of clinical and pathologic response to preoperative doxorubicin and paclitaxel followed by weekly paclitaxel in stage II /III breast cancer. Secondary objective included the determination of time to progression, over all survival, the rate of breast conservation surgery, feasibility and safty. Saitama breast cancer clinical study group-07 study (SBCCSG-07; CTR:UMIN000000504) Methods: Patients were treated with 50 mg/m 2 of doxorubicin intravenously and 150 mg/m 2 of paclitaxel both administered intravenously on day 1 every 21 days for 4 courses followed by 80 mg/m 2 of paclitaxel administered intravenously on day 1 every week for 12 courses(AP-wP). The rate of pathological, clinical response and breast conserving surgery and adverse events (CTCAE ver.3.0) were analyzed in stage II /III breast cancer. Results: From December 2005 to August 2006, 40 planned patients have been enrolled. One patient canceled chemotherapy for interstitial pneumonia. 16 patients have finished their treatment, received surgery and are evaluable for response. Clinical response rate was 81.2% (50.0%CR; 31.2%PR). Stable disease and progressive disease occurred in 2 (12.5%) patients and 1 (6.3%) patient. Four patients (25%) had pathological complete response. Conclusions: Preliminary results indicate that the AP-wP regimen feasible and very active as induction chemotherapy of operable breast cancer. Updated data including evaluation of biological markers will be presented at the meeting. No significant financial relationships to disclose.
Prospective isolation of nonhematopoietic cells of the niche and their differential molecular interactions with HSCs
Authors: Nicole Mende, Adrien Jolly, Gulce I. Percin, Marko Günther, Maria Rostovskaya, Shyam M. Krishnan, Robert A. J. Oostendorp, Andreas Dahl, Konstantinos Anastassiadis, Thomas Höfer, Claudia Waskow
Journal: Blood (2019)
VCP functions in aggresome formation
Authors: Changcheng Song, Edward Cho, Stephen Lockett, Nancy Colburn, Chou-Chi Li
Journal: Cancer Research (2006)

4683  Valosin-containing protein (VCP), an AAA family member, has been found to colocalize with the protein aggregates present in cells treated with cancer therapy and in cells derived from neurodegenerative disease samples, To understand how VCP accumulates in these protein aggregates, we studied the distribution of VCP in cells treated with proteasome inhibitors. We found that the treatment induces the formation of aggresome which contains insoluble protein aggregates, and immuno-fluorescence staining further showed that VCP, ubiquitin, proteasome, HDAC6, and γ-tubulin colocalize with the aggresome which is surrounded by vimentin. Using a VCP-GFP protein as an indicator, we then traced the distribution of VCP in the cells treated with proteasome inhibitors to study the involvement of VCP in aggresome formation. Our study showed that an HDAC6 inhibitor, stripoid, and a microtubule disruptor, nocodazole, suppress the accumulation of VCP in the aggresome, suggesting that VCP is transported into the aggresome by HDAC6 along the microtubules. Structure-functional analyses further showed that although the N domain (residues 1-200) and the C-terminal region (residues 779-806) of VCP are necessary for mediating the aggresome formation, they are not sufficient. Since VCP has been reported to physically associate with HDAC6, we propose that VCP brings the ubiquitinated protein and physically associates with HDAC6, and the complex travels along the microtubule to form the aggresome. (DHHS #NO1-CO-12400)
Barriers to accrual and enrollment in brain tumor trials
Authors: Eudocia Q Lee, Ugonma N Chukwueke, Shawn L Hervey-Jumper, John F de Groot, Jose Pablo Leone, Terri S Armstrong, Susan M Chang, David Arons, Kathy Oliver, Kay Verble, Al Musella, Nicole Willmarth, Brian M Alexander, Amanda Bates, Lisa Doherty, Evanthia Galanis, Sarah Gaffey, Thomas Halkin, Bret E Friday, Maryam Fouladi, Nancy U Lin, David Macdonald, Minesh P Mehta, Marta Penas-Prado, Michael A Vogelbaum, Solmaz Sahebjam, David Sandak, Martin van den Bent, Michael Weller, David A Reardon, Patrick Y Wen
Journal: Neuro-Oncology (2019)

Abstract Many factors contribute to the poor survival of malignant brain tumor patients, some of which are not easily remedied. However, one contributor to the lack of progress that may be modifiable is poor clinical trial accrual. Surveys of brain tumor patients and neuro-oncology providers suggest that clinicians do a poor job of discussing clinical trials with patients and referring patients for clinical trials. Yet, data from the Cancer Action Network of the American Cancer Society suggest that most eligible oncology patients asked to enroll on a clinical trial will agree to do so. To this end, the Society for Neuro-Oncology (SNO) in collaboration with the Response Assessment in Neuro-Oncology (RANO) Working Group, patient advocacy groups, clinical trial cooperative groups, including the Adult Brain Tumor Consortium (ABTC), and other partners are working together with the intent to double clinical trial accrual over the next 5 years. Here we describe the factors contributing to poor clinical trial accrual in neuro-oncology and offer possible solutions.
Opportunities, resources, and techniques for implementing genomics in clinical care
Authors: Teri A Manolio, Robb Rowley, Marc S Williams, Dan Roden, Geoffrey S Ginsburg, Carol Bult, Rex L Chisholm, Patricia A Deverka, Howard L McLeod, George A Mensah, Mary V Relling, Laura Lyman Rodriguez, Cecelia Tamburro, Eric D Green
Journal: The Lancet (2019)
CSF-1 controls cerebellar microglia and is required for motor function and social interaction
Authors: Veronika Kana, Fiona A. Desland, Maria Casanova-Acebes, Pinar Ayata, Ana Badimon, Elisa Nabel, Kazuhiko Yamamuro, Marjolein Sneeboer, I-Li Tan, Meghan E. Flanigan, Samuel A. Rose, Christie Chang, Andrew Leader, Hortense Le Bourhis, Eric S. Sweet, Navpreet Tung, Aleksandra Wroblewska, Yonit Lavin, Peter See, Alessia Baccarini, Florent Ginhoux, Violeta Chitu, E. Richard Stanley, Scott J. Russo, Zhenyu Yue, Brian D. Brown, Alexandra L. Joyner, Lotje D. De Witte, Hirofumi Morishita, Anne Schaefer, Miriam Merad
Journal: The Journal of Experimental Medicine (2019)

Microglia, the brain resident macrophages, critically shape forebrain neuronal circuits. However, their precise function in the cerebellum is unknown. Here we show that human and mouse cerebellar microglia express a unique molecular program distinct from forebrain microglia. Cerebellar microglial identity was driven by the CSF-1R ligand CSF-1, independently of the alternate CSF-1R ligand, IL-34. Accordingly, CSF-1 depletion from Nestin+ cells led to severe depletion and transcriptional alterations of cerebellar microglia, while microglia in the forebrain remained intact. Strikingly, CSF-1 deficiency and alteration of cerebellar microglia were associated with reduced Purkinje cells, altered neuronal function, and defects in motor learning and social novelty interactions. These findings reveal a novel CSF-1–CSF-1R signaling-mediated mechanism that contributes to motor function and social behavior.
Changes in pulse pressure upon exposure to electromagnetic fields modulated at specific frequencies in healthy individuals, HBsAg positive cancer-free patients (HBsAg+), and patients with advanced hepatocellular carcinoma (HCC).
Authors: Frederico Costa, Edison Roberto Parise, Brenda Pires Gumz, Tatiana Zanesco, Antonio Francisco Iemma, Alexandre Barbault, Boris Pasche
Journal: Journal of Clinical Oncology (2013)

e15155 Background: Werecently described the antiproliferative effects of low levels of electromagnetic fields, amplitude-modulated at disease-specific frequencies (AM EMF) in patients with HCC (Br J Cancer, 2011,105:640) and on HCC cells (Br J Cancer, 2012,106:307). We identified HCC-specific modulation frequencies using a patient based biofeedback approach (J Exp Clin Cancer Res, 2009,28:51). Specific frequencies cause changes in pulse pressure in patients with HCC but not in healthy individuals. The effects of AM EMF in HBsAg+ patients, a pre-malignant condition, are unknown. Methods: 17 healthy individuals and 17 patients (5 HCC and 12 HBsAg+) were exposed to 206 HCC-specific modulation frequencies ranging from 100 Hz to 21 kHz (HCC-frequencies) and 237 random chosen frequencies (non-specific frequencies) within the same frequency range. All participants were exposed to both AM EMF and each frequency was tested separately. Changes in pulse pressure were recorded as previously described (J Exp Clin Cancer Res, 2009, 28:51). Results: HCC-frequencies caused changes in pulse pressure in all HBsAg+ and patients with HCC but no changes were observed in healthy individuals. The median number of frequencies causing changes in pulse pressure in patients with HCC was 175 (range: 97-206) and 7 (range: 3-16) in HBsAg+ patients. The non-specific frequencies did not cause changes in pulse pressure in patients with HCC but it caused changes in pulse pressure in 9 HBsAg+ (75%) with a median number of responding frequencies of 2 (range: 1-6). Non-specific frequencies also caused changes in pulse pressure in 11 healthy individuals (64%) with a median number of responding frequencies of 11 (range: 1-15). The pattern of changes in pulse pressure were significant between the 3 groups (p=0.0001). Conclusions: EMF modulated at specific frequencies cause a significantly different pattern of changes in pulse pressure in the three groups. These findings provide support for the development of EMF as a new diagnostic procedure. Clinical trial information: NCT01641276.
Phase I dose escalation and PK study of thermally sensitive liposomes containing doxorubicin given during radiofrequency ablation (RFA) in patients with non-resectable primary and metastatic liver cancer
Authors: B. J. Wood, R. T. Poon, Z. Neeman, M. Eugeni, J. Locklin, S. Dromi, S. Kachala, R. Prabhakar, W. Hahne, S. K. Libutti
Journal: Journal of Clinical Oncology (2007)

15010 Purpose: This phase I dose escalation and pharmacokinetic (PK) study in patients with non-resectable primary or metastatic hepatic tumors undergoing radiofrequency ablation (RFA) uses a 30-minute IV infusion of ThermoDox (TDox) starting 15 minutes prior to RFA treatment. TDox liposomes are engineered to release doxorubicin (Dox) locally at temperatures greater than 39.5 °C. High local concentrations of Dox could allow for increased drug concentration targeted at the tumor margins in an effort to achieve improved local recurrence and tumor control near these RFA-induced thermal lesions. The phase I study goals are to determine the maximum tolerated dose and dose-limiting toxicity of TDox. Patients and Methods: Patients (pts) must be eligible for RFA for primary (HCC) or metastatic liver cancer (MLC). Main inclusion criteria are = 4 lesions and = 7 cm in greatest diameter. Dose escalation is: cohorts of 3–6 pts treated with a single dose of 20, 30, 40, 50, 60 or 70 mg/m 2 . RFA is administered via percutaneous or surgical approach. RFA treatment without TDox can be repeated for recurrent hepatic (distant or local) tumors. Patients requiring systemic chemotherapy following RFA are removed from the study. MRI, PET and contrast enhanced CT (CE-CT) scans are done pre-, one and three months post-treatment (q3 months thereafter for patients on trial). CE-CT scans are also performed immediately following RFAs. Patients are assessed for safety, PK, and lesion diameters on CT. RFA+TDox lesion diameters will be compared to patients treated by RFA alone (control) at the same institution. Results: A total of 22 pts have been treated as of January 2007 submission date (3, 6, 6, 6, 1 patients at 20, 30, 40, 50, and 60 mg/m 2 , respectively). This population includes 8 pts with HCC and 14 pts with MLC. Grade 3/4 toxicity (reversible neutropenia) has been observed to be dose dependent. 1 patient at 50 mg/m 2 has met DLT criteria. Conclusions: TDox has been safely administered in combination with percutaneous or surgical RFA procedures in 22 patients with liver tumors. There has been limited, manageable toxicity thus far. Enrollment continues as the MTD and DLT have yet to be defined. [Table: see text]
Interim Results from a Phase I/II Clinical Gene Therapy Study for Newly Diagnosed Infants with X-Linked Severe Combined Immunodeficiency Using a Safety-Modified Lentiviral Vector and Targeted Reduced Exposure to Busulfan
Authors: Ewelina Mamcarz, Sheng Zhou, Timothy Lockey, Hossam Abdelsamed, Shane Cross, Zhijun Ma, Jola Dowdy, Brandon Triplett, Mitchell J. Weiss, Byoung Y. Ryu, Elif Dokmeci, Juan Carlos Aldave, Suk See De Ravin, Benjamin Youngblood, Janel R. Long-Boyle, Michael M Meagher, Harry L Malech, Jennifer Puck, Morton Jerome Cowan, Brian Sorrentino
Journal: Blood (2017)
Regulation of expression of drug-metabolizing enzymes by oncogenic signaling pathways in liver tumors: a review
Authors: Albert Braeuning, Michael Schwarz
Journal: Acta Pharmaceutica Sinica B (2019)

Mutations in genes encoding key players in oncogenic signaling pathways trigger specific downstream gene expression profiles in the respective tumor cell populations. While regulation of genes related to cell growth, survival, and death has been extensively studied, much less is known on the regulation of drug-metabolizing enzymes (DMEs) by oncogenic signaling. Here, a comprehensive review of the available literature is presented summarizing the impact of the most relevant genetic alterations in human and rodent liver tumors on the expression of DMEs with a focus on phases I and II of xenobiotic metabolism. Comparably few data are available with respect to DME regulation by p53-dependent signaling, telomerase expression or altered chromatin remodeling. By contrast, DME regulation by constitutive activation of oncogenic signaling via the RAS/RAF/mitogen-activated protein kinase (MAPK) cascade or via the canonical WNT/β-catenin signaling pathway has been analyzed in greater depth, demonstrating mostly positive-regulatory effects of WNT/β-catenin signaling and negative-regulatory effects of MAPK signaling. Mechanistic studies have revealed molecular interactions between oncogenic signaling and nuclear xeno-sensing receptors which underlie the observed alterations in DME expression in liver tumors. Observations of altered DME expression and inducibility in liver tumors with a specific gene expression profile may impact pharmacological treatment options.
Prognostic relevance at 5 years of the early monitoring of neoadjuvant chemotherapy using FDG PET in luminal HER2-negative breast cancer.
Authors: Olivier Humbert, Alina Berriolo-Riedinger, Alexandre Cochet, Mélanie Gauthier, Celine Charon-Barra, Isabelle Desmoulins, Séverine Guiu, Michel Toubeau, Inna Dygai-Cochet, Charles Coutant, Pierre Fumoleau, Francois Brunotte
Journal: Journal of Clinical Oncology (2013)

11007 Background: To evaluate, in the luminal breast cancer subtype, the prognostic value of tumor glucose metabolism at baseline and of its changes after one cycle of neoadjuvant chemotherapy (NAC). Methods: This prospective study included 61 women with immunophenotypically defined luminal HER2-negative breast cancer treated with NAC. 18F-FDG PET was performed at baseline. Hepatic activity was used as a reference to distinguish between low-metabolic and hypermetabolic tumors. In hypermetabolic tumors, a PET exam was repeated after the first course of NAC. The relative change in the maximal Standardized Uptake Value of the tumor (ΔSUV), corresponding to the metabolic response, was calculated. Results: Forty-two women had hypermetabolic tumors at baseline, corresponding to more proliferative breast cancers with higher Ki-67 expression (p=0.017) and higher grade (p=0.04). Nineteen women had low-metabolic tumors with lower proliferation indexes. Worse overall survival was associated with larger tumor size (&gt;5cm, HR=6.52, P=0.009) and with hypermetabolic tumors achieving a low metabolic response after one cycle of NAC (ΔSUV&lt;16%, HR=10.63, P=0.004). Five-year overall survival in these poor-response patients was 49.22% (95% CI=[14.76%-76.90%]). In contrast, overall survival in women with low-metabolic tumors or hypermetabolic/good-response tumors (ΔSUV≥16%) was good, 100% and 96.15%, respectively (95% CI=[75.69%-99.45%]). Conclusions: In luminal HER2-negative breast tumors, tumor metabolism at baseline and changes after the first course of NAC are surrogate markers of patients’ survival. A subgroup of women with hypermetabolic/bad-responding tumors correlated with poor prognosis can be identified. These results may create the ability to tailor the NAC regimen to the metabolic response at an early stage.
Multiple Atrophic Papules and Plaques on the Trunk and Extremities of a Young Man
Authors: Kimberly A. Huerth, Dominique C. Pichard, Scott A. Norton
Journal: JAMA Dermatology (2019)

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