tbuckley/cabot-search huggingface dataset:
<i>MDM2</i> Derived from Dedifferentiated Liposarcoma Extracellular Vesicles Induces MMP2 Production from Preadipocytes
Authors: Lucia Casadei, Federica Calore, Danielle A. Braggio, Abeba Zewdu, Ameya A. Deshmukh, Paolo Fadda, Gonzalo Lopez, Martin Wabitsch, Chi Song, Jennifer L. Leight, Valerie P. Grignol, Dina Lev, Carlo M. Croce, Raphael E. Pollock
Journal: Cancer Research (2019)

Dedifferentiated liposarcoma (DDLPS) is frequently diagnosed late, and patients typically respond poorly to treatments. DDLPS is molecularly characterized by wild-type p53 and amplification of the MDM2 gene, which results in overexpression of MDM2 protein, a key oncogenic process in DDLPS. In this study, we demonstrate that extracellular vesicles derived from patients with DDLPS or from DDLPS cell lines are carriers of MDM2 DNA that can be transferred to preadipocytes, a major and ubiquitous cellular component of the DDLPS tumor microenvironment, leading to impaired p53 activity in preadipocytes and increased proliferation, migration, and production of matrix metalloproteinase 2; treatment with MDM2 inhibitors repressed these effects. Overall, these findings indicate that MDM2 plays a crucial role in DDLPS by enabling cross-talk between tumor cells and the surrounding microenvironment and that targeting vesicular MDM2 could represent a therapeutic option for treating DDLPS. SIGNIFICANCE: Extracellular vesicles derived from dedifferentiated liposarcoma cells induce oncogenic properties in preadipocytes.
Hidden Markov models lead to higher resolution maps of mutation signature activity in cancer
Authors: Damian Wojtowicz, Itay Sason, Xiaoqing Huang, Yoo-Ah Kim, Mark D. M. Leiserson, Teresa M. Przytycka, Roded Sharan
Journal: Genome Medicine (2019)

Knowing the activity of the mutational processes shaping a cancer genome may provide insight into tumorigenesis and personalized therapy. It is thus important to characterize the signatures of active mutational processes in patients from their patterns of single base substitutions. However, mutational processes do not act uniformly on the genome, leading to statistical dependencies among neighboring mutations. To account for such dependencies, we develop the first sequence-dependent model, SigMa, for mutation signatures. We apply SigMa to characterize genomic and other factors that influence the activity of mutation signatures in breast cancer. We show that SigMa outperforms previous approaches, revealing novel insights on signature etiology. The source code for SigMa is publicly available at https://github.com/lrgr/sigma .
Obese Individuals with and without Type 2 Diabetes Show Different Gut Microbial Functional Capacity and Composition
Authors: Louise B. Thingholm, Malte C. Rühlemann, Manja Koch, Brie Fuqua, Guido Laucke, Ruwen Boehm, Corinna Bang, Eric A. Franzosa, Matthias Hübenthal, Ali Rahnavard, Fabian Frost, Jason Lloyd-Price, Melanie Schirmer, Aldons J. Lusis, Chris D. Vulpe, Markus M. Lerch, Georg Homuth, Tim Kacprowski, Carsten O. Schmidt, Ute Nöthlings, Tom H. Karlsen, Wolfgang Lieb, Matthias Laudes, Andre Franke, Curtis Huttenhower
Journal: Cell Host & Microbe (2019)
Proteomic analysis of lung cancer tumors
Authors: T. Kikuchi, P. P. Massion, Y. Shyr, N. K. Altorki, A. J. Dannenberg, M. Li, A. Gonzalez, P. Chaurand, R. Caprioli, D. P. Carbone
Journal: Journal of Clinical Oncology (2006)

7028 Background: In this study we assess the utility of direct tumor tissue MALDI-MS in a large prospective collection of surgically resected lung cancers to distinguish cancer from non-cancer, histology, occult lymph node involvement, and survival. Methods: 175 non-small cell lung cancer specimens and 62 histologically normal lung tissues obtained at the time of surgery were used in this analysis. Twelve micron thick frozen sections were placed on conductive glass slides. Sections were stained with Cresyl Violet and matrix applied to areas identified by a pathologist under microscopic guidance as containing greater than 80% tumor before three separate areas involved with tumor was analyzed by MALDI MS. Relative intensities of selected peaks were used for class comparison. A class prediction model was built based on the weighted flexible compound covariate method of analysis (WFCCM). Results: We created a prediction model from a training cohort consisting 81 tumors and 19 histologically normal tissue samples. A total of 221 peaks were used for statistical analysis. In tumor/normal discrimination, 46 peaks were used for the prediction model (p&lt;0.0001), while, 22 were used (p&lt;0.005) to predict histology, 11 (p&lt;0.05) to predict nodal involvement, and 14 (p&lt;0.005) in survival prediction. Using these prediction models, classification accuracy was 90% in normal/tumor discrimination, 81.8% in histology and 61.7% in nodal involvement prediction. In the survival prediction model, patients with longer than median survival could be distinguished from those with shorter than median survival (p&lt;0.0001, Log-rank test). We then validated the same features in a blind test set from the remaining 93 tumors and 43 normals. For tumor/normal discrimination, prediction accuracy in test cohort was 94.3%. Histology prediction accuracy was 93.9% in predicting squamous cell carcinoma. Nodal involvement prediction accuracy was 49.3%. Longer or shorter median survival was also predicted in this set with statistical significance p&lt;0.08. (Log rank test). Conclusion: We report the analysis of a large set of tumor and normal samples by MALDI MS and confirm similar accuracy in tumor/normal, histology and survival discrimination to previous our report. This project was supported by the Lung SPORE P50 CA90949 (DPC) and NCI 5R33CA86243 (RMC). No significant financial relationships to disclose.
Inhibition of ROS-Induced Nrf2 Antioxidant Pathway Activation May Explain Synergy between Venetoclax and Hypomethylating Agents Against Acute Myeloid Leukemia
Authors: Le Xuan Truong Nguyen, Estelle Troadec, Arjun Kalvala, Dinh Hoa Hoang, Domenico Viola, Stephen J. Forman, Guido Marcucci, Vinod Pullarkat
Journal: Blood (2017)
Prognostic analysis of Chinese patients with metastasic renal cell cancer (mRCC) receiving sorafenib: A multicenter retrospective study.
Authors: Fang Guo, Xiaodong Xie, Zhaozhe Liu, Xishuang Song, Qifu Zhang, Xiangbo Kong, Changfu Li, Zhenhua Li, Chengge Li, Shuxian Qu, Xuefeng Liang, Zhendong Zheng, Ying Piao
Journal: Journal of Clinical Oncology (2013)

e15582 Background: This study was to investigate long-term efficacy of sorafenib and survival-related factors in Chinese patients with mRCC. Methods: 406 consecutive patients enrolled in this study between Oct. 2006 and Oct. 2009 from 6 comprehensive cancer centres in China. All cases were diagnosed as mRCC histopathologically without exception. 400mg sorafenib was orally taken twice daily until PD, death or intolerable toxic reaction. The primary endpoint was OS. The secondary endpoints were PFS and survival-related factors such as gender, age, ECOG PS, previous therapy and primary metastatic lesions. Data was analyzed using the SPSS statistical software. OS and PFS curves were output using the Kaplan-Meier method. Clinical parameters were included on univariate and multivariate analysis to evaluate associations with OS and PFS by the log-rank test and Cox proportional hazard models, P&lt;0.05 (two-sided) was considered statistically significant. Results: 131 patients were available for survival analysis, including 96 males and 35 females. The median age was 60 years old. The median follow-up periods were 16.9 months. The median OS was 16.1 months. 1-year, 2-year and 3-year survival rates were 64.9%, 35.9% and 5.3%, respectively. The median PFS was 10.5 months. Univariate analysis demonstrated that OS was significantly associated with ECOG PS, metastatic lesions and previous therapy, whereas PFS was merely associated with ECOG PS and previous therapy. Multivariate analysis suggested that ECOG PS and previous therapy were independent prognostic factors for OS(P=0.004, P=0.019) and PFS (P=0.000, P=0.003), metastatic lesions was merely independent prognostic factor for OS (P=0.003). In the subgroup of patients with visceral metastasis, patients with lung metastasis alone had better prognosis than those with liver metastasis or dimerous metastasis. Conclusions: This long-term study demonstrated that sorafenib had good effects on Chinese patients with mRCC, especially for patients with lung metastasis alone. ECOG PS, metastatic lesions and previous therapy could be important parameters for survival and need attention in future.
Retrospective analysis of sorafenib as first or second target therapy in mRCC patients in Italian centers: An update.
Authors: Lisa Derosa, Angela Gernone, Franco Morelli, Teodoro Sava, Fable Zustovich, Lorena Rossi, Vittorio D. Ferrari, Roberto Sabbatini, Donatello Gasparro, Alessandra Felici, Stefano Cascinu, Nicola Calvani, Giovanni Lo Re, Mimma Rizzo, Roberto Iacovelli, Sergio Bracarda, Camillo Porta, Enzo Galligioni, Alessio Aligi Cogoni, Giuseppe Procopio
Journal: Journal of Clinical Oncology (2013)

e15524 Background: With several agents available for the treatment of metastatic renal cell carcinoma (mRCC) a better understanding of their use in daily clinical practice is fundamental in the decision-making process. Methods: The REtrospective analysis of Sorafenib (So) as 1st or 2nd targET therapy (RESET) in mRCC was a retrospective, observational field study that assessed the use and safety of So in clinical practice in Italian centers. Treatments were determined by physicians per local prescribing guidelines. Patients (pts) treated with So single agent as 1st or 2nd target therapy (TT) for mRCC between 1st Jan 2008 and 31st Dec 2010 were eligible for inclusion. Endpoints included safety, overall survival (OS), progression-free survival, response rate and treatment duration. Subgroup analyses included age, ECOG performance status, prior therapy, number of metastases and line of TT with So. Results: From Feb to Jul 2012, 358 pts from 37 Italian centers were enrolled. The most common ≥ grade 3 drug-related adverse events were hand-foot skin reaction (6.7%), rash (2.2%), hypertension, fatigue and diarrhea (1.7% each). In the overall population, median OS was 17.2 months (mos) (95% CI 15.4 – 19.6 mos) and median PFS was 5.9 mos (95% CI 4.9-6.7 mos). Median duration of treatment with So was 5.03 mos. Disease control (complete response + partial response + stable disease) was observed in 198(56%) pts. In pts receiving So as first or as second TT median OS was 19.9 mos (95% CI 15.9-25.3 mos) and 16.3 mos (95% CI 13.0-18.2 mos) respectively. In the subgroup of pts treated with So 1st TT followed by sunitinib (Su) 2nd TT (44 pts) and Su 1st TT followed by So 2nd TT (173 pts), median OS was 30.4 mos (95% CI 22.0-34.8 mos) and 16.6 mos (95% CI 13.1-18.2 mos) respectively. There were 269(76%) pts that received a total of 2 lines of therapy for mRCC, 133(38%) pts 3 lines and 43(12%) pts 4 lines of therapy. Conclusions: The efficacy and safety profile of So in the setting of Italian community-based daily clinical practice was similar to data reported in prospective clinical trials. The efficacy of So was observed in both the subgroups of pts receiving So as either the first or second TT for mRCC, with intriguing OS data in first line.
CD98hc (SLC3A2), a novel biomarker correlating with grade of malignancy in renal cell cancer.
Authors: Marina Pöttler, Andrea Aaitel, Manuela Schmidinger, Christoph Zielinski, Gerald Prager
Journal: Journal of Clinical Oncology (2012)

e15083 Background: In a variety of malignant diseases certain malignant markers either predict treatment response towards systemic therapies or have a prognostic impact for cancer patients. While a variety of such actionable as well as treatable targets have been characterized, although only in certain cancers, in renal cell cancer (RCC) no prognostic markers have so far been identified. Thus, grading according to the S.A. Fuhrman grading system from 1982 is the only prognostic feature and currently widely considered for treatment assessment. Methods: Paraffin-embedded tumor tissue sections derived from clear cell RCCs were immuno-histochemically analyzed for expression of embryonic transmembrane antigen CD98hc (SLC3A2). Expression levels were semi-quantitative analyzed and results were correlated with grade of differentiation, using the widely accepted Fuhrman classification. Results: We found that grade of malignancy of ccRCCs were directly correlated with high CD98hc expression levels. Semi-quantivative analyses revealed that 0 % (0/2) of grade 1 ccRCC, 70.0 % of grade 2 ccRCC (14/20), 86.6 % of grade 3 (26/30) and 100 % of grade 4 (10/10) were CD98hc positive. (p &lt; 0.01, Qui-Quadrat Pearson test, n = 62). In contrast, tumor stage as determined by the WHO TNM system did not correlate with CD98hc levels (p &gt; 0.05). Conclusions: From these data, we conclude that CD98hc is expressed in RCCs, whereby the extent of expression is likely to correlate directly with grade of malignancy. In ccRCCs, CD98hc might represent a novel and reliable marker for more aggressive and less differentiated subtypes.
Cancer statistics for adults aged 85 years and older, 2019
Authors: Carol E. DeSantis, Kimberly D. Miller, William Dale, Supriya G. Mohile, Harvey J. Cohen, Corinne R. Leach, Ann Goding Sauer, Ahmedin Jemal, Rebecca L. Siegel
Journal: CA A Cancer Journal for Clinicians (2019)

Abstract Adults aged 85 years and older, the “oldest old,” are the fastest‐growing age group in the United States, yet relatively little is known about their cancer burden. Combining data from the National Cancer Institute, the North American Association of Central Cancer Registries, and the National Center for Health Statistics, the authors provide comprehensive information on cancer occurrence in adults aged 85 years and older. In 2019, there will be approximately 140,690 cancer cases diagnosed and 103,250 cancer deaths among the oldest old in the United States. The most common cancers in these individuals (lung, breast, prostate, and colorectum) are the same as those in the general population. Overall cancer incidence rates peaked in the oldest men and women around 1990 and have subsequently declined, with the pace accelerating during the past decade. These trends largely reflect declines in cancers of the prostate and colorectum and, more recently, cancers of the lung among men and the breast among women. We note differences in trends for some cancers in the oldest age group (eg, lung cancer and melanoma) compared with adults aged 65 to 84 years, which reflect elevated risks in the oldest generations. In addition, cancers in the oldest old are often more advanced at diagnosis. For example, breast and colorectal cancers diagnosed in patients aged 85 years and older are about 10% less likely to be diagnosed at a local stage compared with those diagnosed in patients aged 65 to 84 years. Patients with cancer who are aged 85 years and older have the lowest relative survival of any age group, with the largest disparities noted when cancer is diagnosed at advanced stages. They are also less likely to receive surgical treatment for their cancers; only 65% of breast cancer patients aged 85 years and older received surgery compared with 89% of those aged 65 to 84 years. This difference may reflect the complexities of treating older patients, including the presence of multiple comorbidities, functional declines, and cognitive impairment, as well as competing mortality risks and undertreatment. More research on cancer in the oldest Americans is needed to improve outcomes and anticipate the complex health care needs of this rapidly growing population.
Preliminary activity in adrenocortical tumor (ACC) in phase I dose escalation study of intermittent oral dosing of OSI-906, a small-molecule insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor in patients with advanced solid tumors
Authors: C. P. Carden, S. Frentzas, M. Langham, I. Casamayor, A. W. Stephens, S. Poondru, J. Wheaton, S. M. Lippman, S. B. Kaye, E. S. Kim
Journal: Journal of Clinical Oncology (2009)

3544 Background: IGF-1R is overexpressed in various malignancies, and implicated in proliferation, survival, and metastasis. IGF-1R blockade increases apoptosis and reduces tumor growth in preclinical models. OSI-906 is an oral small molecule tyrosine kinase IGR-1R inhibitor. Methods: Patients (pt) with advanced solid tumours were enrolled to determine safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity. Results: 26 pt have been treated (14M:12F, median age 61 yrs) at 10, 20, 40, 80, 150, 300, and 450 mg on days (d) 1–3 q14 d. No dose-limiting toxicities have been observed to date. Drug-related toxicities include grade 1 fatigue, nausea, rash, diarrhea, tachycardia, proteinuria, pruritis and peripheral oedema. Linear PK was observed, with median terminal t 1/2 3.5 hr; AUC 0-∞ 25.8 μg.hr/mL; C max 3.20 μg/ml at 450mg. Plasma OSI-906 concentrations above the estimated efficacious concentration (1 μM) were attained at doses &gt; 40mg. Glucose did not increase with rising OSI-906 concentration, but plasma insulin levels showed an upward trend, indicating potential PD effects. PD data on IGFR phosphorylation were analyzed. In total, 11 pt were treated for &gt; 12 weeks (w). Of 3 pt with ACC, 1 pt had a partial response (43% reduction in primary and multiple lung metastases) and remains on treatment after 16 w, 1 pt was treated for 32 w, and 1 pt progressed after 4 w at 40mg. In addition, 1 pt with heavily pretreated NSCLC was treated for 43 w and 1 pt with progressive myxoid chondrosarcoma remains on treatment after 38 w. Conclusions: OSI 906 had minimal toxicity, dose proportional PK at dose levels up to 450mg tested d 1–3 q14 d, with preliminary antitumor activity seen, particularly in ACC. Dose escalation with 5 and 7 d schedules q14 d continues. [Table: see text]
Pharmacokinetics (PK), tolerability, and efficacy of APF530 in patients receiving moderately (MEC) and highly (HEC) emetogenic chemotherapy: Phase II trial results.
Authors: Nashat Y. Gabrail, Ronald H. Yanagihara, William Cooper, Erin O'Boyle, Carrie L. Smith, Marek Spaczynski
Journal: Journal of Clinical Oncology (2013)

e20518 Background: Up to 30% of patients continue to have chemotherapy-induced nausea and vomiting (CINV) despite use of antiemetics. APF530 is a sustained-release subcutaneous (SC) formulation of granisetron for preventing CINV. APF530 PK, tolerability, and efficacy were studied in two open-label, single-dose trials (1 US, 1 EU) in patients receiving MEC or HEC. Methods: In the US study, 45 patients received 250, 500, or 750 mg APF530 SC (5, 10, or 15 mg granisetron, respectively). In the EU study, 35 patients were randomized to 250 or 500 mg APF530 SC. Injections were given 30 to 60 minutes before single-day MEC or HEC. Plasma granisetron was measured from pre-dose to 168 hours. Safety, tolerability, and efficacy were also evaluated. Results: APF530 PK was dose proportional with slow absorption and elimination of granisetron after a single SC dose. Median t max , exposure, and t 1/2 were similar for 250 and 500 mg APF530 in both trials, with no differences between MEC and HEC groups. Adverse events in both trials were as expected for granisetron; injection-site reactions (eg, erythema, induration), predominantly mild, were seen in ≤ 20% of patients. Complete responses (no emesis, no rescue medication) were obtained in ≥ 80% and ≥ 75% of patients in both trials with the 250- and 500-mg doses, respectively. Conclusions: APF530 showed dose-proportional PK and sustained concentrations of granisetron over 168 hours. The 250- and 500-mg doses were carried into phase III; both were well tolerated, and maintained therapeutic granisetron levels for ≥ 5 days. Clinical trial information: 2007-005068-29. [Table: see text]
Joint American Academy of Dermatology–National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis with phototherapy
Authors: Craig A. Elmets, Henry W. Lim, Benjamin Stoff, Cody Connor, Kelly M. Cordoro, Mark Lebwohl, April W. Armstrong, Dawn M.R. Davis, Boni E. Elewski, Joel M. Gelfand, Kenneth B. Gordon, Alice B. Gottlieb, Daniel H. Kaplan, Arthur Kavanaugh, Matthew Kiselica, Dario Kivelevitch, Neil J. Korman, Daniela Kroshinsky, Craig L. Leonardi, Jason Lichten, Nehal N. Mehta, Amy S. Paller, Sylvia L. Parra, Arun L. Pathy, Elizabeth A. Farley Prater, Reena N. Rupani, Michael Siegel, Bruce E. Strober, Emily B. Wong, Jashin J. Wu, Vidhya Hariharan, Alan Menter
Journal: Journal of the American Academy of Dermatology (2019)
Survival outcomes in U.S. patients with metastatic colorectal cancer: A retrospective database analysis.
Authors: Kevin B. Knopf, Sheikh Usman Iqbal, Stephen F. Thompson, Elisabetta Malangone, Magdaliz Gorritz-Kindu, Lee Stern, Steven A. Sherman, Sarah Naoshy, Michael Wooten, Michael L. Andria
Journal: Journal of Clinical Oncology (2013)

e14576 Background: An increase in survival seen in recent years in patients with metastatic colorectal cancer (mCRC) has been attributed to improvements in treatments, including introduction of targeted biologic agents. Objectives of this retrospective, observational study are to investigate recent treatment patterns in US mCRC patients and examine real-world survival outcomes. Methods: Data were obtained from a large US database (SDI/IMS Health) of mCRC patients diagnosed between January 1, 2004, and June 30, 2011, ≥18 years of age at diagnosis, who received chemotherapy and/or biologic treatment. Complete follow-up was defined as those who died before June 2011 or had at least 1 claim within 30 days of June 30, 2011. Kaplan-Meier curves were generated to determine overall survival (OS) from the date of diagnosis. Results: 1,066 stage IV mCRC patients with complete follow-up were identified (57.5% male; mean age 61.6 years). Approximately 80% were diagnosed after 2006; 51.7% had liver metastases. The most common 1L, 2L, and 3L regimens were FOLFOX plus bevacizumab (34.52%), FOLFIRI plus bevacizumab (21.83%), and irinotecan plus cetuximab (15.83%), respectively. 445 patients died during the study period, yielding a mortality rate of 41.74%. Mean time from diagnosis to first treatment was 3.31 months (SD=7.13). All patients received 1L therapy; OS from diagnosis was 35.77 months (95% CI, 32.57-38.10); 5-year survival was ~28%. After 1L, 591 patients received 2L therapy. For patients who received 2L, median survival from diagnosis was 37.13 months (95% CI, 34.07-40.43); 5-year survival was ~25%. After 2L, 278 patients received 3L therapy. For patients who received 3L, median survival from diagnosis was 38.10 months (95% CI, 34.83-43.13); 5-year survival was ~25%. Conclusions: In this study, OS (35.77 months) was greater than in other mCRC observational studies (25.1-27.9 months), which reported survival from start of treatment, but is more comparable when the ~3 months from diagnosis to treatment are not included. The addition of targeted agents and novel chemotherapy has prolonged OS in mCRC patients, yet there is still need for additional advanced agents in later lines of therapies.
Survival By Race/Ethnicity in Children and Adolescents with Hodgkin Lymphoma Treated on Cooperative Group Trials in the U.S. and Canada: A Pooled Analysis of Children's Oncology Group Trials
Authors: Justine M. Kahn, Kara M. Kelly, Qinglin Pei, Debra L. Friedman, Frank Keller, Rizvan Bush, Smita Bhatia, Tara O. Henderson, Cindy L. Schwartz, Sharon M. Castellino
Journal: Blood (2017)