tbuckley/cabot-search huggingface dataset:
Comparative study of ALK rearrangement between primary tumor and paired lymphatic metastasis in NSCLC patients.
Authors: Likun Hou, Chunyan Wu
Journal: Journal of Clinical Oncology (2015)

e19134 Background: Anaplastic lymphoma kinase gene (ALK) rearrangement represents a novel oncogenic gene in NSCLC patients which show response to crizotinib, an ALK inhibitor. However, ALK rearrangement may be distributed heterogeneously in tumor from different anatomic site of the same patient. To address this issue, we compared the concordance of ALK gene fusion status between primary tumor and paired lymphatic metastasis. Meanwhile, we evaluated the effectiveness of crizotinib treatment of advanced NSCLC patients with ALK rearrangement detected by biopsy or cytology from primary tumors or lymphatic metastasis. Methods: A total of 101 NSCLC patients with lymphatic metastasis by surgical resection were enrolled from 2013 to 2014, we performed immuohistochemical(IHC) staining for the ALK protein with Ventana D5F3 antibody. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to confirm ALK fusion gene. Discordance of ALK fusion gene status between primary tumor and lymphatic metastasis was further confirmed by fluorescence in Situ hybridization (FISH). Progression-free survival (PFS) was evaluated in 13 ALK positive patients with crizotinib treatment including 7 patients who harbored ALK rearrangement detected in primary tumor and 6 patients detected in lymphatic metastasis. Results: The concordance rate of ALK rearrangement between primary tumor and paired lymphatic metastasis was 98%. PFS (11.3 months) was similar in patients with ALK rearrangement detected in primary tumor and patients (PFS, 11 months, P= 0.56) detected in lymphatic metastasis Conclusions: The current results indicated that ALK rearrangement showed a high concordance between primary tumor and lymphatic metastasis and successfully predict response to ALK inhibitor. Biopsy or cytology with limited tissue from primary tumors and metastatic lesions can be important for ALK rearrangement analysis in advanced NSCLC patients.
Two years rituximab maintenance vs. observation after first-line treatment with bendamustine plus rituximab (B-R) in patients with mantle cell lymphoma: First results of a prospective, randomized, multicenter phase II study (a subgroup study of the StiL NHL7-2008 MAINTAIN trial).
Authors: Mathias J. Rummel, Wolfgang Knauf, Martin Goerner, Ulrike Soeling, Elisabeth Lange, Bernd Hertenstein, Jochen Eggert, Georg C Schliesser, Rudolf Weide, Klaus Blumenstengel, Ninia Detlefsen, Axel Hinke, Frank Kauff, Juergen Barth
Journal: Journal of Clinical Oncology (2016)

7503 Background: Rituximab maintenance is part of a standard treatment approach for follicular lymphoma. In mantle cell lymphoma (MCL), however, it is not yet common practice. In this study we compared the effect of rituximab maintenance vs observation after first-line treatment with B-R in patients with previously untreated MCL. Methods: Patients were required to have stage II (with bulky disease > 7 cm), III, or IV disease for registration in this study. Primary endpoint was progression free survival (PFS). Secondary endpoints included response rates, overall survival (OS), time to progression, event free survival, toxicity. Patients were treated with up to 6 cycles of B-R plus 2 additional rituximab cycles. 120 Patients who have responded to B-R were then randomized to either rituximab maintenance (375 mg/m2every 2 months for a total of 2 years) or observation only. Results: A total of 120 patients were evaluable for the analysis, 59 (49%) were randomized to maintenance with rituximab and 61 (51%) to observation, respectively. Patient characteristics were comparable for both groups. Median patient age was 70 years, median time of observation was 54.2 months at the time of this analysis (January 2016). No significant difference in PFS between both arms could be observed (p = 0.130, 47 events, HR 0.64, 95% CI 0.36 – 1.14). The median for R maintenance was not yet reached, whereas for the observation arm the median was 54.7 months (95% CI 40.1. – n. y. r.). The results for overall survival showed no difference (p = 0.271, 27 events, HR 1.53, 95% CI 0.73 – 3.32) with a median of 69.6 months for R maintenance versus a median not yet reached in the observation arm. Conclusions: After a median observation time of 4.5 years, the results are yet inconclusive. Up to date we were not able to demonstrate statistical evidence supporting the benefit of R maintenance after B-R in the treatment of patients with MCL. Longer follow-up is needed before final results can be presented. Clinical trial information: NCT00877214.
Abstract 1669: Inhibition of the Rac1/PAK pathway sensitizes pancreatic cancer cells to gamma-irradiation
Authors: Michel M. Ouellette, Surinder K. Batra, Ying Yan
Journal: Cancer Research (2016)

Abstract Radiation therapy is a staple treatment for pancreatic cancers. However, owing to the intrinsic radioresistance of pancreatic cancer cells, radiation therapy often fails to increase survival of pancreatic cancer patients. Radiation impedes cancer cells by inducing DNA damage, which can activate cell cycle checkpoints. Normal cells possess both G1/S and G2/M checkpoints. However, cancer cells are often defective in G1/S checkpoint due to mutations/alterations in the key regulators of this checkpoint. Accordingly, our results show that normal pancreatic ductal cells respond to ionizing radiation (IR) with activation of both checkpoints whereas pancreatic cancer cells respond to IR with G2/M arrest only. Overexpression/hyperactivation of Rac1 GTPase is detected in the majority of pancreatic cancers. Rac1 plays important roles in survival and Ras mediated transformation. Here, we show that Rac1 and its downstream effector, the PAK kinases, also plays a critical role in the response of pancreatic cancer cells to IR. Inhibition of Rac1/PAK pathway with pharmacological inhibitors (Ehop-016, AZA1, NSC23766, and FRAX597) or a dominant negative mutant of Rac1 (Rac1T17N) blocks activation of the ATM/Chk2 and ATR/Chk1 pathways, abrogates activation of the IR-induced G2/M checkpoint, delays the repair of IR-induced double-stranded DNA breaks, and increases the radiosensitivity of pancreatic cancer cells through induction of apoptosis. These results implicate Rac1 signaling in the survival of pancreatic cancer cells following IR, raising the possibility that this pathway contributes to the intrinsic radioresistance of pancreatic cancer. Citation Format: Michel M. Ouellette, Surinder K. Batra, Ying Yan. Inhibition of the Rac1/PAK pathway sensitizes pancreatic cancer cells to gamma-irradiation. [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 1669.
Discordance with estrogen receptor alpha status estimated by immunohistochemical and immunofluorescent method associated with flowcytometry in breast cancer tissue
Authors: M.V. Rodionova, T.A. Bogush, E.A. Dudko, E.A. Shestakova, E.A. Bogush, V.J. Kirsanov, I.K. Vorotnikov
Journal: Annals of Oncology (2015)
Dose-escalated adaptive image-guided radiotherapy versus high-dose-rate brachytherapy monotherapy for low-risk prostate cancer.
Authors: Ovidiu Marina, Daniel J. Krauss, Donald Brabbins, Michelle Wallace, Alvaro A Martinez, Hong Ye, Gary S. Gustafson
Journal: Journal of Clinical Oncology (2013)

145 Background: Both IGRT and HDR are used for definitive treatment of low-risk prostate. No comparative study of these contemporary modalities exists. Methods: Charts for patients with low-risk prostate cancer by NCCN criteria treated 1999-2012 were reviewed. For IGRT, the clinical target volume (CTV) included the prostate and proximal seminal vesicles. A CT-based, off-line adaptive treatment plan was made with a patient-specific confidence-limited planning target volume (cl-PTV) based on the planning plus four additional daily CT scans. Overall survival (OS) was calculated by the Kaplan-Meier method (log-rank test), with Cox regression for uni- and multi-variate analysis. Cumulative incidence (Gray’s test), with competing risks analysis (Fine and Gray) were used for biochemical control (BC) and freedom from local recurrence (FFLR). Results: There were 598 IGRT and 399 HDR patients (see Table), with a median follow-up of 6.1 and 3.6 years, respectively (p&lt;0.001). The median prescribed IGRT dose was 75.6 Gy (range 73.8-79.2). HDR doses were 24 Gy (n=126) or 27 Gy (n=151) in 2 fractions, or 36 Gy (n=3) or 38 Gy (n=335) in 4 fractions. Five- and 10-year BC was 99% and 94% for IGRT and 98% and 95% for HDR (p=0.77); FFLR was 100% and 99% for both (p=0.89); and OS was 95% and 75% for IGRT and 97% and 85% for HDR (p=0.04). On multivariate analysis, predictors (p&lt;0.10) for OS were age (p&lt;0.001) and PNI (p=0.04); for LR, PPC (p=0.01); and for BC, a trend for PSA (p=0.08). Treatment type was not a predictor of OS, BC or FFLR (p&gt;0.5). Conclusions: Both dose- escalated IGRT and HDR monotherapy yield similarly excellent outcomes for low-risk prostate cancer. Our experience supports the continued use of brachytherapy as monotherapy in low-risk prostate cancer. [Table: see text]
Abstract 5220: Evaluation of ACMG guideline classified variants in 180 cancer and incidental non-cancer genes in families with breast/ovarian cancer
Authors: Kara N. Maxwell, Steven N. Hart, Joseph Vijai, Kasmintan A. Schrader, Tinu Thomas, Bradley Wubbenhorst, Vignesh Ravichandran, Raymond M. Moore, Chunling Hu, Lucia Guidugli, Brandon Wenz, Thomas P. Slavin, Susan M. Domchek, Mark E. Robson, Csilla Szabo, Susan L. Neuhausen, Jeffrey N. Weitzel, Kenneth Offit, Fergus J. Couch, Katherine L. Nathanson
Journal: Cancer Research (2016)

Abstract Sequencing tests assaying panels of genes or whole exomes are widely available for cancer risk evaluation. However, methods for classification of variants resulting from this testing are not well studied. We evaluated the ability of American College of Medical Genetics and Genomics (ACMG) guidelines to define the rate of mutations and variants of uncertain significance (VUS) in 180 medically relevant genes, including all ACMG designated reportable cancer and non-cancer genes, in individuals who met guidelines for hereditary cancer risk evaluation. We performed whole exome sequencing in 404 individuals in 257 families and classified 1640 variants from these genes. Potentially clinically actionable (likely-pathogenic/pathogenic, LP/P) versus nonactionable (VUS/likely-benign/benign) calls were 92% and 88% concordant with locus specific databases and Clinvar, respectively. LP/P mutations were identified in 11 of 25 breast cancer susceptibility genes in 27 BRCA1/2 negative families (11%). Evaluation of 84 additional autosomal dominant cancer susceptibility genes identified LP/P mutations in only four additional families (1.7%), suggesting they do not influence risk in this cohort. However, individuals from nine of 257 families (3.5%) had incidental LP/P mutations in 32 non-cancer disease genes, and 7% of individuals were monoallelic carriers of an LP/P mutation in 39 autosomal recessive cancer syndrome genes. Furthermore, 90% of individuals had at least one VUS. In summary, these data support the clinical utility of ACMG variant classification guidelines. In addition, evaluation of extended panels of cancer genes in breast/ovarian cancer families leads to only an incremental clinical benefit but substantially increases the complexity of the results. Citation Format: Kara N. Maxwell, Steven N. Hart, Joseph Vijai, Kasmintan A. Schrader, Tinu Thomas, Bradley Wubbenhorst, Vignesh Ravichandran, Raymond M. Moore, Chunling Hu, Lucia Guidugli, Brandon Wenz, Thomas P. Slavin, Susan M. Domchek, Mark E. Robson, Csilla Szabo, Susan L. Neuhausen, Jeffrey N. Weitzel, Kenneth Offit, Fergus J. Couch, Katherine L. Nathanson. Evaluation of ACMG guideline classified variants in 180 cancer and incidental non-cancer genes in families with breast/ovarian 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 5220.
Outcomes for FOLFIRI plus bevacizumab (BEV) or cetuximab (CET) in patients previously treated with oxaliplatin-based adjuvant therapy: A combined analysis of data from FIRE-3 and CALGB 80405.
Authors: Volker Heinemann, Donna Niedzwiecki, Rachel V. Pearline, Axel Grothey, Howard S. Hochster, Richard M. Goldberg, Federico Innocenti, Robert J. Mayer, Richard L. Schilsky, Charles David Blanke, Monica M. Bertagnolli, Alan P. Venook, Sebastian Stinzing, Bert H. O'Neil
Journal: Journal of Clinical Oncology (2015)

3585 Background: mCRC previously treated with adjuvant therapy may differ biologically from untreated mCRC. This study examines outcomes for BEV vs. CET in the patients on FIRE-3 and C80405 who previously received adjuvant oxaliplatin (OX). Methods: In both studies, pts with KRAS wt (codons 12 and 13) mCRC and performance status 0-1 were treated with standard chemotherapy and randomized to either CET 400 mg/m2 X 1, then 250 mg/m2 qw or BEV 5 mg/kg q2w. Rx continued until progression, death, unacceptable toxicity, or surgery with curative intent. Patients previously treated with adjuvant oxaliplatin ( < 12 months prior to enrollment in 80405, < 6 months prior for FIRE-3) were identified for this analysis. Results: 125 patients received adjuvant OX (67 from 80405 and 58 from FIRE-3); 56 were randomized to BEV and 69 to CET. Baseline demographics were similar for both treatment groups and similar between patients enrolled in FIRE-3 vs. 80405. All received FOLFIRI as the chemotherapy regimen. In the combined analysis, CR + PR in the CET arm vs. BEV was 58% vs 42%, respectively (chi square p = 0.08). PFS was 11.3 mos for BEV and 10.2 mos for CET (HR 1.2, p = 0.24) with 117 PFS events. Median OS for BEV was 41.0 mo vs. 28.5 mo for CET (HR 1.4, p = 0.18) with 79 OS events. Conclusions: No significant difference in OS by biologic was found in this unplanned subset analysis. Patients with prior OX exposure had very good overall outcomes with both biologics.
Abstract 2222: Dual inhibition of cancer stemness and immune checkpoint genes by targeting Stat3
Authors: Yuan Gao, Sarah Keates, Eric Hsu, Janet Huang, Emily Brooks, Matt Hitron, Youzhi Li, Harry A. Rogoff, Chiang Li
Journal: Cancer Research (2016)

Abstract Highly malignant stemness-high cancer cells, also termed cancer stem cells, have been found to hijack stemness genes important for embryonic stem cells to acquire a state of high-stemness. Cancer stemness has been associated with enhanced tumorigenicity and resistance to chemotherapies. Moreover, stemness-high cancer cells have been isolated from a variety of human cancer types. Therefore, targeting cancer stemness holds significant promise for advancing cancer treatment. Recent clinical success with antibodies targeting PD1 and PDL1 has validated that cancer cells can hijack immune checkpoint genes to subvert endogenous anticancer surveillance by the immune system. It is, therefore, highly desirable to develop therapeutics that simultaneously target both cancer cell stemness and immune checkpoints. The transcription factor Signal Transducer and Activator of Transcription 3 (Stat3) is activated by a multitude of upstream oncogenic pathways and cytokine receptors. Aberrant and constitutive activation of Stat3 has been found in a wide variety of human cancers, and has also been implicated in cancer cell proliferation, survival, and immune evasion. By using aiRNA (asymmetric RNA duplexes) we have achieved potent Stat3 silencing with precision in stemness-high cancer cells. We observed that Stat3 silencing leads to simultaneous down regulation of cancer cell stemness and immune checkpoint gene expression. Treatment of stemness-high cancer cells with BB608, a small molecule inhibitor of Stat3, led to simultaneous inhibition of stemness-high cancer cell survival and self-renewal, as well as downregulation of immune checkpoint genes, including IDO1 in vitro and in vivo. Furthermore, while expression of stemness genes and immune checkpoint genes in tumor tissues are known to predict poor patient survival, patients with higher expression levels of stemness genes and immune checkpoint genes showed prolonged overall survival after treatment with BB608 in clinical trials. Targeting Stat3 is, therefore, a promising strategy to achieve dual inhibition of cancer cell stemness and immune evasion. Citation Format: Yuan Gao, Sarah Keates, Eric Hsu, Janet Huang, Emily Brooks, Matt Hitron, Youzhi Li, Harry A. Rogoff, Chiang Li. Dual inhibition of cancer stemness and immune checkpoint genes by targeting Stat3. [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 2222.
A Novel Alkylating Agent Melphalan Flufenamide Ethyl Ester Induces an Irreversible DNA Damage in Multiple Myeloma Cells
Authors: Arghya Ray, Durgadevi Ravillah, Deepika Sharma Das, Yan Song, Eva Nordström, Jakob Lindberg, Paul G. Richardson, Dharminder Chauhan, Kenneth C. Anderson
Journal: Blood (2014)
Phase I trial of intravenous attenuated vaccinia virus (GL-ONC1) with concurrent chemoradiotherapy (CRT) for locoregionally advanced head and neck carcinoma.
Authors: Loren K. Mell, Yong A. Yu, Kevin T. Brumund, Gregory A. Daniels, Sunil J. Advani, Robert A. Weisman, Parag R. Sanghvi, Peter J. Martin, Mary E. Wright, Sara-Jane Onyeama, Qian Zhang, Anu Pold, Terry Chamberlin, Alexa Frentzen, Aladar A Szalay
Journal: Journal of Clinical Oncology (2015)

6026 Background: We aimed to test the safety of GL-ONC1, an attenuated vaccinia virus, delivered intravenously (IV) with concurrent CRT for locoregionally advanced head and neck carcinoma (LA-HNC). Secondary objectives were to test for tumor susceptibility to viral infection in baseline specimens and for tumor infection on mid-treatment biopsies. Methods: This was a 3+3 phase I dose escalation trial for unresected LA-HNC, excluding HPV-positive oropharyngeal cancer (NCT01584284). CRT was given in 33-35 fractions of 2.00-2.12 Gy over 6.5-7 weeks using IMRT with concurrent cisplatin 100 mg/m2 given on days 1, 22, and 43. Escalating doses of GL-ONC1 were given as follows: cohort 1, 3×108 pfu on day 3; cohort 2, 1×109 pfu on day 3; cohort 3, 3×109 pfu on day 3; cohort 4, 3×109 pfu on days 3 and 8; and cohort 5, 3×109pfu on days 3, 8, 15, and 22. Dose-limiting toxicity (DLT) was defined as grade ≥ 4 toxicity or grade ≥ 3 mucositis or skin reaction persisting > 6 weeks after CRT attributed to GL-ONC1. Results: From May 2012 to Dec 2014, 24 patients consented (19 enrolled, 5 screen failures). 18 patients completed CRT, with 1 currently on treatment. Mean age was 56 years. 74% had stage IVA and 26% had stage IVB disease. 26% were HPV-positive. One DLT occurred in cohort 4. Maximum tolerated dose was not reached. Adverse events included grade ≥ 2 rigors (47%), grade ≥ 2 thrombocytopenia (32%), grade ≥ 2 fever (26%) and grade ≥ 1 rash (21%). The rash was confirmed to be viral in origin in 2 patients. Viral tumor infection was confirmed by qPCR for A21L gene in 4 patients. No viral shedding was detected on urine or oral swab 1-2 days post infusion of GL-ONC1. Serious adverse events considered unrelated to GL-ONC1 were myocardial infarction (1), pulmonary embolism (1), syncope (1), grade 3 emesis (1), and grade 3 neutropenia (1). Of 18 patients completing CRT, 78% had 3 cycles of cisplatin and 22% had 2 cycles. With median 17 month follow-up, Kaplan-Meier estimates of 1-year (2-year) PFS and OS were 82% (75%) and 87% (75%) respectively. Conclusions: This is the first trial to establish the safety of IV GL-ONC1 for LA-HNC patients undergoing concurrent CRT. A phase II trial in this population is warranted. Clinical trial information: NCT01584284.
Unsatisfactory Outcome of Pediatric Relapsed and Refractory AML Treated with Clofarabine Combined with Topotecan, Vinorelbine and Thiotepa (TVTC)
Authors: Jolanta Skalska-Sadowska, Anna Pieczonka, Katarzyna Smalisz-Skrzypczyk, Michal Matysiak, Katarzyna Muszynska-Roslan, Maryna Krawczuk-Rybak, Katarzyna Drabko, Jerzy Kowalczyk, Malgorzata Czogala, Walentyna Balwierz, Grazyna Karolczyk, Irena Karpinska-Derda, Mariola Woszczyk, Tomasz Szczepanski, Jacek Wachowiak
Journal: Blood (2015)
Utility Of An Algorithm For Use Of Plerixafor In Filgrastim-based Hematopoietic Progenitor Cell Mobilization In Patients With Plasma Cell Myeloma Treated With Carfilzomib-Lenalidomide-Dexamethasone.
Authors: Susan F. Leitman, Nishant Tageja, Neha Korde, Yu Ying Yau, Sheila Phang, Jennifer Hsu, Kristin Cole, Hanh Khuu, Ola Landgren, Claude Sportes
Journal: Blood (2013)
Killed surgeon at Berlin hospital had treated patient who shot him
Authors: Ned Stafford
Journal: BMJ (2016)

An oral surgeon at the Charite university hospital in Berlin, Germany, has died from gunshot wounds after an elderly patient in an examination room opened fire with a handgun. After shooting the doctor several times the patient then shot himself.

The surgeon, a chief doctor and tumour specialist, had previously performed surgery on and provided postoperative care for the patient, a 72 year old man who had been seriously ill for several years. Under Germany’s strict privacy laws the doctor was identified in the German press only as Thomas P, age 55, married, and the father of two children under 18.

With Germany …
Abstract 1257: A MYC-Aurka protein complex represents an actionable target in p53 altered liver cancer
Authors: Dauch Daniel, Ramona Rudalska, Giacomo Cossa, Jean Charles Nault, Sandrine Imbeaud, Nisar P. Malek, Thomas Longerich, Stefan Laufer, Antti Poso, Jessica Zucman-Rossi, Martin Eilers, Lars Zender
Journal: Cancer Research (2016)

Abstract Myc oncoproteins are causally involved in the genesis of a large fraction of human tumors. Three closely related Myc proteins, c-myc, N-myc and L-myc, have been implicated in cancer, whereas c-myc was identified as an important oncogenic driver in frequent solid tumors.Applying transposon-based mosaic liver cancer mouse models and direct in vivo shRNA screening technology, we found that bypassing a latent p19Arf- and Aurka mediated G2/M cell cycle arrest is required for development of p53 altered liver carcinomas with activated Ras/MAPK signalling. The resulting tumors depend on high MYC levels for survival. A direct interaction of Aurka and MYC was identified in p53 altered liver cancer cells, which could be efficiently disrupted by conformation changing Aurka inhibitors, resulting in MYC degradation and cell death specifically of p53 altered human and murine hepatoma cells. Treatment studies in mouse models of p53 deficient therapy resistant liver cancer revealed marked therapeutic efficacy of conformation changing Aurka inhibitors, thus suggesting a new therapeutic strategy against this major lethal cancer. Citation Format: Dauch Daniel, Ramona Rudalska, Giacomo Cossa, Jean Charles Nault, Sandrine Imbeaud, Nisar P. Malek, Thomas Longerich, Stefan Laufer, Antti Poso, Jessica Zucman-Rossi, Martin Eilers, Lars Zender. A MYC-Aurka protein complex represents an actionable target in p53 altered liver 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 1257.