tbuckley/cabot-search huggingface dataset:
Phase Ib study of oral panobinostat (LBH589) plus intravenous bortezomib in patients (Pts) with relapsed (Rel) or Rel and refractory (Ref) multiple myeloma (MM).
Authors: J. F. San-Miguel, O. Sezer, D. S. Siegel, A. Guenther, J. Blade, I. W. Prosser, B. Bengoudifa, M. Klebsattel, P. M. Bourquelot, K. C. Anderson
Journal: Journal of Clinical Oncology (2010)

8001 Background: Panobinostat (PAN; LBH589) is a potent pan-deacetylase inhibitor (pan-DACi) that disrupts aggresome and HSP90 function via inhibition of HDAC6, promoting cytotoxic misfolded protein aggregates and MM cell death. Combination of PAN with the proteasome inhibitor bortezomib (BTZ) demonstrated synergistic cytotoxicity in preclinical studies. Methods: Pts with Rel or Rel and Ref MM receive PAN (po thrice weekly) and BTZ (iv days 1, 4, 8, 11) on a 21-day cycle to establish the MTD of the combination. Results: Per October 9, 2009, cutoff, 38 pts were treated in 5 cohorts (Co) (Table): median age 62 (range 46–78), median 2 prior therapies (range 1–7), including stem cell transplant (n=30) and BTZ (n=22; 13 pts BTZ-refractory). No dose-limiting toxicities (DLTs) occurred in Co 1 or 3, 1 DLT in Co 2 (neutropenia [NP]), 4 DLTs in Co 4 (2 thrombocytopenia [TCP], 1 pneumonia/TCP/NP, 1 fatigue), and 1 DLT in Co 5 (TCP/asthenia/dizziness). Hematologic adverse events (AEs) included Gr 3/4 TCP (n=30), NP (n=23), and anemia (n=6). Other AEs included diarrhea (n=23), nausea (n=18), pyrexia (n=17), fatigue (n=16), and asthenia (n=13). There has been no Gr 3/4 peripheral neuropathy and no treatment-related death. Responses were observed in 26/38 pts (68%) across all Co (Table). Notably, responses were also seen in 8/13 (62%) BTZ-refractory pts. Management of AEs, including TCP, permitted by dose reduction or interruption, allowed for longer time on study in Co 3, which also had the most favorable efficacy profile (7/8 pts responded). These results support the use of Co 3 dose levels in subsequent trials. Conclusions: The combination of oral PAN and BTZ has a predictable and manageable safety profile with promising activity in pts with Rel or Rel and Ref MM, including MM refractory to prior BTZ. Enrollment at 20 mg PAN + 1.3 mg/m2 BTZ is ongoing to determine MTD. A modified dose schedule is now introduced in phase II and III trials with this combination in order to maximize therapy duration. Cohort (Co) 1 2 3 4 5 PAN 10 mg 20 mg 20 mg 30 mg 25 mg BTZ 1.0 mg/m2 1.0 mg/m2 1.3 mg/m2 1.3 mg/m2 1.3 mg/m2 Total, n 7 7 8 7 9 BTZ refractory, n 4 5 2 0 2 CR 1 2 1 VGPR 1 1 PR 3 3 3 1 4 6 2 MR 1 1 2 1 1 SD 1 1 1 PD 4 2 3 2 NE 1 1 1 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Celgene, Janssen-Cilag, Millennium, Novartis Novartis Celgene, Janssen-Cilag, Millennium, Novartis Celgene, Janssen-Cilag, Millennium, Novartis Novartis
A phase I study of a novel inhibitor of protein phosphatase 2A alone and with docetaxel.
Authors: Aaron Scott Mansfield, Vincent M. Chung, John S. Kovach
Journal: Journal of Clinical Oncology (2015)

TPS2602 Background: Protein phosphatase (PP2A) is a multifunctional protein involved in regulation of cell cycle, DNA-damage response, and apoptosis. In pre-clinical studies, LB-100, a novel small molecule inhibitor of PP2A, inhibits the growth of a broad spectrum of leukemic and solid tumor cell lines. In cancer xenografts, LB100 potentiates the effectiveness of cytotoxic drugs (temozolomide, docetaxel, doxorubicin, cisplatin) and radiation without significant increases in toxicity. The predominant mechanisms responsible for potentiation are inhibition of mitotic exit and homologous recombination repair. PP2A inhibition also results in synthetic lethality of cancer cells overexpressing Mad2 (mitotic arrest deficiency protein 2) as a result of mutations in Rb and/or p53 pathways, suggesting that Mad2-overexpression may be a biomarker for LB100 responsiveness. In addition, cancers deficient in PP2A by somatic mutation such as (del)5q MDS are vulnerable to further PP2A inhibition, raising the possibility that other cancers with decreased PP2A resulting from increased endogenous PP2A inhibitors, CIP2A and SET, which include blast crisis CML, NSCLC (40%) and prostate cancers (60%), may also be vulnerable. PP2A has not been considered a practical target for anti-cancer therapy for concern of off-target effects. This trial seeks to determine appropriate doses of LB100 alone and LB100 plus docetaxel for phase II studies in (del)5q MDS and in cancers for which docetaxel is appropriate 2nd line treatment. Methods: This two-part phase I study aims to determine the MTD of LB100 alone given intravenously over 15 minutes daily for 3 days q3w and when given on the same schedule with docetaxel on day 2. In part 2, the starting dose of LB-100 is two levels lower than its single agent MTD combined with docetaxel at 60mg/m2. LB100 is escalated to its MTD, and if tolerated, docetaxel is increased to 75mg/m2 and LB-100 re-escalated. Eligible patients are ≥ 18 y with progressive or metastatic tumors having failed standard treatment. In part 2, patients are also docetaxel-naive. Enrollment through the 5th dose level of LB100 alone was completed in January 2015. Clinical trial: NCTO1837667. Clinical trial information: NCTO1837667.
Familial white lentiginosis
Authors: I. Neri, A. Bassi, C. Misciali, A. Bagni, A. Patrizi
Journal: British Journal of Dermatology (2016)

The term “white lentiginosis” (WL) was first reported in 1994 by Grosshans E et al (1), identifying a hypopigmented disorder of healthy individuals, clinically characterized by lenticular white macules and occurring most frequently in dark-colored individuals of phototype IV-V with a typical distribution on the trunk, decollete, neck, hands and on the extensor surface of the upper arms. It is an acquired disorder with a chronic course and characterized by peculiar histhopathological features of lentiginosis hyperplasia with hypopigmentation.

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Twitter and Cardiovascular Disease
Authors: Mintu P. Turakhia, Robert A. Harrington
Journal: JAMA Cardiology (2016)

Lauren Sinnenberg, BA; Christie L. DiSilvestro, BA; Christina Mancheno, BA; Karl Dailey, BA; Christopher Tufts, MS; Alison M. Buttenheim, PhD, MBA; Fran Barg, PhD, MEd; Lyle Ungar, PhD; H. Schwartz, PhD; Dana Brown, BA; David A. Asch, MD, MBA; Raina M. Merchant, MD, MSHP
Feasibility of twice-weekly schedule of paclitaxel and carboplatin for solid tumors: A 119 patients study
Authors: M. Bibas, G. Zampa, M. Moscato
Journal: Journal of Clinical Oncology (2004)

2121 Background: To determine the feasibility and the toxicity of the biweekly P and C combination chemotherapy for solid tumors, we evaluate 119 patients 67 M and 52 F with perfomance status WHO 0–3, age range between 35–96, and with ovarian cancer (34 pts), esophageal cancer ( 1 pt), head-neck cancer (15 pts), bladder cancer (26 pts), anal cancer (8 pts) cervical cancer ( 4 pts), and lung cancer (24 pts). Chemotherapy consisted of paclitaxel 175mg/m2 day1 and carboplatin AUC 4 day 1 every 15 days. This schedule was used for metastatic cancer and also in aduvant/neoaduvant setting. Results: A total number of 619 chemotherapy cycles was administered (range 2–17). Dose intensity (DI) reached for paclitaxel were 87,5mg/m2 and a AUC of 2 for carboplatin (Bookman MA ASCO 1995 abs 755 suggests DI AUC 2,5 for carboplatin and 58,3mg/m2 for paclitaxel). Toxicities were of wide range but neurological grade 3–4 limiting toxicity occurred only in 11.9 % of patients, other grade 3 common toxicities were neutropenia and anemia. Conclusion: The biweekly regimen was well tolerated also in elderly patients with a low performane status and insufficent renal functions. We are evaluating the paclitaxel dose redution to 150mg/m2 in attemp to reduce neurotoxicity. No significant financial relationships to disclose.
Safety and Clinical Utility of Four Clinical Decision Rules In the Diagnostic Management of Acute Pulmonary Embolism – the Prometheus Diagnosis Study
Authors: Inge CM Mos, Renée A Douma, Petra MG Erkens, Tessa AC Nizet, Marc F Durian, Anja A van Houten, Marcel M Hovens, Herman MA Hofstee, Frederikus A Klok, Hugo Ten Cate, Erik F Ullmann, Harry R Büller, Pieter W Kamphuisen, Menno V Huisman
Journal: Blood (2010)
Development of distant metastases during adjuvant therapy with trastuzumab (H) in premenopausal patients with HER2-positive breast cancer
Authors: D. Donat, J. Pesic, J. Trifunovic, L. Muzikravic, S. Tesanovic, D. D. Donat, T. Pesic
Journal: Journal of Clinical Oncology (2008)

11574 Background: Breast cancer patients with positive HER2 have more aggressive disease with increased metastatic potential and poorer prognosis. Methods: From June 2006 to September 2007, 45 premenopausal patients were treated with adjuvant H therapy every 3 weeks at our Institute. Average age of the patients was 45 years (range: 31–52 years). Before the said therapy was applied the patients were treated with adjuvant chemo- and hormonal therapy (if indicated) and radiotherapy. All patients were given 6 cycles of adjuvant FAC chemotherapy. Radiotherapy was applied in 37 (82.22%) patients after completion of adjuvant chemotherapy. Thirty-four (75.55%) patients were steroid receptor dependent and all of them were treated with tamoxifen after completion of chemotherapy. Tamoxifen therapy was continued during radiotherapy and H therapy. After completion of chemotherapy and radiotherapy (if necessary treatment with H was initiated between day 14 and day 46 (average: day 26). Results: During the H therapy distant metastases developed in three (6.67%) patients. After cycle 3 of the therapy one patient developed bone metastases; one patient had CNS metastases after cycle 4, and one patient had liver metastases after cycle 6 of the therapy. Two of these 3 patients were steroid receptor independent and one was steroid receptor dependent. All of them were previously treated with FAC regimen and radiotherapy. After the appearance of distant metastases was confirmed H therapy was discontinued and these patients were treated according to our standard protocol. Conclusions: This small retrospective study showed that premenopausal patients with HER2 positive breast cancer have higher risk for development of metastatic disease, including brain metastases, even during the treatment with adjuvant H therapy. No significant financial relationships to disclose.
ANG1005, a novel brain-penetrant taxane derivative, for the treatment of recurrent brain metastases and leptomeningeal carcinomatosis from breast cancer.
Authors: Priya Kumthekar, Shou-Ching Tang, Andrew Jacob Brenner, Santosh Kesari, David Eric Piccioni, Carey K. Anders, Jose Arganda Carrillo, Pavani Chalasani, Peter Kabos, Shannon Puhalla, Agustin A. Garcia, Katherine Hanna Tkaczuk, Manmeet Singh Ahluwalia, Nehal J. Lakhani, Nuhad K. Ibrahim
Journal: Journal of Clinical Oncology (2016)

2004 Background: Treatment options for brain metastases (BM) and leptomeningeal carcinomatosis (LC) are limited due to the inability of most anti-cancer agents to cross the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCB). ANG1005 is a novel taxane derivative, consisting of 3 paclitaxel molecules covalently linked to Angiopep-2, designed to cross the BBB and the BCB and to penetrate malignant cells via the LRP-1 transport system. Methods: Adult patients with measurable recurrent BM from breast cancer, with or without LC, were enrolled in this multi-center, open-label study (n = 72 safety population; n = 57 efficacy population). ANG1005 was administered IV at 600 mg/m2 q3w. HER2+ patients were allowed to continue trastuzumab +/- pertuzumab. Intracranial (IC) response was assessed by Gd-MRI using CNS RECIST 1.1 and extracranial response was evaluated per RECIST 1.1. Results: Median age was 47.5 years. Safety profile was similar to that of paclitaxel with myelosuppression as the predominating toxicity. Patients received a median of 5 prior therapies for breast cancer, including 89% with prior taxane treatment. In addition to surgery and/or radiation, 26% of the patients had prior systemic therapies for BM. Clinical benefit (best IC PR + SD) was seen in 70% of the patients. Best IC response in the efficacy population included 8/57 (14%) patients with PRs [3 (5%) confirmed PRs] and 32/57 (56%) with SD. For evaluable patients with LC, best IC responses included 5/23 (22%) PRs [2 (9%) confirmed PRs] and 12/23 (52%) SDs. Importantly, estimated median OS was 34.6 weeks (95% CI 23.3-NE) for patients with LC. Improvement of clinical symptoms post-ANG1005 treatment was seen, including in patients with LC. Furthermore, completed extracranial tumor evaluations in 29 patients showed disease control in 79% of the patients [2 (7%) CRs, 2 (7%) PRs and 19 (66%) SDs]. Conclusions: Anti-tumor activity with ANG1005 was seen both intracranially and extracranially. Response was notable in patients with LC, resulting in prolonged OS compared to historical control and improvement of clinical symptoms in patients with a poor prognosis. Clinical trial information: NCT02048059.
HER2-positive early breast cancers: What proportion are receiving adjuvant trastuzumab therapy? A multicenter audit.
Authors: S. Marla, J. Cardale, D. J. Dodwell, A. Skene, O. Gojis, C. Palmieri, P. Abram, S. Cleator, A. Bowman, J. C. Doughty
Journal: Journal of Clinical Oncology (2010)

668 Background: Various trials have shown substantial benefits from adjuvant trastuzumab therapy in HER2+ early breast cancer (EBC). Trastuzumab was licensed for adjuvant therapy in EBC in the United Kingdom in 2006. The objectives of this multicenter audit were to determine the incidence of HER2+ breast cancers, the proportion of HER2+ EBC women who received trastuzumab, and to ascertain the reasons why some HER2+ patients did not receive trastuzumab. Methods: Data were collected for all invasive breast cancers diagnosed at 7 U.K. centers over 18 months from 2007 onward. All HER2+ cancers diagnosed by a combination of IHC and FISH were identified using each center's breast cancer database. Case records were checked and reasons noted if they had not received trastuzumab. Results: Over 18 months, 4,488 patients were diagnosed with invasive breast cancer at the 7 centers. There were 645 (14%) HER2+ cancers. 523 were EBCs. 326 (62%) HER2+ EBCs received trastuzumab therapy. Conclusions: The incidence of HER2+ breast cancers is 14% with majority being EBCs (81%). Only 62% of the HER2+ EBC patients received trastuzumab. While the most common reason for not receiving trastuzumab is small node-negative tumors (which is compatible with U.K. guidelines), an equal number of patients potentially missed optimal therapy for reasons not noted in the guidelines. Recent studies have demonstrated that being HER2+ is a significant risk factor for relapse in patients previously perceived to be at low risk (small node-negative grade 1 or 2 tumors) and no HER2+ patient should now be considered low risk (Tovey et al. Br J Cancer 2009). Further trials are required to evaluate whether elderly HER2+ patients who are only eligible for trastuzumab after adjuvant chemotherapy may derive benefit from trastuzumab alone or in combination with endocrine therapy. Reasons for not receiving trastuzumab (n=197) Reasons Number of patients (%) Tumor ≤ 10 mm, node negative 65 (33) Small node negative tumors (11-20 mm) 18 (9) Age 42 (21) Comorbidities 27 (13) Patients refused therapy 28 (14) Other reasons 17 (9) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sekhar Marla
Brentuximab Vedotin in Combination with Dacarbazine or Bendamustine for Frontline Treatment of Hodgkin Lymphoma in Patients Aged 60 Years and Above: Interim Results of a Multi-Cohort Phase 2 Study
Authors: Christopher A. Yasenchak, Andres Forero-Torres, Vivian Jean Mikao Cline-Burkhardt, Rodolfo E Bordoni, Dipti Patel-Donnelly, Patrick J. Flynn, Robert Chen, Abraham Fong, Jonathan W. Friedberg
Journal: Blood (2015)
Identification of synthetic lethal interactions with the BRAF oncogene in colorectal cancer.
Authors: Loredana Vecchione, Valentina Gambino, Giovanni d'Ario, Sun Tian, Iris Simon, Vlad Calin Popovici, Mauro Delorenzi, Rene Bernards, Sabine Tejpar
Journal: Journal of Clinical Oncology (2013)

403 Background: Approximately 8-15% of colorectal (CRC) patients carry an activating mutation in BRAF. This CRC subtype is associated with poor outcome and with resistance, both to chemotherapeutic treatments and to tailored drugs. We recently showed that BRAF (V600E) colon cancers (CCs) have a characteristic gene expression signature (1, 2) which is found also in subsets of KRAS mutant and KRAS-BRAF wild type (WT2) tumors. Tumors having this gene signature, referred as “BRAF-like”, have a similar poor prognosis irrespective of the presence of the BRAF (V600E) mutation. By using a shRNA-based genetic screen in BRAF mutant CC cell lines we aimed to identify genes and pathways necessary for survival and growth of BRAFmutant CC. Such studies may reveal additional targets for therapy and potentially provide new biomarkers for patient stratification Methods: We identified 363 genes that are selectively overexpressed in BRAF mutant tumors as compared to WT2 type tumors, based on gene expression profiles of the PETACC3 (1) and Agendia (2) datasets. The TRC human genome-wide shRNA collection (TRC-Hs1.0) was used to generate a 1815 hairpins sub-library targeting those identified genes (BRAF library). BRAF(V600E) CC cell lines were infected with the BRAF library and screened for shRNAs that cause lethality. LIM1215 CC cell line (WT2) was used as a control. Cells stably expressing the shRNA library were cultured for 13 days, after which shRNAs were recovered by PCR. Deep sequencing was applied to determine the specific depletion of shRNA in BRAF(V600E) cells as compared to LIM1215 cells Results: Candidate genes were identified by using following filtering criteria: depletion in BRAF(V600E) cells by at least 50% and depletion in BRAF(V600E) cells 1, 5-fold higher than in control cells with the corresponding p-value to be ≤ 0.1. A total of 34 genes met our criteria of which 6 genes were presented with more than one hairpin and were concordant across the cell lines selected for validation. Conclusions: We identified candidate synthetic lethal genes in BRAF mutant CC cell lines. Functional analysis is ongoing. Data will be presented. References 1. J Clin Oncol 2012 Apr 20;30(12):1288-9 2. Gut (2012). doi:10.1136/gutjnl-2012-302423
Activity of the anti-IGF-1R antibody dalotuzumab (MK-0646) in KRAS-mutant colorectal cancer: Preclinical and clinical data.
Authors: Sriram Sathyanarayanan, Mark Ayers, David Cunningham, Sabine Tejpar, Josep Tabernero, Eliza Anne Hawkes, Tae Won Kim, Tae-You Kim, Sun Young Kim, Andrey Loboda, Michael Nebozhyn, Robin Mogg, George Naumov, Andrew Bloecher, Erin Valentine, Holly M. Brown, David J. Watkins, David J. Mauro
Journal: Journal of Clinical Oncology (2012)

3587 Background: KRAS mutated metastatic colorectal cancer (mCRC) is inherently resistant to EGFR targeted therapy and carries an inferior prognosis to wild-type disease with a median survival of approximately 16 months. Methods: The activity of dalotuzumab (Dz) has been investigated in KRAS mutant pre-clinical colon cancer models. In addition efficacy data relating to a sub-set of KRAS mutant mCRC patients enrolled in a randomized phase II/III study (initiated prior to the introduction of KRAS genotyping) of Dz in combination with cetuximab (Cx) and irinotecan (Ir) are reported. All patients had received Cx and Ir with either placebo (n=20), weekly Dz (n=18), or 2 weekly Dz (n=31). Results: In pre-clinical models, Dz was found to be effective in inhibiting IGF-1 mediated cellular growth. Furthermore, in colorectal cancer xenograft models high IGF-1 was found to identify a sub-set of Dz responsive tumours. Combination studies demonstrated that Irinotecan exposure resulted in the activation of IGF-1R and PI3K signaling pathways, representing a possible cellular survival mechanism. In xenograft models the combination of Dz with irinotecan produced lasting tumor growth inhibition that persisted even after treatment withdrawal. Outcome data are reported for 69 patients with KRAS mutant mCRC enrolled in the randomized study. Efficacy data demonstrated differential activity between colon versus rectal tumours with evidence of activity in the rectal subgroup. Molecular analysis suggests that this observation may be mediated by differential IGF-1 expression. Conclusions: These data suggest that Dz in combination with irinotecan may have utility in the treatment of KRAS mutated colorectal cancer patients. Based on these data Dz is being further evaluated in a molecularly selected population of mCRC. [Table: see text]
Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma
Authors: S.M. Dieter, C. Heining, A. Agaimy, D. Huebschmann, D. Bonekamp, B. Hutter, K.R. Ehrenberg, M. Fröhlich, M. Schlesner, C. Scholl, H.-P. Schlemmer, S. Wolf, A. Mavratzas, C.S. Jung, S. Gröschel, C. von Kalle, R. Eils, B. Brors, R. Penzel, M. Kriegsmann, D.E. Reuss, P. Schirmacher, A. Stenzinger, P.A. Federspil, W. Weichert, H. Glimm, S. Fröhling
Journal: Annals of Oncology (2016)
Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer
Authors: Johannes Brägelmann, Niklas Klümper, Anne Offermann, Anne von Mässenhausen, Diana Böhm, Mario Deng, Angela Queisser, Christine Sanders, Isabella Syring, Axel S. Merseburger, Wenzel Vogel, Elisabeth Sievers, Ignacija Vlasic, Jessica Carlsson, Ove Andrén, Peter Brossart, Stefan Duensing, Maria A. Svensson, David Adler, Jutta Kirfel, Sven Perner
Journal: Clinical Cancer Research (2016)

Purpose: The Mediator complex is a multiprotein assembly, which serves as a hub for diverse signaling pathways to regulate gene expression. Because gene expression is frequently altered in cancer, a systematic understanding of the Mediator complex in malignancies could foster the development of novel targeted therapeutic approaches.Experimental Design: We performed a systematic deconvolution of the Mediator subunit expression profiles across 23 cancer entities (n = 8,568) using data from The Cancer Genome Atlas (TCGA). Prostate cancer-specific findings were validated in two publicly available gene expression cohorts and a large cohort of primary and advanced prostate cancer (n = 622) stained by immunohistochemistry. The role of CDK19 and CDK8 was evaluated by siRNA-mediated gene knockdown and inhibitor treatment in prostate cancer cell lines with functional assays and gene expression analysis by RNAseq.Results: Cluster analysis of TCGA expression data segregated tumor entities, indicating tumor-type-specific Mediator complex compositions. Only prostate cancer was marked by high expression of CDK19 In primary prostate cancer, CDK19 was associated with increased aggressiveness and shorter disease-free survival. During cancer progression, highest levels of CDK19 and of its paralog CDK8 were present in metastases. In vitro, inhibition of CDK19 and CDK8 by knockdown or treatment with a selective CDK8/CDK19 inhibitor significantly decreased migration and invasion.Conclusions: Our analysis revealed distinct transcriptional expression profiles of the Mediator complex across cancer entities indicating differential modes of transcriptional regulation. Moreover, it identified CDK19 and CDK8 to be specifically overexpressed during prostate cancer progression, highlighting their potential as novel therapeutic targets in advanced prostate cancer. Clin Cancer Res; 23(7); 1829-40. ©2016 AACR.
43P Prognostic Value of Detection Mode in Over 1000 Consecutively Treated Grade 2 Breast Cancers (BC)
Authors: O. Brouckaert, B. Van Calster, K. Van Hoorde, E. Van Limbergen, H. Wildiers, C. Van Ongeval, A. Van Steen, I. Vergote, M. Christiaens, P. Neven
Journal: Annals of Oncology (2012)