tbuckley/cabot-search huggingface dataset:
Association of abnormal cytogenetics at date of morphologic complete remission (CR) with overall (OS), disease-free survival (DFS) and higher relapse rate in acute myeloid leukemia (AML): Results from Cancer and Leukemia Group B (CALGB) 8461
Authors: G. Marcucci, K. Mrózek, A. S. Ruppert, M. J. Pettenati, N. A. Heerema, A. J. Carroll, P. R. K. Koduru, J. Anastasi, R. A. Larson, C. D. Bloomfield
Journal: Journal of Clinical Oncology (2004)

6514 Background: As most AML patients (pts) with morphologic CR ultimately relapse, better predictors for outcome are needed. Recently, Cheson et al. (JCO 2003;21:4642) proposed cytogenetic remission as part of the criteria for CR (CRc). This is the 1st large study of usefulness of CRc. Methods: Karyotypes at diagnosis (dx) and at date of 1st CR from pts treated on CALGB front-line studies were centrally reviewed. Pts with abnormal cytogenetics at dx and normal cytogenetics at CR (NCR; n=103) were compared to pts with abnormal cytogenetics both at dx and CR (ACR; n=16) for OS, DFS and cumulative incidence of relapse (CIR). Cox proportional hazards models assessed the prognostic impact of cytogenetics at CR, adjusting for other covariates. Results: Clinical features were similar for both groups, except favorable cytogenetics [t(8;21), inv(16), t(15;17)] at dx was present in 60 (58%) NCR vs 4 (25%) ACR pts (P=0.02) and NCRs had higher % marrow blasts (P=0.03). Median follow-up was 3.1 years (range, 1.0–11.4). ACRs had shorter OS (P=0.003) and DFS (P<0.0001) and higher CIR (P<0.0001). At 3 and 5 years, the rate of relapse or death was worse for ACRs. Similar trends were observed when only pts without favorable cytogenetics were analyzed. In multivariable models, the NCR/ACR groups were significant predictors for OS (P=0.02), DFS (P=0.01) and CIR (P=0.03). The relative risk of relapse or death for ACRs was 2.0 - 2.2 times that of NCRs (95%CI: 1.1–1.2 to 3.8–4.3 depending on endpoint). Conclusions: Our data suggest that reverting to a normal karyotype at time of 1st CR is an important prognostic factor and support the use of cytogenetic remission (CRc) as a criterion for CR in AML. No significant financial relationships to disclose.
Chemokine Induction by All-Trans Retinoic Acid in Acute Promyelocytic Leukemia - Triggering the Retinoic Acid Syndrome
Authors: Maaike Luesink, Jeroen Pennings, Willemijn Wissink, Peter Linssen, Petra Muus, Rolf Pfundt, Richard Huijbens, Theo de Witte, Bert van der Reijden, Joop H. Jansen
Journal: Blood (2008)
Long-term survival in patients with metastatic castration resistant prostate cancer (mCRPC) treated with enzalutamide in a named patient programs (NPP)
Authors: A.V. Tamma, A. Guida, C. Masini, C. Omarini, V. Clo', F. Gelsomino, P. Mighali, R. Sabbatini
Journal: Annals of Oncology (2015)
Abstract 4400: Anti-tumor activity of liposomal docetaxel prodrug MNK-010 on PC3 human prostate xenografts in mice
Authors: Richard M. Fitch, Jolette K. Wojdyla, James A. Blackledge, William D. McGhee
Journal: Cancer Research (2015)

Abstract The anti-mitotic taxanes are one of the most important families of anticancer drugs that have broad anti-tumor activity and are widely used for a variety of human cancer types. However, the taxanes are limited by a number of serious pharmacological and toxicological effects, including dose limiting myelosuppression, neurotoxicity and serious hypersensitivity reactions. We are developing a unique delivery system for docetaxel, comprised of a PEGylated liposomal nanoparticle containing a prodrug of docetaxel to improve solubility, tolerability and increase efficacy through improved pharmacokinetics and biodistribution. In this study we evaluated the antitumor activity of MNK-010 on the growth of established human PC3 xenografts in male immunodeficient mice. This study tested the hypothesis that MNK-010 can provide greater efficacy than Taxotere (docetaxel) at equivalent maximum tolerated doses (MTD) in mice implanted with human PC3 tumor cells. Male nude mice bearing PC3 human prostate xenografts were given two or four intravenous (IV) doses of MNK-010, Taxotere or saline. Dosing intervals were twenty-one days for two cycles or every four days for four cycles. The doses of Taxotere and MNK-010 were based on maximum tolerated dose (MTD) or highest dose tested for a given dose interval. Tumor volume was measured twice per week using the Biopticon tumor imaging system and tumor volume data was analyzed to determine tumor growth delay and partial tumor regression. Survival analysis was conducted and median survival time determined. MNK-010 significantly (p &amp;lt;0.05) inhibited PC3 human tumor growth in nude mice at all dose regimens evaluated compared to saline and Taxotere treatment. MNK-010 delayed tumor growth up to 145 days, which was 59 days longer than Taxotere at its MTD. MNK-010 also partially regressed 90% - 100% of tumors in all dose groups. This antitumor activity contributed to achieving median survival of 177 days, which was 150 days longer than saline control and 80 days longer than Taxotere at its MTD. This study demonstrated that Mallinckrodt Pharmaceuticals’ PEGylated liposomal docetaxel prodrug nanoparticle MNK-010 is an active antitumor agent in the PC3 prostate xenograft and possess significantly greater antitumor activity compared to the standard of care Taxotere. Citation Format: Richard M. Fitch, Jolette K. Wojdyla, James A. Blackledge, William D. McGhee. Anti-tumor activity of liposomal docetaxel prodrug MNK-010 on PC3 human prostate xenografts in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4400. doi:10.1158/1538-7445.AM2015-4400
615. Characterizing the Endogenous MTM1 Promoter
Authors: Angela McCall, Denise Cloutier, Darin Falk, Nathalie Clement, Barry Byrne
Journal: Molecular Therapy (2015)

X-linked myotubular myopathy (XLMTM) is caused by a deficiency in the phosphatase myotubularin 1 (MTM1), and affects 1 in 50,000 males. Dysregulation of MTM1 expression and function directly affects the myocyte morphology as noted by centrally located nuclei of skeletal muscle fibers. Clinically, patients present with severe hypotonia, leading to respiratory failure by one year of age and those who survive have a high risk of developing hepatis peliosis in early adolescence. Currently patients with XLMTM receive palliative care, as there is no FDA approved treatment. Initial studies have already demonstrated great promise using adeno-associated (AAV)-based gene therapy strategies in treating MTM1 deficiency. However, toxicity in cardiac muscle after delivery of AAV-DESPro-Mtm1 has been observed in mice, possibly related to the level of Mtm1 expression. Here, we characterized a region of the endogenous MIM1 promoter (MTMPro) using a Luciferase Reporter Assay in vitro and in vivo, in order to regulate the expression of MTM1 associated with toxicity. A 1.3kb region of DNA upstream of the human MIM1 gene was analyzed and confirmed to contain promoter elements. The DNA sequence was examined using TFSEARCH and results indicate the presence of both ubiquitous and muscle-specific transcription factorbinding sites. MTMPro was cloned in front of a luciferase reporter gene and its activity was first verified in HEK293 cells, murine myoblasts, and HepG2 cells, in which we found expression of the two promoters to be cell type specific. C57BL/6 mice were administered by an intravenous injection of rAAV2/9 vectors containing DESPro-Luc and MTMPro-Luc. Bioluminescent scanning and tissue analysis was completed one month post-injection. Preliminary results indicate that MTMPro expresses at a higher level than DESPro in most tissues. The luciferase gene was then swapped out for a codon optimized human MIM1 transgene. These vectors were first administered locally to the Tibialis Anterior of wt mice. Myotubularin 1 was observed via western blot and shown to be functionally active from the rAAV2/9-DESPro-hMIM1 samples. Levels of hMTM1 were below detection in the rAAV2/9-MTMPro-hMTM1 samples. The cause of the discrepancy between the reporter and therapeutic vectors will be further investigated. We believe that systemically delivering a vector containing either the MTMPro or a lower dose of DESPro to drive MTM1 expression in an AAV9 vector will result in therapeutic levels of gene expression without causing cellular toxicity in a mouse model of XLMTM.
Long-term bosutinib (BOS) for Philadelphia Chromosome–Positive (Ph+) advanced (ADV) chronic myeloid leukemia (CML) after prior tyrosine kinase inhibitor (TKI) failure.
Authors: Carlo Gambacorti-Passerini, Hagop M. Kantarjian, Dong-Wook Kim, Hanna Jean Khoury, Jeffrey Howard Lipton, Tim H. Brümmendorf, Kay Noonan, Ewa Matczak, Eric Leip, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2015)

7068 Background: ADV Ph+ CML pts have worse outcomes vs chronic CML pts. In this first report of BOS activity in this cohort as fully enrolled, we evaluate long-term efficacy and safety of BOS in ADV pts ≥4 vs ≥1 y from last enrolled pt. Methods: Ongoing phase 1/2 BOS study in 79 accelerated (AP) and 64 blast phase (BP) pts with prior TKI failure Results: For AP and BP pts, 18% and 3% remained on BOS at 4 y (vs 48%; 13% at 1 y; 1 y = 48 wk); 57% and 28% newly attained or maintained baseline overall hematologic response (OHR) by 4 y (most by 12 mo); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 y (most by 12 mo). Kaplan-Meier (KM) probabilities of maintaining OHR in responders at 4 vs 1 y were 49% vs 78% (AP) and 19% vs 28% (BP); KM MCyR probabilities at 4 vs 1 y were 49% vs 65% (AP) and 21% vs 21% (BP). AP and BP pts were treated for median 10.2 (range, 0.1–88.6); 2.8 (0.03–55.9) mo. Most common AEs were gastrointestinal (AP, 96%; BP, 83%), primarily diarrhea (85%; 64%), which was typically low grade (grade 1/2: 96%; 93%), transient (median duration/any grade AE: 2 [range, 1–910] d; 2 [1–211] d); no pt discontinued due to this AE. Newly occurring AEs arose mostly in y1; new cardiac/vascular AEs occurring in y4 were pericardial effusion, sinus bradycardia/1st degree atrioventricular block (same pt), and hypertension (all n=1); those in y1 (>2 pts either cohort) were pericardial effusion (AP, n=4; BP, n=1), tachycardia (n=2; n=4), hypertension (n=3; n=2; Table). Serious AEs occurred in 56% AP and 58% BP pts, most commonly pneumonia (n=9; n=5). 11 AP and 13 BP pts died within 30 d of last dose; 2 BOS-related (AP). Treatment discontinuations were mostly due to PD (AP, ≤1/>1 y, n=10/13; BP, n=29/3) and AEs in AP (n=16/5); death (n=6/0) and symptomatic deterioration (n=6/0) in BP. Conclusions: Durable response was seen in ~50% AP responders (~25% BP responders at y1, for whom BOS may be bridge to transplant); toxicity was manageable with long-term treatment. Clinical trial information: NCT00261846.Newly Occurring AEs*. n Y1 Y2 Y3 Y4 AP n=79 BP n=64 AP n=34 BP n=5 AP n=19 BP n=3 AP n=15 BP n=2 Diarrhea 67 41 0 0 0 0 0 0 Cardiac 12 7 1 1 1 1 2 0 Vascular 4 7 4 0 1 0 1 0 *Not experienced by same pt previously (denominator=pts on treatment each y [1 y = 52 wk]).
132. Gene Therapy With Self-Complementary Recombinant Adeno-Associated Virus in Models of Autosomal Dominant Retinitis Pigmentosa Cause by RHO Mutations
Authors: Brian Rossmiller, Danny Zakria, Arathi Nandyala, Hiral Jivanji, Lewin Alfred
Journal: Molecular Therapy (2015)

Retinitis pigmentosa is the leading hereditary cause of blindness with 30-40% of cases attributable to autosomal dominant retinitis pigmentosa (ADRP). ADRP arises from mutations in at least 24 known genes with 30% arising in the rhodopsin gene (RHO). Given the large heterogeneity of mutations in RHO leading to ADRP, we propose knocking down of endogenous RHO and replacing it with a "hardened" copy, or a RHO with nucleotide changes that preserve the amino acid sequence but decrease the efficiency of knock-down. Here we report the use of a scAAV serotype 8 (Y733F) to express a hardened human rhodopsin (hRHO) under the control of the human opsin proximal promoter (HOPS) and an H1 promoter driven shRNA. Four different knock-down methods were tested, ribozyme (Rz) 407 and Rz525, miRNA 301 and shRNA 301 against both the wildtype and hardened RHO target regions. The transfections were done in HEK293 cells (n=6) with (1) the target plasmid psiCheck2 dual luciferase containing RHO target region, (2) plasmid expressing the shRNA, miRNA or ribozyme against the target region and (3) a control miRNA. The reduction in expression of luciferase was measured at 24 and 48 hours post transfection. We are using adeno-associated virus vectors to deliver these RNA knockdown agents to mouse models of ADRP: Rho I307N and human RHO transgenic T17M and P23H. Mice were injected with AAV-HOP-hRHO and knockdown agents at postnatal day 5. I307N Rho mice were created through the use of N-ethyl-N-nitrosourea (Budzynski et al. JBC 2010). The I307N mouse model exhibits very slow degeneration under ambient light but is reduced in visual response to light by 50% in one week post exposure to 10,000 lux. Intravitreal injections with one of the two constructs, hRHO+shRNA301, or hRHO+shRNA750 in one eye and AAV-HOPS-mCherry or sham injection in the other. The mice were followed using electroretinogram and optical coherence tomography. The knock-down results show shRNA301 and ribozyme 525 to cause the largest reduction of RHO mRNA. At one month post injection there was statistically significant difference between T17M RHO eyes injected with AAV-hRHO-shRNA750 and the sham injected eyes. We have generated a series of combination RNA knockdown and replacement AAV vectors that may be useful for the treatment of ADRP. At early time points, our tests of these specific vectors have not been conclusive. The injected mice will be followed for longer intervals and additional mice will be added to the study to determine if the difference in visual function of the experimentally treated eyes versus the control is statistically significant.
Serum Ghrelin and Leptin Levels of Patients With Inflammatory Bowel Disease Compared to a Control Group and its Association With Nutritional Status: A Case-Control Study
Authors: Firas Ghomraoui, Sami Alotaibi, Meshal Alharthi, Saeed Asiri, Majid Almadi, Othman Alharbi, Nahla Azzam, Abdulrahman Aljebreen, Maria Saeed, Baraa Hajkhder, Waleed Saeed, Mohammed Alzoghaibi
Journal: Clinical Gastroenterology and Hepatology (2016)
The Role of Omalizumab in Patients With Eosinophilic Granulomatosis With Polyangiitis (Churg‐Strauss): Comment on the Article by Jachiet et al
Authors: Aikaterini Detoraki, Gilda Varricchi, Arturo Genovese, Gianni Marone, Giuseppe Spadaro
Journal: Arthritis & Rheumatology (2016)
Use of detailed pathologic characteristics of the primary colorectal tumor to predict outcome after hepatectomy for metastases.
Authors: Kenneth Cardona, Francesco D'Amico, Jinru Shia, Mithat Gönen, Martin R. Weiser, Philip Paty, T. Peter Kingham, Peter J Allen, Ronald P. DeMatteo, Yuman Fong, William R. Jarnagin, Michael Ian D'Angelica
Journal: Journal of Clinical Oncology (2012)

559 Background: Outcome after hepatic resection for colorectal liver metastases (CRLM) is heterogeneous and accurate predictors of survival are lacking. The aim of our study was to analyze the prognostic relevance of pathologic details of the colorectal primary tumor in patients undergoing hepatic resection of CRLM. Methods: Retrospective review of a prospective database identified patients who underwent potentially curative hepatic resection of CRLM. Clinicopathological variables were investigated and their association with outcome was analyzed. Results: From 1997-2007, 1004 patients underwent hepatic resection for CRLM. The median follow-up for survivors was 59 months with a 5-year predicted survival of 47%. Ninety-two percent of patients received perioperative chemotherapy and 34% received adjuvant hepatic artery infusion chemotherapy. Univariate analysis identified 10 factors associated with poor survival. Three of these related to the pathology of the primary tumor: lymphovascular invasion (LVI, p&lt;0.0001), perineural invasion (p=0.005), and degree of regional lymph node involvement (N0 vs N1 vs N2, p&lt;0.0001). Multivariate analysis identified 7 factors associated with poor survival. Two of these related to the pathology of the primary tumor: LVI (HR 1.3, 95% CI 1.06-1.64, p=0.01) and degree of regional lymph node involvement where an increase in the number of metastatic regional lymph nodes from N1 (HR 1.3, 95% CI 1.04-1.69, p=0.02) to N2 (HR 1.7, 95% CI 1.27-2.21, p &lt;0.0005) was associated with a reduced survival. LVI positive patients had a median survival of 48 months compared to 69 months for LVI negative patients (p&lt;0.0001); moreover, patients who were LVI positive with N2 nodal disease had a reduced survival to 40 months compared to 74 months for patients who were LVI negative with no nodal disease (p&lt;0.0001). Conclusions: Resection of CLRM is associated with long-term survival. Pathologic details of the primary colorectal tumor, particularly LVI and the degree of lymph node involvement, are strong predictors of survival. Future biomarker studies should consider utilizing factors related to the primary colorectal tumor.
Effect of hospitals on survival and postoperative mortality of stomach cancer: A population-based study on type, referral, and volume-effect in the northeast Netherlands
Authors: E. Siemerink, M. Schaapveld, G. A. Hospers, N. H. Mulder, J. T. Plukker
Journal: Journal of Clinical Oncology (2009)

e15564 Background: To optimize treatment results of patients with stomach cancer some institutions prompt referral to high volume hospitals with experienced surgeon's analogue to esophageal cancer. We analyzed if evidence can be found for superior treatment outcome depending on hospital type, referral pattern or hospital volume. Methods: Data from all patients diagnosed with primary invasive stomach cancer from 1994–2006 were obtained from the nationwide Netherlands Cancer Registry of the north-east part of the Netherlands. This area is served by one university hospital (U), 4 teaching hospitals (T), and 18 non-teaching hospitals (N-T). Results: In the study period, 5243 patients were diagnosed with stomach cancer (65.6% men, 34.4% female), 44.5% underwent surgery. Older age, advanced stage and proximal tumor location resulted in a lower probability of tumor resection. The 5 year relative survival (5yrsurv) was similar in the three hospital types. However, patients with proximal tumors were more often referred for surgery to U (18%), especially by N-T hospitals. In the non-proximal tumors the 5yrsurv was significantly better in U versus T and N-T hospitals, also after multivariate analysis. The significantly better 5yrsurv of low referral centers disappeared after excluding hospital U. No volume effect could be observed. Postoperative mortality registered in the period from 2004–2006 showed no differences between the hospitals. Conclusions: We found highly superior survival for non-proximal tumors but not for proximal cancer in an university hospital. In this study no evidence was found for a referral or volume effect. [Table: see text] No significant financial relationships to disclose.
Abstract 5395: Anti-tumor activity of BMS-595, a novel CK2 kinase inhibitor
Authors: Brent A. Rupnow, Chiang Yu, Jonathan G. Pabalan, Urvashi V. Roongta, Jonathan S. Lippy, Ashok R. Dongre, Mary T. Obermeier, Aberra Fura, Paul A. Elzinga, Benjamin J. Henley, Joseph Fargnoli, Francis Y. Lee, William R. Foster, Christine M. Tarby, Brian E. Fink, John S. Tokarski, Ashvinikumar V. Gavai, Tai W. Wong, John T. Hunt, Gregory D. Vite, Ashok V. Purandare
Journal: Cancer Research (2015)

Abstract The CK2 protein kinases are a small family of two highly related serine/threonine kinases composed of two catalytic subunits, α and α’, and a single β subunit. Numerous substrates have been reported for CK2 and these proteins are known to participate in diverse cellular processes, including cell signaling, transcription, DNA repair, apoptosis regulation and tumor suppression. Elevated CK2 expression and kinase activity has been observed in many cancer types. Further, mRNA knockdown and enzyme inhibition studies have demonstrated that many cancer cell lines are dependent on CK2 for growth and survival. To further evaluate CK2 kinases as targets for therapeutic intervention in cancer, we identified BMS-595, a potent and selective, ATP-competitive CK2 inhibitor. BMS-595 inhibits the in vitro proliferation of human colorectal and lung cancer cell lines with IC50s ranging from less than 10 nM to greater than 1 μM. In sensitive cell lines, anti-proliferative effects of BMS-595 and structurally related analogs strongly correlated with cellular CK2 kinase inhibition. Oral administration of BMS-595 to mice bearing colorectal cancer and lung cancer xenografts demonstrated pharmacodynamic effects and robust efficacy at tolerated doses. These studies confirm the dependence of a subset of human colon and lung cancer cell lines on CK2 activity for growth and demonstrate that pharmacologic inhibition of CK2 can produce anti-tumor efficacy at tolerated doses. Citation Format: Brent A. Rupnow, Chiang Yu, Jonathan G. Pabalan, Urvashi V. Roongta, Jonathan S. Lippy, Ashok R. Dongre, Mary T. Obermeier, Aberra Fura, Paul A. Elzinga, Benjamin J. Henley, Joseph Fargnoli, Francis Y. Lee, William R. Foster, Christine M. Tarby, Brian E. Fink, John S. Tokarski, Ashvinikumar V. Gavai, Tai W. Wong, John T. Hunt, Gregory D. Vite, Ashok V. Purandare. Anti-tumor activity of BMS-595, a novel CK2 kinase inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5395. doi:10.1158/1538-7445.AM2015-5395
Identification of Candida Albicans
Journal: JAMA (1963)

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