tbuckley/cabot-search huggingface dataset:
Multicenter Phase IB trial of carboxyamidotriazole orotate (CTO) combined with temozolomide (TMZ) for recurrent glioblastoma (GBM) and other malignant gliomas (MG).
Authors: Xuling Lin, Thomas Joseph Kaley, Elena Pentsova, Lisa Marie DeAngelis, Mariza Daras, Igor T. Gavrilovic, Ingo K. Mellinghoff, Andrew McKeown, Malbora Manne, Jessica Hansen, Linda M. Bavisotto, Greg Gorman, Michael Lamson, Rashida A. Karmali, Antonio Marcilio Padula Omuro
Journal: Journal of Clinical Oncology (2016)

2064 Background: CTO is an oral inhibitor of non-voltage-dependent calcium signaling that results in simultaneous modulation of several receptor-mediated calcium-dependent signaling pathways. This study (NCT01107522) evaluated the combination of a standard TMZ schedule with escalating doses of CTO (219-812.5 mg/m2/day) in TMZ-refractory mg pts. Methods: Eligible pts (≥ 18years) had recurrent mg and ECOG ≤ 2. Using a 3+3 design, pts received escalating daily doses of CTO combined with TMZ 150 mg/m2 x 5/28 days. Primary objectives were safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of CTO; secondary objectives were antitumor activity and pharmacokinetic (PK) characterization. Results: Accrual has been completed, with N = 27 pts (8 women, median age 49, range 28-78); 44% had ≥ 2 recurrences and 15% previously failed bevacizumab. Histology was GBM in 16, anaplastic glioma in 11. Molecular studies revealed IDH-1/2mutation in 8/21 (38%), 1p19q codeletion in 1/17 (5%), and MGMT promoter methylation in 9/18 (50%). The combination was well tolerated with no dose-limiting toxicities (DLT) observed at doses 219-812mg/m2. Most frequent adverse events were fatigue, nausea, vomiting, constipation and headache, all grades 1 or 2. PK showed inter-patient variability, with no proportional drug exposure increase beyond 600mg. Given the lack of DLTs, and based on PK data, the 600mg flat dose was chosen as RP2D, and this level accrued 6 more pts. Analysis of drug concentrations in two pts undergoing surgery on study showed therapeutic concentrations (1705 ng/g and 6,200 ng/g). Exploratory efficacy analysis among evaluable pts (N = 23) showed a partial response in 5 and stable disease in 10, for a clinical benefit (PR+SD) rate of 65% (43-84%). Response duration ranged from 2-15 months. The 6m-PFS was 29% (95% CI 11-49) and 1y-OS was 50% (95% CI 27-69). Conclusions: In this heavily pre-treated population, CTO combined with TMZ was safe and well tolerated. The MAD was 812 mg/m2/day and RP2D was 600mg/day. CTO crosses the blood-brain barrier. Responses were seen, and given encouraging signals of activity, further development is warranted. Clinical trial information: NCT01107522.
The Dark Matter of Cerebral Microbleeds—Reply
Authors: Georgios Tsivgoulis, Aristeidis H. Katsanos, Andrei V. Alexandrov
Journal: JAMA Neurology (2016)

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Influence Of Expression Levels Of ATP-Binding-Cassette Transporters (ABC-B1, ABC-G2) On Survival Outcome In Adults Patients With Acute Lymphoblastic Leukemia
Authors: Carolina Balderas Delgado, Alvaro Cabrera Garcia, Irma Olarte Carrillo, Etta Rozen Fuller, Christian Omar Ramos Peñafiel, Juan Collazo Jaloma, Humberto Baldemar Castellanos Sinco
Journal: Blood (2013)
International Comparison of Smoking and Metabolic Control in Patients With Type 1 Diabetes
Authors: Sabine E. Hofer, Kellee Miller, Julia M. Hermann, Daniel J. DeSalvo, Michaela Riedl, Irl B. Hirsch, Wolfram Karges, Roy W. Beck, Reinhard W. Holl, David M. Maahs
Journal: Diabetes Care (2016)

Smoking may influence metabolic control and increase the risk of vascular complications in type 1 diabetes (T1D) (1,2). Antismoking public health policy may influence smoking habits in the population with diabetes; therefore, different behaviors between Europe and the U.S. may be expected (3,4). The T1D Exchange Registry (T1DX) in the U.S. and the Prospective Diabetes Follow-up Registry (DPV) in Germany and Austria are two large consortia of diabetes centers, which used their data sets to describe the prevalence of smoking habits in adults with T1D and analyzed the relationship between smoking status and metabolic outcomes.

Our analyses include 20,405 patients with T1D aged ≥18 years and with T1D duration ≥1 year (10,579 participants from 65 T1DX centers and 9,826 participants from 297 DPV centers). Smoking status was defined by smoking at least one cigarette per day, former smokers reported smoking in the past, and nonsmokers never smoked. Smoking data were self-reported in …
Is liver stiffness equal to liver fibrosis?
Authors: Maja Thiele, Bjørn Stæhr Madsen, Aleksander Krag
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. To the Editor: We read with interest the article by Koehler and colleagues.1 The elaborate study provides important information on the prevalence of increased liver stiffness in a suburban population in the Netherlands. By systematically investigating 3,041 participants, the authors conclude that 5.6% of the general population over 45 years of age has increased liver stiffness above 8 kPa, suggestive of clinically relevant fibrosis. Diabetes and ultrasound‐assessed steatosis in combination was a particularly strong predictor of increased liver stiffness. We commend the authors for their large‐scale, thorough work, which is an important step toward early detection of chronic liver disease in the general population. With increasing availability of noninvasive markers of liver fibrosis, it is likely that more studies similar to the Rotterdam Study will be conducted. We therefore wish to use the opportunity to discuss the pitfalls of equating liver stiffness with liver fibrosis in a population with a low prevalence of chronic liver disease. The authors chose 8 kPa as a cutoff for clinically relevant fibrosis (≥F3). The biopsy‐controlled study used for reference2 assessed transient elastography in 246 nonalcoholic fatty liver disease patients referred for investigations at a hospital liver clinic, where 23% of patients had severe fibrosis. When this result is extrapolated to the general population, one should consider the problem of spectrum bias—that disease prevalence affects test performance. In an unsorted background population, the prevalence of severe fibrosis is most likely lower than the 5.6% with elevated liver stiffness reported in the Rotterdam Study. An "optimistic" estimate is 5%. Given this prevalence and assuming that transient elastography has the same accuracy as in the index study—a sensitivity of 91% and a specificity of 75% for detecting severe fibrosis—the positive predictive value is only 16%. As an example of spectrum bias, in a recent screening study of type 2 diabetics, 18% had elevated liver stiffness, whereas only half of those with elevated liver stiffness undergoing liver biopsy had severe fibrosis.3 Consequently, we need strategies to increase the positive predictive value when screening for chronic liver diseases in the general population or in groups with low prevalence such as those with diabetes or alcoholism. We suggest considering pretest probabilities or disease prevalence before interpreting the result of a diagnostic test. Only in high‐prevalence populations can liver stiffness with certainty be equated with liver fibrosis.
Subsequent Malignant Neoplasms After Allogeneic Hematopoietic Stem Cell Transplantation Using Reduced-Intensity Conditioning and Outpatient Conduction
Authors: Gabriela Zamora-Ortiz, Sara Velazquez-Sanchez-de-Cima, Sergio Ponce-de-Leon, César H. Gutiérrez-Aguirre, Guillermo J. Ruiz-Delgado, David Gomez-Almaguer, Guillermo J. Ruiz-Arguelles
Journal: Blood (2013)
Changes in the clinical presentation of patients with rheumatoid arthritis from the early 1990s to the years 2010: earlier identification but more severe patient reported outcomes
Authors: Wouter P Nieuwenhuis, Maarten PT de Wit, Annelies Boonen, Annette HM van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2016)

The relevance of early identification of rheumatoid arthritis (RA) is acknowledged for several decades. Over time the interpretation of early has changed: in the early 1990s a symptom duration <2 years was considered early. Nowadays earlier identification is recommended,1 some suggest that identification within 12 weeks after symptom onset is optimal. In this study, we evaluated the presentation of RA over the past decennia. We assessed whether patients with RA were recognised earlier and if this affected the phenotype of RA at first presentation. We observed that patients with RA are indeed identified after a shorter symptom duration, that this was paralleled with less severe inflammation at presentation, but paradoxically also with increased severity of patient reported outcomes (PROMs).

All patients in the Leiden Early Arthritis Clinic (EAC) cohort that fulfilled the 2010 European League Against Rheumatism/American College of Rheumatology RA criteria were studied (n=1406).2 ,3 In short, the EAC was started in 1993 and inclusion criteria …
Persistent detection of Zika virus RNA in semen for six months after symptom onset in a traveller returning from Haiti to Italy, February 2016
Authors: Emanuele Nicastri, Concetta Castilletti, Giuseppina Liuzzi, Marco Iannetta, Maria R Capobianchi, Giuseppe Ippolito
Journal: Eurosurveillance (2016)

A man in his early 30s reported in January 2016 a history of fever, asthenia and erythematous rash during a stay in Haiti. On his return to Italy, ZIKV RNA was detected in his urine and saliva 91 days after symptom onset, and in his semen on day 188, six months after symptom onset. Our findings support the possibility of sexual transmission of ZIKV and highlight the importance of continuing to investigate non-vector-borne ZIKV infection.
Paediatric primary cutaneous marginal zone B-cell lymphoma: does it differ from its adult counterpart?
Authors: I. Amitay-Laish, M. Tavallaee, J. Kim, R.T. Hoppe, L. Million, M. Feinmesser, E. Fenig, M.E.L. Wolfe, E. Hodak, Y.H. Kim
Journal: British Journal of Dermatology (2016)

Primary cutaneous marginal zone B‐cell lymphoma (PCMZL) has rarely been reported in patients younger than 20 years. To report our experience with PCMZL in the paediatric/adolescent age group. Medical records of patients diagnosed with PCMZL before age 20 years and managed at two cutaneous lymphoma clinics in the U.S.A. and Israel from 1992 to 2015 were reviewed. The study group included 11 patients (six girls; median age 16 years, range 6–19·5); 10 had generalized/multifocal (T3) and one had regional/localized (T2) disease. Lesions were located on the limbs in all patients and the trunk in six; two had facial lesions. Staging in all but one was based on whole‐body computed tomography or positron emission tomography. Initial management in most patients included nonradiation modalities: one patient with localized disease received intralesional steroids; six patients with multifocal disease received the following: topical/intralesional steroids (n = 3); excision (n = 2); 'watch and wait' (n = 1). No extracutaneous progression was noted during a median follow‐up of 5·5 years (mean 7·5, range 0·5–14). At present, five patients are in complete remission. Based on our data (largest series in the literature with the longest follow‐up), the clinicopathological presentation and course of PCMZL in the paediatric/adolescent age group are similar to those in adults. Given the indolent course and the long life expectancy of these young patients, the cumulative risk of imaging studies and the age‐related potential toxicity of treatment, especially radiation, should be taken into consideration.
The findings and recommendations of a breast Multidisciplinary Genomic Tumor Board.
Authors: Karen Tsung, Cheryl L. Thompson, Joy Knight, Steve Maximuk, Navid Sadri, Paula Silverman
Journal: Journal of Clinical Oncology (2016)

e23138 Background: Advancements in precision medicine and genomic sequencing are evolving rapidly. To apply the results of complex genomic assays to breast cancer patient (pt) care, University Hospitals Case Medical Center (UHCMC) initiated a Multidisciplinary Genomic Tumor Board (MGTB). This study describes the largest reported experience to-date of a breast MGTB. Methods: Data was collected retrospectively from UHCMC breast cancer pts who received genomic testing (GT) and were discussed at MGTB between 11/2013 and 9/2015. Recommendations for treatment based on GT were made at MGTB and level of evidence assigned. The cohort was divided into earlier (N = 37) and later halves (N = 38) to assess changes over time. Results: 72 females/1 male (median age 55.5, range 33-77) were eligible; all had metastatic breast cancer (MBC). The median time from receipt of GT to discussion with the pt was 30 days (range 1-129, N = 47), and did not significantly change over time. A total of 404 genomic alterations were identified with 1-18 alterations/pt (median = 5). The most common reported were TP53 (54.8%, N = 40), PIK3CA (31.5%, N = 23), MYC (21.9%, N = 16), FGFR1 (17.8%, N = 13), and FGF19 (16.4%, N = 12). Examining pathways rather than individual mutations, we found frequent mutations in the receptor tyrosine kinase signaling pathway (79.5%, N = 58), the p53 signaling pathway (65.8%, N = 48), and the ER activation pathway (31.5%, N = 23). GT prompted level 1 recommendations for 13 pts (17.8%) and this did not change over time. The number of pts with specific clinical trial recommendations made by MGTB increased from 24.3% in the earlier half to 68.4% in the later half (p < 0.001). Patient survival after MGTB discussion was 91.7% at 3 months (mos), 76.6% at 6 mos, 65.9% at 9 mos, and 46.1% at 12 mos. Conclusions: Elapsed time from testing to reporting results to pts was clinically feasible. We found expected mutations and impacted pathways in our pts. MGTB was helpful in developing genomically driven recommendations. Over time the recommendations for clinical trials that target specific pathways increased. Survival data demonstrates that pts were presented at MGTB with sufficient time to potentially benefit from recommendations; long-term follow up will demonstrate any impact.
Sequential and intermittent docetaxel (D) and imatinib (Im) in hormone-refractory prostate cancer patients (NYU 04–47)
Authors: A. Gómez-Pinillos, H. Ballard, G. Shelton, M. M. Reilly, A. Chachoua, S. Taneja, A. C. Ferrari
Journal: Journal of Clinical Oncology (2009)

e16108 Background: Platelet-derived growth factor is frequently expressed in advanced prostate cancer (PC) lesions where it supports PC cell growth and neo-angiogenesis. Im. is a PDGF inhibitor that blocks cell cycle in G1-S due to MEK/erk inhibition. D blocks cell cycle progression in G2-M. Sequential block of the cell cycle progression in G2-M followed by G1-S may increase anti-tumor responses. The phase II study dose of sequential D on day 1 and Im started 24–36h later given daily for 14 d was established in a previous phase I. Methods: Eligibility: at least 2 prior hormone manipulations and up to one prior chemotherapy, PSA&gt;5ng/ml, ECOG PS 0–2. Treatment schedule: D 70mg/m2 day 1 followed 24–36 hours later by Im 600mg PO daily × 14 days. Cycles were repeated every 21d until toxicity or progression. Pegfilgrastim was given each cycle for neutropenia prevention. A two steps design was planned to assess activity (PSA decline &gt;50% and/or measurable or symptomatic response) and tolerance including interim analysis to determine if 37 patients (pts) should be enrolled. Results: Of 15 pts enrolled, 13 had metastasis and 5(33%) received prior chemotherapy. There were 98 cycles of trial therapy administered and 9 events (PSA or bone progression) registered at the time of analysis. Median baseline PSA 73,5ng/ml (2.1–1954.3). Median follow-up estimated by inverse Kaplan Meier: 308 days (CI95%, 133–482). Median of cycles administrated 6 (1–12). PSA decline &gt;50% observed in 7/15pts (46.67%) of which 3 was &gt;80% (20%). PSA decline &lt;50%, observed in 6/15(40%). 2/15(15.3%) were non-responders. Pain scores improved in all symptomatic pts. Median duration of response was 162 days (42- 281). Estimated median progression free survival by Kaplan-Meier was 155 days (CI95%, 80–339). Toxicity: there was G1–2 fatigue, anorexia, weight change in 66% pts; nausea, vomiting, taste changes in 66% pts, anemia in 46% and neuropathy in 46% pts. G3 fatigue in 2 pts, neuropathy and CHF in 1 pt. No G4 toxicities were observed. Conclusions: Sequential and intermittent D every 21 days and Im for 14 days is tolerable and active by PSA decline and symptomatic improvement. Compared to previous report with weekly D and continuous Im, this alternative schedule appears to have similar activity with better tolerance. [Table: see text]
A double-blind, randomized, placebo-controlled, phase II study of maintenance enzastaurin with 5-FU/leucovorin plus bevacizumab following first-line therapy for metastatic colorectal cancer (mCRC).
Authors: R. A. Wolff, W. Schepp, M. Di Bartolomeo, A. Hossain, C. Stoffregen, S. Nicol, V. Heinemann
Journal: Journal of Clinical Oncology (2011)

3527 Background: Maintenance therapy is designed to maximize progression-free survival (PFS) and minimize toxicity in mCRC. Enzastaurin (ENZ) is an oral serine/threonine kinase inhibitor targeting PKCβ and AKT/PI3K pathways. Preclinical studies showed synergistic antitumor effects when ENZ was combined with bevacizumab (BV). In phase I studies, the combination was well tolerated. Our phase II study assessed ENZ with 5-FU/Leucovorin (5-FU/LV) plus BV as maintenance therapy for mCRC. Methods: Patients had locally advanced or mCRC, and completed 6 cycles of first-line chemotherapy ≤4 wks prior to randomization. Arm A received a loading dose of ENZ 1125 mg, then 500 mg/d subsequent doses. Arm B received placebo. Both groups received 5-FU/LV (LV 400 mg/m2 IV, 5-FU 400 mg/m2 bolus, 5-FU 2400 mg/m2 IV) plus BV 5 mg/kg IV, every 2 wks. Patients were treated with 5-FU/LV plus BV plus either ENZ or placebo until disease progression (PD) or 1 yr. Primary endpoint: PFS from randomization. Secondary endpoints were overall survival (OS) from randomization, and OS and PFS from start of first-line therapy. Analysis was done after 50 events (objective or clinical PD or death) to compare endpoints between the treatment arms. Results: 58 patients were randomized to Arm A (57 treated), 59 to Arm B (58 treated). 82 (70.1%) patients discontinued treatment (Arm A, 42 [72.4%]; Arm B, 40 [67.8%]), mostly due to PD. Median cycles were 9 in Arm A, 10 in Arm B. Median PFS (months) was 5.8 in Arm A and 8.1 in Arm B (hazard ratio [HR]=1.35, 95% CI: 0.84, 2.16; protocol specified one-sided test, p=0.896). Median OS was not calculable due to high censoring (77.6% in Arm A and 91.5% in Arm B). Median PFS (months) from start of first-line therapy was 8.9 in Arm A and 11.3 in Arm B (HR=1.39, 95% CI: 0.86, 2.23; one-sided, p=0.913). More patients developed thrombosis or embolism (TE), including pulmonary embolism, on Arm A (5 [8.8%] patients had grade 3 and 5 [8.8%] grade 4 TE); Arm B had (no grade 3 and 1 [1.7%] grade 4 TE). Conclusions: ENZ did not show an advantage in PFS compared to BV-based therapy alone. Development of maintenance therapy with ENZ is not recommended for mCRC.
Diagnosis of Primary Intestinal-Type Adenocarcinoma in the Nasal Cavity by 18F-FDG PET/CT
Authors: Zhanli Fu, Jin Zhang, Meng Liu, Ziao Li, Qian Li
Journal: Clinical Nuclear Medicine (2016)

A soft-tissue lesion in the left nasal cavity was found on a 70-year-old man, which was pathologically proved to be an intestinal-type adenocarcinoma (ITAC) by biopsy. 18F-FDG PET/CT scan was performed to exclude the possibilities of metastasis from the other primary adenocarcinomas, but the nasal tumor was found to be the only lesion with 18F-FDG avidity. The primary ITAC in the nasal cavity was diagnosed, and it was resected successfully.
Pediatric Dose Determinations for the Phase I Study of the DOT1L Inhibitor, EPZ-5676, in MLL-r Acute Leukemia: Leveraging Early Clinical Data in Adults through Physiologically-Based Pharmacokinetic Modeling
Authors: Nigel J Waters, Blythe Thomson, Iain Gardner, Trevor N Johnson, Edward J Olhava, Roy M Pollock, Michelle Legler, Robert A Copeland, Eric E Hedrick
Journal: Blood (2014)
Non Synonymous SNP-Array-Based Disease Association Analysis in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria.
Authors: Bianca Serio, Aaron D. Viny, Ramon Tiu, Bartlomej Przychodzen, Alan Lichtin, Christine O’Keefe, Jaroslaw M.D. Maciejewski
Journal: Blood (2007)
Association of treatment for late-onset tMDS with glioblastoma recurrence in a patient displaying long-term disease response and survival.
Authors: Jennifer E. Adair, Sara Kubek, Bart L. Scott, Jason Rockhill, Maciej M. Mrugala, Hans-Peter Kiem
Journal: Journal of Clinical Oncology (2016)

e13506 Background: Gene therapy with autologous, mutant methylguanine methyltransferase (MGMT) modified blood cells prevents myelosuppression from O6-benzylguanine and temozolomide (O6BG/TMZ) chemotherapy, improving survival in glioblastoma (GBM) patients with unmethylated tumor MGMT promoters. We report a patient with therapy-related myelodysplastic syndrome (tMDS) years after GBM treatment, but eligible for allogeneic bone marrow (BM) transplantation.However, after tMDS treatment, diffuse GBM recurrence appeared. Methods: The patient received single-agent carmustine and gene-modified blood cells in 2009, then nine cycles of O6BG/TMZ. Complete blood cell counts and gene modified blood cells were monitored. GBM disease response was measured by cranial imaging and neurological evaluation. BM was assessed by hematopathology, cytogenetic and chromosome genomic array testing. Resected primary and recurrent GBM tumors were sequenced by Oncoplex. Treatment for tMDS included azacitidine and two cycles of granulocyte colony stimulating factor (G-CSF), cladribine, cytarabine, and dose-escalated mitoxantrone. Results: Gene modified blood cells disappeared after nine cycles of O6BG/TMZ, halting therapy. BM displayed normal cytogenetics, no MDS or leukemia. Complete GBM response was observed for 4 years with no further therapy. The patient presented in 2014 with fatigue and syncopy, without GBM recurrence. Macrocytic anemia ( < 5% blasts) and low megakaryocytes were observed in BM. A copy number neutral LOH on chromosome 11p was identified without gene modification. Within 5 months, blasts were 19.4%, consistent with tMDS. Treatment for tMDS achieved remission, but caused transient, severe myelosuppression, fever and aphasia. Cranial MRI then showed six enhancing foci. Biopsy confirmed recurrent GBM consistent with the primary lesion but MGMT promoter methylated. Conclusions: Delayed tMDS onset suggests longer survival may unveil a higher incidence of therapy-related hematologic abnormalities. Multiple foci of GBM recurrence after immunosuppression from tMDS treatment suggests immunologic activity against the GBM which was disrupted by the treatment.