tbuckley/cabot-search huggingface dataset:
An alvocidib-containing regimen is highly effective in AML patients through a mechanism dependent on MCL1 expression and function.
Authors: B. Douglas Smith, Steven L Warner, Clifford Whatcott, Adam Siddiqui-Jain, Brigham Bahr, Elisha Dettman, Camille Doykan, Michael H. Cardone, Steven D. Weitman, David Bearss
Journal: Journal of Clinical Oncology (2015)

7062 Background: Through multiple Phase I/II studies, alvocidib (flavopiridol) has proven to be highly effective in both frontline and relapsed/refractory AML when sequentially administered before ara-C and mitoxantrone (FLAM). In frontline patients, FLAM resulted in a complete remission (CR) rate of 70% versus 46% CR with ara-C and daunorubicin (7+3). Among patients with secondary (s)AML, FLAM produced 60% CR versus 35% CR with 7+3. The clinical activity of alvocidib in AML strongly correlates with inhibition of cyclin-dependent kinase-9 (CDK9) and disruption of super enhancer mediated transcription. The myeloid leukemia cell 1 (MCL1) gene is critically regulated by CDK9 activity under SE-mediated transcriptional control. Methods: Studies with AML cell lines were conducted to model the sequential treatment of the FLAM regimen. MCL1 expression and apoptosis were monitored in these nonclinical experiments. To further substantiate this mechanism clinically, mitochondrial profiling was conducted on 63 archived FLAM-treated samples. Results: Treatment with alvocidib results in a rapid downregulation of MCL1. In AML cell lines, we observe a two-fold decrease in MCL1 following alvocidib treatment that is associated with increased sensitivity to subsequent treatment with ara-C and mitoxantrone and enhanced apoptosis. Analysis of the BH3 priming states in AML clinical samples revealed NOXA priming was significantly higher in CR bone marrow samples (44.5% primed) compared with samples from non-responders (NR) (5.2% primed) (p = 0.006). NOXA is known to interact most directly with MCL1, suggesting that the AML samples that are most responsive to FLAM treatment may have a high survival dependence on MCL1. Interestingly, combining NOXA priming data with cytogenetic risk factors in pts with sAML, increased the predictive power of the assay as evident by a receiver operating characteristic (ROC) analysis yielding an AUC of 0.92 with p = 0.0002. Importantly, the correlation between NOXA and FLAM response is distinct from priming states predicting response to other ara-C regimens. Conclusions: This work reveals a potential biomarker for identification of patients likely to respond to FLAM.
Case 38-1983
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Edward A. Nardell, Eugene J. Mark
Journal: New England Journal of Medicine (1983)

Presentation of CaseA 68-year-old woman was admitted to the hospital because of fever of unknown origin.She was well until three months earlier, when she experienced abdominal discomfort. Several days later she found that her temperature was 38.3°C. She telephoned her physician and on his advice took ampicillin, erythromycin, sulfamethoxazole–trimethoprim, and cephalexin in sequence during the next few weeks, without improvement. She remained active, although she had transient aches in the neck and right elbow and a dry cough at night and observed that her twice-daily temperature reading ranged between 36.7 and 37.9°C. Another physician found no abnormality on . . .
Effects of Cyclic Short Recruitment Maneuvers (Sigh) in Acute Respiratory Failure Patients Undergoing Pressure Support Ventilation: an Electrical Impedance Tomography Study
Authors: T Mauri, G Bellani, M Turella, Sala, F Leone, A Perri, A Coppadoro, R Marcolin, G Citerio, N Patroniti, A Pesenti
Journal: Intensive Care Medicine (2012)
Hepatitis E virus mutations associated with ribavirin treatment failure result in altered viral fitness and ribavirin sensitivity
Authors: Yannick Debing, Christophe Ramière, Kai Dallmeier, Géraldine Piorkowski, Mary-Anne Trabaud, Fanny Lebossé, Caroline Scholtès, Magali Roche, Catherine Legras-Lachuer, Xavier de Lamballerie, Patrice André, Johan Neyts
Journal: Journal of Hepatology (2016)
Safety and activity of pembrolizumab in melanoma patients with untreated brain metastases.
Authors: Harriet M. Kluger, Sarah B. Goldberg, Mario Sznol, John Tsiouris, Alexander Vortmeyer, Lucia Jilaveanu, Amanda L. Ralabate, Angel L. Rivera, Matthew M. Burke, Upendra P. Hegbe, Justine Vanessa Cohen, Xiaopan Yao, Stephanie Speaker, Matthew Madura, Elizabeth Knapp-Perry, Amit Mahajan, Veronica Chiang
Journal: Journal of Clinical Oncology (2015)

9009 Background: Brain metastases (BrMs) develop in 40% of metastatic melanoma (MM) patients (pts). Untreated BrMs exclude from most clinical trials. In prior trials, treatment of MM with pembrolizumab (pembro), an IgG4 antagonist of the immune checkpoint PD-1, produced response rates of > 30%. A phase 2 study (NCT02085070) was initiated to assess safety and activity of pembro in pts with previously untreated or progressing BrMs. Methods: Pts with BrMs from melanoma (reported here) or lung cancer are eligible if at least 1 asymptomatic 5-20mm BrM not requiring immediate local therapy or systemic steroids is present, and at least 1 BrM is amenable to biopsy or resection. Prior PD-1/PD-L1 inhibitors are excluded. Pembro 10mg/kg is administered every 2 weeks (wks). Brain MRI is repeated at 4 wks to assess safety and restaging is done every 8 wks. Primary endpoint is BrM response by modified RECIST (lesions ≥ 5mm are measurable on MRIs with 1mm slices; up to 5 BrMs are used to determine response). Results: Between April and December 2014, 17 pts were accrued, 6 with BRAF mutations, 10 previously received ipilimumab. Activity at interim analysis was sufficient to continue. Four were unevaluable for BrM response (3 due to rapid extracerebral disease progression (PD), 1 due to intralesional hemorrhage), and 1 was too early. Among 12 evaluable pts, BrM partial responses (PRs) were observed in 3 pts (1 with prior ipilimumab), stable disease in 2, PD in 7 (2 with a mixed response and 1 with PD by imaging but pseudoprogression on histology). BrM responses are ongoing at 7+, 6+ and 3+ months. One CR and 3 PRs were observed in extra-cerebral metastatic disease, 3 of these 4 with concordant BrM response. The only grade 3 adverse event clearly related to pembro was liver function abnormalities (1 pt). Two pts had seizures, 1 from perilesional edema, 1 from tumor growth, treated with anti-convulsants and a brief course of steroids. Conclusions: Early results from this ongoing trial suggest that pembro has promising activity in untreated melanoma BrMs. CNS symptoms were controllable with anti-convulsants and transient use of steroids. Accrual is ongoing and correlative studies from pre-treatment brain and extra-cerebral tumor samples are being conducted. Clinical trial information: NCT02085070.
Changes in Bone Turnover Marker Levels and Clinical Outcomes in Patients with Advanced Cancer and Bone Metastases Treated with Bone Antiresorptive Agents
Authors: Allan Lipton, Matthew R. Smith, Karim Fizazi, Alison T. Stopeck, David Henry, Janet E. Brown, Neal D. Shore, Fred Saad, Andrew Spencer, Li Zhu, Douglas J. Warner
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Bone antiresorptive agents can significantly reduce bone turnover markers (BTM) in patients with advanced cancer. We evaluated association of changes in BTMs with overall survival (OS), disease progression (DP), and disease progression in bone (DPB) in patients with advanced cancer and bone metastases following denosumab or zoledronic acid treatment. Experimental Design: This is an integrated analysis of patient-level data from three identically designed, blinded, phase III trials with patients randomized to subcutaneous denosumab or intravenous zoledronic acid. Levels of the BTMs urinary N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (sBSAP) measured at study entry and month 3 were analyzed. OS, DP, and DPB were compared in patients with BTMs ≥ median versus &amp;lt; median based on month 3 assessments. Results: uNTx levels ≥ the median of 10.0 nmol/mmol at month 3 were associated with significantly reduced OS compared with levels &amp;lt; median (HR for death, 1.85; P &amp;lt; 0.0001). sBSAP levels ≥ median of 12.6 ng/mL were associated with significantly reduced OS compared with levels &amp;lt; median (HR, 2.44; P &amp;lt; 0.0001). uNTx and sBSAP levels ≥ median at month 3 were associated with significantly greater risk of DP (HR, 1.31; P &amp;lt; 0.0001 and HR, 1.71; P &amp;lt; 0.0001, respectively) and DPB (HR, 1.11; P = 0.0407 and HR, 1.27; P &amp;lt; 0.0001, respectively). Conclusions: BTM levels ≥ median after 3 months of bone antiresorptive treatment were associated with reduced OS and increased risk of DP and DPB. Assessment of uNTx and sBSAP levels after bone antiresorptive therapy may add to identification of patients at risk for worse clinical outcomes. Clin Cancer Res; 22(23); 5713–21. ©2016 AACR.
Pain severity and survival of terminal cancer patients
Authors: B. M. Kinzbrunner, D. C. Tanis
Journal: Journal of Clinical Oncology (2004)

8030 Background: Studies suggest that cancer patients with severe and/or poorly controlled pain have shorter survivals. Whether this is related to poor pain control or the advanced state of disease is less clear. To further evaluate this, a retrospective analysis examined the survival of cancer patients admitted to hospice with different levels of pain and the effects on survival of controlling pain within 48 hours. Methods: From 4/1/02 to 3/31/03, 41,712 patients were admitted to hospices of Vitas Healthcare Corporation, a national hospice company. At each patient contact, caregivers record patient-generated pain severity scores based on a Visual Analog Scale (range 0–10) in the Vitas clinical database. Of the 41,712 patients, 8,680 patients had cancer, had an initial pain reading recorded on admission, and died by 7/24/03. Patients were grouped based on initial pain scores: Severe (7–10); Moderate (4–6); Mild (1–3); or None (0). Survival curves were compared using the Gehan-Wilcoxon statistic. Results: Initial pain levels were similar across types of cancer. Median survival for all study patients was 18 days (range 1–429). Median survival for patients admitted with severe or moderate pain was significantly shorter than for those with mild or no pain (see table). A subset of 5,168 patients had one or more pain readings on Day 2. Patients with severe pain that was reduced to 5 or less within 48 hours had a significantly longer median survival compared to patients whose pain remained greater than 5 (18 vs. 12 days, p < .001). Conclusions: Even in the face of terminal cancer, uncontrolled pain on presentation adversely affects patient survival. Rapid reduction of severe pain may offer a small but significant survival advantage. Extrapolating these results to patients earlier in the course of disease emphasizes the importance of effective and rapid pain control in all cancer patients. No significant financial relationships to disclose.
Treatment of recurrent glioblastoma multiforme with GliaSite brachytherapy
Authors: T. A.-T. Chan, J. D. Weingart, M. Parisi, M. A. Hughes, A. Olivi, S. Borzillary, D. Alahakone, N. A. Detorie, M. D. Wharam, L. Kleinberg
Journal: Journal of Clinical Oncology (2005)

1544 Background: Glioblastoma multiforme is a primary malignancy of the central nervous system that is fatal despite treatment with surgery and standard adjuvant therapy. Long-term control of these tumors is rarely achieved and GBM frequently recurs. In this study, we assess the efficacy of GliaSite brachytherapy in the treatment of patients with recurrent glioblastoma multiforme (GBM). Methods: Between 1999 and 2004, twenty-four patients with recurrent glioblastoma multiforme were treated with the GliaSite Radiation Therapy System (RTS). The GliaSite is an inflatable balloon catheter that is placed in the resection cavity at the time of surgical resection. Low-dose rate radiation is then delivered locally by temporarily inflating the balloon with an aqueous solution of organically bound I-125 (Iotrex [sodium 3-(I-125)-iodo-4-hydroxybenzenesulfonate]). Patients at the Johns Hopkins Hospital with recurrent GBM underwent surgical reresection followed by GliaSite balloon implantation. Subsequently, the patients received radiation therapy using the GliaSite to a mean dose of 53.1 Gy. The mean age was 48.1 years. The median Karnofsky performance status (KPS) was 80. Median followup time was 21.8 months. Results: At the time of analysis, 18 patients (75%) had died; 6 patients (25%) were alive. Median survival from diagnosis for all patients was 23.3 months. Median survival after GliaSite brachytherapy was 9.1 months. Patients with a KPS ≥ 70 had a median survival of 9.3 months while patients with a KPS < 70 had a median survival of 3.1 months (p<0.003). Survival was not significantly different between patients receiving 45 Gy and patients receiving a dose greater than 45 Gy. Acute side effects and late sequelae were rare. Conclusions: GliaSite radiotherapy confers a prolongation of survival in patients with recurrent glioblastoma multiforme compared to historical controls with recurrent GBM. GliaSite therapy leads to a favorable survival outcome of 9.3 months in patients with KPS ≥ 70, but only 3.1 months in patients with KPS < 70. Favorable survival is observed for patients within each recursive partitioning analysis (RPA) class. Treatment with GliaSite is safe and generally well tolerated. No significant financial relationships to disclose.
Longevity of Strains From Individual Foci of Human Amnion Cells Transformed by Simian Virus 40&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Jorgen Fogh
Journal: JNCI Journal of the National Cancer Institute (1971)

Sixteen cell strains, derived from isolated individual foci (“focus srrains”) in cultures of primary human amnion cells transformed by simian virus 40 (SV40), varied considerably in longevity (170–268 days after infection) and in number of cell divisions (16–45) before “crisis.” The comparison with strains composed of pools of cells derived from these foci (“pool strains”), and with strains derived from whole cultures of transformed primary amnion cells (“whole culture strains”), supported the following conclusion: The longevity of a cell strain derived from a culture containing several foci is expressed by the strain component with the highest longevity potentials. This observation provides an explanation for the increased longevity observed for strains of SV40-transformed amnion cells initially infected with a high multiplicity of virus and under favorable cultural conditions. Some focus strains consisted of cells of fibroblast-like morphology. However, the cells in most of these strains, in the pool strains, and in all whole culture strains were epithelial-like. Four focus strains and three whole culture strains were recovered as postcrisis cell lines. It is proposed that many changes during the precrisis period after SV40 transformation reflect variations in the relative representation of the components derived from individual foci. This representation, at any time, appears to be determined by the different times at which the individual components cease to divide.
Abstract 299: Pulmonary Hypertension Activates Cardiac Fibroblasts To Release Paracrine Factors Regulating Cardiac Myocyte Dedifferentiation
Authors: Lori A Walker, R. D Brown, Kurt R Stenmark, Peter M Buttrick
Journal: Circulation Research (2014)

In virtually all models of heart failure, prognosis is ultimately determined by right ventricular (RV) function. Thus understanding the unique cellular mechanisms that contribute to RV dysfunction is of critical importance. We have approached this question by studying a large animal model that has significant resonance with human disease: exposure of the neonatal calf to hypobaric hypoxia. This model demonstrates rapid onset of severe pulmonary hypertension (PH) and significant RV dysfunction. Strikingly, the RV of these animals shows a chamber-specific increase in markers of inflammation and local infiltration of activated pro-remodeling macrophages that are proportionate to the rise in PA pressure. In order to test the hypothesis that this inflammatory milieu directly contributes to myocyte dysfunction, we examined the effects of conditioned media (CM) from cardiac fibroblasts isolated from the PH calf on normal adult rat ventricular myocytes (ARVM) in culture. Even brief exposure (&lt;2 days) to RV-CM results in rapid and marked dedifferentiation of ARVM to a neonatal-like phenotype that exhibits spontaneous contractile behavior. Dedifferentiated cells maintain viability for over 30 days with continued expression of cardiomyocyte proteins including TnI, sarcomeric actinin, and desmin. This response is not seen in ARVM exposed to CM from fibroblasts collected from the hypoxic LV or from the normoxic RV. We have characterized the factor(s) that are present in the RV-CM and have established that the active components are proteins with a mol wt &gt;30 kDa and that inflammatory cytokines such as IL-18 are necessary but not sufficient to effect this phenotypic change. These data suggest that local and perhaps focal inflammation in the RV, induced by the combination of pressure overload and hypoxia, has the capacity to signal a phenotypic transformation in a population of RV cardiocytes, which likely contributes to chamber specific dysfunction. Therapies that target and interrupt this inflammatory process either by preventing in-migration of inflammatory cells or by blocking cell-cell signaling have the potential to prevent RV dysfunction.
Etiology of Sudden Death in Sports
Authors: Gherardo Finocchiaro, Michael Papadakis, Jan-Lukas Robertus, Harshil Dhutia, Alexandros Klavdios Steriotis, Maite Tome, Greg Mellor, Ahmed Merghani, Aneil Malhotra, Elijah Behr, Sanjay Sharma, Mary N. Sheppard
Journal: Journal of the American College of Cardiology (2016)
Phase 1/2a study of double immune suppression blockade by combining a CSF1R inhibitor (pexidartinib/PLX3397) with an anti PD-1 antibody (pembrolizumab) to treat advanced melanoma and other solid tumors
Authors: S. Hu-Lieskovan, A. Patnaik, P. Eisenberg, J. Sachdev, A. Weise, D.R. Kaufman, I. Aromin, B.L. West, S. Tong, A. Ribas
Journal: Annals of Oncology (2015)
A Phase III Randomized, Double Blind, Placebo Controlled Multi-Center Study Of Panobinostat For Maintenance Of Response In Patients With Hodgkin Lymphoma Who Are At Risk For Relapse After High Dose Chemotherapy and Autologous Stem Cell Transplant: Final Results After Early Trial Discontinuation
Authors: Bastian von Tresckow, Aleksander Skotnicki, Igur Lisukov, Shivani Srivastava, David S. Morgan, Franck Morschhauser, Caterina Stelitano, Jeffrey Szer, Dennis A. Eichenauer, Jeremy S. Abramson, Anna Sureda, Christophe Ferme, Andreas Engert
Journal: Blood (2013)
SP0201 New Developments in Antiphospholipid Syndrome
Authors: D. D'Cruz
Journal: Annals of the Rheumatic Diseases (2015)

Antiphospholipid syndrome (APS) is characterised by recurrent pregnancy morbidity and venous and arterial thromobotic events. Considerable progress has been made in understanding the mechanisms of thrombosis and pregnancy loss which have led to improved clinical outcomes for patients. APS vasculopathy is characterised by vascular intimal hyperplasia which may lead to stenotic lesions in the renal arteries resulting in hypertension. APS nephropathy may lead to renal impairment. However, renal biopsy is associated with significantly increased risks of bleeding complications as a result of renal vessel intimal hyperplasia. This brief lecture will review recent developments in APS nephropathy and will address the risks of renal biopsy and strategies to minimise biopsy complications. <h3>Disclosure of Interest</h3> None declared
Epidemiologic Pathology of Gastric Ulcer and Gastric Carcinoma Among Japanese in Hawaii2
Authors: G. Stemmermann, W. Haenszel, F. Locke
Journal: JNCI Journal of the National Cancer Institute (1977)

This case-control study of Hawaiian Japanese indicated that gastric ulcer in the proximal portion of the pyloric antrum has features similar to those of gastric cancer. Such ulcers occurred at sites most frequently and most severely affected by intestinal metaplasia, although metaplasia tended to be more extensive with cancer than with ulcer. Metaplastic mucosa was more vulnerable to the action of pepsin and acid than was normal mucosa. The risk of ulceration would rise when a sufficiently large area of the antrum was intestinalized and when the corpus continued to produce significant quantities of these substances. This study showed a strong association between salt intake, ulcer, and metaplasia. Significant but less dramatic associations were demonstrated between metaplasia and the use of traditional Japanese foods and smoking. The question was raised as to whether salt promotes ulceration or whether it potentiates the action of a mutagen that causes intestinal metaplasia.
Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial
Authors: Kei Muro, Hyun Cheol Chung, Veena Shankaran, Ravit Geva, Daniel Catenacci, Shilpa Gupta, Joseph Paul Eder, Talia Golan, Dung T Le, Barbara Burtness, Autumn J McRee, Chia-Chi Lin, Kumudu Pathiraja, Jared Lunceford, Kenneth Emancipator, Jonathan Juco, Minori Koshiji, Yung-Jue Bang
Journal: The Lancet Oncology (2016)
Phase II trial of CAT-3888 (BL22) in chemo-resistant hairy cell leukemia
Authors: R. J. Kreitman, W. H. Wilson, M. Stetler-Stevenson, P. Noel, D. J. FitzGerald, I. Pastan
Journal: Journal of Clinical Oncology (2007)

7095 Background: CAT-3888 (BL22) is a recombinant anti-CD22 immunotoxin which showed phase I activity in chemo-resistant hairy cell leukemia (HCL). Methods: Eligible patients had relapsed HCL &lt; 4-years after prior cladribine (CdA) and needed additional treatment based on blood counts. Patients were stratified into 2 groups by most recent CdA response of &lt; 1 year or 1–4 years. A 3 rd group was added for patients with uncontrolled infection. The study used a 2-stage design of 10 patients each for the first two strata with expansion to 17–30 if hematological remission (HR, i.e. ANC, platelets and Hgb at least 1.5, 100, and 11, respectively) was achieved in at least 3/10. The third strata allowed up to 5 patients. Patients received 40 ug/Kg every other day (QOD) ×3 on cycle 1. Those achieving HR were observed. Patients without a HR and no neutralizing antibodies were retreated at 30 ug/Kg QOD ×3 every 4 weeks beginning at least 8 weeks after cycle 1. Results: 35 patients were enrolled including 25, 9 and 1 in groups 1–3, respectively. CR (44% vs 48%) and overall response (ORR)(64% vs 89%) were similar in strata 1 and 2 with 16 (47%) CRs and 8 (24%) partial responses (PRs) overall. Response was particularly high in 22 with baseline spleen size &lt; 200 mm (95% ORR; 59% CR, 36% PR) compared to patients with spleen height &gt; 200 (ORR 20%, p = 0.001) or patients post-splenectomy (ORR 25%, p = 0.0003). The only serious toxicity was completely reversible grade 3 hemolytic uremic syndrome, not requiring plasmapheresis, in 1 (3%) patient on cycle 2. Neutralizing antibodies which prevented additional cycles were observed in 4 (11%) patients. Conclusions: The activity of CAT-3888 (BL22) in HCL is confirmed in this phase II trial. Toxicity may be limited by retreating only those who do not respond to 1 cycle. Optimal response to CAT-3888 (BL22) following CdA failure may be achieved before the occurrence of massive splenomegaly or splenectomy. No significant financial relationships to disclose.
Study on suicide risk assessment in mental illness underestimates inpatient suicide risk
Authors: Matthew Large
Journal: BMJ (2016)

In their recent state of the art clinical review, Bolton and colleagues state “A meta-analysis of 27 studies reported a rate of 147 suicides per 100 000 inpatient years, with individual studies reporting figures as high as 860 suicides per 100 000 inpatient years.”1 However, the paper …