tbuckley/cabot-search huggingface dataset:
A puzzling case of methemoglobinemia
Authors: Audrey Morris, Barbara J. Bain, Maria Atta, D. Mark Layton
Journal: American Journal of Hematology (2017)

A 36-year-old Northern European female was referred for a tertiary opinion regarding an unexplained anemia. She had a 6-month history of a symptomatic anemia, jaundiced sclerae, and dark urine. At the age of 34 years, she had received dapsone therapy for a suspected autoimmune disease. This had been discontinued because of anemia. There was no family history of anemia or other hematological abnormality. Her blood count on presentation showed a macrocytic anemia with a hemoglobin concentration (Hb) of 88 g/L and an MCV of 101 fL. The white cell count was 6.6 × 109/L with a normal differential count, and the platelet count was 314 × 109/L. The reticulocyte count was elevated to 326 × 109/L (12%). Bilirubin was 33 μmol/L and lactate dehydrogenase was 372 iu/L. A direct antiglobulin test was negative. Her blood film showed irregularly contracted cells, bite cells, Howell–Jolly bodies and polychromasia (top Image). Protrusions from red cells and dense areas within hemighosts (top right Image, arrow) suggested the presence of Heinz bodies, this being confirmed on a Heinz body preparation (bottom left Image). The findings supported a diagnosis of oxidative hemolysis but no clear underlying cause could be identified. High performance liquid chromatography was performed and showed a small peak eluting at 4.09 minutes in the hemoglobin D window (bottom right Image). However, no variant hemoglobin was detected by mass spectrometry and sequencing of the alpha and beta globin genes did not reveal any mutation. Red cell glucose-6-phosphate dehydrogenase activity was elevated at 13.9 units/g of hemoglobin, consistent with the degree of reticulocytosis. At subsequent follow up the patient was noted to have dusky skin discolouration centrally and peripherally. Blood gas analysis revealed a methemoglobin level of 28%. The patient was admitted for further management. Methylene blue treatment was followed by a significant fall of methemoglobin to under 5%, but the reduction was transient and levels rose to over 20% within 24 hours. Red cell cytochrome b5 reductase activity was normal, excluding congenital methemoglobinemia. Acquired methemoglobinemia due to ongoing exposure to an oxidant drug or chemical was suspected. A toxicology screen revealed a significant quantity of dapsone, a potent oxidant, in the patient's urine and blood samples. The patient was unable to explain the findings but after discussion of these results, the methemoglobin level fell rapidly and Hb together with markers of hemolysis progressively improved. Psychological support was arranged. Nothing to report.
Abstract 128: Nuclear Targeting of the α1A-Adrenergic Receptors Is Required for Cardiac Myocyte Contractility
Authors: Steven C Wu, Casey D Wright, Andrew L Cypher, Timothy D O'Connell
Journal: Circulation Research (2012)

In the heart, α1-adrenergic receptors (α1-ARs) regulate physiologic hypertrophy, cardiac myocyte survival, and contractility. Conventionally, G protein-coupled receptors such as α1-ARs are thought to localize and signal at the plasma membrane. However, we demonstrated that endogenous α1-ARs localize to the nucleus in wild-type (WT) adult cardiac myocytes, and identified nuclear localization sequences (NLS) in the α1A- and α1B-subtypes. Mutation of the NLS in each subtype resulted in mis-localization of the receptors and loss of signaling. Here, we examined how nuclear α1-ARs induce inotropic responses through regulation of cardiac troponin I (cTnI). In unloaded WT cardiac myocytes, the α1-agonist phenylephrine (PE) reduced sarcomeric shortening and increased cTnI phosphorylation at the protein kinase C (PKC) site threonine 144 (Thr144). PE had no effect in cardiac myocytes lacking both α1A- and α1B-subtypes (α1ABKO), but reconstitution of the α1A-subtype restored PE effects. Conversely, reconstitution of an NLS-mutant-α1A-subtype blunted the effects of PE on shortening and cTnI phosphorylation. Furthermore, in WT cardiac myocytes, the nuclear export inhibitor leptomycin B also blunted the effects of PE. With nuclei isolated from WT cardiac myocytes, we found high levels of PKCδ with lower levels of PKCα and ε, and that PE induced PKCδ activation in isolated nuclei. We also examined endogenous PKC translocation induced by PE in membrane, cytosolic, nuclear, and myofilament fractions, and found that PKCδ translocated from the nuclear to the myofilament fraction. Finally, expression of a dominant-negative PKCδ in WT myocytes blunted PE-induced effects on shortening and cTnI phosphorylation. Our data show that α1A-subtype nuclear localization is required for activation of PKCδ in the nucleus, subsequent phosphorylation of cTnI at Thr144 at the sarcomere to regulate myocyte contractility.
Obsessive-Compulsive Disorder
Authors: Matthew E. Hirschtritt, Michael H. Bloch, Carol A. Mathews
Journal: JAMA (2017)

<h3>Importance</h3> Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder associated with significant impairment and a lifetime prevalence of 1% to 3%; however, it is often missed in primary care settings and frequently undertreated. <h3>Objective</h3> To review the most current data regarding screening, diagnosis, and treatment options for OCD. <h3>Evidence Review</h3> We searched PubMed, EMBASE, and PsycINFO to identify randomized controlled trials (RCTs), meta-analyses, and systematic reviews that addressed screening and diagnostic and treatment approaches for OCD among adults (≥18 years), published between January 1, 2011, and September 30, 2016. We subsequently searched references of retrieved articles for additional reports. Meta-analyses and systematic reviews were prioritized; case series and reports were included only for interventions for which RCTs were not available. <h3>Findings</h3> Among 792 unique articles identified, 27 (11 RCTs, 11 systematic reviews or meta-analyses, and 5 reviews/guidelines) were selected for this review. The diagnosis of OCD was revised for the<i>Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition</i>, which addresses OCD separately from anxiety disorders and contains specifiers to delineate the presence of tics and degree of insight. Treatment advances include increasing evidence to support the efficacy of online-based dissemination of cognitive behavioral therapies, which have demonstrated clinically significant decreases in OCD symptoms when conducted by trained therapists. Current evidence continues to support the use of selective serotonin reuptake inhibitors as first-line pharmacologic interventions for OCD; however, more recent data support the adjunctive use of neuroleptics, deep-brain stimulation, and neurosurgical ablation for treatment-resistant OCD. Preliminary data suggest safety of other agents (eg, riluzole, ketamine, memantine,<i>N</i>-acetylcysteine, lamotrigine, celecoxib, ondansetron) either in combination with selective serotonin reuptake inhibitors or as monotherapy in the treatment of OCD, although their efficacy has not yet been established. <h3>Conclusions and Relevance</h3> The dissemination of computer-based cognitive behavioral therapy and improved evidence supporting it represent a major advancement in treatment of OCD. Although cognitive behavioral therapy with or without selective serotonin reuptake inhibitors remains a preferred initial treatment strategy, increasing evidence that supports the safety and efficacy of neuroleptics and neuromodulatory approaches in treatment-resistant cases provides alternatives for patients whose condition does not respond to first-line interventions.
Early sensitization of myofilaments to Ca2+ prevents genetically linked dilated cardiomyopathy in mice
Authors: Marco L. Alves, Chad M. Warren, Jillian N. Simon, Robert D. Gaffin, Eric M. Montminy, David F. Wieczorek, R. John Solaro, Beata M. Wolska
Journal: Cardiovascular Research (2017)

Dilated cardiomoypathies (DCM) are a heterogeneous group of inherited and acquired diseases characterized by decreased contractility and enlargement of cardiac chambers and a major cause of morbidity and mortality. Mice with Glu54Lys mutation in α-tropomyosin (Tm54) demonstrate typical DCM phenotype with reduced myofilament Ca2+ sensitivity. We tested the hypothesis that early sensitization of the myofilaments to Ca2+ in DCM can prevent the DCM phenotype.To sensitize Tm54 myofilaments, we used a genetic approach and crossbred Tm54 mice with mice expressing slow skeletal troponin I (ssTnI) that sensitizes myofilaments to Ca2+. Four groups of mice were used: non-transgenic (NTG), Tm54, ssTnI and Tm54/ssTnI (DTG). Systolic function was significantly reduced in the Tm54 mice compared to NTG, but restored in DTG mice. Tm54 mice also showed increased diastolic LV dimensions and HW/BW ratios, when compared to NTG, which were improved in the DTG group. β-myosin heavy chain expression was increased in the Tm54 animals compared to NTG and was partially restored in DTG group. Analysis by 2D-DIGE indicated a significant decrease in two phosphorylated spots of cardiac troponin I (cTnI) in the DTG animals compared to NTG and Tm54. Analysis by 2D-DIGE also indicated no significant changes in troponin T, regulatory light chain, myosin binding protein C and tropomyosin phosphorylation.Our data indicate that decreased myofilament Ca2+ sensitivity is an essential element in the pathophysiology of thin filament linked DCM. Sensitization of myofilaments to Ca2+ in the early stage of DCM may be a useful therapeutic strategy in thin filament linked DCM.
Use of autologous bone marrow cells following high-dose chemotherapy (HDCT) for patients (pts) with recurrent lymphoma in whom stem cell harvesting from the peripheral blood was inadequate
Authors: G. Kumaran, J. Murray, D. Sweeney, E. Liakopoulou, J. A. Radford
Journal: Journal of Clinical Oncology (2007)

8124 Background: HDCT with autologous stem cell rescue (ASCR) is an established treatment for recurrent Hodgkin and non- Hodgkin lymphoma (HL, NHL) but some of these pts fail to mobilise adequate numbers of CD34 + cells from the peripheral blood (PB). Harvest of bone marrow (BM) stem cells and use of these alone or in combination with PB derived cells is an option but there are concerns about feasibility and outcome. Methods: 29 pts who had HDCT after failed PB stem cell harvest between July 1999 and December 2005 were studied in terms of CD34 + cell yield (PB and BM), transfusion dependence, engraftment and survival. Results: There were 17 males and 12 females (median age 49yrs, range 19–66) with recurrent HL (n=16) or NHL (n=13). All had received at least 2 lines of chemotherapy (10 pts =3) and 7 had received radiotherapy (5 mediastinal, one neck and one abdominal field). Mobilisation of CD34 + cells from PB was attempted using chemotherapy followed by filgrastim. 22 pts proceeded to leukapheresis on the basis of predictive CD34 + counts (median collects 2; range 0–4) with a median total collect of 0.98×10 6 CD34 + cells/kg (range 0.03–1.84). Subsequently, all pts had a BM harvest producing a median collect of 1.63x10 6 CD34 + cells/kg (range 0.45–4.75). 29 pts then received BEAM/CBV followed by re-infusion of PB+BM cells except in 7 pts where only BM cells were available. In 26/29 pts surviving to day 100; total CD34 + cells infused, 2.37×10 6 /kg (range 1.73- 5.0), time to neutrophils &gt;0.5×10 9 /L, 12 days (range 9–23), platelet units transfused, 6 (range 0–24), red cells units transfused 6 (range 0–18) (all medians). 2 pts continued to have red cell transfusions beyond day 100. 3/29 pts died due to severe neutropenia/septicaemia at days 23–25 (treatment related mortality 10.3%); the CD34 + dose received by these pts was 1.97×10 6 /kg in 2 and 1.84×10 6 /kg in 1. Beyond day 100, 9 pts have died from HL/NHL and 2 are lost to follow-up. Conclusions: In patients with HL/NHL who fail to mobilise adequate numbers of CD34 + cells from PB, a BM harvest can produce a combined BM/PB collect capable of producing haemopoeitic reconstitution following HDCT without excessive toxicity. No significant financial relationships to disclose.
States Worse Than Death
Authors: Stephanie Nothelle, Tom Finucane
Journal: JAMA Internal Medicine (2017)

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Clinical impact of differential risk stratification by breast cancer index (BCI) versus recurrence score (RS) in HR+ early-stage breast cancer: A TransATAC study.
Authors: Ivana Sestak, Yi Zhang, Catherine A. Schnabel, Brock Schroeder, Mark Erlander, Paul E. Goss, Jack M. Cuzick, Mitchell Dowsett, Dennis Sgroi
Journal: Journal of Clinical Oncology (2014)

532 Background: BCI is a genomic signature that significantly predicts risk of both early (0-5y) and late (5-10y) distant recurrence (DR) in HR+, LN- breast cancer. Previous results from the TransATAC study showed that both BCI and Oncotype Dx RS added significant prognostic information for 10y DR risk. Here, pre-defined risk stratification with BCI vs RS and its potential clinical impact were comparatively evaluated. Methods: 665 HR+, LN- patients were examined. BCI and RS risk groups were determined using pre-defined clinical cut-points. Kaplan-Meier estimates of 10y risk of DR and log-rank tests were used to examine cross-stratification between BCI and RS. Likelihood Ratio (LR) tests were used to quantitate relative prognostic information beyond CTS. Results: BCI re-stratification of the RS-Intermediate (RS-I) and RS-Low (RS-L) groups significantly impacted risk of 10y DR (P=0.003 and P<0.001), whereas RS did not significantly re-stratify BCI risk prediction (Table). BCI identified a small subset (20 pts in RS-L) with a high risk of DR (23.3%). Furthermore, BCI identified a large (95 pts in RS-I) and smaller (34 pts in RS-I) subset with 7.1% and 27.8% 10y DR risk, respectively. BCI added significant prognostic information beyond CTS+ RS (p=0.0009), whereas RS did not provide additional prognostic information beyond CTS+ BCI (p=0.1). Conclusions: In this retrospective analysis evaluating individualized risk stratification, BCI identified subsets of RS-L and RS-I LN- patients with significant and clinically distinct rates of DR. BCI identified a small subset of RS-L and RS-I LN- patients that would potentially benefit from additional therapy. Risk stratification and 10-year distant recurrence rates (%). No. of patients BCI risk groups Low Inter High Total P value RS risk groups Low 283 (3.9%) 85 (12.2%) 20 (23.3%) 388 (6.6%) <0.001 Inter 95 (7.1%) 49 (24.3%) 34 (27.8%) 178 (15.8%) 0.003 High 12 (10%) 32 (25.4%) 55 (31.5%) 99 (26.9%) 0.2 Total 390 (4.8%) 166 (18.3%) 109 (29.0%) 665 P value 0.4 0.07 0.6
Paclitaxel (P) (day 1 and 8) and carboplatin (C) given on every 3 weeks in advanced (stage III-IV) non-small cell lung cancer (NSCLC)
Authors: P. F. Yumuk, N. S. Turhal, M. Gumus, N. F. Hatabay, O. Turken, A. Ozkan, T. Salepci, M. Aliustaoglu, M. Ekenel, R. Ahiskali
Journal: Journal of Clinical Oncology (2004)

7321 Background: Both P and C have significant activity in NSCLC. Earlier reports on the weekly administration of P showed that it is active, dose intense, and has a favorable toxicity profile. We reviewed the efficacy and toxicity of this combination in 51 patients with advanced stage NSCLC. Methods: Eligible patients had pathologically proven NSCLC, stage III, IV disease, no CNS metastases, adequate organ function and performance status (PS) ECOG 0–2. Patients were treated with P 112.5mg/m2 iv. over 1 hour on day 1 and 8, followed by C AUC 5–6 iv. over 1 hour, repeated in every 3 weeks. PC was given for maximum of 6 courses. Results: Median age was 58 (39–77), 41 patients (80.4%) were male. PS was 0/1/2 in 29/17/5 patients and stage was IIIA/IIIB/IV in 3/14/34 patients, respectively. Histology was squamous cell in 18, adenocarcinoma in 16, undifferentiated in 16 and adenosquamous in 1. The median number of cycles administered was 3 (range, 1–6). Eight patients (15.6%) did not complete the first 3 cycles either due to death (2), progression (3), grade 3 hypersensitivity reaction to P (1) or lost to follow up (2). Best evaluable response was PR in 45% and SD in 15.6%. Nine patients (18%) with stage III disease received local RT. Eleven patients received 2nd line CT at progression. At a median follow-up of 5 months (1–17), 17 patients died. Median overall survival (OS) was 12±3 months (95%CI; 7 to17), 1-year OS ratio was 48%. Median time to progression (TTP) was 5±1 months (95%CI; 4 to 6), 1-year TTP ratio was 20.5%. Most frequent toxicity related symptoms were asthenia (60%), neuropathy (37%) and anorexia (35%). Grade 3 toxicities: asthenia (10%), neuropathy (4%), anorexia (4%), hypersensitivity to P (2%), nausea/vomiting (2%), anemia (4%) and neutropenia (2%). Grade 5 (fatal) febrile neutropenia was observed in 2 patients (4%). Dose of CT was reduced or delayed in 11 patients (21.6%). Conclusion: P on day 1 and 8 and C every 3 weeks is well tolerated and moderately active regimen in patients with advanced stage NSCLC. Patients need to be followed carefully with blood counts during treatment. No significant financial relationships to disclose.
Evaluation of the association of CXCR4 expression with HER2 status or mTOR expression levels
Authors: M. H. Smith, B. D. Li, G. Sun, Q. D. Chu
Journal: Journal of Clinical Oncology (2009)

e22192 Introduction: CXCR4 is a chemokine receptor that is linked to breast cancer metastasis. The putative mechanism involves activation of the HER-2/PI3K/PTEN/Akt/mammalian target of rapamycin (mTOR) pathway, resulting in enhanced synthesis of downstream proteins such as CXCR4 and eukaryotic initiation factor 4E (eIF4E). Overexpression of eIF4E has been shown to be an independent predictor of breast cancer outcome. Because HER-2/mTOR/CXCR4 pathway has mainly been observed in vitro, it deserves scrutiny to determine whether it is also seen in human breast cancers. We hypothesize that HER-2/mTOR axis is not significantly associated with CXCR4 regulation in human breast cancers. Method: 107 stages 1 - 3 breast cancers from a prospective breast cancer database were analyzed. Samples were quantified for mTOR, CXCR4, and eIF4E levels by Western Blot. mTOR, and eIF4E levels were quantified as fold-over benign breast tissues and CXCR4 levels were quantified as fold-over Hela cells. CXCR4 overexpression was defined as low (&lt; 6.0 fold) or high (≥ 6.0 fold), and eIF4E expression level was separated into tertiles. Primary end points were cancer recurrence and death. Statistical analyses performed were independent student t-test, Spearman correlation, Kaplan-Meier survival curves, log-rank test, and Cox proportional hazard model. Results: All 59 HER-2 (-) and 48 HER-2 (+) breast cancer specimens overexpressed CXCR4 (mean=6.18 ±4.4), mTOR (mean=1.24 ±1.58), and eIF4E (mean=9.53 ±6.42). Unlike in vitro data, there was no difference in mean CXCR4 expression level between HER-2 (-) and HER-2 (+) tumors (mean=6.55, 5.72, respectively) (p=0.33). While mTOR correlated significantly with eIF4E level (p=0.0006, r = 0.34), it did not correlate with CXCR4 level (p=0.713, r=0.036). Only nodal status (p=0.04) and eIF4E level (p=0.03) were independent predictors of breast cancer death. Conclusions: We demonstrate that CXCR4 regulation in human breast cancers is more complex than previously thought. There was no correlation between mTOR and CXCR4 levels, nor was there a difference in mean CXCR4 overexpression levels between HER-2 (+) and HER-2 (-) tumors. Pathways regulating CXCR4 expression warrant further investigation. No significant financial relationships to disclose.
Feasibility of capturing radiation oncology quality metrics in a large integrated oncology practice.
Authors: Ajay Dubey, Jeff Bernard, Jeffrey Limmer, Bret Heintz, Kyle Antes, Stacy Hartman, Bernard Taylor, Brennan Scott Cheek, Lalan S. Wilfong, John Russell Hoverman
Journal: Journal of Clinical Oncology (2017)

83 Background: Metrics to assess quality are important to improve processes of care. While such capture and reporting are common in medical oncology practices, it is less common with radiation oncology. As part of a large integrated oncology practice with more than 400 physicians and 57 radiation oncologists, we explored the feasibility of capturing and reporting a bundle of metrics at each of 52 radiation oncology practice sites. Methods: At the beginning of each quarter, the first 20 charts were sampled at each rad onc site of service to capture the following metrics: performance status at the start of radiation therapy, pain level at the start of XRT for patient with bone metastasis, cancer staging documented, dose limits to normal tissue tissues established and clearly documented for IMRT cases, and adherence to the 2015 US Oncology Breast Cancer XRT Pathways. Pathways adherence was captured via physician attestation. Beginning in the second quarter, Breast Cancer Pathways concordance with the final delivered plan was reported. Beginning in the 3 rd quarter, additional pathways were captured (but not reported) for NSCLC, Prostate, Rectal Cancer, and Bone Metastasis sites. Results: See table. Conclusions: Availability of metrics data and compliance was greater than 80% in all 52 radiation oncology practice sites. Documentation of dose limits was seen as an opportunity for improvement via standardization of workflows, as there were multiple workflows within the record and verify system. Concordance rate between attestation of pathways compliance and the delivered plan was high. Breast cancer pathways compliance fell in the third quarter when additional pathways were added, suggesting that increasing complexity of metrics requirements may decrease performance. [Table: see text]