tbuckley/cabot-search huggingface dataset:
Phase I ascending single and multiple dose studies to assess the safety, tolerability and pharmacokinetics of AZD0530, a highly selective, dual-specific Src-Abl inhibitor
Authors: J. A. Lockton, D. Smethurst, M. Macpherson, R. Tootell, A. L. Marshall, G. Clack, N. J. Gallagher
Journal: Journal of Clinical Oncology (2005)

3125 Background: AZD0530 is a highly selective, dual-specific, orally available, small molecule inhibitor of Src kinase and Bcr-Abl. Methods: Two studies were conducted in healthy male volunteers to assess the safety, tolerability and pharmacokinetic (PK) profile. Firstly, in a single ascending dose study, 27 volunteers in cohorts of 9 were randomly assigned to receive AZD0530 or placebo in a rotating manner between dose levels. Subjects received single doses between 2.5 mg and 1000 mg. Results: Dose-limiting toxicities of diarrhea and vomiting occurred at 1000 mg. Adverse events at lower doses were mild and included nausea and diarrhea. In the second study, a multiple ascending dose study 60 volunteers were randomized in cohorts of 12 to receive AZD0530 (n=9) or placebo (n=3) as a single dose (for PK) followed by a washout period and then multiple daily dosing for up to 14 days. Doses up to 250 mg/day were administered in this manner. Adverse events have been generally mild and have included rash, flu-like symptoms, myalgia, arthalgia, headache, loose stools and raised creatinine. Tmax was approximately 6 hours and mean terminal half-life was approximately 40 hours at steady state. Plasma Cmin concentrations remained above the IC50 for Src kinase as predicted from preclinical modeling. Conclusions: In conclusion, AZD0530 is a small molecule inhibitor of Src kinase and Bcr-Abl. The drug is tolerated when administered in single doses up to 500 mg and in multiple, once-daily doses up to 250 mg. The pharmacokinetic profile of AZD0530 is consistent with once-daily oral dosing Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca
Involuntary Smoking and Lung Cancer: A Case-Control Study
Authors: L Garfinkel, O Auerbach, L Joubert
Journal: JNCI Journal of the National Cancer Institute (1985)

In a case-control study in 4 hospitals from 1971 to 1981, 134 cases of lung cancer and 402 cases of colon-rectum cancer (the controls) were identified in nonsmoking women. All cases and controls were confirmed by histologic review of slides, and nonsmoking status and exposures were verified by interview. Odds ratios (OR) increased with increasing number of cigarettes smoked by the husband, particularly for cigarettes smoked at home. The OR for women whose husbands smoked 20 or more cigarettes at home was 2.11 (95% confidence limits: 1.13, 3.95). A logistic regression analysis showed a significant positive trend of increasing risk with increased exposure to the husband's smoking at home, controlled for age, hospital, socioeconomic class, and year of diagnosis. Comparison of women classified by number of hours exposed a day to smoke in the last 5 years and in the last 25 years showed no increase in risk of lung cancer.
Abstract 12162: Trends of Thoracic Endovascular Repair of Aortic Dissection among Medicare Beneficiaries, 2005-2010
Authors: Purav Mody, Arnar Geirsson, Mayur Desai, Yun Wang, Nancy Kim, Aakriti Gupta, John Dodson, Harlan Krumholz
Journal: Circulation (2012)

Background: Thoracic endovascular aortic repair (TEVAR) has emerged as an effective alternative to open surgical repair for the management of complicated distal aortic dissection. Data on its adoption as well as long-term outcomes of this procedure, especially among older patients, are scarce. Accordingly, we analyzed national Medicare data to determine use of and outcomes after TEVAR from 2005 to 2010. Methods: Inpatient Medicare standard analytic files were used to identify 100% of fee-for-service (FFS) patients aged ≥65 years who had a primary discharge diagnosis of aortic dissection (ICD-9-CM codes 441.01 or 441.03) and who underwent TEVAR (ICD-9-CM procedure code 39.73) from 2005 to 2010. We linked inpatient data with the Medicare denominator file to report operative rates per 1 million person-years. Thirty-day and 1-year mortality rates as well as 30-day readmission rates were ascertained through corresponding vital status and inpatient files. Results: A total of 1,577 TEVAR procedures were performe...
Precision Medicine for Diffuse Large B-cell Lymphoma
Authors: Megan S. Lim, Kojo S.J. Elenitoba-Johnson
Journal: Clinical Cancer Research (2016)

This study demonstrates the clinical utility of a targeted gene sequencing panel "the Lymphopanel," which enables the detection of actionable mutations and subtype-enriched gene alterations in diffuse large B-cell lymphoma that will pave the way to precision therapy era for patients with this form of aggressive lymphoma. Clin Cancer Res; 22(12); 2829-31. ©2016 AACRSee related article by Dubois et al., p. 2919.
Increased expression of constitutive nitric oxide synthase III, but not inducible nitric oxide synthase II, in human heart failure 11During publication process the following related paper has been published by Vejlstrup NG, Bouloumie A, Boesgaard S, Andersen CB, Nielsen-Kudsk JE, Mortensen SA, Kent JD, Harrison DG, Busse R, Alsershvile J. Inducible nitric oxide synthase (iNOS) in the human heart: Expression and localization in congestive heart failure. J Mol Cell Cardiol 1998;30:1215–23.
Authors: Birgitt Stein, Thomas Eschenhagen, Jochen Rüdiger, Hasso Scholz, Ulrich Förstermann, Ingolf Gath
Journal: Journal of the American College of Cardiology (1998)
Studies on Carcinogenesis of Human Prostate. II. Long-Term Explant Culture of Normal Prostate and Benign Prostatic Hyperplasia: Light Microscopy&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN4"&gt;4&lt;/xref&gt;
Authors: H Sanefuji, B M Heatfield, B F Trump, J D Young
Journal: JNCI Journal of the National Cancer Institute (1982)

Light microscopic and histochemical changes in normal human prostate and benign prostatic hyperplasia (BPH) during long-term explant culture were characterized. Normal human prostate obtained at immediate autopsy of young adults or BPH obtained at the time of surgery were maintained in explant culture as long as 24 weeks. Morphologic alterations in glandular epithelium and stroma in response to culture conditions were assessed by light microscopy and histochemistry of mucosubstances. The histologic and histochemical responses of normal prostate and BPH to in vitro conditions were essentially identical. Within 1 week, secretory epithelial cells became necrotic and sloughed into acinar lumina. Remaining epithelial cells proliferated, repopulated acinar structures, and migrated onto explant surfaces forming a new well-differentiated epithelium characterized by synthesis and secretion of neutral and acidic mucosubstances. During subsequent periods in vitro, synthesis and secretion of mucosubstances gradually diminished whereas the stroma and deep glandular structures became necrotic. Our observations suggest that cells comprising the new epithelium in cultured explants of normal human prostate and BPH are derived from prostatic basal cells.
Time for doctors to practise what they preach and preach what they practise
Authors: Fabian Sanchis-Gomar, María Morán, Alejandro Lucia
Journal: British Journal of Sports Medicine (2016)

We frequently stumble across colleagues who do not believe in exercise as a legitimate therapy. Much less so will they consider physical exercise as a component of the medical armamentarium to prevent and treat chronic conditions such as cardiovascular and metabolic disorders, the sarcopenia of ageing or several types of cancer. In a recent appeal for reaction, Berra et al 1 underlined that recommending exercise to …
Induction of Therapeutic Senescence in Vemurafenib-Resistant Melanoma by Extended Inhibition of CDK4/6
Authors: Akihiro Yoshida, Eric K. Lee, J. Alan Diehl
Journal: Cancer Research (2016)

Dysregulation of the p16-cyclin D1-CDK4/6-Rb pathway occurs frequently in melanoma; however, the therapeutic efficacy of CDK4/6 inhibition remains to be critically evaluated. We demonstrate that CDK4/6 inhibition inhibits melanoma progression through induction of senescence. Palbociclib, a specific CDK4/6 inhibitor, rapidly induces cell cycle arrest within 24 hours and continued exposure for 8 days or longer induces senescence. The induction of senescence correlates with inhibition of mTOR and more specifically mTORC1 signaling. Vemurafenib, a specific BRAF(V600E) inhibitor, has significant clinical efficacy in BRAF(V600E)-positive melanomas, but its impact is hampered by a rapid acquisition of resistance. Strikingly, we found that vemurafenib-resistant tumors remain sensitive to palbociclib, suggesting that initial treatment with vemurafenib followed by palbociclib with or without mTOR inhibitors might provide an avenue to overcome recurrence of vemurafenib-resistant metastatic disease. Taken together, these results support palbociclib as a promising therapeutic for treatment of melanoma. Cancer Res; 76(10); 2990-3002. ©2016 AACR.
Patient position and hypoxemia during propofol sedation for colonoscopy: a randomized trial
Authors: Peter Klare, Raffaela Huth, Bernhard Haller, Martin Huth, Andreas Weber, Christoph Schlag, Wolfgang Reindl, Roland Schmid, Stefan von Delius
Journal: Endoscopy (2015)

<b>Aim: </b>To evaluate the benefits of the left lateral position in avoiding hypoxemic events in patients undergoing colonoscopy. <b>Methods: </b>We conducted a randomized, prospective, controlled trial at two study sites in Germany. Patients undergoing colonoscopy under propofol sedation were randomized to either the supine or left lateral position. The primary outcome was oxygen desaturation (SaO<sub>2</sub> < 90 %). Secondary outcome measures were apneic events, hypotension, patient satisfaction, propofol dosage, cecal intubation time, and adenoma detection. <b>Results: </b>A total of 412 patients were randomized 1:1 to undergo colonoscopy in the supine or left lateral position. No severe adverse events were observed in either group. Intention-to-treat analysis revealed no significant difference in the frequency of desaturation in the left lateral arm compared with the supine arm (6.8 % vs. 12.1 %; <i>P</i> = 0.064). Patients in the left lateral arm showed lower apnea rates (9.4 % vs. 16.2 %; <i>P</i> = 0.040), but had more episodes of hypotension (12.3 % vs. 2.9 %; <i>P</i> < 0.001). The frequency of repositioning was higher in the left lateral group. No significant differences were observed in patient satisfaction and cooperation, propofol dosage, or adenoma detection rate. Patients who were repositioned to facilitate endoscope passage were excluded from per-protocol analysis. The incidence of hypoxemia was lower for the left lateral than for the supine group in per-protocol analysis (1.8 % vs. 11.2 %; <i>P</i> = 0.003). <b>Conclusion: </b>The positioning of patients in the left lateral position during propofol sedation for colonoscopy results in lower desaturation rates provided the position can be maintained throughout endoscopy. ClinicalTrials.gov NCT02001792.
Risk-adapted treatment of acute promyelocytic leukemia: Updated results of the Spanish PETHEMA LPA99 Trial using ATRA and anthracycline monochemotherapy
Authors: M. A. Sanz, G. Martin, E. Vellenga, P. Bolufer, M. Gonzalez, C. Rayon, J. de la Serna, R. Parody, J. Bergua, S. Negri, C. Rivas
Journal: Journal of Clinical Oncology (2005)

6515 Background: A first report of the PETHEMA LPA99 trial in acute promyelocytic leukemia (APL) showed that a risk-adapted treatment strategy combining ATRA and anthracycline alone for induction and consolidation results in high antileukemic efficacy and low toxicity. We report here an updated analysis of this trial including a significantly higher number of patients and longer follow-up. Methods: Since November 1999, 463 patients with APL received induction with ATRA (45 mg/m2/d) until CR and idarubicin (12 mg/m2/d) on days 2, 4, 6 and 8. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy as follows: i) “low-risk” patients (WBC <10×109/l and platelets >40×109/l), idarubicin 5 mg/m2/d x 4 (course #1), mitoxantrone 10 mg/m2/d x 5 (course #2), and idarubicin 12 mg/m2/d x 1 (course #3); ii) “intermediate-risk ” (WBC <10×109/l and platelet <40×109/l) and “high-risk” (WBC >10×109/l) patients received ATRA (45 mg/m2/d x 15) in combination with reinforced chemotherapy (Idarubicin 7 mg/m2/d in the course #1 and two days instead of one in the course #3). Maintenance therapy consisted of 50 mg/m2/d mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and 45 mg/m2/d ATRA for 15 days every 3 months. Results: CR was achieved in 422 patients (91%). Except for one case labeled as resistant, of the remaining 40 patients 57%, 28% and 10% died due to hemorrhage, infection, and retinoic acid syndrome, respectively. Multivariate analysis showed that WBC >10×109/l, age >70 years and serum creatinine >1.4 mg/dl at presentation had independent predictive value of early death during induction. Eleven patients (age range: 58–81 years) died in remission and 99% of patients completed the entire assigned therapy. Overall, the 5-year cumulative incidence of relapse (CIR), DFS, and OS were 9%, 88%, and 85%, respectively. The 5-year CIR for low-, intermediate- and high-risk patients were 4%, 5% and 24%, respectively. Conclusions: A risk-adapted strategy combining ATRA and anthracycline monochemotherapy for induction and consolidation therapy results in high antileukemic efficacy, low toxicity and a high degree of compliance in newly diagnosed APL. No significant financial relationships to disclose.
Association of genetic variations in DNA-methyltransferases, histone-methyltransferases, and methylated DNA-binding proteins with recurrence and survival in early-stage non-small cell lung cancer treated with surgery alone or surgery and chemotherapy.
Authors: K. W. Wagner, Y. Ye, J. Lin, A. A. Vaporciyan, J. A. Roth, M. R. Spitz, X. Wu
Journal: Journal of Clinical Oncology (2010)

7010 Background: Genetic polymorphic variants (SNPs) of DNA- and histone-modifying genes, in particular O6- methylguanine DNA-methyltransferase (MGMT), have been implicated in increased risk for development of lung cancer. Methods: 165 SNPs in these genes were genotyped in 461 stage 1 and 2 non-small cell lung cancer (NSCLC) patients treated with surgery (N=337) or surgery and chemotherapy (N=124) and analyzed for association with recurrence and survival. Median survival times and recurrence rates were 89.1 months and 27.5 % (93/337) for surgery and >133.6 months and 29% (36/124) for surgery and chemotherapy, respectively. Results: We identified three classes of SNPs that were differentially prognostic or predictive of recurrence and survival in early stage NSCLC. Class 1 contained two SNPs (in MGMT) which were prognostic biomarkers for clinical outcome independent of treatment modality. Six SNPs in class 2 (MBD2, SUV39H2, MBD4, EZH1(2x), EZH2) correlated with treatment outcome for surgery alone, but not with surgery and chemotherapy, hence their effect could be reversed by chemotherapy. The last class 3 contained SNPs, which were associated with surgery and chemotherapy, but not surgery alone. For example, we observed hazard ratios for rs4751104 for recurrence of surgery and chemotherapy of 4.94 (95% CI, 1.92-12.71) and 0.89 (95% CI, 0.47- 1.67) for surgery alone. The association of most SNPs remained significant after adjusting for multiple comparisons using a q-value at 10%. By using a combination of SNPs in class 2 or 3, we were able to build genetic predictors for outcome of surgery or surgery and chemotherapy, with p < 10-6 and < 10-4, respectively. Conclusions: These results suggest that specific genetic variations in the genes mentioned above modulate clinical outcomes in patients who undergo surgery or surgery and chemotherapy for early stage NSCLC. These results may be used to build predictive models for identifying surgical patients at increased risk of adverse outcome, who may benefit from addition of chemotherapy independent of clinical stage. No significant financial relationships to disclose.
Anomalous High p27/KIP1 Expression in a Subset of Aggressive B-Cell Lymphomas Is Associated With Cyclin D3 Overexpression. p27/KIP1—Cyclin D3 Colocalization in Tumor Cells
Authors: Margarita Sánchez-Beato, Francisca I. Camacho, Juan C. Martı́nez-Montero, Ana I. Sáez, Raquel Villuendas, Lydia Sánchez-Verde, Juan F. Garcı́a, Miguel A. Piris
Journal: Blood (1999)
PWE-194 The routine use of transient elastography to detect liver changes in chronic pancreatitis patients
Authors: A Yee, S Chin, RA Adair, DG Jayne, AM Smith
Journal: Gut (2015)

<h3>Introduction</h3> Chronic Pancreatitis (CP) can cause obstruction of the common bile duct. Biliary drainage is often suboptimal due to coexistent CP complications. The effect of protracted biliary obstruction on liver fibrosis has not been assessed in CP patients. The aim of the study is to determine the usefulness of non-invasive transient elastography (TE) - FibroScan© in detecting changes to the liver in CP patients with and without biliary obstruction. <h3>Method</h3> 194 CP patients were identified from a prospectively maintained database from 2006 to 2012. 59 patients were scanned, including patients with normal liver function tests (LFTs) and those with abnormal LFTs +/- dilated common bile duct. FibroScan© readings were graded as absent/mild fibrosis (≤ 7.0 kPa), significant fibrosis (7.1–9.4 kPa), severe fibrosis (9.5–12.4 kPa), cirrhosis (≥12.5 kPa). <h3>Results</h3> The study group included 44 males and 15 females with CP. Median age was 69 yrs (37–88). The aetiological agent was alcohol in 43%. The median TE was 8.2 (2.5–34.3) kPa with 59.3% normal. Correlation for the whole group was found between pancreas atrophy (p = 0.017, median 7.7 kPa), Cambridge classification III (p = 0.010, median 10.7 kPa) and Creon® &gt;80000 units tds (p = 0.010, median 7.8 kPa). For alcohol aetiology only, this was found with Creon® &gt;80000 units tds (p = 0.018, median 11.2 kPa), abnormal bilirubin (p = 0.005, median 13.6 kPa) and intrahepatic duct dilatation (p = 0.027, median 12.0 kPa). 22% had significant fibrosis, 6.8% had severe fibrosis and 11.9% had values consistent with possible cirrhosis. The rate of fibrosis in this group was determined to be 28.8% with 47% (8/17) having normal serum LFTs. <h3>Conclusion</h3> This study suggests that even asymptomatic CP patients with normal liver function tests may have changes of their liver ranging from mild fibrosis to cirrhosis. Routine use of FibroScan© may be useful for the surveillance and detection of early liver disease in CP patients in the outpatient setting so that timely management can be initiated. <h3>Disclosure of interest</h3> None Declared. <h3>References</h3> Frossard JL, <i>et al</i>. The role of transient elastography in the detection of liver disease in patients with chronic pancreatitis. Liver Int. 2013;33(7):1121–1127 Fraquelli M, <i>et al</i>. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut 2007;56(7):968–973 Braganza JM, <i>et al</i>. Chronic pancreatitis. Lancet 2011;377(9772): 1184–1197 Scobie BA, Summerskill WH. Hepatic Cirrhosis Secondary to Obstruction of the Biliary System. Am J Dig Dis. 1965;10:135–146
The Complete Type I VWD Cohort Of The Zimmerman Program For The Molecular and Clinical Biology Of VWD - Phenotypic Assignment, Mutation Frequency, and Bleeding Assessment
Authors: Robert R. Montgomery, Pamela Christopherson, Daniel B. Bellissimo, Joan Cox Gill, Sandra L. Haberichter, Veronica H. Flood, David Lillicrap, Anne C. Goodeve, Kenneth D Friedman, Thomas C. Abshire, Amy D. Shapiro, Margaret V. Ragni, Steven R. Lentz, Cindy A. Leissinger, Amy L. Dunn, Jeanne Lusher, Deborah Brown
Journal: Blood (2013)
A painful foot: Lisfranc fracture-dislocations
Authors: Matthew Welck, Ruslan Zinchenko, Francois Tudor
Journal: BMJ (2016)

A fit and well 25 year old man presented to the emergency department with a painful left foot after being tackled while playing football. His left foot had been in plantar flexion when he was tackled just as he was about to kick the ball.

He could not continue playing but could bear weight straight away. His teammates brought him to the emergency department after the match because of increasing pain. A detailed clinical examination showed marked swelling over the dorsum of the left foot, tenderness in the dorsomedial midfoot, and plantar ecchymosis. Weight bearing anteroposterior, internal oblique (figs 1 and 2⇓), and lateral radiographs of the left foot showed a Lisfranc fracture-dislocation of the second tarsometatarsal joint.



Fig 1  Weight bearing anteroposterior radiograph of both feet showing injury to the left foot—subtle diastasis between the metatarsal base and the medial cuneiform (white line) and malalignment of the medial border of the second metatarsal base with the medial border of the middle cuneiform (black lines)





Fig 2  Weight bearing oblique radiograph of the left foot showing a more obvious opening between the second metatarsal base and the medial cuneiform (white lines) and an avulsion fracture from the medial border of the first metatarsal base (arrow)



1.  What is the anatomy of the Lisfranc joint?

2.  How do acute and chronic Lisfranc injuries usually present?

3.  How do you investigate Lisfranc injuries?

4.  How do you manage Lisfranc injuries?

### 1. What is the anatomy of the Lisfranc joint?

#### Short answer

The Lisfranc (tarsometatarsal) joints are formed by the five metatarsal bones distally and the cuboid bone and three cuneiform bones proximally. The Lisfranc ligament attaches the medial cuneiform bone to the base of the second metatarsal.

#### Discussion

The Lisfranc joint is considered to be S shaped and is made up of three columns. The medial cuneiform bone and the first metatarsal make up the medial column. …
Immunosuppression and Secondary Infection in Sepsis
Authors: Derek C. Angus, Steven Opal
Journal: JAMA (2016)

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