tbuckley/cabot-search huggingface dataset:
Clinical relevance of lymph node ratio in resected oral cavity squamous cell carcinoma in patients with N2 disease.
Authors: Ali Hosni, David Paul Goldstein, Shao Hui Huang, Wei Xu, Yuyao Song, Andrew Bayley, Scott Victor Bratman, John Cho, Meredith Elana Giuliani, John Kim, Jolie Ringash, John N. Waldron, Patrick Gullane, Ralph William Gilbert, Jonathan Crawford Irish, Brian O'Sullivan, Andrew J. Hope
Journal: Journal of Clinical Oncology (2016)

6019 Background: Lymph node ratio (LNR, number of positive lymph nodes/total number of excised lymph nodes) has been shown to be associated with outcomes in multiple malignancies. In this study, the impact of LNR on distant metastasis (DM) and overall survival (OS) in oral cavity squamous cell carcinoma (OSCC) was investigated. Methods: Retrospective review of pN0-2 OSCC patients (pts) treated between 1994-2012 with curative surgery with neck dissection (ND) +/- postoperative radiotherapy (PORT) with or without concurrent chemotherapy (CCT). LNR was subjected to multivariable analysis (MVA) of DM and OS, adjusted for pT3-4, extracapsular extension (ECE), high grade (G3), lymphovascular invasion (LVI), perineural invasion (PNI), and tumor subsite. Results: Overall 914 pts were identified; median age: 61 yr (18-92); median follow-up: 51 months (1–189); pT3-4: 283 (31%); pN-classification: N0: 482 (53%), N1: 128 (14%), N2a: 6 (0.5%); N2b: 225 (24.5%); N2c: 73 (8%); median number of dissected nodes: 36 (6-125); median number of pN+: 2 (1-49); median LNR for pN+ pts: 0.06; ECE: 187 (20%); G3: 147 (16%); LVI: 115 (13%); PNI: 416 (46%). Bilateral ND was performed in 367 (40%); PORT was used in 452 (49%); and CCT in 80 (9%). The 5-yr distant control (DC) and OS were 89% and 70%; respectively. pT3-4 (p<0.001), G3 (p<0.001), LVI (p=0.0013), and PNI (p<0.001) were all associated with high LNR. On MVA, LNR >0.06 was associated with more DM (HR=1.8; 95%CI=1.1-3.1; p=0.017) and lower OS (HR=2; 95%CI=1.4–2.8; p<0.001). In subgroup analysis of pN2 pts (n=304): higher LNR (>0.14) was associated with lower 5yr- DC (67%, p=0.014) and OS (25%, p<0.001), and on MVA within the pN2 subgroup, both higher LNR (p<0.001) and ECE (p=0.006) were associated with lower OS. Conclusions: High LNR is associated with higher rate of DM and lower OS in OSCC. LNR should be assessed in pN2 pts in future prospective trials to select patients for adjuvant therapies.
Added diagnostic value and impact on antimicrobial therapy of 16S rRNA PCR and amplicon sequencing on resected heart valves in infective endocarditis: a prospective cohort study
Authors: B. Peeters, P. Herijgers, K. Beuselinck, J. Verhaegen, W.E. Peetermans, M.-C. Herregods, S. Desmet, K. Lagrou
Journal: Clinical Microbiology and Infection (2017)
Elevated medial-frontal cerebral blood flow in obsessive-compulsive patients: a SPECT study
Authors: S R Machlin, G J Harris, G D Pearlson, R Hoehn-Saric, P Jeffery, E E Camargo
Journal: American Journal of Psychiatry (1991)

Regional cerebral blood flow was measured with single photon emission computed tomography in 10 obsessive-compulsive patients and eight comparison subjects. The patients had a significantly higher ratio of medial-frontal to whole cortex blood flow; this was unrelated to symptom severity but was correlated negatively with anxiety. No differences in orbital-frontal blood flow were found.
Implantable Cardioverter-Defibrillators for Primary Prevention in Patients With Ischemic or Nonischemic Cardiomyopathy
Authors: Michalina Kolodziejczak, Felicita Andreotti, Mariusz Kowalewski, Antonino Buffon, Marco Matteo Ciccone, Gianfranco Parati, Pietro Scicchitano, Julia M. Uminska, Stefano De Servi, Kevin P. Bliden, Jacek Kubica, Alessandro Bortone, Filippo Crea, Paul Gurbel, Eliano P. Navarese
Journal: Annals of Internal Medicine (2017)

Implantable cardioverter-defibrillators (ICDs) have a role in preventing cardiac arrest in patients at risk for life-threatening ventricular arrhythmias.To compare ICD therapy with conventional care for the primary prevention of death of various causes in adults with ischemic or nonischemic cardiomyopathy.MEDLINE, Cochrane Central Register of Controlled Trials, Google Scholar, and EMBASE databases, as well as several Web sites, from 1 April 1976 through 31 March 2017.Randomized controlled trials, published in any language, comparing ICD therapy with conventional care and reporting mortality outcomes (all-cause, sudden, any cardiac, or noncardiac) in the primary prevention setting.2 independent investigators extracted study data and assessed risk of bias.Included were 11 trials involving 8716 patients: 4 (1781 patients) addressed nonischemic cardiomyopathy, 6 (4414 patients) ischemic cardiomyopathy, and 1 (2521 patients) both types of cardiomyopathy. Mean follow-up was 3.2 years. An overall reduction in all-cause mortality, from 28.26% with conventional care to 21.37% with ICD therapy (hazard ratio [HR], 0.81 [95% CI, 0.70 to 0.94]; P = 0.043), was found. The magnitude of reduction was similar in the cohorts with nonischemic (HR, 0.81 [CI, 0.72 to 0.91]) and ischemic (HR, 0.82 [CI, 0.63 to 1.06]) disease, although the latter estimate did not reach statistical significance. The rate of sudden death fell from 12.15% with conventional care to 4.39% with ICD therapy (HR, 0.41 [CI, 0.30 to 0.56]), with a similar magnitude of reduction in patients with ischemic (HR, 0.39 [CI, 0.23 to 0.68]) and those with nonischemic disease (HR, 0.44 [CI, 0.17 to 1.12]). Noncardiac and any cardiac deaths did not differ significantly by treatment.Heterogeneous timing of ICD placement; heterogeneous pharmacologic and resynchronization co-interventions; trials conducted in different eras; adverse events and complications not reviewed.Overall, primary prevention with ICD therapy versus conventional care reduced the incidence of sudden and all-cause death.None.
Improved survival outcomes for orthotopic liver transplant (OLT): 12 years experience at Irish transplant
Authors: A Qasim, B Zaman, B Blake, T Tajuddin, J Geoghegan, D Maguire, O Traynor, J Hegarty, A McCormick
Journal: Endoscopy (2005)

Introduction: Multiple factors including patient selection, disease type, peri-and postoperative care and centre experience are prone to influence OLT success.
Phase 1b of WNT inhibitor ipafricept (IPA, decoy receptor for WNT ligands) with carboplatin (C) and paclitaxel (P) in recurrent platinum-sensitive ovarian cancer (OC).
Authors: Roisin Eilish O'Cearbhaill, D. Scott McMeekin, Gina Mantia-Smaldone, Camille Gunderson, Paul Sabbatini, Fiore Cattaruzza, Marcus Fischer, Ann M. Kapoun, Lu Xu, Jakob Dupont, Rainer Karl Brachmann, Azeez Farooki, Kathleen N. Moore
Journal: Journal of Clinical Oncology (2016)

2515 Background: The WNT pathway is an important oncologic driver of OC. The first-in-class recombinant fusion protein IPA blocks WNT signaling through binding of WNT ligands. In patient-derived OC xenografts, IPA inhibits growth, reduces cancer stem cell frequency, promotes differentiation, synergizes with taxanes and shows greatest efficacy when given 2 to 3 days before the taxane. In Phase 1a, IPA was well tolerated with dysgeusia, fatigue, muscle spasms and anorexia as most common adverse events (AEs). Target modulation was observed in hair follicles at ≥ 2.5 mg/kg every 3 weeks (q3w). Consequent to the clinical experience with, mainly, vantictumab (VAN), a 2nd WNT inhibitor, serum biochemical markers of bone turnover were used to trigger bone-protective zoledronic acid (ZA)therapy, if appropriate. Methods: Dose escalation started with a standard 3+3 design for IPA/C/P with q3w intravenous IPA on Day 1, in cycles 1 to 6 with C (AUC = 5 mg/mL · min) and P (175 mg/m2). For enhanced bone safety the trial was revised to 6-patient cohorts with a q3w regimen of IPA on Day 1 and C/P on Day 3 (IPA→C/P). Objectives were determination of maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and efficacy. Results: To date, 17 patients have been treated; the 1st 7 patients in 2 cohorts of q3w IPA/C/P (5 & 10 mg/kg) and the next 10 patients in 2 cohorts of q3w IPA→C/P (2 & 4 mg/kg). The revised safety schedule was implemented following fragility fractures in the VAN and IPA Phase 1 programs, including 1 G1 pelvic fracture in this study. All 10 IPA→C/P patients received ZA at baseline for postmenopausal status without further fragility fractures. IPA-related AEs ≥ 15% were nausea, fatigue, neutropenia, alopecia, anorexia and vomiting. Only related G ≥ 3 AEs were neutropenia (3 x G3, 1 x G4) and hypophosphatemia (1 x G3). Of the 17 evaluable patients, 6 (35%) had a best response of complete response (CR), 8 (47%) partial response (PR) and 3 (18%) stable disease. Conclusions: IPA is well tolerated in combination with sequential C/P. The revised safety plan resulted in baseline bone-protective ZA for 100% of patients. 82% of patients achieved CR or PR. Dose escalation continues. Clinical trial information: NCT02092363.
Six members quit US presidential AIDS council as Trump “simply does not care”
Authors: Owen Dyer
Journal: BMJ (2017)

Six of the 21 members of the US Presidential Advisory Council on HIV and AIDS (PACHA) have resigned, saying that their advice has been ignored by an administration uninterested in the wellbeing of people with HIV. Three of the six are doctors.

Speaking out on behalf of the six members in Newsweek ,1 Scott Schoettes, counsel and HIV project director at Lambda Legal, wrote that, “as advocates for people living with HIV, we have dedicated our lives to combating this disease and no longer feel we can do so effectively within the confines of an advisory body to a president who simply does not care.”

He added, “The Trump …
The utility of genomics and functional imaging to predict irinotecan pharmacokinetics and pharmacodynamics: The PREDICT IR study.
Authors: Michael Michael, Winston Liauw, Sue-Anne McLACHLAN, Emma Link, Anetta Matera, Mick Thompson, Michael Jefford, Rodney J Hicks, Carleen Cullinane, Ian Campbell, Philip James Beale, Christos Stelios Karapetis, Timothy Price, Matthew E. Burge
Journal: Journal of Clinical Oncology (2017)

2564 Background: BSA-based dosing of Irinotecan (IR), does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variability. Given IR’s unique metabolism, functional hepatic nuclear imaging (HNI) with probes for hepatic transporters correlated with its PK. This study further evaluated the utility of HNI combined with extensive excretory/metabolic/PD pharmacogenomics (PG) to predict IR PK and PD in patients (pts) treated with FOLFIRI to enable dose individualization. Methods: Eligible pts had advanced colorectal cancer, suitable for 1 st /2 nd -line FOLFIRI± Bevacizumab. Pts had blood analyzed by Affymetrix DMET™ Plus Array and additional SNPs were genotyped. For HNI, pts were given IV 250MBq 99m Tc-IDA and imaging data analyzed for hepatic extraction/excretion parameters (clearance [CL], 1hour retention [1hRET], deconvulutional CL [DeCL], hepatic extraction fraction [HEF]). Pts treated with chemotherapy, q2-weekly, and restaged after 4 cycles. Blood taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1, PK parameters derived by non-compartmental analysis. Statistical correlations were evaluated between (i) IDA HNI and (2) PGs, with IR PK, toxicity, objective response (ORR) and progression-free survival (PFS). Results: 32 pts analysed, 31 pts completed 4 cycles. (1) PK correlates: (a) HNI CL and 1hRET with SN38 Metabolic CL, (P = 0.04) and (b) HNI DeCL with IR AUC (0-∞) (P = 0.04). (2) Grade 3+ diarrhea (N = 4, 13%) predicted by SN38 AUC (0-∞) and Metabolic CL (P = 0.04), and gene variants for SCL22A2 and -28A3, ABCC2, UGT2B17, CYP2C18 and DPYD (P &lt; 0.05). (3) Grade 3+ neutropenia (N = 9, 28%) predicted by SN38 PK exposure (P &lt; 0.02), HNI CL and 1hRET (P &lt; 0.0001) and variants for SLC7A7-, SLC22A2-, CHST1-, UGT1A1-, -2B7, ABCB1. (4) ORR (N = 6, 20%) predicted by Methylene tetrahydrofolate reductase (MTHFR) 677C &gt; T (P = 0.002), SN38 exposure (P &lt; 0.003), and variants in metabolic/transporter genes (P &lt; 0.05). (5) PFS by SN38 PK exposure, MTHFR 677C &gt; T, HNI CL, HNI HEF and variants in PK genes (P &lt; 0.05). Conclusions: Hepatic functional imaging with extensive pharmacogenomics correlate with Irinotecan PK and PD enabling the development of nomograms to individualize dosing. Clinical trial information: ACTRN12610000898055.
Abstract 151: A Novel Role for DDiT4L in Regulation of mTOR and Autophagy in the Heart
Authors: Bridget Simonson, Hannabeth Franchino, Ashley Knight, Anthony Rosenzweig, Saumya Das
Journal: Circulation Research (2013)

Introduction: DDiT4L is a known negative regulator of mTOR signaling in skeletal muscle; however its role in the heart is unknown. We have recently showed increased DDiT4L mRNA in a murine transgenic model of pathological but not physiological hypertrophy. Here we test the hypothesis that DDiT4L is a regulator of mTOR signaling in the heart and may play a role in pathological hypertrophy and heart failure. Methods: We investigated the regulation of DDiT4L in murine models of hypertrophy and in cultured neonatal rat ventricular cardiomyocytes (NRVMs). Loss and gain of function of DDiT4L in mTOR regulation and autophagy was investigated using confocal imaging, immunoblotting, and qRT-PCR in NRVMs. Results: DDiT4L gene and protein expression was increased four-fold in pressure overload hypertrophy (n = 4-6, p&lt;0.001), but not in a swim model of physiological hypertrophy. DDiT4L gene expression also significantly increased in a genetic model of dilated cardiomyopathy model (n = 4, p&lt;0.001). In NRVMs, DDiT4L was induced by cardiac stressors such as pathological stretch, hypoxia, and glucose deprivation (n = 3-5 in duplicate, p&lt;0.05-0.01). Increased DDiT4L expression correlated with inhibition of mTOR signaling, and an increase in autophagy markers. siRNA ablation of DDiT4L revealed that inhibition of mTOR signaling by DDiT4L was necessary for glucose deprivation induced autophagy, as determined by imaging of GFP-LC3 autophagosomes (n = 3 in duplicate, p&lt;0.01), and immunoblotting of autophagy markers. Conversely, adenoviral-driven overexpression of DDiT4L inhibited mTOR signaling and significantly increased basal autophagy (n = 3 in duplicate, p&lt;0.05). In TAC mice, the increase in DDiT4L protein expression correlated to inhibition of mTOR signaling, increases in autophagy markers (p&lt;0.01), and preceded the transition to LV dilation and HF. Conclusion: Our data suggests that DDiT4L expression is altered in diverse models of pathological hypertrophy and precedes the development of LV dilatation and overt heart failure. DDiT4L inhibition of mTOR and modulation of autophagy may play a role in the progression to heart failure. DDiT4L may represent a novel therapeutic target to prevent this transition.
Regional trends in telithromycin and azithromycin resistance among Streptococcus pneumoniae isolates
Authors: V. Allizond, G. Banche, J. Roana, N. Li Vigni, N. Mandras, D. Scalas, V. Tullio, N. Carlone, D. Savoia, A. Barbui, A Cuffini
Journal: Clinical Microbiology and Infection (2008)
WEE1 Kinase Inhibitor AZD1775 Has Preclinical Efficacy in LKB1-Deficient Non–Small Cell Lung Cancer
Authors: Amanda L. Richer, Jacqueline M. Cala, Kelley O'Brien, Vashti M. Carson, Landon J. Inge, Timothy G. Whitsett
Journal: Cancer Research (2017)

G1-S checkpoint loss contributes to carcinogenesis and increases reliance upon the G2-M checkpoint for adaptation to stress and DNA repair, making G2-M checkpoint inhibition a target for novel therapeutic development. AZD1775, an inhibitor against the critical G2-M checkpoint protein WEE1, is currently in clinical trials across a number of tumor types. AZD1775 and DNA-damaging agents have displayed favorable activity in several preclinical tumor models, often in the molecular context of TP53 loss. Whether AZD1775 efficacy is modulated by other molecular contexts remains poorly understood. The tumor suppressor serine/threonine kinase 11 (LKB1/STK11) is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC) and is commonly comutated with oncogenic KRAS mutations. We investigated the preclinical effects of AZD1775 in the context of KRAS/LKB1 in NSCLC. Using NSCLC cell lines, we found that AZD1775 alone and in combination with DNA-damaging agents (e.g., cisplatin and radiation) decreased tumor cell viability in LKB1-deficient NSCLC cells. In vitro, LKB1 deficiency enhanced DNA damage and apoptosis in response to AZD1775 exposure compared with wild-type LKB1 cells. In a genetically engineered mouse model of mutant Kras with concomitant loss of Lkb1, combined AZD1775 and cisplatin extended overall survival compared with cisplatin alone. Our data suggest that lack of phosphorylation of LKB1 by ATM was involved in AZD1775-mediated cytotoxicity. Collectively, these findings provide a clinical application for AZD1775 with DNA-damaging agents in KRAS/LKB1 NSCLC. Cancer Res; 77(17); 4663-72. ©2017 AACR.
Prognostic value of tumor response in pediatric and adult patients with Ewing sarcoma.
Authors: Melanie Ann Chihak, Michael Gary Keeney, Karen Fritchie, William S. Harmsen, Carola A. S. Arndt, Kathryn Jean Ruddy, Safia K. Ahmed, Nadia N. Laack
Journal: Journal of Clinical Oncology (2016)

10543 Background: European Ewing sarcoma (ES) regimens use histologic response to chemotherapy at the time of local control to identify patients for treatment intensification. Prognostic importance of histologic response has not been confirmed in North American regimens and is currently under study in the most recent COG protocol. We aim to characterize histologic tumor response at time of local therapy in ES and correlate tumor response with patient outcomes. Methods: The Mayo Clinic tumor registry was used to retrospectively identify patients with non-metastatic ES from January 1977 to December 2012. Only patients who had neoadjuvant chemotherapy with surgery as the initial local control modality were included. Two pathologists reviewed stored surgical specimens and documented the percent necrosis and remaining viable tumor. A chart review collected demographic, treatment and outcome data. Results: Registry review identified 360 patients with ES, of which 87 met inclusion criteria. Median patient age was 15.7 years (range 2.4 – 54.5 years). Distribution of primary tumor sites included 66% extremity, 22% axial and 13% pelvic. Median time interval from diagnosis to surgery was 3.6 months (range 1.5-13.7 months). A vincristine, doxorubicin, cyclophosphamide (VDC) backbone was used in 97% of patients; 77% received VDC/IE (ifosfamide, etoposide). Median follow up was 6.6 years (range 0.38 – 36.1 years). Twenty-seven patients developed recurrence (31%); 3 local only, 19 distant only, 4 local and distant, and 1 unknown. The 5 year event-free survival (EFS) of patients with ≤ 5% viable tumor at the time of local control surgery compared to patients with > 5% viability was 76% and 59% respectively (p = 0.0141). The 5 year overall survival (OS) of these two groups was 83% and 62% respectively (p = 0.0146). When analysis was limited to patients treated with VDC/IE (n = 66), the trend was similar (5 year EFS of 80% vs 69%, p = 0.1907). Conclusions: Histological tumor response of ≤ 5% tumor viability at the time of local control surgery in pediatric and adult ES patients is associated with improved EFS and OS. Patients with greater than 5% viability are at an increased risk of recurrence and may benefit from treatment intensification.
Leads from the MMWR. Acquired immunodeficiency syndrome (AIDS) in western Palm Beach County, Florida
Journal: JAMA (1986)

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Nomogram to predict recurrence after curative resection of pancreatic neuroendocrine tumors.
Authors: Cansu Guney Genc, Stefano Partelli, Massimo Falconi, Francesca Muffatti, Susan van Dieren, Heinz-Josef Klumpen, Casper H.J. van Eijck, Els J.M. Nieveen van Dijkum
Journal: Journal of Clinical Oncology (2016)

e15654 Background: Early stagenon-functioning pancreatic neuroendocrine tumors (NF-pNETs) are diagnosed more often due to improved recognition and imaging. Surgical resection is the preferred treatment, but recurrence still occurs frequently. Aim of this study is to predict recurrence after resection in order to identify patients that are at risk and might benefit from intense follow-up or adjuvant treatment. Methods: Retrospectively patients with curative resection of NF-pNET of two institutions were included. Distant metastasis, hereditary syndromes and grade 3 tumors were excluded. Recurrence was scored, defined as local tumor recurrence or new localization as lymph node- or distant metastasis. Independent predictors were identified with multivariable Cox regression. Based on hazard ratios a nomogram was developed to predict recurrence within 5-years. External validation with a retrospective cohort from a third center was performed using Harrell’s concordance index. Results: A total of 97 patients with grade 1 or 2 NF-pNET were included; 24% developed recurrence. Independent predictors were positive lymph nodes, perineural invasion and tumor size > 2cm. Patients with these characteristics scored 3, 5 or 11 points respectively on the nomogram. High risk patients had a nomogram score of > 14 as this cutoff showed 50% recurrence within 5 years. External validation with 144 patients of which 11% had recurrence was performed. The c-statistic of 0.69 (CI95% 0.54 – 0.83) indicated that the ability to separate patients who will develop recurrence is reasonable. Conclusions: Positive lymph nodes, perineural invasion and tumor size > 2cm predict recurrence after curative resection of grade 1 and 2 NF-pNET. Patients with a nomogram score of > 14 are at risk and a more intense follow-up can be recommended. A larger validation cohort is needed for a more accurate analysis of the discrimination and calibration qualities of the nomogram.