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1.
Phys Rev Lett ; 132(15): 155102, 2024 Apr 12.
Article in English | MEDLINE | ID: mdl-38683000

ABSTRACT

We present the first experimental study of plasmoid formation in a magnetic reconnection layer undergoing rapid radiative cooling, a regime relevant to extreme astrophysical plasmas. Two exploding aluminum wire arrays, driven by the Z machine, generate a reconnection layer (S_{L}≈120) in which the cooling rate far exceeds the hydrodynamic transit rate (τ_{hydro}/τ_{cool}>100). The reconnection layer generates a transient burst of >1 keV x-ray emission, consistent with the formation and subsequent rapid cooling of the layer. Time-gated x-ray images show fast-moving (up to 50 km s^{-1}) hotspots in the layer, consistent with the presence of plasmoids in 3D resistive magnetohydrodynamic simulations. X-ray spectroscopy shows that these hotspots generate the majority of Al K-shell emission (around 1.6 keV) prior to the onset of cooling, and exhibit temperatures (170 eV) much greater than that of the plasma inflows and the rest of the reconnection layer, thus providing insight into the generation of high-energy radiation in radiatively cooled reconnection events.

2.
Biochem J ; 477(1): 45-60, 2020 01 17.
Article in English | MEDLINE | ID: mdl-31820794

ABSTRACT

Membrane-active peptides have been extensively studied to probe protein-membrane interactions, to act as antimicrobial agents and cell-penetrating peptides (CPPs) for the delivery of therapeutic agents to cells. Hundreds of membrane-active sequences acting as CPPs have now been described including bioportides that serve as single entity modifiers of cell physiology at the intracellular level. Translation of promising CPPs in pre-clinical studies have, however, been disappointing as only few identified delivery systems have progressed to clinical trials. To search for novel membrane-active peptides a sequence from the EGFR juxtamembrane region was identified (named EJP18), synthesised, and examined in its L- and D-form for its ability to mediate the delivery of a small fluorophore and whole proteins to cancer cell lines. Initial studies identified the peptide as being highly membrane-active causing extensive and rapid plasma membrane reorganisation, blebbing, and toxicity. At lower, non-toxic concentrations the peptides outperformed the well-characterised CPP octaarginine in cellular delivery capacity for a fluorophore or proteins that were associated with the peptide covalently or via ionic interactions. EJP18 thus represents a novel membrane-active peptide that may be used as a naturally derived model for biophysical protein-membrane interactions or for delivery of cargo into cells for therapeutic or diagnostic applications.


Subject(s)
Cell-Penetrating Peptides/pharmacology , Drug Carriers/pharmacology , Drug Delivery Systems/methods , Neoplasms/drug therapy , ErbB Receptors/pharmacology , Green Fluorescent Proteins/administration & dosage , HeLa Cells , Humans , MCF-7 Cells , Protein Domains
3.
Rev Sci Instrum ; 90(12): 124707, 2019 Dec 01.
Article in English | MEDLINE | ID: mdl-31893831

ABSTRACT

The MAIZE Linear Transformer Driver consists of 40 capacitor-switch-capacitor "bricks" connected in parallel. When these 40 bricks are charged to ±100-kV and then discharged synchronously, the MAIZE facility generates a 1-MA current pulse with a 100-ns rise time into a matched load impedance. Discharging each of the capacitors in a brick is carried out by the breakdown of a spark-gap switch, a process that results in the emission of light. Monitoring this output light with a fiber optic coupled to a photomultiplier tube (PMT) and an oscilloscope channel provides information on switch performance and timing jitter-whether a switch fired early, late, or in phase with the other switches. However, monitoring each switch with a dedicated detector-oscilloscope channel can be problematic for facilities where the number of switches to be monitored (e.g., 40 on MAIZE) greatly exceeds the number of detector-oscilloscope channels available. The technique of using fibers to monitor light emission from switches can be optimized by treating a PMT as a binary digit or bit and using a combinatorial encoding scheme, where each switch is monitored by a unique combination of fiber-PMT-oscilloscope channels simultaneously. By observing the unique combination of fiber-PMT-oscilloscope channels that are turned on, the prefiring or late-firing of a single switch on MAIZE can be identified by as few as six PMT-oscilloscope channels. The number of PMT-oscilloscope channels, N, required to monitor X switches can be calculated by 2N = X + 1, where the number "2" is selected because the PMT-oscilloscope acts as a bit. In this paper, we demonstrate the use of this diagnostic technique on MAIZE. We also present an analysis of how this technique could be scaled to monitor the tens of thousands of switches proposed for various next generation pulsed power facilities.

4.
Rev Sci Instrum ; 89(10): 10D123, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30399676

ABSTRACT

In the self-magnetic-pinch diode, the electron beam, produced through explosive field emission, focuses on the anode surface due to its own magnetic field. This process results in dense plasma formation on the anode surface, consisting primarily of hydrocarbons. Direct measurements of the beam's current profile are necessary in order to understand the pinch dynamics and to determine x-ray source sizes, which should be minimized in radiographic applications. In this paper, the analysis of the C IV doublet (580.1 and 581.2 nm) line shapes will be discussed. The technique yields estimates of the electron density and electron temperature profiles, and the method can be highly beneficial in providing the current density distribution in such diodes.

5.
Clin Otolaryngol ; 43(2): 638-644, 2018 04.
Article in English | MEDLINE | ID: mdl-29194991

ABSTRACT

BACKGROUND: To report our experience of postoperative haemorrhage in patients following transoral robotic surgery (TORS). METHODS: Data were collected on patients having TORS. Postoperative haemorrhage within 30 days was graded using the Mayo Clinic grading system. RESULTS: Transoral robotic surgery operations were performed on 122 patients. There were 23 bleeding events classified as minor to severe following 19 operations (16%). Haemorrhage requiring a return to the operating room occurred after 7 operations (6%). The odds of an emergent haemorrhage were 5.19 times greater in patients who had a staged neck dissection after TORS (P = .05). The odds of a postoperative bleeding event were 2.6 times greater in patients receiving a larger resection (P = .107). There were no haemorrhage events in the 36 patients who received a synchronous neck dissection with transcervical ligation of the external carotid artery. CONCLUSIONS: Surgical intervention for TORS haemorrhage occurred in 6% patients. No haemorrhage occurred in patients who had ligation of the external carotid artery.


Subject(s)
Carcinoma, Squamous Cell/surgery , Mouth Neoplasms/surgery , Neck Dissection/adverse effects , Otorhinolaryngologic Neoplasms/surgery , Postoperative Hemorrhage/epidemiology , Robotic Surgical Procedures/adverse effects , Aged , Carcinoma, Squamous Cell/pathology , Female , Humans , Male , Middle Aged , Mouth Neoplasms/pathology , Neoplasm Staging , Otorhinolaryngologic Neoplasms/pathology , Retrospective Studies
7.
Br J Surg ; 103(3): 218-25, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26511531

ABSTRACT

BACKGROUND: The role of prophylactic central neck dissection (CND) in the management of papillary thyroid cancer (PTC) is controversial. This report describes outcomes of an observational approach in patients without clinical evidence of nodal disease in PTC. METHODS: All patients who had surgery between 1986 and 2010 without CND for PTC were identified. All patients had careful clinical assessment of the central neck during preoperative and perioperative evaluation, with any suspicious nodal tissue excised for analysis. The cohort included patients in whom lymph nodes had been removed, but no patient had undergone a formal neck dissection. Recurrence-free survival (RFS), central neck RFS and disease-specific survival (DSS) were calculated using the Kaplan-Meier method. RESULTS: Of 1798 patients, 397 (22.1 per cent) were men, 1088 (60.5 per cent) were aged 45 years or more, and 539 (30.0 per cent) had pT3 or pT4 disease. Some 742 patients (41.3 per cent) received adjuvant treatment with radioactive iodine. At a median follow-up of 46 months the 5-year DSS rate was 100 per cent. Five-year RFS and central neck RFS rates were 96.6 and 99.1 per cent respectively. CONCLUSION: Observation of the central neck is safe and should be recommended for all patients with PTC considered before and during surgery to be free of central neck metastasis.


Subject(s)
Carcinoma/surgery , Lymph Nodes/pathology , Neck Dissection/methods , Neoplasm Recurrence, Local/epidemiology , Thyroid Neoplasms/surgery , Thyroidectomy/methods , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma/diagnosis , Carcinoma/secondary , Carcinoma, Papillary , Child , Disease-Free Survival , Female , Follow-Up Studies , Humans , Incidence , Lymphatic Metastasis/prevention & control , Male , Middle Aged , Prognosis , Retrospective Studies , Survival Rate/trends , Thyroid Cancer, Papillary , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/secondary , Treatment Outcome , United States/epidemiology , Young Adult
8.
Rev Sci Instrum ; 86(11): 113506, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26628134

ABSTRACT

In this work, we describe a technique for fabricating ultrathin foils in cylindrical geometry for liner-plasma implosion experiments using sub-MA currents. Liners are formed by wrapping a 400 nm, rectangular strip of aluminum foil around a dumbbell-shaped support structure with a non-conducting center rod, so that the liner dimensions are 1 cm in height, 6.55 mm in diameter, and 400 nm in thickness. The liner-plasmas are imploded by discharging ∼600 kA with ∼200 ns rise time using a 1 MA linear transformer driver, and the resulting implosions are imaged four times per shot using laser-shadowgraphy at 532 nm. This technique enables the study of plasma implosion physics, including the magneto Rayleigh-Taylor, sausage, and kink instabilities on initially solid, imploding metallic liners with university-scale pulsed power machines.

9.
Ann Surg Oncol ; 22 Suppl 3: S985-91, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26314876

ABSTRACT

BACKGROUND: The American Joint Committee on Cancer (AJCC) stage III classification of oral cavity squamous cell carcinoma (OCSCC) represents a heterogeneous group of patients with early local disease with regional metastases (T1N1 and T2N1) and advanced local disease with or without regional metastasis (T3N0 and T3N1). OBJECTIVE: The aim of this study was to evaluate prognostic heterogeneity in the stage III category. METHODS AND PATIENTS: An international retrospective multicenter study of 1815 patients who were treated for OCSCC from 2003 to 2011. RESULTS: Kaplan-Meier survival analysis and multivariate models of stage III patients revealed better overall survival (OS; HR 2.12, 95 % CI 1.03-4.15; p = 0.01) and disease-specific survival (DSS; HR 1.7, 95 % CI 1.16-4.12; p = 0.04) rates for patients with T1-2N1/T3N0 disease than for patients with T3N1 disease. The outcomes of patients with T3N1 and stage IVa disease were similar (p = 0.89 and p = 0.78 for OS and DSS, respectively). Modifying stage classification by transferring the T3N1 category to the stage VIa group resulted in a better prognostic performance [Harrell's concordance index, C index 0.76; Akaike's Information Criterion (AIC) 4131.6] compared with the AJCC 7th edition staging system (C index 0.65; AIC 4144.9) for OS. When DSS was assessed, the suggested staging system remained the best performing model (C index 0.71; AIC 1061.3) compared with the current AJCC 7th edition staging (C index 0.64; AIC 1066.2). CONCLUSIONS: The prognosis of T3N1 and stage IVa disease are similar in OCSCC, suggesting that these categories could be combined in future revisions of the nodal staging system to enhance prognostic accuracy.


Subject(s)
Carcinoma, Squamous Cell/pathology , Mouth Neoplasms/pathology , Neoplasm Staging/standards , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/surgery , Female , Follow-Up Studies , Humans , International Agencies , Male , Middle Aged , Mouth Neoplasms/surgery , Neoplasm Invasiveness , Prognosis , Retrospective Studies , Survival Rate , United States , Young Adult
10.
Am J Gastroenterol ; 110(7): 956-62, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25803401

ABSTRACT

OBJECTIVES: The Accreditation Council for Graduate Medical Education (ACGME) emphasizes the importance of medical trainees meeting specific performance benchmarks and demonstrating readiness for unsupervised practice. The aim of this study was to examine the readiness of Gastroenterology (GI) fellowship programs for competency-based evaluation in endoscopic procedural training. METHODS: ACGME-accredited GI program directors (PDs) and GI trainees nationwide completed an online survey of domains relevant to endoscopy training and competency assessment. Participants were queried about current methods and perceived quality of endoscopy training and assessment of competence. Participants were also queried about factors deemed important in endoscopy competence assessment. Five-point Likert items were analyzed as continuous variables by an independent t-test and χ(2)-test was used for comparison of proportions. RESULTS: Survey response rate was 64% (94/148) for PDs and 47% (546/1,167) for trainees. Twenty-three percent of surveyed PDs reported that they do not have a formal endoscopy curriculum. PDs placed less importance (1­very important to 5­very unimportant) on endoscopy volume (1.57 vs. 1.18, P<0.001), adenoma detection rate (2.00 vs. 1.53, P<0.001), and withdrawal times (1.96 vs. 1.68, P=0.009) in determining endoscopy competence compared with trainees. A majority of PDs report that competence is assessed by procedure volume (85%) and teaching attending evaluations (96%). Only a minority of programs use skills assessment tools (30%) or specific quality metrics (28%). Specific competencies are mostly assessed by individual teaching attending feedback as opposed to official documentation or feedback from a PD. PDs rate the overall quality of their endoscopy training and assessment of competence as better than overall ratings by trainees. CONCLUSIONS: Although the majority of PDs and trainees nationwide believe that measuring specific metrics is important in determining endoscopy competence, most programs still rely on procedure volume and subjective attending evaluations to determine overall competence. As medical training transitions from an apprenticeship model to competency-based education, there is a need for improved endoscopy curricula which are better suited to demonstrate readiness for unsupervised practice.


Subject(s)
Clinical Competence , Competency-Based Education , Curriculum , Education, Medical, Graduate , Endoscopy, Digestive System/education , Fellowships and Scholarships , Gastroenterology/education , Accreditation , Adult , Benchmarking , Competency-Based Education/methods , Competency-Based Education/standards , Competency-Based Education/trends , Data Collection , Education, Medical, Graduate/methods , Education, Medical, Graduate/standards , Education, Medical, Graduate/trends , Female , Humans , Male , Middle Aged , Program Evaluation , United States
11.
Dig Dis Sci ; 60(3): 748-61, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25698379

ABSTRACT

Colorectal cancer (CRC) incidence and mortality are steadily declining and CRC screening rates are increasing in the United States. Although this a very good news, several definable groups still have very low screening rates including younger (under age 50) members of high-risk CRC families. This opinion piece describes five strategies that could be incorporated into routine practice to improve identification and guideline-based screening in members of high-risk families. Routine incorporation of a simple family history screening tool and outreach to high-risk family members could substantially improve guideline-based screening in this population. Identification of CRCs and advanced adenomas in the endoscopy suite defines another group of high-risk families for similar outreach. Lynch syndrome families can be identified by testing CRCs and selected adenomas for microsatellite instability or loss of DNA repair protein expression. Finally, selective addition of aspirin to surveillance endoscopy can decrease the risk of new adenomas and CRCs. The rationale for these strategies as well as mechanisms for their implementation and evaluation in clinical practice is described.


Subject(s)
Adenoma/diagnosis , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Colorectal Neoplasms/prevention & control , Early Diagnosis , Humans , Mass Screening , Practice Guidelines as Topic , Primary Prevention
12.
Prostate Cancer Prostatic Dis ; 17(3): 286-91, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25027862

ABSTRACT

BACKGROUND: Small-cell carcinoma of the prostate is an aggressive cancer whose rarity has prevented the development of a consensus management approach. The objective of the current study was to determine the treatment patterns and evaluate factors affecting overall survival for patients with localized small-cell carcinoma of the prostate. METHODS: After querying the National Cancer Database, we identified all patients diagnosed with localized small-cell carcinoma of the prostate between 1998 and 2011 (n=287). Using Kaplan-Meier curves and Cox regression analyses, we assessed the effect of treatment and clinical stage on overall survival. RESULTS: Treatments included radiation therapy in 46% (n=131), chemotherapy in 38% (n=107), androgen deprivation therapy (ADT) in 22% (n=63) and radical prostatectomy in 13% (n=38). Median overall survival was 14.8 months. Upon multivariate analysis, local therapy (radical prostatectomy or radiation therapy) was associated with improved survival (hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.14-0.38, P<0.001). Advanced clinical stage predicted worse survival among all men (cT3: HR 2.83, 95% CI 1.27-6.32, P=0.011; cT4: HR 3.26, 95% CI 1.50-7.07, P=0.003) and men who received local therapy (cT3: HR 4.67, 95% CI 1.41-15.44, P=0.012; cT4: HR 4.01, 95% CI 1.14-14.08, P=0.03) but not among men who received no local therapy (cT3: HR 1.64, 95% CI 0.51-5.27, P=0.4; cT4: HR 2.35, 95% CI 0.74-7.48, P=0.15). Age, receipt of chemotherapy and ADT, and clinical stage T2 disease (compared with T1) did not predict survival. CONCLUSION: Men with localized small-cell carcinoma of the prostate have a poor overall survival. Local therapy may represent a suitable and underused modality for select patients.


Subject(s)
Population Surveillance , Prostatic Neoplasms/epidemiology , Aged , Aged, 80 and over , Cause of Death , Combined Modality Therapy , Databases, Factual , Humans , Male , Middle Aged , Mortality , Neoplasm Staging , Proportional Hazards Models , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/therapy , United States/epidemiology , United States/ethnology
13.
J Clin Endocrinol Metab ; 99(4): 1245-52, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24512493

ABSTRACT

BACKGROUND: Poorly differentiated thyroid cancer (PDTC) accounts for only 1-15% of all thyroid cancers. Our objective is to report outcomes in a large series of patients with PDTC treated at a single tertiary care cancer center. METHODS: A total of 91 patients with primary PDTC were treated by initial surgery with or without adjuvant therapy at Memorial Sloan-Kettering Cancer Center from 1986 to 2009. Outcomes were calculated by the Kaplan-Meier method. Clinicopathological characteristics were compared for PDTC patients who died of disease to those who did not by the χ(2) test. Factors predictive of disease-specific survival (DSS) were calculated by univariate and multivariate analysis using the log rank and Cox proportional hazards method, respectively. RESULTS: With a median follow-up of 50 months, the 5-year overall survival and DSS were 62 and 66%, respectively. The 5-year locoregional and distant control were 81 and 59%, respectively. Of 27 disease-specific deaths, 23 (85%) were due to distant disease. Age ≥ 45 years, pathological tumor size >4 cm, extrathyroidal extension, higher pathological T stage, positive margins, and distant metastases (M1) were predictive of worse DSS on univariate analysis. Multivariate analysis showed that only pT4a stage and M1 were independent predictors of worse DSS. CONCLUSIONS: With appropriate surgery and adjuvant therapy, excellent locoregional control can be achieved in PDTC. Disease-specific deaths occurred due to distant metastases and rarely due to uncontrolled locoregional recurrence in this series.


Subject(s)
Carcinoma/pathology , Carcinoma/therapy , Thyroid Neoplasms/pathology , Thyroid Neoplasms/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma/mortality , Combined Modality Therapy/statistics & numerical data , Female , Follow-Up Studies , Humans , Iodine Radioisotopes/therapeutic use , Male , Middle Aged , Prognosis , Recurrence , Thyroid Neoplasms/mortality , Thyroidectomy/statistics & numerical data , Treatment Outcome , Young Adult
14.
Article in English | MEDLINE | ID: mdl-24530708

ABSTRACT

Two methods, absorption correction and multivariate spectrophotometric methods were developed for simultaneous estimation of Celecoxib (CEL) and Diacerein (DIA) in combined dosage form. Absorption correction method involves direct estimation of DIA at wavelength 341 nm in which CEL has zero absorbance and shows no interference. For estimation of CEL, corrected absorbance was calculated at 253 nm due to the interference of DIA at this wavelength. Linearity was observed in the range of 6-22 µg mL(-1) for CEL and 3-11 µg mL(-1) for DIA. The method was validated as per ICH guidelines. Chemometric methods including classical least square (CLS), inverse least square (ILS), principal component regression (PCR) and partial least square (PLS) were studied for simultaneous determination of CEL and DIA in capsule using spectrophotometry. A set of 25 standard mixtures containing both drugs were prepared in range of 5-25 µg mL(-1) for CEL and 3-15 µg mL(-1) for DIA. Analytical figure of merit (FOM), such as sensitivity, selectivity, analytical sensitivity, limit of detection and limit of quantitation were determined for chemometric methods. The proposed methods were applied for determination of two components from combined dosage form.


Subject(s)
Anthraquinones/analysis , Pyrazoles/analysis , Spectrophotometry/methods , Statistics as Topic/methods , Sulfonamides/analysis , Absorption , Anthraquinones/chemistry , Calibration , Capsules , Celecoxib , Least-Squares Analysis , Limit of Detection , Pyrazoles/chemistry , Regression Analysis , Reproducibility of Results , Sulfonamides/chemistry
15.
Ann Surg Oncol ; 21(5): 1665-70, 2014 May.
Article in English | MEDLINE | ID: mdl-24554064

ABSTRACT

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is among the most aggressive solid tumors accounting for 1-5 % of primary thyroid malignancies. In this retrospective review, we aim to evaluate the prognostic factors, treatment approaches, and outcomes of patients with ATC treated at a single institution. MATERIALS AND METHODS: We retrospectively identified 95 patients with ATC from an institutional database between 1985 and 2010. A total of 83 patients with sufficient records were included in this study. Patient, tumor, and treatment characteristics were recorded. Disease-specific survival (DSS) was determined by the Kaplan-Meier method, and factors predictive of outcome were determined by univariate and multivariate analysis. RESULTS: Of the 83 patients, 41 were male and 42 were female. The median age at presentation was 60 years (range 28-89 years) with a median survival of 8 months. The 1- and 2-year DSS were 33 and 23 %, respectively. On univariate analysis, age less than 60 years, clinically N0 neck, absence of clinical extrathyroidal extension (cETE), gross total resection, and multimodality treatment were statistically significant predictors of improved survival. On multivariate analysis, absence of cETE, multimodality therapy, and gross total resection were predictors of improved outcome. CONCLUSIONS: In patients with locoregional limited disease, multimodality treatment with gross total surgical resection and postoperative radiotherapy with or without chemotherapy offers the best local control and DSS.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Radiotherapy , Thyroid Carcinoma, Anaplastic/therapy , Thyroid Neoplasms/therapy , Thyroidectomy , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Prognosis , Retrospective Studies , Survival Rate , Thyroid Carcinoma, Anaplastic/mortality , Thyroid Carcinoma, Anaplastic/pathology , Thyroid Neoplasms/mortality , Thyroid Neoplasms/pathology
16.
Br J Cancer ; 109(8): 2087-95, 2013 Oct 15.
Article in English | MEDLINE | ID: mdl-24064974

ABSTRACT

BACKGROUND: Lymph node density (LND) has previously been reported to reliably predict recurrence risk and survival in oral cavity squamous cell carcinoma (OSCC). This multicenter international study was designed to validate the concept of LND in OSCC. METHODS: The study included 4254 patients diagnosed as having OSCC. The median follow-up was 41 months. Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional control and distant metastasis rates were calculated using the Kaplan-Meier method. Lymph node density (number of positive lymph nodes/total number of excised lymph nodes) was subjected to multivariate analysis. RESULTS: The OS was 49% for patients with LND0.07 compared with 35% for patients with LND>0.07 (P<0.001). Similarly, the DSS was 60% for patients with LND0.07 compared with 41% for those with LND>0.07 (P<0.001). Lymph node density reliably stratified patients according to their risk of failure within the individual N subgroups (P=0.03). A modified TNM staging system based on LND ratio was consistently superior to the traditional system in estimating survival measures. CONCLUSION: This multi-institutional study validates the reliability and applicability of LND as a predictor of outcomes in OSCC. Lymph node density can potentially assist in identifying patients with poor outcomes and therefore for whom more aggressive adjuvant treatment is needed.


Subject(s)
Carcinoma, Squamous Cell/pathology , Lymph Nodes/pathology , Mouth Neoplasms/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/surgery , Cohort Studies , Disease-Free Survival , Female , Humans , Lymph Nodes/surgery , Lymphatic Metastasis , Male , Middle Aged , Mouth Neoplasms/surgery , Multivariate Analysis , Neoplasm Metastasis , Neoplasm Staging , Predictive Value of Tests , Reproducibility of Results , Retrospective Studies , Survival Rate , Young Adult
17.
Ann Surg Oncol ; 20(11): 3575-81, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23775408

ABSTRACT

BACKGROUND: We aimed to study the importance of clinical N classification (cN) in a subgroup of patients with oral cavity squamous cell carcinoma (OSCC) and pathologically negative neck nodes (pN-). METHODS: A total of 2,258 patients from 11 cancer centers who underwent neck dissection for OSCC (1990-2011) had pN- disease. The median follow-up was 44 months. 5-year overall survival (OS), disease-specific survival (DSS), disease free survival, local control, locoregional control, and distant metastasis rates were calculated by the Kaplan-Meier method. cN classification and tumor, node, metastasis classification system staging variables were subjected to multivariate analysis. RESULTS: A total of 345 patients were preoperatively classified as cN+ and 1,913 were classified as cN-. The 5-year OS and DSS of cN- patients were 73.6 and 82.2 %, respectively. The 5-year OS and DSS of cN+ patients were 64.9 and 76.9 %, respectively (p < 0.0001 each). A cN+ classification was a significant predictor of worse OS (p = 0.03) and DSS (p = 0.016), regardless of treatment, depth of invasion, or extent of neck dissection. cN classification was associated with recurrence-free survival (p = 0.01) and locoregional (neck and primary tumor) control (p = 0.004), but not with local (p = 0.19) and distant (p = 0.06) recurrence rates. CONCLUSIONS: Clinical evidence of neck metastases is an independent predictor of outcome, even in patients with pN- nodes.


Subject(s)
Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/secondary , Lymph Nodes/pathology , Mouth Neoplasms/mortality , Mouth Neoplasms/pathology , Neck Dissection/mortality , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , International Agencies , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Staging , Prognosis , Retrospective Studies , Survival Rate
18.
Mol Psychiatry ; 18(10): 1136-45, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23032873

ABSTRACT

Fear memories are acquired through neuronal plasticity, an orchestrated sequence of events regulated at circuit and cellular levels. The conventional model of fear acquisition assumes unimodal (for example, excitatory or inhibitory) roles of modulatory receptors in controlling neuronal activity and learning. Contrary to this view, we show that protease-activated receptor-1 (PAR1) promotes contrasting neuronal responses depending on the emotional status of an animal by a dynamic shift between distinct G protein-coupling partners. In the basolateral amygdala of fear-naive mice PAR1 couples to Gαq/11 and Gαo proteins, while after fear conditioning coupling to Gαo increases. Concurrently, stimulation of PAR1 before conditioning enhanced, but afterwards it inhibited firing of basal amygdala neurons. An initial impairment of the long-term potentiation (LTP) in PAR1-deficient mice was transformed into an increase in LTP and enhancement of fear after conditioning. These effects correlated with more frequent 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) receptor-mediated miniature post synaptic events and increased neuronal excitability. Our findings point to experience-specific shifts in PAR1-G protein coupling in the amygdala as a novel mechanism regulating neuronal excitability and fear.


Subject(s)
Amygdala/physiology , Fear/physiology , Long-Term Potentiation/physiology , Receptor, PAR-1/physiology , Amygdala/chemistry , Animals , Conditioning, Classical/drug effects , Conditioning, Classical/physiology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Fear/drug effects , Freezing Reaction, Cataleptic/drug effects , Freezing Reaction, Cataleptic/physiology , GTP-Binding Protein alpha Subunits, Gq-G11/physiology , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Long-Term Potentiation/drug effects , Male , Maze Learning/drug effects , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Miniature Postsynaptic Potentials/drug effects , Miniature Postsynaptic Potentials/physiology , Nerve Net/drug effects , Nerve Net/physiology , Nerve Tissue Proteins/analysis , Nerve Tissue Proteins/physiology , Pain Threshold , Patch-Clamp Techniques , Pyrroles/pharmacology , Quinazolines/pharmacology , Receptor, PAR-1/antagonists & inhibitors , Receptor, PAR-1/deficiency , Receptor, PAR-1/genetics , Recognition, Psychology/drug effects , Recognition, Psychology/physiology
19.
Ann Surg Oncol ; 19(13): 4307-13, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22766985

ABSTRACT

BACKGROUND: Desmoplastic melanoma (DM), a variant of spindle cell melanoma, has a higher propensity for local recurrence and a lower incidence of nodal metastasis. In this retrospective review, we evaluated the risk for regional nodal metastases and the need for sentinel lymph node biopsy (SLNB) in patients with head and neck DM. METHODS: We identified 103 patients with DM from an institutional database of patients with head and neck melanomas treated between 1985 and 2009. Forty-seven patients had their primary treatment at Memorial Sloan-Kettering Cancer Center, and 56 patients were treated for recurrent or metastatic disease. RESULTS: Of the 47 study patients, 27 were men and 20 were women with a median age of 71 years. All patients underwent wide excision, and 21 (44 %) underwent SLNB. None of the patients who underwent SLNB had positive nodes. The mean Breslow thickness for the 45 reported patients was 6.1 mm, with 84 % of tumors >2 mm in thickness and 55 % >4 mm. All known Clark thickness levels (n = 40) were IV or V. The overall survival was 73 %, with disease-specific survival of 84 %, local recurrence-free survival of 75 %, and neck recurrence-free survival of 97 % at 5 years. CONCLUSIONS: Although DM is diagnosed at higher Breslow thickness and Clark level, neck metastases are rare and prognosis is favorable compared to conventional melanoma. The low incidence of lymphovascular invasion, high frequency of histopathologically negative sentinel lymph nodes, and low neck recurrence rates indicate that staging of neck disease by SLNB is not necessary in patients with pure DM of the head and neck.


Subject(s)
Head and Neck Neoplasms/surgery , Melanoma/surgery , Sentinel Lymph Node Biopsy , Skin Neoplasms/surgery , Aged , Disease Management , Female , Follow-Up Studies , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/pathology , Humans , Male , Melanoma/mortality , Melanoma/pathology , Neoplasm Staging , Prognosis , Retrospective Studies , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Survival Rate
20.
J Clin Oncol ; 20(20): 4199-208, 2002 Oct 15.
Article in English | MEDLINE | ID: mdl-12377963

ABSTRACT

PURPOSE: Patients with recurrent head and neck squamous cell carcinoma (HNSCC) present a diagnostic and therapeutic challenge. We evaluated the diagnostic accuracy and prognostic value of [(18)F]fluorodeoxyglucose positron emission tomography (PET) in this patient population. PATIENTS AND METHODS: We performed a retrospective review of 143 patients with previously treated HNSCC who underwent 181 PET scans at our institution from May 1996 through April 2001 to detect recurrent disease. Disease recurrence within 6 months was used as the gold standard for assessing true disease status at PET. RESULTS: With equivocal sites considered positive, the sensitivity and specificity of PET for detecting recurrence overall were 96% and 72%, respectively. PET was highly sensitive and specific at regional and distant sites. At local sites, sensitivity was high, but specificity was lower because of false-positive findings. One fifth of all false-positive PET scans occurred at sites of known inflammation or infection. The area under the curve for a receiver operator characteristic curve on the basis of standardized uptake value (SUV) was 0.882 +/- 0.025. PET interpretation, SUV, and physical examination were independent predictors of relapse-free and overall survival in a time-dependent, multivariate proportional hazards model. An increase in SUV by one unit increased the relative risk (RR) of relapse by 11% and the RR of death by 14%. A positive PET interpretation increased the RR of relapse by four-fold and the RR of death by seven-fold. CONCLUSION: PET was a highly sensitive method of detecting recurrent HNSCC and provided important prognostic information for relapse-free and overall survival.


Subject(s)
Head and Neck Neoplasms/diagnostic imaging , Neoplasm Recurrence, Local/diagnostic imaging , Tomography, Emission-Computed , Adolescent , Adult , Aged , Aged, 80 and over , Female , Fluorodeoxyglucose F18 , Head and Neck Neoplasms/therapy , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/therapy , Predictive Value of Tests , Prognosis , Proportional Hazards Models , Radiopharmaceuticals , Retrospective Studies , Sensitivity and Specificity
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