tbuckley/cabot-search huggingface dataset:
Non-Sentinel Node Risk Score (N-SNORE): A Scoring System for Accurately Stratifying Risk of Non-Sentinel Node Positivity in Patients With Cutaneous Melanoma With Positive Sentinel Lymph Nodes
Authors: Rajmohan Murali, Chitra Desilva, John F. Thompson, Richard A. Scolyer
Journal: Journal of Clinical Oncology (2010)

Sentinel node (SN) biopsy allows identification of patients with melanoma at risk of further metastatic disease in regional non-sentinel nodes (NSN). We investigated clinicopathologic factors that predict NSN positivity in an attempt to identify patients who may be safely spared completion lymph node dissection (CLND).Clinicopathologic factors previously shown to be predictive of NSN positivity were analyzed in 409 patients with SN-positive disease (309 of whom underwent CLND) managed at a single melanoma center. A weighted score Non-Sentinel Node Risk Score [N-SNORE] incorporating predictive factors was derived, and the efficacy of N-SNORE at stratifying risk of NSN involvement was studied.Factors independently predictive of NSN positivity included primary tumor regression, proportion of harvested SNs involved by melanoma (%PosSN), sex (trend), and SN tumor burden indices (maximum size of largest deposit [MaxSize], % cross-sectional area of SN occupied by tumor, tumor penetrative depth, intranodal location of tumor) and perinodal lymphatic invasion (PLI). Of SN tumor burden criteria, MaxSize was the strongest predictor. N-SNORE was the sum of scores for five parameters: sex (female = 0, male = 1), regression (absent = 0, present = 2), %PosSN (absent = 0, present = 2), MaxSize (≤ 0.5 mm = 0, 0.51 to 2.00 mm = 1, 2.01 to 10.00 mm = 2, > 10.00 mm = 3), and PLI (absent = 0, present = 3). N-SNOREs of 0, 1 to 3, 4 to 5, 6 to 7, and ≥ 8 were associated with very low (0%), low (5% to 10%), intermediate (15% to 20%), high (40% to 50%), and very high (70% to 80%) risks of NSN involvement.A weighted score (N-SNORE) based on clinicopathologic characteristics accurately stratifies risk of NSN involvement in patients with melanoma. If validated in future studies, N-SNORE will better predict prognosis, aid in management decisions, and stratify patient groups for entry into clinical trials.
Training residents in dermatopathology: Why, when, where, and how
Authors: A. Bernard Ackerman
Journal: Journal of the American Academy of Dermatology (1990)

The observations and conclusions that follow are mine alone.They derive from more than 20 years of teaching dermatopathology full-time to residents in dermatology and surgical pathology, fellows in dermatopathology, and practicing dermatologists and pathologists.Colleagues may disagree with the accuracy of my observations and the validity of my conclusions.This essay makes no pretense to being scientific; it aspires to making sense.No two training programs in dermatology and surgical pathology have the same philosophy about teaching dermatopathology to residents or the same method for accomplishing that aim.In. all too many departments of dermatology and pathology throughout the world there is neither philosophy nor method with regard to teaching dermatopathology.Most residents learn dermatopathology by (I) memorizing "Lever" (which, they are told, is excellent preparation for Board examinations), (2) studying "unknown" slides to be discussed at conferences, usually weekly, (3) attending episodic lectures about various aspects of dermatopathology, and (4) "catch as catch can" time at a microscope in tutorial instruction or on their own.In my view these are not effectiveways to learn dermatopathology.What follows are reasons why and a proposal for how that desideratum can be achieved with repeatability.Why is it essential for residents in dermatology and surgical pathology to be competent in dermatopathology?The reasons are compelling for both groups but different for each of them.Surgical pathologists have responsibility for accurate diagnosis of sectionsfrom specimens of skin, just as they do for those from every organ.The riveting fact is that specimens of skin constitute about 25% of all specimens received in a laboratory of general surgical pathology, whereas specimens of kidney, spleen, and liver comprise less than I% of the total.Theoreti-
Efficacy of low-dose ketoconazole in hormone refractory prostate cancer patients (HRPC): A single institution experience
Authors: C. Coronado, A. Rodriguez-Antolin, J. Sepulveda, I. Diaz Padilla, E. Holgado, I. Garcia Escobar, D. E. Castellano
Journal: Journal of Clinical Oncology (2008)

16117 Background: The management of HRPC remains controversial. Among the options, second-line hormonal therapy is commonly used. Ketoconazole, an antimycotic which affects the synthesis of androgens and other steroids, has shown direct cytotoxic effects in prostate cancer. This study describes our experience with low-dose ketoconazole treatment for HRPC. Methods: All eligible pts had histologically proven adenocarcinoma of the prostate, and all pts had progressive castration resistant prostate cancer by consensus criteria and had received no prior hormonotherapy. Pts received 400 mg ketoconazole orally 3 times daily, and orally replacement hydrocortisone. PSA response was defined as a >50% fall in PSA from baseline, confirmed by a second PSA value 4 or > weeks later. Pts with measurable soft tissue disease met traditional guidelines for tumour responses. Progression was defined by objective disease progression or PSA increase of >50% above nadir or >25% above baseline. Pts were monitored clinically and with serial PSA measurements every 1 month. Results: Data for 73 pts were analysed. Median age was 73 years(57–89), median PSA was 67.8 ng/ml (range: 7.5–347.0), with a median performance status of 90%(range: 70–90%). Of the 70 pts (PSA data missing in 3 pts), 33 (47.0%) showed a decrease in PSA >50% (95% CI 37.5%-61.4%) with a median duration of 7.8 months (range 4–41 months). We observed objective responses in 12 of 34 pts(35%) with measurable soft tissue disease and bone metastasis. Age, PSA at diagnosis, Performance status, Gleason score and bone scan result were not significantly associated with response to ketoconazole treatment in univariate or multivariate analyses. A longer duration of primary androgen deprivation therapy (ADT) and total duration of previous hormonal therapy was associated with a longer time to progression.Toxicity was mild with 5 of 73 patients(7.0%) discontinued therapy because of gastrointestinal side-effects or moderate elevated transaminases. No acute hepatitis or adrenal insufficiency was observed. Conclusions: Low-dose Ketoconazol is an effective and well-tolerated treatment in pts with HRPC and should be considerate in a subset of pts with low-volume disease and a rising PSA level despite ADT. No significant financial relationships to disclose.
Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma
Authors: Michael L. Wang, Simon Rule, Peter Martin, Andre Goy, Rebecca Auer, Brad S. Kahl, Wojciech Jurczak, Ranjana H. Advani, Jorge E. Romaguera, Michael E. Williams, Jacqueline C. Barrientos, Ewa Chmielowska, John Radford, Stephan Stilgenbauer, Martin Dreyling, Wieslaw Wiktor Jedrzejczak, Peter Johnson, Stephen E. Spurgeon, Lei Li, Liang Zhang, Kate Newberry, Zhishuo Ou, Nancy Cheng, Bingliang Fang, Jesse McGreivy, Fong Clow, Joseph J. Buggy, Betty Y. Chang, Darrin M. Beaupre, Lori A. Kunkel, Kristie A. Blum
Journal: New England Journal of Medicine (2013)

Bruton's tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma.
Ventilator associated pneumonia: asking the right question
Authors: R B LIGHT
Journal: Thorax (1999)

Everything about ventilator associated pneumonia is contentious. What is the microbial pathogenesis? How can it be prevented? How should it be treated? One strongly advocated preventive strategy consists of intensive topical and systemic antimicrobial prophylaxis. An opposing but equally strongly advocated approach is the use of conventional but firmly applied infection control measures together with limitation of antibiotic use. For treatment, questions abound. One drug or two? Which drug? For how long?

There are two main reasons which underlie our failure to move toward consensus on many of these questions. Firstly, the magnitude and nature of the problem varies widely between intensive care units. The incidence of pneumonia in mechanically ventilated patients ranges from as little as 5% in some units to more than 50% in others.1-4 This may represent, in part, differences in diagnostic approach, but most of the difference in incidence is probably real, reflecting differences in patient population, medical and nursing practice, and infection control practices. Because many studies of pneumonia are generated by intensive care units with high pneumonia rates, questions naturally arise about whether their conclusions are necessarily applicable to units with lower rates.

The second main cause of contention is the problem of definition. How is the diagnosis of ventilator associated pneumonia made? One point of view is that reliable diagnosis must rely on bronchoscopy combined with quantitative bacteriology of the specimens so obtained. An alternative view is that clinical and radiological evidence of infection combined with conventional semi-quantitative bacteriology is sufficient for diagnosis in most cases, and reduces morbidity caused by delay in treatment while waiting for quantitative bacteriological results.

Advocates of bronchoscopy point out that at least half of ventilated patients who might be diagnosed with pneumonia using a standard infection control definition (radiological pulmonary infiltrate, a fever, raised white blood …
Long-term outcomes of patients with advanced hepatocellular carcinoma who achieved complete remission after sorafenib therapy
Authors: Jung Gil Park
Journal: Clinical and Molecular Hepatology (2015)

Sorafenib is currently the sole molecular targeted agent that improves overall survival in advanced hepatocellular carcinoma (HCC). Despite the efficacy of sorafenib, the response rate varies in patients with advanced HCC. We retrospectively analyzed a series of Korean patients with advanced HCC with complete remission (CR) after sorafenib therapy.In total, 523 patients with advanced HCC were treated with sorafenib in 3 large tertiary referral hospitals in Korea. A survey was conducted to collect data on patients who experienced CR after sorafenib monotherapy, and their medical records and follow-up data were analyzed. The tumor response and recurrence rates were assessed by radiologic study, based on modified response evaluation criteria in solid tumors.Seven patients with advanced HCC experienced CR after sorafenib therapy. The median time to tumor disappearance and the median disease-free survival time were 3 months and 9 months, respectively. HCC recurrence was identified in three cases (42.9%). Of these, two patients discontinued sorafenib before or after achieving CR and the other patient continued sorafenib after achieving CR. HCC recurred at 3, 10, and 42 months after CR in these three patients. Three patients needed dose reduction for toxicity and adverse events.Though CR was achieved after sorafenib therapy in patients with advanced HCC, the recurrence rate was relatively high. Subsequent strategies to reduce a chance of recurrence after sorafenib therapy are required to investigate.
Prognosis of Acute Monocytic Leukemia (French-American-British Classification M5)
Authors: Michael Darmon, Elie Azoulay
Journal: Journal of Clinical Oncology (2005)

I was interested to read the report of Carter et al of a conservative management strategy for early prostate cancer, 1 and I agree with the authors that the term "watchful waiting" does not accurately describe their strategy.Given the overdiagnosis and lead-time bias associated with prostate-specific antigen (PSA) screening, 2 the natural history of prostate cancer following diagnosis is now far more favorable than it was in the pre-PSA era, making a conservative management strategy an attractive option for many patients.However, clinicians and patients need to understand the important distinctions between the different conservative strategies now available.The term watchful waiting was widely used during the pre-PSA era to describe a policy of observation with palliative treatment for symptomatic cancer progression.Such a policy remains appropriate for patients who, by virtue of age and comorbidities, have a relatively short life expectancy and do not have a radical treatment option.A second, and quite distinct, approach to favorable-risk early prostate cancer is to determine the need for radical treatment based on biochemical or histologic evidence of disease progression during close monitoring.The aim of this approach is to target curative treatment to the minority of patients who need it, so that the majority are spared the side effects of unnecessary treatment.This strategy was first described by Richard Choo et al as, "watchful observation with selective delayed intervention." 3At the Royal Marsden Hospital, we use the term "active surveillance" to describe this strategy. 4 These initial studies have demonstrated the feasibility of this approach, which offers patients a realistic hope of avoiding treatment side effects without detriment to their survival.Active surveillance requires a clear definition of the indications for radical treatment (usually based on PSA doubling time and the results of repeat biopsies), together with a commitment to the policy from both patient and clinician.If these are lacking, the result will be "temporarily deferred therapy," as described by Carter et al, in which men with early prostate cancer who are almost inevitably going to have radical treatment, choose to delay such therapy. 1
CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women with Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial
Authors: Meredith M. Regan, Brian Leyland-Jones, Mark Bouzyk, Olivia Pagani, Weining Tang, Roswitha Kammler, Patrizia Dell’Orto, Maria Olivia Biasi, Beat Thürlimann, Maria B. Lyng, Henrik J. Ditzel, Patrick Neven, Marc Debled, Rudolf Maibach, Karen N. Price, Richard D. Gelber, Alan S. Coates, Aron Goldhirsch, James M. Rae, Giuseppe Viale
Journal: JNCI Journal of the National Cancer Institute (2012)

BackgroundAdjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the clinical relevance of CYP2D6 polymorphisms.
The 6 minute walk in idiopathic pulmonary fibrosis: longitudinal changes and minimum important difference
Authors: J. J. Swigris, F. S. Wamboldt, J. Behr, R. M. du Bois, T. E. King, G. Raghu, K. K. Brown
Journal: Thorax (2009)

<h3>Rationale</h3> The response characteristics of the 6 minute walk test (6MWT) in studies of idiopathic pulmonary fibrosis (IPF) are only poorly understood, and the change in walk distance that constitutes the minimum important difference (MID) over time is unknown. <h3>Objectives</h3> To examine changes over time in distance walked (ie, 6MWD) during the 6MWT and to estimate the change in distance that constitutes the MID in patients with IPF. <h3>Methods</h3> Data from a recently completed trial that included subjects with IPF who completed the 6MWT, Saint George9s Respiratory Questionnaire (SGRQ) and forced vital capacity (FVC) at 6 and 12 months were used to examine longitudinal changes in 6MWD. Both anchor- and distribution-based approaches as well as linear regression analyses were used to determine the MID for 6MWD. The SGRQ Total score and FVC were used as clinical anchors. <h3>Main results</h3> Among 123 subjects alive and able to complete the 6MWT at both follow-up time points, 6MWD did not change significantly over time (378.1 m at baseline vs 376.8 m at 6 months vs 361.3 m at 12 months, p=0.5). The point estimate for the 6MWD MID was 28 m with a range of 10.8–58.5 m. <h3>Conclusion</h3> In a group of patients with IPF with moderate physiological impairment, for those alive and able to complete a 6MWT, 6MWD does not change over 12 months. At the population level, the MID for 6MWD appears to be ∼28 m. Further investigation using other anchors and derivation methods is required to refine estimates of the MID for 6MWD in this patient population.
Distinct Functions of Activated Protein C Differentially Attenuate Acute Kidney Injury
Authors: Akanksha Gupta, Bruce Gerlitz, Mark A. Richardson, Christopher Bull, David T. Berg, Samreen Syed, Elizabeth J. Galbreath, Barbara A. Swanson, Bryan E. Jones, Brian W. Grinnell
Journal: Journal of the American Society of Nephrology (2008)

Administration of activated protein C (APC) protects from renal dysfunction, but the underlying mechanism is unknown. APC exerts both antithrombotic and cytoprotective properties, the latter via modulation of protease-activated receptor-1 (PAR-1) signaling. We generated APC variants to study the relative importance of the two functions of APC in a model of LPS-induced renal microvascular dysfunction. Compared with wild-type APC, the K193E variant exhibited impaired anticoagulant activity but retained the ability to mediate PAR-1-dependent signaling. In contrast, the L8W variant retained anticoagulant activity but lost its ability to modulate PAR-1. By administering wild-type APC or these mutants in a rat model of LPS-induced injury, we found that the PAR-1 agonism, but not the anticoagulant function of APC, reversed LPS-induced systemic hypotension. In contrast, both functions of APC played a role in reversing LPS-induced decreases in renal blood flow and volume, although the effects on PAR-1-dependent signaling were more potent. Regarding potential mechanisms for these findings, APC-mediated PAR-1 agonism suppressed LPS-induced increases in the vasoactive peptide adrenomedullin and infiltration of iNOS-positive leukocytes into renal tissue. However, the anticoagulant function of APC was responsible for suppressing LPS-induced stimulation of the proinflammatory mediators ACE-1, IL-6, and IL-18, perhaps accounting for its ability to modulate renal hemodynamics. Both variants reduced active caspase-3 and abrogated LPS-induced renal dysfunction and pathology. We conclude that although PAR-1 agonism is solely responsible for APC-mediated improvement in systemic hemodynamics, both functions of APC play distinct roles in attenuating the response to injury in the kidney.
Seasonal risk factors for asthma exacerbations among inner-city children
Authors: Stephen J. Teach, Peter J. Gergen, Stanley J. Szefler, Herman E. Mitchell, Agustin Calatroni, Jeremy Wildfire, Gordon R. Bloomberg, Carolyn M. Kercsmar, Andrew H. Liu, Melanie M. Makhija, Elizabeth Matsui, Wayne Morgan, George O'Connor, William W. Busse
Journal: Journal of Allergy and Clinical Immunology (2015)
Parallel Evolution between Aromatase and Androgen Receptor in the Animal Kingdom
Authors: Besant K. Tiwary, Wen-Hsiung Li
Journal: Molecular Biology and Evolution (2008)

There are now many known cases of orthologous or unrelated proteins in different species that have undergone parallel evolution to satisfy a similar function. However, there are no reported cases of parallel evolution for proteins that bind a common ligand but have different functions. We focused on two proteins that have different functions in steroid hormone biosynthesis and action but bind a common ligand, androgen. The first protein, androgen receptor (AR), is a nuclear hormone receptor and the second one, aromatase (cytochrome P450 19 [CYP19]), converts androgen to estrogen. We hypothesized that binding of the androgen ligand has exerted common selective pressure on both AR and CYP19, resulting in a signature of parallel evolution between these two proteins, though they perform different functions. Consistent with this hypothesis, we found that rates of amino acid change in AR and CYP19 are strongly correlated across the metazoan phylogeny, whereas no significant correlation was found in the control set of proteins. Moreover, we inferred that genomic toolkits required for steroid biosynthesis and action were present in a basal metazoan, cnidarians. The close similarities between vertebrate and sea anemone AR and CYP19 suggest a very ancient origin of their endocrine functions at the base of metazoan evolution. Finally, we found evidence supporting the hypothesis that the androgen-to-estrogen ratio determines the gonadal sex in all metazoans.
Impact of toll-like receptor 4 on the severity of acute pancreatitis and pancreatitis-associated lung injury in mice
Authors: R Sharif, R Dawra, K Wasiluk, P Phillips, V Dudeja, E Kurt-Jones, R Finberg, A Saluja
Journal: Gut (2009)

The purpose of this study was to evaluate the role of <sup>68</sup>Ga-labeled DOTANOC PET/CT for baseline evaluation of patients with head and neck paragangliomas (HNPs). <b>Methods:</b> The data for 26 patients (mean age ± SD, 34.3 ± 10.4 y; 50% men) with known or suspected HNPs who underwent <sup>68</sup>Ga-DOTANOC PET/CT for staging were retrospectively analyzed. PET/CT was performed after intravenous injection of 132–222 MBq of <sup>68</sup>Ga-DOTANOC. The images were evaluated by 2 experienced nuclear medicine physicians in consensus, both qualitatively and quantitatively. The PET/CT findings were grouped as HNPs, paraganglioma at other sites (non-HNPs), and metastatic disease. The size and maximum standardized uptake values (SUVmax) were measured for all lesions. All of the patients also underwent whole-body <sup>131</sup>I-metaiodobenzylgunanidine (<sup>131</sup>I-MIBG) scintigraphy and conventional imaging (CT/MR imaging) of the head and neck region. Their results were compared with those of <sup>68</sup>Ga-DOTANOC PET/CT. <b>Results:</b><sup>68</sup>Ga-DOTANOC PET/CT findings were positive in all 26 patients, and 78 lesions were detected. PET/CT imaging demonstrated 45 HNPS, 10 non-HNPs, and 23 metastatic sites. Fifteen patients (57.6%) had more than one site of disease on PET/CT. Among 45 HNPs, 26 were carotid body tumors (CBTs), 15 glomus jugulare, 3 glomus tympanicum, and 1 laryngeal paraganglioma. A positive correlation was seen between size and SUVmax of HNPs (ρ = 0.323; <i>P</i> = 0.030). The SUVmax of the CBTs was higher than that of jugulotympanic paragangliomas (<i>P</i> = 0.026). No correlation was seen between size and SUVmax (ρ = 0.069; <i>P</i> = 0.854) of non-HNPs. The size and SUVmax of non-HNPs were significantly less than those of HNPs (<i>P</i> = 0.029 and 0.047, respectively). <sup>131</sup>I-MIBG scintigraphy showed only 30 of the 78 lesions and was inferior to PET/CT (<i>P</i> &lt; 0.0001). Conventional imaging (CT/MR imaging) was positive for 42 of 49 head and neck lesions and was inferior to PET/CT on direct comparison (<i>P</i> = 0.015). A combination of CT/MR imaging and <sup>131</sup>I-MIBG scintigraphy detected only 53 of 78 (67.9%) lesions and was also inferior to PET/CT (<i>P</i> &lt; 0.0001). <b>Conclusion:</b><sup>68</sup>Ga-DOTANOC PET/CT is useful for the baseline evaluation of patients with HNPs and can demonstrate synchronous paragangliomas at other sites and distant metastases. It is superior to <sup>131</sup>I-MIBG scintigraphy and conventional imaging (CT/MR imaging) for this purpose.
TYPING GROUP A HEMOLYTIC STREPTOCOCCI BY M PRECIPITIN REACTIONS IN CAPILLARY PIPETTES
Authors: Homer F. Swift, Armine T. Wilson, Rebecca C. Lancefield
Journal: The Journal of Experimental Medicine (1943)

A method is described for performing type-specific anti-M precipitin tests on group A hemolytic streptococci in 1 mm. capillary pipettes. These tests require so much less precipitating serum than was formerly used that the method now seems to be practical.