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Background The pharmacodynamics of propofol are closely linked to gender. Dexmedetomidine can decrease propofol needs during propofol anesthesia. The aim of this study was to compare the gender differences on the calculated effect site median effective concentration (EC50) of propofol for loss of consciousness (LOC) after pretreatment with different concentrations of dexmedetomidine. Methods In this study 60 male and 60 female patients were randomly allocated to receive dexmedetomidine at target plasma concentrations of 0.0 ng/ml (0.0 group), 0.4 ng/ml (0.4 group), 0.6 ng/ml (0.6 group) and 0.8 ng/ml (0.8 group). Propofol was administered after dexmedetomidine had been intravenously infused for 15 min. The propofol infusion was targeted to provide an initial effect-site concentration of 1.0 μg/ml, followed by increments by 0.2 μg/ml when the effect-site concentration and target concentration of propofol were in equilibrium until LOC was established, where LOC was defined by the observer’s assessment of alertness/sedation scale (OAA/S) score

Background Combined image-guided fine-needle aspiration biopsy (FNA) and core needle biopsy (CNB) has become the standard of care for diagnosis and/or molecular testing for patients with a solitary lung nodule at our institution. Our purpose was to evaluate the efficacy of this practice. Methods We identified patients who underwent combined lung FNA/CNB during 2012 at our institution. A total of 667 patients who underwent 682 combined lung FNA/CNB procedures were included in the study, including 355 men and 312 women. Combined lung FNA/CNB procedures were performed by a radiologist. The adequacy of FNA specimens was assessed immediately by a cytopathologist. The FNA and CNB specimens were interpreted separately by a cytopathologist and a surgical pathologist, respectively. The diagnostic accuracy of the combined technique was determined. Results The rate of diagnostic consistency between FNA and CNB was 83.4%, and the rate of diagnostic accuracy for malignancy was 98.5% for combined FNA/CNB. Combined FNA/CNB showed a high diagnostic efficacy for malignancy (sensitivity, 97.6%; specificity, 100%). Combined FNA/CNB had a lower false-negative rate for malignancy (2.2%) than either FNA (7.2%) or CNB (6.2%) alone. FNA contributed to 10.3% of molecular analyses as a complementary tissue source. Conclusions Combined lung FNA/CNB has high diagnostic efficacy for malignancy and a lower false-negative rate than either procedure alone. FNA was a valuable complement to CNB for molecular testing, potentially reducing patient inconvenience and morbidity associated with repeated lung needle biopsy.

This study aimed to retrospectively analyze risk factors for the prognosis of Chinese patients with endometrial carcinoma. Total 600 patients who were admitted to the Department of Gynecology, the Fourth Hospital of Hebei Medical University and were pathologically diagnosed as endometrial carcinoma after surgery from January 1, 1997 to December 31, 2006 were selected, and the related factors affecting their prognosis were analyzed. The survival of 600 patients with endometrial carcinoma was 2 to 136.5 months (average survival 57.39 ± 33.55 months), and 109 cases (18.2%) died from endometrial cancer. The overall survival rate of 1, 3, and 5 years after surgery was 96.8%, 89.9%, and 82.1%, respectively. Univariate analysis showed that age, menopausal status, pathological type, histological grade, pathological staging, tumor size, myometrial invasion, cervical involvement, ovarian metastasis, lymph node metastasis, and treatment method were the factors affecting the prognosis of endometrial carcinoma. Multivariate regression analysis showed that pathological type, histological grade, pathological staging, and cervical involvement were independent risk factors for the prognosis of endometrial carcinoma. The patients with high-grade and deep myometrial invasion, cervical involvement, full cavity tumor, and lymph node metastasis had a high incidence of ovarian metastasis. Pathological type, histological grade, pathological staging, and cervical involvement are independent risk factors affecting the prognosis of Chinese patients with endometrial carcinoma.

Author(s): MacKenzie-Graham, Allan; Brook, Jenny; Kurth, Florian; Itoh, Yuichiro; Meyer, Cassandra; Montag, Michael J; Wang, He-Jing; Elashoff, Robert; Voskuhl, Rhonda R | Abstract: IntroductionProgressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%-70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of estriol treatment in women with relapsing-remitting MS (RRMS), higher estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in estriol-treated compared to placebo-treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes.MethodsSixty-two estriol- and forty-nine placebo-treated RRMS patients underwent clinical evaluations and brain MRI. Voxel-based morphometry (VBM) was used to evaluate voxelwise GM sparing from high-resolution T1-weighted scans.ResultsA region of treatment-induced sparing (TIS) was defined as the areas where GM was spared in estriol- as compared to placebo-treated groups, localized primarily within the frontal and parietal cortices. We observed that TIS volume was directly correlated with improvement on the PASAT. Next, a longitudinal cognitive disability-specific atlas (DSA) was defined by correlating voxelwise GM volumes with PASAT scores, that is, areas where less GM correlated with less improvement in PASAT scores. Finally, overlap between the TIS and the longitudinal cognitive DSA revealed a specific region of cortical GM that was preserved in estriol-treated subjects that was associated with better performance on the PASAT.ConclusionsDiscovery of this region of overlap was biology driven, not based on an a priori structure of interest. It included the medial frontal cortex, an area previously implicated in problem solving and attention. These findings indicate that localized GM sparing during estriol treatment was associated with improvement in cognitive testing, suggesting a clinically relevant, disability-specific biomarker for clinical trials of candidate neuroprotective treatments in MS.

Objectives This open-label, randomized phase II trial evaluated antitumor efficacy of an antiestrogen, fulvestrant, in combination with human epidermal growth factor receptor (EGFR) inhibitor, erlotinib, in advanced non-small cell lung cancer (NSCLC) patients. Materials and Methods Patients with advanced or metastatic NSCLC, ECOG 0–2, previous chemotherapy unless patient refusal, and no prior EGFR-directed therapy were randomized 2:1 to erlotinib 150 mg oral daily plus 500 mg intramuscular fulvestrant on day 1, 15, 29 and every 28 days thereafter or erlotinib alone 150 mg oral daily. The primary end point was objective response rate (ORR); secondary endpoints included progression free survival (PFS) and overall survival (OS). Results Among 106 randomized patients, 100 received at least one dose of study drug. ORR was 16.4% (11 of 67 patients) for the combination versus 12.1% (4 of 33 patients) for erlotinib (p = 0.77). PFS median 3.5 versus 1.9 months [HR = 0.86, 95% CI (0.52–1.43), p = 0.29] and OS median 9.5 versus 5.8 months [HR = 0.92, 95% CI (0.57–1.48), p = 0.74] numerically favored the combination. In an unplanned subset analysis, among EGFR wild type patients (n = 51), but not EGFR mutant patients (n = 17), median PFS was 3.5 versus 1.7 months [HR = 0.35, 95% CI (0.14-0.86), p = 0.02] and OS was 6.2 versus 5.2 months [HR = 0.72, 95% CI (0.35–1.48), p = 0.37] for combined therapy versus erlotinib, respectively. Notably, EGFR WT patients were more likely to be hormone receptor-positive (either estrogen receptor α- and/or progesterone receptor-positive) compared to EGFR mutant patients (50% versus 9.1%, respectively) (p = 0.03). Treatment was well tolerated with predominant grade 1–2 dermatologic and gastrointestinal adverse effects. Conclusion Addition of fulvestrant to erlotinib was well tolerated, with increased activity noted among EGFR wild type patients compared to erlotinib alone, albeit in an unplanned subset analysis.

Supplemental Digital Content is available in the text, To determine the prevalence of pulmonary complications in primary Sjögren syndrome (pSS), and to identify the risk factors and the prognosis associated with pulmonary involvement in pSS patients. A total of 1341 hospitalized patients (853 with pSS and 488 with secondary Sjögren syndrome [sSS]) were retrospectively reviewed. Of these, 165 hospitalized patients with pSS-associated interstitial lung disease (ILD) were analyzed and recruited as a study group. Eighty-four pSS patients without organ damage were included as a control group. One hundred and sixty-five patients (19.34%) from the pSS group and 126 patients (25.82%) from the sSS group presented with lung involvement. Of the 165 pSS patients with lung complications, 151 (91.5%) were women. The mean age was 61.25 ± 9.79 years, and the median disease duration was 84 (24–156) months. Non-specific interstitial pneumonia (NSIP; 39.1%) was the predominant pattern on high-resolution computed tomography (HRCT). The total HRCT score was 9.71 ± 4.77. Impairment in diffusion capacity was the most common (74.3%) and severe complication (predicted value of TLCO was 57.5 ± 21.2%). The 5-year survival rate for all patients with pSS-ILD was 88.5%. Age, disease duration, rheumatoid factor (RF), and C-reactive protein (CRP) were significantly higher than in controls, whereas anti-SSA was less common. Age, RF, and CRP were independent predictors of ILD after adjustment for confounders. Lung involvement is a common and severe complication of Sjögren syndrome. Age and disease activity are correlated with pulmonary involvement in pSS patients.

To determine the association in amount of daily coffee consumption with incidence of stroke in a broad cohort, considering other vascular risk factors.We utilized the Third National Health and Nutrition Examination Survey (1988-1994; NHANES III) data on participants aged ≥17 years old to examine coffee consumption and stroke. Multivariate logistic regression models related the amount of coffee use reported in a food frequency questionnaire with stroke, controlling for other vascular risk factors.Of 33 994 NHANES III subjects, coffee consumption and stroke data in adults ≥17 years old were available in 19 994. Daily coffee consumption ranged from 0 to 20 (median 1) cups and 644 (3.2%) participants had a stroke diagnosed by a physician. Coffee intake varied with age, gender, and ethnicity (P 0.001). Interestingly, heart failure, diabetes, and hypertension were less frequent, and high cholesterol more frequent in those consuming ≥3 cups per day (P 0.001). Smoking was more frequent in all coffee drinkers (P 0.0001). Multivariate analyses revealed an independent effect of heavier coffee consumption (≥3 cups/day) on reduced stroke (OR 0.44, 95% CI 0.22-0.87, P 0.02) in healthy subjects that was attenuated by vascular risk factors (OR 0.78, 95% CI 0.58-1.07, P ≈ 0.12).Heavier daily coffee consumption is associated with decreased stroke prevalence, despite smoking tendency in heavy coffee drinkers.

Our study was designed to evaluate the efficacy and safety of everolimus in patients with pre-treated metastatic gastric and esophagus cancers in a US-based population focusing on biomarker correlation. Patients with advanced upper GI adenocarcinomas who progressed after 1–2 prior regimens received everolimus 10 mg PO daily. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression-free survival (PFS), toxicity, overall survival (OS) and biomarker correlatives of the mTOR pathway. Target accrual was 50 patients based on one-sided type I error of 10 % and power of 90 %. Forty-five patients were evaluable, 21 gastric, 11 esophagus and 13 from the GEJ. The median age was 64 (range 38–73); all patients had an ECOG of 0 or 1; and 18 patients (40 %) had only 1 prior regimen. The most common grade 3–4 adverse events included fatigue (24 %) and thrombocytopenia (22 %). We observed 1 partial response with 39 % of evaluable patients having stable disease. Median OS was 3.4 months (95 % CI 2.7–5.6 months), and PFS was 1.8 months (95 % CI 1.7–2.2 months). There was a strong correlation between ≥2 + IHC staining for p-S6 in tumor samples with better PFS (p

Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P

Background Hypertension is considered the most important risk factor for cardiovascular diseases, but its control is poor worldwide. We aimed to assess the availability and affordability of blood pressure-lowering medicines, and the association with use of these medicines and blood pressure control in countries at varying levels of economic development. Methods We analysed the availability, costs, and affordability of blood pressure-lowering medicines with data recorded from 626 communities in 20 countries participating in the Prospective Urban Rural Epidemiological (PURE) study. Medicines were considered available if they were present in the local pharmacy when surveyed, and affordable if their combined cost was less than 20% of the households' capacity to pay. We related information about availability and affordability to use of these medicines and blood pressure control with multilevel mixed-effects logistic regression models, and compared results for high-income, upper-middle-income, lower-middle-income, and low-income countries. Data for India are presented separately because it has a large generic pharmaceutical industry and a higher availability of medicines than other countries at the same economic level. Findings The availability of two or more classes of blood pressure-lowering drugs was lower in low-income and middle-income countries (except for India) than in high-income countries. The proportion of communities with four drug classes available was 94% in high-income countries (108 of 115 communities), 76% in India (68 of 90), 71% in upper-middle-income countries (90 of 126), 47% in lower-middle-income countries (107 of 227), and 13% in low-income countries (nine of 68). The proportion of households unable to afford two blood pressure-lowering medicines was 31% in low-income countries (1069 of 3479 households), 9% in middle-income countries (5602 of 65 471), and less than 1% in high-income countries (44 of 10 880). Participants with known hypertension in communities that had all four drug classes available were more likely to use at least one blood pressure-lowering medicine (adjusted odds ratio [OR] 2·23, 95% CI 1·59–3·12); pInterpretation A large proportion of communities in low-income and middle-income countries do not have access to more than one blood pressure-lowering medicine and, when available, they are often not affordable. These factors are associated with poor blood pressure control. Ensuring access to affordable blood pressure-lowering medicines is essential for control of hypertension in low-income and middle-income countries. Funding Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Canadian Institutes of Health Research Strategy for Patient Oriented Research through the Ontario SPOR Support Unit, the Ontario Ministry of Health and Long-Term Care, pharmaceutical companies (with major contributions from AstraZeneca [Canada], Sanofi Aventis [France and Canada], Boehringer Ingelheim [Germany amd Canada], Servier, and GlaxoSmithKline), Novartis and King Pharma, and national or local organisations in participating countries.

Summary Background The relationship between macronutrients and cardiovascular disease and mortality is controversial. Most available data are from European and North American populations where nutrition excess is more likely, so their applicability to other populations is unclear. Methods The Prospective Urban Rural Epidemiology (PURE) study is a large, epidemiological cohort study of individuals aged 35–70 years (enrolled between Jan 1, 2003, and March 31, 2013) in 18 countries with a median follow-up of 7·4 years (IQR 5·3–9·3). Dietary intake of 135 335 individuals was recorded using validated food frequency questionnaires. The primary outcomes were total mortality and major cardiovascular events (fatal cardiovascular disease, non-fatal myocardial infarction, stroke, and heart failure). Secondary outcomes were all myocardial infarctions, stroke, cardiovascular disease mortality, and non-cardiovascular disease mortality. Participants were categorised into quintiles of nutrient intake (carbohydrate, fats, and protein) based on percentage of energy provided by nutrients. We assessed the associations between consumption of carbohydrate, total fat, and each type of fat with cardiovascular disease and total mortality. We calculated hazard ratios (HRs) using a multivariable Cox frailty model with random intercepts to account for centre clustering. Findings During follow-up, we documented 5796 deaths and 4784 major cardiovascular disease events. Higher carbohydrate intake was associated with an increased risk of total mortality (highest [quintile 5] vs lowest quintile [quintile 1] category, HR 1·28 [95% CI 1·12–1·46], p trend =0·0001) but not with the risk of cardiovascular disease or cardiovascular disease mortality. Intake of total fat and each type of fat was associated with lower risk of total mortality (quintile 5 vs quintile 1, total fat: HR 0·77 [95% CI 0·67–0·87], p trend trend =0·0088; monounsaturated fat: HR 0·81 [0·71–0·92], p trend trend vs quintile 1, HR 0·79 [95% CI 0·64–0·98], p trend =0·0498). Total fat and saturated and unsaturated fats were not significantly associated with risk of myocardial infarction or cardiovascular disease mortality. Interpretation High carbohydrate intake was associated with higher risk of total mortality, whereas total fat and individual types of fat were related to lower total mortality. Total fat and types of fat were not associated with cardiovascular disease, myocardial infarction, or cardiovascular disease mortality, whereas saturated fat had an inverse association with stroke. Global dietary guidelines should be reconsidered in light of these findings. Funding Full funding sources listed at the end of the paper (see Acknowledgments).

13 p., Background The association between intake of fruits, vegetables, and legumes with cardiovascular disease and deaths has been investigated extensively in Europe, the USA, Japan, and China, but little or no data are available from the Middle East, South America, Africa, or south Asia. Methods We did a prospective cohort study (Prospective Urban Rural Epidemiology [PURE] in 135335 individuals aged 35 to 70 years without cardiovascular disease from 613 communities in 18 low-income, middle-income, and highincome countries in seven geographical regions: North America and Europe, South America, the Middle East, south Asia, China, southeast Asia, and Africa. We documented their diet using country-specific food frequency questionnaires at baseline. Standardised questionnaires were used to collect information about demographic factors, socioeconomic status (education, income, and employment), lifestyle (smoking, physical activity, and alcohol intake), health history and medication use, and family history of cardiovascular disease. The follow-up period varied based on the date when recruitment began at each site or country. The main clinical outcomes were major cardiovascular disease (defined as death from cardiovascular causes and non-fatal myocardial infarction, stroke, and heart failure), fatal and non-fatal myocardial infarction, fatal and non-fatal strokes, cardiovascular mortality, non-cardiovascular mortality, and total mortality. Cox frailty models with random effects were used to assess associations between fruit, vegetable, and legume consumption with risk of cardiovascular disease events and mortality. Findings Participants were enrolled into the study between Jan 1, 2003, and March 31, 2013. For the current analysis, we included all unrefuted outcome events in the PURE study database through March 31, 2017. Overall, combined mean fruit, vegetable and legume intake was 3·91 (SD 2·77) servings per day. During a median 7·4 years (5·5–9·3) of followup, 4784 major cardiovascular disease events, 1649 cardiovascular deaths, and 5796 total deaths were documented. Higher total fruit, vegetable, and legume intake was inversely associated with major cardiovascular disease, myocardial infarction, cardiovascular mortality, non-cardiovascular mortality, and total mortality in the models adjusted for age, sex, and centre (random effect). The estimates were substantially attenuated in the multivariable adjusted models for major cardiovascular disease (hazard ratio [HR] 0·90, 95% CI 0·74–1·10, ptrend=0·1301), myocardial infarction (0·99, 0·74–1·31; ptrend=0·2033), stroke (0·92, 0·67–1·25; ptrend=0·7092), cardiovascular mortality (0·73, 0·53–1·02; ptrend=0·0568), non-cardiovascular mortality (0·84, 0·68–1·04; ptrend =0·0038), and total mortality (0·81, 0·68–0·96; ptrend

Sentinel-node biopsy, a minimally invasive procedure for regional melanoma staging, was evaluated in a phase 3 trial.We evaluated outcomes in 2001 patients with primary cutaneous melanomas randomly assigned to undergo wide excision and nodal observation, with lymphadenectomy for nodal relapse (observation group), or wide excision and sentinel-node biopsy, with immediate lymphadenectomy for nodal metastases detected on biopsy (biopsy group). Results No significant treatment-related difference in the 10-year melanoma-specific survival rate was seen in the overall study population (20.8% with and 79.2% without nodal metastases). Mean (± SE) 10-year disease-free survival rates were significantly improved in the biopsy group, as compared with the observation group, among patients with intermediate-thickness melanomas, defined as 1.20 to 3.50 mm (71.3 ± 1.8% vs. 64.7 ± 2.3%; hazard ratio for recurrence or metastasis, 0.76; P=0.01), and those with thick melanomas, defined as3.50 mm (50.7 ± 4.0% vs. 40.5 ± 4.7%; hazard ratio, 0.70; P=0.03). Among patients with intermediate-thickness melanomas, the 10-year melanoma-specific survival rate was 62.1 ± 4.8% among those with metastasis versus 85.1 ± 1.5% for those without metastasis (hazard ratio for death from melanoma, 3.09; P0.001); among patients with thick melanomas, the respective rates were 48.0 ± 7.0% and 64.6 ± 4.9% (hazard ratio, 1.75; P=0.03). Biopsy-based management improved the 10-year rate of distant disease-free survival (hazard ratio for distant metastasis, 0.62; P=0.02) and the 10-year rate of melanoma-specific survival (hazard ratio for death from melanoma, 0.56; P=0.006) for patients with intermediate-thickness melanomas and nodal metastases. Accelerated-failure-time latent-subgroup analysis was performed to account for the fact that nodal status was initially known only in the biopsy group, and a significant treatment benefit persisted.Biopsy-based staging of intermediate-thickness or thick primary melanomas provides important prognostic information and identifies patients with nodal metastases who may benefit from immediate complete lymphadenectomy. Biopsy-based management prolongs disease-free survival for all patients and prolongs distant disease-free survival and melanoma-specific survival for patients with nodal metastases from intermediate-thickness melanomas. (Funded by the National Cancer Institute, National Institutes of Health, and the Australia and New Zealand Melanoma Trials Group; ClinicalTrials.gov number, NCT00275496.).

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Current standard treatment for GBM includes cyto-reductive surgery followed by radiation (RT) and chemotherapy with temozolomide (TMZ).1 CpG methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter has emerged as the most robust predictor of TMZ treatment outcome for newly diagnosed GBM with prognostic implications.2–6 MGMT encodes for a DNA repair enzyme that provides resistance to alkylating chemotherapies, such as TMZ. Because MGMT transcription can be silenced by promoter methylation in tumor cells,7 it is widely assumed that MGMT promoter methylation in patient tumors causes decreased MGMT protein expression, thereby abrogating DNA repair activity necessary for TMZ resistance. However, the relationship between MGMT protein expression and promoter methylation in patient tumor samples has remained controversial.8–13 Furthermore, studies examining MGMT immunohistochemistry (IHC) and survival have not shown consistent correlation with outcome.4,5,9,10,13–19 The lack of definitive evidence has been attributed primarily to difficulty with MGMT IHC scoring; however, other possible reasons include small cohort size,4,5,10,13,18 nonuniform treatments,20,21 and various IHC scoring categories and cutoffs.4,9,10,21 Because of the importance of MGMT status for predicting treatment outcome, stratifying clinical trial patients, and guiding treatment decisions, the aims of the current single-arm retrospective study were to evaluate MGMT protein expression as a prognostic marker for patients with newly diagnosed GBM who were receiving standard of care RT/TMZ, to investigate the relationship between MGMT promoter methylation and protein expression, and to optimize the assessment of MGMT status. On the basis of a large cohort of 418 patients with newly diagnosed primary GBM, 410 of whom received chemoradiation with TMZ, we show that, although MGMT IHC is prognostic of patient survival, the combination of IHC and methylation testing provides optimized assessment of MGMT status.

ImportanceMultiple sclerosis (MS) is characterized by progressive gray matter (GM) atrophy that strongly correlates with clinical disability. However, whether localized GM atrophy correlates with specific disabilities in patients with MS remains unknown.ObjectiveTo understand the association between localized GM atrophy and clinical disability in a biology-driven analysis of MS.Design, setting, and participantsIn this cross-sectional study, magnetic resonance images were acquired from 133 women with relapsing-remitting MS and analyzed using voxel-based morphometry and volumetry. A regression analysis was used to determine whether voxelwise GM atrophy was associated with specific clinical deficits. Data were collected from June 28, 2007, to January 9, 2014.Main outcomes and measuresVoxelwise correlation of GM change with clinical outcome measures (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores).ResultsAmong the 133 female patients (mean [SD] age, 37.4 [7.5] years), worse performance on the Multiple Sclerosis Functional Composite correlated with voxelwise GM volume loss in the middle cingulate cortex (P

BackgroundIt is unclear whether the transcriptional subtypes of high grade serous ovarian cancer (HGSOC) apply to high grade clear cell (HGCCOC) or high grade endometrioid ovarian cancer (HGEOC). We aim to delineate transcriptional profiles of HGCCOCs and HGEOCs.MethodsWe used Agilent microarrays to determine gene expression profiles of 276 well annotated ovarian cancers (OCs) including 37 HGCCOCs and 66 HGEOCs. We excluded low grade OCs as these are known to be distinct molecular entities. We applied the prespecified TCGA and CLOVAR gene signatures using consensus non-negative matrix factorization (NMF).ResultsWe confirm the presence of four TCGA transcriptional subtypes and their significant prognostic relevance (p

Purpose The outcomes of patients with melanoma who have sentinel lymph node (SLN) metastases can be highly variable, which has precluded establishment of consensus regarding treatment of the group. The detection of high-risk patients from this clinical setting may be helpful for determination of both prognosis and management. We report the utility of multimarker reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) detection of circulating tumor cells (CTCs) in patients with melanoma diagnosed with SLN metastases in a phase III, international, multicenter clinical trial. Patients and Methods Blood specimens were collected from patients with melanoma (n = 331) who were clinically disease-free after complete lymphadenectomy (CLND) before entering onto a randomized adjuvant melanoma vaccine plus bacillus Calmette-Guérin (BCG) versus BCG placebo trial from 30 melanoma centers (United States and international). Blood was assessed using a verified multimarker RT-qPCR assay (MART-1, MAGE-A3, and GalNAc-T) of melanoma-associated proteins. Cox regression analyses were used to evaluate the prognostic significance of CTC status for disease recurrence and melanoma-specific survival (MSS). Results Individual CTC biomarker detection ranged from 13.4% to 17.5%. There was no association of CTC status (zero to one positive biomarkers v two or more positive biomarkers) with known clinical or pathologic prognostic variables. However, two or more positive biomarkers was significantly associated with worse distant metastasis disease-free survival (hazard ratio [HR] = 2.13, P = .009) and reduced recurrence-free survival (HR = 1.70, P = .046) and MSS (HR = 1.88, P = .043) in a multivariable analysis. Conclusion CTC biomarker status is a prognostic factor for recurrence-free survival, distant metastasis disease-free survival, and MSS after CLND in patients with SLN metastasis. This multimarker RT-qPCR analysis may therefore be useful in discriminating patients who may benefit from aggressive adjuvant therapy or stratifying patients for adjuvant clinical trials.

Objective To verify circulating tumor cell (CTC) prognostic utility in stage IV resected melanoma patients in a prospective international phase III clinical trial. Background Our studies of melanoma patients in phase II clinical trials demonstrated prognostic significance for CTCs in patients with AJCC stage IV melanoma. CTCs were assessed to determine prognostic utility in follow-up of disease-free stage IV patients pre- and during treatment. Methods After complete metastasectomy, patients were prospectively enrolled in a randomized trial of adjuvant therapy with a whole-cell melanoma vaccine, Canvaxin, plus Bacille Calmette-Guerin (BCG) versus placebo plus BCG. Blood specimens obtained pretreatment (n = 244) and during treatment (n = 214) were evaluated by quantitative real-time reverse-transcriptase polymerase chain reaction (qPCR) for expression of MART-1, MAGE-A3, and PAX3 mRNA biomarkers. Univariate and multivariate Cox analyses examined CTC biomarker expression with respect to clinicopathological variables. Results CTC biomarker(s) (≥ 1) was detected in 54% of patients pretreatment and in 86% of patients over the first 3 months. With a median follow-up of 21.9 months, 71% of patients recurred and 48% expired. CTC levels were not associated with known prognostic factors or treatment arm. In multivariate analysis, pretreatment CTC (> 0 vs. 0 biomarker) status was significantly associated with disease-free survival (DFS; HR 1.64, P = 0.002) and overall survival (OS; HR 1.53, P = 0.028). Serial CTC (>0 vs. 0 biomarker) status was also significantly associated with DFS (HR 1.91, P = 0.02) and OS (HR 2.57, P = 0.012). Conclusion CTC assessment can provide prognostic discrimination before and during adjuvant treatment for resected stage IV melanoma patients.

We performed a multicenter retrospective comparative study to assess the impact of age on potential differences in clinical characteristics, treatment patterns, and outcome in HCC patients. Characteristics that distinguish elderly from younger HCC patients include lower M/F ratio, worse performance status, lower rate of HCV infection, and less advanced underlying cirrhosis. Elderly patients were less likely to have a liver transplant and more likely to receive supportive care only. However, overall and HCC-specific survival were similar between the two groups., Background. There is a paucity of information on the clinical presentation and outcome of elderly hepatocellular carcinoma (HCC) patients. We performed a multicenter retrospective comparative study to assess the impact of age on potential differences in clinical characteristics, treatment patterns, and outcome in HCC patients. Methods. We retrospectively analyzed HCC patients treated at two U.S. tertiary institutions from 1998 to 2008. Demographics, tumor parameters, etiology and severity of cirrhosis, treatment, and survival from diagnosis were collected and analyzed. After exclusion of transplanted patients, survival analyses were performed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards models. Results. Three hundred thirty-five HCC patients were divided into two groups: “elderly” (95 patients, age ≥70 years) and “younger” (240 patients, aged

Complete lymph node dissection, the current standard treatment for nodal metastasis in melanoma, carries the risk of significant morbidity. Clinically apparent nodal tumor is likely to impact both preoperative lymphatic function and extent of soft tissue dissection required to clear the basin. We hypothesized that early dissection would be associated with less morbidity than delayed dissection at the time of clinical recurrence.The Multicenter Selective Lymphadenectomy Trial I randomized patients to wide excision of a primary melanoma with or without sentinel lymph node biopsy. Immediate completion lymph node dissection (early CLND) was performed when indicated in the SLN arm, while therapeutic dissection (delayed CLND) was performed at the time of clinical recurrence in the wide excision-alone arm. Acute and chronic morbidities were prospectively monitored.Early CLND was performed in 225 patients, and in the wide excision-alone arm 132 have undergone delayed CLND. The 2 groups were similar for primary tumor features, body mass index, basin location, and demographics except age, which were higher for delayed CLND. The number of nodes evaluated and the number of positive nodes was greater for delayed CLND. There was no significant difference in acute morbidity, but lymphedema was significantly higher in the delayed CLND group (20.4% vs. 12.4%, P = .04). Length of inpatient hospitalization was also longer for delayed CLND.Immediate nodal treatment provides critical prognostic information and a likely therapeutic effect for those patients with nodal involvement. These data show that early CLND is also less likely to result in lymphedema.

Background and objectives: Hepcidin, the principal regulator of iron homeostasis, may play a critical role in the response of patients with anemia to iron and erythropoiesis-stimulating agent therapy; however, the contribution of hepcidin to iron maldistribution and anemia in hemodialysis (HD) patients and the ability of HD to lower serum hepcidin levels have not been fully characterized. Design, setting, participants, & measurements: We measured serum hepcidin using a competitive ELISA in 30 pediatric and 33 adult HD patients. In addition, we determined serum hepcidin kinetics and calculated hepcidin clearance by measuring serum hepcidin before, during, and after HD in eight pediatric and six adult patients. Results: Hepcidin was significantly increased in pediatric (median 240.5 ng/ml) and adult HD patients (690.2 ng/ml) when compared with their respective control subjects (pediatric 25.3 ng/ml, adult 72.9 ng/ml). Multivariate regression analysis showed that serum hepcidin was independently predicted by ferritin and high-sensitivity C-reactive protein in the pediatric group and ferritin, percentage of iron saturation, and high-sensitivity C-reactive protein in the adult group. Hepcidin levels decreased after dialysis from 532 ± 297 to 292 ± 171 ng/ml. Hepcidin clearance by HD was 141 ± 40 and 128 ± 44 ml/min in pediatric and adult patients, respectively (NS). Conclusions: These findings suggest that hepcidin may mediate the negative effects of inflammation on both disordered iron metabolism and erythropoiesis in HD patients and that intensification of HD could be used therapeutically to reduce hepcidin concentrations and thereby improve erythropoiesis-stimulating agent responsiveness.

The tight junction (TJ) proteins claudin-3 and claudin-4 have been reported to be differentially expressed in uterine serous papillary carcinoma (USPC), a rare form of endometrial cancer characterized by a particularly high recurrence rate and poor prognosis. Preclinical experiments suggest that increased expression of both TJ proteins may in part mediate the biologically aggressive phenotype of USPC. Our aim was to determine claudin-3 and claudin-4 expression in a large cohort of surgically staged patients with USPC and clear cell endometrial cancer (n=137), and to compare the expression pattern and prognostic relevance of both claudins with that seen in patients with endometrioid endometrial cancer (n=150). The rate of claudin-3 and claudin-4 expression was significantly higher in USPC and clear cell endometrial cancer compared to endometrioid endometrial cancer (claudin-3: 78% and 61% versus 38%, p

Background Roux-en-Y gastric bypass patients often undergo preoperative dieting and psychological assessment before surgery. We examined preoperative weight loss, binge eating disorder (BED), and sexual abuse history and the interactions of these predictors to determine whether a cautionary approach to Roux-en-Y gastric bypass is warranted. Methods Consecutive subjects undergoing Roux-en-Y gastric bypass at our institution from January 1997 to December 2002 were reviewed. The postoperative excess weight loss (EWL) at 1, 3, 6, 12, 18, and 24 months and the perioperative complications were measured. EWL was compared at 12 and 24 months postoperatively in the categories of the presence/absence of preoperative weight loss, BED, and sexual abuse history. The perioperative complications were examined in the preoperative weight change groups. Results Of 154 patients, 121 were included. No significant difference in EWL or perioperative complications was observed between those who lost or gained weight preoperatively. Of the 121 patients, 32% and 17% reported a history of BED and sexual abuse, respectively. No statistically significant difference was observed in the EWL between those with and without BED at 12 and 24 months postoperatively. The EWL in those with and without a sexual abuse history at 12 and 24 months was 57.67% and 66.32% ( P P = NS). No statistically significant interaction between EWL and sexual abuse*BED/sexual abuse*preoperative weight loss was observed. Conclusion Only sexual abuse history at postoperative month 12 had a negative effect on EWL. Otherwise, physicians can expect to see successful EWL in these subjects up to 24 months postoperatively. We recommend that additional investigation be done of those with BED and a sexual abuse history.

Purpose: Somatic B-RAF gene mutation has been identified in many malignancies and detected at a high frequency in cutaneous malignant melanoma. However, the significance of the B-RAF mutation (B-RAFmt) in terms of its prognostic and predictive capabilities for treatment response or disease outcome is not known. We hypothesized that circulating serum B-RAFmt (B-RAFsmt) at V600E, detected in serum, predicts response in melanoma patients receiving concurrent biochemotherapy. Experimental Design: A real-time clamp quantitative reverse transcription-PCR assay was designed to assess B-RAFsmt by peptide nucleic acid clamping and a locked nucleic acid hybrid probe. Normal (n = 18) and American Joint Committee on Cancer stage I to IV melanoma patients (n = 103) were evaluated. These included stage IV patients (n = 48) with blood drawn before and after biochemotherapy. Patients were classified as biochemotherapy responders or nonresponders. Responders (n = 24) had a complete or partial response following biochemotherapy; nonresponders (n = 24) developed progressive disease. Results: Of the 103 melanoma patients, 38 (37%) had B-RAFsmt DNA, of which 11 of 34 (32%) were stage I or II, and 27 of 69 (39%) were stage III or IV. Of the 48 biochemotherapy patients, 10 of 24 (42%) patients were positive for the B-RAFsmt in the respective responder and nonresponder groups before treatment. After biochemotherapy, B-RAFsmt was detected in only 1 of 10 patients (10%) in the responder group and 7 of 10 patients (70%) in the nonresponder group. B-RAFsmt is associated with significantly worse (P = 0.039) overall survival in patients receiving biochemotherapy. Conclusion: These studies show the presence and utility of circulating B-RAFsmt DNA in melanoma patients.

© 2015 Elsevier Ltd. Background: Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women. Methods: We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0·10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204. Findings: We enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0·25 relapses per year (95% CI 0·17-0·37) in the estriol group versus 0·37 relapses per year (0·25-0·53) in the placebo group (adjusted rate ratio 0·63, 95% CI 0·37-1·05; p=0·077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0·0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0·0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy. Interpretation: Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial. Funding: National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.

Cyclooxygenase 2 (COX-2)-dependent signaling represents a potential mechanism of resistance to therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. This is mediated in part through an EGFR-independent activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) by prostaglandin E2 (PGE2). PGE2 promotes downregulation of E cadherin and epithelial to mesenchymal transition. The current study investigated EGFR and COX-2 inhibition in patients with non-small cell lung cancer (NSCLC) and elevated baseline urinary metabolite of PGE2 (PGEM).Patients with stage IIIB/IV (AJCC 6th edition) NSCLC who progressed after at least 1 line of therapy or refused standard chemotherapy were randomized to receive erlotinib and celecoxib versus erlotinib and placebo. The primary endpoint was progression-free survival (PFS) with 80% power to detect a 50% improvement with a 1-sided significance level of .2 in the intent-to-treat and elevated baseline PGEM populations. Secondary endpoints included response rate, overall survival, and evaluation of molecular markers to assess targeting COX-2-related pathways and evaluate EGFR tyrosine kinase inhibitor resistance.A total of 107 patients were enrolled with comparable baseline characteristics. Among the patients treated with celecoxib, those with wild-type EGFR were found to have an increased PFS (3.2 months vs 1.8 months; P = .03). PFS was numerically improved among patients in the intent-to-treat group who received erlotinib and celecoxib compared with those treated with erlotinib and placebo (5.4 months vs 3.5 months; P = .33) and was increased in patients in the erlotinib and celecoxib arm with elevated baseline PGEM (5.4 months vs 2.2 months; P = .15). Adverse events were similar in both treatment arms.The combination of erlotinib and celecoxib did not appear to improve outcomes in an unselected population, but selection by elevated baseline PGEM led to an increase in PFS with this combination. Patients with EGFR wild-type status may benefit from the combination of erlotinib and celecoxib.

Although previous studies have separately shown the utility of circulating tumor cells (CTC) or cell-free tumor-related DNA in blood of cancer patients, there has been no investigation of their association and/or the prognostic value of combining these assessments. To date, the true source of tumor-related DNA in serum remains unknown. We hypothesized that CTC is a possible origin of serum tumor-related methylated DNA and their combination can predict disease outcome. To test this hypothesis, we obtained matched pairs of peripheral blood lymphocytes and serum specimens simultaneously from 50 American Joint Committee on Cancer stage IV melanoma patients before administration of biochemotherapy. Peripheral blood leukocytes were analyzed for three mRNA markers of CTC: MART-1, GalNAc-T, and MAGE-A3. Sera were analyzed for two methylated DNA markers: RASSF1A and RAR-β2. CTC were detected in 13 of 15 (86%) patients with serum tumor-related methylated DNA and only in 13 of 35 (37%) patients without methylated DNA (P = 0.001). The number of CTC markers detected significantly correlated with methylated DNA (P = 0.008). CTC and methylated DNA were significantly correlated with biochemotherapy-treated patients' outcome. Patients with both CTC and methylated DNA showed significantly poorer response to biochemotherapy (P = 0.02) and worse time to progression and overall survival (P = 0.009 and 0.02, respectively). The correlation between CTC and serum tumor-related methylated DNA and the significant effect of this correlation on disease outcome indicate that a composite molecular assessment in blood may be a useful determinant of disease status and efficacy of systemic therapy for melanoma. (Cancer Res 2006; 66(12): 6111-7)

PURPOSE: Microphthalmia transcription factor (Mitf), which is important in melanocyte development and melanoma growth, was assessed using real-time quantitative reverse transcription-PCR assay to investigate its expression as a marker for circulating melanoma cells in blood and determine the correlation with disease stage and survival in melanoma patients. EXPERIMENTAL DESIGN: In optimization studies for Mitf, we tested 15 melanoma cell lines, 41 peripheral blood lymphocytes from healthy volunteers, and 21 metastatic melanoma tissues. Blood specimens were procured from 90 patients with stage I (n = 20), stage II (n = 20), stage III (n = 28), and stage IV (n = 22) melanoma. Blood specimens were also obtained at four bleed intervals from 58 patients enrolled in a prospective multicenter trial of biochemotherapy before and after surgical treatment of American Joint Committee on Cancer stage III melanoma. RESULTS: Under the optimized conditions, Mitf was negative in healthy peripheral blood lymphocytes and positive in all melanoma cell lines and 18 (86%) melanoma tissues. In the 90 patients, the rate of Mitf detection was higher with increasing American Joint Committee on Cancer stage (P < 0.0001). In the 58 patients treated with biochemotherapy and surgery, Mitf detection decreased with treatment (P = 0.019). Mitf detection after treatment was associated with a significantly lower relapse-free (P < 0.0001) and overall (P = 0.001) survival and was a significant independent prognostic factor for relapse-free (risk ratio, 5.63; P = 0.0004) and overall (risk ratio, 5.36; P = 0.005) survival. CONCLUSIONS: Mitf detection in blood can indicate subclinical metastatic disease and predict treatment outcome in melanoma patients.

Purpose Currently, no validated blood-based assays accurately predict treatment response or outcome in melanoma patients. We hypothesized that methylation of tumor-related genes detected in serum DNA could predict disease outcome and therapeutic response in patients receiving concurrent biochemotherapy (BC) for metastatic melanoma. Patients and Methods American Joint Committee on Cancer stage IV melanoma patients (N = 50) had blood drawn before administration of BC. Patients (n = 47) were classified as BC responders or nonresponders. Responders (n = 23) demonstrated a complete or partial response following BC; nonresponders (n = 24) demonstrated progressive disease. Hypermethylation of Ras association domain family 1 (RASSF1A), retinoic acid receptor-β2 (RAR-β2), and O6-methylguanine DNA methyltransferase (MGMT) genes were assessed by methylation-specific polymerase chain reaction. Results Circulating methylated RASSF1A was significantly less frequent for responders (three of 23 patients; 13%) than nonresponders (10 of 24 patients; 42%; P = .028). Patients with RASSF1A, RAR-β2, or at least one serum methylated gene had significantly worse overall survival than patients with no methylated genes (log-rank, P = .013, .021, and .01, respectively). Methylated RASSF1A was the only factor that significantly correlated with overall survival and BC response (risk ratio, 2.38; 95% CI, 1.16 to 4.86; P = .018; odds ratio = 0.21; 95% CI, 0.05 to 0.90; P = .036). Conclusion Detection of circulating methylated DNA in serum can predict response to BC and disease outcome.

PurposeLiver metastasis is the predominant cause of colorectal cancer (CRC) related mortality. Chemokines, soluble factors that orchestrate hematopoetic cell movement, have been implicated in directing cancer metastasis, although their clinical relevance in CRC has not been defined. Our hypothesis was that the chemokine receptor CXCR4 expressed by CRC is a prognostic factor for poor disease outcome.MethodsCRC cell lines (n = 6) and tumor specimens (n = 139) from patients with different American Joint Committee on Cancer (AJCC) stages of CRC were assessed. Microarray screening of select specimens and cell lines identified CXCR4 as a prominent chemokine receptor. CXCR4 expression in tumor and benign specimens was assessed by quantitative real-time reverse transcription polymerase chain reaction and correlated with disease recurrence and overall survival.ResultsHigh CXCR4 expression in tumor specimens (n = 57) from AJCC stage I/II patients was associated with increased risk for local recurrence and/or distant metastasis (risk ratio, 1.35; 95% CI, 1.09 to 1.68; P = .0065). High CXCR4 expression in primary tumor specimens (n = 35) from AJCC stage IV patients correlated with worse overall median survival (9 months v 23 months; RR, 2.53; 95% CI, 1.19 to 5.40; P = .016). CXCR4 expression was significantly higher in liver metastases (n = 39) compared with primary CRC tumors (n = 100; P < .0001).ConclusionCXCR4, a well-characterized chemokine receptor for T-cells, is differentially expressed in CRC. CXCR4 gene expression in primary CRC demonstrated significant associations with recurrence, survival, and liver metastasis. The CXCR4-CXCL12 signaling mechanism may be clinically relevant for patients with CRC and represents a potential novel target for disease-directed therapy.

Many laboratory-based studies have shown that soy can suppress breast cancer proliferation. However, given the recent controversy generated by animal experiments that soy may under certain conditions stimulate breast cancer growth, we decided to carry out a pilot clinical trial in order to elucidate any interaction(s) between short-term isoflavone supplement administration and breast cancer growth. After a core-needle biopsy established the diagnosis of breast cancer, 17 patients were administered soy isoflavone tablets for two weeks. This surgically based study provided the unique opportunity to make objective observations based on human breast cancer tissues and blood obtained prior to and after isoflavone supplement treatment in the same patient. Twenty-six historical control cases with similar characteristics to the experimental patients were selected for comparison. We observed that the apoptosis/mitosis ratios in isoflavone-treated cancer specimens were not significantly different from those of control untreated cancer specimens. Furthermore, there appeared to be a statistically nonsignificant trend towards cancer growth inhibition in the isoflavone treatment group, as manifested by higher apoptosis/mitosis ratios compared with those from the control untreated group. Ex vivo/in vitro assays using serum from breast cancer patients prior to and at the conclusion of soy treatment reveal no significant proliferative changes on both breast cancer cells and endothelial cells. We concluded that the effect of soy on breast cancer deserves further studies in larger clinical trials.

Although biochemotherapy appears to be a promising treatment for metastatic melanoma, its impact remains unpredictable. Microsatellite markers for loss of heterozygosity (LOH) appear to have prognostic significance when identified in primary tumors and serum and/or plasma from cancer patients. However, their association with response to systemic therapy has yet to be assessed. To determine whether microsatellite markers are associated with response to therapy, serum from 41 patients with metastatic melanoma, drawn before the initiation of biochemotherapy, was analyzed for LOH with nine microsatellite markers. During a median follow-up of 13 months, the overall response rate for these 41 patients was 56%, including 13 (32%) complete responses and 10 (24%) partial responses. LOH was detected in sera from 12 (29%) of the 41 patients. The response rate of these 12 patients was 17% (95% confidence interval [CI] = 5% to 45%), whereas that of the 29 patients without LOH was 72% (95% CI = 54% to 85%) (P = .001). All statistical tests were two-sided. The presence of LOH was statistically significant and independently associated with disease progression (multivariable analysis, P = .003). Circulating tumor DNA markers may be useful in assessing prognosis for advanced melanoma patients and their response to biochemotherapy.

Purpose: A significant number of patients who develop recurrence after a histopathologically negative sentinel lymph node (SLN) biopsy will demonstrate occult metastases on re-evaluation of the SLNs with serial sectioning and immunohistochemistry. Reverse transcriptase polymerase chain reaction (RT-PCR) has been evaluated to improve disease staging and avoid false-negative findings in fresh or frozen-section SLNs. The purpose of this study was to develop a multimarker RT-PCR assay for assessing melanoma patients’ archived paraffin-embedded (PE) SLNs. Patients and Methods: Archived PE histopathologically positive (n = 37) and negative (n = 40) SLNs from patients with primary melanoma were analyzed using a semiquantitative multimarker RT-PCR assay. Results: Marker expression in histopathologically positive and negative SLNs were as follows: 89%, 92%, 35%, and 43% (positive) and 40%, 33%, 5%, and 13% (negative) for tyrosinase, melanoma antigen recognized by T cells-1, tyrosinase-related protein-1, and tyrosinase-related protein-2, respectively. Twenty-five percent of histopathologically negative SLN patients were upstaged using at least two markers. Of these, 80% developed a recurrence. Furthermore, at a median follow-up of 55 months, patients with histopathologically negative SLNs who expressed zero or one marker had a significantly improved disease-free (P < .002) and overall (P < .03) survival versus those expressing two or more markers. Conclusion: These findings demonstrate the feasibility of a multimarker RT-PCR assay for evaluating archived PE SLNs. More significantly, identification of molecular risk factors can be detected in histopathologically negative SLNs for distinguishing early-stage melanoma patients with a worse prognosis.

Purpose Adjuvant chemotherapy for breast cancer can have adverse effects on bone. We investigated the effects of adjuvant chemotherapy on bone mineral density in postmenopausal women with early-stage breast cancer. Methods We performed a chart review of all our breast center patients who had spine or hip bone density measured by dual-energy X-ray absorptiometry at our institution after treatment for stage I or II breast cancer. Patients who had other causes of metabolic bone disease were excluded. Multivariate regression analysis was used to adjust for confounding factors. Results were expressed as age-adjusted standard deviation units (Z scores). Results Of the 130 eligible women, 36 (28%) received adjuvant chemotherapy and 94 (72%) did not. Mean adjusted bone density scores in both the hip (0.65 SD units; 95% confidence interval [CI]: 0.32 to 0.98 SD units; P = 0.0002) and spine (0.60 SD units; 95% CI: 0.01 to 1.19 SD units; P = 0.05) were significantly lower in patients who had received adjuvant chemotherapy compared with those who had not. Conclusion Women who were postmenopausal when they developed breast cancer and who received adjuvant chemotherapy had lower bone density than those who did not. Whether this effect is caused by adjuvant chemotherapy remains to be determined.

Background: HER-2/neu, which encodes a receptor tyrosine kinase, is amplified and overexpressed in 20%-25% of human breast cancers. Such tumors are often resistant to hormone therapy. Despite a general inverse association between HER-2/neu amplification/overexpression and estrogen receptor (ER) and/or progesterone receptor (PR) expression, a fraction of patients are both HER-2/neu- and hormone receptor (HR)-positive. The efficacy of hormone therapy in this group is currently a matter of debate. To better understand the relationship between HER-2/neu positivity and HR expression, we analyzed HER-2/neu, ER, and PR as continuous variables in breast cancer cell lines and two cohorts of primary breast cancer patients. Methods: HER-2/neu and ER/PR expression was analyzed by enzyme-linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA), respectively, in 14 human breast cancer cell lines, some of which had been transfected with the HER-2/neu gene. For the clinical study population, HER-2/neu protein levels were assessed by ELISA (cohort A, n = 665), and HER-2/neu gene copy number was determined using fluorescence in situ hybridization (cohort B, n = 894). ER/PR expression was analyzed by EIA (cohort A) or radioligand binding (cohort B). Associations between HER-2/neu and ER/PR expression were analyzed using Spearman's rho correlation and the chi-square test, and absolute levels were compared using the Mann-Whitney U test. All statistical tests were two-sided. Results: HR-positive human breast cancer cell lines transfected with the HER-2/neu gene expressed statistically significantly lower levels of ER and PR than parental lines. In the clinical cohorts, levels of HER-2/neu overexpression and gene amplification were inversely correlated with ER/PR levels (Cohort A [n = 112]: for ER, r = -0.34, P

Molecular classification of high-grade serous ovarian cancer (HGSOC) using transcriptional profiling has proven to be complex and difficult to validate across studies. We determined gene expression profiles of 174 well-annotated HGSOCs and demonstrate prognostic significance of the prespecified TCGA Network gene signatures. Furthermore, we confirm the presence of four HGSOC transcriptional subtypes using a de novo classification. Survival differed statistically significantly between de novo subtypes (log rank, P = .006) and was the best for the immunoreactive-like subtype, but statistically significantly worse for the proliferative- or mesenchymal-like subtypes (adjusted hazard ratio = 1.89, 95% confidence interval = 1.18 to 3.02, P = .008, and adjusted hazard ratio = 2.45, 95% confid ence interval = 1.43 to 4.18, P = .001, respectively). More prognostic information was provided by the de novo than the TCGA classification (Likelihood Ratio tests, P = .003 and P = .04, respectively). All statistical tests were two-sided. These findings were replicated in an external data set of 185 HGSOCs and confirm the presence of four prognostically relevant molecular subtypes that have the potential to guide therapy decisions. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The relation between insulin-leptin-visceral fat axis during weight loss has not been studied previously.To evaluate the insulin, leptin, and abdominal adiposity relation during weight loss in patients with upper body obesity.Twenty volunteers (7 men, 13 women) with mean age 50.6+/-6.3 (SD) and upper body obesity (weight 105.4+/-12.3 kg, BMI 35.9+/-2.5 kg/m2) were recruited. Participants were enrolled in a one-arm clinical study using a calorie-deficient diet and an escalating dose regimen of sibutramine, starting with 5 mg daily and increasing in 5-mg increments to 20 mg per day. Body weight, insulin, leptin, glucose, lipids, abdominal computed tomography (CT), and total body electrical conductance (TOBEC) were measured serially at weeks 0, 4, 8, 12, and 24.Eighteen patients completed the 6-month study: one man and one woman discontinued because of adverse events. With diet and sibutramine, body weight was significantly and continuously reduced throughout the 6-month study. There was a 16.0% (p = 0.0001) reduction in body weight (p0.001) and 22.5% (p = 0.0001) decrease in total body fat mass. Abdominal CT scans showed a 28.3% (p = 0.0001) reduction in total abdominal fat, a 26.0% (p = 0.0001) reduction in subcutaneous fat (p0.001), and a 31.0% (p = 0.0003) reduction in visceral fat (p0.001). There was a 32.0% (p = 0.0008) reduction in leptin levels and 37.9% (p = 0.0001) reduction in insulin levels between baseline and week 4, but no further significant reduction in leptin and insulin levels was observed for the duration of the study. There was a significant correlation between insulin and leptin concentrations throughout the study (p = 0.0001). Leptin was presented as a function of insulin measured at the same time. Significant associations between visceral abdominal fat, subcutaneous fat, and leptin were also observed.In this study, we found that leptin and insulin were related in weight loss. The data suggest that insulin may act as a strong regulator of leptin secretion during weight loss and that circulating leptin levels can be predicted by insulin level. Using sibutramine in conjunction with hypocaloric diet reduced body weight and decreased fat mass significantly. Visceral and subcutaneous abdominal fat depots were shown to decrease. Whether sibutramine exerts any selective reduction of visceral abdominal fat as opposed to total body fat mass will require further clinical investigation.

BACKGROUND The sentinel lymph nodes (SLNs) as the primary targets for lymphatic metastases can be removed selectively by γ probe-guided sentinel lymph nodectomy (SLNE) in nearly all patients with cutaneous melanoma. Correspondingly high standards in terms of specificity, sensitivity, and microstaging are required for the evaluation of SLNs. METHODS Since 1995, the authors have performed SLNE in 389 lymph node regions (LNRs) on 342 patients with melanoma. The harvested 636 SLNs and a further 1394 nonsentinel lymph nodes (non-SLNs) were evaluated by standardized, semiserial section histology, including immunohistochemistry. For each LNR, this technique permitted routine S classification using two simple morphometric parameters: the number of tumor-involved, 1-mm slices of the SLNs (n) and the centripetal depth of metastatic cell invasion (d). S1 was defined by 1 ≤ n ≤ 2 and d ≤ 1 mm, equivalent to localized peripheral tumor cell deposits; S2 was defined by n > 2 and d ≤ 1 mm, indicating more extended peripheral metastases; S3 was defined by d > 1 mm in SNLs with deeper metastatic infiltration; and S0 meant no detectable tumor cells (n = 0). RESULTS The authors diagnosed 325 SLNs as S0, 24 SLNs as S1, 22 SLNs as S2, and 18 SLNs as S3. The occurrence of at least one melanoma-positive non-SLN subsequent regional completion lymph node dissection (RCLND) significantly increased from 0 of 12 in S1 SLNs to 2 of 13 in S2 SLNs and 9 of 15 in S3 SLNs (P = 0.001; chi-square test). Like the T classification of the primary melanoma, the S classification proved to be a highly significant predictor for distant metastasis (P < 0.001). It turned out to be an independent factor of influence on distant metastasis and survival in multivariate Cox analyses, which included tumor thickness, primary tumor site, patient gender, and patient age as covariates. CONCLUSIONS The data presented recommend the S-staging concept as a promising option to fill a gap between the T and conventional N component of the pTNM classification. If its predictive capacity can be confirmed in multicenter studies, then the S classification may become the decisive criterion for or against RCLND, and a combined T plus S staging system will help to improve prognostically relevant stratification of melanoma patients in adjuvant therapy trials. Cancer 2001;91:2110–20. © 2001 American Cancer Society.