Weil's Disease from a Local New Orleans Bar.

INTRODUCTION: Leptospirosis is a zoonotic infection that typically presents with fever, myalgias, nausea, and vomiting after contact with contaminated waters or infected animals (typically rodents); and their excrements. Conditions favorable to the transmission of leptospirosis are common in LA and, without treatment, leptospirosis can lead to both liver and renal failure, meningitis, pulmonary hemorrhage and ultimately death. CASE: A 56 year old woman with no past medical history presented to the Emergency Department with weakness, myalgias, jaundice and decreased urine output for one week. On arrival, she appeared septic with a heart rate of 130 and fever. Her exam was significant for significant jaundice and diffuse abdominal pain. Laboratory studies were notable for WBC 14, hemoglobin of 12 and platelet count of 63. Creatinine was 8.5mg/dL with a blood-urea nitrogen of 96mg/dl. Total bilirubin was 19.4mg/dL and direct bilirubin was 13.7mg/dL. AST/ALT were 69/38 U/L, respectively and the alkaline phosphate was 160U/L. The patient was admitted to the hospital medicine wards for sepsis and multi-organ failure. She was started on broad spectrum antibiotics but her clinical condition continued to worsen with progressive decline in her hemoglobin and thrombocytopenia and worsening liver failure. She quickly became anuric necessitating dialysis and developed respiratory distress with bilateral pulmonary infiltrates and hemoptysis. Additional history was obtained from her employer that she works at a local New Orleans bar and had been cleaning out rats from the kitchen. Leptospirosis antibody was sent, which returned as positive. Her antibiotics were de-escalated to IV Ceftriaxone. She made a slow recovery over the next two-week period. DISCUSSION: Since 1987, there has been an average of 3 cases of Leptospirosis diagnosed per year, most of which have been from southeast LA. This case illustrates the importance of considering the diagnosis of Leptospirosis and Weil's Disease in patients in the southeast region of LA who present with multi-organ failure. In addition, our patient's occupational exposure was key to her diagnosis which emphasizes the importance of a detailed history in clinical decision making and patient outcomes.

Insulin like growth factor binding protein-7 reduces growth of human breast cancer cells and xenografted tumors.

Previously, we have shown that insulin-like growth factor binding protein-7 (IGFBP-7) expression is inversely correlated with disease progression in breast cancer and is associated with poor outcome. To further investigate the role of IGFBP-7 in the growth and metastatic behavior of breast cancer, primary breast tumors and metastatic tumors derived from the same patients were analyzed for IGFBP-7 expression. Immunohistochemical analysis revealed that IGFBP-7 is downregulated in half of the human metastatic breast tumors tested. IGFBP-7 has been linked to suppression of oncogenic pathways and can directly restore cellular senescence in melanomas, leading to their regression. It is possible that breast tumors with metastatic potential have escaped from IGFBP-7-induced suppression by its down-regulation. Twenty-two human primary breast tumor specimens were transplanted into human-bone NOD/SCID mice. One of the two triple negative primary breast tumors was serially xenotransplanted more than five times. Each serial transplant resulted in increased tumor take and rate of growth. Expression of IGFBP-7 was downregulated upon each serial implantation. To investigate the role of IGFBP-7 in breast tumor suppression, IGFBP-7 was overexpressed in the triple negative MDA-MB-468 human breast cancer line by stable transfection of a pSec-tag2-IGFBP-7 vector. The parental MDA-MB-468 breast cancer cells expressed extremely low levels of endogenous IGFBP-7. The production of IGFBP-7 protein by the MDA-MB-468 cells stably transfected with IGFBP-7 was confirmed by immunoblotting with anti-IGFBP-7 antibody. Ectopic overexpression of IGFBP-7 significantly reduced the growth of the IGFBP-7 transfected MDA-MB-468 cells compared to the parental MDA-MB-468 cells. We also assessed the role of IGFBP-7 on cell migration, a key determinant of malignant progression and metastasis. When parental MDA-MB-468 cells were treated with various amounts of conditioned medium derived from the IGFBP-7 overexpressing cell line, a significant difference in cell migration rate was observed between untreated and treated cells. IGFBP-7 strongly suppressed the phosphorylation of the mitogen-activated protein kinases (MAPK) ERK-1/2, suggesting that IGFBP-7 mediates its anti-proliferative effects through negative feedback signaling. Levels of phospho-ERK-1/2 were higher in the parental MDA-MB-468 than in IGFBP-7-expressing cells derived from it. When injected subcutaneously into NOD/SCID mice, the increased expression of IGFBP-7 in the MDA-MB-468 transfected cells reduced the rate of tumor growth in comparison to the parental MDA-MB-468 controls. These results suggest that the growth of breast cancer could be prevented by the forced expression of IGFBP-7 protein.

Recent population changes in HbA(1c) and fasting insulin concentrations among US adults with preserved glucose homeostasis.

AIMS/HYPOTHESIS: Although diagnosed type 2 diabetes has increased in the past decade, little is known about accompanying changes in fasting plasma glucose (FPG), HbA(1c) and fasting serum insulin (FI) levels in the non-diabetic population. METHODS: Using population estimates from National Health and Nutrition Examination Surveys, we compared distribution of FPG, HbA(1c) and FI in non-diabetic US persons who were >or=20 years old in 1999 to 2006 with that in persons of the same age in 1988 to 1994. RESULTS: Age-, sex- and race-adjusted mean FPG levels between the two study periods did not change, but mean HbA(1c) and FI levels increased (0.10% and 4.8 pmol/l, respectively; p < 0.001 for both). The increased HbA(1c) level was driven largely by an upward shift in the lower end of the HbA(1c) distribution. In contrast, the increased FI level was driven primarily by an upward shift in the middle and higher end of FI distribution, especially among persons aged 20 to 44 years. After adjustments for BMI or waist circumference, the increase in the mean HbA(1c) level was attenuated (0.06%; p < 0.001), whereas the mean FPG level decreased by 0.1 mmol/l (p < 0.001) and the mean FI level no longer demonstrated significant change. CONCLUSIONS/INTERPRETATION: Despite little change in the distribution of FPG levels, HbA(1c) and FI levels increased in the non-diabetic population in the past decade. The increase in FI levels suggests that levels of insulin resistance were greater among US adults, especially young adults, than in the previous decade.

A randomized trial exploring the biomarker effects of neoadjuvant sequential treatment with exemestane and anastrozole in post-menopausal women with hormone receptor-positive breast cancer.

Several adjuvant endocrine strategies exist for postmenopausal women with breast cancer. This study compared the effect of two sequences of aromatase inhibitor use [steroidal (exemestane) and non-steroidal (anastrozole)] on serological and pathological biomarkers when given in the neoadjuvant setting to postmenopausal women with breast cancer. Thirty women were assigned to receive exemestane 25 mg or anastrozole 1 mg each given for 8 weeks in a randomized sequence. The effect of this treatment on serum estrone sulfate and estradiol levels, as well as tumor changes in the proliferation biomarker Ki67 were evaluated at baseline, 8 weeks and 16 weeks. WHO clinical response criteria, patient preference, and quality of life were also assessed. Assessable data was available from 28 patients. There were no differences in concentration changes of serum estradiol or Ki67 between patients in the two arms. Overall clinical response rate was 68% (19/28 assessable patients) and clinical benefit was 93% (26/28 assessable patients). There was no significant difference in toxicity or quality of life scores. The majority of patients expressed a personal preference for anastrozole over exemestane. Results suggest that the order of steroidal and non-steroidal aromatase inhibitors has little effect on outcome. The majority of patients express clear preferences for drug treatments.

Chemical-mineralogical characterization of C&D waste recycled aggregates from São Paulo, Brazil.

This study presents a methodology for the characterization of construction and demolition (C&D) waste recycled aggregates based on a combination of analytical techniques (X-ray fluorescence (XRF), soluble ions, semi-quantitative X-ray diffraction (XRD), thermogravimetric analysis (TGA-DTG) and hydrochloric acid (HCl) selective dissolution). These combined analytical techniques allow for the estimation of the amount of cement paste, its most important hydrated and carbonated phases, as well as the amount of clay and micas. Details of the methodology are presented here and the results of three representative C&D samples taken from the São Paulo region in Brazil are discussed. Chemical compositions of mixed C&D aggregate samples have mostly been influenced by particle size rather than the visual classification of C&D into red or grey and geographical origin. The amount of measured soluble salts in C&D aggregates (0.15-25.4mm) is lower than the usual limits for mortar and concrete production. The content of porous cement paste in the C&D aggregates is around 19.3% (w/w). However, this content is significantly lower than the 43% detected for the C&D powders (<0.15 mm). The clay content of the powders was also high, potentially resulting from soil intermixed with the C&D waste, as well as poorly burnt red ceramic. Since only about 50% of the measured CaO is combined with CO(2), the powders have potential use as raw materials for the cement industry.

Longitudinal changes in BMI and in an index estimating excess lipids among white and black adults in the United States.

BACKGROUND: Adult obesity prevalence is influenced by rates of weight gain or loss among individual persons, but few studies have measured individual weight change in large populations. Changes in weight may not coincide with changes in the lipid accumulation product (LAP), a continuous index derived from waist circumference and triglycerides concentration for estimating excess lipids. DESIGN AND MEASUREMENTS: Descriptive report of longitudinal changes from US studies that included body mass index (BMI, kg/m(2)) and LAP. SUBJECTS: A total of 16 763 white and black adults studied between 1989 and 1996 in three observational cohorts (Coronary Artery Risk Development in Young Adults, Atherosclerosis Risk in Communities Study and Cardiovascular Health Study). RESULTS: The means of individual annual changes in BMI were positive for young adults, but the mean changes were reduced at older ages (P for linear trend <0.001), becoming negative after 73-83 years old. These mean, individual changes in BMI, specific to sex and age, were approximately 0.1 U/year greater than those reported from previous, representative, longitudinal measurements collected in the United States between 1971 and 1984. Mean, individual annual changes in LAP were strongly positive before middle age. For men, the annual LAP changes were reduced at older ages (P linear trend <0.05). For women, they were greater at older ages (white women, P<0.001) or remained unchanged (black women, P>0.3). With increasing age, there was a greater proportion of persons whose positive LAP change was accompanied by simultaneous BMI change that was negative or zero. CONCLUSIONS: These longitudinal observations made during 1989-1996 suggest greater annual changes in BMI compared to an adult cohort studied during 1971-1984. As estimated by LAP, adults of all ages tended to accumulate excess lipids, including circumstances in which they lost weight.

Factors affecting axillary lymph node retrieval and assessment in breast cancer patients.

BACKGROUND: Breast cancer is the most common female cancer in North America. Axillary lymph node dissection (ALND) is important for staging, prognosis, and adjuvant treatment decisions. The purpose of this study was to identify factors that affect the number of lymph nodes (LN) retrieved in ALND for breast cancer. METHODS: All patients who underwent ALND for breast cancer at Sunnybrook Health Sciences Centre and Women's College Hospital between July 1999 and June 2006 were included. The number of LN retrieved was identified from pathology reports. Univariate and multivariate analysis was undertaken to identify variables influencing this outcome. RESULTS: 1084 patients were identified with a mean number of LN of 14.5. In multivariate analyses, significant covariates included sentinel LN biopsy (P = 0.011), degree of extranodal extension (P = 0.005), tumor grade (P = 0.058), and age (P = 0.043). Thirteen percent of the variation in LN yield was accounted for by institutional, provider, patient, and tumor related factors, leaving 87% attributable to inherent biological or other differences between patients. CONCLUSION: The yield of ALND may be influenced by multiple factors, often not related to the surgery. In settings where >10 LNs are routinely retrieved at ALND, biological variation between patients should be recognized as major a contributor to the LN yield. Adjuvant treatment decisions based on this outcome should take this into consideration.

Discordance between receptor status in primary and metastatic breast cancer: an exploratory study of bone and bone marrow biopsies.

AIMS: The treatment of bone metastases in breast cancer is traditionally based upon the receptor status of the primary tumour. However, retrospective studies have shown significant discordance in receptor expression between primary and metastatic tumours. Therefore, the aim of this study was to prospectively assess the incidence of discordant receptor status in primary and metastatic disease and evaluate the role of bone marrow biopsies for the reassessment of receptor status. MATERIALS AND METHODS: Nine patients with known bone metastases were assessed with both a radiologically guided bone biopsy and a bone marrow aspirate and trephine. The oestrogen receptor and progesterone receptor status of these samples was assessed and compared with the primary breast cancer. Bone and bone marrow samples were also evaluated for HER2/neu status and compared with the status of the primary tumour if available. RESULTS: Tumour cells were found in six of the nine bone metastasis specimens and five of the nine bone marrow samples. A discordance rate for the oestrogen receptor was seen in five of nine patients (56%) and for the progesterone receptor in four patients (44%). There seemed to be a correlation between bone and bone marrow biopsies. CONCLUSION: The receptor discordance rate in this study was similar to previous retrospective studies. It seems that bone marrow biopsy may be a simple, safe and well-tolerated way to obtain tissue to reassess the receptor status of metastatic breast cancer.

Inhibition of norepinephrine-induced cardiac hypertrophy in s100beta transgenic mice.

We have recently reported that the Ca2+-binding protein S100beta was induced in rat heart after infarction and forced expression of S100beta in neonatal rat cardiac myocyte cultures inhibited alpha1-adrenergic induction of beta myosin heavy chain (MHC) and skeletal alpha-actin (skACT). We now extend this work by showing that S100beta is induced in hearts of human subjects after myocardial infarction. Furthermore, to determine whether overexpression of S100beta was sufficient to inhibit in vivo hypertrophy, transgenic mice containing multiple copies of the human gene under the control of its own promoter, and CD1 control mice were treated with norepinephrine (NE) (1.5 mg/kg) or vehicle, intraperitoneally twice daily for 15 d. In CD1, NE produced an increase in left ventricular/body weight ratio, ventricular wall thickness, induction of skACT, atrial natriuretic factor, betaMHC, and downregulation of alphaMHC. In transgenic mice, NE induced S100beta transgene mRNA and protein, but provoked neither hypertrophy nor regulated cardiac-specific gene expression. NE induced hypertrophy in cultured CD1 but not S100beta transgenic myocytes, confirming that the effects of S100beta on cardiac mass reflected myocyte-specific responses. These transgenic studies complement in vitro data and support the hypothesis that S100beta acts as an intrinsic negative regulator of the myocardial hypertrophic response.

Nano measurements with micro-devices: mechanical properties of hydrated collagen fibrils.

The mechanical response of a biological material to applied forces reflects deformation mechanisms occurring within a hierarchical architecture extending over several distinct length scales. Characterizing and in turn predicting the behaviour of such a material requires an understanding of the mechanical properties of the substructures within the hierarchy, the interaction between the substructures, and the relative influence of each substructure on the overall behaviour. While significant progress has been made in mechanical testing of micrometre to millimetre sized biological specimens, quantitative reproducible experimental techniques for making mechanical measurements on specimens with characteristic dimensions in the smaller range of 10-1000 nm are lacking. Filling this void in experimentation is a necessary step towards the development of realistic multiscale computational models useful to predict and mitigate the risk of bone fracture, design improved synthetic replacements for bones, tendons and ligaments, and engineer bioinspired efficient and environmentally friendly structures. Here, we describe a microelectromechanical systems device for directly measuring the tensile strength, stiffness and fatigue behaviour of nanoscale fibres. We used the device to obtain the first stress-strain curve of an isolated collagen fibril producing the modulus and some fatigue properties of this soft nanofibril.

Overexpression of p53 is a late event in the development of malignant melanoma.

Overexpression of the p53 gene product has been observed in a high percentage of malignant melanomas. To evaluate the role of this protein in the development of melanoma, we examined p53 expression in benign, premalignant, and malignant melanocytic lesions. Using the antibodies DO-7 and 1801, which recognize both wild-type and most mutant forms of the p53 protein, we analyzed by immunohistochemical staining 26 benign nevi, 34 dysplastic nevi from patients at low risk for the development of melanoma, 22 dysplastic nevi from patients at high risk for the development of melanoma, 61 primary melanomas (including 15 that arose from dysplastic nevi), and 10 metastatic melanomas. Expression of the p53 protein was not observed in any of the benign or dysplastic nevi. Of the primary melanomas only 3 (5%) demonstrated nuclear staining, whereas 70% of the metastatic melanomas showed a positive reaction for p53. These data suggest that overexpression of the p53 gene product is a late event in the progression of melanoma and consequently indicate that expression of this protein cannot be used as a marker to identify patients at high risk for the subsequent development of melanoma.

Monoclonal antibodies to an epithelial ovarian adenocarcinoma: distinctive reactivity with xenografts of the original tumor and a cultured cell line.

Four monoclonal antibodies (mAb) (8C, 10B, M2A, and M2D) were produced against the human epithelial ovarian adenocarcinoma cell line, HEY. The affinity constants of binding of the mAb to cultured HEY cells were 8 X 10(8) M-1 (M2D) and 10(9) M-1 (8C and 10B). mAb 8C reacted with a major glycoprotein of Mr 90,000 on the surface of HEY cells. The four mAb differed from previously reported mAb to epithelial ovarian adenocarcinomas on the basis of their reactivity with cultured ovarian adenocarcinoma cell lines using a cell-binding radioimmunoassay, and their staining of cryostat sections of various human normal and tumor tissues using an immunoperoxidase reaction. All four mAb reacted with s.c. tumors derived by injecting cultured HEY cells into thymectomized CBA/CJ mice. However, only two of the four mAb (8C and 10B) also reacted with s.c. tumors of the original HEY xenograft from which the cultured cell line was derived. In addition, mAb 8C and 10B reacted by immunoperoxidase staining with 2 and 4 different cases, respectively, of 11 epithelial ovarian adenocarcinomas examined. Cultured HEY cells were adapted to grow i.p. in BALB/c-nu/nu mice and the i.p. tumors retained their reactivity with the monoclonal antibodies. These tumor-bearing mice offer a useful model system for studying the potential of mAb, especially 8C and 10B, for the diagnosis and treatment of patients with peritoneal extension of epithelial ovarian adenocarcinomas.

Acute biologic response to excimer versus thermal laser angioplasty in experimental atherosclerosis.

Vascular injury and platelet accumulation after balloon angioplasty are two potentially important triggers of the process of restenosis that may be minimized by the use of laser energy to ablate atherosclerotic plaque. The type of laser most suitable to achieve these goals remains unknown. Accordingly, angiographic and histologic studies and quantitative platelet deposition analysis were performed on 27 atherosclerotic rabbit iliac arteries randomized to treatment with excimer laser or thermal laser angioplasty. Excimer laser angioplasty was achieved with 35 to 40 mJ/mm2 of 308 nm xenon chloride irradiation delivered through a 4.5F catheter made of 13 concentrically arranged 200 microns fiber optics, at a repetition rate of 25 to 30 Hz and a pulse duration of 135 ns; thermal laser angioplasty was achieved with a 1.7 mm metal probe heated with 10 W of continuous wave argon laser energy. The baseline and post-laser luminal diameters of excimer laser-treated vessels (0.92 +/- 0.28 and 1.56 +/- 0.48 mm, respectively) were similar to those observed in thermal laser-treated vessels (1.05 +/- 0.44 and 1.61 +/- 0.41 mm, respectively). Perforation occurred in 4 (29%) of 14 thermal laser-treated arteries and in 0 of 13 excimer laser-treated arteries (p = 0.04); spasm was observed in only 1 thermal laser-treated vessel. On the basis of a quantitative histologic grading scheme (damage scores of 0 to 4), greater degrees of injury were measured in thermal versus excimer laser-treated vessels (2.4 +/- 1.0 versus 1.3 +/- 0.4, p = 0.009).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary excimer laser angioplasty: reduced complications and indium-111 platelet accumulation compared with thermal laser angioplasty.

The relative safety and thrombogenicity of pulsed excimer and thermal laser angioplasty systems were compared in 20 normal coronary artery segments in a total of seven pigs. Using similar over the wire catheter systems and laser delivery periods of 3 to 5 s, thermal laser angioplasty was achieved with a 1.3 mm metal probe heated with 10 W of continuous argon laser energy and excimer laser angioplasty was performed with a 4.5F excimer laser catheter consisting of 13 concentrically arranged 200 microns fiber optics delivering 35 to 40 mJ/mm2 of xenon chloride (308 nm) excimer laser irradiation at a repetition rate of 25 to 30 Hz and a pulse duration of 120 ns. On angiography, the incidence of vessel perforation (1 in 10 versus 3 in 10) and abrupt vessel closure (0 in 10 versus 2 in 10) was less with excimer compared with thermal laser angioplasty. Macroscopically, there was a greater incidence of mural and occlusive thrombus formation after thermal laser than after pulsed excimer laser angioplasty. Histologic examination confirmed that this thrombogenicity was associated with greater charring and coagulation necrosis of the media. Quantitative indium-111-labeled platelet deposition was significantly increased after thermal laser angioplasty (median 87.2 x 10(6)/cm length) compared with excimer-treated (0.4 x 10(6)/cm length) or control (1.2 x 10(6)cm length) segments (p less than 0.001). Thus, excimer laser angioplasty was found to result in fewer complications and, as a consequence, less thrombosis and platelet accumulation than did thermal laser angioplasty.

The 10-year incidence of overweight and major weight gain in US adults.

We estimated the 10-year incidence of major weight gain (a gain in body mass index of greater than or equal to 5 kg/m2 and overweight (a body mass index of greater than or equal to 27.8 for men and greater than or equal to 27.3 for women) in US adults using data from the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Persons aged 25 to 74 years at baseline were reweighed a decade after their initial examination (men, 3727; women, 6135). The incidence of major weight gain was twice as high in women and was highest in persons aged 25 to 34 years (men, 3.9%; women, 8.4%). Initially overweight women aged 25 to 44 years had the highest incidence of major weight gain of any subgroup (14.2%). For person not overweight at baseline (men, 2760; women, 4295), the incidence of becoming overweight was similar in both sexes and was highest in those aged 35 to 44 years (men, 16.3%; women, 13.5%). We conclude that obesity prevention should begin among adults in their early 20s and that special emphasis is needed for young women who are already overweight.

Drug-induced liver injury. In vitro demonstration of hypersensitivity to both phenytoin and phenobarbital.

Fever, lymphadenopathy, exfoliative dermatitis, and evidence of drug-induced liver injury developed in a 16-year-old girl three weeks after beginning therapy with phenytoin and phenobarbital. This clinical syndrome can be caused by either of these structurally related drugs but has been more frequently attributed to phenytoin. In vitro studies disclosed marked reactivity of this patient's lymphocytes to concentrations of both drugs, which encompassed their measured serum levels. The demonstration of dual reactivity raises concerns about continuing administration of phenobarbital during an apparent phenytoin-induced reaction. Whether this potential risk is greater than the risk of stopping all anticonvulsant medications in a patient with a seizure disorder is not known and remains to be established.

Health-related behaviors of women physicians vs other women in the United States.

OBJECTIVE: To examine the health-related behaviors of women physicians compared with those of other women of high and not high socioeconomic status and with national goals. METHODS: We examined the results of a questionnaire-based survey of a stratified random sample, the Women Physicians' Health Study, and a US telephone survey (Behavioral Risk Factor Surveillance System of the Centers for Disease Control and Prevention, Atlanta, Ga). We analyzed 3 samples of women aged 30 to 70 years: (1) respondents from the Women Physicians' Health Study (n = 4501); (2) respondents from the Behavioral Risk Factor Surveillance System (n = 1316) of the highest socioeconomic status; and (3) all other respondents from the Behavioral Risk Factor Surveillance System (n = 35,361). RESULTS: Women physicians were more likely than other women of high socioeconomic status and even more likely than other women not to smoke. The few physicians (3.7%) who smoked reported consuming fewer cigarettes per day, and physicians who had stopped smoking reported quitting at a younger age than women in the general population. Women physicians were less likely to report abstaining from alcohol, but those who drank reported consuming less alcohol per episode than other women and were less likely to report binging on alcohol than women in the general population. Unlike women in the general population and even other women of high socioeconomic status, women physicians' reported behaviors exceeded national goals for the year 2000 in all examined behaviors and screening habits. CONCLUSIONS: Women physicians report having generally good health habits even when compared with other socioeconomically advantaged women and report exceeding all examined national goals for personal screening practices and other personal health behaviors. Women physicians' behaviors may provide useful standards for other women in the United States.

Hyperinsulinemia predicts fatal liver cancer but is inversely associated with fatal cancer at some other sites: the Paris Prospective Study.

OBJECTIVE: To investigate whether insulin is a risk factor for death by site-specific cancers. RESEARCH DESIGN AND METHODS: This was a prospective cohort study of 6,237 nondiabetic French working men between ages 44 and 55 years at baseline from the Paris Prospective Study cohort. Death by site-specific cancers was investigated in relation to baseline insulin concentrations during fasting and 2 h after a 75-g oral glucose tolerance test. RESULTS: Of the original 6,237 men in the cohort, 1.739 died over the 23.8 years of follow-up. 778 (45%) from cancer. Baseline hyperinsulinemia, both fasting and 2-h, was significantly associated with fatal liver cancer, with age-adjusted standardized hazards ratios of 2.72 (95% CI 1.87-3.94) and 3.41 (2.23-5.21). In contrast, fasting hyperinsulinemia was inversely associated with fatal lip, oral cavity, and pharynx cancer and larynx cancer, with hazards ratios of 0.55 (0.41-0.75) and 0.63 (0.47-0.83), respectively; 2-h insulin concentrations were inversely associated with stomach and larynx cancers (hazards ratios 0.62 [0.43-0.90] and 0.66 [0.50-0.891, rcspectively). These relationships were stable after adjusting for other risk factors. Insulin concentrations remained negatively associated with deaths from these cancers in analyses restricted to men who smoked and in those who were not chronic alcohol consumers.

MIB-1 proliferative activity is a significant prognostic factor in primary thick cutaneous melanomas.

Although the Breslow measurement of tumor thickness of melanoma is the most significant predictor of survival, the biologic behavior of thick lesions remains unpredictable. MIB-1, a monoclonal antibody to a Ki-67 epitope, recognizes all proliferating cells. Unlike Ki-67 antibody, which requires frozen tissue, MIB-1 can be used on formalin-fixed tissue. Proliferation, measured by MIB-1 expression and mitotic index, was assessed as a prognostic factor in a group of patients with clinical stage I thick cutaneous melanoma (tumor thickness 4 mm or greater), for which predicted survival is low. From a melanoma data base, 97 patients with this type of melanoma were identified. Of these, 64 had lesional tissue available for study. The median follow-up time was 3.8 years (range 0.42-13.6 years). The percentage of MIB-1 reactivity was scored as low at less than 10% (n = 33), intermediate at 10% to 20% (n = 17), and high at greater than 20% (n = 14). Melanomas with high MIB-1 reactivity were associated with significantly poorer cause-specific survival compared with tumors with intermediate (p < 0.0001) or low MIB-1 reactivity (p = 0.0025). Multivariate analysis demonstrated that MIB-1 reactivity was a significant independent prognostic factor related to cause-specific survival (p = 0.0002) and was more sensitive than tumor thickness or mitotic index in this select group of high-risk patients. Identification of individuals with stage I thick cutaneous melanoma who are at risk of recurrent disease may improve patient management as new therapeutic modalities become available.