A pilot study of cabergoline for the treatment of metastatic breast cancer.

PURPOSE: The prolactin (PRL) receptor is over-expressed in breast cancer, and pre-clinical data indicate that it contributes to breast oncogenesis. Cabergoline is a potent dopamine receptor agonist of D2 receptors and has a direct inhibitory effect on pituitary PRL secretion. METHODS: A phase II study of cabergoline in patients with metastatic breast cancer was conducted. The primary end point of the study was to determine the clinical benefit rate (CBR) at 2 months. Eligible patients had tumors of any receptor status with no limit of prior lines of therapy. Measurable and unmeasurable diseases were allowed. Cabergoline 1 mg orally, twice weekly (1 cycle = 4 weeks) was given until disease progression or unacceptable toxicity. PRL receptor immunohistochemical staining was performed on available baseline tumor tissue; serial serum PRL levels were assessed. RESULTS: Twenty women were enrolled; 18 were evaluable for CBR. Tumor receptor status was distributed as follows: HR-any/HER2+ 2(10%), HR+/HER2- 18 (90%). The CBR was 33% (6/18), median progression free survival was 1.8 months, and median overall survival was 10.4 months. Two patients experienced disease control for over 12 months. Most common treatment-related adverse events were nausea (30%), fatigue (25%), and elevation in alkaline phosphatase (15%). Nine patients had baseline tissue for analysis; there was no association between baseline tumor PRL receptor expression and clinical benefit (p = 0.24). Change in serum PRL level and response were not correlated after 2 months of treatment (p = 0.64). CONCLUSION: Cabergoline was well tolerated, and while the ORR was low, a small subset of patients experienced extended disease control.

Clinical and genetic predictors of weight gain in patients diagnosed with breast cancer.

BACKGROUND: Post-diagnosis weight gain in breast cancer patients has been associated with increased cancer recurrence and mortality. Our study was designed to identify risk factors for this weight gain and create a predictive model to identify a high-risk population for targeted interventions. METHODS: Chart review was conducted on 459 breast cancer patients from Northwestern Robert H. Lurie Cancer Centre to obtain weights and body mass indices (BMIs) over an 18-month period from diagnosis. We also recorded tumour characteristics, demographics, clinical factors, and treatment regimens. Blood samples were genotyped for 14 single-nucleotide polymorphisms (SNPs) in fat mass and obesity-associated protein (FTO) and adiponectin pathway genes (ADIPOQ and ADIPOR1). RESULTS: In all, 56% of patients had >0.5 kg m(-2) increase in BMI from diagnosis to 18 months, with average BMI and weight gain of 1.9 kg m(-2) and 5.1 kg, respectively. Our best predictive model was a primarily SNP-based model incorporating all 14 FTO and adiponectin pathway SNPs studied, their epistatic interactions, and age and BMI at diagnosis, with area under receiver operating characteristic curve of 0.85 for 18-month weight gain. CONCLUSION: We created a powerful risk prediction model that can identify breast cancer patients at high risk for weight gain.

Age, sex, and smoking are predictors of circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3.

PURPOSE: Insulin-like growth factor (IGF-1) and its major binding protein (IGF-BP3) have recently been implicated in the pathogenesis of several malignancies. However, anthropometric and lifestyle predictors of these hormones have not been elucidated. Here we report the results of a cross-sectional study. SUBJECTS AND METHODS: This cross-sectional study examines the relationship of a series of epidemiologic parameters (age, sex, height, body mass index, smoking, alcohol consumption, and coffee drinking) with IGF-1 and IGF-BP3 in a sample of 130 healthy adults. RESULTS: We observed that serum levels of IGF-1 are higher, whereas levels of IGF-BP3 are lower, in men than in women. In addition, serum levels of IGF-1 are independently and negatively associated with age and positively associated with pack-year history of smoking. Finally, serum levels of IGF-BP3 are independently and negatively associated with the number of cigarettes smoked per day or pack-year history of smoking. CONCLUSION: Age, sex, and smoking are independent predictors of IGF-1 and/or IGF-BP3. The influence of these epidemiologic variables on the pathogenesis of disease states associated with IGF-1 and IGF-BP3 warrants further exploration.

Dietary fat and carbohydrates are independently associated with circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 concentrations in healthy adults.

PURPOSE: To evaluate and quantify the association between consumption of specific food groups/macronutrients and concentrations of serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3). SUBJECTS AND METHODS: Data from a comprehensive food-frequency questionnaire administered to 115 healthy subjects were used to study cross-sectionally the relationship between nutritional factors and circulating IGF-1 and IGFBP-3 concentrations. Adjustment for the effect of total energy intake and a series of epidemiologic parameters (age, sex, height, body mass index, smoking, alcohol consumption, and coffee drinking) was implemented through multivariate linear regression. RESULTS: We observed that serum levels of IGF-1 are positively associated with consumption of red meats, fats, and oils. In addition, serum levels of IGF-1 are independently and positively associated with energy intake from lipids and negatively associated with energy intake from carbohydrates. Finally, serum levels of IGFBP-3 are independently and negatively associated with energy intake from saturated fat. CONCLUSION: Serum IGF-1 and/or IGFBP-3 concentrations are associated with red meat, carbohydrate intake, and fat intake and, thus, may mediate the effect of these dietary factors on the pathogenesis of several disease states. Additional studies are needed to further quantify these associations and elucidate the underlying mechanisms.

Behçet's disease associated with malignancies. Report of two cases and review of the literature.

OBJECTIVE: To investigate the incidence of malignancies in a cohort of Behçet's disease patients and review the world literature. METHODS: Our database of 128 patients was searched and the age standardized rate (ASR) for cancer was calculated. Furthermore, we performed a MEDLINE search from 1970 through 2003, as well as, a search in the proceedings of international conferences for cases of malignancies associated with Behçet's disease. RESULTS: Two of our 128 patients with Behçet's disease were found to have solid tumors. One male had lung cancer and the other female had kidney cancer. The ASR for cancer cases in our population was investigated and it was found to be 1,600 per 100,000 in 10 years. The ASR for cancer cases in Greece according to WHO is 272.51 per 100,000 per year and therefore 2,725 per 100,000 in 10 years. In the world literature 112 cases of malignancies associated with Behçet's disease were found: Sixty five cases were of male patients and 46 of female with 1 case of unknown gender. The solid malignancies associated with Behçet's disease included cases of bladder, breast, uterus, thyroid and stomach cancer, whereas haematological malignancies included leukemia, myelodysplastic syndrome, lymphoma, multiple myeloma, Hodgkin's disease and lymphosarcoma. The treatment administered in these patients with their disease is also reported. CONCLUSION: The age standardized rate of cancer in our population was lower than that of the general population in Greece, although the difference was not statistically significant. However, there is discrepancy in the world literature and the possibility of development of malignancies in Behçet's disease patients should not be ignored.

Adjuvant therapy of breast cancer.

In the past few years the treatment of early stage breast cancer has gone through several important changes. Both chemotherapy and hormonal therapy have been shown by large, randomized trials to offer a survival advantage. The most commonly used chemotherapeutic agents used in the US are doxorubicin and cyclophosphamide (AC). However, 3 studies have suggested that there may be an advantage in the use of taxanes in the adjuvant treatment of breast cancer. Furthermore the use of dose dense chemotherapy, incorporating AC and paclitaxel, has shown very promising results. It is well established that tamoxifen (T), a selective estrogen receptor modulator (SERM), improves overall survival (OS) in women with hormone receptor (HR) positive breast cancer. However, the results from large multicenter, randomized trials, suggest the potential superiority of aromatase inhibitors (AIs), compared to T or an advantage of sequencing T followed by an AI. The role ovarian suppression is still being investigated in patients who have received prior chemotherapy. Newer agents, such as the monoclonal antibody against the her2/neu receptor, trastuzumab, are now being studied as adjuvant therapy in early stage breast cancer. In the next few years, with the completion of several large randomized trials, we will be able to answer several questions, including the optimal way of incorporating AIs into the adjuvant therapy, the long-term sequella of using trastuzumab in the adjuvant treatment of breast cancer and the role of ovarian suppression combined with an AI in premenopausal women with breast cancer.

Effect of birth weight and maternal smoking on cord blood leptin concentrations of full-term and preterm newborns.

Prematurity, maternal smoking, and low birth weight each result in neuroendocrine dysfunction and increased perinatal morbidity and mortality. Leptin, an adipocyte-secreted protein, has provided the first physiological link to the regulatory system controlling starvation-induced neuroendocrine changes in rodents. This study investigated whether leptin concentrations were detectable in cord blood of newborns, and assessed the effect of birth weight, prematurity, and maternal smoking on cord blood leptin concentrations. Fifty consecutively enrolled full-term and 12 preterm newborns born to mothers who smoked during pregnancy were compared to 50 full-term and 12 preterm newborns born to parents who were nonsmokers. RIA for leptin was performed using cord blood samples collected immediately after birth. Leptin concentrations were detectable in newborns and correlated positively with obesity (full-term, r = 0.30, P < 0.01; preterm, r = 0.47, P < 0.05). Maternal smoking during pregnancy was associated with decreased leptin concentrations in the cord blood of both full-term and preterm newborns. This effect was independent of obesity (full-term newborns: 5.25 +/- 2.48 vs. 4.21 +/- 2.71 ng/ml, P = 0.01) and was more pronounced in premature newborns (5.67 +/- 3.6 vs. 2.46 +/- 2.03, P = 0.02), and its magnitude in full-term newborns was directly related to the reported number of cigarettes the mothers of the full-term newborns smoked per day (r = -0.438, P < 0.001). Thus, low birth weight and maternal smoking are both associated with decreased leptin concentrations, and these effects are more pronounced in premature newborns. Future studies will be needed to determine whether administration of leptin might reverse the neuroendocrine dysfunction caused by maternal smoking.

Dietary factors in relation to rheumatoid arthritis: a role for olive oil and cooked vegetables?

BACKGROUND: Although several studies showed that risk of rheumatoid arthritis (RA) is inversely associated with consumption of n-3 fatty acids, the one study showing that olive oil may have a protective role has not yet been confirmed. OBJECTIVE: We examined the relation between dietary factors and risk of RA in persons from southern Greece. DESIGN: We studied 145 RA patients and 188 control subjects who provided information on demographic and socioeconomic variables, prior medical and family history, and present disease status. Subjects responded to an interviewer-administered, validated, food-frequency questionnaire that assessed the consumption of >100 food items. We calculated chi-square statistics for linear trend and odds ratios (ORs) for the development of RA in relation to the consumption of olive oil, fish, vegetables, and a series of food groups classified in quartiles. RESULTS: Risk of developing RA was inversely and significantly associated only with cooked vegetables (OR: 0.39) and olive oil (OR: 0.39) by univariate analysis. A significant trend was observed with increasing olive oil (chi-square: 4.28; P = 0.03) and cooked vegetable (chi-square: 10. 48; P = 0.001) consumption. Multiple logistic regression analysis models confirmed the independent and inverse association between olive oil or cooked vegetable consumption and risk of RA (OR: 0.38 and 0.24, respectively). CONCLUSIONS: Consumption of both cooked vegetables and olive oil was inversely and independently associated with risk of RA in this population. Further research is needed to elucidate the underlying mechanisms of this finding, which may include the antioxidant properties or the high n-9 fatty acid content of the olive oil.

Treatment of Behçet's disease--an update.

OBJECTIVES: To report the experience of the investigators and review the major treatment trials conducted for Behçet's disease (BD). METHODS: A MEDLINE literature review from 1970 to date was performed on the drugs prescribed for the treatment of BD. Open and controlled clinical studies and indications for the treatment of affected organs are analyzed. RESULTS: Glucocorticoids are indicated for the treatment of BD, although no controlled studies have been reported. The combination of corticosteroids and immunosuppressant drugs is used when vital organs are involved. Nonsteroidal anti-inflammatory drugs are of little value in arthritis. In controlled trials, colchicine was efficacious for erythema nodosum and arthritis, particularly in women. Cyclosporine A has a rapid action and when combined with azathioprine is effective in patients with severe uveitis and extraocular manifestations. Chlorambucil is indicated for uveitis and meningoencephalitis. In controlled studies, azathioprine prevented unilateral uveitis from becoming bilateral and improved extraocular symptoms. Pulse cyclophosphamide combined with corticosteroids improves severe systemic vasculitis. Interferon alpha benefits ocular and extraocular manifestations, but controlled studies are lacking. Methotrexate is indicated for uveitis and arthritis, and sulfasalazine improves gastrointestinal vasculitis. In controlled trials, thalidomide was effective for mucocutaneous manifestations, but on its discontinuation the disease exacerbated. Orogenital manifestations are treated with local application of corticosteroids or other medications. CONCLUSIONS: Combination therapy is not always efficacious in controlling inflammation. The goal of management is to treat early to avoid recurrences and irreversible damage to the vital organs. With proper management of BD, loss of useful vision was reduced from 75% to 20% of the affected eyes. However, less favorable results are seen for central nervous system and large artery and vein involvement.

Behçet's Disease.

OBJECTIVES: To review the new data on the epidemiology, etiopathogenesis, clinicolaboratory spectrum, prognosis, and treatments of Behçet's disease (BD). METHODS: The information concerning the etiopathogenesis of the disease is divided into infection, immune, and genetic factors. The clinical features of the disease are discussed according to the organ or system involved. Treatment is described as general, local, and systemic. RESULTS: BD is a multisystem vasculitis with recurrent symptoms. It affects mainly people living around the Mediterranean basin and in Japan. The mean age at onset is the third decade. Children are rarely affected, and few neonatal cases have been reported. In large series of patients, men predominate over women. Infectious agents, immune mechanisms, and genetic factors are implicated in the etiopathogenesis of the disease, which remains to be elucidated. The pathology of the lesions consists of widespread vasculitis. Eyes, skin, joints, the oral cavity, blood vessels, and central nervous system are usually involved, although less frequently the heart, lung, kidney, genital system, and gastrointestinal tract may be affected. The prognosis of the disease has been improved because of early diagnosis and suitable treatment. Local remedies and systemic administration of colchicine, corticosteroids, immunosuppressives, and other agents have been applied. CONCLUSION: BD is a widespread vasculitis affecting young people and involving concurrently or consecutively nearly all organs and systems. Treatment results in better prognosis even when vital organs are involved.

Renal involvement in Adamantiades-Behçet's disease. Case report and review of the literature.

A patient with Adamantiades-Behçet's disease with renal involvement is reported. This patient fulfilled the International Study Group criteria for the disease. Kidney biopsy was performed and proliferative glomerulonephritis with deposition of IgA and IgM immunoglobulins were demonstrated. Review of the literature demonstrates that renal involvement in this disease is not so rare as it was believed. Crescent formation and IgA nephropathy are infrequently observed. Treatment of renal involvement may require immunosuppressive drugs.

Clinical features of juvenile Adamantiades-Behçet's disease in Greece.

Adamantiades-Behçet's disease (A-BD) is a chronic relapsing vasculitis of unknown etiology. This disease is relatively rare in children and only recently have series of patients been reported. The objective of this study was to describe the clinical features of the disease in juvenile patients, and to compare them with adult cases and with those juveniles reported in the literature.

Assessment of physician responses to abnormal results of bone densitometry studies.

OBJECTIVE: To assess how physicians who have ordered bone densitometry studies respond to abnormal results. METHODS: We conducted a retrospective review of cases from physicians affiliated with a community teaching hospital. The study sample consisted of 142 female patients with abnormal bone mineral density (BMD) who had been referred by 50 physicians (internists or gynecologists). A questionnaire was completed for each patient, providing data about further investigations, treatment interventions, and frequency of referral to a specialist in bone diseases. RESULTS: Of the patients diagnosed with osteoporosis on the basis of BMD studies, 20.4% had no further investigations, and 27.8% underwent only mammography. Of all the patients with osteoporosis, 10.6% received no therapy (calcium and vitamin D excluded). The majority of all patients (71.8%) received a combination of calcium and vitamin D. The most common treatment modality was hormone replacement therapy. The second most common treatment strategy was bisphosphonates. The percentage of all referrals to specialists in metabolic bone diseases was low--11.3% in the patients of internists and 14.5% in the patients of gynecologists. CONCLUSION: In this study, the information provided by bone densitometry did not affect management in a substantial percentage of patients. A considerable percentage of patients underwent no further investigations to rule out secondary causes of osteoporosis.

Recurrent epididymo-orchitis in patients with Behçet's disease.

PURPOSE: We study the clinical features of epididymo-orchitis in patients with Behçet's disease. MATERIALS AND METHODS: Of 57 men with Behçet's disease 7 had epididymo-orchitis during the course of disease. A questionnaire was applied to all cases and the clinical features were recorded. HLA class 1 was determined and a pathergy test was performed. RESULTS: All 7 patients fulfilled the international study group criteria for Behçet's disease. All patients had recurrent oral ulcers, skin lesions (folliculitis, erythema nodosum-like lesions) and uveitis, and 6 had recurrent genital ulcers, 2 arthritis, 1 vasculitis and 4 central nervous system involvement. The pathergy test was positive in 4 patients and all had B5(51). The allele B5101 was present in 6 patients and 1 had B5102. Recurrences were observed in 5 patients. Concurrent symptoms with epididymo-orchitis consisted of oral ulcers, fever, uveitis, arthritis and penile ulcer. Colchicine, glucocorticoids, nonsteroidal anti-inflammatory drugs and cyclosporine were administered. CONCLUSIONS: Epididymo-orchitis in patients with Behçet's disease is not as infrequent as believed. It was not the first manifestation of the disease but developed during followup. In any patient with epididymo-orchitis Behçet's disease should be considered, particularly in regions with a high prevalence of the disease.

Circulating insulin concentrations, smoking, and alcohol intake are important independent predictors of leptin in young healthy men.

OBJECTIVE: Leptin, an adipocyte-secreted hormone, has been shown to signal the status of energy stores to the brain, regulate energy homeostasis, and mediate the neuroendocrine response to food deprivation. Obesity is associated with increased leptin levels, and several hormones, including insulin and glucocorticoids, have been associated with leptin levels and expression in rodents. Although obesity has been strongly associated with increased leptin in humans, a significant percentage of leptin's variability remains unexplained. The role of endogenous hormones, demographic factors, or certain life-style factors in explaining the residual variability of leptin levels has not yet been clarified. We performed this cross-sectional study to document the relative importance of obesity, lifestyle factor, and endogenous hormones in determining serum leptin levels. RESEARCH METHODS AND PROCEDURES: We measured serum concentrations of insulin, cortisol, testosterone, growth hormone, and dehydroepiandrosterone sulfate; ascertained anthropometric, demographic, and lifestyle characteristics; and studied these variables in relationship to serum leptin concentrations in a sample of young healthy men. RESULTS: Obesity and alcohol intake were independently and positively associated with circulating leptin concentrations. Additionally, cigarette smoking was negatively and independently associated with leptin concentrations. Finally, serum insulin concentration was an independent hormonal determinant of circulating leptin concentrations, whereas serum testosterone was negatively associated with leptin only by bivariate analysis. DISCUSSION: We conclude that, in addition to obesity, cigarette smoking, alcohol intake, and serum insulin levels are associated with leptin levels in a population of healthy young men.