CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations.

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

A polymorphism in the G protein beta3-subunit gene is associated with bone metastasis risk in breast cancer patients.

Breast cancer is the most frequently diagnosed cancer among women in western countries and bone metastases of breast cancer cause significant morbidity. G proteins are important components of a multitude of transmembrane receptors and are involved in the regulation of intracellular signaling pathways such as parathormone receptors 1 and 2 (PTH1 and 2), extracellular calcium-sensing receptor, the calcitonin receptor and the OPG/RANKL-system. A common polymorphism in the gene encoding the G protein beta3-subunit, GNB3 825C > T, has been linked to increased G protein activation. To analyse the role of this polymorphism in bone metastasis of breast cancer, we determined GNB3 825C > T genotypes in 500 female breast cancer patients. According to breast cancer staging, patients were divided in three groups, representing patients without metastases (n = 250), those with metastases other than bone (n = 117), and those with bone metastasis (n = 133). Frequency of the GNB3 825 TT genotype was significantly lower among patients with bone metastases (3.1%) than among those with other metastases (12.8%; P = 0.004) or no metastases (13.3%; P < 0.001). In a Cox regression analysis, relative risk of the GNB3 TT genotype for bone metastasis was 0.22 (95% CI 0.08-0.61; P = 0.004) for bone metastasis. We conclude that the homozygous GNB3 825 TT genotype may be protective against development of bone metastasis in breast cancer patients. The precise mechanism for this remains to be determined, but could be due to a direct involvement of G protein-coupled receptors in bone metabolism.

The use of confocal laser-scanning microscopy in microsurgery for invasive squamous cell carcinoma.

BACKGROUND: Ex-vivo confocal laser-scanning microscopy offers rapid imaging of excised tissue specimens without conventional histotechnical procedures. As vertical sections are prepared, morphological features can be assessed according to standard criteria used in conventional histopathology. OBJECTIVES: To validate the diagnostic confocal examination of squamous cell carcinoma (SCC) in microscopy-guided surgery. METHODS: Four independent observers received standardized instructions about diagnostic confocal microscopy features of SCC. Subsequently, 120 confocal images of fresh excisions from SCC or normal skin, imaged using a commercially available, near-infrared, reflectance confocal laser-scanning microscope, were evaluated by each observer. RESULTS: General morphology, such as location, size and shape of the cancer area could be visualized by the imaging system. Furthermore, densely packed and irregularly organized nuclei and nuclear atypia could be delineated. Overall, a sensitivity of 95% and a specificity of 96.25% were achieved by the four observers (positive predictive value 96.25%, negative predictive value 95.23%). CONCLUSIONS: This study provides a set of well-described morphological criteria with obvious diagnostic impact which should be used in further investigations. In the future, confocal laser-scanning microscopy may guide microsurgery of any skin cancer.

Immunohistochemical analysis of desmoid tumours.

BACKGROUND/AIMS: Although the standard treatment for desmoid tumours is complete surgical resection with wide margins, the optimal adjuvant treatment for recurrent or inoperable disease is unclear, often being based on sporadic immunohistochemical reports with a low number of cases. Therefore, a large immunohistochemical study was performed, to provide a theoretical basis for adjuvant treatment regimens. METHODS: One hundred and sixteen tissue samples from 80 patients (49 female, 31 male; mean age, 34 years; range, 0-83) with desmoid tumours (46 extra-abdominal, 21 abdominal, 13 intra-abdominal) were tested for oestrogen receptors alpha and beta, progesterone and androgen receptors, and somatostatin, in addition to HER2, cathepsin D, Ki-67, and c-KIT by immunohistochemistry. RESULTS: All samples were negative for oestrogen receptor alpha, HER2, and the progesterone receptor. Positive staining for the androgen receptor was found in six extra-abdominal cases. Staining for oestrogen receptor beta was positive in four extra-abdominal, two abdominal, and one intra-abdominal case. Staining for somatostatin was positive in six extra-abdominal, two abdominal, and one intra-abdominal case, and staining for cathepsin D was positive in all cases. Positive staining for Ki-67 was found in 14 extra-abdominal, three abdominal, and three intra-abdominal cases. C-KIT was detectable in one abdominal case only. CONCLUSIONS: The data from this immunohistochemical study show that the published effects of antioestrogens and imatinib mesylate in the treatment of aggressive fibromatoses may not be attributable to oestrogen receptor alpha or c-KIT expression.

Low-fat, high-carbohydrate (low-glycaemic index) diet induces weight loss and preserves lean body mass in obese healthy subjects: results of a 24-week study.

BACKGROUND: The traditional treatment for obesity which is based on a reduced caloric diet has only been partially successful. Contributing factors are not only a poor long-term dietary adherence but also a significant loss of lean body mass and subsequent reduction in energy expenditure. Both low-fat, high-carbohydrate diets and diets using low-glycaemic index (GI) foods are capable of inducing modest weight loss without specific caloric restriction. The purpose of this study was to investigate the feasibility and medium-term effect of a low-fat diet with high (low GI) carbohydrates on weight loss, body composition changes and dietary compliance. METHODS: Obese patients were recruited from two obesity outpatient clinics. Subjects were given advise by a dietician, then they attended biweekly for 1-hour group meetings. Bodyweight and body composition were measured at baseline and after 24 weeks. RESULTS: One hundred and nine (91%) patients completed the study; after 24 weeks the average weight loss was 8.9 kg (98.6 vs. 89.7 kg; p < or = 0.0001). There was a significant 15% decrease in fat mass (42.5 vs. 36.4 kg; p < or = 0.0001) and a decrease in lean body mass of 5% (56.1 vs. 53.3 kg; p < or = 0.0001). DISCUSSION: In this 6-month study, a low-fat, low-GI diet led to a significant reduction of fat mass; adherence to the diet was very good. Our results suggest that such a diet is feasible and should be evaluated in randomized controlled trials.

Diminished response to activated protein C is not correlated with severity of peripheral arterial occlusive disease.

INTRODUCTION: Poor response to activated Protein C (APC) is a well established risk factor for venous thromboembolism. More recently, the hypercoagulable state which results from diminished response to APC has also been associated with arterial thrombosis. Some studies showed a clear association between low response to APC with advanced arterial disease, others, however, failed to support these data. Thus, there is ongoing dispute about the impact of a hypercoagulable state upon progression of atherosclerosis. MATERIAL AND METHODS: We investigated APC ratios and the existence of Factor V Leiden in 800 patients with documented peripheral arterial occlusive disease (PAD). Clinical symptoms according to Fontaine stages II (intermittent claudication), III (rest pain) and IV (gangrene) and the ankle/brachial index served as parameters for the severity of PAD. RESULTS: There was no association between low response to APC or existence of Factor V Leiden and the clinical stage of PAD or ankle/ brachial index. CONCLUSION: Our data suggest that poor response to APC is not correlated with the severity of peripheral arterial occlusive disease.

Pathology results in [18F]fluorodeoxyglucose positron emission tomography of the thyroid gland.

The aim of this retrospective study was to evaluate pathologically increased uptake of [18F]fluorodeoxyglucose (18F-FDG) in positron emission tomography (PET) results of the thyroid gland. Results of 18F-FDG PET and [99mTc]pertechnetate scintigraphy of the thyroid gland are shown, compared to each other and discussed. In a retrospective study 16 patients underwent whole-body 18F-FDG PET and [99mTc]pertechnetate scintigraphy of the thyroid gland within 3 weeks. In addition, an examination of the thyroid gland by using ultrasound and laboratory tests was carried out. The 18F-FDG PET studies were carried out on a dedicated whole-ring PET scanner. Eight patients had a pathological FDG uptake in the thyroid and a cold nodule in [99mTc]pertechnetate scintigraphy of the thyroid gland (in 7/8 cases histology showed malignancy). Five patients had an inhomogeneous FDG uptake in the thyroid gland and were suspected of thyroiditis in 18F-FDG PET (in 3/5 cases thyroiditis was confirmed). Three patients had an especially low FDG uptake compared to normal physiological FDG uptake (no malignancy). Results from studies using 18F-FDG represent a growing body of evidence showing the differentiation between malignant and benign disease: we saw many pathological results in the thyroid gland. High uptake of 18F-FDG in the thyroid gland suggests possible malignancy. Thyroiditis can only be suspected based upon the results of 18F-FDG PET. We conclude that 18F-FDG PET has a potential clinical impact for detecting possible malignant lesions of the thyroid gland, but further studies, in which a higher number of patients are evaluated, are necessary.

Diagnosis of a contralateral second testicular carcinoma by F18-FDG PET.

BACKGROUND: In testicular carcinoma the early diagnosis is very important because with an early therapy there are good chances for long-term survival (50-90%). Metastases of a testicular carcinoma are at first lymphogenous, hematogenous only in late stages. CASE REPORT: This is a case report about a 28-year-old man, whose testicular carcinoma (left testis) had already been operated on (unripe teratoma with parts of an embryonic carcinoma, an endodermal sinus tumor and a chorion carcinoma). Because of the elevated tumor marker AFP an FDG PET (F18-fluorodeoxyglucose positron emission tomography) investigation was made. CT (covering thorax, abdomen and pelvis) and ultrasound of the testis showed no pathological results. In the FDG PET a significant pathological FDG uptake in the right testis was found. Histology showed an unripe teratoma with parts of an embryonic carcinoma, an endodermal sinus tumor, and a chorion carcinoma. It was a second carcinoma of the contralateral testis. CONCLUSION: F18-FDG PET was a sensitive and reliable modality for diagnosis in this patient.

[Renal cell carcinoma metastasis in a microfollicular adenoma of the thyroid gland]. / Nierenzellkarzinom-Metastase in einem mikrofollikulären Adenom der Schilddrüse.

A 60-year-old woman had a nephrectomy of her left kidney because of a renal cell carcinoma. She came to us for an oncologic F-18-fluordeoxyglucose-positron emission tomography (F-18-FDG-PET). In the positron emission tomography there was a pathologic fluordeoxyglucose-uptake in the left thyroid gland lobe. Thyroid investigation and Tc-99 m pertechnetate scintigraphy of the thyroid gland was done. It showed a hyperfunctioning nodule in the left thyroid gland lobe. Surgery was suggested. Histology showed a metastasis of a clear cell renal carcinoma in a microfollicular adenoma of the thyroid gland--a very rare combination.

Seminoma metastases mimicking primary pancreatic cancer.

BACKGROUND: A case of seminoma clinical stage III, arising from the right testis and mimicking a primary pancreatic malignancy is reported. CASE REPORT: A 57-year-old male patient presented with obstructive jaundice. He suffered from recurrent abdominal pain and significant weight loss over the past 4 months. Abdominal CT scan showed a tumor in the head of the pancreas and multiple pathologically enlarged peripancreatic lymph nodes. In the laboratory findings there were signs of cholestasis and infection. A laparoscopic biopsy out of a suspicious lesion of the head of the pancreas and a surrounding lymph node was done. Histopathological examination reported metastasis of seminoma in a lymph node. Further laboratory findings showed an elevation of the human placental alkaline phosphatase (HPLAP) and urological examination revealed a suspect right testis. The patient underwent castration of the right testis and histopathological examination confirmed a seminoma. 4 cycles of chemotherapy including cisplatinum, etoposide and bleomycin led into complete response that is still ongoing. CONCLUSION: This case shows a seminoma with metastases at retroperitoneal site, mimicking a primary pancreatic neoplasm. It provides an example of the possibility of an uncommon clinical appearance of seminoma metastases and again underlines the importance of exact radiological and histopathological examination to distinguish between curable and incurable tumor.