Revised contraindications for the use of non-medical WB-electromyostimulation. Evidence-based German consensus recommendations.

Whole-body electromyostimulation has proven to be a highly effective alternative to conventional resistance-type exercise training. However, due to adverse effects in the past, very extensive contraindications have been put in place for the commercial, non-medical WB-EMS market. Considering recent positive innovations e.g., federal regulation, mandatory trainer education, revised guidelines, and new scientific studies on WB-EMS application, we believe that a careful revision of the very restrictive contraindications on WB-EMS is needed. This applies all the more because many cohorts with limited options for conventional exercise have so far been excluded. During a first meeting of an evidence-based consensus process, stakeholders from various backgrounds (e.g., research, education, application) set the priorities for revising the contraindications. We decided to focus on four categories of absolute contraindications: "Arteriosclerosis, arterial circulation disorders", "Diabetes mellitus" (DM), "Tumor and cancer" (TC), "Neurologic diseases, neuronal disorders, epilepsy". Based on scientific studies, quality criteria, safety aspects and benefit/risk assessment of the category, DM and TC were moved to the relative contraindication catalogue, while arteriosclerosis/arterial circulation disorders and neurologic diseases/neuronal disorders/epilepsy were still considered as absolute contraindications. While missing evidence suggests maintaining the status of neurologic diseases/neuronal disorders as an absolute contraindication, the risk/benefit-ratio does not support the application of WB-EMS in people with arteriosclerosis/arterial circulation diseases. Despite these very cautious modifications, countries with less restrictive structures for non-medical WB-EMS should consider our approach critically before implementing the present revisions. Considering further the largely increased amount of WB-EMS trials we advice regular updates of the present contraindication list.

The role of genes co-amplified with nicastrin in breast invasive carcinoma.

Breast cancer accounts for more than 450,000 deaths per year worldwide. Discovery of novel therapeutic targets that will allow patient-tailored treatment of this disease is an emerging area of scientific interest. Recently, nicastrin has been identified as one such therapeutic target. Its overexpression is indicative of worse overall survival in the estrogen-receptor-negative patient population. In this paper, we analyze data from a large invasive breast carcinoma study and confirm nicastrin amplification. In search for genes that are co-amplified with nicastrin, we identify a potential novel breast cancer-related amplicon located on chromosome 1. Furthermore, we search for "influential interactors," i.e., genes that interact with a statistically significantly high number of genes which are co-amplified with nicastrin, and confirm their involvement in this female neoplasm. Among the influential interactors, we find genes which belong to the core diseasome (a recently identified therapeutically relevant set of genes which is known to drive disease formation) and propose that they might be important for breast cancer onset, and serve as its novel therapeutic targets. Finally, we identify a pathway that may play a role in nicastrin's amplification process and we experimentally confirm downstream signaling mechanism of nicastrin in breast cancer cells.

SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1.

BACKGROUND: We have previously identified kinase suppressor of ras-1 (KSR1) as a potential regulatory gene in breast cancer. KSR1, originally described as a novel protein kinase, has a role in activation of mitogen-activated protein kinases. Emerging evidence has shown that KSR1 may have dual functions as an active kinase as well as a scaffold facilitating multiprotein complex assembly. Although efforts have been made to study the role of KSR1 in certain tumour types, its involvement in breast cancer remains unknown. METHODS: A quantitative mass spectrometry analysis using stable isotope labelling of amino acids in cell culture (SILAC) was implemented to identify KSR1-regulated phosphoproteins in breast cancer. In vitro luciferase assays, co-immunoprecipitation as well as western blotting experiments were performed to further study the function of KSR1 in breast cancer. RESULTS: Of significance, proteomic analysis reveals that KSR1 overexpression decreases deleted in breast cancer-1 (DBC1) phosphorylation. Furthermore, we show that KSR1 decreases the transcriptional activity of p53 by reducing the phosphorylation of DBC1, which leads to a reduced interaction of DBC1 with sirtuin-1 (SIRT1); this in turn enables SIRT1 to deacetylate p53. CONCLUSION: Our findings integrate KSR1 into a network involving DBC1 and SIRT1, which results in the regulation of p53 acetylation and its transcriptional activity.

Claudin-1 as a promoter of EMT in hepatocellular carcinoma.

Claudins are integral structural and functional components of apical cell adhesions (tight junctions). Loss of such adhesions has been associated with malignant transformation, a process most often accompanied by a concomitant loss of claudin expression. A growing body of evidence reveals the highly contextual upregulation of claudin expression in certain cancer types, and moreover their relevance in promoting cancer cell invasion and metastatic progression. In this issue of Oncogene, Suh et al. reported on claudin-1 expression in hepatocellular carcinoma (HCC), including its role as a promoter of the epithelial-to-mesenchymal transition via the c-Abl/Raf/Ras/ERK signaling pathway. Considering the limited therapeutic options in HCC, evaluation of its role as a target merits further investigation.

LMTK3 is implicated in endocrine resistance via multiple signaling pathways.

Resistance to endocrine therapy in breast cancer is common. With the aim of discovering new molecular targets for breast cancer therapy, we have recently identified LMTK3 as a regulator of the estrogen receptor-alpha (ERα) and wished to understand its role in endocrine resistance. We find that inhibition of LMTK3 in a xenograft tamoxifen (Tam)-resistant (BT474) breast cancer mouse model results in re-sensitization to Tam as demonstrated by a reduction in tumor volume. A whole genome microarray analysis, using a BT474 cell line, reveals genes significantly modulated (positively or negatively) after LMTK3 silencing, including some that are known to be implicated in Tam resistance, notably c-MYC, HSPB8 and SIAH2. We show that LMTK3 is able to increase the levels of HSPB8 at a transcriptional and translational level thereby protecting MCF7 cells from Tam-induced cell death, by reducing autophagy. Finally, high LMTK3 levels at baseline in tumors are predictive for endocrine resistance; therapy does not lead to alteration in levels, whereas in patient's plasma samples, acquired LMTK3 gene amplification (copy number variation) was associated with relapse while receiving Tam. In aggregate, these data support a role for LMTK3 in both innate (intrinsic) and acquired (adaptive) endocrine resistance in breast cancer.

Somatostatin-producing duodenal carcinoma: clinicopathological description of a case.

Somatostatinomas are rare functioning neoplasms usually arising in the pancreas and duodenum. They are seldom associated with typical clinical symptoms. Their diagnosis is confirmed only by histological and immunohistochemical studies and the presence of specific hormones. Two distinct clinicopathological forms of somatostatinoma exist: duodenal and pancreatic somatostatinomas. Clinically, compared to pancreatic somatostatinomas, duodenal somatostatinomas are more often associated with nonspecific symptoms and neurofibromatosis, but less often with somatostatinoma syndrome or metastasis. We report a case of somatostatin-producing duodenal carcinoma in a 45-year-old female with neither neurofibromatosis nor somatostatinoma syndrome. Abdominal computed tomography showed a 18 mm mass in the duodenum which had given rise to multiple lymph node metastases. Although the endoscopic biopsies were free of malignancy, the patient subsequently underwent Whipple's operation for the duodenal mass. Immunohistochemical analysis confirmed the diagnosis of somatostatin-producing carcinoma.

[Influence of lymphocitic thyroiditis on prognostic outcome differentiated thyroid carcinoma].

BACKGROUND/AIM: Thyroid carcinoma is rare malignant tumors. They are typically presented with slow progression and clinical course. Lymphocytic infiltration, including fagocytosis of neoplastic cells by macrophage plays an important role in preventing development of distant metastases. This paper sets the following objectives: Establish whether presence or absence of Hashimoto thyroiditis in differentiated thyroid carcinoma (DTC) is a favourable prognostic factor. METHODS: The group under examination here are all newly diagnosed patients with differentiated thyroid carcinoma surgically treated at the Surgery Clinic in Podgorica from 2003. to 2010. A total of 125 patients, aged 11 to 79, were included in this research. The patients were divided in two groups, those with and those without lymphocytic infiltration. Both groups were mutually compared for their prognostic factors. For the identification of T and B lymphocytes, anti-CD 3 and anti-CD 20 antibodies were used. Student t-test was used for comparison of clinical and pathological parameters among groups, Hi square test for comparison of frequency, and Coxs regression model for time dependant variables as frequency of recurrence among groups with various stages of disease. Survival curve (Kaplan-Meier) is used for comparison of time dependant variables (survival, recurrence, death). The follow-up time ranges from 10 to 70 months in both groups of patients. RESULTS ARE AS FOLLOWS: presence of lymphocytic infiltration in thyroid tissue in patients with differentiated thyroid carcinoma is significant prognostic factor (P < 0.0001). But, absence of lymphocytic infiltration is a poor prognostic factor in patients with invasive extra thyroid tumours (P < 0.0001). Also, absence of lymphocytic infiltration is a poor prognostic factor for development of lymphogenic and hematogenic metastases. The presence of T or B lymphocytes and varying degree of their presence is not a significant prognostic factor (P < 0.0046). Patients without lymphocytic infiltration are significantly more numerous in the fourth stage of disease (P < 0.0001). There is no statistically significant difference in terms of the presence of T or B lymphocytes in the tissue. Chronic lymphocytic thyroidis hahshimoto is a favourable prognostic factor in our examined group (P < 0.0001). Local invasiveness and extrathyroid expansion is significantly smaller in the group of patients with the presence of lymphocytic infiltration (P < 0.0001). By means of univariate analysis, we found that factors with a significant impact on survival rate include age (P < 0.0001), size of tumour (P < 0.018), extrathyroid invasiveness (P < 0.0001), hematogenic metastases (P < 0.049). Lymphocytic infiltration is present in 81% of patients in their thyroid gland, and in 19% patients there are no lymphocytes in tissue. Limphocitic infiltration has a favourable influence on tumor variables. CONCLUSION. This research has shown that lymphocytes in tissue as part of Hashimoto thzroiditis have an effect on certain prognostic factors of differentiated thyroid carcinoma as size, smaller invasiveness and extrathyroid tumour growth and incidence of hematogenic metastases.

Inhibition of gamma-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells.

Gamma-secretase activity is vital for the transmembrane cleavage of Notch receptors and the subsequent migration of their intracellular domains to the nucleus. Notch overexpression has been associated with breast, colon, cervical and prostate cancers. We tested the effect of three different gamma-secretase inhibitors (GSIs) in breast cancer cells. One inhibitor (GSI1) was lethal to breast cancer cell lines at concentrations of 2 muM and above but had a minimal effect on the non-malignant breast lines. GSI1 was also cytotoxic for a wide variety of cancer cell lines in the NCI60 cell screen. GSI1 treatment resulted in a marked decrease in gamma-secretase activity and downregulation of the Notch signalling pathway with no effects on expression of the gamma-secretase components or ligands. Flow cytometric and western blot analyses indicated that GSI1 induces a G2/M arrest leading to apoptosis, through downregulation of Bcl-2, Bax and Bcl-XL. GSI1 also inhibited proteasome activity. Thus, the gamma-secretase inhibitor GSI1 has a complex mode of action to inhibit breast cancer cell survival and may represent a novel therapy in breast cancer.

Sensitivity, specificity, positive and negative predictive value of serum S-100 beta protein in patients with malignant melanoma.

PURPOSE: To establish the sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of serum S-100 beta protein (sSB) in patients with malignant melanoma (MM), based on its concentration in the peripheral blood and the likelihood ratio (LR) for the whole group of patients with MM, as well as for each separate clinical stage. PATIENTS AND METHODS: sSB was determined immunoluminometrically in 172 patients with histologically confirmed MM. Sera from 64 healthy subjects were used as controls. RESULTS: Increased values of sSB were detected in 65 out of 172 patients with MM, and in 5 cases among healthy subjects. Sensitivity, specificity, PPV and NPV were 38%, 92%, 93% and 35%, respectively. In stage I 1/29 patients had increased values of sSB, in stage II 3/34, in stage III 13/47 and in stage IV 48/62 patients. Sensitivity, specificity, PPV and NPV for stage I were 3%, 92%, 17% and 68%, respectively/ for stage II 9%, 92%, 37% and 65%, respectively; for stage III 28%, 92%, 72% and 63%, respectively; and for stage IV 77%, 92%, 91%, and 81%, respectively. The LR for sSB values of >13 mug/l was 5 for the whole group of patients with MM, 0.4 for stage I, 1 for stage II, 3 for stage III and 10 for stage IV. CONCLUSION: Based on our results we conclude that sSB is a reliable serum marker for the diagnosis of stage IV MM.

Epidemiology of breast cancer in the city of Nis, Serbia.

PURPOSE: Over the past 10 years, Serbia has been affected by a heavy economic and political crisis that in 1999 even led to war and bombardment. Numerous facts indicate that the crisis has resulted in low-level health protection, increasing mortality, as well as other deteriorating effects over the general health of the population. The aim of the study was to assess mortality trends in female breast cancer in the city of Nis prior to (1986-1993) and following (1995- 1999) the socio-economic crisis peak. MATERIALS AND METHODS: Population and hospital cancer registry data for the 1986-1999 period were used for analysis, as well as death certificate data for all women who lived and died in the city of Nis in the given period. Survival was calculated according to the Kaplan-Meier method. The rates were calculated per 100,000 inhabitants (1991 census) and were not standardized. RESULTS: A total of 455 women in the city of Nis died of breast cancer during 1986-1999. The polynomial trend in mortality revealed an increasing (1986-1992) and decreasing (1993-1996) tendency, although the first period showed a lower average mortality (28.7) than did the second one (30.45). Survival rates were calculated for the periods 1986- 1993 and 1995-1998. The 12-month survival rate was 84.7% in the first and 92% in the second period; the 24-month survival rate for the first period was 76.6% and 87.9% for the second; the 36-month survival was 67.7% in the first and 80.5% in the second period; the 4-year survival rate for 1986-1993 was 64.1% and 78.1% for 1995-1999. CONCLUSION: The socio-economic and political crisis has proved to affect breast cancer patients in Serbia. Overall, the mortality rate increased. Calculated upon division of the whole period into two, mortality shows an upward trend in the first period (1986-1992) and a downward trend in the second. Although 1993-1999 was more difficult for the Serbian and Yugoslavian population (manifested in the therapy of all diseases, including breast cancer), the diagnosis of breast cancer improved and the disease was detected at earlier stages, the result of which were better survival rates in the 1986-1992 period.

[Characteristics of thyroid carcinoma in Grave's disease Hashimoto's thyroiditis and nodular goiter]. / Karakteristike karcinoma stitaste zlijezde u Graves-ovoj bolesti, Hasimotovom tiroiditisu i polinodoznoj strumi.

The biology of thyroid cancer represents a spectrum of behavior ranging from well-differentiated lesions with an excellent prognosis to anaplastic carcinoma, which is almost fatal. For this reason, it is important that clinicians have methods at their disposal to asses the characteristics of patient's thyroid malignancy. In this work we discuss the behavior of differentiated thyroid cancer in associated diseases of thyroid as: Graves' disease, chronic lymphocytic thyroiditis--Hashimoto and nodular goiter. This is retrospectively reviewing of 50 patients treated for differentiated thyroid carcinoma at Department of surgery, Clinical Centre of Montenegro in Podgorica from 1998 until 2003. We evaluated occurrence, as well as the role of this diseases in patients with thyroid cancer. We found a more favorable course of thyroid cancer in the presence of chronic lymphocytic thyroiditis and nodular goiter, a contrary Graves' disease. In associated diseases of thyroid, a significantly greater proportion of patients with thyroid cancer, have modular goiter.

Symptomatic physiologic hydronephrosis in pregnancy: incidence, complications and treatment.

OBJECTIVE: We present the incidence and results of treatment of symptomatic physiologic hydronephrosis in 3,400 pregnant women. METHODS: We analyzed 103 consecutive women who presented with clinical signs and symptoms related to the upper urinary system. Renal sonography, urinalysis, serum creatinine levels, white blood cell (WBC) count, and urine culture were done in all patients at first visit and repeated at least once a month until 1 month after delivery. In patients who manifested acute pyelonephritis, urinalysis, WBC count, erythrocyte sedimentation rate and C-reactive protein levels were repeated every 3 days until normalization, and urine culture as well as renal sonography were performed once a week until 1 month after delivery. Conservative measures (positioning, analgesia, antibiotics) were performed in all patients with symptomatic physiologic hydronephrosis. If the patient's condition was refractory to medical management, drainage of the ureter with a double pigtail stent was performed. RESULTS: Conservative measures were successful in 97 (94%) of 103 patients but 6 (6%) patients had ongoing signs and symptoms of acute pyelonephritis progressing to urosepsis. In all of them, antibiotics were continued and a double pigtail stent was placed resulting in fast regression of symptoms, curing of renal infection and progress of the pregnancies to the term with vaginal delivery. CONCLUSIONS: Symptomatic hydronephrosis in pregnancy can be treated conservatively. If the patient's condition is refractory to medical management, an internal drainage with double pigtail stent may be necessary.