Detection of splenic microabscesses with ultrasound as a marker for extrapulmonary tuberculosis in patients with HIV: A systematic review.

BACKGROUND: In 2015, 1.2 million new cases of tuberculosis (TB) were diagnosed in patients with HIV. Diagnostic limitations and resource shortages in endemic areas can delay diagnosis and treatment, particularly with extrapulmonary TB (EPTB). Research suggests that ultrasound can identify splenic microabscesses caused by EPTB, but data are limited on the frequency of this finding in patients with culture-proven EPTB. OBJECTIVES: To estimate the frequency of splenic EPTB microabscesses detected with ultrasound in patients with HIV and TB co-infection. METHODS: Studies published in six major databases as of November 2017 were systematically reviewed based on the PRISMA guidelines. Cohen's kappa test was used to determine inter-rater agreement. Articles included for data abstraction passed the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) evaluation. Freeman-Tukey transformation was used to calculate weighted proportions. Heterogeneity was evaluated by Forest plot and I2 calculation. RESULTS: After abstract screening, article review and QUADAS-2 evaluation, five studies were selected for data extraction. A total of 774 patients in these studies were infected with HIV. Splenic lesions were seen with ultrasound in 21.0% of patients with HIV (95% confidence interval (CI) 10.6 - 33.8). TB diagnosed by culture, biopsy, smear, or molecular methods was found to be the cause of 88.3% (95% CI 72.3 - 97.9) of splenic microabscesses seen on ultrasound in patients with HIV. CONCLUSIONS: Ultrasound evaluation of the spleen in patients with HIV and symptoms suggestive of TB in endemic regions is a viable diagnostic adjunct. Ultrasound detection of splenic microabscesses in HIV patients is probably sufficient indication to initiate TB treatment prior to obtaining culture data. Strong conclusions cannot be drawn owing to the high heterogeneity of this small number of studies.

Detection of splenic microabscesses with ultrasound as a marker for extrapulmonary tuberculosis in patients with HIV: a systematic review

Background. In 2015, 1.2 million new cases of tuberculosis (TB) were diagnosed in patients with HIV. Diagnostic limitations and resource shortages in endemic areas can delay diagnosis and treatment, particularly with extrapulmonary TB (EPTB). Research suggests that ultrasound can identify splenic microabscesses caused by EPTB, but data are limited on the frequency of this finding in patients with culture-proven EPTB. Objectives. To estimate the frequency of splenic EPTB microabscesses detected with ultrasound in patients with HIV and TB co-infection. Methods. Studies published in six major databases as of November 2017 were systematically reviewed based on the PRISMA guidelines. Cohen's kappa test was used to determine inter-rater agreement. Articles included for data abstraction passed the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) evaluation. Freeman-Tukey transformation was used to calculate weighted proportions. Heterogeneity was evaluated by Forest plot and I2 calculation. Results. After abstract screening, article review and QUADAS-2 evaluation, five studies were selected for data extraction. A total of 774 patients in these studies were infected with HIV. Splenic lesions were seen with ultrasound in 21.0% of patients with HIV (95% confidence interval (CI) 10.6 - 33.8). TB diagnosed by culture, biopsy, smear, or molecular methods was found to be the cause of 88.3% (95% CI 72.3 - 97.9) of splenic microabscesses seen on ultrasound in patients with HIV. Conclusions. Ultrasound evaluation of the spleen in patients with HIV and symptoms suggestive of TB in endemic regions is a viable diagnostic adjunct. Ultrasound detection of splenic microabscesses in HIV patients is probably sufficient indication to initiate TB treatment prior to obtaining culture data. Strong conclusions cannot be drawn owing to the high heterogeneity of this small number of studies

[Effectively Preventing Eating Disorders with the School-Based Programs "PriMa" and "Torera" for Adolescents in the 6th and 7th Grades]. / Essstörungen wirksam vorbeugen mit den Schulprogrammen "PriMa" und "Torera" für Jugendliche in Klasse 6 und 7.

The aim of this study was to assess the effects of 2 German school-based primary prevention programmes for (pre)adolescents, aged 11-13 years, with 9 manual-guided lessons. 92 (PriMa, n=1,553 girls) and 22 (Torera, n=256 boys, 277 girls) Thuringian secondary schools participated in controlled trials with pre-post assessment. Girls and students at risk showed significant improvements of conspicuous eating behaviour and body self-esteem with small to medium effect sizes. Implementation costs were € 2.50 per student.

c-Met-induced epithelial carcinogenesis is initiated by the serine protease matriptase.

The progression and negative outcome of a variety of human carcinomas are intimately associated with aberrant activity of the c-Met oncogene. The underlying cause of this dysregulation, however, remains a subject of discussion, as the majority of cancer patients do not present with activating mutations in c-Met receptor itself. In this study, we show that the oncogenic protease matriptase is ubiquitously co-expressed with the c-Met in human squamous cell carcinomas and amplifies migratory and proliferative responses of primary epithelial cells to the cognate ligand for c-Met, pro-hepatocyte growth factor/scatter factor (proHGF/SF), through c-Met and Gab1 signaling. Furthermore, the selective genetic ablation of c-Met from matriptase-expressing keratinocytes completely negates the oncogenic potential of matriptase. In addition, matriptase-dependent carcinoma formation could be blocked by the pharmacological inhibition of the Akt-mammalian target of Rapamycin (mTor) pathway. Our data identify matriptase as an initiator of c-Met-Akt-mTor-dependent signaling axis in tumors and reveal mTor activation as an essential component of matriptase/c-Met-induced carcinogenesis. The study provides a specific example of how epithelial transformation can be promoted by epigenetic acquisition of the capacity to convert a widely available paracrine growth factor precursor to its signaling competent state.

Effects of the new selective estrogen receptor modulator LY353381.HCl (Arzoxifene) on human endometrial cancer growth in athymic mice.

PURPOSE: Arzoxifene (Arzox) is a novel benzothiophene analogue with selective estrogen receptor modulator activity similar to raloxifene. Arzox is being developed as a treatment for breast cancer and has a predominantly antiestrogenic effect on the rodent uterus. Our objectives were to verify whether the novel selective estrogen receptor modulator, Arzox, can be a good first-line agent and also be effective at controlling the growth of endometrial cancer after exposure to tamoxifen (Tam). EXPERIMENTAL DESIGN: We compared the effects of Tam and Arzox on the growth of estrogen responsive ECC-1 endometrial cancer cells in vitro, and we determined their antitumor effects on ECC-1 and EnCa101 endometrial carcinoma growth in athymic mice. RESULTS: We observed that estrogen receptor protein expression is down-regulated by Arzox to the same extent as raloxifene, whereas 4-hydroxytamoxifen, the active metabolite of Tam, does not affect estrogen receptor protein levels. Tam and Arzox inhibit the growth of Tam-naïve ECC-1 tumors in athymic mice. However when Tam-stimulated or estrogen-stimulated (which had been treated with Tam previously) EnCa101 endometrial tumors were treated with Tam or Arzox, we observed a stimulatory effect of both compounds in these models. CONCLUSIONS: The results indicate that Arzox may be a good first-line agent, but it may be ineffective at controlling the growth of endometrial cancer after exposure to Tam. Our data suggest that Arzox stimulates endometrial tumor growth to at least the same extent as Tam, thereby suggesting a limited role as a second-line agent for the patient on Tam who develops occult endometrial cancer.

Molecular classification of estrogens.

Estrogens are involved in a multiplicity of programmed events in target tissues e.g.: uterus, breast, and pituitary gland, and hormone-responsive tumors occur at these target sites. We have addressed the possibility that all of the estrogens do not produce the same conformation of estrogen receptor alpha (ER). A novel assay in vitro was used to activate the transforming growth factor alpha (TGF-alpha) gene in situ in MDA-MB-231 cells stably transfected with cDNA for D351 ER or D351G ER. Three estrogen types were used: estradiol, diethylstilbestrol, and a triphenylethylene (TPE) derivative of tamoxifen without the antiestrogenic side chain. Computer molecular modeling was used to interpret data. A flat estrogen such as estradiol or diethylstilbestrol can induce TGF-alpha through a correctly positioned activating function 2 (AF2) and bind SRC-1. The TPE did not activate AF2 but activated the TGF-alpha gene through AF2b. This was demonstrated because D351 but not D351G ER activated the TGF-alpha gene with the TPE. We propose two classes of estrogens with different ER complexes that may incorporate different coactivators to function. Phytoestrogens and environmental xenoestrogens will fall into different classes based on structure and may exhibit selective actions and carcinogenic potential based on different ER conformations.

Analysis of cross-resistance of the selective estrogen receptor modulators arzoxifene (LY353381) and LY117018 in tamoxifen-stimulated breast cancer xenografts.

PURPOSE: Cross-resistance is the primary issue facing the evaluation of new antiestrogens to treat metastatic breast cancer because they may be tested, initially, in populations of patients that have failed long-term adjuvant tamoxifen (Tam) therapy. EXPERIMENTAL DESIGN: We have tested the benzothiophene derivatives, arzoxifene (Arzox; LY353381) and LY117018 in two models of Tam-stimulated tumor growth derived from either MCF-7 (M. M. Gottardis and V. C. Jordan, Cancer Res., 48: 5183-5187, 1988) or T47D (J. MacGregor Schafer et al., Clin. Cancer Res., 6: 4373-4380, 2000) breast cancer cells. RESULTS: Using the MCF-7:Tam model, we found that both Arzox and LY117018 (1.5 mg/day) resulted in tumor growth and, therefore, were partially cross-resistant with Tam. Next, using the T47D:17beta-estradiol (E(2)) model, we compared the antiestrogenic/antitumor properties of Arzox and LY117018 and determined that neither Arzox nor LY117018 caused T47D:E(2) tumor growth after 21 weeks. In addition, we determined that long-term treatment does not result in failure and subsequent development of transplantable Arzox- or LY117018-stimulated tumors. To establish whether Arzox and LY117018 are cross-resistant in T47D:Tam tumors, mice were treated with Arzox or LY117018 (1.5 mg/day), and, again, we found that neither resulted in the growth of transplantable tumors. Lastly, we showed that Arzox and LY117018 were only partially able to compete with postmenopausal E(2) (0.3 cm silastic capsule) in T47D:Tam tumors. However, when T47D:E(2) tumors were treated for 7 days instead of 5 days, both Arzox and LY117018 were more effective. CONCLUSIONS: Arzox is not cross-resistant with Tam in the T47D athymic mouse model but does exhibit cross-resistance in the MCF-7 model.

Rapid development of tamoxifen-stimulated mutant p53 breast tumors (T47D) in athymic mice.

MCF-7 cells are used routinely to study tamoxifen-stimulated drug resistance in vivo. However, unlike MCF-7 cells, T47D cells express mutant p53 protein and lose the estrogen receptor (ER) during long-term estrogen deprivation in vitro [Pink et al., Br. J. Cancer, 74: 1227-1236, 1996 (erratum, Br. J. Cancer, 75: 1557, 1997)]. As a result, T47D tumors may respond differently from MCF-7 tumors to long-term tamoxifen treatment. Ovariectomized athymic mice were given injections bilaterally with T47D cells (5 x 10(5)) into the mammary fat pads. A rapidly growing estradiol responsive tumor (T47D:E2) was established and 0.5 mg of tamoxifen given daily blocked estrogen-stimulated growth. In subsequent experiments, low doses of tamoxifen (0.17 mg or 0.5 mg) did not produce tamoxifen-stimulated tumors at 14 weeks, whereas high-dose tamoxifen (1.5 mg) consistently produced tamoxifen-stimulated tumors (T47D:Tam; 17 tumors/20 sites) at 8 weeks. In contrast, 1.5 mg of tamoxifen produced tamoxifen-stimulated MCF-7 tumors (MCF-7: Tam2) at a slower rate (20 weeks) and less consistently (14 tumors/26 sites). When the T47D:Tam tumor was passaged, it grew maximally with either 1.5 mg of tamoxifen or a 1-cm estradiol (premenopausal levels) capsule, and similar results were obtained with MCF-7:Tam2 tumors. Interestingly, when T47D:Tam tumors were treated with the 0.5 mg of tamoxifen, tumors grew only to 50% maximum. All of the tumors originating from MCF-7 and T47D cells expressed ER at similar levels; therefore, tamoxifen did not select for an ER-negative tumor. In conclusion, we have shown that tamoxifen-stimulated T47D p53 mutant tumors can be developed rapidly with high-dose therapy (1.5 mg daily). The results from this model provide new opportunities to investigate the rapid development of drug resistance to adjuvant tamoxifen in patients with mutant p53 breast tumors.

Cross-resistance of triphenylethylene-type antiestrogens but not ICI 182,780 in tamoxifen-stimulated breast tumors grown in athymic mice.

The triphenylethylene antiestrogens, idoxifene (Idox) and toremifene (Tor), are structurally related analogues of tamoxifen (Tam) and were developed to improve the therapeutic index for advanced breast cancer patients. However, the issue of cross-resistance with Tam for these new agents is critical for clinical testing because the majority of breast cancer patients have already received or failed adjuvant Tam. The goal of this study was to determine the effectiveness of Idox as an antitumor agent in three models of Tam-stimulated breast cancer in athymic mice and compare the results with the actions of Tor and ICI 182,780 in a Tam-stimulated MCF-7 tumor model. We first compared the activities of Tam and Idox in the 17beta-estradiol (E2)-stimulated MCF-7 tumor line MT2:E2. Tam and Idox reduced E2-stimulated growth by 65-70% (week 9: P = 0.0009 for Tam, P = 0.0005 for Idox versus E2 alone). However, Tam (1.5 mg daily) and Idox (1.0 mg daily) both produced T47D breast tumors in athymic mice during 23 weeks of treatment (12 tumors/22 sites and 15 tumors/18 sites, respectively). Tam and Idox stimulated tumor growth equally in two different Tam-stimulated MCF-7 models and in a T47D model. Tor was completely cross-resistant with Tam in the MCF-7 tumor model, which implied that neither Idox nor Tor would be effective as a second-line endocrine therapy after Tam failure and may offer no therapeutic advantages over Tam as adjuvant therapies. In contrast, ICI 182,780, a pure antiestrogen currently being tested as a treatment for breast cancer after Tam failure, had no growth-stimulatory effect on the MCF-7 Tam-stimulated breast tumor line. This agent may provide an advantage as an adjuvant therapy and increase the time to treatment failure.