A review of endovascular stenting for superior vena cava syndrome in fibrosing mediastinitis.

Fibrosing mediastinitis (FM) is a rare disorder of inflammation and fibrosis involving the mediastinum. The formation of fibroinflammatory mass in the mediastinum can lead to obstruction of mediastinal structures and cause severe debilitating and life-threatening symptoms. Superior vena cava syndrome (SVCS) is a dreaded complication of FM with no medical therapy proven to be efficacious. Spiral vein grafting has long been utilized as first-line therapy for SVC syndrome due to FM. Endovascular repair with stents and angioplasty for malignant causes of SVC syndrome is well established. However, there are limited data on their utility in SVC syndrome due to FM. We present two cases of SVC syndrome due to FM treated with endovascular stenting and a detailed review of current literature on its utility in SVCS due to benign causes.

Inferior Vena Cava Filters: Indications, Outcomes, and Evidence.

OPINION STATEMENT: Filter technology seems relatively stable, although absorbable devices are an area of investigational interest. The indications for filter placement remain controversial, with wide variations in adherence to guidelines, and relatively poor quality of data about the specific prophylactic indications of trauma or bariatric surgery. The outcomes of filters are not well-defined despite widespread clinical use, and good data remains difficult to obtain. Several larger database and institutional retrospective studies support the notions that while filters prevent pulmonary embolism, they may be associated with venous thrombotic complications. Some subsets of cancer patients may be at increased risk of these complications, but whether the filter or the underlying hypercoagulable state is the cause is not clear. Lastly, although the benefits of filter retrieval are widely assumed (but not proven), filter retrieval rates remain lower than expected. The single most influential factor in improving filter retrieval rates is dedicated follow-up with intent to retrieve the filter.

Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice.

OBJECTIVE: Cells of the monocytic lineage play fundamental roles in the regulation of health, ranging from the initiation and resolution of inflammation to bone homeostasis. In rheumatoid arthritis (RA), the inflamed synovium exhibits characteristic infiltration of macrophages along with local osteoclast maturation, which, together, drive chronic inflammation and downstream articular destruction. The aim of this study was to explore an entirely novel route of immunoglobulin-mediated regulation, involving simultaneous suppression of the inflammatory and erosive processes in the synovium. METHODS: Using in vivo and in vitro studies of human cells and a murine model of RA, the ability of staphylococcal protein A (SPA) to interact with and modulate cells of the monocytic lineage was tested. In addition, the efficacy of SPA as a therapeutic agent was evaluated in murine collagen-induced arthritis (CIA). RESULTS: SPA showed a capacity to appropriate circulating IgG, by generating small immunoglobulin complexes that interacted with monocytes, macrophages, and preosteoclasts. Formation of these complexes resulted in Fcγ receptor type I-dependent polarization of macrophages to a regulatory phenotype, rendering them unresponsive to activators such as interferon-γ. The antiinflammatory complexes also had the capacity to directly inhibit differentiation of preosteoclasts into osteoclasts in humans. Moreover, administration of SPA in the early stages of disease substantially alleviated the clinical and histologic erosive features of CIA in mice. CONCLUSION: These findings demonstrate the overarching utility of immunoglobulin complexes for the prevention and treatment of inflammatory diseases. The results shed light on the interface between immunoglobulin complex-mediated pathways, osteoclastogenesis, and associated pathologic processes. Thus, therapeutic agents designed to harness all of these properties may be an effective treatment for arthritis, by targeting both the innate inflammatory response and prodestructive pathways.

Herbal tonic does not inhibit estrogen receptor negative mammary tumor development in a transgenic mouse model.

Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence® herbal tonic is a complex mixture of eight herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. In this study four experimental groups of female MMTV-Neu mice were left untreated or treated with 3% Flor-Essence® in utero, from birth until 5 weeks of age, or throughout their lifetime. Palpable mammary tumor incidence and body weight was determined weekly for each group. The mice were sacrificed at 28 weeks of age and mammary tumors were enumerated to determine average tumor incidence and multiplicity for each group. Female mice exposed to Flor-Essence® herbal tonic in utero weighed significantly more than the control group (p < 0.001). The average tumor incidence and tumor multiplicity in the experimental mice treated with Flor-Essence® herbal tonic did not differ from the control animals. Flor-Essence® does not inhibit mammary tumor incidence or mammary tumor multiplicity in MMTV-Neu transgenic mice. Flor-Essence® exposure in utero causes increased body weight in experimental animals. This conclusion challenges widely available anecdotal information as well as the hopes of the consumer that this product will inhibit or suppress tumor development.

Hemoglobin monitoring in head and neck cancer patients undergoing radiotherapy.

OBJECTIVES: Anemia is a well-recognized factor for local recurrence and decreased survival in cancer patients undergoing radiotherapy. Additionally, lower hemoglobin (Hb) levels have a negative impact on radiotherapy efficacy and response rates. The objective of this audit was to investigate how frequently Hb levels were observed in head and neck cancer patients receiving radiotherapy within a multidisciplinary team setting. METHODS: We performed a retrospective first-cycle audit in a university hospital in Glasgow that is a tertiary referral center for head and neck cancer. Included were 78 patients with head and neck cancer who were undergoing radiotherapy. Online laboratory services and clinical case sheets were checked for each patient to monitor the frequency of observation of Hb levels before, during, and after radiotherapy. RESULTS: Of these 78 patients, only 49 had their Hb level checked before radiotherapy treatment, only 9 during radiotherapy, and only 27 after completion of radiotherapy treatment (p < 0.0001). Of the 49 patients with preradiotherapy Hb levels available, 24% were found to be anemic; none of these patients had their Hb monitored during radiotherapy, and only 4 had Hb levels recorded after completion of treatment. CONCLUSIONS: This audit has highlighted that despite evidence emphasizing that anemia in cancer is an independent prognostic factor for recurrence, there is no formal protocol for Hb monitoring in head and neck cancer patients undergoing radiotherapy. The audit has also demonstrated that Hb monitoring is infrequently performed and that subsequent observation of the Hb level is suboptimal.

A double-blind randomized controlled trial of management of recurrent nosebleeds in children.

BACKGROUND: To establish whether a treatment regimen of silver nitrate cautery and 4 weeks of antiseptic nasal cream is superior to antiseptic cream treatment alone in the management of pediatric epistaxis. STUDY DESIGN: Double-blind randomized controlled trial. SUBJECTS AND METHODS: Children with epistaxis and visible anterior septal vessels were invited to participate. Patients were randomized to receive treatment or control. Treatment patients received silver nitrate cautery, followed by antiseptic cream for 4 weeks. Control patients received sham cautery followed by antiseptic cream for 4 weeks. RESULTS: A total of 109 patients were randomized and results were available for 93 (85%). Of those receiving cautery, 21 (45.7%) of 46 had no bleeding in the 4 weeks before follow-up. Of those receiving only antiseptic cream 14 (29.8%) of 47 had no bleeding. (chi(2) = 2.49; P = 0.114). More children in the active treatment group had an improvement in their symptoms compared with controls (42 of 46; 91.3%) in the treatment group vs 33 of 47 (70.2%) controls (chi(2) = 6.626; P = 0.01; relative risk reduction = 71 percent, number needed to treat = 4.7). CONCLUSION: When using subjective improvement in symptoms as the outcome measure, silver nitrate cautery with antiseptic cream twice daily for 4 weeks appears to give a small but statistically significant benefit when compared to antiseptic cream alone.

Endothelin receptor B antagonists decrease glioma cell viability independently of their cognate receptor.

BACKGROUND: Endothelin receptor antagonists inhibit the progression of many cancers, but research into their influence on glioma has been limited. METHODS: We treated glioma cell lines, LN-229 and SW1088, and melanoma cell lines, A375 and WM35, with two endothelin receptor type B (ETRB)-specific antagonists, A-192621 and BQ788, and quantified viable cells by the capacity of their intracellular esterases to convert non-fluorescent calcein AM into green-fluorescent calcein. We assessed cell proliferation by labeling cells with carboxyfluorescein diacetate succinimidyl ester and quantifying the fluorescence by FACS analysis. We also examined the cell cycle status using BrdU/propidium iodide double staining and FACS analysis. We evaluated changes in gene expression by microarray analysis following treatment with A-192621 in glioma cells. We examined the role of ETRB by reducing its expression level using small interfering RNA (siRNA). RESULTS: We report that two ETRB-specific antagonists, A-192621 and BQ788, reduce the number of viable cells in two glioma cell lines in a dose- and time-dependent manner. We describe similar results for two melanoma cell lines. The more potent of the two antagonists, A-192621, decreases the mean number of cell divisions at least in part by inducing a G2/M arrest and apoptosis. Microarray analysis of the effects of A-192621 treatment reveals up-regulation of several DNA damage-inducible genes. These results were confirmed by real-time RT-PCR. Importantly, reducing expression of ETRB with siRNAs does not abrogate the effects of either A-192621 or BQ788 in glioma or melanoma cells. Furthermore, BQ123, an endothelin receptor type A (ETRA)-specific antagonist, has no effect on cell viability in any of these cell lines, indicating that the ETRB-independent effects on cell viability exhibited by A-192621 and BQ788 are not a result of ETRA inhibition. CONCLUSION: While ETRB antagonists reduce the viability of glioma cells in vitro, it appears unlikely that this effect is mediated by ETRB inhibition or cross-reaction with ETRA. Instead, we present evidence that A-192621 affects glioma and melanoma viability by activating stress/DNA damage response pathways, which leads to cell cycle arrest and apoptosis. This is the first evidence linking ETRB antagonist treatment to enhanced expression of DNA damage-inducible genes.

Chemical and biological differentiation of three human breast cancer cell types using time-of-flight secondary ion mass spectrometry.

We use time-of-flight secondary ion mass spectrometry (TOF-SIMS) to image and classify individual cells on the basis of their characteristic mass spectra. Using statistical data reduction on the large data sets generated during TOF-SIMS analysis, similar biological materials can be differentiated on the basis of a combination of small changes in protein expression, metabolic activity and cell structure. We apply this powerful technique to image and differentiate three carcinoma-derived human breast cancer cell lines (MCF-7, T47D, and MDA-MB-231). In homogenized cells, we show the ability to differentiate the cell types as well as cellular compartments (cytosol, nuclear, and membrane). These studies illustrate the capacity of TOF-SIMS to characterize individual cells by chemical composition, which could ultimately be applied to detect and identify single aberrant cells within a normal cell population. Ultimately, we anticipate characterizing rare chemical changes that may provide clues to single cell progression within carcinogenic and metastatic pathways.

Behavioral stress and tumor progression.

BACKGROUND: A number of laboratories have reported a possible link between behavioral stress and cancer progression. Previously published findings demonstrated a stress-induced increase in tumor growth of implanted lymphosarcoma in C3H mice. Here, two mouse models were utilized to investigate whether stress alters the growth of solid tumors. MATERIALS AND METHODS: We developed a stress paradigm that involves alternating established stressors for 12 days. FVB mice implanted with melanoma were subjected to this stress protocol. We also attempted to duplicate Riley's finding. RESULTS: Our stress paradigm markedly increased serum corticosterone levels and thymus involution. No alteration in the growth of the melanoma tumors was observed. There was also no significant effect on lymphosarcoma progression using either our own or Riley's stress protocol. CONCLUSION: Under the conditions used in this study, strong behavioral stress did not influence tumor progression.

Essiac and Flor-Essence herbal tonics stimulate the in vitro growth of human breast cancer cells.

BACKGROUND: People diagnosed with cancer often self-administer complementary and alternative medicines (CAMs) to supplement their conventional treatments, improve health, or prevent recurrence. Flor-Essence and Essiac Herbal Tonics are commercially available complex mixtures of herbal extracts sold as dietary supplements and used by cancer patients based on anecdotal evidence that they can treat or prevent disease. In this study, we evaluated Flor-Essence and Essiac for their effects on the growth of human tumor cells in culture. METHODS: The effect of Flor-Essence and Essiac((R)) herbal tonics on cell proliferation was tested in MCF-7, MDA-MB-436, MDA-MB-231, and T47D cancer cells isolated from human breast tumors. Estrogen receptor (ER) dependent activation of a luciferase reporter construct was tested in MCF-7 cells. Specific binding to the ER was tested using an ICI 182,780 competition assay. RESULTS: Flor-Essence and Essiac herbal tonics at 1%, 2%, 4% and 8% stimulated cell proliferation relative to untreated controls in both estrogen receptor positive (MCF-7 and T47D) and estrogen receptor negative (MDA-MB-231 and MDA-MB-436) cell lines. Exposure to the tonics also produced a dose-dependent increase in ER dependent luciferase activity in MCF-7 cells. A 10(-7) M concentration of ICI 182,780 inhibited the induction of ER dependent luciferase activity by Flor-Essence and Essiac, but did not affect cell proliferation. CONCLUSION: Flor-Essence and Essiac Herbal Tonics can stimulate the growth of human breast cancer cells through ER mediated as well as ER independent mechanisms of action.

PhIP carcinogenicity in breast cancer: computational and experimental evidence for competitive interactions with human estrogen receptor.

Many carcinogens have been shown to cause tissue specific tumors in animal models. The mechanism for this specificity has not been fully elucidated and is usually attributed to differences in organ metabolism. For heterocyclic amines, potent carcinogens that are formed in well-done meat, the ability to either bind to the estrogen receptor and activate or inhibit an estrogenic response will have a major impact on carcinogenicity. Here, we describe our work with the human estrogen receptor alpha (ERalpha), the mutagenic/carcinogenic heterocyclic amines PhIP, MeIQx, and IFP, and the hydroxylated metabolite of PhIP, N2-hydroxy-PhIP. We demonstrate both by computational docking and NMR analysis that PhIP binds with the ligand binding domain (LBD). This binding competes with estradiol (E2) in the native E2 binding cavity of the receptor. In vitro assays show that PhIP, in contrast to the other heterocyclic amines, increases cell proliferation in MCF-7 human breast cancer cells and activates the ERalpha receptor. We also find that other heterocyclic amines and N2-hydroxy-PhIP inhibit ERalpha activation. We propose that the mechanism for the tissue-specific carcinogenicity seen in the rat breast tumors and the presumptive human breast cancer associated with the consumption of well-done meat maybe mediated by this receptor activation.

Flor-Essence herbal tonic does not inhibit mammary tumor development in Sprague Dawley rats.

BACKGROUND: Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence tonic is a complex mixture of herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. METHODS: Female Sprague-Dawley rats were given water or exposed to 3 or 6% Flor-Essence beginning at 1 day of age. Mammary tumors were induced with a single oral 40 mg/kg/bw dose of dimethyl-benz[a]anthracene at 50 days of age and sacrificed at 23 weeks. Rats were maintained on AIN-76A diet. RESULTS: Control rats had palpable mammary tumor incidence of 51.0% at 19 weeks of age compared to 65.0 and 59.4% for the 3 and 6% Flor-Essence groups respectively. Overall, no significant difference in time until first palpable tumor was detected among any of the groups. At necropsy, mammary tumor incidence was 82.5% for controls compared to 90.0 and 97.3% for rats consuming 3 and 6% Flor-Essence, respectively. Mean mammary tumor multiplicity (+/-SES) for the controls was 2.8 (+/-0.5) and statistically different from the 3 or 6% Flor-Essence groups with 5.2 (+/-0.7), and 4.8 (+/-0.6), respectively (p < or = 0.01). As expected, the majority of isolated tumors were diagnosed as adenocarcinomas. CONCLUSIONS: Flor-Essence can promote mammary tumor development in the Sprague-Dawley rat model. This observation is contrary to widely available anecdotal evidence as well as the desire of the consumer that this commercially available herbal tonic will suppress and/or inhibit tumor growth.