Identifying people at risk of fuel poverty to prevent excess winter deaths

An analysis of excess winter deaths across the West Midlands found higher levels in the NHS Birmingham East and North area than in the rest of the region. The trust created an algorithm to identify those at risk of excess winter death and fuel poverty.     

Informational needs of patients and perceived adequacy of information available before and after treatment of cancer

To examine the various concerns of patients after being diagnosed with cancer as well as the availability of information to address concerns from the time of diagnosis to the completion of treatment, we analyzed data from a longitudinal study of 731 adults recently diagnosed with cancer. Concerns about the effectiveness and side effects of treatment and family stress were most common after diagnosis. Information about the diagnosis and treatment plan was readily available to patients, but information addressing social, lifestyle, and financial concerns was less available. Significantly more information was desired regarding the long-term implications of treatment and disease.     

Pediatric tracheotomy: 17 year review

OBJECTIVE: To study the outcomes, complications, and indications for pediatric tracheotomies performed at a major tertiary care children's hospital, Starship Children's Hospital in Auckland, New Zealand, over the period 1987-2003. METHODS: A retrospective review of hospital records from 1987 to 2003 was conducted to assess all pediatric patients who had undergone tracheotomies. RESULTS: A total of 122 tracheotomies (119 surgical, 3 percutaneous) were performed on patients less than 16 years of age. Upper airway obstruction (including craniofacial dysmorphism, n=40, and subglottic stenosis, n=18) was the most common indication for surgery (n=86; 70%) with a lesser number (n=36; 30%) requiring tracheotomy for prolonged ventilation. The median age at tracheotomy was 4.5 months in patients with upper airway obstruction and 16 months in those requiring prolonged ventilation. Decannulation was carried out successfully in 92 patients (75%), although 6 (6.5%) subsequently required recannulation. The overall complication rate was 51% (n=62). Early postoperative complications occurred in a total of 9 (7.4%) patients, including difficulties with ventilation in intensive care due to inadequate seal or tube position in 5 (4.1%), and accidental decannulation in 3 (2.5%). Late complications included localized granulation in most patients, for which 15 (12.3%) required intervention whilst under a routine planned general anesthetic. Major vascular erosion was not encountered in any patient, although 5 (4.1%) required intervention for minor bleeding associated with granulation tissue. Suprastomal collapse occurred in 13 patients (10.7%); but did not affect their subsequent decannulation, although 2 (1.6%) developed tracheotomy-related subglottic stenosis. Closure of tracheocutaneous fistulas was required in 16 (13.1%) decannulated patients. Only 2 patients (1.6%) died from tracheotomy-related complications, with an overall mortality rate of 14%. CONCLUSIONS: Pediatric tracheotomies performed at Starship Children's Hospital between 1987 and 2003 were associated with a low incidence of procedure-related mortality and morbidity and successful decannulation in most cases. The majority of procedures were performed to treat upper airway obstruction, most commonly caused by craniofacial dysmorphism or subglottic stenosis.     

Effect of pepsin on laryngeal stress protein (Sep70, Sep53, and Hsp70) response: role in laryngopharyngeal reflux disease

OBJECTIVES: The objectives of this study were to define the conditions that give rise to a stress protein response in laryngeal epithelium and to investigate whether and how stress protein dysfunction contributes to reflux-related laryngeal disease. METHODS: Western analysis was used to measure stress protein (squamous epithelial proteins Sep70 and Sep53 and heat shock protein Hsp70) and pepsin levels in esophageal and laryngeal tissue specimens taken from both normal control subjects and patients with pH-documented laryngopharyngeal reflux (LPR) who had documented lesions, some of whom had laryngeal cancer. A porcine organ culture model was used to examine the effects of low pH and pepsin (0.1% porcine pepsin A) on stress protein levels. A laryngeal squamous carcinoma (FaDu) cell line was used to examine uptake of human pepsin 3b-tetramethyl-5 and -6 isothiocyanate. RESULTS: Sep70, Sep53, and Hsp70 were found to be expressed at high levels, and pepsin was not detected, in esophageal and laryngeal specimens taken from normal control subjects and in esophageal specimens taken from LPR patients. The patients with LPR were found to have significantly less laryngeal Sep70 (p = .027) and marginally less laryngeal Sep53 (p = .056) than the normal control subjects. Laryngeal Hsp70 was expressed at high levels in the LPR patients. The patients with laryngeal cancer had significantly lower levels of Sep70, Sep53 (p < .01), and Hsp70 (p < .05) than the normal control subjects. A significant association was found between the presence of pepsin in laryngeal epithelium from LPR patients and depletion of laryngeal Sep70 (p < .001). Using the organ culture model, we demonstrated that laryngeal Sep70 and Sep53 proteins are induced after exposure to low pH. However, in the presence of pepsin, Sep70 and Sep53 levels are depleted. Confocal microscopy analysis of cultured cells exposed to labeled pepsin revealed that uptake is by receptor-mediated endocytosis. CONCLUSIONS: These findings suggest that receptor-mediated uptake of pepsin by laryngeal epithelial cells, as may occur in LPR, causes a change in the normal acid-mediated stress protein response. This altered stress protein response may lead to cellular injury and thus play a role in the development of disease.     

Identifying Muir-Torre syndrome in a patient with glioblastoma multiforme

Patients with Muir-Torre syndrome, an autosomal-dominant familial tumor condition caused by germline mutation of the DNA mismatch repair genes, MSH2 or MLH1, present with tumors of the sebaceous gland and visceral malignancies characterized by microsatellite instability. Here we show development of glioblastoma multiforme in a patient with Muir-Torre syndrome. Immunohistochemical analysis of the brain tumor and colon cancer revealed loss of the DNA mismatch repair gene detected by the genetic test, suggesting a pathogenic link.Muir-Torre syndrome is a rare autosomal-dominant familial tumor condition clinically characterized by tumors of the sebaceous gland and visceral malignancies.^1–3 The underlying molecular pathogenesis involves a germline mutation of the DNA mismatch repair genes, MSH2 or MLH1.^3,4 Here we describe the development of glioblastoma multiforme (GBM), a grade IV glioma, in a patient with Muir-Torre syndrome. In addition we present the clinical-pathological findings from the proband. A 58-year-old man with a history of colon cancer sought medical attention in October 2007 with complaints of episodic left hemisensory disturbance. The colon cancer had been addressed with a right hemicolectomy followed by 5-FU adjuvant chemotherapy in 1999. He has been disease free since the initial treatment. The initial as well as subsequent surveillance colonoscopies failed to demonstrate presence of colonic polyps. The current physical examination revealed presence of multiple skin lesions described by a dermatologist as sebaceous adenomas (Fig. 1A) and lateralizing signs. Magnetic resonance imaging study of the brain revealed a 2.2-cm enhancing mass in the right parietal lobe without significant mass effect (Fig. 1B). Due to the eloquent location of the tumor, a biopsy was initially performed, but it was nondiagnostic. He then underwent an awake craniotomy with intraoperative mapping of the sensory cortex for resection of the tumor. Histopathological analysis revealed a GBM (Fig. 2A) with a Ki-67 proliferation index of 25%. Immunohistochemical study showed presence of glial fibrillary acidic protein, p53 (Fig. 2B), and epidermal growth factor receptor (EGFR). EGFR showed no amplification by fluorescence in situ hybridization. Loss of heterozygosity studies by polymerase chain reaction revealed partial loss of 1p and complete loss of 17p. Detection of the p16 gene by fluorescence in situ hybridization analysis revealed deletion of the gene in 25% of the tumor cells. Molecular phenotype was consistent with the histological diagnosis of GBM.Open in a separate windowFig. 1.A) Multiple skin lesions present on face (arrow), trunk, and limbs were described by a dermatologist as sebaceous adenomas. B) Magnetic resonance imaging study of the brain of our patient revealed a 2.2-cm enhancing mass in the right parietal lobe without significant mass effect.Open in a separate windowFig. 2.A) Histopathological analysis of the resected tumor revealed a glioblastoma multiforme with a Ki-67 proliferation index of 25%. B) Immunohistochemical staining shows cells expressing p53.The diagnosis of Muir-Torre syndrome in this gentleman was suspected due to the colon cancer in the background of the sebaceous adenomas, as well as extensive family history for colorectal cancers (Fig. 3). In addition to the colon cancers, his sister passed away at the age of 44 from GBM. Genetic tests of our patient revealed a heterozygous deletion of AG dinucleotide at position 1226 in exon 7 of MSH2 gene located on chromosome 2p, confirming the clinical suspicion. Immunohistochemical staining of the colon cancer demonstrated absence of MSH2 expression (Fig. 4A). The immunohistochemical stain was performed on formalin fixed paraffin-embedded tissue cut at 6-micron thickness. Heat-induced antigen retrieval (Ventana Medical Systems, Tucson, AZ, USA) method was used followed by incubation with anti-MSH2 monoclonal antibody (BD Biosciences, San Jose, CA, USA) at 1:200 dilution. To establish a pathogenic link between the Muir-Torre–associated genetic defect and the GBM, we analyzed the brain tumor for MSH2 expression. Similar to the colon cancer, immunohistochemistry revealed absence of MSH2 expression, suggesting a potentiating role of the DNA mismatch repair dysfunction on the GBM pathogenesis. Fig. 4B shows the immunohistochemical staining of MSH2 protein in the GBM from this patient. The bulk tumor failed to stain for MSH2 while the intravascular lymphocytes and few infiltrating inflammatory cells retained the enzyme expression. In agreement with impaired DNA mismatch repair activity, this tumor showed microsatellite instability at 5 of the 10 loci tested.Open in a separate windowFig. 3.Many members of this patient’s family were afflicted by development of colon cancer. Our patient had both colon cancer and glioblastoma multiforme (arrow).Open in a separate windowFig. 4.A) Immunohistochemical staining of the colon cancer demonstrated absence of MSH2 expression. B) Labeling of the glioblastoma multiforme tissue for MSH2 by immunohistochemistry demonstrates the presence of the DNA repair enzyme in scattered inflammatory cells while the bulk tumor fails to stain.Common visceral malignancies associated with Muir-Torre syndrome are largely gastrointestinal and urogenital.^5,6 Unusual histopathological phenotypes include cancers of the breast, parotid gland, larynx, and hematopoietic system.^1,6,7 Similar to other familial tumor syndromes, patients with Muir-Torre syndrome inherit a mutated copy of one gene. Somatic inactivation of the second gene leads to the complete loss of enzymatic activity, development of microsatellite instability, and presumably the neoplasm in the affected site. Mechanism governing tissue specificity of tumorigenesis is unknown.Although the role of DNA mismatch repair activity in gliomas is a subject of intense study, to our knowledge there are no reported cases of GBM in Muir-Torre syndrome. Gliomas have been described in another familial tumor syndrome with an underlying DNA mismatch repair defect, hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome.⁸ Turcot syndrome, the brain tumor-polyposis syndrome, also links malignant gliomas with colorectal cancer.⁹ Although Turcot syndrome is classically characterized as a manifestation of defect of the adenomatous polyposis coli gene, DNA mismatch repair defects were also seen in patients originally described by Turcot.⁹ Therefore, Turcot syndrome can include gliomas and either familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer. Such observations have resulted in debates over whether Turcot syndrome is a distinct entity and in need of reclassification.¹⁰ It is also unclear whether Muir-Torre syndrome represents a variant of Lynch syndrome or is a distinct clinical entity. The observation that loss of MSH2 can occur in both Muir-Torre syndrome and HNPCC, with Muir-Torre having a distinctive skin manifestation not seen in the latter, suggests the presence of additional molecular disruptions in Muir-Torre. This may provide an important insight into the pathogenesis of GBM. The GBM from this particular individual demonstrated complete loss of the DNA mismatch repair gene, MSH2. Since most sporadic GBM retain the expression of MSH2, the loss of DNA repair activity likely contributed to the pathogenesis of the GBM in this patient.A remaining question is whether the loss of MSH2 activity alone is sufficient for tumorigenesis. Is it necessary to incur additional genetic “hits” in the background of lost MSH2 activity to develop gliomas? For instance, impaired DNA repair activity may lead to mutation of critical genes such as p16 to assist in the formation of GBM. This also implies the presence of multiple pathways in the pathologic development of GBM and further hints at the heterogeneous nature of the disease. Disease heterogeneity is supported by predictably different clinical responses to chemotherapy in patients with gliomas based on molecular characterization. Our patient began concurrent temozolomide chemotherapy with external beam radiation therapy. Interestingly, upon treatment with temozolomide, he began to note reduction in the size of the sebaceous adenomas.     

Yes‐associated protein is an independent prognostic marker in hepatocellular carcinoma

BACKGROUND:

Yes‐associated protein (YAP), a downstream target of the Hippo signaling pathway, was recently linked to hepatocarcinogenesis in a mouse hepatocellular carcinoma (HCC) model. The objective of the current study was to investigate the clinical significance of YAP in HCC and its prognostic values in predicting survival and tumor recurrence.

METHODS:

The authors collected 177 pairs of tumor and adjacent nontumor tissue from HCC patients with definitive clinicopathologic and follow‐up data. YAP expression was determined by immunohistochemistry, Western blot analysis, and quantitative polymerase chain reaction. Association of YAP with each clinicopathologic feature was analyzed by Pearson chi‐square test, and HCC‐specific disease‐free survival and overall survival by Kaplan‐Meier curves and log‐rank test. Multivariate Cox regression analyses of YAP in HCC were also performed.

RESULTS:

YAP was expressed in the majority of HCC cases (approximately 62%) and mainly accumulated in the tumor nucleus. Overexpression of YAP in HCC was significantly associated with poorer tumor differentiation (Edmonson grade; P = .021) and high serum α‐fetoprotein (AFP) level (P < .001). Kaplan‐Meier and Cox regression data indicated that YAP was an independent predictor for HCC‐specific disease‐free survival (hazards ratio [HR], 1.653; 95% confidence interval [95% CI], 1.081‐2.528 [P = .02]) and overall survival (HR, 2.148; 95% CI, 1.255‐3.677 [P = .005]).

CONCLUSIONS:

YAP is an independent prognostic marker for overall survival and disease‐free survival times of HCC patients and clinicopathologically associated with tumor differentiation and serum AFP level. It is a potential therapeutic target for this aggressive malignancy. Cancer 2009. © 2009 American Cancer Society.     

Abrogation of TGF-β signaling enhances chemokine production and correlates with prognosis in human breast cancer

In human breast cancer, loss of carcinoma cell–specific response to TGF-β signaling has been linked to poor patient prognosis. However, the mechanisms through which TGF-β regulates these processes remain largely unknown. In an effort to address this issue, we have now identified gene expression signatures associated with the TGF-β signaling pathway in human mammary carcinoma cells. The results strongly suggest that TGF-β signaling mediates intrinsic, stromal-epithelial, and host-tumor interactions during breast cancer progression, at least in part, by regulating basal and oncostatin M–induced CXCL1, CXCL5, and CCL20 chemokine expression. To determine the clinical relevance of our results, we queried our TGF-β–associated gene expression signatures in 4 human breast cancer data sets containing a total of 1,319 gene expression profiles and associated clinical outcome data. The signature representing complete abrogation of TGF-β signaling correlated with reduced relapse-free survival in all patients; however, the strongest association was observed in patients with estrogen receptor–positive (ER-positive) tumors, specifically within the luminal A subtype. Together, the results suggest that assessment of TGF-β signaling pathway status may further stratify the prognosis of ER-positive patients and provide novel therapeutic approaches in the management of breast cancer.     

Open Doorway to Truth: Legacy of the Minnesota Tobacco Trial

More than a decade has passed since the conclusion of the Minnesota tobacco trial and the signing of the Master Settlement Agreement (MSA) by 46 US State Attorneys General and the US tobacco industry. The Minnesota settlement exposed the tobacco industry''s long history of deceptive marketing, advertising, and research and ultimately forced the industry to change its business practices. The provisions for public document disclosure that were included in the Minnesota settlement and the MSA have resulted in the release of approximately 70 million pages of documents and nearly 20,000 other media materials. No comparable dynamic, voluminous, and contemporaneous document archive exists. Only a few single events in the history of public health have had as dramatic an effect on tobacco control as the public release of the tobacco industry''s previously secret internal documents. This review highlights the genesis of the release of these documents, the history of the document depositories created by the Minnesota settlement, the scientific and policy output based on the documents, and the use of the documents in furthering global public health strategies.BAT = British American Tobacco; FCTC = Framework Convention on Tobacco Control; JAMA = Journal of the American Medical Association; LTDL = Legacy Tobacco Documents Library; MSA = Master Settlement Agreement; NCI = National Cancer Institute; PMI = Philip Morris International; RICO = Racketeer Influenced and Corrupt Organizations; TobReg = Study Group on Tobacco Control Regulation; TTC = transnational tobacco company; UCSF = University of California, San Francisco; WHO = World Health OrganizationMore than a decade has passed since Minnesota settled its litigation against the tobacco industry. The Minnesota settlement has been recognized as one of the most important public health events of the second half of the 20th century because it exposed the tobacco industry''s long history of deceptive marketing, advertising, and research.¹ It has also been more than 10 years since the tobacco industry''s individual settlements with the states of Mississippi (1997), Florida (1997), and Texas (1998) and since the signing of the Master Settlement Agreement (MSA) between 46 US State Attorneys General and the tobacco companies (1998). These agreements are the 5 largest settlements in the history of litigation.²Before the Minnesota tobacco case, filed in 1994 by the Minnesota Attorney General and Blue Cross Blue Shield of Minnesota, successful litigation against the cigarette manufacturers had been almost universally unsuccessful. The “first wave” of suits from the 1950s to the 1970s were met by an industry that had adopted a “scorched earth” litigation strategy, outspending individual litigants by orders of magnitude while vehemently denying any association between their product and diseases such as lung cancer.² Through hundreds of cases between 1950 and 1970, the tobacco industry disclosed only a few thousand internal documents, thereby maintaining an impregnable wall of silence.³ The first crack in this wall occurred during the “second wave” of tobacco litigation; this wave was marked by the 1983 Cipollone case, in which plaintiffs aggressively sought and received a small cache of damning documents.⁴Other events converged in the mid-1990s to expose the tobacco industry''s wrongdoing. In 1994, copies of internal documents from the Brown & Williamson Tobacco Corporation were leaked and were ultimately published in the Journal of the American Medical Association (JAMA) in 1995.⁵ Although these documents were not numerous (4000 pages), they were selected because of their damning content and were sent anonymously to Stanton A. Glantz, PhD, a widely recognized tobacco control researcher. These documents became the basis not only for the articles in JAMA but also for the book The Cigarette Papers.⁶ The publication of this book was a historic event and provided the deepest look inside the tobacco industry before the Minnesota litigation. In 1994, the US Food and Drug Administration, under the leadership of then-director David A. Kessler, MD, sought to regulate tobacco products by claiming not only that these products were drug delivery devices but also that the industry controlled and manipulated the form and quantity of nicotine contained within their products.⁷ In addition, Jeffrey Wigand, PhD, a former vice president at Brown & Williamson, began to cooperate with the Food and Drug Administration and ultimately told his story on the television program 60 Minutes.⁸ The industry was further exposed in Congressional hearings chaired by Representative Henry Waxman (Democrat, California), during which chief executives were forever immortalized on videotape as they swore before Congress and the American people that nicotine was not addictive.⁹ All of these events were damaging to the tobacco industry, but even collectively their legacy does not compare with that of the Minnesota tobacco trial, which changed the tobacco control landscape forever.Although the terms of the massive tobacco settlements included large monetary awards and unprecedented public health relief (Open in a separate windowThe first peer-reviewed article based on tobacco companies'' internal documents introduced during the Minnesota trial by the plaintiffs'' witnesses was published 10 years ago in JAMA.¹⁰ The article and the authors'' testimony focused on nicotine addiction, pH manipulation, and low-tar/low-nicotine cigarettes. Since then, several hundred peer-reviewed articles have been published. We summarize the multiple legacies of the Minnesota trial and the MSA by highlighting the effect that these internal documents from the tobacco industry have had on tobacco control around the world.