Assessment of DNA methylation status in early stages of breast cancer development.

BACKGROUND: Molecular pathways determining the malignant potential of premalignant breast lesions remain unknown. In this study, alterations in DNA methylation levels were monitored during benign, premalignant and malignant stages of ductal breast cancer development. METHODS: To study epigenetic events during breast cancer development, four genomic biomarkers (Methylated-IN-Tumour (MINT)17, MINT31, RARß2 and RASSF1A) shown to represent DNA hypermethylation in tumours were selected. Laser capture microdissection was employed to isolate DNA from breast lesions, including normal breast epithelia (n=52), ductal hyperplasia (n=23), atypical ductal hyperplasia (n=31), ductal carcinoma in situ (DCIS, n=95) and AJCC stage I invasive ductal carcinoma (IDC, n=34). Methylation Index (MI) for each biomarker was calculated based on methylated and unmethylated copy numbers measured by Absolute Quantitative Assessment Of Methylated Alleles (AQAMA). Trends in MI by developmental stage were analysed. RESULTS: Methylation levels increased significantly during the progressive stages of breast cancer development; P-values are 0.0012, 0.0003, 0.012, <0.0001 and <0.0001 for MINT17, MINT31, RARß2, RASSF1A and combined biomarkers, respectively. In both DCIS and IDC, hypermethylation was associated with unfavourable characteristics. CONCLUSION: DNA hypermethylation of selected biomarkers occurs early in breast cancer development, and may present a predictor of malignant potential.

'We just need to find space for them to practice so that we can help to make a stronger society': Perceived barriers and facilitators to employing health psychologists in UK public health and clinical health settings.

INTRODUCTION: In recent years, health psychology has received significant attention within the health sector, due to its application to understanding influences on health and well-being and translation of health psychology into interventions to support behaviour change. The number of health psychologists in public health and healthcare settings is growing but remains limited, and is it unclear why. This study aimed to explore the views of potential and current employers of health psychologists, to elucidate barriers and facilitators of employing health psychologists in healthcare settings. METHODS: Semi-structured interviews were carried out to explore the experiences of working with and/or employing health psychologists. Opportunities and barriers were explored for increasing access to health psychology expertise in the NHS and public health. Interviews were analysed using inductive thematic analysis. RESULTS: Fifteen participants took part in interviews. Participants were mid-senior-level professionals working in varied healthcare settings and/or academic institutions. The majority had experience of health psychology/working with health psychologists, whilst others had limited experience but an interest in employing health psychologists. Three key themes were identified: (1) the organizational fit of health psychologists, (2) perception of competition for roles and (3) ideas for changing hearts, minds and processes. CONCLUSION: Barriers exist to employing health psychologists in healthcare settings. These barriers include misunderstandings of the role of health psychologists and the need to preserve other disciplines due to perceived competition. Recommendations for change included showcasing the benefits and skills of health psychologists and having transparent conversations with employees and multi-disciplinary colleagues about roles.

Aberrant hypermethylation in primary tumours and sentinel lymph node metastases in paediatric patients with cutaneous melanoma.

BACKGROUND: Debate on how to manage paediatric patients with cutaneous melanoma continues, particularly in those with sentinel lymph node (SLN) metastases who are at higher risk of poor outcomes. Management is often based on adult algorithms, although differences in clinical outcomes between paediatric and adult patients suggest that melanoma in paediatric patients differs biologically. Yet, there are no molecular prognostic studies identifying these differences. OBJECTIVES: We investigated the epigenetic (methylation) regulation of several tumour-related genes (TRGs) known to be significant in adult melanoma progression in histopathology(+) SLN metastases (n = 17) and primary tumours (n = 20) of paediatric patients with melanoma to determine their clinical relevance. METHODS: Paediatric patients (n = 37; ≤ 21 years at diagnosis) with American Joint Committee on Cancer stage I-III cutaneous melanoma were analysed. Gene promoter methylation of the TRGs RASSF1A, RARß2, WIF1 and APC was evaluated. RESULTS: Hypermethylation of RASSF1A, RARß2, WIF1 and APC was found in 29% (5/17), 25% (4/16), 25% (4/16) and 19% (3/16) of histopathology(+) SLNs, respectively. When matched to adult cutaneous melanomas by Breslow thickness and ulceration, hypermethylation of all four TRGs in SLN(+) paediatric patients with melanoma was equivalent to or less than in adults. With a median follow-up of 55 months, SLN(+) paediatric patients with melanoma with hypermethylation of > 1 TRG vs. ≤ 1 TRG had worse disease-free (P = 0·02) and overall survival (P = 0·02). CONCLUSIONS: Differences in the methylation status of these TRGs in SLN(+) paediatric and adult patients with melanoma may account for why SLN(+) paediatric patients have different clinical outcomes. SLN biopsy should continue to be performed; within SLN(+) paediatric patients with melanoma, hypermethylation of TRGs can be used to identify a subpopulation at highest risk for poor outcomes who warrant vigilant clinical follow-up.

Using behavioural science in public health settings during the COVID-19 pandemic: The experience of public health practitioners and behavioural scientists.

INTRODUCTION: The emergence of COVID-19 and the importance of behaviour change to limit its spread created an urgent need to apply behavioural science to public health. Knowledge mobilisation, the processes whereby research leads to useful findings that are implemented to affect positive outcomes, is a goal for researchers, policy makers and practitioners alike. This study aimed to explores the experience of using behavioural science in public health during COVID-19, to discover barriers and facilitators and whether the rapidly changing context of COVID-19 influenced knowledge mobilisation. METHODS: We conducted a semi-structured interview study, with ten behavioural scientists and seven public health professionals in England, Scotland, Wales, The Netherlands and Canada. We conducted an inductive thematic analysis. RESULTS: We report three key themes and 10 sub-themes: 1.Challenges and facilitators of translation of behavioural science into public health (Methods and frameworks supported translation, Lack of supportive infrastructure, Conviction and sourcing of evidence and Embracing behavioural science) 2. The unique context of translation (Rapid change in context, the multi-disciplinary team and the emotional toll). 3. Recommendations to support future behavioural science translation (Embedding experts into teams, Importance of a collaborative network and showcasing the role of behavioural science). DISCUSSION: Barriers and facilitators included factors related to relationships between people, such as networks and teams; the expertise of individual people; and those related to materials, such as the use of frameworks and an overwhelming amount of evidence and literature. CONCLUSION: People and frameworks were seen as important in facilitating behavioural science in practice. Future research could explore how different frameworks are used. We recommend a stepped competency framework for behavioural science in public health and more focus on nurturing networks to facilitate knowledge mobilisation in future emergencies.

Atmospheric deposition of metals to forest vegetation.

Atmospheric deposition during the growing season contributes one-third or more of the estimated total flux of lead, zinc, and cadium from the forest canopy to soils beneath an oak stand in the Tennessee Valley but less than 10 percent of the flux of manganese. The ratio of the wet to dry deposition flux to the vegetation during this period ranges from 0.1 for manganese to 0.8 for lead to approximately 3 to 4 for cadmium and zinc. Interactions between metal particles deposited on dry leaf surfaces and subsequent acid precipitation can result in metal concentrations on leaves that are considerably higher than those in rain alone.

Current and historical rates of input of mercury to the Penobscot River, Maine, from a chlor-alkali plant.

Mercury inputs by surface and ground water sources to Penobscot River from a defunct Hg-cell chlor-alkali plant were measured in 2009-10 and estimated for the entire period of operation of this facility. Over the measured interval (422 days) approximately 2.3 kg (5.4 g day-1) of mercury was discharged to the Penobscot River by the two surface streams that drain the site, with most of the combined loading (1.8 kg Hg, 78%) associated with a single storm with rainfall in excess of 100 mm. Groundwater seepage rates from the site, as estimated from both a radon tracer and seepage meter methods were in the range of 3 to 4 cm day-1 and, when combined with a best estimate of the area of groundwater discharge (11,000 m2) and average seepage/porewater mercury concentration (242 ng L-1, UCL95), yielded a loading of 0.11 g day-1 for site groundwater. None of the municipal or other industrial point sources of mercury to the river between Veazie and Bucksport, Maine exceeded 1 g day-1 individually, nor was the aggregate loading of all such sources >3 g day-1 (based on State of Maine data). Mercury loadings for the three largest tributaries downstream of Veazie Dam were estimated to contribute 4.2, 3.7 and 2.5 g day-1, respectively, to the Penobscot River. Based on sampling (total Hg ~ 2 to 4 ng L-1) and historical mean discharge data (340-460 m3 s-1), the Penobscot River upstream of the plant site contributes as much as 160 g day-1 to the downstream reach depending on river discharge. Estimates of historical (1967-2012) mercury loading using both generic emission factors and measured releases ranged from 2.6 to 27 MT while the mass of mercury found in downstream sediments amounted to 9 MT.

Tidal fluxes of mercury and methylmercury for Mendall Marsh, Penobscot River estuary, Maine.

Tidal marshes are both important sites of in situ methylmercury production and can be landscape sources of methylmercury to adjacent estuarine systems. As part of a regional investigation of the Hg-contaminated Penobscot River and Bay system, the tidal fluxes of total suspended solids, total mercury and methylmercury into and out of a regionally important mesohaline fluvial marsh complex, Mendall Marsh, were intensively measured over several tidal cycles and at two spatial scales to assess the source-sink function of the marsh with respect to the Penobscot River. Over four tidal cycles on the South Marsh River, the main channel through which water enters and exits Mendall Marsh, the marsh was a consistent sink over typical 12-h tidal cycles for total suspended solids (8.2 to 41 g m-2), total Hg (9.2 to 47 µg m-2), total filter-passing Hg (0.4 to 1.1 µg m-2), and total methylmercury (0.2 to 1.4 µg m-2). The marsh's source-sink function was variable for filter-passing methylmercury, acting as a net source during a large spring tide that inundated much of the marsh area and that is likely to occur during approximately 17% of tidal cycles. Additional measurements on a small tidal channel draining approximately 1% of the larger marsh area supported findings at the larger scale, but differences in the flux magnitude of filter-passing fractions suggest a highly non-conservative transport of these fractions through the tidal channels. Overall the results of this investigation demonstrate that Mendall Marsh is not a significant source of mercury or methylmercury to the receiving aquatic systems (Penobscot River and Bay). While there is evidence of a small net export of filter-passing (<0.4 µm pore size) methylmercury under some tidal conditions, the mass involved represents <3% of the mass of filter-passing methylmercury carried by the Penobscot River.

Evolution of recurrent herpes simplex lesions. An immunohistologic study.

We performed immunoperoxidase stains on skin biopsies taken from nine patients with recurrent peripheral herpes simplex lesions at 12 h to 6 d after onset of signs of symptoms to phenotype the inflammatory infiltrate, to detect cells producing interferons alpha and gamma, and to locate herpes simplex virus antigen-containing cells. Viral glycoprotein antigen was located in the nuclei and cytoplasm of necrotic epidermal cells, often within vesicles, in biopsies taken between the first and third day. Histologically, biopsies of all stages showed intradermal focal perivascular and diffuse mononuclear inflammatory infiltrates. The cells constituting the infiltrates were predominantly T lymphocytes with lesser numbers of histiocytes; Leu 7+ (most natural killer/killer) cells and B cells were rare in the biopsy specimens. Leu 3a+ ("helper") T lymphocytes predominated in both subepidermal and perivascular regions of early lesions (12-24 h). Tissue helper/suppressor ratios ranged from 6.3 to 3.4 compared with 1.9-1.0 in blood. In later lesions (after 2 d), monocytes/macrophages were more prominent in tissue sections and the helper/suppressor ratios (2.3-2.5) more nearly approximated those of blood (1.6-2.7). The negative correlation of tissue ratios with time was significant (P less than or equal to 0.02). A large proportion of the infiltrated T lymphocytes expressed DR antigens. There was also diffuse strong DR expression on epidermal cells in five cases (all of two or more days). In six biopsies, scattered macrophages and small cells, presumably lymphocytes, demonstrated cytoplasmic or membrane staining for a substance which copurifies with interferon gamma. We identified such stained cells within vessels, suggesting that these cells circulate. Gamma interferon might have an important role within the herpetic lesions, possibly inducing macrophage activation and cytotoxic T lymphocytes and increasing DR expression on monocyte and epidermal cells.

Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node-negative breast cancer.

PURPOSE: Immediate complete axillary lymphadenectomy (ALND) after sentinel lymphadenectomy (SLND) has confirmed that tumor-negative sentinel nodes accurately predict tumor-free axillary nodes in breast cancer. Therefore, we hypothesized that SLND alone in patients with tumor-negative sentinel nodes would achieve axillary control, with minimal complications. PATIENTS AND METHODS: Between October 1995 and July 1997, 133 consecutive women who had primary invasive breast tumors clinically

Prognostic significance of occult metastases detected by sentinel lymphadenectomy and reverse transcriptase-polymerase chain reaction in early-stage melanoma patients.

PURPOSE: Detection of micrometastases in the regional tumor-draining lymph nodes is critical for accurate staging and prognosis in melanoma patients. We hypothesized that a multiple-mRNA marker (MM) reverse transcriptase-polymerase chain reaction (RT-PCR) assay would improve the detection of occult metastases in the sentinel node (SN), compared with hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC), and that MM expression is predictive of disease relapse. PATIENTS AND METHODS: Seventy-two consecutive patients with clinical early-stage melanoma underwent sentinel lymphadenectomy (SLND). Their SNs were serially sectioned and assessed for MAGE-3, MART-1, and tyrosinase mRNA expression by RT-PCR, in parallel with H&E staining and IHC, for melanoma metastases. MM expression in the SNs was correlated with H&E and IHC assay results, standard prognostic factors, and disease-free survival. RESULTS: In 17 patients with H&E- and/or IHC-positive SNs, 16 (94%) expressed two or more mRNA markers. Twenty (36%) of 55 patients with histopathologically negative SNs expressed two or more mRNA markers. By multivariate analysis, patients at increased risk of metastases to the SN had thicker lesions (P =.03), were 60 years of age or younger (P <.05), and/or were MM-positive (P <.001). Patients with histopathologically melanoma-free SNs who were MM-positive, compared with those who were positive for one or fewer mRNA markers, were at increased risk of recurrence (P =.02). Patients who were MM-positive with histopathologically proven metastases in the SN were at greatest risk of disease relapse (P =. 01). CONCLUSION: H&E staining and IHC underestimate the true incidence of melanoma metastases. MM expression in the SN more accurately reflects melanoma micrometastases and is also a more powerful predictor of disease relapse than are H&E staining and IHC alone.

Molecular staging of early colon cancer on the basis of sentinel node analysis: a multicenter phase II trial.

PURPOSE: Approximately 30% of patients with American Joint Committee on Cancer stage I or II colorectal cancer (CRC) develop systemic disease. We hypothesized that multimarker reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of sentinel lymph nodes (SNs) draining a primary CRC could detect micrometastases not detected by conventional histopathologic analysis. PATIENTS AND METHODS: In a multi-institutional study, 40 patients with primary CRC underwent dye-directed lymphatic mapping at the time of colon resection. Each dye-stained SN was tagged, and the tumor and regional nodes were resected en bloc. All lymph nodes were examined by conventional hematoxylin and eosin (HE) staining. In addition, each SN was cut into multiple sections for cytokeratin immunohistochemical (CK-IHC) staining and for RT-PCR and electrochemiluminescent detection of three markers: beta-chain human chorionic gonadotropin, hepatocyte growth factor receptor, and universal melanoma-associated antigen. Whenever possible, RT-PCR assay was also performed on primary tumor tissue. The detection sensitivity of individual markers was 10(-3) to 10(-4) microg of RNA and one to five tumor cells in 10(7) lymphocytes of healthy donors. RESULTS: One to three SNs were identified in each patient. An average of 15 nodes were removed from each CRC specimen. No nonsentinel (untagged) node contained evidence of tumor if all tagged (sentinel) nodes in the same specimen were histopathology tumor-negative. HE staining of SNs identified tumor in 10 patients (25%), and CK-IHC of SNs identified occult micrometastases in four patients (10%) whose SNs were negative by HE. Of the remaining 26 patients with no evidence of SN involvement by HE or CK-IHC, 12 (46%) had positive RT-PCR results. The number of markers expressed in each SN correlated (P <.04) with the T stage of the primary tumor. There was 79% concordance in marker expression for the respective pairs (n = 38) of primary tumor and histopathologically positive SNs, and 86% (12 of 14) concordance between RT-PCR positive and histopathologically positive SNs. CONCLUSION: Identification and focused examination of the SN is a novel method of staging CRC. CK-IHC and RT-PCR identified occult micrometastases in 53% of patients whose SNs were negative by conventional staging techniques. These ultrasensitive assays of the SN can identify patients who may be at high risk for recurrence of CRC and therefore are more likely to benefit from systemic adjuvant therapy.

Valuing quality of life and improvements in glycemic control in people with type 2 diabetes.

Outcomes research is used increasingly for assessing the health economic benefits of new therapeutic programs and interventions. The measurement properties of the outcomes assessment tools are important. If overlooked, they can mislead health care administrators and caregivers regarding the importance and value of these programs and interventions. We reviewed the literature and conducted two analyses to determine the absolute, relative, and operative quality-of-life ranges for people with type 2 diabetes. Quality of life and fasting blood glucose and HbA1c concentrations were measured at baseline and at 4, 8, and 12 weeks of treatment in 569 men and women randomized to either glipizide gastrointestinal therapeutic system (GITS) or placebo in a double-blind, multicenter clinical trial. A subgroup of 290 patients completed a diabetes-specific health states questionnaire at endpoint (week 12 or early termination) rating 10 health-state descriptions on a health thermometer scale ranging from 0 (death) to 100 (full health). Health losses at the higher end of the scale had a greater negative utility than did comparable losses at lower health states, indicating patients' strong preferences for maintaining asymptomatic or mildly symptomatic conditions. Patients rated their current health state at 83.4 +/- 0.8% of full health and indicated that a loss of 27 points below this value would prevent them from living and working as they currently do. The calibration analysis applied to the quality-of-life scales suggested that the targeted range for clinical investigation and quality-of-care evaluation must be more narrowly focused. Effect sizes as seemingly small as 2% (0.25 responsiveness units) on the absolute scale can correspond to quality-of-life losses of 15-20% on the personal operative scale. Differences in glycemic control clearly affected quality of life. Those patients with the best HbA1c responses (decreasing 1.5% or more from baseline) versus those with the worst responses (increasing 1.5% or more from baseline) were separated by 0.6 responsiveness units for the overall quality-of-life summary measure. The calibration analysis suggested that this degree of better glycemic control provides a nearly 50% gain in quality of life according to personal expectations within the operative range. In conclusion, general measures of quality of life may be too crude and insensitive to capture the important gains in health outcomes due to new therapeutic interventions and programs in diabetes. Quality-of-care evaluations for diabetes are at risk of favoring inferior programs with lower costs simply because gains or losses in health outcomes go undetected.

Necrotizing lymphadenitis. A study of 30 cases.

Thirty patients with necrotizing lymph-adenitis, a disorder initially described in Japan and commonly misdiagnosed as malignant lymphoma, have been studied, in addition, stains for immunologic markers were performed. The patients included 21 United States residents and most commonly were young women with a subacute illness characterized by persistent, painless cervical adenopathy with or without fever. The excised lymph nodes were moderately enlarged and typically showed focal, well-circumscribed, paracortical, necrotizing lesions, and abundant karyorrhectic debris, scattered fibrin deposits, aggregates of large mononuclear cells, and a paucity of plasma cells and neutrophils. Immunohistochemical stains on frozen tissue sections were positive for 63D3 and Leu-2a, indicating an admixture of of histiocytes/macrophages and cytotoxic/suppressor T-lymphocytes in the necrotizing lesions. The etiology of necrotizing lymphadenitis and its distinction from other causes of reactive lymphadenitis are discussed. To our knowledge, this disorder has not previously been reported in the United States.

Optimal histopathologic examination of the sentinel lymph node for breast carcinoma staging.

Sentinel lymph node dissection is a minimally invasive surgical technique for staging of breast carcinoma. The optimal pathologic examination of the sentinel node (SN) has not yet been determined. Our standard protocol for evaluation of the SN in patients with breast cancer included frozen section at one level, plus paraffin sections at two levels, separated by 40 microm, and stained with hematoxylin and eosin and cytokeratin immunohistochemistry (IHC) at each paraffin section level. In the current study, we evaluated the use of step sections and cytokeratin IHC in 60 SNs (42 consecutive patients) that were tumor-negative on frozen section and hematoxylin and eosin staining at permanent section levels 1 and 2. The SN were reexamined with cytokeratin IHC at eight additional levels (levels 3-10) of the paraffin block, each separated by 40 microm. Previous IHC sections from levels 1 and 2 had shown micrometastases in nine SNs (eight patients) and no tumor cells in the remaining 51 SNs (34 patients). Of the 51 previously negative SNs, only two (4%) SNs from one (3%) patient had metastatic carcinoma cells in levels 3-10. Thus, the additional step sections with cytokeratin IHC did not significantly increase the number of patients with tumor-positive SNs. We currently recommend that the SN be examined with cytokeratin IHC at two levels of the paraffin block. This should optimize sentinel lymph node dissection as a staging technique and minimize the labor and financial burden associated with multiple step sections and IHC stains.

Progressive histopathologic abnormalities in the persistent generalized lymphadenopathy syndrome.

Using a quantitative classification, we evaluated serial lymph node biopsies in 20 homosexual men with Persistent Generalized Lymphadenopathy (PGL), and correlated the results with peripheral blood lymphocyte counts and clinical findings. In a median follow-up interval of 19 months, ten patients (50%) had progression from one histologic subtype of this disorder to another. Lymph nodes from the other 10 patients also demonstrated decreased numbers of organized follicles in the most recent specimens, in addition to progressive abnormalities of other histologic parameters and peripheral blood T4 counts. This suggests that these patients do not have stable disease. However, in a median follow-up interval of 19 months, only one (5%) of the patients had developed AIDS. We conclude that progressive lymph node histopathologic subtypes do not correlate well with decreased T4 lymphocyte counts or clinical course over a short time interval.

Smooth muscle tumors of the gastrointestinal tract. Flow cytometric quantitation of DNA and nuclear antigen content and correlation with histologic grade.

Simultaneous flow cytometric quantitation of DNA content and the proliferation-associated nuclear antigen p105 was performed on 41 gastrointestinal smooth muscle neoplasms and the results were correlated with histologic features. Aneuploid DNA stemlines were found in 17 cases (41%), including four of 15 (21%) tumors of unknown malignant potential, eight of 17 (47%) low-grade leiomyosarcomas, and five of seven (71%) high-grade leiomyosarcomas. In 10 of the 17 aneuploid tumors, an aneuploid peak was clearly identified on the single parameter DNA histogram, with a mean DNA index of 1.36. In the other seven aneuploid cases, a near-diploid, aneuploid population (mean DNA index, 1.08) was identified only by simultaneous immunofluorescence for p105. Clinical follow-up information was available for 14 patients. Mean survival of 10 patients with aneuploid tumors was 32 months, whereas mean survival of four patients with diploid tumors was 51 months. Of the seven patients who died within 1 year of diagnosis, six had aneuploid leiomyosarcomas. These findings demonstrate that DNA aneuploidy is common in high-grade gastrointestinal leiomyosarcomas and may be associated with shortened survival.

Malignant fibrous histiocytoma tumor cells resemble fibroblasts.

The malignant fibrous histiocytomas (MFHs) are a histologically heterogeneous group of sarcomas that have been postulated to be derived from, or have the capacity to differentiate into, histiocytes. To determine whether MFH tumor cells actually express the features of histiocytes, i.e., bone marrow-derived cells of monocyte-macrophage lineage, we studied the antigenic and enzymatic phenotype of 13 MFHs in situ using frozen and plastic sections, respectively. Five pleomorphic three fibrous, two myxoid, two giant cell, and one histiocytic MFH were studied. While tumor cells in 12 of 13 cases were positive for HLA-A,B,C, tumor cells in all cases failed to express antigens present on bone marrow-derived macrophages, i.e., leukocyte common antigen (L3B12), HLA-DR, Leu-M3, and Leu-3a. Interestingly 8 of 13 cases were positive for CALLA. Although nonspecific, this may prove useful in differential diagnosis. Enzyme histochemistry demonstrated that tumor cells in 9 of 13 cases were positive for membrane 5' nucleotidase (5'N+). Four of these were also alkaline phosphatase positive (ALKP+). All cases were either negative or weakly positive for acid phosphatase (ACIDP) and alpha-naphthyl acetate esterase (ANAE). Tumor cells were unreactive for alpha-naphthyl butyrate esterase (ANBE) and adenosine triphosphatase (ATP). These findings indicate that MFH tumor cells do not express the enzymatic profile of cells of monocyte/macrophage lineage which are membrane 5'N-/ALKP- and ACIDP+/ANAE+/ANBE+/ membrane ATP+. In fact, these data suggest a similarity to fibroblasts which are membrane 5'N+, variably ALKP+, weakly ACIDP+/ANAE+, and ANBE-/membrane ATP-. Osteoclast-like giant cells present in two cases did express a histiocytic phenotype, suggesting that they are reactive elements not derived from admixed tumor cells. These results suggest that MFHs are primitive mesenchymal neoplasms, most likely sarcomas composed of poorly differentiated fibroblasts, and are unrelated to true histiocytic neoplasms.

Histiocytic malignancies. Morphologic, immunologic, and enzymatic heterogeneity.

We have studied 14 hematopoietic malignancies with histologic features of histiocytic differentiation, using frozen section immunologic stains, plastic section enzyme histochemistry, and paraffin section immunocytochemistry. There was morphologic, immunologic, and enzymatic heterogeneity, including findings in seven cases that suggested differentiation toward specialized subsets of histiocytes. Four cases expressed a mature monocyte/macrophage phenotype by frozen section monoclonal antibody staining and three of these had histologic patterns diagnostic of malignant histiocytosis; two other cases had ATPase and S100 protein reactivity and morphologic features consistent with interdigitating (reticulum) cell proliferations; and one case was alkaline phosphatase positive, suggestive of differentiation toward fibroblastic reticulum cells. Four cases had histologic findings consistent with malignant histiocytosis, but weak or unreactive staining patterns and were considered poorly differentiated histiocytic or primitive hematopoietic malignancies. Three other cases, also morphologically consistent with malignant histiocytosis, were identified as probably T-cell lymphomas. The morphologic and phenotypic characteristics of non-neoplastic histiocytes and dendritic cell types and their related neoplasms are discussed. Histiocytic malignancies comprise a diverse group that can be identified and subclassified by immunologic and enzymatic techniques.

Double-blind, parallel, comparative study on quality of life during treatment with amlodipine or enalapril in mild or moderate hypertensive patients: a multicentre study.

OBJECTIVE: To compare tolerance, antihypertensive efficacy and impact on quality of life of amlodipine and enalapril in patients with mild or moderate hypertension. DESIGN: Multicentre, double-blind, double-dummy, comparative trial in general practice. Three phases were conducted: 4 weeks on placebo, 12 weeks of dose adjustment (amlodipine or enalapril) and a 38-week maintenance period. PATIENTS: Four hundred and sixty-one patients of both sexes were enrolled; 451 were available for efficacy evaluation at the end of the trial. TREATMENT: The patients were allocated to either amlodipine (231) or enalapril (230) treatment. If at the end of dose adjustment (amlodipine 5-10 mg/day, enalapril 10-40 mg/day) diastolic blood pressure was > or = 95 mmHg, hydrochlorothiazide (25-50 mg/day) was added (27 amlodipine patients and 45 enalapril patients). MAIN OUTCOME MEASURES: Blood pressure changes after 1 year of treatment; between- and within-group changes in quality of life as assessed by psychological general well-being, social and sexual functioning, health-risk perception, alertness, behaviour, and impact of symptom and side effects. RESULTS: Indices on quality of life were unchanged or increased (2-9%) in both groups. Blood pressure was normalized or reduced by > or = 10 mmHg in 204 (90%) and 190 (85%) patients on amlodipine and enalapril, respectively. Cough was the most frequently reported adverse event in the enalapril group (13%) and oedema in the amlodipine group (22%). Only eight (4%) patients on amlodipine and nine (4%) on enalapril were withdrawn because of drug-related adverse events. CONCLUSION: At similar blood pressure reduction in mild and moderate hypertension, quality of life is equally well maintained on amlodipine and enalapril therapy.

Quality of life and calcium channel blockade with nifedipine GITS versus amlodipine in hypertensive patients in Spain. Gastrointestinal Therapeutic System.

OBJECTIVE: Compliance with hypertension treatment is affected by treatment-related factors (complexity, side effects), efficacy and compound-specific effects that impact on quality of life. This study examined the differences in quality of life produced by two once-daily calcium channel blockers using different delivery systems: nifedipine gastrointestinal therapeutic system (GITS) and amlodipine. DESIGN: This was a double-blind, double-dummy, randomized clinical trial comparing nifedipine GITS (30 mg) and amlodipine (5 mg) for 24 weeks following a placebo run-in. Clinical, laboratory evaluations and quality-of-life data were assessed at screening, baseline randomization and three times during active therapy. SETTING: The study was conducted in 13 medical clinics in Spain. PATIENTS: The sample comprised 430 screened and 356 randomized patients with mild to moderate hypertension (diastolic blood pressure 95-114 mmHg). MAIN OUTCOME MEASURES: Change in systolic and diastolic blood pressure and in health-related quality of life were the main outcome measures. RESULTS: There were no significant differences between active treatment groups in the blood pressure changes (systolic blood pressure: nifedipine GITS -15.5 mmHg; amlodipine -15.7 mmHg). Spontaneous adverse events consistent with calcium channel blockage were not different. The nifedipine GITS group improved in all quality-of-life measures except Sexual Symptom Distress and showed a significantly greater improvement than amlodipine in overall Quality of Life (P< 0.05), General Perceived Health (P < 0.026) and its subscale Vitality (P < 0.019). The amlodipine group declined in overall Quality of Life, General Perceived Health, Vitality and Sleep Disturbance, and significantly in Sexual Symptom Distress (P < 0.045). However, this group improved in self-reported Cognitive Functioning (P=0.036), Mental Acuity (P < 0.005) and Detachment/disorientation (P=0.01). CONCLUSIONS: These results suggest compound-specific effects on quality of life that may be due to differences in the delivery system. Nifedipine GITS is short-acting (2 h half-life) and is delivered continuously over a 24 h period, while amlodipine has a half-life of 40 h, which may produce more sustained low-level effects. While a more beneficial profile was observed for nifedipine, amlodipine demonstrated potential positive effects on cognitive functioning.