Diagnosing cancer in primary care
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Journal Article↗
Biomedical subjects
J Holden
Publications and source records attributed to J Holden.
Rapid progression of primary vaginal squamous cell carcinoma in a young HIV-infected woman.
BACKGROUND: The association of human immunodeficiency virus (HIV) infection with rapid progression of cervical and anal squamous cell carcinoma has been clearly established by several studies. Human papilloma virus (HPV) infection of the anogenital tract is believed to be the causative agent of cervical, anal, vaginal, and vulvar squamous cell carcinoma. While a myriad of reports exist in the literature pertaining to the rapid progression of cervical and anal carcinoma in HIV-infected patients, no association of HIV infection and vaginal carcinoma has been reported. We present an unusual case of a young woman infected with HIV who was diagnosed with advanced vaginal carcinoma and succumbed to her disease shortly thereafter despite aggressive treatment. CASE: A 40-year-old woman with a 2-year history of HIV infection presented with Stage IVA squamous cell carcinoma of the vagina and a large vesicovaginal fistula from the tumor eroding through the posterior bladder wall. Computed tomography (CT) of the abdomen and pelvis revealed a large tumor replacing the vagina with mild hydronephrosis and diffuse pelvic and inguinal lymphadenopathy. She underwent urinary diversion with a transverse colon conduit followed by pelvic radiation with weekly cisplatin chemosensitization. A repeat CT scan of the abdomen and pelvis upon completion of her treatment revealed progression of disease with multiple liver metastases and gastrohepatic ligament adenopathy. She subsequently died of advanced metastatic vaginal carcinoma 2 months after completion of treatment. CONCLUSION: Due to the rarity of primary vaginal carcinoma, the clinical behavior of this neoplasm in the HIV-infected patient is poorly understood. Our case indicates that, although vaginal carcinoma is a disease of the elderly, young women infected with HIV and HPV are predisposed not only to develop cervical or anal carcinoma but also may be at increased risk for vaginal carcinoma with more aggressive and less responsive disease. Furthermore, although vaginal carcinoma is usually a slow-growing neoplasm, this case illustrates the aggressive behavior of such a tumor when associated with HIV infection.
Adult↗
Inhibition of MAP kinase kinase causes morphological reversion and dissociation between soft agar growth and in vivo tumorigenesis in angiosarcoma cells.
Activated ras causes increased activity of several signal transduction systems, including the mitogen-activated protein kinase kinase (MAPKK) pathway and the phosphoinositol-3-kinase (PI-3-K) pathway. We have previously shown that the PI-3-K pathway plays a major role in regulation of ras-mediated tumor angiogenesis in angiosarcoma cells. However, the contribution of the MAPKK pathway to tumorigenesis and angiogenesis is not fully understood. Overexpression of constitutively active forms of MAPKK has previously been shown to transform nonmalignant NIH3T3 fibroblasts, but the effect of down-regulation of MAPKK on tumorigenesis and angiogenesis in a well established tumor has not been fully explored. We introduced a dominant negative MAPKK gene into SVR murine angiosarcoma cells. Introduction of a dominant negative MAPKK causes a significant decrease in proliferation rate in vitro and morphological reversion. Cells expressing the dominant negative MAPKK have a greatly decreased ability to form colonies in soft agar compared with wild-type cells. Despite the decreased cell growth in vitro and inability to grow in soft agar, the cells were equally tumorigenic in nude mice. Our results suggest that the MAPKK pathway is required for soft agar growth of angiosarcoma cells, and separates the phenotypes of soft agar growth versus in vivo tumorigenicity. These findings have implications in the development of signal transduction modulators as potential antineoplastic agents.
Agar↗
Cell proliferation and apoptosis in stage III inoperable non-small cell lung carcinoma treated by radiotherapy.
PURPOSE: The purpose of this study was to assess the prognostic value of the expression of p53 and bcl-2, the apoptotic index and the expression of topoisomerase II alpha in patients with inoperable non-small cell lung cancer (NSCLC) treated with high dose radiotherapy. PATIENTS AND METHODS: A number of 161 patients with inoperable NSCLC treated with high dose radiotherapy (60 Gy) were included. Immunohistochemical analysis was used to assess the expression of nuclear p53-protein, topoisomerase II alpha and cytoplasmatic expression of bcl-2, while spontaneous apoptosis was assessed using in situ labeling. The minimal follow up period was 2 years. RESULTS: Local control did not only depend on the presence of p53 expression, but also on the proportion of p53 positive cells. The most important prognostic factor was the apoptotic index. A high apoptotic index was associated with worse local control, more distant metastases and a significantly worse overall survival. No association was noted between the expression of bcl-2 and topoisomerase II alpha with any of the endpoints. CONCLUSION: This study indicates that p53 expression and the apoptotic index are prognostic factors with regard to local control in patients with inoperable NSCLC treated with radiotherapy and by combining these 2 factors, a clinically relevant estimation of the local control probability can be made. The apoptotic index turned out to be the only factor significantly related to survival.
Adult↗
CD40 ligand upregulates expression of the IL-3 receptor and stimulates proliferation of B-lineage acute lymphoblastic leukemia cells in the presence of IL-3.
The proliferative response of B cell precursor acute lymphoblastic leukemia (BCP-ALL) cells to IL-3 is dependent on the expression of functional IL-3 receptors (IL-3R). Here we report that CD40 ligand (CD40L) in the presence of recombinant IL-3 increased proliferation of BCP-ALL cells by upregulating expression of IL-3R. Upregulation of IL-3R in BCP-ALL cells was observed as early as 1 h after treatment with CD40L, and a 50- to 500-fold increase of IL-3R expression after 24 h was detected in all 12 cases studied. Moreover, expression of receptors for IL-7 (IL-7R) and stem cell factor (SCF-R, c-Kit) was also induced by CD40L in the majority of BCP-ALL cases examined; however, levels of induction were low compared to those for IL-3R. To test the functional activity of upregulated receptors for IL-3, SCF and IL-7, we evaluated the proliferation and growth of BCP-ALL cells cultured in serum-free media with CD40L plus these factors. When CD40L was added with either a single cytokine (IL-3, SCF and IL-7) or their combinations, cell proliferation was significantly increased as detected by DNA synthesis assay. Combinations of CD40L plus IL-3 and either SCF or IL-7 were able to support long-term growth of BCP-ALL cells for at least 8 weeks in three of the seven cases studied. Immunophenotyping and gene rearrangement studies indicated that cells in long-term cultures were monoclonal and retained their original phenotypes. The leukemic cells remained primarily dependent on the presence of IL-3 and its receptor for long-term growth, as shown by selective withdrawal of growth factors or antibody blockade of receptors. These results suggest an important role for CD40L in upregulating expression of IL-3R on BCP-ALL cells and enabling these cells to proliferate in long-term cultures in the presence of IL-3 and either SCF or IL-7.
Burkitt Lymphoma↗
Comparative effectiveness of general practitioner versus pharmacist dosing of patients requiring anticoagulation in the community.
OBJECTIVE: To compare pharmacist- with general practitioner-managed anticoagulation in the community. DESIGN: Included in the study were all patients who had been managed by general practitioners (GPs) and subsequently referred to the pharmacist-led outreach service within Gateshead & South Tyneside Health Authority. A retrospective analysis was carried out recording individual international normalized ratio (INR) estimations, the time interval between successive tests and whether the result resided within the prescribed therapeutic range. These values were derived for both the GP- and pharmacist-managed elements of care. SUBJECTS: Fifty-one patients who met the inclusion criteria identified from eight practices had been successively treated by GPs and then by pharmacists. Eighteen patients (35.3%) had a diagnosis of non-rheumatic atrial fibrillation, 10 (19.6%) had thromboembolic disease and 13 (25.5%) had valvular disease. RESULTS: In total, 1782 INR results were analysed. GPs were responsible for 1075 (60.3%) of these estimations and pharmacists for the remaining 707 (39.7%). Of the GP-monitored results the patient-mean proportion of estimates that resided within the prescribed therapeutic range was 0.6 (SD = 0. 21, n = 51) compared with pharmacist management where patients showed a mean in range proportion of 0.7 (SD = 0.18, n = 51, P = 0. 03). The mean inter-test interval was 28.6 days (SD = 8.65, n = 51) for GPs compared with 34.1 days (SD = 12.3, n = 51, P = 0.01) for pharmacists. The weighted INR index for GPs was 17.2 (SD = 7.93, n = 51) compared with 24.7 (SD = 13.15, n = 51, P < 0.001) for pharmacists. CONCLUSION: There is no apparent detriment to INR control when pharmacist management is compared with that of GPs. The overall proportion of INR estimations within the prescribed range is greater for pharmacists than for GPs and the interval between tests is longer for pharmacists compared with GPs.
Aged↗
Lentivirus infection in the brain induces matrix metalloproteinase expression: role of envelope diversity.
Infection of the brain by lentiviruses, including human immunodeficiency virus (HIV) and feline immunodeficiency virus (FIV), causes inflammation and results in neurodegeneration. Molecular diversity within the lentivirus envelope gene has been implicated in the regulation of cell tropism and the host response to infection. Here, we examine the hypothesis that envelope sequence diversity modulates the expression of host molecules implicated in lentivirus-induced brain disease, including matrix metalloproteinases (MMP) and related transcription factors. Infection of primary macrophages by chimeric HIV clones containing brain-derived envelope fragments from patients with HIV-associated dementia (HAD) or nondemented AIDS patients (HIV-ND) showed that MMP-2 and -9 levels in conditioned media were significantly higher for the HAD clones. Similarly, STAT-1 and JAK-1 levels were higher in macrophages infected by HAD clones. Infections of primary feline macrophages by the neurovirulent FIV strain (V(1)CSF), the less neurovirulent strain (Petaluma), and a chimera containing the V(1)CSF envelope in a Petaluma background (FIV-Ch) revealed that MMP-2 and -9 levels were significantly higher in conditioned media from V(1)CSF- and FIV-Ch-infected macrophages, which was associated with increased intracellular STAT-1 and JAK-1 levels. The STAT-1 inhibitor fludarabine significantly reduced MMP-2 expression, but not MMP-9 expression, in FIV-infected macrophages. Analysis of MMP mRNA and protein levels in brain samples from HIV-infected persons or FIV-infected cats showed that MMP-2 and -9 levels were significantly increased in lentivirus-infected brains compared to those of uninfected controls. Elevated MMP expression was accompanied by significant increases in STAT-1 and JAK-1 mRNA and protein levels in the same brain samples. The present findings indicate that two lentiviruses, HIV and FIV, have common mechanisms of MMP-2 and -9 induction, which is modulated in part by envelope sequence diversity and the STAT-1/JAK-1 signaling pathway.
AIDS Dementia Complex↗
Membership by Assessment of Performance: developing a method for assessing established general practitioners.
Over 200 general practitioners (GPs) and others have contributed to the development of Membership by Assessment of Performance (MAP): a new scheme for assessing established GPs. By means of a Delphi consultation with a broad cross-section of the profession, a working conference, piloting with potential candidates, and repeated checking with reference panels, the assessment was developed within two years. We report the development of MAP, including the results of the Delphi consultation, which asked 'Which aspects of a general practitioners performance are important to assess?'.
Delphi Technique↗
The Shipman inquiry.
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Death Certificates↗
Prognostic value of immunohistochemical expression of topoisomerase alpha II, MIB-1, p53, E-cadherin, retinoblastoma gene protein product, and HER-2/neu in adrenal and extra-adrenal pheochromocytomas.
No reliable pathologic criteria have been identified that predict clinical behavior in adrenal and extra-adrenal pheochromocytomas (PHEOs). Reliable prognostic markers for the prediction of clinical outcome are needed to assign optimal treatment for potentially malignant tumors. In this report, we evaluated several molecular markers (topoisomerase II alpha, E-cadherin, HER-2/neu, and retinoblastoma (RB) gene protein) that have not been previously studied in PHEOs. Paraffin-embedded, formalin-fixed tissue blocks from 50 cases of PHEO (30 benign and 20 malignant, 31 adrenal and 19 extra-adrenal) were obtained from University of Utah Health Sciences Center, Salt Lake City, and the Medical College of Wisconsin, Milwaukee. Gross (tumor size, weight, local extension, cyst formation, hemorrhage, necrosis), microscopic (pleomorphism, hyaline globules, intranuclear inclusion, mitotic count, capsular and vascular invasion, ganglionic/neuronal differentiation), and immunohistochemical features (topoisomerase II alpha, p53, MIB-1, E-cadherin, RB, and HER-2/neu) were studied. With the exception of vascular invasion (P = 0.025), there were no unequivocal gross or microscopic characteristics that distinguished benign from malignant lesions (P approximately = 0.11-0.71). Topoisomerase III and MIB-1 indices in malignant lesions were significantly higher than those observed in benign lesions (P = 0.012 and 0.019). Differences in p53 expression were not statistically significant (P = 0.082). Loss in RB protein product expression was significantly more common in malignant lesions (P = 0.001), E-cadherin loss and HER-2/-neu overexpression were not observed in any of the benign or malignant lesions. We studied the immunohistochemical expression of topoisomerase II alpha, MIB-1, p53, RB gene protein product, E-cadherin, and HER-2/neu in a series of adrenal and extra-adrenal PHEOs. Overexpression of topoisomerase II alpha and MIB-1 and loss of RB protein product were more common in malignant lesions, whereas p53, E-cadherin, and HER-2/neu do not seem to have diagnostic utility in the prediction of biologic behavior in these neoplasms.
Adolescent↗
Proliferation, C-myc, and cyclin D1 expression in diffuse alveolar damage: potential roles in pathogenesis and implications for prognosis.
In this study we compared expression of DNA topoisomerase IIalpha, a marker of cellular proliferation, c-myc, and cyclin D1 in lung biopsy specimens showing diffuse alveolar damage (DAD) with control lung tissues. We subsequently correlated DNA topoisomerase IIalpha, c-myc, and cyclin D1 expression with survival. We hypothesized that poor outcome may correlate with a higher proliferation index, and that c-myc and cyclin D1 activation are potentially important regulators of both proliferation and apoptosis in DAD. Immnuohistochemical stains for c-myc, cyclin D1, and DNA topoisomerase IIalpha were performed on 10 cases of DAD (15 cases for DNA topoisomerase IIalpha) and 10 control lungs. A proliferation index for each case was calculated by dividing the number of nuclei expressing DNA topoisomerase IIalpha by the total number of nuclei counted. The percentages of alveolar pneumocytes and interstitial cells staining positively for c-myc and cyclin D1 were estimated. The average proliferation index (DNA topoisomerase IIalpha index) in DAD (0.16 +/- 0.06, n = 15) was significantly greater than in control lungs (0.00 +/- 0.01, n = 10) (P < .0001). The average proliferation index of patients with DAD who died of respiratory failure (0.18 +/- 0.05, n = 9) was significantly greater than the average proliferation index of patients whose respiratory disease resolved or stabilized (0.11 +/- 0.05, n = 5) (P < .03). Expression of c-myc in alveolar pneumocytes and interstitial cells was more intense and slightly more widespread in cases of DAD compared with control lungs. In 9 of 10 cases of DAD, cyclin D1 expression was present in up to 30% of alveolar pneumocytes and up to 10% of interstitial cells. No staining for cyclin D1 was present in control lungs. These results show that the proliferation index in DAD potentially correlates with patient survival. Furthermore, enhanced expression of c-myc and cyclin D1 may contribute to dysregulation of cellular proliferation and apoptosis observed in DAD.
Adolescent↗
Isoflavones in retail and institutional soy foods.
A national sampling plan was developed to select the most widely used isoflavone-containing foods in the United States. Foods were selected based on their retail volume and sampled in five geographical areas representing seven metropolitan areas. Isoflavones were analyzed from composite samples, raw and cooked, and reported by brand. Quality control measures were evaluated throughout the study. Isoflavone levels ranged from 1 microg/g in soy sauces to 540 microg/g in tempeh. Soymilk and tofu represented the major portion of soy foods evaluated. These data will appear in the electronic version of USDA Handbook No. 8 of Food Composition Data in 1999.
Isoflavones↗
Hepatitis B vaccination for occupational risk: an audit in general practice.
Surveys of hepatitis B vaccine coverage among patients at risk of infection in an urban practice in north west England in 1992 and 1998 showed that the proportion of patients ascertained to be at risk had increased from 4% (194) to 5% (258) and coverage (with a full course of hepatitis B vaccine, with or without confirmed immunity) from 46% to 78%. The contribution from occupational health departments was poorly documented, identifying a need for increased communication.
Adolescent↗
Small groups and preparation for FBA.
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Clinical Competence↗
Laboratory consolidation. Minimizing the angst and aggravation.
In response to decreasing payment structures, many labs have begun considering those programs that strike fear in the hearts of employees everywhere--consolidation. To avoid whispers of layoffs, salary cuts, and scheduling disasters that become grist for the rumor mill, try constant communication and a structured management.
Health Facility Merger↗
Is international travel useful for general practitioners? A survey of international travel scholarships.
BACKGROUND: The Royal College of General Practitioners has offered international travel scholarships for the past decade. Each year a number of general practitioners travel from the UK to work or study assisted by the scheme, while others come to this country for similar purposes. AIM: To investigate the value of international scholarships for recipients and others. METHOD: All those receiving awards in 1988-94 were surveyed by postal questionnaire. RESULTS: Fifty-one out of 58 award winners (88%) replied. Almost all cited some of a wide variety of personal benefits from international travel, and some established continuing links with colleagues overseas. Many gave examples of useful results for others, both patients and colleagues. Scholarships appear to have made a significant contribution to careers, especially for those based outside Britain. CONCLUSION: Relatively modest travel scholarships were viewed both favourably in hindsight and produced a wide range of benefits to recipients, colleagues, and patients. International travel should probably be considered more widely in career planning.
Education, Medical, Continuing↗
Analysis of 1263 deaths in four general practices.
BACKGROUND: The death of a patient is a significant event that occurs often enough in general practice for it to have the potential to tell us much about the care we provide. There are few large series in the literature and we still know little about the collaborative use of this outcome measure. AIM: To determine the pattern of deaths and potentially preventable factors in our practices. METHOD: We completed a standard data collection form after each death in four general practices over a 40-month period. The results were discussed at quarterly meetings. RESULTS: A total of 1263 deaths occurred among our registered patients during the period of the audit. Preventable factors contributing to deaths were considered to be attributable to: patients (40%): mainly cigarette smoking, poor compliance, and alcohol problems; general practice teams (5%): mainly delayed referral, diagnosis and treatment, and failure to prescribe aspirin to patients with vascular disease; hospitals (6%): mainly delayed diagnosis and perceived treatment problems; the environment (3%): mainly falls, principally resulting in fractured neck of femur. CONCLUSION: A simple audit of deaths along the lines that we describe gives important information about the care provided by general practice teams and those in hospital practice. It has both educational value and is a source of ideas for service improvement and further study, particularly when carried out over several years.
Accidental Falls↗
Topoisomerase II expression in osseous tissue.
The molecular mechanisms that mediate the transition from an osteoprogenitor cell to a differentiated osteoblast are unknown. We propose that topoisomerase II (topo II) enzymes, nuclear proteins that mediate DNA topology, contribute to coordinating the loss of osteoprogenitor proliferative capacity with the onset of differentiation. The isoforms topo II-alpha and -beta, are differentially expressed in nonosseous tissues. Topo II-alpha expression is cell cycle-dependent and upregulated during mitogenesis. Topo II-beta is expressed throughout the cell cycle and upregulated when cells have plateaued in growth. To determine whether topo II-alpha and -beta are expressed in normal bone, we analyzed rat lumbar vertebrae using immunohistochemical staining. In the tissue sections, topo II-alpha was expressed in the marrow cavity of the primary spongiosa. Mature osteoblasts along the trabecular surfaces did not express topo II-alpha, but were immunopositive for topo II-beta, as were cells of the marrow cavity. Confocal laser scanning microscopy was used to determine the nuclear distribution of topo II in rat osteoblasts isolated from the metaphyseal distal femur and the rat osteosarcoma cells, ROS 17/2.8. Topo II-alpha exhibited a punctate nuclear distribution in the bone cells. Topo II-beta was dispersed throughout the interior of the nucleus but concentrated at the nuclear envelope. Serum starvation of the cells attenuated topo II-alpha expression but did not modulate expression of the beta-isoform. These results indicate that the loss of osteogenic proliferation correlates with the downregulation of topo II-alpha expression.
Animals↗