Epidemiology of biopsy-proven giant cell arteritis in South Australia.

BACKGROUND/AIM: To determine the epidemiology and clinical features of biopsy-proven giant cell arteritis (GCA) in South Australia (SA). METHODS: Patients with biopsy-proven GCA were identified from pathology reports of temporal artery biopsies at SA Pathology laboratories, from 1 January 1992, to 31 July 2011. Epidemiological data were collected through patient questionnaires and standardised case note reviews. Incidence was estimated using Australian Bureau of Statistics population data for SA. Seasonality was analysed by Cosinor analysis, and time-to- event analysis was performed for the duration of steroid use. RESULTS: There were 314 cases of biopsy-proven GCA (72% female). The mean age at diagnosis of GCA was 78 years (interquartile range 72-82). The estimated population incidence for people over 50 was 3.2 per 100,000 person years. The female : male incidence ratio was 2.3 (P < 0.001), and incidence increased with each age decade. There was evidence of seasonal variation (P = 0.015), with higher rates observed in the summer months. Clinical data were available for 163 patients (68% female, median age 78 years). The most common presenting clinical features were temporal headache (74%), visual disturbance (68.4%), jaw claudication (59.3%) and symptoms of polymyalgia rheumatica (56%). The median initial steroid dose was 60 mg, with median duration of steroid use 4.5 years. Corticosteroid side-effects were common, affecting 89%, with 34% reporting five or more. CONCLUSIONS: This is the first epidemiological study of Australian biopsy-proven GCA patients. Age at onset and gender associations were similar to other Western populations. There was a high burden of steroid use in these patients.

Antigenic variation of Borrelia hermsii.

At least 24 different serotypes were detected in populations of Borrelia hermsii that originated from a single organism. These serotypes were identified by staining with specific fluoresceinated antisera prepared against cloned populations of living organisms of each type. In the order of decreasing frequency, the 10 types more often encountered were 7, which was clearly dominant, and 2, 17, 24, 13, 2, 1, 21, 11, and 12. Each of the 24 types were shown to change to 7 or more other serotypes. Spirochetemia in mice was persistent, and relapses occurred when the concentration of organisms was sufficient for detection by visual means. After mice were inoculated with a single organism, peak spirochetemia usually occurred on day 4, after which clearance of organisms occurred, and an apparently pure population was replaced by a mixed population consisting of as many as seven variants. These types persisted for 2-3 d before being replaced by other types. Conversions occurred constantly and were independent of relapses. The rate of conversion in mice treated with cyclophosphamide to delay antibody production was comparable to that of controls. Spontaneous conversion was clearly demonstrated in tubes of fortified Kelly's medium inoculated with a single organism of type 7 or 21. 11 different variants appeared in eight cultures of type 21 by the time growth had reached 4 X 10(6)-10(7) organisms/ml. The rate of spontaneous change was estimated to be or approximately 10(-4)-10(-3) per cell per generation.

Serous carcinoma of the uterus-determination of HER-2/neu status using immunohistochemistry, chromogenic in situ hybridization, and quantitative polymerase chain reaction techniques: its significance and clinical correlation.

Uterine serous papillary carcinoma (USPC) are high-grade tumors with Her2 gene expression and poor prognosis. The human gene Her2 is a proto-oncogene that encodes a protein with tyrosine kinase activity. The objective of this study was to determine Her2 protein expression and gene amplification in USPC using three methods: immunohistochemistry (IHC), chromogenic in situ hybridization (CISH), and quantitative polymerase chain reaction (Q-PCR), to compare the three techniques, and to correlate Her2 expression and amplification with clinical outcome. Clinical data were obtained from the records of the patients provided by the database of the Gynaecological Cancer Unit at the Royal Adelaide Hospital. Paraffin-embedded tissues of 45 cases were examined using three techniques. Her2 positive rate was 40%. About 13% was strongly positive by all three methods. About 67% Her2 positive patients had advanced-stage disease. Relapse rate was 61% (P = 0.6). Stages I and II had a better survival with negative receptor. Age and stage were major prognostic variables in Cox analysis. Marker status did not reach statistical significance in overall survival (OS) and relapse-free survival (RFS), but had a hazard ratio (HR) of 1.5 in RFS. Five-year OS with Her2 negative was 39%. HR was 0.97 (95% CI 0.46-2.1). RFS was 39% and HR was 1.4 (95% CI 0.65-2.9). The three methods have strong correlation. IHC, 3+ positive cases should be regarded as exhibiting evidence of gene amplification and do not require further testing. Equivocal results require further testing by CISH or PCR. Age and stage are strong prognostic variables and receptor status has a HR of 1.5 in RFS. The therapeutic role of Trastuzumab should be tested in clinical trial setting.

Inhalation of iron-abundant gas metal arc welding-mild steel fume promotes lung tumors in mice.

Welding fumes were reclassified as a Group 1 carcinogen by the International Agency for Research on Cancer in 2017. Gas metal arc welding (GMAW) is a process widely used in industry. Fume generated from GMAW-mild steel (MS) is abundant in iron with some manganese, while GMAW-stainless steel (SS) fume also contains significant amounts of chromium and nickel, known carcinogenic metals. It has been shown that exposure to GMAW-SS fume in A/J mice promotes lung tumors. The objective was to determine if GMAW-MS fume, which lacks known carcinogenic metals, also promotes lung tumors in mice. Male A/J mice received a single intraperitoneal injection of corn oil or the initiator 3-methylcholanthrene (MCA; 10 µg/g) and, one week later, were exposed by whole-body inhalation to GMAW-MS aerosols for 4 hours/day x 4 days/week x 8 weeks at a mean concentration of 34.5 mg/m3. Lung nodules were enumerated by gross examination at 30 weeks post-initiation. GMAW-MS fume significantly increased lung tumor multiplicity in mice initiated with MCA (21.86 ± 1.50) compared to MCA/air-exposed mice (8.34 ± 0.59). Histopathological analysis confirmed these findings and also revealed an absence of inflammation. Bronchoalveolar lavage analysis also indicated a lack of lung inflammation and toxicity after short-term inhalation exposure to GMAW-MS fume. In conclusion, this study demonstrates that inhalation of GMAW-MS fume promotes lung tumors in vivo and aligns with epidemiologic evidence that shows MS welders, despite less exposure to carcinogenic metals, are at an increased risk for lung cancer.

Limb ischaemia after intra-arterial injection of Temazepam gel: histology of nine cases.

AIMS: To record the histopathological findings associated with intra-arterial injection of Temazepam gel by nine drug misusers. METHODS: Standard histological examination and immunocytochemistry for endothelial markers (factor VIII related antigen, Ulex europaeus lectin) were carried out. RESULTS: Intra-arterial injection of Temazepam gel may cause severe vascular injury and lead to amputation of fingers or limbs. Histological changes include myocyte necrosis, interstitial oedema, extensive arterial, venous, and capillary thrombosis, and sometimes vasculitis, endothelial swelling, and denudation. CONCLUSIONS: Inadvertent injection of Temazepam gel into arteries may cause catastrophic ischaemic damage, possibly as a result of toxic effects on endothelial cells.

Efficacy of cytotoxic agents for the prevention of laparoscopic port-site metastases.

BACKGROUND: Recent experimental studies support initial clinical impressions that laparoscopic surgery for malignant neoplasms may be associated with an increased incidence of metastases to port sites. This study investigated in an experimental model the influence of cytotoxic agents (administered intraperitoneally or intramuscularly) on the development of port-site metastases following laparoscopic surgery. METHODS: Seven days after the implantation of an adenocarcinoma in the left abdominal flank, 72 Dark Agouti rats underwent laparoscopy with carbon dioxide insufflation, instillation of an intraperitoneal agent, and intraperitoneal tumor laceration within the following study groups (12 rats in each group): (1) control (no intraperitoneal instillation); (2) intraperitoneal instillation of isotonic sodium chloride solution (0.9%); (3) intraperitoneal instillation of povodine-iodine (1:10 dilution of povidine-iodine and isotonic sodium chloride solution); (4) intraperitoneal instillation of methotrexate (0.125 mg of methotrexate in 3 mL of isotonic sodium chloride solution); and (5) intraperitoneal instillation of aqueous chlorhexidine acetate. Twelve additional rats underwent laparoscopic tumor laceration following intramuscular injection of 0.125 mg of methotrexate (no intraperitoneal agent). Rats were killed 7 days after the procedure, and the wounds were examined histologically by a blinded histopathologist for the presence of tumor metastases. RESULTS: No tumor was found in any port site following the intraperitoneal administration of povidine-iodine (P=.04). In contrast, port-site metastases developed in the control group (5 [41.7%] of 12), the isotonic sodium chloride solution group (4 [33.3%] of 12), the chlorhexdine group (4 [33.3%] of 12), the intraperitoneal methotrexate group (2 [16.7%] of 12), and the parenteral methotrexate group (5 [41.7%] of 12). CONCLUSIONS: The results of this study suggest that the development of metastases to port sites following laparoscopic surgery may be prevented by the intraperitoneal instillation of diluted povodine-iodine. Other agents failed to influence the incidence of port-site metastases. Further studies are needed to determine if these findings can be applied to humans.

Mitomycin C as an adjunct in the treatment of localised ocular surface squamous neoplasia.

AIM: To report the outcome of topical mitomycin C (MMC) used as adjunctive treatment following primary excision of ocular surface squamous neoplasia (OSSN). METHOD: Prospective, non-comparative interventional case series of 27 primary OSSN lesions from 26 patients treated in a single ocular oncology centre over a 4 year period. RESULT: 27 cases of OSSN received a treatment regimen of surgical excision, followed by topical MMC. Mean follow up of 27 (SD 12) months (range 12-50, median 25 months) revealed zero recurrences. CONCLUSION: MMC treatment following surgical excision decreases the recurrence rate of primary ocular surface neoplasia and should be considered as adjunctive therapy in primary treatment.

In vitro bacteriological evaluation of the effectiveness of antimicrobial irrigating solutions.

Nineteen strains of pathogenic aerobic bacteria were exposed for fifteen seconds in vitro to varying concentrations of five antibiotics and of polyvinyl povidone iodine in saline solution. The presence of human plasma in the solution (30 per cent by volume) did not affect bacterial sensitivity to the antibiotics. Most of the bacteria were sensitive to the solutions during that brief exposure. Bacteria which were more sensitive by disc sensitivity tests were more sensitive to the solutions. Polyvinyl povidone iodine sterilized all cultures in concentrations as low as 25 per cent. It is proposed that the use of appropriate antimicrobial solutions as wound irrigants may reduce postoperative infection rates by killing bacteria which contaminate the surface of the wound during operation.

Excision of laparoscopic port sites increases the likelihood of wound metastases in an experimental model.

BACKGROUND: Case reports of patients developing tumor metastases at port sites following laparoscopic surgery have prompted the development of preventive strategies to address this potential problem, including local excision of the port sites. While it has been suggested that this strategy could be used clinically, its efficacy has not been established. METHODS: Twenty four immune-competent Dark Agouti rats underwent laparoscopy and standardized intraperitoneal laceration of an implanted abdominal flank tumor, using an established laparoscopic cancer model. Rats were randomized to either control (n = 12) or wound excision (n = 12) groups. Both groups underwent laparoscopy using carbon dioxide (CO2) insufflation and two mini-laparoscopy ports. In the wound excision group, one of the port site wounds was excised following desufflation of the abdominal cavity. One week later, the port site wounds were excised for histological examination. RESULTS: Wound involvement with tumor was significantly more common following wound excision than with untreated control wounds (nine of 12 vs two of 12, p = 0.002). In the wound excision group, tumor metastases arose preferentially in the excised port site wound. CONCLUSION: This study suggests that excision of laparoscopy port site wounds following laparoscopic surgery for cancer does not prevent the subsequent development of port site tumors. Furthermore, the excision of port sites may actually increase the risk of tumor metastases arising in port sites, suggesting that the clinical application of this strategy should be avoided pending further evaluation.

Hematogenous spread as a mechanism for the generation of abdominal wound metastases following laparoscopy.

BACKGROUND: We designed this study to determine whether hematogenous spread has a role in the etiology of port site metastases following laparoscopic surgery. METHODS: The study design had two parts. In experiment 1, two groups (n = 30) of male Dark Agouti rats were studied. Under general anesthesia, the first group (20 rats) underwent 15 mins of laparoscopic insufflation, followed by an injection of a suspension of 105 Dark Agouti mammary adenocarcinoma (DAMA) cells into the internal jugular vein and a further 15-mins period of insufflation. The laparoscopic ports were then removed, and the wounds were closed and marked. In the second group (n = 10), the procedure was identical except that a 2.5-cm midline laparotomy was performed 15 mins after the commencement of anesthesia and insufflation was not used. The laparotomy was closed in two layers. In experiment 2, one group (n = 4) was studied. The study protocol was identical to the first laparoscopic group except that a larger number of 106 DAMA cells were injected. All rats in both experiments were killed 15 days later, and the injection site, laparoscopy wounds, and laparotomy wound were examined histologically by a blinded histopathologist. RESULTS: In experiment 1, one port site tumor was detected in the laparoscopic group and no wound metastases were found in the laparotomy group. Postoperative weight loss was significantly less in the laparoscopic group (p < 0.001). In experiment 2, no port site metastases were detected. CONCLUSION: Although hematogenous spread is a possible mechanism in the development of port site metastases, judging from the low number of port site metastases in this study as compared to previous reports using this tumor model, this mechanism is unlikely to be a major contributor to the problem of wound metastasis following laparoscopy.

186Re-labeled antibodies to p185HER2 as HER2-targeted radioimmunopharmaceutical agents: comparison of physical and biological characteristics with 125I and 131I-labeled counterparts.

Overexpression of the HER2/neu protooncogene has been shown to correlate with poor clinical prognosis. A murine monoclonal antibody (4D5) directed against the extracellular domain (ECD) of p185HER2 has been shown to inhibit in vitro and in vivo growth of carcinomas overexpressing HER2 and has been humanized (rhuMAb HER2). The objective of the study was the identification of an agent which might be useful for in vitro studies, tumor imaging and/or radioimmunotherapy by linking beta-emitting radionuclides to these HER2-targeted antibodies. Murine 4D5 and humanized rhuMAb HER2 were radiolabeled with 125I, 131I or 186Re. Physical characteristics (TCA precipitability, SDS-PAGE, size exclusion chromatography), binding affinities to the HER2 ECD (in an ELISA and on SK-BR-3 cells) and antiproliferative activities of the radiolabeled antibodies were determined. Although 131I-4D5 and 131I-rhuMAb HER2 usually retained > 85% ECD binding, they exhibited increased aggregation and fragment content, drastically reduced antiproliferative activities and poor stability upon storage at 4 degrees C. For these antibody preparations, conservation of binding did not necessarily correlate with preservation of bioactivity indicating the importance of bioactivity determinations in radiolabeled antibody studies. Conversely, 4D5 and rhuMAb HER2 labeled with 125I or 186Re maintained physical properties, ECD binding, antiproliferative activities and were stable upon storage at 4 degrees C for at least 8 days. The superior retention of physical and biological characteristics of 186Re-labeled 4D5 and rhuMAb HER2 compared with their 131I-labeled counterparts suggests the potential for their use as radioimaging and radioimmunotherapeutic agents in the treatment of HER2 overexpressing tumors.

Prospective audit of costs and outcome of aminoglycoside treatment and of therapy for gram-negative bacteraemia.

The aims of this study were to audit the monitoring of aminoglycoside treatment to develop a method for measurement of the cost and outcome of treatment, and to assess the accuracy of a previously published sepsis score to predict cost and outcome. Measurements of costs and outcomes were also made for all patients (n = 85) with Gram-negative bacteraemia. Of these, 40 received an aminoglycoside and an additional 215 patients received aminoglycosides for other indications (total aminoglycoside patients 255; total patients 300). There were no interpretable assays for 82 (32%) of the aminoglycoside patients and only 33/173 (19%) patients assayed had first peak serum concentrations within the recommended range of 8-10 mg/L. Median costs of aminoglycoside treatment were 599 pounds in neutropenic patients, 471 pounds in ICU patients and 185 pounds in other patients. In the bacteraemic patients, median costs of aminoglycoside regimens (278 pounds) were higher than for non-aminoglycoside regimens (97 pounds). Death in hospital was twice as common in bacteraemic patients (20% versus 10%) and there was a stepwise increase in rate of mortality with sepsis scores. Treatment costs were markedly higher in patients who failed to respond to initial treatment, the mean difference in cost was 418 pounds per patient (95% CI 89 pounds - 747). Sepsis scores only explained 2.6% of the variance in treatment costs, and 22 patients with zero sepsis scores received prolonged courses of i.v. antibiotic treatment at an average cost of 209 pounds per patient. In conclusion, aminoglycoside regimens rarely conformed to accepted standards of care and treatment failure was associated with markedly increased treatment costs. Three readily measurable indicators of adverse outcome were identified (death in hospital, change of i.v. treatment and readmission within 2 weeks of discharge) and all were related to initial severity of illness as measured by sepsis score. The sepsis score may prove useful for assessment of individual risk but would benefit from further analysis to validate and possibly reduce the number of items in the score.

Drug-related problems in elderly patients admitted to Tayside hospitals, methods for prevention and subsequent reassessment.

INTRODUCTION: although drug-related problems (DRPs) are known to be prevalent in elderly patients, the literature on prevention of iatrogenic disease is sparse. The present study addresses this requirement. OBJECTIVES: to assess the incidence of DRPs in elderly patients admitted to Tayside hospitals before (phase I) and after (phase II) implementation of preventive strategies. DESIGN: all elderly people admitted to hospital were screened by a pharmacist; individual case reviews were prepared for all those with a potential DRP and reviewed by a three-member panel which made a final decision on the presence of a DRP and its contribution to admission. SETTING: all hospital wards admitting elderly patients in the Tayside region of Scotland. SUBJECTS: 1011 elderly patient admissions over a 9-month period (phase I); 857 elderly patient admissions over an 8-month period (phase II). MAIN OUTCOME MEASURES: incidence of DRPs before and after targeted intervention strategies (information bulletin for general practitioners, patient information leaflet, oral presentation to trainee general practitioners). RESULTS: in phase I, the incidence of DRPs was 144/1011 (14.2%), with 54/1011 (5.3%) of the admissions identified as being definitely or probably drug-related. Non-steroidal anti-inflammatory drugs (NSAIDs) were the main drug group involved, being responsible for 15/54 (28%) of admissions primarily due to a DRP. Over 66% of admissions due to adverse effects of NSAIDs were considered to be definitely preventable. In phase II, after targeted intervention strategies, there was no significant reduction in total incidence of DRPs or incidence of DRPs related to NSAIDs. However, there appeared to be an improvement in the first 4 months, and a significant drop in NSAID prescribing in Tayside compared with the rest of Scotland was observed. CONCLUSION: DRPs remain a significant problem in elderly patients and NSAIDs are the major contributor. The intervention strategies used in the study were not demonstrably effective, but a continuous programme of education may be necessary to limit NSAID use.

Cyclo-oxygenase-2 expression in esophageal adenocarcinoma as a determinant of clinical outcome following esophagectomy.

The aim of this study was to determine if cyclo-oxygenase-2 (COX-2) expression in adenocarcinoma of the esophagus affects survival outcome in patients undergoing esophagectomy. Ten patients surviving more than 3 years following an esophagectomy for adenocarcinoma of the esophagus were identified from an esophagectomy database maintained by the University of Adelaide Department of Surgery. An additional group of 10 patients, who underwent esophagectomy for adenocarcinoma, but who died within 12 months of surgery due to recurrent disease, were also identified. Pieces of the original formalin fixed carcinoma tissue embedded in paraffin blocks from all of these patients were obtained, and slices of the tumor specimens underwent immunohistochemical staining with COX-2 protein. The extent of staining was then graded by a single 'blinded' pathologist: grade 0, no staining; grade 1 +, limited staining; and grade 2 +, strong staining. Kaplan-Meier survival curves were then constructed and used to determine correlations between survival and COX-2 staining, tumor T-stage, local lymph node metastases, and tumor vascular invasion. Ninety-five percent (19/20) of patients stained positively for COX-2. Patients with grade 2 + staining had a significantly poorer survival outcome compared to grade 1 + patients (P = 0.03). There were also trends towards shorter survival with worsening T-stage, lymph node metastasis and vascular invasion. COX-2 protein appears to be expressed by most esophageal adenocarcinomas. An increased level of expression of COX-2 was associated with a poorer survival outcome in this study. COX-2 protein expression association could be a better prognostic indicator for esophageal adenocarcinoma than traditional histopathological staging.