Charley A. Budgeon

Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease

OBJECTIVES The objective of this study was to determine whether colchicine 0.5 mg/day can reduce the risk of cardiovascular events in patients with clinically stable coronary disease. BACKGROUND The presence of activated neutrophils in culprit atherosclerotic plaques of patients with unstable coronary disease raises the possibility that inhibition of neutrophil function with colchicine may reduce the risk of plaque instability and thereby improve clinical outcomes in patients with stable coronary disease. METHODS In a clinical trial with a prospective, randomized, observer-blinded endpoint design, 532 patients with stable coronary disease receiving aspirin and/or clopidogrel (93%) and statins (95%) were randomly assigned colchicine 0.5 mg/day or no colchicine and followed for a median of 3 years. The primary outcome was the composite incidence of acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke. The primary analysis was by intention-to-treat. RESULTS The primary outcome occurred in 15 of 282 patients (5.3%) who received colchicine and 40 of 250 patients (16.0%) assigned no colchicine (hazard ratio: 0.33; 95% confidence interval [CI] 0.18 to 0.59; p < 0.001; number needed to treat: 11). In a pre-specified secondary on-treatment analysis that excluded 32 patients (11%) assigned to colchicine who withdrew within 30 days due to intestinal intolerance and a further 7 patients (2%) who did not start treatment, the primary outcome occurred in 4.5% versus 16.0% (hazard ratio: 0.29; 95% CI: 0.15 to 0.56; p < 0.001). CONCLUSIONS Colchicine 0.5 mg/day administered in addition to statins and other standard secondary prevention therapies appeared effective for the prevention of cardiovascular events in patients with stable coronary disease.

Post-radioembolization yttrium-90 PET/CT - part 2: dose-response and tumor predictive dosimetry for resin microspheres

BackgroundCoincidence imaging of low-abundance yttrium-90 (90Y) internal pair production by positron emission tomography with integrated computed tomography (PET/CT) achieves high-resolution imaging of post-radioembolization microsphere biodistribution. Part 2 analyzes tumor and non-target tissue dose-response by 90Y PET quantification and evaluates the accuracy of tumor 99mTc macroaggregated albumin (MAA) single-photon emission computed tomography with integrated CT (SPECT/CT) predictive dosimetry.MethodsRetrospective dose quantification of 90Y resin microspheres was performed on the same 23-patient data set in part 1. Phantom studies were performed to assure quantitative accuracy of our time-of-flight lutetium-yttrium-oxyorthosilicate system. Dose-responses were analyzed using 90Y dose-volume histograms (DVHs) by PET voxel dosimetry or mean absorbed doses by Medical Internal Radiation Dose macrodosimetry, correlated to follow-up imaging or clinical findings. Intended tumor mean doses by predictive dosimetry were compared to doses by 90Y PET.ResultsPhantom studies demonstrated near-perfect detector linearity and high tumor quantitative accuracy. For hepatocellular carcinomas, complete responses were generally achieved at D70 > 100 Gy (D70, minimum dose to 70% tumor volume), whereas incomplete responses were generally at D70 < 100 Gy; smaller tumors (<80 cm3) achieved D70 > 100 Gy more easily than larger tumors. There was complete response in a cholangiocarcinoma at D70 90 Gy and partial response in an adrenal gastrointestinal stromal tumor metastasis at D70 53 Gy. In two patients, a mean dose of 18 Gy to the stomach was asymptomatic, 49 Gy caused gastritis, 65 Gy caused ulceration, and 53 Gy caused duodenitis. In one patient, a bilateral kidney mean dose of 9 Gy (V20 8%) did not cause clinically relevant nephrotoxicity. Under near-ideal dosimetric conditions, there was excellent correlation between intended tumor mean doses by predictive dosimetry and those by 90Y PET, with a low median relative error of +3.8% (95% confidence interval, -1.2% to +13.2%).ConclusionsTumor and non-target tissue absorbed dose quantification by 90Y PET is accurate and yields radiobiologically meaningful dose-response information to guide adjuvant or mitigative action. Tumor 99mTc MAA SPECT/CT predictive dosimetry is feasible. 90Y DVHs may guide future techniques in predictive dosimetry.

Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients

Human leukocyte antigen (HLA) mismatches have been shown to adversely affect renal allograft outcomes and remain an important component of the allocation of deceased donor (DD) kidneys. The ongoing importance of HLA mismatches on transplant outcomes in the era of more potent immunosuppression remains debatable. Using Australia and New Zealand Dialysis and Transplant Registry, live and DD renal transplant recipients between 1998 and 2009 were examined. The association between the number of HLA mismatches and HLA‐loci mismatches and outcomes were examined. Of the 8036 renal transplant recipients, 59% had between 2 and 4 HLA mismatches. Compared with 0 HLA mismatch, increasing HLA mismatches were associated with a higher risk of graft failure and patient death in the adjusted models. HLA mismatches were associated with an incremental risk of rejection although the relative risk was higher for live donor kidney transplants. Increasing HLA‐AB and HLA‐DR mismatches were associated with a greater risk of acute rejection, graft failure, death‐censored graft failure, and/or death. There was no consistent association between initial immunosuppressive regimen and outcomes. Our results corroborate and extend the previous registry analyses demonstrating that HLA mismatches are associated with poorer transplant outcomes independent of immunosuppression and transplant era.

Insertion of peripheral intravenous cannulae in the Emergency Department: factors associated with first-time insertion success

Background We sought to identify the reasons for peripheral intravenous cannulae insertion in the emergency department (ED), and the first-time insertion success rate, along with patient and clinician factors influencing this phenomenon. Methods A prospective cohort study of patients requiring peripheral cannulae insertion in a tertiary ED. Clinical and clinician data were obtained. Results A total 734 peripheral intravenous cannula (PIVC) insertions were included in the study where 460 insertions were analysed. The first-time insertion success incidence was 86%. The antecubital fossa (ACF) site accounted for over 50% of insertions. Multivariate logistic regression modelling to predict first-time insertion success for patient factors found: age <40 versus 80+ years, emaciated versus normal patient size, having a visible or palpable vein/s, and ACF versus forearm insertion site to be statistically significant. Statistically significant clinician factors predicting success were: higher number of prior cannulation procedures performed, and increased clinician perception of the likelihood of a successful insertion. When patient and clinician factors were combined in a logistic regression model, emaciated versus normal, visible vein/s, ACF versus forearm site, higher number of prior PIVC procedures performed and increased clinician perceived likelihood of success were statistically associated with first-time insertion success. Conclusions Peripheral intravenous cannulation insertion success could be improved if performed by clinicians with greater procedural experience and increased perception of the likelihood of success. Some patient factors predict cannulation success: ‘normal’ body weight, visible vein/s and cubital fossa placement; venepuncture may be a cheaper alternative for others if intravenous therapy is not imperative.

Dysphagia and factors associated with respiratory infections in the first week post stroke.

Background: Dysphagia occurs in approximately half of the stroke patients and is associated with respiratory infections; however, it is unclear what other factors contribute to an increased risk. This study aimed to provide evidence on factors associated with respiratory infections in the very acute stroke period. Methods: Retrospective review of 536 stroke patients admitted to Australian Hospitals in 2010. Data were collected on 37 clinical and demographic parameters. Univariable and multivariable logistic regression was performed. Results: The overall incidence of respiratory infection was 11%. On admission, requiring full assistance with mobility [OR 6.48, 95% CI 1.35, 31.16] and urinary incontinence [OR 3.21, 95% CI 1.16, 8.87] were associated with respiratory infections. During the first week post stroke nasogastric tubes (NGT) [OR 3.91, 95% CI 1.73, 8.80] and Nil By Mouth (NBM) [OR 5.62, 95% CI 1.54, 20.46] were associated with respiratory infections. Impaired GCS, ischaemic stroke and significantly impaired mobility were associated with swallowing difficulties. Conclusion: This study of a large cohort of acute stroke patients supports research indicating aspiration pneumonia is multifactorial in nature. NGT were associated with increased risk of respiratory infections and may contribute to infections by promoting oropharyngeal colonisation. Patients with severely impaired mobility were also at very high risk of respiratory infection.

Interobserver variability in the diagnosis of circumscribed sebaceous neoplasms of the skin

Aims: Separation of sebaceous adenoma, sebaceoma and well differentiated sebaceous carcinoma is a clinically important distinction which relies on a number of subjective criteria. In routine practice we had noted significant interobserver variability in the classification of these lesions. This study sought to determine the degree of interobserver variability between general surgical pathologists and dermatopathologists in the diagnosis of well differentiated cutaneous sebaceous neoplasms. Methods: We circulated 61 examples of well circumscribed cutaneous sebaceous neoplasms to nine pathologists, including dermatopathologists and general surgical pathologists who were asked to submit a diagnosis for each case. Fleiss’ kappa statistic was used for assessment of interobserver agreement. Results: We found that only seven cases (11%) had consensus agreement across all nine pathologists. Many cases had multiple diagnoses suggested, with three or more submitted diagnoses in 26 cases (43%), while 38 cases (62%) were diagnosed as sebaceous carcinoma by at least one pathologist. There was marked variability amongst the individual pathologists in the proportion of cases diagnosed as carcinoma, ranging from 5% to 57% of cases. Fleiss’ kappa statistic for all pathologists across all diagnostic categories was 0.44, amounting to only fair to moderate agreement. Conclusions: These data indicate that there is substantial interobserver variability in the diagnosis of well circumscribed sebaceous neoplasms. This was seen in both the separation of benign and malignant lesions, as well as in the classification of the benign entities. This interobserver variability is likely to have significant clinical implications in terms of potential for over- or under-treatment, as well as in selection of cases for mismatch repair protein evaluation.

The effect of an acidic cleanser versus soap on the skin pH and micro-flora of adult patients: A non-randomised two group crossover study in an intensive care unit

OBJECTIVES To test the effects of two different cleansing regimens on skin surface pH and micro-flora, in adult patients in the intensive care unit (ICU). RESEARCH METHODOLOGY Forty-three patients were recruited from a 23-bed tertiary medical/surgical ICU. The nineteen patients in Group One were washed using soap for daily hygiene care over a four week period. In Group 2, 24 patients were washing daily using an acidic liquid cleanser (pH 5.5) over a second four week period. Skin pH measurements and bacterial swabs were sampled daily from each for a maximum of ten days or until discharged from the ICU. MAIN OUTCOME MEASURES Skin surface pH and quantitative skin cultures (colony forming units). FINDINGS Skin pH measurements were lower in patients washed with pH 5.5 cleanser than those washed with soap. This was statistically significant for both the forearm (p = 0.0068) and leg (p = 0.0015). The bacterial count was not statistically significantly different between the two groups. Both groups demonstrated that bacterial counts were significantly affected by the length of stay in ICU (p = 0.0032). CONCLUSION This study demonstrated that the product used in routine skin care significantly affects the skin pH of ICU patients, but not the bacterial colonisation. Bacterial colonisation of the skin increases with length of stay.

Immunophenotypic analysis of ovarian endometrioid adenocarcinoma: Correlation with KRAS mutation and the presence of endometriosis

Aims: The relationship between endometriosis and ovarian endometrioid adenocarcinoma (OEC) is well recognised but it is unclear whether endometriosis positive and negative OECs develop via similar pathogenetic mechanisms. Materials: Sixty-seven low grade OECs (35 associated with endometriosis) were stained immunohistochemically for &bgr;-catenin, cyclin D1, BAF250a, PTEN, p53, WT1 and the mismatch repair (MMR) proteins MLH1, PMS2, MSH2 and MSH6. The results were correlated with KRAS mutation analysis and the presence of concurrent endometriosis. Results: Abnormal &bgr;-catenin, cyclin D1, BAF250a, PTEN, p53 and MMR protein expression was identified in 61.2%, 50.7%, 19.4%, 23.9%, 9.0%, and 6.0% of cases, respectively; these changes were equally common in endometriosis positive and negative tumours. WT1 expression was restricted to endometriosis negative EOC (8/32, 25%) and four WT1 positive cases showed sertoliform/spindle cell histological patterns. Abnormal &bgr;-catenin expression correlated with cyclin D1 overexpression but was inversely related to KRAS mutation. Immunophenotypic abnormalities were present in four of 17 histologically benign endometriotic lesions. Conclusions: Most immunophenotypic alterations were equally common in endometriosis associated and independent OECs but only the latter were associated with abnormal WT1 expression. The inverse relationship between abnormal &bgr;-catenin expression and KRAS mutation merits further study. Histologically benign endometriotic epithelium may show immunophenotypic abnormalities similar to those present in associated carcinomas.

Can’t swallow, can’t transfer, can’t toilet: Factors predicting infections in the first week post stroke

Post stroke infections are a significant clinical problem. Dysphagia occurs in approximately half of stroke patients and is associated with respiratory infections; however it is unclear what other factors contribute to an increased risk. This study aimed to determine which factors are most strongly predictive of infections in the first 7 days post stroke admission. A retrospective review of 536 stroke patients admitted to Australian hospitals in 2010 was conducted. Data were collected on 37 clinical and demographic parameters. Univariate and multivariate logistic regression analysis was performed. The overall incidence of infection was 21%. Full assistance with mobility and incontinence on admission were associated with increased odds of general infection. Nil by mouth and presence of a nasogastric tube were significantly associated with patients developing respiratory infections. Urinary incontinence was a significant predictor for a urinary tract infection. Incidence of infection was highest on day two post admission. This study found enteral feeding, requiring full assistance with mobility and incontinence were significantly associated with developing infections in acute stroke. It contributes valuable new data from a large cohort of stroke patients demonstrating a period of susceptibility to infection in the very acute post stroke period.

Merkel cell Polyomavirus and p63 status in Merkel cell carcinoma by immunohistocnemistry: Merkel cell Polyomavirus positivity is inversely correlated with sun damage, but neither is correlated with outcome

Summary The aim of this study was to determine the frequency of Merkel cell polyomavirus (MPyV) and p63 positivity by immunohistochemistry in a large cohort of primary Merkel cell carcinoma (MCC) from a region with high rates of actinic damage. We also aimed to determine whether there is any relationship between these markers and histological correlates of chronic sun exposure and to identify whether these markers have prognostic significance in our population. Ninety-five cases of primary cutaneous MCC were identified and stained with immunohistochemical markers for MPyV and p63. The presence of solar elastosis and squamous dysplasia in the overlying/adjacent skin were recorded as markers of actinic damage. Follow up data were obtained from the Western Australian Cancer Registry. MPyV was detected by immunohistochemistry in 23% of cases. There was a statistically significantly lower rate of positivity in tumours associated with markers of chronic sun damage as assessed by the presence of solar elastosis and squamous dysplasia. There was no association with overall or disease specific survival. p63 positivity was detected in 17% of cases. There was no association with markers of actinic damage or with overall or disease specific survival. Our data demonstrate a significant difference in rates of immunohistochemical positivity for MPyV between MCC in sun-damaged and non-sun-damaged sites. This may go some way to explaining previously identified geographical differences. When compared with a number of studies from Europe and North America, p63 positivity is less common in our population and does not show the strong prognostic significance that has been found in these other regions.