Risk factors for inflammatory and non-inflammatory breast cancer in North Africa.

PURPOSE: Studies of the etiology of inflammatory breast cancer (IBC), a rare but aggressive breast cancer, have been hampered by limited risk factor information. We extend previous studies by evaluating a broader range of risk factors. METHODS: Between 2009 and 2015, we conducted a case-control study of IBC at six centers in Egypt, Tunisia, and Morocco; enrolled were 267 IBC cases and for comparison 274 non-IBC cases and 275 controls, both matched on age and geographic area to the IBC cases. We administered questionnaires and collected anthropometric measurements for all study subjects. We used multiple imputation methods to account for missing values and calculated odds ratios (ORs) and 95% confidence intervals (CIs) using polytomous logistic regression comparing each of the two case groups to the controls, with statistical tests for the difference between the coefficients for the two case groups. RESULTS: After multivariable adjustment, a livebirth within the previous 2 years (OR 4.6; 95% CI 1.8 to 11.7) and diabetes (OR 1.8; 95% CI 1.1 to 3.0) were associated with increased risk of IBC, but not non-IBC (OR 0.9; 95% CI 0.3 to 2.5 and OR 0.9; 95% CI 0.5 to 1.6 for livebirth and diabetes, respectively). A family history of breast cancer, inflammatory-like breast problems, breast trauma, and low socioeconomic status were associated with increased risk of both tumor types. CONCLUSIONS: We identified novel risk factors for IBC and non-IBC, some of which preferentially increased risk of IBC compared to non-IBC. Upon confirmation, these findings could help illuminate the etiology and aid in prevention of this aggressive cancer.

Association of Aggresomes with Survival Outcomes in Pediatric Medulloblastoma.

Aggresomes are inclusion bodies for misfolded/aggregated proteins. Despite the role of misfolded/aggregated proteins in neurological disorders, their role in cancer pathogenesis is poorly defined. In the current study we aimed to investigate whether aggresomes-positivity could be used to improve the disease subclassification and prognosis prediction of pediatric medulloblastoma. Ninety three pediatric medulloblastoma tumor samples were retrospectively stratified into three molecular subgroups; WNT, SHH and non-WNT/non-SHH, using immunohistochemistry and Multiplex Ligation Probe Amplification. Formation of aggresomes were detected using immunohistochemistry. Overall survival (OS) and event-free survival (EFS) were determined according to risk stratification criteria. Multivariate Cox regression analyses were carried out to exclude confounders. Aggresomes formation was detected in 63.4% (n = 59/93) of samples. Aggresomes were non-randomly distributed among different molecular subgroups (P = 0.00002). Multivariate Cox model identified aggresomes' percentage at ≥20% to be significantly correlated with patient outcome in both OS (HR = 3.419; 95% CI, 1.30-8.93; P = 0.01) and EFS (HR = 3; 95% CI, 1.19-7.53; P = 0.02). The presence of aggresomes in ≥20% of the tumor identified poor responders in standard risk patients; OS (P = 0.02) and EFS (P = 0.06), and significantly correlated with poor outcome in non-WNT/non-SHH molecular subgroup; OS (P = 0.0002) and EFS (P = 0.0004).

LC3A Silencing Hinders Aggresome Vimentin Cage Clearance in Primary Choroid Plexus Carcinoma.

Aggresomes are transient microtubule-dependent inclusion bodies that sequester misfolded proteins and are ultimately removed by autophagy. Here we report the generation of a choroid plexus carcinoma cell line; Children's Cancer Hospital Egypt (CCHE)-45, which is characterized by the constitutive formation of aggresomes. When examining the autophagy pathway as the main route for aggresomes clearance, CCHE-45 cells displayed increased autophagy flux mediated by MAP1LC3B. MAP1LC3A-Variant1 gene expression was silenced by promoter methylation. Restoring MAP1LC3A-Variant1 expression resulted in the formation of MAP1LC3A positive autophagosmes and the disruption of the aggresomes' vimentin cage independent of MAP1LC3B positive autophagosomes. Our data supports the notion that basal quality control autophagy and vimentin cage clearance in CCHE-45 are mediated by MAP1LC3A. Hence we propose that absence of MAP1LC3A disrupts the autophagic pathway and leads to the failure of aggresome vimentin cage degradation. Consequently, this could represent a targetable pathway in autophagy-dependent cancers.

Assessment of current practice and barriers to antimicrobial prophylaxis in peritoneal dialysis patients.

BACKGROUND: Existing Australasian and international guidelines outline antibiotic and antifungal measures to prevent the development of treatment-related infection in peritoneal dialysis (PD) patients. Practice patterns and rates of PD-related infection vary widely across renal units in Australia and New Zealand and are known to vary significantly from guideline recommendations, resulting in PD technique survival rates that are lower than those achieved in many other countries. The aim of this study was to determine if there is an association between current practice and PD-related infection outcomes and to identify the barriers and enablers to good clinical practice. METHODS: This is a multicentre network study involving eight PD units in Australia and New Zealand, with a focus on adherence to guideline recommendations on antimicrobial prophylaxis in PD patients. Current practice was established by asking the PD unit heads to respond to a short survey about practice/protocols/policies and a 'process map' was constructed following a face-to-face interview with the primary PD nurse at each unit. The perceived barriers/enablers to adherence to the relevant guideline recommendations were obtained from the completion of 'cause and effect' diagrams by the nephrologist and PD nurse at each unit. Data on PD-related infections were obtained for the period 1 January 2011 to 31 December 2011. RESULTS: Perceived barriers that may result in reduced adherence to guideline recommendations included lack of knowledge, procedural lapses, lack of a centralized patient database, patients with non-English speaking background, professional concern about antibiotic resistance, medication cost and the inability of nephrologists and infectious diseases staff to reach consensus on unit protocols. The definitions of PD-related infections used by some units varied from those recommended by the International Society for Peritoneal Dialysis, particularly with exit-site infection (ESI). Wide variations were observed in the rates of ESI (0.06-0.53 episodes per patient-year) and peritonitis (0.31-0.86 episodes per patient-year). CONCLUSIONS: Despite the existence of strongly evidence-based guideline recommendations, there was wide variation in adherence to these recommendations between PD units which might contribute to PD-related infection rates, which varied widely between units. Although individual patient characteristics may account for some of this variability, inconsistencies in the processes of care to prevent infection in PD patients also play a role.

Incidence of kiaa1549-braf fusion gene in Egyptian pediatric low grade glioma.

BACKGROUND: Low grade gliomas are the most common brain tumor in children. Tandem duplication involving the KIAA1549 and the BRAF kinase genes results in a gene fusion that has been recently characterized in a subset of low grade glioma While there is no clear evidence that the KIAA1549-BRAF gene fusion has an effect on prognosis, it is an attractive target for therapy development and as a diagnostic tool. METHODS: In the current study we examine the prevalence of KIAA1549-BRAF gene fusion in pediatric patients diagnosed with low grade glioma in the Egyptian population and its relationship to clinical and histological subtypes. Sixty patients between the ages of 1 to 18 years were analyzed for the presence of KIAA1549-BRAF fusion gene products using reverse transcription-PCR and sequencing. The clinicopathologic tumor characteristics were then analyzed in relation to the different fusion genes. RESULTS: KIAA1549-BRAF fusion genes were detected in 56.6% of patients. They were primarily associated with pilocytic astrocytoma (74.2%) and pilomyxoid astrocytoma (60%). Translocation 15-9 was the most common, representing (55.8%) of all positive samples followed by 16-9 (26.4%) and 16-11 (8.8%). Pilocytic astrocytomas presented primarily with 15-9 (32.2%), 16-9 (25.8%) and 16-11 (6.4%) while pilomyxoid astrocytomas presented with 15-9 (46.6%), 16-9 (6.6%) and 16-11 (6.6%) translocations. CONCLUSION: Gene fusion is found to be significantly increased in cerebellar pilocytic astrocytoma tumors. Furthermore, 15-9 was found to have a higher incidence among our cohort compared to previous studies. While most of the gene fusion positive pilomyxoid astrocytomas were 15-9, we find the association none significant.

Incidence and features of dual anti-GBM-positive and ANCA-positive patients.

AIMS: Goodpasture's syndrome, glomerulonephritis and pulmonary haemorrhage, may be due to a variety of causes. Rarely, patients with Goodpasture's syndrome present with both anti-glomerular basement membrane (GBM) and antineutrophil cytoplasmic antibody (ANCA). The aim of this report was to determine the incidence, clinical features, management and outcomes of patients presenting with concurrent ANCA and anti-GBM disease in Auckland. METHODS: Potential patients were identified by an electronic search of serology for ANCA and anti-GBM antibody, diagnostic renal biopsy, or in-hospital admissions using ICD9 and ICD10 codes between 1998 and 2008. A retrospective case-note review of all potential cases was performed. RESULTS: Six cases were identified: two women and four men. The incidence was estimated at 0.47 cases per million people per year. The mean age of presentation was 59 years (range 25-85 years). One patient was a smoker and two patients were ex-smokers. All subjects were anaemic, had haemoptysis and an abnormal chest X-ray at presentation. The mean creatinine at presentation was 225 µmol/L (range 126-406 µmol/L); all patients had haematuria and proteinuria. All patients received corticosteroids and cyclophosphamide. Two patients were not plasma exchanged and died. Four patients received plasma exchange and are alive. One patient had a clinical relapse 6 years after their initial presentation and is on renal replacement therapy. CONCLUSION: Concurrent ANCA and anti-GBM disease is rare. The mortality rate is high. Aggressive immunosuppression with steroids, cyclophosphamide and plasma exchange can induce remission and preserve renal function. Long-term monitoring for relapses should occur.

Is computerized tomography useful in identifying abdominal catastrophes in patients presenting with peritonitis?

BACKGROUND: Peritonitis is a significant source of morbidity and mortality in patients on peritoneal dialysis (PD). Symptoms may persist, requiring an emergency laparotomy. Although increasingly used, we find that, in PD patients, abdominal computerized tomography (CT) is ineffective in determining significant pathology. This study was undertaken to assess the diagnostic utility of CT for the identification of intra-abdominal collections in PD patients presenting with peritonitis. METHODS: A retrospective chart review was undertaken of all patients that underwent abdominal CT scanning in the context of severe PD peritonitis in the past 2 years. All of these patients had at least one CT scan preoperatively. RESULTS: 133 patients presented with PD peritonitis; 19 patients had a contrast CT procedure (12 females, 7 males). Average age was 59.2 years; mean duration on PD was 43.8 months. 13 of 19 patients had gram-negative bacillary peritonitis, 6 of whom had polymicrobial peritonitis; 4 patients had fungal peritonitis and 2 had Staphylococcus aureus peritonitis. 26 CT scans were done in 19 patients an average of 10 days after presentation. 21 of 26 scans revealed no collections of surgical interest. 12 laparotomies were performed, with an average delay of 10.4 days from presentation to laparotomy. Of the 12 laparotomies, 6 found a drainable collection not seen on CT. Seven of the 19 patients died (37%) and no patient was able to return to PD. CONCLUSION: PD patients requiring emergency laparotomy following PD peritonitis have a high mortality rate. A negative abdominal CT in the setting of ongoing symptoms should not be taken as reassuring, nor should it delay proceeding to emergency laparotomy.

Atrial fibrillation in haemodialysis patients: do the guidelines for anticoagulation apply?

AIM: Atrial fibrillation (AF) is common in haemodialysis patients, but the risks and benefits of anticoagulation in this group are not well characterized. We investigated the prevalence of AF, its associated risk factors, and the incidence of stroke and haemorrhage in a cohort of haemodialysis patients. METHODS: We retrospectively reviewed 155 patients undergoing maintenance haemodialysis on 1 April 2003 (age 56.9 +/- 13.5 years; men 62.6%; mean duration of haemodialysis 39.3 +/- 37.5 months). Patients with paroxysmal or permanent AF were identified, and baseline clinical and echocardiographic data were obtained. The incidence of cerebrovascular accidents, major haemorrhage and all-cause mortality was assessed during the 26 month average follow-up period. RESULTS: AF was present in 25.8% of patients, paroxysmal in 18.1%, and permanent in 7.7%. Patients with AF were more likely to be older (64.2 +/- 9.4 vs 54.4 +/- 13.8 years; P < 0.005), have underlying ischaemic heart disease or congestive heart failure, and have a lower serum albumin (P < 0.05 for all). Only 12.5% of AF patients were anticoagulated, although 47.5% had contraindications to warfarin. Cerebrovascular events occurred in 5.2% of all patients (30.4 episodes/1000 patient-years), and major haemorrhage in 20.0% (106.4 episodes/1000 patient-years). All-cause mortality was 29.7%. The endpoints for the AF group did not significantly differ from the non-AF group. CONCLUSION: AF is common in haemodialysis patients. The incidence of major haemorrhage was over three times that of cerebrovascular accidents. Guideline recommendations for anticoagulation in AF in the general population may not be appropriate for the haemodialysis population.

Predictors of chronic allograft nephropathy from protocol biopsies using histological and immunohistochemical techniques.

AIM: Chronic allograft nephropathy is a predictor of poor allograft survival. Protocol and diagnostic biopsies were used to identify markers contributing to its pathogenesis. METHODS: Diagnostic, 3- and 12-month protocol biopsies in renal transplant recipients were examined. Immunohistochemical staining with monoclonal antibodies for memory T cells (CD45RO), macrophages (CD68) and alpha smooth muscle actin was undertaken on protocol biopsies. RESULTS: Protocol biopsies revealed the incidence of chronic allograft nephropathy to be 10.7% (3/28) at 3 and 57.6% (19/33) at 12 months. There was a trend towards a higher serum creatinine in patients with chronic allograft nephropathy compared with those without (0.15 +/- 0.04 vs 0.12 +/- 0.04 mmol/L, P = 0.047). The strongest predictor of chronic allograft nephropathy at 12 months was the presence of arteriolar hyaline change (P = 0.035; odds ratio 1.22, 95% CI 0.036-0.887) whereas a higher CD45RO and CD68 count at 12 months was associated with chronic allograft nephropathy (74.7 +/- 56.9 cells/mm(2) and 22.4 +/- 23.5 cells/mm(2)) compared with patients without it (29.2 +/- 29.2 cells/mm(2) and 8.3 +/- 9.9 cells/mm(2), P = 0.006 and P = 0.03, respectively). The number of smooth muscle actin positive cells correlated significantly with chronic allograft nephropathy at 12 month (107.6 +/- 44 vs 73.9 +/- 20.8 cells/mm(2), P = 0.009). CONCLUSION: The high prevalence of chronic allograft nephropathy in renal transplant recipients is associated with renal dysfunction. Arteriolar hyalinosis was the most significant predictor at 12 months. There was a significantly higher macrophage and T cell infiltrate in stable grafts undergoing chronic allograft nephropathy at 12 months post transplant.

Acute renal failure in patients with pre-existing renal dysfunction following coronary artery bypass grafting.

BACKGROUND: Pre-existing renal dysfunction predisposes to acute renal failure (ARF) in patients undergoing coronary artery bypass grafting. We assessed the incidence and impact of the development of ARF in this patient population in our unit. METHODS: One-hundred and six patients had a preoperative serum creatinine of >or=0.13 mmol/L and underwent coronary artery bypass grafting in the year 2000. The incidence of ARF (as defined by a >or=50% rise in postoperative serum creatinine), hospitalization days, dialysis requirement, in-hospital and 1-year mortality, and potential risk factors for ARF were recorded. RESULTS: Of the patients recorded, 43/104 (41.35%) developed ARF following coronary artery bypass grafting. Patients with ARF stayed in hospital longer (P < 0.02). Ten out of forty-three patients required some form of dialysis and the in-hospital mortality of the renal failure group was 23% compared to 3.1% in the other group (P < 0.002). One year postoperatively, the group with renal failure had significantly worse survival (71.8% vs 98%P < 0.0001). CONCLUSION: For patients undergoing coronary artery bypass grafting, pre-existing renal dysfunction predisposes to the development of ARF, this is associated with prolonged hospitalization and increased mortality.

Subcutaneous black fungus (phaeohyphomycosis) infection in renal transplant recipients:three cases.

We describe three cases of subcutaneous phaeohyphomycosis developing in the lower limbs of renal transplant recipients shortly after transplantation. Each case presented with dark-colored nodules that subsequently ulcerated. Histopathologic examination revealed dematiaceous fungal hyphae with a surrounding granulomatous reaction. The fungi were subsequently identified as Alternaria alternatum in two cases and Phialophora richardsiae in one case. In one case, the lesions resolved during a prolonged (6-month) course of itraconazole without the requirement for surgical excision. In the other two cases, combined medical and surgical treatment resulted in cure. A review of the literature on phaeohyphomycosis is presented.

The management and outcome of occluded haemodialysis access: a retrospective audit.

AIM: To identify best clinical practice for the management of occluded haemodialysis access. Surgery or percutaneous thrombolysis with or without angioplasty, has been used for the management of clotted haemodialysis access, with variable reported success rates. Concerns over high morbidity rates and delays in achieving satisfactory patent arterio-venous (AV) access, led to a retrospective audit of all patients with occluded haemodialysis vascular access between 1 June 1995 and 30 June 2001. METHODS: Data recorded included type of access, procedure used, outcome, complications and hospital stay. RESULTS: There were 45 episodes occurring in 17 patients. 33 of the 45 episodes occurred in synthetic grafts. Eleven of the 17 patients had multiple episodes (range 2 to 11), nine of whom had synthetic grafts. Forty three of the 45 episodes initially underwent DSA on presentation. There was a low success rate with thrombolysis, with only 20 cases effective in re-establishing dialysis. Surgery revision was required to re-establish effective dialysis in 25 of the 45 episodes. Six of 43 thrombolysis procedures experienced a major complication related to excessive bleeding. Primary patency was slightly better for surgery compared with thrombolysis (4.9 months versus 3.8 months). Temporary catheters were inserted for dialysis in 19 of 45 episodes and remained for a mean of 5.8 days. Four patients had a major episode of catheter-related sepsis. Two patients required admission to the Intensive Care Unit (ICU) for management of their sepsis. Patients who failed thrombolysis and required surgery had a prolonged stay, averaging 8.2 days. This was associated with a marked increase in hospital costs. The average cost for successful thrombolysis was $1976, compared with $5348 where surgery was subsequently required. Costing of surgical intervention alone was similar to that of thrombolysis. CONCLUSION: Surgery with dedicated vascular surgeons remains the safest, most rapid and most effective approach to treating occluded dialysis AV fistulae and grafts.