The Contribution of Kaposi's Sarcoma-Associated Herpesvirus to Mortality in Hospitalized Human Immunodeficiency Virus-Infected Patients Being Investigated for Tuberculosis in South Africa.

BACKGROUND: Despite increasing numbers of human immunodeficiency virus (HIV)-infected South Africans receiving antiretroviral therapy (ART), tuberculosis (TB) remains the leading cause of mortality. Approximately 25% of patients treated for TB have microbiologically unconfirmed diagnoses. We assessed whether elevated Kaposi's sarcoma-associated herpesvirus (KSHV) viral load (VL) contributes to mortality in hospitalized HIV-infected patients investigated for TB. METHODS: Six hundred eighty-two HIV-infected patients admitted to Khayelitsha Hospital, South Africa, were recruited, investigated for TB, and followed for 12 weeks. KSHV serostatus, peripheral blood KSHV-VL, and KSHV-associated clinical correlates were evaluated. RESULTS: Median CD4 count was 62 (range, 0-526) cells/µL; KSHV seropositivity was 30.7% (95% confidence interval [CI], 27%-34%); 5.8% had detectable KSHV-VL (median, 199.1 [range, 13.4-2.2 × 106] copies/106 cells); 22% died. Elevated KSHV-VL was associated with mortality (adjusted odds ratio, 6.5 [95% CI, 1.3-32.4]) in patients without TB or other microbiologically confirmed coinfections (n = 159). Six patients had "possible KSHV-inflammatory cytokine syndrome" (KICS): 5 died, representing significantly worse survival (P < .0001), and 1 patient was diagnosed with KSHV-associated multicentric Castleman disease at autopsy. CONCLUSIONS: Given the association of mortality with elevated KSHV-VL in critically ill HIV-infected patients with suspected but not microbiologically confirmed TB, KSHV-VL and KICS criteria may guide diagnostic and therapeutic evaluation.

CD73 expression in tissue granulomas in distinguishing intestinal tuberculosis from Crohn's disease in a South African cohort.

INTRODUCTION: Overlap of clinical, endoscopic and radiographic features, coupled with a poor microbiological yield makes differentiating Crohn's disease (CD) from intestinal tuberculosis (ITB) challenging. A potential histological differentiating mechanism is the use of immunohistochemical staining for the mesenchymal stem cell marker CD73, as a pilot study showed ITB but not CD granulomas stained positive for this marker. The aim of this study was to assess the value of CD73 in differentiating ITB from CD granulomas in a South African cohort. METHODS: Patients with confirmed CD or ITB were identified from a pathology database. Tissue sections were reviewed by a pathologist to confirm the presence of granulomas. These were then stained with a mouse monoclonal anti-CD73 antibody. The slides were examined together by a pathologist and gastroenterologist in a blinded manner for anti-CD73 staining around granulomas. RESULTS: Ninety six cases were available for analysis; 50 cases of ITB and 46 cases of CD. Thirty percent of CD granulomas (14/46) stained positive for CD73, whereas CD73 positivity was seen in 52% (26/50) of cases of ITB. This was statistically significant (OR 2.48, 95% CI 1.1-5.72, p = .03). The area under the curve (AUC) was 0.61. Sensitivity of CD73 in predicting ITB was 52% and specificity was 70%. Overall CD73 staining of granulomas correctly classified only 60% of cases. CONCLUSIONS: In our study we have shown that significantly more patients with ITB express CD73 in their granulomas than those with CD. However the relatively poor sensitivity, specificity and AUC make this test unlikely to be of value in our clinical practice.

A dimorphic fungus causing disseminated infection in South Africa.

BACKGROUND: The genus emmonsia contains three species that are associated with human disease. Emmonsia crescens and Emmonsia parva are the agents that cause adiaspiromycosis, and one human case of Emmonsia pasteuriana infection has been described. We report a fungal pathogen within the genus emmonsia that is most closely related to E. pasteuriana in human immunodeficiency virus (HIV)-infected adults in South Africa. METHODS: Between July 2008 and July 2011, we conducted enhanced surveillance to identify the cause of systemic, dimorphic fungal infections in patients presenting to Groote Schuur Hospital and other hospitals affiliated with the University of Cape Town, Cape Town, South Africa. DNA sequencing was used to identify pathogenic fungi. RESULTS: A total of 24 cases of dimorphic fungal infection were diagnosed, 13 of which were caused by an emmonsia species. All 13 patients were HIV-infected, with a median CD4+ T-cell count of 16 cells per cubic millimeter (interquartile range, 10 to 44), and all had evidence of disseminated fungal disease. Three patients died soon after presentation, but the others had a good response to a variety of antifungal agents and antiretroviral therapy. Phylogenetic analysis of five genes (LSU, ITS1-2, and the genes encoding actin, ß-tubulin, and intein PRP8) revealed that this fungus belongs in the genus emmonsia and is most closely related to E. pasteuriana. CONCLUSIONS: The findings suggest that these isolates of an emmonsia species represent a new species of dimorphic fungus that is pathogenic to humans. The species appears to be an important cause of infections in Cape Town.

Evaluation of the utility of serum prolidase as a marker for liver fibrosis.

BACKGROUND: Liver dysfunction is common and often unrecognized. Liver biopsy is the gold standard in the assessment of liver fibrosis, but has disadvantages. We assessed the diagnostic accuracy of serum prolidase enzyme activity (SPA) in predicting the presence and degree of liver fibrosis, as compared with liver biopsy. Further, we evaluated the effect of hemolysis on measured SPA levels. METHODS: We undertook a prospective case control study. Thirty eight outpatients without apparent liver illness and 20 patients with liver pathology scheduled to undergo liver biopsy had their SPA levels measured. RESULTS: Patients undergoing liver biopsy had higher SPA levels (361 (268) IU/l [median (interquartile range)]) compared with controls (169 (160) (P < 0.001)). A SPA cutoff value of 200 IU/l yielded a sensitivity of 89%, specificity of 59%, an odds ratio of 11.5, negative predictive value of 92%, and a positive predictive value of 50%. Hemolysis causes an apparent increase in SPA levels. CONCLUSION: Higher SPA levels in patients undergoing liver biopsies compared with controls may reflect the presence of liver fibrosis. SPA levels could not be used to stage the degree of fibrosis. SPA measurement may be useful in the diagnostic workup of suspected liver disease.

Challenge of coexisting type 2 diabetes mellitus and insulinoma: a case report.

BACKGROUND: Insulinomas are rare clinical entities, but concurrent diabetes mellitus is even more uncommon, and the combination is easily missed. Recurrent hypoglycemia could be misconstrued as improved glycemic control. We present an unusual patient with type 2 diabetes and neuroglycopenia, with apparent improved glycemic control due to an insulinoma. CASE PRESENTATION: A 54-year-old mixed ancestry man with a positive family history of type 2 diabetes mellitus was diagnosed with type 2 diabetes mellitus and hypertension 8 years prior to admission. He presented with episodes of abnormal behavior and hypoglycemia. Inappropriately high insulin and C-peptide concentrations were identified at the time of hypoglycemia. Despite poor adherence to his diabetic treatment, he had no target organ damage relating to diabetes, and his hemoglobin A1c (HbA1c) was 5.3%. A diagnosis of insulinoma was made, and he was started on diazoxide, with endoscopic ultrasound revealing a possible lesion in the pancreatic tail measuring 12 mm × 12 mm. A fine-needle aspiration biopsy could not be performed due to overlying splenic arteries and the risk of vascular perforation. An intraoperative ultrasound confirmed a 15 mm × 10 mm tumor in the pancreatic tail, necessitating a partial pancreatectomy and splenectomy, which were curative. A well-differentiated intermediate grade 2 pancreatic neuroendocrine tumor producing insulin was confirmed on histopathology. CONCLUSIONS: Recurrent, progressive hypoglycemia and improved glycemic control in a diabetic, without an alternative explanation, may suggest an insulinoma. Insulinomas that exist with type 1 diabetes mellitus, particularly malignant insulinomas, must have escaped autoimmune attack through lack of autoantigen expression. Computed tomography on its own may be insufficiently sensitive for diagnosis of insulinomas, whereas endoscopic and intraoperative ultrasonography may improve the identification of the culprit lesion.

Blastic Plasmacytoid Dendritic Cell Neoplasm: An Uncommon Entity to Consider in the Differential Diagnosis of Cutaneous Lymphoma.

Cutaneous lymphomas are encountered infrequently in general surgical pathology practice, and the broad array of pathological entities poses a diagnostic challenge. Integration of clinical information, results of additional laboratory investigations, and an extensive immunohistochemical panel are essential in arriving at the correct diagnosis. We present a case of blastic plasmacytoid dendritic cell neoplasm that occurred in an unusual clinical setting. This case highlights the need for a broad differential diagnosis and an extensive immunohistochemical workup when approaching a cutaneous lymphoma.

Fibrolamellar hepatocellular carcinoma at a tertiary centre in South Africa: a case series.

BACKGROUND: Fibrolamellar carcinoma (FLC) is an uncommon malignant tumour of hepatocyte origin that differs from hepatocellular carcinoma (HCC) in aetiology, demographics, condition of the affected liver, and tumour markers. Controversy exists whether FLC demonstrates a more favourable prognosis than typical HCC. A review of existing literature reveals a dearth of FLC data from the African continent. METHODS: We utilised the prospective liver resection database at Groote Schuur Hospital to identify all patients who underwent surgery for FLC between 1990 and 2008. RESULTS: Seven patients (median age 21 years, range 19 - 42, 5 men, 2 women) underwent surgery for FLC. No patient had underlying liver disease or an elevated alpha fetoprotein (AFP) at either initial presentation or recurrence. Six patients had a solitary tumour at diagnosis (mean largest diameter = 12cm), and underwent left hepatectomy (N=2), right hepatectomy (N=1), extended right hepatectomy (N=1), right hepatectomy (N=1), extended right hepatectomy (N=1), and segmentectomies (N=2). Three patients underwent a portal lymphadenectomy for regional lymphatic tumour involvement. One patient with advanced extrahepatic portal nodal metastasis was unresectable. No peri-operative deaths occurred. Recurrence occurred post resection in all 6 patients. Median overall survival was 60 months, and overall 5-year survival was 4 out of 7 (57%). Post-resection survival (N=6) was 61 months, with a 5-year survival rate of 4 out of 6 (67%). The patient with unresectable disease survived 38 months after tumour embolisation with Lipiodol. CONCLUSION: Our series suggests that despite (i) a high resection rate of solitary lesions with clear tumour resection margins, and (ii) absence of underlying liver disease, FLC has a high recurrence rate with an ultimately poor clinical outcome. These findings concur with recent international experience of FLC. experience of FLC.

The role of miRNA-21 and epithelial mesenchymal transition (EMT) process in colorectal cancer.

AIMS: The study was conducted to assess the expression levels of epithelial mesenchymal transition (EMT) proteins (E-cadherin, N-cadherin, snail-1 and vimentin) and miRNA-21. In addition, we correlated these data with clinicopathological features in Colorectal cancer. METHODS: H&E slides from a total of 59 formalin fixed paraffin embedded tissue blocks were examined by a pathologist to demarcate normal and tumour regions. Immunohistochemical analysis of mismatch repair proteins (MLH1, MSH2 and MSH6) and EMT markers (E-cadherin, N-cadherin, snail-1 and vimentin) was performed. The miRNA-21 expression levels were determined using qRT-PCR and the data was analysed using the relative quantification method. The Fisher's exact and Pearson's χ2 tests were used to correlate snail-1, E-cadherin, miRNA-21 and clinicopathological data. RESULTS: Our results showed a statistically significant correlation between high miRNA-21 expression levels and E-cadherin positive cases. There was also an association between high miRNA-21 expression levels and negative snail-1 expression. No significant correlation was seen between miRNA-21 expression levels and clinicopathological features. Moreover, high expression levels of miRNA-21 were significantly associated with the sporadic cases. CONCLUSIONS: Our data suggest that miRNA-21 in association with E-cadherin and snail-1 does not play a significant role in the development and progression of this disease.

Disseminated Emmonsia in an HIV-HBV co-infected man.

The differential diagnoses in patients with advanced HIV/AIDS presenting with fever and systemic illness is wide and warrants both infectious and non-infectious considerations. The need to make an early and accurate diagnosis is important to effect correct therapy and thus improve outcome. We describe a patient with several co-morbidities and an unusual disseminated fungal infection.

A multi-centre pathologist survey on pathological processing and regression grading of colorectal cancer resection specimens treated by neoadjuvant chemoradiation.

To ascertain the approach and degree of consensus of pathologists in the handling and regression grading of colorectal cancer resection specimens treated with neoadjuvant chemoradiation, a ten-part questionnaire was circulated to 18 gastrointestinal pathologists in eight countries. The questions were specific and addressed pertinent issues related to colorectal cancer with neoadjuvant chemoradiation. There is a lack of consensus on how to handle the specimen, number of sections taken, correlation with pre- and post-operative radiological imaging, and especially, regression grading schema employed. Consensus in the form of guidelines is required so that the pathological assessment of these specimens will provide clinically relevant information for patient management, irrespective of location.

International study group on rectal cancer regression grading: interobserver variability with commonly used regression grading systems.

The aim of this study was to ascertain the level of concordance among gastrointestinal pathologists for regression grading in rectal cancers treated with neoadjuvant chemoradiation. Seventeen gastrointestinal pathologists participated using the Mandard, Dworak, and modified rectal cancer regression grading systems to grade 10 representative slides that were selected from 10 cases of rectal cancer treated with long-course neoadjuvant chemoradiation. The slides were scanned with a whole-slide scanner generating dynamic digitized images. The results showed very little concordance across the 3 grading systems, with κ values of 0.28, 0.35, and 0.38 for the Mandard, Dworak, and modified rectal cancer regression grading systems, respectively. In only 1 of 10 study cases was there unanimous grading concordance using the modified rectal cancer regression grading system. It was felt that these systems lacked precision and clarity for reproducible, accurate regression grading. The study concluded that there was a need for a simple, reproducible regression grading system with clear criteria, a cumulative or composite score taking into account all sections of the tumor bed that is sampled rather than the worst section (highest grade), and there should be a uniform method of sampling of these specimens.

Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism.

The progression of human tuberculosis (TB) to active disease and transmission involves the development of a caseous granuloma that cavitates and releases infectious Mycobacterium tuberculosis bacilli. In the current study, we exploited genome-wide microarray analysis to determine that genes for lipid sequestration and metabolism were highly expressed in caseous TB granulomas. Immunohistological analysis of these granulomas confirmed the disproportionate abundance of the proteins involved in lipid metabolism in cells surrounding the caseum; namely, adipophilin, acyl-CoA synthetase long-chain family member 1 and saposin C. Biochemical analysis of the lipid species within the caseum identified cholesterol, cholesteryl esters, triacylglycerols and lactosylceramide, which implicated low-density lipoprotein-derived lipids as the most likely source. M. tuberculosis infection in vitro induced lipid droplet formation in murine and human macrophages. Furthermore, the M. tuberculosis cell wall lipid, trehalose dimycolate, induced a strong granulomatous response in mice, which was accompanied by foam cell formation. These results provide molecular and biochemical evidence that the development of the human TB granuloma to caseation correlates with pathogen-mediated dysregulation of host lipid metabolism.

Composite adrenal phaeochromocytoma-ganglioneuroma causing watery diarrhoea, hypokalaemia and achlorhydria syndrome.

The watery diarrhoea, hypokalaemia and achlorhydria syndrome is a rare cause of secretory diarrhoea. In this case report, we highlight a young female with watery diarrhoea, hypokalaemia and achlorhydria syndrome as a consequence of a vasoactive intestinal peptide producing composite adrenal phaeochromocytoma-ganglioneuroma. She made a complete recovery after curative surgical resection.