Gavin S.W. Chan

Somatic mutations in the BRCA1 gene in Chinese sporadic breast and ovarian cancer

Inherited mutations in the BRCA1 gene confer increased susceptibility to breast and ovarian cancer. Its role in sporadic carcinogenesis is not well defined. Somatic mutations in breast cancers have not been reported and to date there are only three reports of somatic mutations in sporadic ovarian cancers. To investigate the contribution of BRCA1 mutations to sporadic breast and ovarian cancer in the Chinese population, we analysed 62 samples from Chinese women using the protein truncation test. There were 40 cases of breast cancer under age 50 and 22 cases of ovarian cancer, all unselected for family history. There was no age selection for the ovarian cancers. We found two somatic BRCA1 mutations in exon 11, one in a breast cancer and the other in an ovarian cancer, both of which result in truncated proteins. Our results indicate that somatic BRCA1 mutations, like somatic mutations in the BRCA2 gene, though very rare, can be found in both breast and ovarian cancers and support a tumor suppressor function for BRCA1 in sporadic tumors.

Clinicopathologic analysis of renal biopsies after haematopoietic stem cell transplantation

Aim:  The ever‐growing number and increasing survival of haematopoietic stem cell transplantation (HSCT) allow better recognition of its associated renal injuries. We aimed to study the clinicopathologic features of renal biopsies after HSCT by reviewing 13 percutaneous renal biopsies in our institute (Queen Mary Hospital).

Sudden death from massive pulmonary tumor embolism due to hepatocellular carcinoma

Massive pulmonary embolism in cancer patients can be due to detached thrombi or tumor. Pulmonary tumor embolism is often undiagnosed antemortem. We report a 52-year-old Chinese man admitted for management of hepatocellular carcinoma (HCC). Computerized tomography showed tumor involvement of hepatic vein and inferior vena cava. He died suddenly on the day of admission. At autopsy the main pulmonary arteries of both lungs were blocked by large tumor emboli, the immediate cause of death. Although rapid death in patients with HCC is usually caused by intraperitoneal hemorrhage from spontaneous rupture of tumor, massive pulmonary tumor embolism should also be considered in these patients, especially when antemortem evidence of hepatic vein and/or inferior vena cava invasion is present.

Incidence and outcome of antiglomerular basement membrane disease in Chinese.

Background:  Antiglomerular basement membrane (anti‐GBM) disease is an uncommon disease, especially among Asian population. Many reports and studies on this condition in the Caucasian population are available, but little information exists on anti‐GBM disease in Asians. To study the incidence and clinical characteristics of anti‐GBM disease among Chinese patients, we reviewed our experience of anti‐GBM disease in our hospital (Queen Mary Hospital, Hong Kong) from 1992 to 2003.

BK Virus Nephropathy Due to KOM-3 Strain

Interstitial nephritis caused by BK polyomavirus is an important complication of kidney transplantation. A diagnosis of BK virus nephropathy is established by a combination of characteristic histological, immunostaining, and ultrastructural findings. We report the first documented case of BK virus nephropathy caused by the KOM-3 strain in a patient after kidney transplantation. The biopsy specimen showed the characteristic histological and ultrastructural findings of BK virus, but was negative on immunostaining with a monoclonal antibody directed against BK virus large T antigen (LTag). Kidney tissue was subjected to polymerase chain reaction amplification using BK virus LTag-specific primers followed by DNA sequencing. Sequence results showed 100% homology to the KOM-3 strain, which has a 4-amino acid deletion in the C terminus of LTag compared with the reference sequence DUN strain. This deletion can explain the negative immunostaining results because the monoclonal antibody is directed against an epitope in this region. The patient lost his graft 2 months after diagnosis. Pathologists should be aware of this potential pitfall in interpreting immunostaining for BK virus. The incidence and prognostic implications of KOM-3 strain require additional studies.

Determination of mismatched donor HLA in kidney transplant recipients with unknown donor HLA phenotypes

Kwok J, Chan GSW, Lam MF, Yan T, Tang L, Kwong KM, Chan KW, Chan TM. Determination of mismatched donor HLA in kidney transplant recipients with unknown donor HLA phenotypes.
Clin Transplant 2010 DOI: 10.1111/j.1399‐0012.2010.01246.x 
© 2010 John Wiley & Sons A/S.

Pneumococcal native aortic valve endocarditis with mycotic abdominal aortic aneurysm, paraspinal and iliopsoas abscesses and pneumonia revealing a multiple myeloma

We report a rare case of multiple myeloma presenting with native aortic valve endocarditis with secondary embolic mycotic abdominal aortic aneurysm, contiguous paraspinal and iliopsoas abscesses, and pneumonia due to Streptococcus pneumoniae in a Chinese man. He was treated with aortic valve replacement, endovascular stenting of aneurysm, image-guided drainage of abscesses, and a 6-week course of endocarditic antibiotic therapy followed by chronic suppressive antibiotic therapy. Cases of multiple myeloma presenting with invasive pneumococcal infection were reviewed.

Renal allograft tissue: its new role in patient management

epithelioid features (Figure 1B–D). DNA profiling of the tumour was performed and compared to that of host tissue (a previous hysterectomy specimen) and tissue from the previously removed kidney allograft (donor tissue). One nanogram of DNA from each sample was profiled using the AmpFISTR Identifiler PCR Amplification Kit (Applied Biosystems, Foster City, CA, USA). The resulting profile of the tumour was a complete match with the patient’s (host) tissue (Figure 2). STR (microsatellite) analysis has been used for genetic fingerprinting since the early 1990s. The number of repeats in forensic STR loci is highly variable among individuals, making them effective for human identification purposes. Furthermore, the small size of STR alleles (100–400 bp) allows their use in forensic applications where degraded DNA is commonly encountered. To create a genetic profile of an individual, STR alleles are amplified by polymerase chain reaction (PCR) using fluorescent-labelled primers based on the invariant regions flanking the repeats. This kit allows simultaneous genotyping of 15 STR loci, with a combined power of discrimination of approximately 1 in 270 quadrillion in the local population. The use of genetic analysis to identify the origin of a tumour occurring in a transplanted individual is uncommon. Boix et al. reported a case of renal cell carcinoma (RCC) whereby DNA microsatellite analysis was used to identify recipient cell origin. There have been some genetic studies to determine tumour origin in a few cases of RCC in transplanted kidneys, but all of them revealed donor origin. In some of these cases, fluorescence in-situ hybridization (FISH) of sexual chromosomes was used for analysis, as the donor and recipient were sex-mismatched. To conclude, STR analysis is a useful and efficient tool for elucidating donor versus recipient origin when tumours develop at anastomotic sites of organ transplantation.

Cortical necrosis in a kidney transplant recipient due to leptospirosis

A 64-year-old woman suffered from end-stage renal failure due to unknown cause. She received kidney transplantation in 2003 and her maintenance immunosuppression comprised corticosteroids, cyclosporine A and azathioprine. She presented with fever, graft pain and reduced urine output in May 2013. Her serum creatinine level rose from 82 μmol/L to 279 μmol/L, and then rapidly deteriorated into oliguric renal failure. Complete blood picture revealed leukocytosis (13.3 × 10/L; neutrophil predominant) and concomitant liver derangement (aspartate aminotransferase, 724 U/L; alanine aminotransferase, 288 U/L; total bilirubin, 33 μmol/L; lactate dehydrogenase, 2183 U/L). The haemoglobin level, platelet counts, clotting profiles and urinalysis were unremarkable. Blood film showed no fragmented red cells and lupus anticoagulant was negative. Ultrasound did not demonstrate vascular thrombosis or obstruction and renal isotope scan only showed mildly impaired perfusion. Allograft biopsy revealed extensive cortical necrosis involving both glomeruli and tubules, with thrombi within the glomeruli (Fig. 1A) and fibrinoid necrosis of arterioles but no evidence of rejection (Fig. 1B). The Panbio Leptospira IgM ELISA (Standard Diagnostic, Gyeonggi-Do, Korea) was repeatedly positive. In retrospect, the patient volunteered that she had experienced occupational exposure to sewage water. Her urine output returned to normal after 2 weeks of temporary haemodialysis and i.v. meropenem. Her serum creatinine was 324 μmol/L 6 months after her initial presentation. Leptospirosis is a zoonotic disease caused by the spirochete Leptospira spp. Classical renal histological changes of leptospirosis include tubulointerstitial nephritis and acute tubular necrosis, while extensive cortical necrosis has not been reported previously. As the Doppler ultrasound and renal isotope scan did not reveal significant abnormalities, we postulate that the extensive renal necrosis in this case might have been related to thrombosis and fibrinoid necrosis of small intrarenal vasculatures triggered by severe Leptospira infection. Indeed, cerebral venous thrombosis due to severe vasculitis has previously been reported in leptospirosis. Data regarding leptospirosis in renal transplant recipients are limited but these immunocompromised subjects can develop fulminant leptospirosis and succumb to multi-organ failure. Another reason for the poor outcomes is due to the diagnostic difficulty of leptospirosis in renal transplant recipients as it may mimic more common conditions such as graft pyelonephritis or acute rejection, and serological confirmation is often delayed. Therefore, one should initiate empirical antibiotics with activity against leptospirosis given a compatible clinical context and history of exposure, as this will significantly improve patient outcomes.

A Modified Protocol with Improved Detection Rate for Mis-Matched Donor HLA from Low Quantities of DNA in Urine Samples from Kidney Graft Recipients

Background Urine from kidney transplant recipient has proven to be a viable source for donor DNA. However, an optimized protocol would be required to determine mis-matched donor HLA specificities in view of the scarcity of DNA obtained in some cases. Methods In this study, fresh early morning urine specimens were obtained from 155 kidney transplant recipients with known donor HLA phenotype. DNA was extracted and typing of HLA-A, B and DRB1 loci by polymerase chain reaction-specific sequence primers was performed using tailor-made condition according to the concentration of extracted DNA. Results HLA typing of DNA extracted from urine revealed both recipient and donor HLA phenotypes, allowing the deduction of the unknown donor HLA and hence the degree of HLA mis-match. By adopting the modified procedures, mis-matched donor HLA phenotypes were successfully deduced in all of 35 tested urine samples at DNA quantities spanning the range of 620–24,000 ng. Conclusions This urine-based method offers a promising and reliable non-invasive means for the identification of mis-matched donor HLA antigens in kidney transplant recipients with unknown donor HLA phenotype or otherwise inadequate donor information.