Belatacept as maintenance immunosuppression for postrenal transplant de novo drug-induced thrombotic microangiopathy.

De novo posttransplant thrombotic microangiopathy (TMA) is a complication of solid organ transplantation, which remains difficult to treat. In many cases, immunosuppressants and particularly calcineurin inhibitors, trigger TMA. Although withdrawing the offending drug may lead to resolution of TMA, graft and patient outcomes are poor. Specific treatments, including plasma exchange, have not gained widespread acceptance in those with fulminant disease and new approaches to the condition are urgently needed. We report a case of posttransplant de novo TMA presenting serially in association with ciclosporin, tacrolimus and sirolimus in a young recipient of a living donor kidney transplant. We describe a patient treated with belatacept, a novel CTLA4 Ig fusion protein, as ongoing maintenance immunosuppression to allow avoidance of conventional agents once associated with TMA. We report excellent early graft outcome, with no adverse events using this strategy. We suggest that belatacept may have a role in this traditionally difficult-to-treat group of patients.

Renal ageing.

The function of the kidney, as well as its morphology, changes markedly with age. The glomerular filtration rate falls progressively, independent of overt pathology. Glomerular, vascular and accompanying parenchymal changes occur and other disorders associated with ageing, such as diabetes and hypertension, have a stochastic deleterious effect on both form and function. Declining renal function with age has important implications, not only for individual homeostasis but also for the use of drug therapy and for the receipt and donation of organs for transplantation. Molecular mechanisms and cellular changes underlying some of the functional and structural changes associated with ageing are becoming clearer, as are some of the ways in which genetic background, age and disease can combine to produce functional damage.

The pathology of ageing: concepts and mechanisms.

The rising numbers and proportion of aged individuals in the population is a global demographic trend. The diseases associated with ageing are becoming more prevalent, and the associated healthcare costs are having a significant economic impact in all countries. With these changes have come great advances in our understanding of the mechanisms of ageing. The mechanisms of cellular ageing at a genetic, protein and organelle level are becoming clearer, as are some of the more complex associations between environment and ageing. System ageing is also becoming better understood, and the potential biological advantages of ageing are being explored. Many of the advances in these fields are opening up the prospect of targeted therapeutic intervention for ageing and age related disease.

Expression and prognostic significance of hypoxia-inducible factor 1alpha (HIF-1alpha) in malignant pleural mesothelioma (MPM).

Malignant pleural mesothelioma (MPM) is a highly chemoresistant cancer with a poor prognosis. Hypoxia is a specific property of solid tumours, contributes to low apoptotic potential, and can be selectively targeted by bioreductive drugs. Hypoxia-inducible factor 1alpha (HIF-1alpha) is a subunit of a heterodimeric transcription complex that regulates several genes associated with tumour progression and anti-apoptosis. In this study, we measured for the first time the expression of HIF-1alpha in MPM. Our results show that HIF-1alpha is commonly expressed in MPM but not in normal mesothelium, consistent with the presence of hypoxia. HIF-1alpha does not appear to predict survival; however, this study suggests that bioreductive drugs should be investigated in clinical trials of MPM.

A review of post-trachelectomy isthmic and vaginal smear cytology.

Currently in the UK cervical cancer has a peak incidence in women aged 35-39. Fertility-conserving surgical treatment by radical trachelectomy is established in the management of early disease. This study aimed at establishing the value of cytology in follow-up after trachelectomy. The cytological features of isthmic-vaginal smears post-trachelectomy for cervical cancer are presented together with a discussion of relevant clinical issues. One hundred and ninety seven smears from 32 women were reviewed. Two of the 32 patients developed pelvic recurrences. In both cases recurrence was detected cytologically long before development of a clinical or radiological abnormality. There is, however, a potential for overcall due to the presence of endometrial cells. These were present in large numbers and varying configurations in 58% of smears and led to a false positive report of malignancy in 2% of smears. The rate of referral for a cytologist opinion was significantly higher in smears containing endometrial cells (26%) than those without (13%). While all smears contained squamous cells, 41% contained squamous cells only and it is proposed that such smears should be reported as unsatisfactory in the first 2 years after surgery and negative thereafter, although the absence of glandular cells should be recorded. When an abnormality is reported, smear review and multidisciplinary discussion may avoid unnecessary investigations.

Inadequate rates are lower when FNAC samples are taken by cytopathologists.

Inadequate rates (IR) in FNAC from different sources were compared. The rates were lowest when FNAC was performed by a cytopathologist (12%) and highest when done by a non-cytopathologist (32%). These differences were mirrored in high IRs in breast cancer cases. IR was not significantly improved when non-cytopathologist FNAC was attended by a cytotechnician.

Fallopian tube ciliary beat frequency in relation to the stage of menstrual cycle and anatomical site.

BACKGROUND: The cyclical changes in ciliary structure and motion within the human Fallopian tube are well documented. Previous investigators have studied ciliary beat frequency (CBF) in relation to menstrual cycle and anatomical site, but with conflicting results. METHODS: Using a technique that records variations in light intensity, we have studied the changes in CBF in relation to the menstrual cycle and anatomical site. Fallopian tubes were collected from 26 women who underwent hysterectomy for benign conditions. Menstrual history, hormone profile and endometrial biopsy results were used to determine the stage of the cycle. Fourteen women were in the proliferative phase, and 12 women in the secretory phase. RESULTS: Mean CBF for all subjects was 5.3 plus minus 0.2 Hz. There was no significant difference in CBF in relation to anatomical site. In the fimbrial region the ciliary beat was faster in the secretory (5.8 plus minus 0.3 Hz) as compared with the proliferative phase (4.9 plus minus 0.2 Hz), P < 0.02. CONCLUSIONS: It is possible that this increase in fimbrial CBF may contribute to ovum retrieval and transport after ovulation. However, the reproductive significance of the changes in CBF in relation to the menstrual cycle needs further investigation.

Intraabdominal desmoplastic small cell tumor mimicking adenocarcinoma. A case report.

BACKGROUND: Fine needle aspirates and washings from intraabdominal desmoplastic small cell tumors (IADSCTs) are rarely encountered by pathologists. Immunocytochemical examination of histologic material is usually necessary for a definitive diagnosis. CASE: A 23-year-old man presented with abdominal pain, ascites and bilateral pleural effusion. Examination of ascitic fluid suggested adenocarcinoma, but histologic and immunocytochemical examination of surgically resected tissue showed features of an IADSCT. CONCLUSION: This case is a reminder that IADSCT should be included in the differential diagnosis of intraabdominal neoplasms and that its diagnosis in cytologic preparations requires a high index of suspicion. In particular, this case appears to be the first reported example of IADSCT mimicking adenocarcinoma.

Platelet-derived growth factor expression in phyllodes tumors and fibroadenomas of the breast.

The development of normal breast tissue and the pathogenesis of various tumors are influenced by growth factor-mediated epithelial-stromal interactions. Similar interactions may occur in fibroepithelial breast tumors. We have studied the expression of platelet-derived growth factor (PDGF) and PDGF beta receptor (PDGFRbeta) in 46 phyllodes tumors (18 benign, 15 borderline, 13 malignant), 11 fibroadenomas, and 6 samples of normal breast. There was neoplastic stromal cell positivity for PDGFRbeta in almost 50% of phyllodes tumors and for PDGF in 24%. Both were associated with prominent nuclear pleomorphism (P<.01), PDGF with high grade (P<.01), and a higher mean Ki-67 labeling index (P = .013), and PDGFRbeta with conspicuous stromal overgrowth (P<.01). Co-positivity for stromal PDGF and PDGFRbeta was found in 15% of phyllodes tumors, and for epithelial PDGF and stromal PDGFRbeta in 43%. Both types of co-positivity were associated with prominent nuclear pleomorphism and the latter type with conspicuous stromal overgrowth (all P<.01). Follow-up of 41 phyllodes tumors showed that disease-related death was associated with established histologic features of malignancy including mitotic count, stromal overgrowth, an infiltrative tumor margin, and nuclear pleomorphism. In addition, stromal PDGFRbeta positivity (P =.013) and epithelial PDGF/stromal PDGFRbeta co-positivity (P =.0075) were associated with disease-related death. Stromal PDGF and PDGFRbeta expression in fibroadenomas was less common and less extensive (P<.05) than in phyllodes tumors. The results suggest that PDGF influences the pathogenesis of fibroepithelial breast tumors and that PDGF-dependent paracrine and autocrine mechanisms may operate. Also, it is possible that assessment of PDGF and PDGFRbeta expression could contribute to the management of these tumors in the future.

Effects of radiation on the normal prostate gland.

Prostate cancer is one of the commonest tumours of adult males. It shows a range of biological behaviour: many tumours are discovered incidentally; others will kill by producing widespread metastatic disease. Despite the fact that radiation is frequently used in the treatment of a range of pelvic lesions, including adenocarcinoma of the prostate itself, studies on the morphological changes in the normal prostate gland after irradiation are limited. This seems particularly surprising following the increasing use of needle biopsy specimens to assess the prostate. Patients who receive pelvic irradiation often suffer from lower urinary tract symptoms such as frequency and dysuria and it is possible that these may be related to prostatic and/or periprostatic injury. We therefore investigated the prostate glands removed at cystoprostatectomy for transitional cell carcinomas of the bladder which had received radiotherapy pre-operatively. The changes were compared to control prostatic tissue from transurethral resection specimens for benign myoadenomatous hyperplasia. We found a range of inflammatory, fibrotic and reactive cytological features, including many of the changes seen in benign hyperplasia, but these were significantly more exaggerated in the post-radiation group. In addition intraprostatic vascular and neural changes were prominent. This study documents radiation-induced changes throughout the normal prostate gland and neighbouring soft tissue and has particular importance in current pathological practice with the increasing and widespread use of needle biopsies in the diagnosis and follow-up of prostate cancer.

beta hCG as a prognostic marker in adenocarcinoma of the prostate.

AIMS: To assess the importance of immunohistological detection of beta-human chorionic gonadotrophin (beta hCG) in localised prostatic adenocarcinoma with regard to prognosis and clinical applications. METHODS: Eighty consecutive cases of clinically localised adenocarcinoma of the prostate were studied retrospectively. Immunohistological analysis on formalin fixed, paraffin wax embedded prostate tissue from transurethral resections was related to clinical outcome and survival. Prognosis was also related to tumour grade. RESULTS: beta hCG was detected in 12 cases. Nine of these patients were found to have metastases (75%) at follow up and 11 (92%) were dead within 18 months. There was no correlation with grade and prognosis in this group. Of the 68 beta hCG negative cases, 21 had developed metastases (31%) and 25 (37%) had died within 18 months. In the beta hCG negative group there was an association between histological grade and survival. CONCLUSION: The demonstration of beta hCG in prostatic adenocarcinoma identifies a group of patients with poor prognosis, irrespective of histological grade. This additional information will be extremely valuable in the subsequent clinical management of such patients.

Relationship between infective load of Helicobacter pylori and reactive oxygen metabolite production in antral mucosa.

Helicobacter pylori infection has been associated with stimulation of gastric mucosal reactive oxygen metabolite production. To provide further evidence of a causal relationship we looked for a dose-response relationship. We studied antral biopsy material from 110 patients. Quantitative H. pylori assessments were made using histologic and microbiologic methods. Reactive oxygen metabolite production was measured by luminol-dependent chemiluminescence. The usefulness of timed urease test colour changes as a guide to infective load was assessed. There was a positive association between mucosal reactive oxygen metabolite production and histologic (p = 0.002, n = 69) and microbiologic (Spearman's R = +0.6, p = 0.05, n = 18) quantitative H. pylori assessments. H. pylori infective load varied markedly over small areas (coefficient of repeatability of paired cultures (in colony-forming units/mg) = 1.9 x 10(6). Urease test timing correlated with histologic (p = 0.01) and microbiologic (p = 0.03) H. pylori quantitation. Histologically assessed mucosal damage was related to quantitative H. pylori assessment and to mucosal reactive oxygen metabolite production (p = 0.0001). These results support the hypothesis that H. pylori stimulates gastric mucosal reactive oxygen metabolite production and that this phenomenon is of pathogenic importance.

Helicobacter pylori stimulates antral mucosal reactive oxygen metabolite production in vivo.

To determine if reactive oxygen metabolites have a pathogenic role in Helicobacter pylori (H pylori) related gastroduodenal disease, this study measured their production in antral mucosal biopsy specimens. Two related chemiluminescence techniques were used comparing H pylori positive (n = 105) and negative patients (n = 64) with a similar spectrum of macroscopic disease. After chemiluminescence assays, biopsy specimens were graded histologically. Increased luminol dependent chemiluminescence (detecting reactive oxygen metabolites through peroxidase catalysed reactions) was found in H pylori positive patients (median photon emission = 6.4 x 10(3)/min/mg wet weight (95% confidence intervals 3.6 to 9.9)) but not H pylori negative cases (-0.9 (-1.3 to -0.6)) (p = 0.0001). Similar results were found using lucigenin (which reacts directly with oxygen metabolites, particularly superoxide): (H pylori positive 0.9 (0.1 to 3.2); H pylori negative -1.2 (-3.4 to -0.6)) (p = 0.0003). Chemiluminescence was greater in H pylori positive compared with negative tissue when samples were grouped by equivalent macroscopic or microscopic damage. This difference was in part accounted for by a greater neutrophil infiltration in the H pylori positive mucosa, but when biopsy specimens with equivalent neutrophil infiltration could be compared directly, positive specimens gave greater chemiluminescence than negative. Smoking, drugs, and alcohol consumption had no independent effect. It is concluded that excess mucosal reactive oxygen metabolite production is associated with H pylori gastric antral infection and may be an important pathogenic mechanism. There is no evidence for reactive oxygen metabolite participation in the pathogenesis of gastric mucosal injury in cases unrelated to H pylori infection.

Prolymphocytic transformation of chronic lymphocytic leukaemia manifesting as a cerebellar lymphoma.

A 75-year-old woman presented with symptoms related to a space occupying lesion in the cerebellum which histology showed to be a malignant lymphoma of prolymphocytic type. A diagnosis of chronic lymphocytic leukaemia (CLL) had been made over 1 year before. This form of lymphoma complicating CLL has not been described previously in the nervous system.