Cardiovascular disease in Alpha 1 antitrypsin deficiency: an observational study assessing the role of neutrophil proteinase activity and the suitability of validated screening tools.

BACKGROUND: Alpha 1 Antitrypsin Deficiency (AATD) is a rare, inherited lung disease which shares features with Chronic Obstructive Pulmonary Disease (COPD) but has a greater burden of proteinase related tissue damage. These proteinases are associated with cardiovascular disease (CVD) in the general population. It is unclear whether patients with AATD have a greater risk of CVD compared to usual COPD, how best to screen for this, and whether neutrophil proteinases are implicated in AATD-associated CVD. This study had three aims. To compare CVD risk in never-augmented AATD patients to non-AATD COPD and healthy controls (HC). To assess relationships between CVD risk and lung physiology. To determine if neutrophil proteinase activity was associated with CVD risk in AATD. Cardiovascular risk was assessed by QRISK2® score and aortic stiffness measurements using carotid-femoral (aortic) pulse wave velocity (aPWV). Medical history, computed tomography scans and post-bronchodilator lung function parameters were reviewed. Systemic proteinase 3 activity was measured. Patients were followed for 4 years, to assess CVD development. RESULTS: 228 patients with AATD, 50 with non-AATD COPD and 51 healthy controls were recruited. In all COPD and HC participants, QRISK2® and aPWV gave concordant results (with both measures either high or in the normal range). This was not the case in AATD. Once aPWV was adjusted for age and smoking history, aPWV was highest and QRISK2® lowest in AATD patients compared to the COPD or HC participants. Higher aPWV was associated with impairments in lung physiology, the presence of emphysema on CT scan and proteinase 3 activity following adjustment for age, smoking status and traditional CVD risk factors (using QRISK2® scores) in AATD. There were no such relationships with QRISK2® in AATD. AATD patients with confirmed CVD at four-year follow up had a higher aPWV but not QRISK2® at baseline assessment. CONCLUSION: aPWV measured CVD risk is elevated in AATD. This risk is not captured by QRISK2®. There is a relationship between aPWV, lung disease and proteinase-3 activity. Proteinase-driven breakdown of elastin fibres in large arteries and lungs is a putative mechanism and forms a potential therapeutic target for CVD in AATD.

Trials based on specific fracture configuration and surgical procedures likely to be more relevant for decision making in the management of fractures of the proximal humerus: Findings of a meta-analysis.

OBJECTIVES: The objective of this study was to perform a meta-analysis of all randomised controlled trials (RCTs) comparing surgical and non-surgical management of fractures of the proximal humerus, and to determine whether further analyses based on complexity of fracture, or the type of surgical intervention, produced disparate findings on patient outcomes. METHODS: A systematic review of the literature was performed identifying all RCTs that compared surgical and non-surgical management of fractures of the proximal humerus. Meta-analysis of clinical outcomes was performed where possible. Subgroup analysis based on the type of fracture, and a sensitivity analysis based on the type of surgical intervention, were also performed. RESULTS: Seven studies including 528 patients were included. The overall meta-analysis found that there was no difference in clinical outcomes. However, subgroup and sensitivity analyses found improved patient outcomes for more complex fractures managed surgically. Four-part fractures that underwent surgery had improved long-term health utility scores (mean difference, MD 95% CI 0.04 to 0.28; p = 0.007). They were also less likely to result in osteoarthritis, osteonecrosis and non/malunion (OR 7.38, 95% CI 1.97 to 27.60; p = 0.003). Another significant subgroup finding was that secondary surgery was more common for patients that underwent internal fixation compared with conservative management within the studies with predominantly three-part fractures (OR 0.15, 95% CI 0.04 to 0.63; p = 0.009). CONCLUSION: This meta-analysis has demonstrated that differences in the type of fracture and surgical treatment result in outcomes that are distinct from those generated from analysis of all types of fracture and surgical treatments grouped together. This has important implications for clinical decision making and should highlight the need for future trials to adopt more specific inclusion criteria.Cite this article: S. Sabharwal, N. K. Patel, D. Griffiths, T. Athanasiou, C. M. Gupte, P. Reilly. Trials based on specific fracture configuration and surgical procedures likely to be more relevant for decision making in the management of fractures of the proximal humerus: Findings of a meta-analysisBone Joint Res 2016;5:470-480. DOI: 10.1302/2046-3758.510.2000638.

Colectomy in pediatric ulcerative colitis: A single center experience of indications, outcomes, and complications.

BACKGROUND/PURPOSE: There is a paucity of data on outcomes and complications of colectomy for pediatric ulcerative colitis (UC). This study reports the experience of a regional center for 18years. METHODS: Patients were identified from a prospective database and data obtained by note review. Median height/weight-SDS were calculated preoperatively and postoperatively. Data are expressed as median values (range). RESULTS: 220 patients with UC (diagnosed <17years) were identified, and 19 (9%) had undergone colectomy. Age at diagnosis was 11.6years (1.3-16.5), and 42% of patients were male. Time from diagnosis to surgery was 2.2years (0.1-13.1). All patients had failed maximal medical therapy. Fifteen patients had urgent scheduled operation, and 4 had emergency procedures, with 2 for (11%) acute-severe colitis (1 Clostridium difficile colitis) and 2 for acute-severe colitis with toxic dilatation. All initial procedures were subtotal-colectomy with ileostomy. Nine patients (47%) had early complications (during initial admission), 7 (37%) requiring reoperation. Six (32%) had late complications, with 5 requiring laparotomy. No patients had both early and late complications. Height-SDS was -0.27 before surgery and -0.23 (maximal follow-up). Weight-SDS was 0.32 and 0.05 (maximal follow-up). CONCLUSION: Approximately 1/11 children with UC required colectomy during childhood. Half of patients had acute complications, and 1/3 of patients required another operation during their first admission. 1/3 of patients developed late complications.

Renal tumours in a Tsc2(+/-) mouse model do not show feedback inhibition of Akt and are effectively prevented by rapamycin.

Tuberous sclerosis (TSC) is an inherited syndrome in which tumours in multiple organs are characterised by activation of mammalian target of rapamycin complex 1 (mTORC1). Previous work suggests that mTORC1 activation is associated with feedback inhibition of Akt, a substrate of mTORC2. This could limit TSC-associated tumour growth but lead to paradoxical promotion of tumour cell survival upon treatment with mTOR inhibitors. However, Akt/mTOR signalling has not been fully investigated in TSC-associated tumours and it has been uncertain whether mTOR inhibition can prevent TSC-associated renal tumourigenesis. In this study, we investigated Akt/mTOR signalling in renal tumours using a Tsc2(+/-) mouse model and tested whether mTOR inhibition could prevent renal tumourigenesis. We found that all renal lesions including cysts, adenomas and carcinomas exhibited activation of both Akt and mTORC1 as evidenced by increased protein expression and phosphorylation of Akt and mTOR and their downstream targets. Protein kinase Cα was also highly expressed and phosphorylated in these lesions, consistent with activation of mTORC2. Surprisingly, IRS proteins were highly expressed, in contrast to a striking decrease seen in cultured Tsc2(-/-) mouse embryonic fibroblasts, suggesting one mechanism through which loss of feedback inhibition of Akt may occur in mTORC1 hyperactivated Tsc-associated tumours. Long-term treatment with rapamycin reduced both Akt and mTORC1 activity in normal kidney tissues and blocked the development of all types of renal lesions. In conclusion, in contrast to previous studies, we found that Akt signalling is not inhibited in Tsc-associated renal lesions and that by partially inhibiting the Akt/mTOR pathway, rapamycin is highly effective in preventing Tsc-associated tumours.

Variation in reporting of cancer extent and benign histology in prostate biopsies among European pathologists.

It is not known how uropathologists currently report histopathological features of prostate biopsies such as core length, tumor extent, perineural invasion, and non-tumor-associated features such as inflammation and hyperplasia in needle biopsies. A web-based survey was distributed among 661 members of the European Network of Uropathology. Complete replies were received from 266 pathologists in 22 European countries. Total core lengths were reported by 64 %. The numbers of cores positive for cancer was given by 79 %. Linear cancer extent was reported by 81 %, most often given in millimeters for each core (53 %) followed by the estimation of percentage of cancer in each core (40 %). A gap of benign tissue between separate cancer foci in a single core would always be subtracted by 48 % and by 63 % if cancer foci were minute and widely separated. Perineural invasion was reported by 97 %. Fat invasion by tumor was interpreted as extraprostatic extension by 81 %. Chronic and active/acute inflammation was always reported by 32 and 56 % but only if pronounced by 54 and 39 %, respectively. While most (79 %) would never diagnose benign prostatic hyperplasia on needle biopsy, 21 % would attempt to make this diagnosis. Reporting practices for prostate biopsies are variable among European pathologists. The great variation in some methodologies used suggests a need for further international consensus, in order for retrospective data to be comparable between different institutions.

Surgery for children with Crohn's disease: indications, complications and outcome.

BACKGROUND: Outcome data for surgery in paediatric Crohn's disease are limited. We report 10 years' experience at a regional paediatric gastroenterology centre. METHODS: Children undergoing surgery for Crohn's disease (January 2002-December 2012) were identified from an onsite patient register. Patients were followed until transition to adult services. Data were obtained from medical records and are expressed as median (range). RESULTS: Sixty-nine children, aged 13.8 years (6.3-17.0) at diagnosis, were included. 42 were male (61%). Follow-up was 1.8 years (27 days-6 years). Surgery followed diagnosis by 9 months (0 days-7 years). 52 children (75%) received thiopurines and 5 (7%) anti-TNF (tumour necrosis factor) therapy preoperatively. 58 (84%) underwent intra-abdominal surgery (40 right hemicolectomy, 8 stoma formation, 2 subtotal colectomy, 2 small bowel resection, 6 other) and 10 (14%) underwent surgery for perianal disease. The commonest indications for intra-abdominal surgery were stricturing disease 35 (60%) and unresponsive luminal disease 13 (22%). There were 13 (22%) early, and 5 (8.6%) late, complications following intra-abdominal surgery. Nine children had disease relapse, five required further surgery. Height SD scores (SDS) did not increase between diagnosis; -0.5 (-3.4-2.1) and most recent follow up; -0.4 (-3.0-1.1). Body Mass Index (BMI) SDS increased from -1.0 (-6.3-1.5) to -0.3 (-3.3-2.0) (p<0.05). CONCLUSIONS: Surgery was associated with a 22% early complication rate and a 15% risk of relapse. 21% of patients required a second unplanned intra-abdominal procedure. Surgical intervention was associated with an increase in BMI SDS, but not in height SDS.

Total colonic aganglionosis: a 15-year single center experience.

PURPOSE: Total colonic aganglionosis (TCA) is a rare condition, which is challenging to manage. Outcome data are sparse. We aimed to review the demographics, treatment, and outcomes of TCA in our center. PATIENTS AND METHODS: A retrospective case note review of 15 years from a single center was undertaken. RESULTS: A total of nine patients (five male) were managed. Gestational age at birth was 39 weeks (range, 32.5-41 weeks). All patients were referred with distal intestinal obstruction at a median of day 2 (range, 1-6 days) of life. Two patients were managed with a long-term stoma. One died with persistent functional obstruction (despite a ganglionic stoma). Of the nine patients, seven patients underwent staged pull-through: three Soave, three Duhamel, and one Martin procedure with no short-term complications. All patients had at least one readmission with enterocolitis, diarrhea, or high stoma output. Further procedures were required in four of the seven patients. Only one child (older than 3 years) has achieved continence. Two children (both aged 8 years) requested reformation of a stoma to manage incontinence. CONCLUSION: In this series, we observed high morbidity and poor functional outcome, which should be anticipated in TCA. Patients with TCA have a high probability of requiring a long-term stoma and this should be considered as a management option.

Inhalation toxicity of 316L stainless steel powder in relation to bioaccessibility.

The Globally Harmonized System for Classification and Labelling of Chemicals (GHS) considers metallic alloys, such as nickel (Ni)-containing stainless steel (SS), as mixtures of substances, without considering that alloys behave differently compared to their constituent metals. This study presents an approach using metal release, explained by surface compositional data, for the prediction of inhalation toxicity of SS AISI 316L. The release of Ni into synthetic biological fluids is >1000-fold lower from the SS powder than from Ni metal, due to the chromium(III)-rich surface oxide of SS. Thus, it was hypothesized that the inhalation toxicity of SS is significantly lower than what could be predicted based on Ni metal content. A 28-day inhalation study with rats exposed to SS 316L powder (<4 µm, mass median aerodynamic diameter 2.5-3.0 µm) at concentrations up to 1.0 mg/L showed accumulation of metal particles in the lung lobes, but no signs of inflammation, although Ni metal caused lung toxicity in a similar published study at significantly lower concentrations. It was concluded that the bioaccessible (released) fraction, rather than the elemental nominal composition, predicts the toxicity of SS powder. The study provides a basis for an approach for future validation, standardization and risk assessment of metal alloys.

Cellular differentiation and proliferation in the ovine lung during gestation and early postnatal development.

This study investigates epithelial cell differentiation and proliferation in specific anatomical regions of the ovine lung during prenatal and postnatal development. Immunohistochemistry was used to identify ciliated epithelial cells, Clara cells, neuroepithelial bodies and type II pneumocytes in the lungs of preterm (67, 127 and 140 days of gestation), full-term (147 days) and postnatal (9, 16 and 91 days old) lambs. Differentiation of ciliated epithelial cells was seen at 67 days of gestation and at term for Clara cells. Neuroepithelial bodies were first detected at 127 days of gestation. From 16 to 91 days of age there was a significant (P <0.05) increase in beta-tubulin (present in ciliated epithelial cells) and Clara cell protein (present in Clara cells) in multiple regions of the lung. Detection of Ki67, a marker of proliferation, in preterm lambs showed a reduction in proliferation index in multiple anatomical regions of the lung between 70 days of gestation and term. Cell proliferation increased following parturition, and then decreased between 16 and 91 days of age, with the largest reduction occurring in the alveolar compartment. Knowledge of which cells are present at specific times of lung development provides valuable information on the anatomy of the ovine lung, improving its use as a model for ovine and human neonatal disease. In addition, the antibodies used here will be valuable for future studies requiring the identification and quantification of respiratory epithelial cell phenotypes in the sheep lung.

Scope and feasibility of operating on the neonatal intensive care unit: 312 cases in 10 years.

PURPOSE: To report the scope, feasibility and learning experience of operating on neonates on the neonatal intensive care unit (NICU). METHODS: (1) Review of all NICU operations performed by general neonatal surgeons over 10 years; (2) 6-month prospective comparison of procedures performed in NICU or operating room; (3) structured interviews with five surgeons with 1-13 years experience of operating on NICU. RESULTS: 312 operations were performed in 249 infants. Median birth weight was 1,494 g (range 415-4,365), gestational age 29 weeks (22-42), and age at operation 25 days (0-163). Nearly half (147) were laparotomy for acute abdominal pathology in preterm, very low birth-weight infants There were no surgical adverse events related to location of surgery. Surgeon satisfaction with operating on NICU for this population was high (5/5). Several factors contribute to making this process a success. CONCLUSIONS: This is the largest reported series of general neonatal surgical procedures performed on NICU. Operating on NICU is feasible and safe, and a full range of neonatal operations can be performed. It removes risks associated with neonatal transfer and is likely to reduce physiological instability. We recommend this approach for all ventilated neonates and urge neonatal surgeons to operate at the cotside of unstable infants.

Suitability of PSA-detected localised prostate cancers for focal therapy: experience from the ProtecT study.

BACKGROUND: Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial. METHODS: Surgical specimens from 525 men who underwent prostatectomy within the ProtecT study were analysed to determine tumour volume, location and grade. These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately. RESULTS: Solitary cancers were found in prostatectomy specimens from 19% (100 out of 525) of men. In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38-66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer's significance in 26% (34 out of 130) of men and resulted in overtreatment in more than half. Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions. CONCLUSION: Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression.

Autoimmune progesterone dermatitis: a diagnosis easily missed.

Autoimmune progesterone dermatitis (AIPD) is a rare, poorly characterized dermatosis, with about 60 previously reported cases. It typically undergoes cyclical flares relating to the menstrual cycle, especially the luteal phase, when levels of progesterone are at their highest. We report the case of a 34-year-old woman with an 8-year history of a profoundly pruritic eruption, associated with her menstrual cycle, in whom the diagnosis had proved elusive. Buserelin nasal spray resulted in complete clearance. AIPD is a diagnosis to consider in intractable eruptions in women, particularly if there is cyclical variation.

Trans-anastomotic tubes reduce the need for central venous access and parenteral nutrition in infants with congenital duodenal obstruction.

PURPOSE: To determine the effect of trans-anastomotic tube (TAT) feeding on outcome following repair of congenital duodenal obstruction (CDO). METHODS: Retrospective comparative study of all infants with CDO over 10 years. Data are median (range). Mann-Whitney U test and Fisher's exact test were used. RESULTS: Of 55 infants with CDO (48 atresia, 7 stenosis), 17 were managed with a TAT, 38 without. Enteral feeds were commenced earlier in infants with a TAT compared to those without (TAT 2 days post-repair [1-4] vs. no-TAT 3 days post-repair [1-7]; p = 0.006). Infants with a TAT achieved full enteral feeds significantly sooner than those without (TAT 6 days post-repair [2-12] vs. no-TAT 9 days post-repair [3-36]; p = 0.005). Significantly fewer infants in the TAT group required central venous catheter (CVC) placement and parenteral nutrition (PN) than in the no-TAT group (TAT 2/17 vs. no-TAT 28/38, p < 0.0001). There were six CVC-related complications (5 infections, 1 PN extravasation) and four TATs became displaced and were removed before achieving full enteral feeds. One infant with a TAT with trisomy 21 and undiagnosed Hirschsprung disease developed an anastomotic leak and jejunal perforation requiring re-operation. CONCLUSIONS: A TAT significantly shortens time to full enteral feeds in infants with CDO significantly reducing the need for central venous access and PN.

Proximal humeral replacement using a fixed-fulcrum endoprosthesis.

Between 1997 and 2007, 68 consecutive patients underwent replacement of the proximal humerus for tumour using a fixed-fulcrum massive endoprosthesis. Their mean age was 46 years (7 to 87). Ten patients were lost to follow-up and 16 patients died. The 42 surviving patients were assessed using the Musculoskeletal Tumor Society (MSTS) Score and the Toronto Extremity Salvage Score (TESS) at a mean follow-up of five years and 11 months (one year to ten years and nine months). The mean MSTS score was 72.3% (53.3% to 100%) and the mean TESS was 77.2% (58.6% to 100%). Four of 42 patients received a new constrained humeral liner to reduce the risk of dislocation. This subgroup had a mean MSTS score of 77.7% and a mean TESS of 80.0%. The dislocation rate for the original prosthesis was 25.9; none of the patients with the new liner had a dislocation at a mean of 14.5 months (12 to 18). Endoprosthetic replacement for tumours of the proximal humerus using this prosthesis is a reliable operation yielding good results without the documented problems of unconstrained prostheses. The performance of this prosthesis is expected to improve further with a new constrained humeral liner, which reduces the risk of dislocation.

Pathology and pathogenesis of ovine pulmonary adenocarcinoma.

Ovine pulmonary adenocarcinoma (OPA), also known as jaagsiekte, is a transmissible lung tumour of sheep caused by jaagsiekte sheep retrovirus (JSRV). JSRV induces neoplastic transformation of alveolar and bronchiolar secretory epithelial cells and the resulting tumours can grow to occupy a significant portion of the lung. Tumour growth is frequently accompanied by the overproduction of fluid in the lung, which further compromises normal respiration. The period between infection and the appearance of clinical signs may be several months or years and many JSRV-infected sheep do not exhibit clinical signs at all during their lifespan. This allows the spread of OPA into new flocks through contact with infected but apparently normal animals. OPA was first described in the early 19th century; however, it has still not been possible to devise effective methods for controlling its spread and it remains an important problem in most countries where sheep are farmed. This is due in part to the absence of an immunological response to JSRV in infected animals, which has hindered the development of serological diagnostic tests and vaccines. In addition to its veterinary importance, OPA is regarded as a potential large animal model for human lung adenocarcinoma and this has stimulated research into the pathogenesis of the ovine disease. This work has produced some significant results, including the finding that one of the JSRV structural proteins is directly involved in oncogenesis. The recent advances in understanding JSRV and the pathogenesis of OPA should lead to novel strategies for diagnosis and control of this disease and for its exploitation as a comparative model for human lung cancer.

Handling and reporting of radical prostatectomy specimens in Europe: a web-based survey by the European Network of Uropathology (ENUP).

AIMS: To survey current European practices in handling and reporting of radical prostatectomy (RP) specimens. METHODS AND RESULTS: A European Network of Uropathology (ENUP) was organized for the dissemination of information, survey studies and research collaborations. Contact data of uropathologists were collected from 321 pathology laboratories in 15 West European countries. In the first ENUP survey, 67.6% (217/321) of the members replied to a web-based questionnaire. Some practices were adopted by a large majority, e.g. inking of the specimen (96.6%), Gleason grading (99.5%), stratifying extraprostatic extension (EPE) according to extent (88.2%), reporting TNM stage (88.6%) and reporting location of positive margins (98%). As many as 71.6% of respondents always embedded the entire prostate and only 10.8% always practised partial embedding. Whole mounts were routinely used by 37.5% and standard blocks by 55.5%. Among areas with variable routines were methods to define focal versus extensive EPE and methods to quantify margin positivity, probably reflecting that the optimal method has yet to be determined. CONCLUSIONS: Some practices are almost universally adopted in Europe, whereas others still need to be standardized. The results of the study may be helpful when judging what recommendations are reasonable to issue.

Combined expression of caveolin-1 and an activated AKT/mTOR pathway predicts reduced disease-free survival in clinically confined renal cell carcinoma.

We previously reported that tumour-associated caveolin-1 is a potential biomarker in renal cell carcinoma (RCC), whose overexpression predicts metastasis following surgical resection for clinically confined disease. Much attention has recently focused on the AKT/mTOR pathway in a number of malignancies, including RCC. Since caveolin-1 and the AKT/mTOR signalling cascade are independently shown to be important regulators of tumour angiogenesis, we hypothesised that caveolin-1 interacts with the AKT/mTOR pathway to drive disease progression and metastasis in RCC. The aims of this study were to determine (i) the expression status of the activated AKT/mTOR pathway components (phosphorylated forms) in RCC and (ii) their prognostic value when combined with caveolin-1. Immunohistochemistry for caveolin-1, pAKT, pmTOR, pS6 and p4E-BP1 was performed on tissue microarrays from 174 clinically confined RCCs. Significantly decreased mean disease-free survival was observed when caveolin-1 was coexpressed with either pAKT (2.95 vs 6.14 years), pmTOR (3.17 vs 6.28 years), pS6 (1.45 vs 6.62 years) or p4E-BP1 (2.07 vs 6.09 years) than when neither or any one single biomarker was expressed alone. On multivariate analysis, the covariate of 'caveolin-1/AKT' (neither alone were influential covariates) was a significant influential indicator of poor disease-free survival with a hazard ratio of 2.13 (95% CI: 1.15-3.92), higher than that for vascular invasion. Tumours that coexpressed caveolin-1 and activated mTOR components were more likely to be larger, higher grade and to show vascular invasion. Our results provide the first clinical evidence that caveolin-1 cooperates with an activated AKT/mTOR pathway in cancer and may play an important role in disease progression. We conclude that evaluation of the 'caveolin-1/AKT/mTOR axis' in primary kidney tumours will identify subsets of RCC patients who require greater postoperative surveillance and more intensive treatment.

Oro-dental features as useful diagnostic tool in Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RTS; OMIM # 180849) is a well-known disorder characterized by mental and growth retardation, broad thumbs and great toes, and unusual facial characteristics. We studied oro-dental findings in a group of RTS patients: 12 from the UK, 2 from Greece, and 26 from France. All were examined by two investigators, using the Diagnosing Dental Defects Database record form to document these. Various oro-dental features were found: small mouth, retrognathia, micrognathia, highly arched and narrow palate, talon cusps, expressed crowding, screwdriver incisors, cross bites, and enamel hypoplasia. Eruption was usually normal. Specific attention for these anomalies should facilitate diagnosis and help adequate management.

A UK-based investigation of inter- and intra-observer reproducibility of Gleason grading of prostatic biopsies.

AIMS: The frequency of prostatic core biopsies to detect cancer has been increasing with more widespread prostate specific antigen (PSA) testing. Gleason score has important implications for patient management but morphological reproducibility data for British practice are limited. Using literature-based criteria nine uropathologists took part in a reproducibility study. METHODS: Each of the nine participants submitted slides from consecutive cases of biopsy-diagnosed cancer assigned to the Gleason score groups 2-4, 5-6, 7 and 8-10 in the original report. A random selection of slides was taken within each group and examined by all pathologists, who were blind to the original score. Over six circulations, new slides were mixed with previously read slides, resulting in a total of 47 of 81 slides being read more than once. RESULTS: For the first readings of the 81 slides, the agreement with the consensus score was 78% and overall interobserver agreement was kappa 0.54 for Gleason score groups 2-4, 5-6, 7, 8-10. Kappa values for each category were 0.33, 0.56, 0.44 and 0.68, respectively. For the 47 slides read more than once, intra-observer agreement was 77%, kappa 0.66. The study identified problems in core biopsy interpretation of Gleason score at levels 2-4 and 7. Patterns illustrated by Gleason as 2 tended to be categorized as 3 because of the variable acinar size and unassessable lesional margin. In slides with consensus Gleason score 7, 13% of readings were scored 6 and in slides with consensus 6, 18% of readings were scored 7. CONCLUSIONS: Recommendations include the need to increase objectivity of the Gleason criteria but limits of descriptive morphology may have to be accepted.