INTU is essential for oncogenic Hh signaling through regulating primary cilia formation in basal cell carcinoma.

Inturned (INTU), a cilia and planar polarity effector, performs prominent ciliogenic functions during morphogenesis, such as in the skin. INTU is expressed in adult tissues but its role in tissue maintenance is unknown. Here, we report that the expression of the INTU gene is aberrantly elevated in human basal cell carcinoma (BCC), coinciding with increased primary cilia formation and activated hedgehog (Hh) signaling. Disrupting Intu in an oncogenic mutant Smo (SmoM2)-driven BCC mouse model prevented the formation of BCC through suppressing primary cilia formation and Hh signaling, suggesting that Intu performs a permissive role during BCC formation. INTU is essential for intraflagellar transport A complex assembly during ciliogenesis. To further determine whether Intu is directly involved in the activation of Hh signaling downstream of ciliogenesis, we examined the Hh signaling pathway in mouse embryonic fibroblasts, which readily responds to the Hh pathway activation. Depleting Intu blocked Smo agonist-induced Hh pathway activation, whereas the expression of Gli2ΔN, a constitutively active Gli2, restored Hh pathway activation in Intu-deficient cells, suggesting that INTU functions upstream of Gli2 activation. In contrast, overexpressing Intu did not promote ciliogenesis or Hh signaling. Taken together, data obtained from this study suggest that INTU is indispensable during BCC tumorigenesis and that its aberrant upregulation is likely a prerequisite for primary cilia formation during Hh-dependent tumorigenesis.

The novel use of commonly captured data to assess a district's diabetes service that encompasses both primary and secondary care.

AIM: To identify commonly captured data in the UK to look at the performance of a district's diabetes care that encompasses both primary and secondary care. METHODS: Primary care quality outcomes framework (QOF) measures for diabetes, referral rates for first appointment for specialist secondary care and emergency admission rates for diabetes (Dr Foster/HES) were used to produce a performance index scoring system. Illustrative measures from QOF were total diabetes points, DM23 attainment of HbA1c <7% (53 mmol/mol) and its exemption rate (number of patients excluded from analysis). The performance index was used to study the effectiveness of the Medway district diabetes service and this was compared to another district (Guildford) within the same Strategic Health Authority and nationally. RESULTS: Medway has the highest prevalence of Diabetes (6.1%) of the 8 Primary Care Trusts examined, the lowest achievement of diabetes QOF points (96.1%) and the lowest achievement of an HbA1c level <7% (53 mmol/mol) (54.3%). Exemption reporting was the 3rd highest. SAR for first diabetes out-patient appointment to the hospital was low at 281 (predicted 576) 48% of expected. The emergency admission rate was high at 225 (predicted 168) 133% of expected. Thus primary care diabetes needs to raise performance and implement a lower threshold for OPD referral to prevent emergency admissions. CONCLUSION: It is possible to produce an assessment of diabetes care that transcends primary/secondary care that gives a true reflection of a district's performance which will be useful to plan future health service provision.

Triangular to square flux lattice phase transition in YBa2Cu3O7.

We have used the technique of small-angle neutron scattering to observe magnetic flux lines directly in a YBa2Cu3O7 single crystal at fields higher than previously reported. For field directions close to perpendicular to the CuO2 planes, we find that the flux lattice structure changes smoothly from a distorted triangular coordination to nearly perfectly square as the magnetic induction approaches 11 T. The orientation of the square flux lattice is as expected from recent d-wave theories but is 45 degrees from that recently observed in La(1.83)Sr(0.17)CuO(4+delta).

Prevalence and correlates of mitral valve prolapse in a population-based sample of American Indians: the Strong Heart Study.

PURPOSE: Mitral valve prolapse is heritable and occurs frequently in the general population despite associations with mitral regurgitation and infective endocarditis, suggesting that selective advantages might be associated with mitral valve prolapse. SUBJECTS AND METHODS: Clinical examination and 2-dimensional and color Doppler echocardiography were performed in 3340 American Indian participants in the Strong Heart Study. RESULTS: Mitral valve prolapse (clear-cut billowing of one or both mitral leaflets across the mitral anular plane in 2-dimensional parasternal long-axis recordings or >2-mm late systolic posterior displacement of mitral leaflets by M mode) occurred in 37 (1.8%) of 2077 women and 20 (1.6%) of 1263 men (P = 0.88); 32 (3.5%) of 907 patients with normal glucose tolerance, 11 (2.3%) of 486 patients with impaired glucose tolerance, and 13 (0.7%) of 1735 patients with diabetes (P <0.0001). Participants with mitral valve prolapse had lower mean (+/- SD) body mass index (28 +/- 5 kg/m(2) vs. 31 +/- 6 kg/m(2), P = 0.001) and blood pressure (124/71 +/- 19/10 mm Hg vs. 130/75 +/- 21/10 mm Hg, P <0.05), as well as lower levels of fasting glucose, triglycerides, serum creatinine, and log urine albumin/creatinine ratio (all P <0.001), than did those without mitral valve prolapse, although all subjects were similar in age (60 +/- 8 years). Participants with mitral valve prolapse had lower ventricular septal (0.87 +/- 0.08 cm vs. 0.93 +/- 0.13 cm) and posterior wall thicknesses (0.82 +/- 0.08 cm vs. 0.87 +/- 0.10 cm), mass (38 +/- 7 g/m(2.7) vs. 42 +/- 11 g/m(2.7)), and relative wall thickness (0.33 +/- 0.04 vs. 0.35 +/- 0.05), and increased stress-corrected midwall shortening (all P <0.01). Mitral valve prolapse was associated with a higher prevalence of mild (16 of 57 [28%] vs. 614 of 3283 [19%]) and more severe mitral regurgitation (5 of 57 [9%] vs. 48 of 3283 [1%], P <0.0001). Regression analyses showed prolapse was associated with low ventricular relative wall thickness, high midwall function, and low urine albumin/creatinine ratio, independent of age, sex, body mass index, and diabetes. CONCLUSIONS: Mitral valve prolapse is fairly common and is strongly associated with mitral regurgitation in the general population. However, it is also associated with lower body weight, blood pressure, and prevalence of diabetes; a more favorable metabolic profile and ventricular geometry; and better myocardial and renal function.

Reliability, validity, and responsiveness of four knee outcome scales for athletic patients.

BACKGROUND: Many patient-based knee-rating scales are available for the evaluation of athletic patients. However, there is little information on the measurement properties of these instruments and therefore no evidence to support the use of one questionnaire rather than another. The goal of the present study was to determine the reliability, validity, and responsiveness of four knee-rating scales commonly used for the evaluation of athletic patients: the Lysholm scale, the subjective components of the Cincinnati knee-rating system, the American Academy of Orthopaedic Surgeons sports knee-rating scale, and the Activities of Daily Living scale of the Knee Outcome Survey. METHODS: All patients in the study had a disorder of the knee and were active in sports (a Tegner score of 4 points). Forty-one patients who had a knee disorder that had stabilized and who were not receiving treatment were administered all four questionnaires at baseline and again at a mean of 5.2 days (range, two to fourteen days) later to test reliability. Forty-two patients were administered the scales at baseline and at a minimum of three months after treatment to test responsiveness. The responses of 133 patients at baseline were studied to test construct validity. RESULTS: The reliability was high for all scales, with the intraclass correlation coefficient ranging from 0.88 to 0.95. As for construct validity, the correlations among the knee scales ranged from 0.70 to 0.85 and those between the knee scales and the physical component scale of the Short Form-36 (SF-36) and the patient and clinician severity ratings ranged from 0.59 to 0.77. Responsiveness, measured with the standardized response mean, ranged from 0.8 for the Cincinnati knee-rating system to 1.1 for the Activities of Daily Living scale. CONCLUSIONS: All four scales satisfied our criteria for reliability, validity, and responsiveness, and all are acceptable for use in clinical research.

Inflammatory pseudotumor and sarcoma of urinary bladder: differential diagnosis and outcome in thirty-eight spindle cell neoplasms.

We assessed diagnostic criteria among 38 spindle cell tumors of the urinary bladder and obtained follow-up in 36 patients. Patients comprised 28 males and 10 females aged 2.5 months to 87 years. Hematuria was the commonest presenting symptom (27 patients). After review and immunohistochemical workup, 17 patients had inflammatory pseudotumor (myofibroblastic tumor), 4 postoperative spindle cell nodule, 1 leiomyoma, 13 sarcoma (7 low-grade; 6 high-grade), and 3 carcinoma. Mean age was 38 years for pseudotumor (range 15 to 74), 65 for postoperative spindle cell nodule, 51 for sarcoma, and 76 for carcinoma. Size of pseudotumor averaged 4.4 +/- 0.7 cm (range 1.5 to 13.0), similar to sarcoma, 4.0 +/- 0.6 cm (range 0.5 to 7.0). Similar proportions of benign tumors and sarcomas had muscularis propria invasion. The criteria that best differentiated sarcoma from inflammatory pseudotumor were presence of necrosis at the tumor-detrusor muscle interface in muscle-invasive cases, and nuclear atypia. Sarcoma also had less prominent microvasculature, less variable cellularity, consistently > or =1 mitotic figure per 10 high-power fields, and predominant acute inflammation without plasma cells. p53 protein nuclear immunostaining was moderate, unlike the rare to absent staining in pseudotumors. Because all 12 sarcomas were desmin-negative, we did not call them leiomyosarcoma; they overlapped with benign tumor in epithelial, mesenchymal, and actin immunostaining. Among 12 sarcoma patients, 2 died of tumor (at 3 months). Two of four experienced tumor recurrence after partial cystectomy (2 and 26 months). No pseudotumors recurred after transurethral resection or partial cystectomy, although one patient, 5 months after transurethral resection, had histologically identical pseudotumor that the surgeon considered residual. Another patient with pseudotumor, not a candidate for tumor ablation after transurethral resection, had continued tumor growth and he died of urosepsis. In conclusion, inflammatory pseudotumor, although overlapping with sarcoma in presentation, age range, and size, does not metastasize and remains histologically distinct from low-grade sarcoma.

Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.

Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, lambda(S), of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P=.033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P=.015) and in combination with a Mexican American study (P=.004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms-L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.

Patients' expectations of knee surgery.

BACKGROUND: Patients' expectations of medical care are linked to their requests for treatment and to their assessments of outcome and satisfaction. Our goals were to measure patients" preoperative expectations of knee surgery and to develop and test patient-derived knee expectations surveys. METHODS: An initial sample of 377 patients (mean age, 54.6 18.2 years; 52% women) was enrolled in the survey-development phase. One hundred and sixty-one (43%) of these patients subsequently underwent total knee arthroplasty; seventy-five (20%), cruciate ligament repair; eighty-five (23%), meniscal surgery; and fifty-six (15%), surgery for another knee condition. Preoperatively, these patients were asked open-ended questions about their expectations of knee surgery. Their responses were grouped with use of qualitative research techniques to generate categories of expectations. Categories were transformed into specific questions and were formatted into two draft surveys, one for patients undergoing total knee arthroplasty and one for patients undergoing other surgical procedures on the knee. A second sample of 163 patients (mean age, 55.1 17.5 years; 49% women) was enrolled in the survey-testing phase, and they completed the draft surveys on two separate occasions to establish test-retest reliability. Items were selected for the final surveys if they were cited by 5% of the patients, if they represented important functional changes resulting from surgery, or if they represented potentially unrealistic expectations. All selected items fulfilled reliability criteria, defined as a kappa (or weighted kappa) value of 0.4, or were deemed to be clinically relevant by a panel of orthopaedic surgeons. RESULTS: From the survey-development phase, a total of fifty-two categories of expectations were discerned; they included both anticipated items such as pain relief and improvement in walking ability and unanticipated items such as improving psychological well-being. Expectations varied by diagnosis and patient characteristics, including functional status. Two final surveys were generated: the seventeen-item Hospital for Special Surgery Knee Replacement Expectations Survey and the twenty-item Hospital for Special Surgery Knee Surgery Expectations Survey. Each required less than five minutes to complete. CONCLUSIONS: Patients have multiple expectations of knee surgery in the areas of symptom relief and improvement of physical and psychosocial function, and these expectations vary according to the diagnosis. We developed two valid and reliable surveys that can be used preoperatively to direct patient education and shared decision-making and to provide a framework for setting reasonable goals. Reexamining patients' responses postoperatively could provide a way to assess fulfillment of expectations, which is a crucial patient-derived measure of outcome and satisfaction.

Mixed epithelial and stromal tumor of the kidney lacks the genetic alterations of cellular congenital mesoblastic nephroma.

Mixed epithelial and stromal tumor of the kidney is a recently recognized neoplasm that occurs almost exclusively in perimenopausal women. Because it frequently contains areas of smooth muscle in which epithelial structures are embedded, some have concluded that it is the adult form of congenital mesoblastic nephroma. Others have concluded that the morphology and epidemiology of mixed epithelial and stromal tumor indicate that it is unrelated to congenital mesoblastic nephroma. Although the genetic alterations of mixed epithelial and stromal tumor have not been previously elucidated, much is known about the genetic alterations of cellular congenital mesoblastic nephroma. The present study was undertaken to determine if mixed epithelial and stromal tumors have any of the genetic alterations recognized as typical of cellular congenital mesoblastic nephroma. RNA extraction was performed on formalin-fixed, paraffin-embedded tissue from 7 mixed epithelial and stromal tumors followed by reverse-transcription polymerase chain reaction to detect the ETV6-NTRK3 gene fusion. Fluorescent in situ hybridization with centromere-specific probes for chromosomes 8, 11, and 17 was performed to evaluate polyploidy of these chromosomes in 11 cases of mixed epithelial and stromal tumor. None of the mixed epithelial and stromal tumors showed any of these genetic alterations. We conclude that mixed epithelial and stromal tumor of the kidney lacks the genetic alterations typical of cellular congenital mesoblastic nephroma, is unrelated to it, and the appellation "adult mesoblastic nephroma" should not be used for these tumors.

Development and evaluation of an activity rating scale for disorders of the knee.

Reports of clinical studies of patients with knee disorders should routinely include their activity levels to enable comparison of treatment groups and to allow generalizability. The goal of this study was to develop and evaluate a new rating scale to measure activity levels of patients. We assessed reliability by administering the scale to 40 subjects on 2 separate occasions, 1 week apart. Validity was evaluated by comparing the activity rating on the new scale with that from other instruments that use activity level scales (concurrent construct validity) and also by correlating the score on the new scale with age (divergent validity). Patients easily understood the scale and were able to complete it in 1 minute. The reliability was high (intraclass correlation coefficient, 0.97). The scale also correlated well with existing activity rating scales: Spearman correlation coefficient for Cincinnati score, 0.67; for Tegner scale, 0.66; for Daniel scale, 0.52. The activity score was significantly inversely correlated with age (P = 0.002), indicating divergent validity. This instrument will facilitate generalizability of results and allow more accurate comparisons among patient groups in outcomes research in sports medicine.

Interobserver reproducibility of Gleason grading of prostatic carcinoma: urologic pathologists.

Gleason grading is now the most widely used grading system for prostatic carcinoma in the United States. However, there are only a few studies of the interobserver reproducibility of this system, and no extensive study of interobserver reproducibility among a large number of experienced urologic pathologists exists. Forty-six needle biopsies containing prostatic carcinoma were assigned Gleason scores by 10 urologic pathologists. The overall weighted kappa coefficient kappa(w) for Gleason score for each of the urologic pathologists compared with each of the remaining urologic pathologists ranged from 0.56 to 0.70, all but one being at least 0.60 (substantial agreement). The overall kappa coefficient kappa for each pathologist compared with the others for Gleason score groups 2-4, 5-6, 7, and 8-10 ranged from 0.47 to 0.64 (moderate-substantial agreement), only one less than 0.50. At least 70% of the urologic pathologists agreed on the Gleason grade group (2-4, 5-6, 7, 8-10) in 38 ("consensus" cases) of the 46 cases. The 8 "nonconsensus" cases included low-grade tumors, tumors with small cribriform proliferations, and tumors whose histology was on the border between Gleason patterns. Interobserver reproducibility of Gleason grading among urologic pathologists is in an acceptable range.

Mapping a tumor suppressor gene to chromosome 2p13 in metanephric adenoma by microsatellite allelotyping.

Twelve metanephric adenomas (MA) were studied for allelic imbalance at chromosomal regions known to be involved in the genetics of papillary renal cell tumors (RCT) and Wilms' tumors as well as for loci on chromosome 2p13-21. DNA was isolated from paraffin slides, and allelic status was established by fluorescently-labeled microsatellite markers. No allelic changes were seen in the Wilms' tumor gene region at chromosome 11p13 and in the papillary RCT gene region at chromosome 17q21.32. We delineated a tumor suppressor gene region of approximately 8-centimorgan genetic distance between loci D2S2153 and D2S380 on chromosome 2p13. Allelic changes at this region occurred in 56% of informative cases. Our results provide molecular evidence that MA is a genetic entity, and it can be differentiated from both Wilms' tumor and papillary renal cell adenoma.

Prevalence and correlates of mitral regurgitation in a population-based sample (the Strong Heart Study).

Evidence suggesting that mitral regurgitation (MR) may be induced by appetite suppressant medications heightens the importance of understanding the prevalence and correlates of MR, especially its relation to obesity, in population-based samples. MR was assessed by color Doppler echocardiography in 3,486 American Indian participants in the Strong Heart Study. Mild (1+) MR was present in 19.2%, moderate (2+) MR in 1.6%, moderately severe (3+) in 0.3%, and severe (4+) in 0.2% of participants. In univariate analyses, MR was unrelated to gender, diabetes, or lipid levels, but was more frequent in North/South Dakota (28.3%) than in Oklahoma (21.6%) or Arizona (14.3%) (p <0.001). MR was related to lower body mass index (BMI) (p <0.001), older age (p <0.001), higher systolic blood pressure (p = 0.003), higher serum creatinine (p <0.001), and higher urine albumin/creatinine ratio (p <0.001). In multivariate analyses, the presence and severity of MR were independently associated with higher serum creatinine, lower BMI, mitral stenosis, prior myocardial infarction, female gender, mitral valve prolapse and, variably, older age. In conclusion, MR, mostly mild, is detected by color Doppler echocardiography in >20% of middle-aged and older adults. MR is independently associated with female gender, lower BMI, older age, and renal dysfunction, as well as with prior myocardial infarction, mitral stenosis, and mitral valve prolapse. It is not related to dyslipidemia or diabetes.

Inflammatory pseudotumor of the urinary bladder: a report of five cases and review of the literature.

We describe five patients who recently presented with gross hematuria secondary to inflammatory pseudotumors of the bladder along with a review of the literature. At presentation, four of the five patients were clinically misdiagnosed as malignancies of which two were further believed to be leiomyosarcomas on initial histological examination because of their spindle-cell appearance. Conservative excision either by transurethral resection or partial cystectomy was curative in all cases. The main importance of these rare, benign lesions is to differentiate them from malignant tumors for which they may be mistaken, thus avoiding radical surgery and its attendant complications.

Effect of tamoxifen on mammographic density.

There are strong data showing that increased breast cancer risk is associated with increased mammographic density. Tamoxifen has been shown to decrease the risk of invasive breast cancer and decrease breast density. We sought to demonstrate and calculate the extent of change in mammographic density in women who have taken tamoxifen for up to 2 years. We evaluated mammograms from 28 high-risk women who were taking tamoxifen. Four different methods of evaluation were used: (a) two qualitative methods (Wolfe criteria and the American College of Radiology Breast Imaging and Reporting Data System criteria); (b) one semiquantitative method (mammograms were assigned one of five semiquantitative scores by visual inspection); and (c) one quantitative method (computer-aided calculation of fibroglandular area from digitized mammograms). The Wolfe criteria showed a 0.03 category decrease per year (P = 0.50). The American College of Radiology Breast Imaging and Reporting Data System criteria showed a 0.1 category decrease per year (P = 0.12). Semiquantitative criteria showed a 0.2 category decrease per year (P = 0.039). Digitized scores showed a 4.3% decrease per year (P = 0.0007). In conclusion, tamoxifen causes a decrease in mammographic density with use, an effect that is better quantitated with semiquantitative criteria or digitized images. Density change might become useful as a surrogate end point for the effect of tamoxifen and other chemopreventive measures, although our data do not predict an individual's degree of risk reduction.

Metabolic and anthropometric consequences of interruption of highly active antiretroviral therapy.

BACKGROUND: HAART has been associated with metabolic abnormalities (hyperlipidemia, insulin resistance, alterations in cortisol metabolism) and fat redistribution. SETTING: A prospective study of 26 Caucasian men (median age 43.5 years) with HIV-1 viral loads < 500 copies/ml for 12 months while on highly active antiretroviral therapy (HAART) who interrupted treatment for a median of 7.0 weeks (range 4.9-10.3 weeks). Seventeen (65.4%) patients reported at least one fat redistribution symptom at baseline. METHOD: Serum lipids, glucose and insulin levels during an oral glucose tolerance test, 24-h urinary free cortisol and 17-hydroxycorticosteroids, and anthropometric parameters were measured before HAART cessation and prior to its reinstitution. RESULTS: When baseline values were compared with those obtained after HAART interruption (means +/- SD), there was a significant decrease in total cholesterol (194+/-47.3 versus 159+/-29.3 mg/dl; P < 0.0001), low density lipoprotein (LDL) cholesterol (114+/-32.6 versus 96+/-24.7 mg/dl; P = 0.0013), triglycerides (261+/-244.3 versus 185+/-165.4 mg/dl; P = 0.008), and 24-hour urinary 17-hydroxycorticosteroids (15+/-7.9 versus 5+/-2.5 mg/24 h, P < 0.0001) and a significant increase in 24-hour urinary free cortisol (45+/-34.1 versus 62+/-32.2 microg/24 h; P = 0.016). There were no significant changes in glucose or insulin levels or in anthropometric measurements. CONCLUSIONS: A relatively brief interruption of HAART resulted in significant improvements in total cholesterol, LDL cholesterol, and triglyceride levels. No changes were observed in insulin resistance profiles or anthropometric measurements, perhaps because of the brief duration of HAART interruption. These results suggest that hyperlipidemia and alterations in corticosteroid metabolism in the setting of HAART are a direct drug effect that reverses with drug withdrawal. However, glucose metabolism and fat redistribution do not change over the short term.

Long-term neoadjuvant hormone therapy prior to radical prostatectomy: evaluation of risk for biochemical recurrence at 5-year follow-up.

OBJECTIVES: To assess the effects of 8 months of neoadjuvant therapy on pathologic stage and biochemical recurrence rates. METHODS: One hundred fifty-six men with clinically localized prostate cancer were treated with neoadjuvant combined androgen withdrawal therapy for 8 months prior to radical prostatectomy. Preoperative clinical stage, Gleason score, and serum prostate-specific antigen (PSA) levels were compared with treatment outcome (pathologic stage and PSA recurrence). RESULTS: PSA at diagnosis was 10 microg/L or higher in 36% with a mean of 11.5 microg/L. Clinical stage was T1c in 18%, T2 in 74%, and T3a in 8%. Gleason score was 6 or lower in 76% and 7 or higher in 24%. Pathologic stage was T0 in 13%, T2 in 66%, T3 (specimen confined) in 13%, T3 (margin positive) in 6%, and TxN+ in 2%. Incidence of positive margins increased with clinical stage T3a versus organ-confined disease (25% versus 4%, P <0.05), pretreatment Gleason scores 7 or higher versus Gleason scores 6 or lower (11% versus 4%, P = NS), and pretreatment PSA levels higher than 10 microg/L compared with PSA levels lower than 10 microg/L (15% versus 0%, P <0.01). Overall PSA recurrence rate was 12.2% after a mean postoperative follow-up of 54 months. Risk of PSA recurrence increased with clinical stage (25% T3 versus 11% organ confined, P <0.01), pretreatment PSA (7% if PSA lower than 10 microg/L versus 21% if 10 microg/L or higher, P <0.02), Gleason score (9% if 6 or lower versus 22% if 7 or higher, P <0.02), and pathologic stage (6% of pT2, 24% of pT3M-, and 56% of pT3M+, P <0.01). PSA recurrences occurred in 6% of patients with no adverse preoperative risk factors, 12% with any one of the high-risk factors, and 29% with any two of the high-risk factors. CONCLUSIONS: Risk of PSA recurrence after 8 months of neoadjuvant therapy is low after 5 years of follow-up and remains proportional to the presence of adverse preoperative risk factors. Prospective randomized studies are required to determine whether longer duration of neoadjuvant therapy reduces the risk of biochemical recurrence after radical prostatectomy.

Mixed epithelial and stromal tumor of the kidney.

We describe the clinicopathologic features of 12 patients with a distinctive tumor of the kidney characterized by a mixture of epithelial and stromal elements that form solid and cystic growth patterns. Similar tumors were reported previously in the literature under various names, including adult mesoblastic nephroma. All but one of the patients were women. The only man had a long history of treatment with lupron and diethylstilbesterol. Seven of the women had histories of long-term oral estrogen use of whom six had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy several years prior, and the seventh patient had been using oral contraceptives for many years. Another woman had this operation but did not receive any hormone therapy. Ages ranged from 31 to 71 years (mean, 56 yrs). Six patients presented with symptoms, including pain and infections attributable to mass effect, and in six the tumor was detected incidentally. Grossly, the tumors were well-circumscribed (mean size, 6 cm; range, 3-12 cm) and consisted of solid and cystic components, most often in equal proportions but in variable distribution. Microscopically, the spindle cell component ranged in appearance from scar-like fibrous tissue to leiomyoma-like interlacing fascicles; usually there was a mixture of both. More cellular foci reminiscent of ovarian stroma or solitary fibrous tumor were also present. No blastema was present. Epithelial elements (composed of clusters of tubules with variable lining) were scattered amidst the spindle cells, and focally transformed into large cysts lined by cells with abundant pink cytoplasm and a hobnail appearance. Immature epithelial elements typical of Wilms' tumor were not present. Muscle markers (desmin and smooth muscle actin) were positive diffusely and strongly in the spindle cells of all tumors, whereas HMB-45 and CD34 were absent. Estrogen receptors were detected in the nuclei of spindle cells in seven tumors and progesterone receptors in three. The distinctive clinicopathologic characteristics of these lesions warrant their classification as a separate category of kidney tumor. We suggest the descriptive term "mixed epithelial and stromal tumor" for this group until its nature and relationship to other kidney lesions are further clarified. Its preponderance in females with a history of long-term estrogen replacement and the history of long-term sex-steroid use in the only male patient, combined with the frequent content of estrogen and progesterone receptors in the spindle cells, suggest that the hormonal milieu plays a role in the evolution of these tumors. The clinical and pathologic parallels with mucinous cystic tumors of pancreas and liver raise the possibility of a common pathogenetic mechanism that may be linked to the periductal fetal mesenchyme. We think this entity is a benign composite neoplasm in which stroma and epithelium are both integral neoplastic components.

No evidence for linkage at candidate type 2 diabetes susceptibility loci on chromosomes 12 and 20 in United Kingdom Caucasians.

Several studies have identified evidence for linkage between type 2 diabetes and the regions on chromosomes 12 and 20 containing the maturity-onset diabetes of the young (MODY) genes, hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-4alpha. Two studies examining the HNF-1alpha region have demonstrated evidence for linkage at genome-wide levels of significance, whereas four studies examining the HNF-4alpha locus have resulted in evidence for linkage at more suggestive levels of significance. The demonstration of linkage to these regions in additional patient series will strengthen the evidence that susceptibility alleles exist at these loci. We therefore assessed the evidence for linkage to these regions using a large cohort of United Kingdom Caucasian type 2 diabetes-affected sibling pairs. A maximum total of 315 affected full sibling pairs were typed for microsatellite markers across the MODY regions and, in a subset of families, for markers spanning the whole of chromosome 20. Evidence for linkage was assessed using a multipoint, mode of inheritance-free method. Linkage analysis did not reveal any significant evidence for excess allele sharing at any of the regions studied. Loci contributing sibling recurrence risks, relative to the general population risk, of 1.75 and 1.25 could be excluded for the HNF-1alpha and HNF-4alpha regions, respectively. We have not confirmed in United Kingdom Caucasians the evidence for linkage previously reported on 12q and 20q. Our results highlight further the problems of replicating previous positive linkage results across different ethnic groups.