Distal urethral carcinoma: Contemporary management with phallus preserving techniques.

INTRODUCTION: Primary urethral carcinoma is a rare clinical entity with an incidence of 1 case per million in the United Kingdom. Cancers of the distal urethra are most commonly of squamous subtype and often associated with Human Papilloma Virus infection. Penile preserving techniques are recommended in tumours of the pendulous urethra with a number of surgical approaches described. Herein, we describe the surgical management of 7 patients presenting with primary urethral carcinoma. METHODS: Seven patients diagnosed with primary urethral carcinoma of the distal urethra were identified using a prospectively maintained penile cancer database at our institution from May 2017 to November 2020. RESULTS: The mean age at presentation was 56.5 (33-80) years. Presenting symptoms included visible lesion, LUTS and a groin mass. Three patients had lesions located within the glanular urethra and had a distal urethrectomy and primary closure. Two patients with lesions extending proximal to the glanular urethra and into or beyond the fossa navicularis had a distal urethrectomy with a hypospadic neomeatus formation. One patient with tumour extending into the glans penis underwent distal urethrectomy and partial glansectomy with split thickness skin graft. A partial penectomy was performed for one patient with urethral tumour invading the corporal heads. Mean follow-up was 23.4 (±17.0) months. There have been no disease recurrences to date. CONCLUSION: Penile preserving techniques are feasible in patients with tumours of the pendulous urethra and do not appear to compromise local control.

Assessment of referral patterns for boys with suspected undescended testes and identification of risk factors to aid diagnosis.

INTRODUCTION: Undescended testis (UDT) is a clinical diagnosis and a common reason for referral to paediatric urology outpatients. Our aim was to assess current referral patterns at our unit and to identify predictive factors that may better aid primary care physicians (PCP) in diagnosing UDT based on history and physical exam. METHODS: A retrospective analysis of referrals to outpatients from 2014 to 2016 was performed to assess current referral patterns including referral source, age, reason for referral and outcome following assessment by a single consultant paediatric urologist.A prospective analysis of new referrals was performed to identify predictive factors which may aid in the diagnosis of UDT including gestational age, presence of scrotal asymmetry and previously obtained imaging. RESULTS: From 2014 to 2016, 259 boys were referred with suspected UDT. The majority of referrals were received from PCPs (62%) followed by Neonatology (29%), Paediatrics (8%) and general surgery (1%). Median age at time of assessment was 29 (5-180) months. One hundred and eight (41.7%) boys were diagnosed with UDT.There were 74 boys assessed prospectively. Median age at assessment was 24.5 (6-171) months. We identified 3 predictors of a diagnosis of UDT; history of prematurity (p = 0.001), UDT mentioned to the parents at birth (p = 0.027) and scrotal asymmetry on examination (p < 0.001). Greatest diagnostic inaccuracy was found in boys referred beyond one year of age (27.7%). In this cohort, the absence of all three risk factors was associated with a negative predictive value of 94.1%. CONCLUSION: The majority of boys with suspected UDT are referred beyond the age recommended for orchidopexy (6-12 months). The majority of boys referred for assessment did not have UDT. We have identified three predictive factors that may aid referring physicians when assessing boys, particularly those older than 1 year.

The osteoporosis treatment gap in patients at risk of fracture in European primary care: a multi-country cross-sectional observational study.

This study in 8 countries across Europe found that about 75% of elderly women seen in primary care who were at high risk of osteoporosis-related fractures were not receiving appropriate medication. Lack of osteoporosis diagnosis appeared to be an important contributing factor. INTRODUCTION: Treatment rates in osteoporosis are documented to be low. We wished to assess the osteoporosis treatment gap in women ≥ 70 years in routine primary care across Europe. METHODS: This cross-sectional observational study in 8 European countries collected data from women 70 years or older visiting their general practitioner. The primary outcome was treatment gap: the proportion who were not receiving any osteoporosis medication among those at increased risk of fragility fracture (using history of fracture, 10-year probability of fracture above country-specific Fracture Risk Assessment Tool [FRAX] thresholds, T-score ≤ - 2.5). RESULTS: Median 10-year probability of fracture (without bone mineral density [BMD]) for the 3798 enrolled patients was 7.2% (hip) and 16.6% (major osteoporotic). Overall, 2077 women (55%) met one or more definitions for increased risk of fragility fracture: 1200 had a prior fracture, 1814 exceeded the FRAX threshold, and 318 had a T-score ≤ - 2.5 (only 944 received a dual-energy x-ray absorptiometry [DXA] scan). In those at increased fracture risk, the median 10-year probability of hip and major osteoporotic fracture was 11.2% and 22.8%, vs 4.1% and 11.5% in those deemed not at risk. An osteoporosis diagnosis was recorded in 804 patients (21.2%); most (79.7%) of these were at increased fracture risk. The treatment gap was 74.6%, varying from 53% in Ireland to 91% in Germany. Patients with an osteoporosis diagnosis were found to have a lower treatment gap than those without a diagnosis, with an absolute reduction of 63%. CONCLUSIONS: There is a large treatment gap in women aged ≥ 70 years at increased risk of fragility fracture in routine primary care across Europe. The gap appears to be related to a low rate of osteoporosis diagnosis.

Real-world effectiveness of osteoporosis treatment in the oldest old.

We studied effectiveness of osteoporosis treatment in women older than 80 years, who often are not included in clinical trials. Treatments were as effective on bone density and fractures as in younger women. INTRODUCTION: To study real-world effectiveness of osteoporosis treatment on BMD and fractures in the oldest old women (≥ 80 years) compared with women (60-79 years) in the clinical setting using Swedish health register data. METHODS: National registers and data from DXA machines were used to study effectiveness of all available osteoporosis treatments in women 60-79 and ≥ 80 years using three approaches: (1) Total Hip BMD change up to 8 years after treatment start; (2) fracture incidence where patients served as their own controls, comparing the first 3 months after treatment start with the subsequent 12 months; and (3) comparison of fracture incidence post-fracture in women ≥ 80 years treated with osteoporosis treatment or calcium/vitamin D. RESULTS: Analysis 1: Total Hip BMD increased by up to 6.7% and 7.7% in women 60-79 and ≥ 80 years old, respectively. The mean increase in BMD was 1.1%-units per year in both age groups. Analysis 2: Relative to the 3-month baseline, fracture incidence decreased during the subsequent 12 months of treatment. Incidence rate ratios were estimated at 0.65, 0.74, 0.29, and 0.81 for any, hip, vertebral, and non-hip-non-vertebral fracture, respectively. Analysis 3: A 24-month incidence of any fracture in women ≥ 80 years given post-fracture osteoporosis treatment was lower (HR = 0.78) than in women given calcium/vitamin D, but treatment allocation was not random, with lower mortality (HR = 0.51) in patients receiving OP treatment. CONCLUSIONS: Osteoporosis medication in women > 80 years in clinical practice likely works, and the magnitude of effect is similar to what was estimated in younger women. The choice between osteoporosis treatment and calcium/vitamin D after fracture in women ≥ 80 years is not random but appears associated with the patient's health status and presence of vertebral fractures, rather than the known risk profile of sustaining a fracture at a high age.

The Predictive Ability of Pre-Operative Magnetic Resonance Imaging to Detect Pathological Outcomes in Prostate Cancer

Aims Accurate preoperative knowledge of tumour stage is important in preoperative planning at radical prostatectomy (RP). The aim of this study was to assess the predictive ability of multiparametric MRI for detecting pathological outcomes. Methods A retrospective review was performed of all patients who underwent RP over a 4 year period. Results Preoperative MRI was reported as showing T3 or T4 disease in 26(17.9%) out of 145 patients undergoing RP. Of these, 10(6.9%) had ECE (extra-capsular extension) and 1(0.7%) had SVI (seminal vesicle invasion) on final histology. The sensitivity and specificity of MRI for detecting ECE were 27.3% and 87.6%, respectively. The sensitivity and specificity of MRI for detecting SVI were 11.1% and 97.8%, respectively. The positive predictive values for determining ECE and SVI were 45.5% and 25%, respectively and negative predictive values were 75.9% and 94.4%. Conclusion MRI has good specificity but poor and heterogeneous sensitivity for predicting T3 disease in RP specimen.

The clinical and economic burden after an osteoporosis fracture in France: a nationwide population-based study.

Osteoporosis-related fragility fractures increase the risk of subsequent fractures and are associated with substantial morbidity and mortality. Emphasis should be placed on the prevention of recurrent fractures, which will decrease both the clinical burden on patients and the economic burden on the health system. INTRODUCTION: Fragility fractures are associated with increased morbidity and mortality. Quantifying the clinical and economic burden of subsequent fractures following an initial osteoporosis-related fracture is a key to informing public health policies. METHODS: A retrospective cohort study, using the national French health insurance claims database. Males and females ≥ 50 years, with a hospital discharge diagnosis of osteoporosis with fracture or a relevant fragility fracture (hip, vertebrae, femur, pelvis, wrist/hand, forearm, humerus/clavicle) between 2011 and 2014, were included and followed until death or end of 2016, whichever came first. Index fracture was the first qualifying hospitalization; subsequent fractures were defined as those occurring either at a different site from the index fracture or at the same site ≥ 90 days apart. Costs abstracted included hospitalization, external consultation, outpatient visits, and treatment. RESULTS: A total of 544,426 participants (132,148 [24.3%] males and 412,278 [75.7%] females), of whom 16,110 (12.2%) males and 73,538 (17.8%) females had at least one subsequent fracture during follow-up, were included. Incidence of subsequent fracture was highest in the first year following index fracture. During follow-up, 161,179 patients died; mortality was highest among those with a hip fracture at index (29,971 (51.6%) males and 65,254 (39.6%) females). Total mean costs per patient in the year following index fracture were highest for males and females with a hip fracture (€18,585 and €15,754, respectively). CONCLUSION: Subsequent fractures among osteoporotic participants with an initial fracture result in increased clinical mortality and high healthcare resource use. Emphasis should be placed on the prevention of recurrent fractures.

Common deleted genes in the 5q- syndrome: thrombocytopenia and reduced erythroid colony formation in SPARC null mice.

The commonly deleted region (CDR) for the 5q- syndrome has been identified as a 1.5-megabase interval on human chromosome 5q32. We studied, by real-time reverse-transcription (RT)-PCR, the expression of 33 genes within the CDR that are known to be expressed in CD34+ hematopoietic stem cells. Genes in the 5q- samples that showed the most pronounced decrease in expression compared to non-5q- samples were: solute carrier family 36, member 1 (SLC36A1; 89% downregulated), Ras-GTPase-activating protein SH3 domain-binding (G3BP; 79%), antioxidant protein 1 (ATOX1; 76%), colony-stimulating factor-1 receptor precursor (CSF1R; 76%), ribosomal protein S14 (RPS14; 74%), platelet-derived growth factor receptor-beta (PDGFRB; 73%), Nef-associated factor 1 (TNIP1; 72%), secreted protein, acidic and rich in cysteine (SPARC; 71%), annexin VI (ANAX6; 69%), NSDT (66%) and TIGD (60%). We further studied the hematopoietic system in SPARC-null mice. These mice showed significantly lower platelet counts compared to wild-type animals (P=0.008). Although hemoglobin, hematocrit and mean corpuscular volume (MCV) were lower in mice lacking SPARC, differences were not statistically significant. SPARC-null mice showed a significantly impaired ability to form erythroid burst-forming units (BFU-E). However, no significant differences were found in the formation of erythroid colony-forming units (CFU-E), granulocyte/monocyte colony-forming units (CFU-GM) or megakaryocyte colony-forming units (CFU-Mk) in these animals. We conclude that many of the genes within the CDR associated with the 5q- syndrome exhibit significantly decreased expression and that SPARC, as a potential tumor suppressor gene, may play a role in the pathogenesis of this disease.

Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive form of B-cell non-Hodgkin's lymphoma, with a mean survival of only 3-5 years and suboptimal therapeutic options. MCL is characterized by a balanced translocation t(11;14)(q13;q32), resulting in overexpression of cyclin D1, a G(1) cyclin regulated by the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. As improved therapy for MCL is required and the mTOR pathway may be involved in its pathophysiology, the antiproliferative effects of RAD001 (everolimus), an mTOR inhibitor, against three MCL cell lines were investigated. As a single agent, RAD001 inhibited proliferation in MCL cell lines (Jeko1, SP49 and NCEB1) approximately 40-65% compared to diluent control cells. This was associated with G(1) cell-cycle arrest and reduced phosphorylation of the mTOR downstream target, 4E-BP1. Furthermore, combination drug studies revealed predominantly synergistic cytotoxicity with RAD001 and several secondary agents, including doxorubicin, vincristine or rituximab (components of the standard MCL regimen), as well as paclitaxel, vorinostat and bortezomib. These data indicate that single agent RAD001 is effective in inhibiting growth of MCL cells in vitro and combination studies with secondary agents further demonstrate synergistic cytotoxicity. Thus, these findings support future clinical studies of RAD001 in the treatment of MCL.

BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27(Kip1).

We have previously shown that the breast cancer susceptibility gene, BRCA1, can transcriptionally activate the p27(Kip1) promoter. The BRCA1-responsive element was defined as a 35 bp region from position -545 to -511. We next determined that within this region is also a potential binding site for the transcription factor Forkhead box (FOX)A1. RNA and protein analysis as well as immunohistochemistry showed that expression of FOXA1 correlated with the expression of the estrogen receptor in a panel of breast cancer cell lines and tissues. In transient transfection reporter assays, FOXA1 could activate the p27(Kip1) promoter. Cotransfection of BRCA1 and FOXA1 resulted in a synergistic activation of the p27(Kip1) promoter. Mutation of the FOXA1 DNA-binding site in the p27(Kip1) promoter-luciferase construct significantly diminished the activity of FOXA1 alone or in combination with BRCA1. Cotransfection of FOXA1 and BRCA1 resulted in a greater amount of each protein compared to transfection of each expression vector alone. The half-life of FOXA1 was increased when coexpressed with BRCA1. Electrophoretic mobility shift assay analysis demonstrated that FOXA1 could bind to a wild-type oligonucleotide containing the FOXA1 binding site in the p27(Kip1) promoter, but this binding was lost upon mutation of this FOXA1 binding site. The protein-DNA binding complex could be supershifted with an antibody directed against FOXA1. The activity of the p27(Kip1) promoter as well as FOXA1 expression was reduced in cells treated with BRCA1 siRNA, thus silencing the expression of BRCA1 protein. In summary, we identified a FOXA1 binding site within the BRCA1-responsive element of the p27(Kip1) promoter and showed that FOXA1 activated the promoter alone and in conjunction with BRCA1. Furthermore, we identified high expression of FOXA1 in breast cancer cell lines and tissues, discovered a role for BRCA1 in the regulation of p27(Kip1) transcription and a possible interaction with BRCA1.

Dlk1 in normal and abnormal hematopoiesis.

Dlk1 (Pref-1) is a transmembrane and secreted protein, which is a member of the epidermal growth factor-like family, homologous to Notch/Delta/Serrate. We have found by real-time RT-PCR that Dlk1 mRNA levels were high in CD34(+) cells in 10 of 12 MDS samples compared with CD34(+) cells from 11 normals. Also, Dlk1 mRNA was elevated in mononuclear, low density bone marrow cells from 11/38 MDS patients, 5/11 AML M6 and 2/4 AML M7 samples. Furthermore, 5/6 erythroleukemia and 2/2 megakaryocytic leukemia cell lines highly expressed Dlk1 mRNA. Levels of Dlk1 mRNA markedly increased during megakaryocytic differentiation of both CMK megakaryoblasts as well as normal CD34(+) hematopoietic stem cells. High serum levels of Dlk1 occurred in RA (4/10) and essential thrombocythemia (2/10) patients. Functional studies showed that forced expression of Dlk1 enhanced proliferation of K562 cells growing in 1% fetal bovine serum. Analysis of hematopoiesis of Dlk1 knockout mice suggested that Dlk1 contributed to granulocyte, megakaryocyte and B-cell clonogenic growth and was needed for generation of splenic B-cells. In summary, Dlk1 is overexpressed in selected samples of MDS (especially RA and RAEB) and AML (particularly M6, M7), and it appears to be associated with normal development of megakaryocytes and B cells.

The lipid composition of erythrocytes in European cattle and buffalo steers.

This study compared the lipid composition of the red blood cells of European cattle and of buffalo steers at the same level of feed intake in a thermoneutral environment. The mean volumes of the erythrocytes and their lipid content were greater in buffalo than those in cattle. However, the amounts of phospholipid and cholesterol in cells of equal volume were higher in buffalo than in cattle. In contrast, the phospholipid level at a given cholesterol level was higher in cattle than in buffalo. The distribution of the different molecular species of phospholipids in the red cells of the two breeds were similar, but there were significant distinctions in their fatty acid patterns, notably in the levels of 24:0 and 24:1 in the sphingomyelin fractions. The proportion of total monounsaturated acids in the erythrocytes were similar from both breeds. However, there was a higher percentage of polyunsaturated fatty acids with a corresponding lower content of total saturated fatty acids in the red cells from buffalo than in those from cattle. The breed differences in erythrocyte lipid composition are discussed in relation to breed differences in red cell characters and could lead to a better understanding of the mechanisms of environmental adaptation.

The effect of environmental temperature on sebum composition of tropical and temperate breeds of cattle.

This study compared to effect of environmental temperature on sebum composition in 2 breeds of cattle, British (SH) and Brahman (GB), which differ in their abilities to tolerate heat. By long-term exposure of both breeds to environmental temperatures of 24 C and 32 C and the more heat-tolerant GB breed to 38 C, it was possible to make breed comparisons at (a) different body temperatures, i.e., when all animals were exposed to the same environmental temperature, and (b), at the same body temperature, i.e., when the 2 breeds were exposed to different ambient temperatures. The composition of sebum excreted to saturation level on the skin surface was determined. At the same body temperatures, the amounts of fatty acids in each lipid class were higher in GB than in SH animals except during hyperthermia when the amounts of triglyceride fatty acids were similar in both breeds. The total amounts of individual fatty acids except 14:1, 16:1, 20:0 and 14:OH were higher in both breeds at 32 C than at 24 C. The GB cattle excreted more essential fatty acids (EFA) than the SH cattle at 24 C and at 32 C. There was a significant genotype by environment interaction in the amount of EFA excreted in triglyceride decreased whereas the amount excreted in wax esters increased with rising body temperature.

Decreased resistance of Bos taurus cattle on a diet supplemented with whole cotton seed to the tick Boophilus microplus (Canestrini).

Resistance to the tick B. microplus was compared in Bos taurus steers fed hay (low fat (LF) diet) with those fed hay supplemented with whole cotton seeds (high fat (CS) diet) which made them hyperlipidaemic. The mean number of adult female ticks maturing from the same artificial doses of larvae was about 2.7 times higher on animals fed the CS diet than on animals fed the LF diet. In both dietary groups the effect of ticks: depressed packed-cell volume, plasma cholesterol and phospholipid levels, serum albumin levels, serum alkaline phosphatase (EC 3.1.3.1) and amylase (EC 3.2.1.1) activities, and monocyte count; increased the serum level of gamma-globulin and eosinophil count. Animals on the LF diet responded to tick infestation with an increase in the number of circulating lymphocytes and a decrease in the neutrophil count. In contrast, the lower tick resistance in hyperlipidaemic animals on the CS diet was associated with a decrease in the number of lymphocytes.

Resistance to Boophilus microplus (Canestrini) in genetically different types of calves in early life.

Tick resistance and blood composition were studied in British (1/2 Shorthorn x 1/2 Hereford) and zebu (1/2 Brahman x 1/2 British) calves from birth to 33 days of age in a tropical grazing area in which B. microplus is endemic. Calves of the 2 breeds were either naturally infested or were, in addition, artificially infested with 5,000 larvae at 2 and 9 days of age. Total numbers of mature female ticks carried from either type of infestation were significantly lower (P less than 0.01) on zebu than on British calves. In the artificially infested calves of both breeds, the total number of ticks maturing between 20 to 26 days of age was significantly higher (P less than 0.01) than the number maturing between 27 to 33 days of age emphasizing that a major component of resistance is acquired. However, in the naturally infested calves, breed differences in the numbers of ticks maturing during these 2 periods suggested the presence of genetic differences in innate resistance. Within breeds, total tick numbers carried during the study were negatively correlated with calf weight gain and with the concentrations of serum albumin, total protein, and cholesterol.

Influence of dietary fat on some metabolic responses of cattle to fasting.

Metabolic responses were compared in Brahman cross and British cattle to 96 hours fasting from two maintenance diets; low fat (2.5 per cent fat) and high fat (9.2 per cent fat), which were isocaloric and isonitrogenous. Within breeds, the plasma concentrations of non-esterified fatty acids were increased (P less than 0.01) and the amounts of urinary urea nitrogen and creatinine excreted and respiratory quotient lowered (P less than 0.01) by feeding the high fat diet beforehand. Within dietary groups, the Brahman crosses showed a higher adaptation to a lipid fuel economy with a concomitant greater conservation of body nitrogen than the British animals. The results point to a role for dietary lipid in ameliorating bodyweight loss in cattle during periods of inadequate nutrition.

Serum immunoglobulin concentrations in genetically different types of suckling beef calves in a tropical environment.

Factors influencing the serum concentrations of gamma-globulin (gamma-G) during the neonatal period were studied in Shorthorn x Hereford (SH), Africander x SH and Brahman x SH calves born to cows grazing in a tropical environment. There were no significant effects of age of dam, sex or breed of calf on the gamma-G concentrations of calves from birth to 48 hours of age. Concentrations of gamma-G fell within two ranges: group A, 10 to 20 g/l and group B, 35 to 70 g/l. The number of calves in each group was not significantly different between breeds and overall 30% of calves were in group A. Body weight gain from birth to 10-day-old was greater (P less than 0.01) in calves in group B than in group A. Plasma cholesterol concentrations in 10-day-old calves were higher in group B than in group A calves supporting the interpretation that group B calves had higher milk intakes. Identification of calves receiving adequate amounts of colostrum has fundamental significance for the efficient production of cattle in the tropics.

Predicting patient benefit from a group-oriented, evening treatment program.

Patients with coexisting mood and personality disorders are a challenge to service care providers who offer treatment. The response of 190 patients with one or both disorders to an intensive group-oriented evening treatment program was investigated. Benefit was assessed using factors derived from pre-post outcome measures and from general impressions of program usefulness. A predictive model consisting of patient levels of psychological mindedness and psychodynamic work was applied. Results indicated that psychological mindedness was significantly related to psychodynamic work in the program, and work was related to general impressions of program usefulness. These results cross-validated findings from a previous study of a day-treatment program. Restricted range may have prevented finding significant results for the pre-post outcome factors. Clinical implications of the findings are discussed.

Staff-staff relations group.

This article describes, through the use of clinical examples, how a staff-staff relations group functions in a brief, evening, partial-hospitalization program, and how it differs from other groups within the program. It further illustrates how the appropriate use of this group allows staff to work together harmoniously and treat patients more effectively. This article also compares and contrasts this method of dealing with staff-staff and staff-patient conflict with other approaches.

Exercise groups in an insight-oriented, evening treatment program.

Exercise groups form an integral part of an insight-oriented, psychodynamic evening treatment program for a patient population characterized predominantly by mood and personality disorders. Clinical examples illustrate how the exercise groups are integrated with other therapy groups in the program. Therapists, who lead and participate in the exercise groups, attempt to maintain professional boundaries while they facilitate permissive activities where enactment of patient conflicts can occur. Events from the exercise groups frequently provide material for work in the more traditional psychodynamic groups of the program. A number of benefits of exercise groups are highlighted.