International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 5: surgical margins.

The 2009 International Society of Urological Pathology Consensus Conference in Boston, made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to surgical margin assessment were coordinated by working group 5. Pathologists agreed that tumor extending close to the 'capsular' margin, yet not to it, should be reported as a negative margin, and that locations of positive margins should be indicated as either posterior, posterolateral, lateral, anterior at the prostatic apex, mid-prostate or base. Other items of consensus included specifying the extent of any positive margin as millimeters of involvement; tumor in skeletal muscle at the apical perpendicular margin section, in the absence of accompanying benign glands, to be considered organ confined; and that proximal and distal margins be uniformly referred to as bladder neck and prostatic apex, respectively. Grading of tumor at positive margins was to be left to the discretion of the reporting pathologists. There was no consensus as to how the surgical margin should be regarded when tumor is present at the inked edge of the tissue, in the absence of transected benign glands at the apical margin. Pathologists also did not achieve agreement on the reporting approach to benign prostatic glands at an inked surgical margin in which no carcinoma is present.

International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 3: extraprostatic extension, lymphovascular invasion and locally advanced disease.

The International Society of Urological Pathology Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to extraprostatic extension (pT3a disease), bladder neck invasion, lymphovascular invasion and the definition of pT4 were coordinated by working group 3. It was agreed that prostate cancer can be categorized as pT3a in the absence of adipose tissue involvement when cancer bulges beyond the contour of the gland or beyond the condensed smooth muscle of the prostate at posterior and posterolateral sites. Extraprostatic extension can also be identified anteriorly. It was agreed that the location of extraprostatic extension should be reported. Although there was consensus that the amount of extraprostatic extension should be quantitated, there was no agreement as to which method of quantitation should be employed. There was overwhelming consensus that microscopic urinary bladder neck invasion by carcinoma should be reported as stage pT3a and that lymphovascular invasion by carcinoma should be reported. It is recommended that these elements are considered in the development of practice guidelines and in the daily practice of urological surgical pathology.

Urologie [Trends in urology]

The systemic treatment of kidney cancers is promising regarding the first results of the inhibiting molecules of the angiogenesis. Projections in research are encouraging for more specific and sensitive markers of the prostate cancer. For this last the intermittent hormonotherapy improves the quality of life of the patients. The overweight control in infertility allows greater chances of giving birth. The morbidity of the kidney percutaneous surgery is decreased by the use of smaller tools. Reduction rate of reobstruction thanks to new manufactoring stents. The botulinic toxin for the hyperactive bladder refunded by the health insurances.

A phase I study of the oral platinum agent satraplatin in sequential combination with capecitabine in the treatment of patients with advanced solid malignancies.

Abstract Background. The broad spectrum of antitumor activity of both the oral platinum analogue satraplatin (S) and capecitabine (C), along with the advantage of their oral administration, prompted a clinical study aimed to define the maximum tolerated dose (MTD) of the combination. Patients and methods. Four dose levels of S (mg/m(2)/day) and C (mg/m(2)/day) were evaluated in adult patients with advanced solid tumors: 60/1650, 80/1650, 60/2000, 70/2000; a course consisted of 28 days with sequential administration of S (days 1-5) and C (days 8-21) followed by one week rest. Results. Thirty-seven patients were treated, 24 in the dose escalation and 13 in the expansion phase; at the MTD, defined at S 70/C 2000, two patients presented dose limiting toxicities: lack of recovery of neutropenia by day 42 and nausea with dose skip of C. Most frequent toxicities were nausea (57%), diarrhea (51%), neutropenia (46%), anorexia, fatigue, vomiting (38% each). Two partial responses were observed in platinum sensitive ovarian cancer and one in prostate cancer. Conclusion. At S 70/C 2000 the combination of sequential S and C is tolerated with manageable toxicities; its evaluation in platinum and fluorouracil sensitive tumor types is worthwhile because of the easier administration and lack of nephro- and neurotoxicity as compared to parent compounds.

Urologie [Urology in 2011].

In 2011, therapeutic acquisitions in urology allow optimizing management of acute uncomplicated cystitis and acute pyelonephritis by female patients and in men clinical implications of benign prostatic hyperplasia opposed to prostate cancer detection as well as hormonal treatment of advanced prostate cancer.

Burden of Disease: Environmental Inequalities

A report on Environmental Inequalities in the UK. Part of the Burden of disease. A clean and healthy environment is a vital component of public health. This is particularly so for children. They are more sensitive to most stressors during development and growth and receive relatively more exposure than adults due to behaviour patterns, lack of awareness, size and biological metabolisms.A study of the contribution of environmental pollutants to the incidence, prevalence, mortality and costs of four categories of paediatric disease in American children estimated total annual costs to be $54.9 billion comprising $43.4 billion for lead poisoning, $2.0 billion for asthma, $0.3 billion for childhood cancer, and $9.2 billion for neurobehavioral disorders; 2.8 % of total U.S. health care costs. As well as childhood conditions, some adult diseases, even those that emerge much later in life, e.g. hypertension, hyperlipidemia, insulin resistance, type 2 diabetes, ischemic heart disease, breast cancer and prostate cancer have some of their origins in utero and childhood. Childhood exposures to environmental health hazards may therefore constitute a source of inequity between generations .

Trends in mortality from major cancers in the americas : 1980-2010

BACKGROUND: Between the 1970's and 2000 mortality in Latin America showed favorable trends for some common cancer sites, including stomach and male lung cancer in most countries. However, major concerns were related to mortality patterns from other cancers, particularly in women. We provide an up-to-date picture of patterns and trends in cancer mortality in Latin America. METHODS: We analyzed data from the World Health Organization mortality database in 2005-2009 for 20 cancer sites in 11 Latin American countries and, for comparative purposes, in the USA and Canada. We computed age-standardized (world) rates (per 100 000 person-year) and provided an overview of trends since 1980 using joinpoint regression models. RESULTS: Cancer mortality from some common cancers (including colorectum and lung) is still comparatively low in Latin America, and decreasing trends continue for some cancer sites (including stomach, uterus, male lung cancers) in several countries. However, there were upward trends for colorectal cancer for both sexes, and for women lung and breast cancer mortality in most countries. During the last decade, lung cancer mortality in women rose by 1-3% per year in all Latin American countries except Mexico and Costa Rica, whereas rises of about 1% were registered for breast cancer in Brazil, Colombia and Venezuela. Moreover, high mortality from cancer of the cervix uteri was recorded in most countries, with rates over 13/100 000 women in Cuba and Venezuela. In men, upward trends were registered in prostate cancer mortality in Brazil and Colombia, but also in Cuba, where the rate in 2005-2009 was more than twice that in the USA (23.6 versus 10/100 000). CONCLUSIONS: Tobacco control, efficient screening programs, early cancer detection and widespread access to treatments continue to be a major priority for most Latin American countries.

Substrate specificity of human kallikrein 2 (hK2) as determined by phage display technology.

Human glandular kallikrein 2 (hK2) is a trypsin-like serine protease expressed predominantly in the prostate epithelium. Recently, hK2 has proven to be a useful marker that can be used in combination with prostate specific antigen for screening and diagnosis of prostate cancer. The cleavage by hK2 of certain substrates in the proteolytic cascade suggest that the kallikrein may be involved in prostate cancer development; however, there has been very little other progress toward its biochemical characterization or elucidation of its true physiological role. In the present work, we adapt phage substrate technology to study the substrate specificity of hK2. A phage-displayed random pentapeptide library with exhaustive diversity was generated and then screened with purified hK2. Phages displaying peptides susceptible to hK2 cleavage were amplified in eight rounds of selection and genes encoding substrates were transferred from the phage to a fluorescent system using cyan fluorescent protein (derived from green fluorescent protein) that enables rapid determination of specificity constants. This study shows that hK2 has a strict preference for Arg in the P1 position, which is further enhanced by a Ser in P'1 position. The scissile bonds identified by phage display substrate selection correspond to those of the natural biological substrates of hK2, which include protein C inhibitor, semenogelins, and fibronectin. Moreover, three new putative hK2 protein substrates, shown elsewhere to be involved in the biology of the cancer, have been identified thus reinforcing the importance of hK2 in prostate cancer development.

Phase I dose-finding study of cabazitaxel administered weekly in patients with advanced solid tumours.

BACKGROUND Cabazitaxel is approved in patients with metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen. This study evaluated a weekly cabazitaxel dosing regimen. Primary objectives were to report dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD). Efficacy, safety and pharmacokinetics were secondary objectives. METHODS Cabazitaxel was administered weekly (1-hour intravenous infusion at 1.5-12 mg/m2 doses) for the first 4 weeks of a 5-week cycle in patients with solid tumours. Monitoring of DLTs was used to determine the MTD and the recommended weekly dose. RESULTS Thirty-one patients were enrolled. Two of six patients experienced DLTs at 12 mg/m2, which was declared the MTD. Gastrointestinal disorders were the most common adverse event. Eight patients developed neutropenia (three ≥ Grade 3); one occurrence of febrile neutropenia was reported. There were two partial responses (in breast cancer) and 13 patients had stable disease (median duration of 3.3 months). Increases in Cmax and AUC0-t were dose proportional for the 6-12 mg/m2 doses. CONCLUSION The MTD of weekly cabazitaxel was 12 mg/m2 and the recommended weekly dose was 10 mg/m2. The observed safety profile and antitumour activity of cabazitaxel were consistent with those observed with other taxanes in similar dosing regimens. TRIAL REGISTRATION The study was registered with ClinicalTrials.gov as NCT01755390.

Do socioeconomic inequalities in mortality vary between different Spanish cities? a pooled cross-sectional analysis.

BACKGROUND The relationship between deprivation and mortality in urban settings is well established. This relationship has been found for several causes of death in Spanish cities in independent analyses (the MEDEA project). However, no joint analysis which pools the strength of this relationship across several cities has ever been undertaken. Such an analysis would determine, if appropriate, a joint relationship by linking the associations found. METHODS A pooled cross-sectional analysis of the data from the MEDEA project has been carried out for each of the causes of death studied. Specifically, a meta-analysis has been carried out to pool the relative risks in eleven Spanish cities. Different deprivation-mortality relationships across the cities are considered in the analysis (fixed and random effects models). The size of the cities is also considered as a possible factor explaining differences between cities. RESULTS Twenty studies have been carried out for different combinations of sex and causes of death. For nine of them (men: prostate cancer, diabetes, mental illnesses, Alzheimer's disease, cerebrovascular disease; women: diabetes, mental illnesses, respiratory diseases, cirrhosis) no differences were found between cities in the effect of deprivation on mortality; in four cases (men: respiratory diseases, all causes of mortality; women: breast cancer, Alzheimer's disease) differences not associated with the size of the city have been determined; in two cases (men: cirrhosis; women: lung cancer) differences strictly linked to the size of the city have been determined, and in five cases (men: lung cancer, ischaemic heart disease; women: ischaemic heart disease, cerebrovascular diseases, all causes of mortality) both kinds of differences have been found. Except for lung cancer in women, every significant relationship between deprivation and mortality goes in the same direction: deprivation increases mortality. Variability in the relative risks across cities was found for general mortality for both sexes. CONCLUSIONS This study provides a general overview of the relationship between deprivation and mortality for a sample of large Spanish cities combined. This joint study allows the exploration of and, if appropriate, the quantification of the variability in that relationship for the set of cities considered.

Myeloid cells contribute to tumor lymphangiogenesis.

The formation of new blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis) promotes tumor outgrowth and metastasis. Previously, it has been demonstrated that bone marrow-derived cells (BMDC) can contribute to tumor angiogenesis. However, the role of BMDC in lymphangiogenesis has largely remained elusive. Here, we demonstrate by bone marrow transplantation/reconstitution and genetic lineage-tracing experiments that BMDC integrate into tumor-associated lymphatic vessels in the Rip1Tag2 mouse model of insulinoma and in the TRAMP-C1 prostate cancer transplantation model, and that the integrated BMDC originate from the myelomonocytic lineage. Conversely, pharmacological depletion of tumor-associated macrophages reduces lymphangiogenesis. No cell fusion events are detected by genetic tracing experiments. Rather, the phenotypical conversion of myeloid cells into lymphatic endothelial cells and their integration into lymphatic structures is recapitulated in two in vitro tube formation assays and is dependent on fibroblast growth factor-mediated signaling. Together, the results reveal that myeloid cells can contribute to tumor-associated lymphatic vessels, thus extending the findings on the previously reported role of hematopoietic cells in lymphatic vessel formation.

Mortality among 24,865 workers exposed to polychlorinated biphenyls (PCBs) in three electrical capacitor manufacturing plants: a ten-year update.

The objective of this analysis was to evaluate mortality among a cohort of 24,865 capacitor-manufacturing workers exposed to polychlorinated biphenyls (PCBs) at plants in Indiana, Massachusetts, and New York and followed for mortality through 2008. Cumulative PCB exposure was estimated using plant-specific job-exposure matrices. External comparisons to US and state-specific populations used standardized mortality ratios, adjusted for gender, race, age and calendar year. Among long-term workers employed 3 months or longer, within-cohort comparisons used standardized rate ratios and multivariable Poisson regression modeling. Through 2008, more than one million person-years at risk and 8749 deaths were accrued. Among long-term employees, all-cause and all-cancer mortality were not elevated; of the a priori outcomes assessed only melanoma mortality was elevated. Mortality was elevated for some outcomes of a priori interest among subgroups of long-term workers: all cancer, intestinal cancer and amyotrophic lateral sclerosis (women); melanoma (men); melanoma and brain and nervous system cancer (Indiana plant); and melanoma and multiple myeloma (New York plant). Standardized rates of stomach and uterine cancer and multiple myeloma mortality increased with estimated cumulative PCB exposure. Poisson regression modeling showed significant associations with estimated cumulative PCB exposure for prostate and stomach cancer mortality. For other outcomes of a priori interest--rectal, liver, ovarian, breast, and thyroid cancer, non-Hodgkin lymphoma, Alzheimer disease, and Parkinson disease--neither elevated mortality nor positive associations with PCB exposure were observed. Associations between estimated cumulative PCB exposure and stomach, uterine, and prostate cancer and myeloma mortality confirmed our previous positive findings.

Nouveautés en médecine interne générale ambulatoire (2) [General internal medicine: review of year 2009 from the ambulatory perspective (2)]

Despite two international studies, there is still no consensus concerning prostate cancer screening. The results of a meta-analysis are making us question our convictions concerning pneumococcal vaccination. The preoperative work-up of cataract surgery can be simplified. When describing the efficacy of a treatment to a patient, relative risks are better understood than absolute risks. For rotator cuff syndrome, intramuscular corticosteroid injections are as efficient as intra-articular injections. In patients prescribed clopidogrel, a proton pump inhibitor is not absolutely necessary. The arrival of a anticoagulant that does not need blood monitoring is an interesting option in atrial fibrillation.

CD10 is inversely associated with nuclear factor-kappa B and predicts biochemical recurrence after radical prostatectomy.

INTRODUCTION: The cell surface endopeptidase CD10 (neutral endopeptidase) and nuclear factor-κB (NF-κB) have been independently associated with prostate cancer (PC) progression. We investigated the correlations between these two factors and their prognostic relevance in terms of biochemical (prostate-specific antigen, PSA) relapse after radical prostatectomy (RP) for localized PC. PATIENTS AND METHODS: The immunohistochemical expression of CD10 and NF-κB in samples from 70 patients who underwent RP for localized PC was correlated with the preoperative PSA level, Gleason score, pathological stage and time to PSA failure. RESULTS: CD10 expression was inversely associated with NF-κB expression (p < 0.001), stage (p = 0.03) and grade (p = 0.003), whereas NF-κB was directly related with stage (p = 0.006) and grade (p = 0.002). The median time to PSA failure was 56 months. CD10 and NF-κB were directly (p < 0.001) and inversely (p < 0.001) correlated with biochemical recurrence-free survival, respectively. CD10 expression (p = 0.022) and stage (p = 0.018) were independently associated with time to biochemical recurrence. CONCLUSION: Low CD10 expression is an adverse prognostic factor for biochemical relapse after RP in localized PC, which is also associated with high NF-κB expression. Decreased CD10 expression which would lead to increased neuropeptide signaling and NF-κB activity may be present in a subset of early PCs.

Trends in mortality from urologic cancers in Europe, 1970-2008.

BACKGROUND: In recent decades, there have been substantial changes in mortality from urologic cancers in Europe. OBJECTIVE: To provide updated information, we analyzed trends in mortality from cancer of the prostate, testis, bladder, and kidney in Europe from 1970 to 2008. DESIGN, SETTING, AND PARTICIPANTS: We derived data for 33 European countries from the World Health Organization database. MEASUREMENTS: We computed world-standardized mortality rates and used joinpoint regression to identify significant changes in trends. RESULTS AND LIMITATIONS: Mortality from prostate cancer has leveled off since the 1990s in countries of western and northern Europe, particularly over the last few years while it was still rising in Bulgaria, Romania, and Russia. In the European Union (EU), it reached a peak in 1995 at 15.0 per 100 000 men and declined to 12.5 per 100 000 in 2006. Mortality from testicular cancer has steadily declined in most countries in western and northern Europe since the 1970s. The declines were later and appreciably lower in central/eastern Europe. In EU, rates declined from 0.75 in 1980 to 0.32 per 100 000 men in 2006, with stronger declines up to the late 1990s and an apparent leveling off in rates thereafter. Over the last 15 years, mortality from bladder cancer has declined in most European countries in both sexes. The major exceptions were Bulgaria, Poland, and Romania. In the EU, bladder cancer mortality was stable until 1992 and declined thereafter from 7.3 to 5.5 per 100 000 men and from 1.5 to 1.2 per 100 000 women in 2006. Mortality from kidney cancer increased throughout Europe until the early 1990s and leveled off thereafter in many countries, except in a few central and eastern ones. Between 1994 and 2006, rates declined from 4.9 to 4.3 per 100 000 in EU men and from 2.1 to 1.8 per 100 000 in EU women. CONCLUSIONS: Over the last two decades, trends in urologic cancer mortality were favorable in Europe, with the exception of a few central and eastern countries.