Neutrophil-to-lymphocyte ratio as a prognostic biomarker for men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy: data from two randomized phase III trials.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), a marker of host inflammation, has been associated with poor outcome in several solid tumors. Here, we investigated associations of the derived NLR (dNLR) and duration of initial androgen deprivation therapy (ADT) with survival of men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line chemotherapy. PATIENTS AND METHODS: Data from the multinational randomized phase III studies VENICE and TAX327 included a total of 2230 men with mCRPC randomized to receive first-line chemotherapy, and were used as training and validation sets, respectively. Associations of dNLR and duration of initial ADT with overall survival (OS) were evaluated by multivariable Cox regression analysis in the training set stratified for performance status and treatment arm. The model was then tested in the validation set. Subsequently, we investigated the treatment effect of docetaxel on OS in subgroups according to dNLR and duration of initial ADT. RESULTS: In the training set, both dNLR ≥median (2) and duration of initial ADT

Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Abiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This study's objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone. PATIENTS AND METHODS: All patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation. RESULTS: A confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%-50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis. CONCLUSIONS: A composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research.

Bias in reporting of end points of efficacy and toxicity in randomized, clinical trials for women with breast cancer.

BACKGROUND: Phase III randomized, clinical trials (RCTs) assess clinically important differences in end points that reflect benefit to patients. Here, we evaluate the quality of reporting of the primary end point (PE) and of toxicity in RCTs for breast cancer. METHODS: PUBMED was searched from 1995 to 2011 to identify RCTs for breast cancer. Bias in the reporting of the PE and of toxicity was assessed using pre-designed algorithms. Associations of bias with the Journal Impact Factor (JIF), changes in the PE compared with information in ClinicalTrials.gov and funding source were evaluated. RESULTS: Of 164 included trials, 33% showed bias in reporting of the PE and 67% in the reporting of toxicity. The PE was more likely to be reported in the concluding statement of the abstract when significant differences favoring the experimental arm were shown; 59% of 92 trials with a negative PE used secondary end points to suggest benefit of experimental therapy. Only 32% of articles indicated the frequency of grade 3 and 4 toxicities in the abstract. A positive PE was associated with under-reporting of toxicity. CONCLUSION: Bias in reporting of outcome is common for studies with negative PEs. Reporting of toxicity is poor, especially for studies with positive PEs.

Translating clinical trials to clinical practice: outcomes of men with metastatic castration resistant prostate cancer treated with docetaxel and prednisone in and out of clinical trials.

BACKGROUND: Multiple factors can influence outcomes of patients receiving identical interventions in clinical trials and in routine practice. Here, we compare outcomes of men with metastatic castrate-resistant prostate cancer (mCRPC) treated with docetaxel and prednisone in routine practice and in clinical trials. PATIENTS AND METHODS: We reviewed patients with mCRPC treated with docetaxel at Princess Margaret Cancer Centre. Primary outcomes were overall survival and PSA response rate. Secondary outcomes were reasons for discontinuation and febrile neutropenia. Outcomes were compared for men treated in routine practice and in clinical trials, and with data from the TAX 327 study. RESULTS: From 2001 to 2011, 438 men were treated, of whom 357 received 3-weekly docetaxel as first-line chemotherapy: 314 in routine practice and 43 in clinical trials. Trial patients were younger and had better performance status. Median survival was 13.6 months [95% confidence interval (95% CI) 12.1-15.1 months] in routine practice and 20.4 months (95% CI 17.4-23.4 months, P = 0.007) within clinical trials, compared with 19.3 months (95% CI 17.6-21.3 months, P < 0.001) in the TAX 327 study. PSA response rates were 45%, 54%, and 53%, respectively (P = NS). Reasons for treatment discontinuation were similar although trial patients received more cycles (median: 6 versus 8 versus 9.5, P < 0.001). Rates of febrile neutropenia were 9.6, 0, and 3% (P < 0.001) while rates of death within 30 days of last dose were 4%, 0%, and 3%, respectively (P = NS). CONCLUSIONS: Survival of patients with mCRPC treated with docetaxel in routine practice is shorter than for men included in trials and is associated with more toxicity.

Impact of Geographic Region on Benefit of Approved Anticancer Drugs Evaluated in International Phase III Clinical Trials.

AIMS: International collaboration allows for enhanced accrual and more generalisable results of phase III randomised controlled trials (RCTs). The impact of geographic region on the outcomes of new anticancer agents is unclear. MATERIALS AND METHODS: International RCTs evaluating approved systemic therapy for advanced solid tumours that reported efficacy of new anticancer drugs based on geographic regions were eligible. Data for overall (OS) or progression-free survival (PFS) were pooled in a meta-analysis. The primary analysis was the comparison of developed versus developing countries. A meta-regression analysis explored the impact of differences in gross national income (GNI) per capita on the hazard ratio comparing developed and developing countries. Secondary analyses compared geographic regions irrespective of GNI. RESULTS: Of the 63 identified studies, 12 independent RCTs were eligible; five reported data for OS and nine for PFS. Improvements in overall survival were greater in developed as compared with developing countries (hazard ratio 0.82, 95% confidence interval 0.68-0.99, P = 0.04). This effect was seen only among studies of cytotoxic chemotherapy and not among those of targeted agents. No difference was seen for PFS (hazard ratio 0.93, 95% confidence interval 0.79-1.09, P = 0.36). Meta-regression showed a significant negative association between GNI per capita and overall survival, but a non-significant negative association with PFS (ß = -0.774, P = 0.05 and ß = -0.211, P = 0.29, respectively). No differences were observed in PFS between Asian and non-Asian countries or North America and Western Europe. CONCLUSION: Compared with patients from developing countries, those from developed countries derive greater improvement in overall survival from cytotoxic chemotherapy, but similar benefit from targeted drugs.

Evolution in the eligibility criteria of randomized controlled trials for systemic cancer therapies.

BACKGROUND: Eligibility criteria in randomized controlled trials (RCTs) reduce inter-patient heterogeneity, but may reduce generalizability of results. Here, we explore temporal changes in eligibility criteria of practice-changing RCTs for systemic cancer therapies and in the proportion of patients excluded from these trials after application of eligibility criteria. METHODS: An electronic search identified practice-changing RCTs published in six major journals between July 2010 and December 2012. Trial protocols were identified through journal websites and communication with authors or study sponsors. Eligibility criteria were extracted from protocols. The number of patients excluded after application of eligibility criteria was extracted from the CONSORT diagrams and text of publications. Changes in eligibility criteria over time were assessed by logistic regression and meta-regression was carried out to evaluate the impact of year of protocol on the proportion of patients who were excluded after screening. RESULTS: Eighty-six protocols written between 1987 and 2012 were included. Over time, there has been an increasing frequency of exclusion of patients with prior cerebrovascular events (OR 1.34, p=0.003), coagulation/bleeding disorders (OR 1.34, p=0.006), prior gastrointestinal bleeding (OR 1.33, p=0.01), cardiac co-morbidities (OR 1.24, p=0.004) and exclusion based on concurrent medication (OR 1.19, p=0.01). There has been a decrease in upper age limit usage (OR 0.83, p=0.01) and leukopenia (OR 0.83, p=0.009). The proportion of patients excluded from trials has increased from 9% prior to 2000 to 18% after 2010 (p-value for trend <0.001). CONCLUSIONS: RCTs have become less representative of cancer patients treated in routine practice with increased use of organ-specific and co-morbidity-based exclusion criteria.

Immunotherapy in prostate cancer: review of the current evidence.

Prostate cancer is the most common male malignancy in the Western world. Once it metastasizes, it is incurable. The current gold standard for metastatic disease is the combined docetaxel/prednisone regimen. Prostate cancer shows several characteristics that make it a suitable candidate for immunotherapy, as recently exemplified by the approval of sipuleucel-T, the first vaccine to treat any malignancy. Here, we review different tumor-associated antigen immunotherapy strategies currently being investigated, from a humanized radiolabeled monoclonal antibody (J-591) that targets radiation into tumor cells, moving on to vaccines and through to immunomodulator agents such as anti-CPLA-4 and anti-PD-1 monoclonal antibodies that activate T-cell responses via immune checkpoint inhibition. We explore different opinions on the best approach to integrate immunotherapy into existing standard therapies, such as androgen-deprivation therapy, radiotherapy or chemotherapy, and review different combination sequences, patient types and time points during the course of the disease to achieve a lasting immune response. We present data from recent phase III clinical trials that call for a change in trial endpoint design with immunotherapy agents, from the traditional tumor progression to overall survival and how such trials should include immune response measurements as secondary or intermediate endpoints to help identify patient clinical benefit in the earlier phases of treatment. Finally, we join in the recent questioning on the validity of RECIST criteria to measure response to immunotherapeutic agents, as initial increases in the size of tumors/lymph nodes, which are part of a normal immune response, could be categorized as disease progression under RECIST.

Environmental lead in Mexico.

From the data presented here, it can be concluded that environmental exposure to lead is a particularly severe problem in Mexico. As has been shown, there are very important sources of exposure to this metal: (a) for rural populations who manufacture and/or utilize lead-glazed pottery, (b) for urban populations who are exposed to high air lead concentrations due to the continued use of lead fuel additives, (c) for workers of several industries, mainly those of batteries and pigments, (d) for consumers who routinely eat canned foods such as hot peppers and fruit products, and (e) for the general population living in the vicinity of smelters, refineries and other industries that emit lead. Therefore, in Mexico only those native populations living in very primitive communities, far away from all civilized life, could be expected to be free from this exposure. At the same time, and despite the relatively few data available, it can be stated that the exposure to lead of populations in Mexico could be approaching levels that might be highly hazardous, in particular for the neuropsychological health of children. Regarding the presence of lead in the environment, despite the fact that the available studies are not enough, it is evident that pollution by this metal is widespread and that there is a serious lack of studies for most regions of the country, including several that might be expected to be highly polluted. At the same time, it is evident that the official attention paid to the problem, either in regulations, support of further studies, or implementation of effective control measures has been far from the level needed according to the available data. Lead in gasoline is still used at very high concentrations in all the country, with the exception of Mexico City and its surrounding area, while no studies have been carried out to determine the potential health and environmental impact of this practice in regions outside Mexico City. Despite the fact that the Torreón smelter is one of the largest in Latin America, and although it is located less than two km from downtown Torreón, with the predominant winds blowing in the direction from the smelter towards the residential and central areas of the city, no large scale study has been carried out on the impact of this source on the health of its residents.(ABSTRACT TRUNCATED AT 400 WORDS)

Vascular control of the renal pedicle using the hem-o-lok polymer ligating clip in 50 consecutive hand-assisted laparoscopic nephrectomies.

BACKGROUND AND PURPOSE: A crucial step in laparoscopic nephrectomy is control and ligation of the renal pedicle. Commonly, an endovascular gastrointestinal anastomosis (GIA) stapling device, titanium staples, or both is employed for vascular control. Herein, we report on the use of the Hem-o-Lok polymer ligating clip (Weck Closure Systems, Research Triangle Park, NC) for the routine control of the renal pedicle (both venous and arterial) during hand-assisted laparoscopic radical nephrectomies. PATIENTS AND METHODS: From March 2001 to December 2002, 50 hand-assisted simple or radical nephrectomies were performed by a single surgeon. The Hem-o-lok polymer ligating clip was utilized exclusively for ligation of the renal pedicle, with placement of two clips on the patient's side and one distally on the specimen side. RESULTS: Vascular control was achieved safely in all cases. Neither slippage nor complications were found in any of these cases. CONCLUSIONS: Vascular control of the renal pedicle via the Hem-o-Lok polymer ligating clip is safe and dependable for laparoscopic radical/simple nephrectomies.

Experience with the MAGPI hypospadias repair.

Over a 9-month period, 25 consecutive patients with subcoronal hypospadias underwent hypospadias repair using the MAGPI technique. Only those patients with subcoronal lesions, and without chordee were included in this series. The mean age at the time of repair was 3 years with a range of 1.2 to 9 years. The average length of hospitalization was eight hours and the overall complication rate was 4%. The technical simplicity and reliability of this procedure as well as the excellent cosmetic and functional results which can be obtained make it an essential adjunct to our surgical armamentarium.

Gastrointestinal helminths of loggerhead turtles (Caretta caretta) from the western Mediterranean: constraints on community structure.

Richness and composition of gastrointestinal helminth communities of 54 loggerhead turtles, Caretta caretta, from the western Mediterranean were interpreted from patterns of helminth exchange at 2 host taxonomic scales: exchange between marine turtles and other marine hosts and exchange within turtles. We predicted exchange of the former to be unimportant ecologically and evolutionarily because of the host phylogenetic distance. The absence of records of successful exchange at this host taxonomic scale confirmed that host physiological barriers seem to prevent contemporary parasite transfer between marine turtles and other sympatric hosts. Marine turtles also seem to exhibit an evolutionary association with their parasites largely independent from that of other marine hosts. Therefore, the composition of gastrointestinal helminth communities of marine turtles is predictably restricted to digeneans, nematodes, and aspidogastreans specific to these reptiles. At the scale of host species, helminth exchange among marine turtle species was expected to be significant. This was suggested by reports indicating a high proportion of parasites common to all sea turtle species. Mediterranean C. caretta harbored only 4 digenean species typical of marine turtles, and immature individuals of 1 digenean species accidentally acquired. Further, no relevant parasite exchange with other marine turtles was expected to occur because C. caretta is the only sea turtle species abundant in the western Mediterranean. Therefore, a predictable composition coupled with low species richness in infracommunities might be accounted for partly by constraints on parasite acquisition at both host scales. Host factors limiting parasite recruitment (mainly ectothermy and a wandering behavior) may also contribute to depauperate and isolationist infracommunities.

Balaenophilus manatorum (Ortíz, Lalana and Torres, 1992) (Copepoda: Harpacticoida) from loggerhead sea turtles, Caretta caretta, from Japan and the western Mediterranean: amended description and geographical comparison.

The ectoparasitic harpacticoid copepod, Balaenophilus manatorum (Ortíz, Lalana and Torres, 1992) (syn. Balaenophilus umigamecolus Ogawa, Matsuzaki and Misaki, 1997), has been reported on 3 species of marine turtles from the Pacific and the Mediterranean and from the West Indian manatee off Cuba in the Caribbean. The 3 available descriptions of this species were made using light microscopy. In this paper, we provide an amended description of B. manatorum using scanning electronic microscopy (SEM) for specimens in the collection from which B. umigamecolus was originally described. This material was collected from 1 loggerhead sea turtle, Caretta caretta, from Japan. The use of SEM allowed us to add several new microcharacters to the original description but, more importantly, allowed us to correct a number of the traits originally described. Some of the corrections could affect the interpretation of putative homology and variability of characters among populations of B. manatorum. A SEM comparison of specimens of B. manatorum from loggerheads from Japan and the western Mediterranean suggested the existence of morphological stasis between these populations. However, there were apparent meristic differences with a recently published description of this species from olive ridleys, Lepidochelys olivacea, in Mexico. Although B. manatorum is currently considered as a single, widespread taxon, the possibility that it actually represents a species complex deserves further attention.

[Aging of the dental pulp]. / Vieillissement de l'organe pulpo-dentinaire.

During life, the modifications of the dental pulp are important mostly in the root portion. This area, more than the coronal part of the tooth is submitted to involution and histologic dedifferentiation. Fibrosis and calcification occur leading to severe difficulty in performing endodontic treatment.

Uretero-fallopian tube fistula secondary to laparoscopic fulguration of pelvic endometriosis.

Ureteral injuries during laparoscopic surgery have been documented. We present a case of the diagnosis and management of a uretero-fallopian tube fistula after laparoscopic laser fulguration of pelvic endometriosis.

Condylomata acuminata: diagnosis and follow-up by retrograde urethrography.

Intraurethral Condylomata acuminata can present as a serious problem. Prior to endoscopy, retrograde urethrography can help in diagnosing and determining the extent of the disease.

Embolization to control iatrogenic ureteral hemorrhage: a case report.

Gross hematuria following percutaneous or endourological intervention is well known and widely documented. We report an unusual case of angiographically documented hemorrhage from a ureteral branch that was injured by cystoscopic removal of a Double-J stent, and subsequent successful transcatheter embolization. This case demonstrates the important role of angiographic diagnosis and therapy in the management of iatrogenic hemorrhage.