Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes

Efecto de la inoculación con bacterias rizosféricas en dos variedades de trigo. Fase I: condiciones controladas

The experiment was carried out in a greenhouse so that the inoculation, both simple and combined (with the rhizospheric bacteria- Sinorhizobium and Azospirllium), en two varieties of Wheat. Materials and methodologies were used in accordance with previously prescribed conventional methodologies for this study. The experimental design was completely randomized, with 4 replicas and 10 treatments. A statistical analysis using two-way variance was done. Fertilized treatment was applied with NH4NO3 (150 ppm/kg soil). The content of chlorophyll foliage was evaluated, dry air weight, dry root weight, length of stem, and germination. In the event that differences appeared, it was determined through use of the Duncan Test, and the differences between varieties with t-Student. It is concluded that combined inoculation with the strain A2 (Sinorhizobium meliloti) and the strain N7 (Azospirillum zeae) had the greatest positive influence on the chlorophyll content of the plants. On the other hand, there was a great difference between the two varieties of wheat in terms of length of stem, dry air weight, and dry root weight. The results of dry air weight and dry root weight, upon combining the two factors that were studied, highly depended on the varietal characteristics of the plant and on the native population of rhizobacteria. The germination of the plants was not linked to any of the applied factors in the experiment.Se llevo a cabo un experimento bajo condiciones controladas para determinar la respuesta de dos variedades de trigo a la inoculacion simple y combinada realizada con Sinorhizobium y Azospirillum. Se utilizo una cepa de A. zeae, y dos cepas pertenecientes a S. meliloti. Los materiales y metodos aplicados correspondieron a lo descrito en las metodologias prestablecidas en este campo de estudio. Diseno experimental: completamente aleatorizado, con 20 tratamientos y 4 replicas. No se utilizo tratamiento fertilizado. Se evaluaron diferentes variables agronomicas, relacionadas con la arquitectura radical y la biomasa aerea. Analisis de varianza bifactorial. En caso de aparecer diferencias, se aplico analisis de varianza de un factor a la interaccion en primera instancia, o a los factores probados. Diferencias entre medias por LSD de Fisher. Se transformaron datos de conteo de digitos por �ãx. Se calculo correlacion y regresion multiple entre variables. Se concluye que la inoculacion combinada de Sinorhizobium con Azospirillum, asi como la inoculacion simple con Sinorhizobium, resultaron de alta importancia en las alternativas de inoculacion que se realizaron en el experimento. Existio una alta diferenciacion entre las dos variedades de trigo en determinadas variables agronomicas, lo que indica una influencia marcada de las caracteristicas varietales de las plantas. Se observó una fuerte relación estadística entre las variables peso seco aéreo y variables de la raíz para los tratamientos inoculados con A2 y A2+N7, respectivamente

Mycoplasmosis in Ferrets

We report an outbreak of severe respiratory disease associated with a novel Mycoplasma species in ferrets. During 2009–2012, a respiratory disease characterized by nonproductive coughing affected ≈8,000 ferrets, 6–8 weeks of age, which had been imported from a breeding facility in Canada. Almost 95% became ill, but almost none died. Treatments temporarily decreased all clinical signs except cough. Postmortem examinations of euthanized ferrets revealed bronchointerstitial pneumonia with prominent hyperplasia of bronchiole-associated lymphoid tissue. Immunohistochemical analysis with polyclonal antibody against Mycoplasma bovis demonstrated intense staining along the bronchiolar brush border. Bronchoalveolar lavage samples from 12 affected ferrets yielded fast-growing, glucose-fermenting mycoplasmas. Nucleic acid sequence analysis of PCR-derived amplicons from portions of the 16S rDNA and RNA polymerase B genes failed to identify the mycoplasmas but showed that they were most similar to M. molare and M. lagogenitalium. These findings indicate a causal association between the novel Mycoplasma species and the newly recognized pulmonary disease

Tissue‐Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC Inhibition

Abstract Lymphangioleiomyomatosis (LAM) is a rare disease involving cystic lung destruction by invasive LAM cells. These cells harbor loss‐of‐function mutations in TSC2, conferring hyperactive mTORC1 signaling. Here, tissue engineering tools are employed to model LAM and identify new therapeutic candidates. Biomimetic hydrogel culture of LAM cells is found to recapitulate the molecular and phenotypic characteristics of human disease more faithfully than culture on plastic. A 3D drug screen is conducted, identifying histone deacetylase (HDAC) inhibitors as anti‐invasive agents that are also selectively cytotoxic toward TSC2−/− cells. The anti‐invasive effects of HDAC inhibitors are independent of genotype, while selective cell death is mTORC1‐dependent and mediated by apoptosis. Genotype‐selective cytotoxicity is seen exclusively in hydrogel culture due to potentiated differential mTORC1 signaling, a feature that is abrogated in cell culture on plastic. Importantly, HDAC inhibitors block invasion and selectively eradicate LAM cells in vivo in zebrafish xenografts. These findings demonstrate that tissue‐engineered disease modeling exposes a physiologically relevant therapeutic vulnerability that would be otherwise missed by conventional culture on plastic. This work substantiates HDAC inhibitors as possible therapeutic candidates for the treatment of patients with LAM and requires further study

Meeting report: Spontaneous Lesions and Diseases in Wild, Captive-Bred, and Zoo-Housed Nonhuman Primates and in Nonhuman Primate Species Used for Drug Safety Studies

The combination of loss of habitat, human population encroachment, and increased demand of select species for biomedical research has expanded the list of emerging diseases. There remains a need for knowledge and expertise in understanding background findings as related to the age, source, strain, and disease status of nonhuman primates. In particular, for safety/biomedical studies, a broader understanding and documentation of lesions would help clarify background from treatment related findings. A workshop and mini-symposium on spontaneous lesions and diseases in nonhuman primates were sponsored by the concurrent Annual Meetings of the American College of Veterinary Pathologists and the American Society for Veterinary Clinical Pathology held December 3-4, 2011 in Nashville, TN. The first session had presentations from Drs. Linda Lowenstine and Richard Montali, pathologists with extensive experience in wild and zoo populations of nonhuman primates, which was followed by presentations of 20 unique case studies of rare or newly observed spontaneous lesions in nonhuman primate species. The mini-symposium concentrated on background and spontaneous lesions in nonhuman primate species used for drug safety studies, and included presentations on incidence and range of spontaneous findings in cynomolgus macaques; lesions in the urogenital system of macaques; gastrointestinal lesions and pathogens in macaques and marmosets; age-associated lesions in rhesus macaques; and effects of Plasmodium infection on drug development. Both sessions were heavily attended by meeting participants that included students, pathology trainees, and experienced pathologists from academia and industry with an interest in spontaneous diseases of nonhuman primates