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1.
BJU Int ; 133(4): 487-490, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38234225

RESUMO

INTRODUCTION: It is challenging to perform prostate biopsy in men with suspicion of prostate malignancy without a rectum to facilitate prostate biopsy. Nevertheless, such patients are presenting at an earlier stage, due to increased PSA testing in association with improved MRI imaging. We describe a novel technique for prostate biopsy in two such cases. TECHNIQUE: The patient is under General Anaesthesia and in lithotomy position. The patient is catheterised and a measured volume of contrast is inserted to the catheter balloon. By using anatomical surface landmarks, placing traction on the catheter to bring the balloon to the level of the bladder neck and using fluoroscopy, the distance to the apical prostate was estimated. This facilitates image intensifier guided trans-perineal prostate biopsy. OUTCOMES: A 67-year-old patient, with a history of panproctocolectomy for ulcerative colitis, presented with increasing PSA and a suspicious prostate on MP-MRI. The prostate couldn't be visualised on transperineal ultrasound and the patient was offered transperineal biopsy using image intensifier guidance. Several biopsy cores were taken and prostate cancer was diagnosed. The second patient was a 68-year-old who presented similarly, but with a history of panproctocolectomy for Crohn's disease. Using the above technique, biopsies were taken with low-risk prostate cancer diagnosed. Subsequently, due to rising PSA levels, a repeat set of prostate biopsies was taken 13 months later in an identical manner, upstaging his disease. There were no post-operative complications after any of the procedures. CONCLUSION: We review the literature and discuss several techniques available to sample the prostate in this patient cohort. We conclude that we have identified a safe and effective technique, which utilises commonly available equipment, to biopsy the prostate in the post proctectomy patient.


Assuntos
Próstata , Neoplasias da Próstata , Masculino , Humanos , Idoso , Próstata/diagnóstico por imagem , Próstata/patologia , Reto , Antígeno Prostático Específico , Biópsia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/cirurgia , Períneo/patologia , Biópsia Guiada por Imagem/métodos
2.
Br J Clin Pharmacol ; 88(12): 5238-5256, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35655123

RESUMO

AIMS: To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase-sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase-1 (CES1). METHODS: This first-in-human study comprised single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1elo mouse strain. RESULTS: ESM-HDAC391 showed transient systemic exposure (plasma half-life of 21-30 min) but selective retention of processed acid for at least 12 hours, resulting in robust targeted mechanistic engagement (increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production). ESM-HDAC391 was well tolerated and clinical toxicities common to non-targeted HDACi were not observed. ESM-HDAC391 treatment was accompanied by the novel finding of a dose-dependent monocyte depletion that was transient and reversible and which plateaued at 0.06 × 109 monocytes/L after repeat dosing with 20 or 40 mg. Characterisation of monocyte depletion in transgenic mice (CES1/Es1elo ) suggested that colony stimulating factor 1 receptor loss on circulating cells contributed to ESM-HDAC-mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi-mediated change in myeloid fate through modulation of colony stimulating factor 1 receptor and downstream effects on cell differentiation. CONCLUSION: These findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM-HDACi treatment, with implications for potential benefit of these molecules in myeloid-driven diseases.


Assuntos
Esterases , Inibidores de Histona Desacetilases , Humanos , Animais , Camundongos , Inibidores de Histona Desacetilases/farmacologia , Fator Estimulador de Colônias de Macrófagos , Citocinas
3.
Blood ; 123(5): 697-705, 2014 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-24335499

RESUMO

The bromodomain and extraterminal (BET) protein BRD2-4 inhibitors hold therapeutic promise in preclinical models of hematologic malignancies. However, translation of these data to molecules suitable for clinical development has yet to be accomplished. Herein we expand the mechanistic understanding of BET inhibitors in multiple myeloma by using the chemical probe molecule I-BET151. I-BET151 induces apoptosis and exerts strong antiproliferative effect in vitro and in vivo. This is associated with contrasting effects on oncogenic MYC and HEXIM1, an inhibitor of the transcriptional activator P-TEFb. I-BET151 causes transcriptional repression of MYC and MYC-dependent programs by abrogating recruitment to the chromatin of the P-TEFb component CDK9 in a BRD2-4-dependent manner. In contrast, transcriptional upregulation of HEXIM1 is BRD2-4 independent. Finally, preclinical studies show that I-BET762 has a favorable pharmacologic profile as an oral agent and that it inhibits myeloma cell proliferation, resulting in survival advantage in a systemic myeloma xenograft model. These data provide a strong rationale for extending the clinical testing of the novel antimyeloma agent I-BET762 and reveal insights into biologic pathways required for myeloma cell proliferation.


Assuntos
Antineoplásicos/uso terapêutico , Benzodiazepinas/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzodiazepinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Camundongos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas de Ligação a RNA/genética , Fatores de Transcrição , Ativação Transcricional/efeitos dos fármacos , Células Tumorais Cultivadas
4.
BJU Int ; 115(4): 595-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25060513

RESUMO

OBJECTIVES: To review outcomes of the treatment of carcinoma in situ (CIS) of the penis at a large supra-regional penile cancer network, where centralisation has permitted greater experience with treatment outcomes, and suggest treatment strategies. PATIENTS AND METHODS: The network penile cancer database, which details presentation, treatment and complications was analysed from 2003 to 2010, identifying patients with CIS, with a minimum follow-up of 2 years, looking at treatments administered and outcomes. RESULTS: In all, 57 patients with mean (range) age of 61 (34-91) years were identified. In all, 18 were treated by circumcision only, 20 by circumcision and local excision (LE) and 19 by circumcision and 5-flurouracil (5-FU). The mean (range) follow-up was 3.5 (2-8) years. Of those treated by circumcision none subsequently developed CIS on the glans. For those who underwent circumcision + LE, five of 20 (25%) developed recurrence requiring further treatment. Of those treated by circumcision + 5-FU, 14/19 (73.7%) completely responded. Of the five incomplete responders, two had focal invasive malignancy at repeat biopsy. One incomplete responder underwent glansectomy and four grafting. No complete responders relapsed. Complications of 5-FU included significant inflammatory response in seven (36.8%), with two requiring hospital admission and one neo-phimosis (5.3%). CONCLUSION: This study suggests that patients undergoing circumcision for isolated CIS and complete responders to 5-FU may require only short-term follow-up, as recurrence is unlikely, whereas longer follow up is required for all other patients. However, numbers in this study are small and larger studies are needed to support this. An incomplete response to 5-FU dictates immediate re-biopsy, as it carries a significant chance of previously undetected invasive disease.


Assuntos
Carcinoma in Situ/tratamento farmacológico , Carcinoma in Situ/cirurgia , Fluoruracila/uso terapêutico , Neoplasias Penianas/tratamento farmacológico , Neoplasias Penianas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Circuncisão Masculina/métodos , Terapia Combinada , Fluoruracila/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Penianas/patologia , Estudos Retrospectivos , Resultado do Tratamento , Reino Unido
5.
Proc Natl Acad Sci U S A ; 109(36): 14532-7, 2012 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-22912406

RESUMO

Bromodomain-containing proteins bind acetylated lysine residues on histone tails and are involved in the recruitment of additional factors that mediate histone modifications and enable transcription. A compound, I-BET-762, that inhibits binding of an acetylated histone peptide to proteins of the bromodomain and extra-terminal domain (BET) family, was previously shown to suppress the production of proinflammatory proteins by macrophages and block acute inflammation in mice. Here, we investigated the effect of short-term treatment with I-BET-762 on T-cell function. Treatment of naïve CD4(+) T cells with I-BET-762 during the first 2 d of differentiation had long-lasting effects on subsequent gene expression and cytokine production. Gene expression analysis revealed up-regulated expression of several antiinflammatory gene products, including IL-10, Lag3, and Egr2, and down-regulated expression of several proinflammatory cytokines including GM-CSF and IL-17. The short 2-d treatment with I-BET-762 inhibited the ability of antigen-specific T cells, differentiated under Th1 but not Th17 conditions in vitro, to induce pathogenesis in an adoptive transfer model of experimental autoimmune encephalomyelitis. The suppressive effects of I-BET-762 on T-cell mediated inflammation in vivo were accompanied by decreased recruitment of macrophages, consistent with decreased GM-CSF production by CNS-infiltrating T cells. These effects were mimicked by an inhibitor of c-myc function, implicating reduced expression of c-myc and GM-CSF as one avenue by which I-BET-762 suppresses the inflammatory functions of T cells. Our study demonstrates that inhibiting the functions of BET-family proteins during early T-cell differentiation causes long-lasting suppression of the proinflammatory functions of Th1 cells.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Regulação da Expressão Gênica/imunologia , Proteínas Nucleares/imunologia , alfa-Amilases Salivares/antagonistas & inibidores , Fatores de Transcrição/imunologia , Transcrição Gênica/imunologia , Transferência Adotiva , Animais , Benzodiazepinas/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Proteínas Nucleares/metabolismo , Fosforilação , Fator B de Elongação Transcricional Positiva/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tiazóis/farmacologia , Fatores de Transcrição/metabolismo
6.
BJU Int ; 114(3): 340-3, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24053106

RESUMO

OBJECTIVE: To assess the role of centralized pathological review in penile cancer management. MATERIALS AND METHODS: Newly diagnosed squamous cell carcinomas (SCC) of the penis, including squamous cell carcinoma in situ (CIS), from biopsy specimens were referred from 15 centres to the regional supra-network multidisciplinary team (Sn-MDT) between 1 January 2008 and 30 March 2011. Biopsy histology reports and slides from the respective referring hospitals were reviewed by the Sn-MDT pathologists. The biopsy specimens' histological type, grade and stage reported by the Sn-MDT pathologist were compared with those given in the referring hospital pathology report, as well as with definitive surgery histology. Any changes in histological diagnosis were sub-divided into critical changes (i.e. those that could alter management) and non-critical changes (i.e. those that would not affect management). RESULTS: A total of 155 cases of squamous cell carcinoma or CIS of the penis were referred from 15 different centres in North-West England. After review by the Sn-MDT, the histological diagnosis was changed in 31% of cases and this difference was statistically significant. A total of 60.4% of the changes were deemed to be critical changes that resulted in a significant change in management. When comparing the biopsy histology reported by the Sn-MDT with the final histology from the definitive surgical specimens, a good correlation was generally found. CONCLUSIONS: In the present study a significant proportion of penile cancer histology reports were revised after review by the Sn-MDT. Many of these changes altered patient management. The present study shows that accurate pathological diagnosis plays a crucial role in determining the correct treatment and maximizing the potential for good clinical outcomes in penile cancer. In the case of histopathology, centralization has increased exposure to penile cancer and thereby increased diagnostic accuracy, and should therefore be considered the 'gold standard'.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Penianas/patologia , Encaminhamento e Consulta/organização & administração , Biópsia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Humanos , Incidência , Comunicação Interdisciplinar , Masculino , Estadiamento de Neoplasias , Neoplasias Penianas/tratamento farmacológico , Neoplasias Penianas/mortalidade , Guias de Prática Clínica como Assunto , Prognóstico , Estudos Retrospectivos , Medição de Risco , Manejo de Espécimes
7.
BJU Int ; 111(8): E365-73, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23714648

RESUMO

OBJECTIVES: To determine the incidence of prostate cancer (PCa), and pathological grade and location of PCa, using a modified transperineal template-guided saturation biopsy (TTSB). To compare the acute urinary retention (AUR) rate found using modified TTSB with that of published reports. PATIENTS AND METHODS: A total of 270 consecutive patients with persistent clinical suspicion of PCa, despite a median (range) of 2 (1-6) sets of negative transrectal ultrasonography-guided biopsies, were enrolled and prospectively studied. All underwent modified TTSB avoiding the peri-urethral area at the base of the prostate under general anaesthesia. Statistical analysis was performed using binary logistic regression to determine the prebiopsy predictors of PCa and AUR. RESULTS: The median (range) patient age was 64 (43-85) years, with a median (range) prostate-specific antigen (PSA) of 10 (1-114) ng/mL and median (range) prostate volume of 45 (17-106) mL. A mean (range) of 28 (16-43) cores were taken at modified TTSB. Prostate cancer was diagnosed in 54.8% (Gleason scores 6 in 27.7%, 7 in 43.2%, 8-10 in 29.1% of patients). The anterior third only was involved in 21%, the middle third in 6.8% and the posterior third in 8.7% of positive cases, although in 75% of positive cases there was some anterior involvement. Comparing uniquely anterior tumours with the 15.5% found uniquely in either the middle or posterior thirds, there was no significant difference between number of positive cores (2 vs 1, P = 0.091), maximum percentage core involvement (30 vs 17.5%, P = 0.315) and maximum tumour length (3.5 vs 2 mm, P = 0.092). Fourteen patients (5.2%) developed AUR. On multivariate analysis, PSA density (PSAD) and pre-TTSB PSA predicted PCa diagnosis, whilst prostate volume, prebiopsy PSA and PSAD predicted AUR. CONCLUSIONS: Modified TTSB has a high cancer yield, especially in the anterior region, in patients with previously negative histology but onward suspicion of PCa. The modified TTSB technique provides a low risk of AUR without compromising cancer yield.


Assuntos
Biópsia por Agulha/instrumentação , Endossonografia/métodos , Gradação de Tumores/métodos , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Desenho de Equipamento , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Períneo , Estudos Prospectivos , Próstata/diagnóstico por imagem , Reprodutibilidade dos Testes
8.
BJU Int ; 107(12): 1923-9, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20950306

RESUMO

OBJECTIVES: • To evaluate changes in bone mineral density (BMD), body composition, muscle strength and health-related quality of life (HRQL) during bicalutamide (150 mg) monotherapy in osteoporotic patients with non-metastatic locally advanced prostate cancer. Osteoporosis is prevalent in men presenting with prostate cancer and also a common side effect of treatment with luteinizing hormone-releasing hormone agonists, which are associated with decreased BMD and loss of lean body mass and suppress testosterone, unlike bicalutamide, which results in an increase in serum testosterone and oestrogen levels. PATIENTS AND METHODS: • Forty-two men with non-metastatic locally advanced prostate cancer and osteoporosis (T-score ≤-2.5) were treated with bicalutamide (150 mg) monotherapy. BMD was measured at baseline and 1 year. HRQL was assessed 3-monthly using the RAND 36-Item Health Survey and University of California Los Angeles Prostate Cancer Index questionnaires. Bone turnover markers, liver function tests, prostate-specific antigen, testosterone, oestradiol and haemoglobin were measured at baseline, at 3 weeks and 3-monthly thereafter. Arm anthropometry and dynamometry assessed fat mass, skeletal muscle mass and quadriceps strength. RESULTS: • BMD was maintained (+2.1% lumbar spine, +1.2% total hip and +1.1% forearm). Prostate-specific antigen decreased by 88% at 3 months. Testosterone and oestradiol had increased at 1 year by 58% and 42%, respectively. No increase in bone turnover markers was seen over 1 year. Quadriceps muscle strength was maintained. General and prostate cancer-specific HRQL were maintained throughout the study, with no significant reductions in physical or sexual function. Adverse events included breast pain and gynaecomastia. CONCLUSIONS: • Bicalutamide preserves BMD, muscle strength and HRQL in osteoporotic men with non-metastatic locally advanced prostate cancer. It provides an alternative to medical castration for well informed men at high fracture risk and those wishing to retain physical and sexual activity, with luteinizing hormone-releasing hormone agonists being reserved for those failing to respond or relapsing.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Anilidas/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Nitrilas/uso terapêutico , Osteoporose/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Compostos de Tosil/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Métodos Epidemiológicos , Humanos , Masculino , Osteoporose/complicações , Neoplasias da Próstata/complicações , Qualidade de Vida , Resultado do Tratamento
9.
BJU Int ; 105(8): 1082-8, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19912210

RESUMO

OBJECTIVE: To evaluate the efficacy of zoledronic acid (ZA) in osteoporotic patients with prostate cancer receiving either luteinizing hormone-releasing hormone agonists (LHRHA, which accelerate bone loss) or bicalutamide (which preserves bone mineral density, BMD) as androgen-deprivation therapy is the mainstay of treatment for advanced prostate cancer, and many patients are osteoporotic at presentation, with others becoming so on treatment. PATIENTS AND METHODS: Fifty-eight osteoporotic men with non-metastatic prostate cancer were followed for 3 years. Patients were randomly assigned to receive either LHRHA (29) or bicalutamide (29). All received 4 mg ZA 3-monthly for 1 year. BMD was measured by dual energy X-ray absorptiometry at four times: 1 year before ZA; immediately before ZA; after five infusions; and 1 year afterwards. Bone turnover markers (BTMs) were measured at 3-monthly intervals on ZA and 1 year later. All patients had radiography of the thoracolumbar spine at baseline and after ZA. RESULTS: Patients on LHRHA showed a 4.9% decrease in BMD before ZA, a 1.6% increase after ZA and a 3.0% decrease 1 year later, compared to 2.0% increase, 7.8% increase and 1.9% decrease, respectively, in those on bicalutamide. BTMs decreased significantly after ZA. Seven patients (12%) had vertebral fractures at baseline, with none deteriorating at 1 year; two (3.5%) developed mandibular osteonecrosis. CONCLUSION: Before ZA, BMD decreased on LHRHA, but was maintained on bicalutamide. Treatment with 3-monthly ZA increased BMD and suppressed BTMs in osteoporotic patients both on LHRHA and bicalutamide, but to a greater extent in the latter. However, 1 year after the last infusion, BMD declined, suggesting that annual administration is inadequate in these patients. The optimum frequency might be related to BMD at time of bisphosphonate initiation.


Assuntos
Antagonistas de Androgênios/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Osteoporose/prevenção & controle , Neoplasias da Próstata/tratamento farmacológico , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Anilidas/efeitos adversos , Seguimentos , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Osteoporose/induzido quimicamente , Estudos Prospectivos , Compostos de Tosil/efeitos adversos , Ácido Zoledrônico
10.
JNCI Cancer Spectr ; 4(2): pkz093, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32328561

RESUMO

BACKGROUND: Bromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors. METHODS: This was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 + 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker. RESULTS: Sixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60-100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%-42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t1/2: 3-7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months. CONCLUSIONS: Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC.

11.
BJU Int ; 104(6): 800-5, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19338564

RESUMO

OBJECTIVE: To study the long-term effects of androgen-deprivation therapy (ADT) using luteinizing hormone-releasing hormone (LHRH) agonists or antiandrogen therapy with bicalutamide on bone mineral density (BMD) of selected groups of patients with newly diagnosed advanced prostate cancer, stratified by BMD at presentation and to predict alterations in fracture risk. PATIENTS AND METHODS: In all, 618 men with a mean (sd, range) age of 73 (7.1, 49-94) years, initiating ADT for prostate cancer were prospectively recruited and followed from October 1999 to January 2007. BMD was measured by forearm dual-energy X-ray absorptiometry (DEXA) before ADT and repeated annually. Patients with osteoporosis (T-score < or =-2.5) were commenced on bicalutamide; patients with osteopenia (T-score between -1.0 and -2.5) and normal BMD (T-score > -1.0) were commenced on an LHRH agonist. Patients with osteopenia and osteoporosis received calcium and vitamin D supplements. RESULTS: Over 7 years, 1690 DEXA scans were performed. In all, 41% of patients with newly diagnosed prostate cancer were osteoporotic, 39% were osteopenic and 20% had normal BMD. In the normal group, treated with an LHRH agonist, there were significant decreases in BMD (1 year 1.2%; 2 year 3.7%; 3 year 6.5%; 4 year 8.9%; 5 year 9.9%; 6 year 12.7%), which also occurred in the patients with osteopenia with 60% developing osteoporosis after 2 years (1 year 1.8%; 2 year 5.1%; 3 year 8.0%; 4 year 8.2%; 5 year 11.5%; 6 year 14.1%). By contrast, the osteoporotic group maintained BMD (1 year 0.5%; 2 year 0%; 3 year +1.2%; 4 year 0.5%; 5 year 1.7%; 6 year 2.2%). CONCLUSION: Patients treated with an LHRH agonist have significant and sustained decreases in BMD, whereas bicalutamide maintains BMD. We advocate routine assessment of BMD before ADT, with surveillance thereafter.


Assuntos
Antagonistas de Androgênios/efeitos adversos , Anilidas/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/induzido quimicamente , Fraturas Ósseas/induzido quimicamente , Nitrilas/efeitos adversos , Neoplasias da Próstata/tratamento farmacológico , Compostos de Tosil/efeitos adversos , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , Anilidas/uso terapêutico , Cálcio/uso terapêutico , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Estudos Prospectivos , Neoplasias da Próstata/complicações , Neoplasias da Próstata/fisiopatologia , Fatores de Risco , Fatores de Tempo , Compostos de Tosil/uso terapêutico , Vitamina D/uso terapêutico
13.
Int Med Case Rep J ; 8: 29-31, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25653561

RESUMO

The ileal conduit for urinary diversion after radical cystectomy is a well-described procedure. Furthermore, parastomal hernias, prolapse, stenosis, and retraction of the stoma have been reported as some of the more common complications of this procedure. The subsequent repair of parastomal hernias with a biological mesh and the potential of the conduit to "tunnel" through it has also been described. In this case report, we present a combined repair of a large incisional hernia with a cystectomy and a pelvic lymphadenectomy for invasive bladder cancer, with the use of a biological mesh for posterior component abdominal wall primary repair as well as for support to the ileal conduit used for urinary diversion.

14.
J Med Chem ; 58(18): 7381-99, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-26301626

RESUMO

Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.


Assuntos
Indazóis/química , Oxazóis/química , Inibidores de Fosfoinositídeo-3 Quinase , Doenças Respiratórias/tratamento farmacológico , Sulfonamidas/química , Administração por Inalação , Animais , Asma/tratamento farmacológico , Feminino , Humanos , Indazóis/farmacocinética , Indazóis/farmacologia , Indóis , Isoenzimas/antagonistas & inibidores , Masculino , Microssomos/metabolismo , Simulação de Acoplamento Molecular , Ovalbumina/imunologia , Oxazóis/farmacocinética , Oxazóis/farmacologia , Piperazinas , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Coelhos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Células Th2/imunologia
15.
Urology ; 73(6): 1347-51, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19362345

RESUMO

OBJECTIVES: To compare aDEXA and pDEXA in patients with advanced prostate cancer (PCa) undergoing androgen deprivation therapy (ADT). A significant proportion of patients presenting with advanced PCa are osteoporotic, and many will become so because of ADT. Guidelines have recommended bone densitometry assessment before beginning ADT, with subsequent monitoring. However, axial dual energy x-ray absorptiometry (aDEXA) scanners, being large, expensive, and hospital-based, are not always widely available. Peripheral DEXA (pDEXA), with portable, office-based machines can be used, but the results have mostly been compared with aDEXA in women without cancer. METHODS: A total of 73 men (mean age 76 years) with advanced PCa, who were receiving ADT and found to be osteoporotic (T score

Assuntos
Absorciometria de Fóton/métodos , Antagonistas de Androgênios/efeitos adversos , Osteoporose/induzido quimicamente , Osteoporose/diagnóstico , Neoplasias da Próstata/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade
16.
Cases J ; 2: 6422, 2009 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-19829803

RESUMO

INTRODUCTION: Urachal cyst is one of a spectrum of urachal abnormalities most commonly found in children. They are very rarely seen in adults because the urachus is normally obliterated in early infancy. CASE PRESENTATION: We describe a case of a 32 year old male Caucasian who presented with a tender, midline, infraumbilical mass and purulent umbilical discharge. Diagnosis of an infected urachal cyst was confirmed on magnetic resonance scan. He was treated initially with broad spectrum antibiotics in order to allow sepsis to resolve prior to surgical excision of the cyst and fibrous tract. Cystoscopy was performed intraoperatively to exclude sinus communication with the bladder. Histology of the excised specimen showed chronic inflammation with no evidence of malignancy. Postoperative recovery was uneventful. CONCLUSION: Urachal abnormalities are rare in adults. Clinical presentation is non-specific; therefore, a high index of suspicion is required in order to make the diagnosis. When diagnosed, surgical excision is advised because of the risk of malignant transformation.

17.
J Med Case Rep ; 3: 4, 2009 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-19126202

RESUMO

INTRODUCTION: Extramammary Paget's disease is a rare cutaneous, slow growing, intraepithelial adenocarcinoma developing in the apocrine gland-bearing areas. Isolated Paget's disease of the penis is extremely rare. CASE PRESENTATION: We describe the case of an 87-year-old Caucasian male who presented with a non-healing erythematous plaque on the shaft of the penis previously misdiagnosed as Bowen's disease. The diagnosis was made histologically on the excised specimen and was supported by immunohistochemical staining. CONCLUSION: Extramammary Paget's disease is a rare disease which can mimic various types of dermatosis. A high index of suspicion is required, combined with biopsy and immunohistochemical staining in order to make the correct diagnosis. Long-term follow-up is mandatory in these patients in order to identify and treat any subsequent recurrence or concurrent malignancy.

19.
Urology ; 74(5): 1152-4, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19758681

RESUMO

OBJECTIVES: To identify any potentially harmful chemical constituents of the gaseous plume produced from urological endoscopic diathermy. METHODS: Chemical analysis was performed on the gaseous plume produced from prostatic resections and vaporizations using gas chromatography with mass spectroscopy and high-performance liquid chromatography using ultraviolet and visible light detection. In addition, carbon monoxide levels were analyzed using a portable catalytic flammable gas sensor. RESULTS: This study identified a cocktail of volatile organic hydrocarbons produced during these procedures, some of which are known carcinogens. The most significant finding being high levels of carbon monoxide. CONCLUSIONS: From this preliminary study, we advocate the use of smoke evacuator systems for all urologists regularly performing these procedures, and suggest that further research is required to investigate potential long-term complications to the urologist.


Assuntos
Eletrocoagulação , Endoscopia , Gases/análise , Exposição Ocupacional/análise , Ressecção Transuretral da Próstata , Urologia , Humanos
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