RESUMO
BACKGROUND AND AIMS: Testicular Germ Cell Tumours (TGCTs) are the commonest young adult male cancer, with excellent survival outcomes even with metastatic disease. Chemotherapy, radiotherapy, and surgery are international guideline-dictated standard of care (SOC) treatments for International Germ Cell Cancer Collaborative Group (IGCCCG) "good risk" TGCT, but are associated with significant toxicities. Therapy de-escalation aims to reduce treatment morbidity whilst preserving cure rates, and has been adopted by some centres for stage IIA/B seminoma. Here, we report on the contemporary UK treatment landscape for stage IIA/B seminoma. METHODS: A questionnaire-based survey of NHS England-designated specialist cancer centres hosting supra-regional specialist multi-disciplinary team (sMDT) services (n = 13) as well those within NHS Scotland, NHS Wales and Health and Social Care Northern Ireland. Respondents were asked to order preferences of SOC and therapy de-escalation treatments for stage IIA/B seminoma. RESULTS: We identified significant geographical heterogeneity in treatment preferences. Whilst up to a third of centres have adopted a treatment de-escalation regimen, the majority deliver combination chemotherapy or radiotherapy. CONCLUSION: A wider recognition of UK treatment heterogeneity and consideration of therapy de-escalation strategies at supra-regional sMDTs will increase stage IIA/B seminoma treatment options as part of clinical trials with oncological and quality of life endpoints.
Assuntos
Seminoma , Neoplasias Testiculares , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas , Qualidade de Vida , Seminoma/patologia , Seminoma/terapia , Neoplasias Testiculares/tratamento farmacológico , Reino Unido/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic. DESIGN: We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval. RESULTS: Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%. CONCLUSIONS: Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required.
Assuntos
COVID-19 , Colonoscopia , Neoplasias Colorretais , Infecção Hospitalar/prevenção & controle , Diagnóstico Tardio , Sangue Oculto , Medição de Risco/métodos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Colonoscopia/métodos , Colonoscopia/normas , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Procedimentos Clínicos , Diagnóstico Tardio/efeitos adversos , Diagnóstico Tardio/estatística & dados numéricos , Detecção Precoce de Câncer , Humanos , Imunoquímica/métodos , Controle de Infecções/métodos , Tábuas de Vida , Mortalidade , SARS-CoV-2 , Reino Unido/epidemiologiaRESUMO
BACKGROUND: During the COVID-19 lockdown, referrals via the 2-week-wait urgent pathway for suspected cancer in England, UK, are reported to have decreased by up to 84%. We aimed to examine the impact of different scenarios of lockdown-accumulated backlog in cancer referrals on cancer survival, and the impact on survival per referred patient due to delayed referral versus risk of death from nosocomial infection with severe acute respiratory syndrome coronavirus 2. METHODS: In this modelling study, we used age-stratified and stage-stratified 10-year cancer survival estimates for patients in England, UK, for 20 common tumour types diagnosed in 2008-17 at age 30 years and older from Public Health England. We also used data for cancer diagnoses made via the 2-week-wait referral pathway in 2013-16 from the Cancer Waiting Times system from NHS Digital. We applied per-day hazard ratios (HRs) for cancer progression that we generated from observational studies of delay to treatment. We quantified the annual numbers of cancers at stage I-III diagnosed via the 2-week-wait pathway using 2-week-wait age-specific and stage-specific breakdowns. From these numbers, we estimated the aggregate number of lives and life-years lost in England for per-patient delays of 1-6 months in presentation, diagnosis, or cancer treatment, or a combination of these. We assessed three scenarios of a 3-month period of lockdown during which 25%, 50%, and 75% of the normal monthly volumes of symptomatic patients delayed their presentation until after lockdown. Using referral-to-diagnosis conversion rates and COVID-19 case-fatality rates, we also estimated the survival increment per patient referred. FINDINGS: Across England in 2013-16, an average of 6281 patients with stage I-III cancer were diagnosed via the 2-week-wait pathway per month, of whom 1691 (27%) would be predicted to die within 10 years from their disease. Delays in presentation via the 2-week-wait pathway over a 3-month lockdown period (with an average presentational delay of 2 months per patient) would result in 181 additional lives and 3316 life-years lost as a result of a backlog of referrals of 25%, 361 additional lives and 6632 life-years lost for a 50% backlog of referrals, and 542 additional lives and 9948 life-years lost for a 75% backlog in referrals. Compared with all diagnostics for the backlog being done in month 1 after lockdown, additional capacity across months 1-3 would result in 90 additional lives and 1662 live-years lost due to diagnostic delays for the 25% backlog scenario, 183 additional lives and 3362 life-years lost under the 50% backlog scenario, and 276 additional lives and 5075 life-years lost under the 75% backlog scenario. However, a delay in additional diagnostic capacity with provision spread across months 3-8 after lockdown would result in 401 additional lives and 7332 life-years lost due to diagnostic delays under the 25% backlog scenario, 811 additional lives and 14â873 life-years lost under the 50% backlog scenario, and 1231 additional lives and 22â635 life-years lost under the 75% backlog scenario. A 2-month delay in 2-week-wait investigatory referrals results in an estimated loss of between 0·0 and 0·7 life-years per referred patient, depending on age and tumour type. INTERPRETATION: Prompt provision of additional capacity to address the backlog of diagnostics will minimise deaths as a result of diagnostic delays that could add to those predicted due to expected presentational delays. Prioritisation of patient groups for whom delay would result in most life-years lost warrants consideration as an option for mitigating the aggregate burden of mortality in patients with cancer. FUNDING: None.
Assuntos
Infecções por Coronavirus/epidemiologia , Neoplasias/mortalidade , Pneumonia Viral/epidemiologia , Encaminhamento e Consulta , Listas de Espera , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , COVID-19 , Inglaterra , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Neoplasias/diagnóstico , Pandemias , SARS-CoV-2 , Análise de SobrevidaRESUMO
The recognition of cancer cells by T cells can impact upon prognosis and be exploited for immunotherapeutic approaches. This recognition depends on the specific interaction between antigens displayed on the surface of cancer cells and the T cell receptor (TCR), which is generated by somatic rearrangements of TCR α- and ß-chains (TCRb). Our aim was to assess whether ultra-deep sequencing of the rearranged TCRb in DNA extracted from unfractionated clear cell renal cell carcinoma (ccRCC) samples can provide insights into the clonality and heterogeneity of intratumoural T cells in ccRCCs, a tumour type that can display extensive genetic intratumour heterogeneity (ITH). For this purpose, DNA was extracted from two to four tumour regions from each of four primary ccRCCs and was analysed by ultra-deep TCR sequencing. In parallel, tumour infiltration by CD4, CD8 and Foxp3 regulatory T cells was evaluated by immunohistochemistry and correlated with TCR-sequencing data. A polyclonal T cell repertoire with 367-16 289 (median 2394) unique TCRb sequences was identified per tumour region. The frequencies of the 100 most abundant T cell clones/tumour were poorly correlated between most regions (Pearson correlation coefficient, -0.218 to 0.465). 3-93% of these T cell clones were not detectable across all regions. Thus, the clonal composition of T cell populations can be heterogeneous across different regions of the same ccRCC. T cell ITH was higher in tumours pretreated with an mTOR inhibitor, which could suggest that therapy can influence adaptive tumour immunity. These data show that ultra-deep TCR-sequencing technology can be applied directly to DNA extracted from unfractionated tumour samples, allowing novel insights into the clonality of T cell populations in cancers. These were polyclonal and displayed ITH in ccRCC. TCRb sequencing may shed light on mechanisms of cancer immunity and the efficacy of immunotherapy approaches.
Assuntos
Carcinoma de Células Renais/imunologia , Neoplasias Renais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Subpopulações de Linfócitos T/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Células Clonais/imunologia , DNA de Neoplasias/genética , Feminino , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T/imunologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Imunidade Celular , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
International Germ Cell Cancer Collaborative Group good-risk metastatic seminoma has cure rates of >95%. Within this risk group, patients with stage II disease exhibit the best oncological outcomes with the standard-of-care treatment strategies of radiotherapy or combination chemotherapy. However, these treatments can be associated with substantial early and late toxic effects. Therapy de-escalation aims to reduce treatment morbidity whilst preserving oncological outcomes. The evidence supporting such approaches is largely from non-randomized institutional data, and therefore this strategy is not recognized as standard of care. Current de-escalation approaches for stage II seminoma include single-agent chemotherapy, radiotherapy and surgery based on early data from clinical studies. Increased recognition of emerging data on treatment modification to reduce morbidity whilst maintaining cure rates and consideration of therapy de-escalation could improve patient survivorship outcomes.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Seminoma , Neoplasias Testiculares , Masculino , Humanos , Seminoma/terapia , Neoplasias Testiculares/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Quimioterapia Adjuvante , Fatores de Risco , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Retroperitoneal lymph node dissection (RPLND) is essential for the treatment of metastatic germ cell tumours of the testis. Recommendations on the referral and management of complex urological cancers in the UK includes centralisation of services to regional centres. OBJECTIVE: To review contemporary PC-RPLND outcomes at a high-volume centre with a complex case-mix, and compare with national registry data. DESIGN SETTING AND PARTICIPANTS: We retrospectively reviewed the medical records of PC-RPLNDs performed for germ cell tumours at our centre between July 2012 and September 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcomes were Clavien 3+ complications, histology, rates of positive margin, relapse, in-field recurrences, and mortality. Secondary outcomes were blood loss, operation time, blood transfusion, adjuvant procedures, length of stay, and lymph node count. Surgical and histological outcomes of all RPLNDs for testicular cancers were compared with national RPLND registry data. For statistical difference, χ2 testing was used. RESULTS AND LIMITATIONS: A total of 178 procedures were performed, including 31 (17%) redo RPLNDs. Clavien 3+ complications occurred in 11 (7%). Histological findings in non-redo cases were the following: necrosis 24%, teratoma 62%, viable germ cell tumour 11%, and dedifferentiated cancers 3%. Rates of positive margin, relapse, and in-field recurrence were 11%, 17%, and 2%, respectively. Overall survival was 89% at a median of 36 mo. The median blood loss was 650 ml (350, 1250), with a transfusion rate of 8%. Nephrectomy, vascular reconstruction, and visceral resection was required in 12%, 6%, and 3% respectively. The median inpatient stay was 6 d (5, 8) and the median node count was 35 (20, 37). A comparison of all RPLNDs with national data showed no statistical difference in primary outcomes. Our blood transfusion rate was significantly lower (12% vs 21%, χ2 [1, N = 322] = 4.296, p = 0.038). CONCLUSIONS: Centralisation led to high quality of RPLND in UK. Within that, our series (the largest in the UK) demonstrates no significant difference in outcomes despite higher complexity cases. Our blood transfusion rates are in fact lower than national figures. Complex RPLNDs should be performed in high-volume centres where possible. PATIENT SUMMARY: In the UK, retroperitoneal lymph node dissections (RPLND) are centralised to specialist centres and the quality of surgery is high, with low complications and good histological outcomes. When compared to national data, we found no significant difference in the majority of outcomes from our high-volume centre despite our complex case-mix.
RESUMO
BACKGROUND: Late relapse (LR) of nonseminomatous germ cell tumour (NSGCT) is uncommon, with limited data published. LR is defined as relapse occurring after a disease-free interval of 2 yr. OBJECTIVE: To review features of NSGCT LR in a UK tertiary centre. DESIGN SETTING AND PARTICIPANTS: A total of 3064 patients were referred from January 2005 to December 2017. We identified patients who experienced LR after initial pathology demonstrated NSGCT and reviewed data for their original and LR presentation and management. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes included time to LR measured from the date of diagnosis, and overall survival. This was assessed using Cox proportional Hazards modelling, with stratification or adjustment for potential confounders. RESULTS AND LIMITATIONS: We identified 101 patients with LR; the median time to LR was 96 mo. Forty-three patients (42.6%) experienced relapse after 10 yr. Univariable log-rank testing revealed that the median time to LR was significantly shorter for patients who had not received induction chemotherapy (iCTx; 54 mo, 95% confidence interval [CI] 48-108) than for those who did (112 mo, 95% CI 84-186; p = 0.04). Patients who had received iCTx were less likely to have elevated tumour markers (36% vs 46%) and more likely to undergo initial surgical resection at LR compared to CTx-naïve patients. Postpubertal teratoma (PPT), yolk sac, and dedifferentiated elements predominated for patients with iCTx exposure, whereas active GCT or fibrosis predominated in postchemotherapy resections for CTx-naïve patients at LR. Forty-one men underwent postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) as part of their initial treatment for metastatic disease. Of these, 20 experienced LR in the retroperitoneum, with 18 undergoing repeat RPLND as part of their LR management. Fifteen of the repeat RPLND histopathology specimens had a PPT component. There have been 23 deaths overall; survival was worse for patients presenting with symptoms (13/36, 33%) and those receiving CTx and no surgery (10/17, 59%) at LR. CONCLUSIONS: When LR of NSGCT occurs, it is frequently after an extended interval and is later among patients with prior iCTx, with PPT predominating. The high frequency of LR within the retroperitoneum following PC-RPLND reinforces the need for good-quality PC-RPLND. PATIENT SUMMARY: We reviewed data for patients who had a late relapse of testicular cancer. We found that patients who did not receive chemotherapy as the first treatment for their initial diagnosis had a shorter time to relapse. Our results highlight the importance of long-term follow-up for testicular cancer.
RESUMO
PSA-RP2 is a variant transcript expressed from the PSA gene that is conserved in gorillas, chimpanzees and humans suggesting a particular relevance for this transcript in these primates. We demonstrated by qRT-PCR that PSA-RP2 is upregulated in prostate cancer compared with benign prostatic hyperplasia tissues. The PSA-RP2 protein was not detected in seminal fluid and was cytoplasmically localised but not secreted from LNCaP or transfected PC3 prostate cells, despite secretion from transfected Cos-7 and HEK293 kidney cell lines. PSA-RP2-transfected PC3 cells showed slightly decreased proliferation and increased migration towards PC3-conditioned medium that could suggest a functional role in prostate cancer.
Assuntos
Regulação Neoplásica da Expressão Gênica , Antígeno Prostático Específico/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Sequência de Aminoácidos , Linhagem Celular Tumoral , Humanos , Masculino , Dados de Sequência Molecular , Antígeno Prostático Específico/química , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transporte ProteicoRESUMO
We report the outcomes of renal transplant patients (n = 43) who received grafts from donors (n = 41) with small (<3 cm) renal tumours removed before transplantation covering the period from May 1996 to September 2007. Patient and graft survival were compared with the outcomes of conventional live unrelated transplants (LURTs) (n = 120) and to patient survival on the transplant waiting list for those who did not receive a kidney during this period (n = 153). Patient survival at 1, 3 and 5 years were 92%, 88% and 88% for recipients of tumourectomized kidneys (TKs), 99%, 97% and 97% for LURTs, and 98%, 92% and 74% for dialysis patients waiting for a deceased donor kidney (log rank score 10.4, P = 0.005). One patient experienced a local tumour recurrence at 9 years following transplantation. This patient declined intervention and is currently under active surveillance. Transplantation of tumourectomized kidneys from patients with small, localized, incidentally detected renal tumours results in similar outcomes to conventional LURTs and confers a significant survival advantage for patients who would otherwise be unable to receive a transplant.
Assuntos
Neoplasias Renais/diagnóstico , Neoplasias Renais/terapia , Transplante de Rim/métodos , Adulto , Idoso , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Falência Renal Crônica/terapia , Neoplasias Renais/mortalidade , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Diálise Renal , Obtenção de Tecidos e Órgãos , Resultado do Tratamento , Listas de EsperaAssuntos
Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Pesquisa Translacional Biomédica/organização & administração , Urologia/organização & administração , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/etiologia , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/etiologiaRESUMO
BACKGROUND: Post-transplant anaemia remains a common problem after kidney transplantation, with an incidence ranging from nearly 80% at day 0 to about 25% at 1 year. It has been associated with poor graft outcome, and recently has also been shown to be associated with increased mortality.Our transplant unit routinely administers oral iron supplements to renal transplant recipients but this is frequently accompanied by side effects, mainly gastrointestinal intolerance. Intravenous iron is frequently administered to dialysis patients and we sought to investigate this mode of administration in transplant recipients after noticing less anaemia in several patients who had received intravenous iron just prior to being called in for transplantation. METHODS: This study is a single-centre, prospective, open-label, randomised, controlled trial of oral versus intravenous iron supplements in renal transplant recipients and aims to recruit approximately 100 patients over a 12-month period. Patients will be randomised to receive a single dose of 500 mg iron polymaltose (intravenous iron group) or 2 ferrous sulphate slow-release tablets daily (oral iron group). The primary outcome is time to normalisation of haemoglobin post-transplant. Prospective power calculations have indicated that a minimum of 48 patients in each group would have to be followed up for 3 months in order to have a 90% probability of detecting a halving of the time to correction of haemoglobin levels to > or =110 g/l in iron-treated patients, assuming an alpha of 0.05. All eligible adult patients undergoing renal transplantation at the Princess Alexandra Hospital will be offered participation in the trial. Exclusion criteria will include iron overload (transferrin saturation >50% or ferritin >800 microg/l), or previous intolerance of either oral or intravenous iron supplements. DISCUSSION: If the trial shows a reduction in the time to correction of anaemia with intravenous iron or less side effects than oral iron, then intravenous iron may become the standard of treatment in this patient group.
Assuntos
Anemia/tratamento farmacológico , Anemia/etiologia , Ferro/administração & dosagem , Ferro/uso terapêutico , Transplante de Rim , Complicações Pós-Operatórias , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Compostos Ferrosos/administração & dosagem , Compostos Ferrosos/efeitos adversos , Compostos Ferrosos/uso terapêutico , Gastroenteropatias/induzido quimicamente , Hemoglobinas/metabolismo , Humanos , Injeções Intravenosas , Ferro/efeitos adversos , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
OBJECTIVE: To report the use of a novel donor source as a further option to increase the number of patients who might be able to receive a renal transplant. PATIENTS AND METHODS: Between May 1996 and July 2007, 43 kidneys were transplanted using kidneys obtained from patients with small (<3 cm diameter) incidentally detected tumours. After bench surgery to excise the tumour, they were all successfully transplanted into patients who were elderly or had significant comorbidities. RESULTS: Apart from four patients who died from unrelated illnesses, all grafts continued to function with a median and mean follow-up of 25 and 32 months. The follow-up, which included 3-monthly renal ultrasonography and chest X-rays, showed only one case of tumour recurrence, which occurred 9 years after transplantation; the patient remains stable under observation after 18 months. CONCLUSIONS: From our experience we consider that where nephrectomy is used for small, localized, incidentally detected renal tumours, the kidney should be considered for transplantation into carefully selected patients. Such patients with numerous medical comorbidities might benefit from renal transplantation, but not survive the waiting period if they are dependent on a deceased donor graft. Paradoxically the use of these marginal kidneys has the potential to increase the quality and length of life of these patients, despite the apparent contradiction of an intuitive principle of organ transplantation and immunosuppression.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Transplante de Rim/métodos , Obtenção de Tecidos e Órgãos/métodos , Idoso , Cadáver , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Humanos , Achados Incidentais , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Transplante de Rim/normas , Doadores Vivos , Pessoa de Meia-Idade , Nefrectomia/métodos , Estudos Prospectivos , Obtenção de Tecidos e Órgãos/normas , Resultado do TratamentoRESUMO
AIM: While deceased donor kidney transplantation rates have remained stagnant, live donor kidney transplantation (LDKT) rates have increased significantly over the last decade, and are now a major component of renal transplantation programmes worldwide. Additionally, there has been an increased utilization of more marginal donors, including donors who are obese, older and subjects with well-controlled hypertension. METHOD: A retrospective audit of all live donors at the Princess Alexandra Hospital Renal Transplantation unit was performed from 24 August 1982 to 29 May 2007 to assess any change in donor characteristics over time. RESULTS: There were 373 live donor operations. Over the last 25 years there has been a significant increase in the number of donors who are either older or obese. Furthermore, there is a greater proportion of spousal and emotionally related LDKT. CONCLUSION: It is imperative that donors, in particular marginal donors, are followed up long-term to determine their risk of kidney and cardiovascular disease and initiation of appropriate treatment if required.
Assuntos
Transplante de Rim , Doadores Vivos , Adulto , Idoso , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Prostate cancer is associated with significant mortality once the tumour has spread outside the gland. Epithelial-mesenchymal transition (EMT) has been proposed to facilitate this dissemination of tumour cells. In this article we summarize the evidence for EMT in prostate cancer, drawing on the expression of EMT-related markers and the functions of factors known to induce EMT in other systems. We also discuss our recent findings that two members of the tissue kallikrein family of serine proteases, prostate-specific antigen (PSA/KLK3) and kallikrein-related peptidase 4 (KLK4), lead to EMT-like changes in PC3 prostate cancer cells.
Assuntos
Epitélio/patologia , Calicreínas/metabolismo , Mesoderma/patologia , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Animais , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Epitélio/metabolismo , Humanos , Calicreínas/genética , Masculino , Mesoderma/metabolismo , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismoRESUMO
OBJECTIVE: To describe the major imaging features, together with clinical data, of paratesticular sarcomas. MATERIALS AND METHODS: A retrospective analysis was performed of available imaging and clinical data of 77 consecutive cases of paratesticular sarcoma referred to the soft tissue sarcoma center at the Royal Marsden hospital between January 2006 and January 2015. RESULTS: Of the total cases, 87% had been referred postoperatively, 43% of which had been imaged preoperatively and 24% of which required re-resection due to incomplete initial excision. On imaging, abnormal fat was present in 73% of paratesticular liposarcomas, with solid or enhancing components indicating high-grade tumors. Leiomyosarcomas and rhabdomyosarcomas were all purely solid masses. CONCLUSION: Paratesticular sarcomas are rare, and lack of awareness may compromise treatment and outcome. They may be mistaken for common clinical problems such as inguinal hernias and epididymal cysts. Surgery for these presumed diagnoses may result in inadequate clearance and an increased risk of recurrence. A low threshold for imaging atypical paratesticular masses is needed, as this may better inform management.
Assuntos
Neoplasias dos Genitais Masculinos/diagnóstico por imagem , Neoplasias dos Genitais Masculinos/patologia , Sarcoma/diagnóstico por imagem , Sarcoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Genitais Masculinos/terapia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Retrospectivos , Sarcoma/terapia , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
BACKGROUND: Current clinical practice guidelines recommend that no particular type of peritoneal dialysis (PD) catheter has been proved superior to another. However, a recent Cochrane review recommended the need for a large, well-designed, randomized, controlled trial of straight versus coiled PD catheters because of the paucity and suboptimal quality of previously performed trials. METHODS: A randomized controlled trial was undertaken at 2 metropolitan teaching hospitals comparing the effects of straight versus coiled PD catheters on time to catheter malposition (primary outcome), catheter-associated infection, technique failure, and all-cause mortality. RESULTS: One hundred thirty-two PD patients were enrolled and randomly assigned to insertion of a coiled (n = 62) or straight catheter (n = 70). There was no significant difference in time to laparoscopic reposition between the 2 cohorts (log-rank score, 0.41; P = 0.52). However, median technique survival was significantly worse for coiled catheters (1.5 years; 95% confidence interval [CI], 1.2 to 1.8) compared with straight catheters (2.1 years; 95% CI, 1.8 to 2.5; P < 0.05), primarily because of increased risk for inadequate dialytic clearance with the former. On univariate Cox proportional hazards model analysis, insertion of a coiled PD catheter was associated significantly with a greater risk for technique failure (unadjusted hazard ratio, 1.86; 95% CI, 1.03 to 3.36). No difference was observed between the 2 groups with respect to catheter-associated infections or overall patient survival. CONCLUSION: Coiled catheters do not influence the risk for drainage failure caused by catheter malposition compared with straight catheters, but are associated with significantly increased risk for PD technique failure, primarily because of inadequate dialytic clearance.
Assuntos
Cateterismo , Diálise Peritoneal/instrumentação , Idoso , Cateterismo/efeitos adversos , Drenagem/instrumentação , Desenho de Equipamento , Falha de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Peritoneal/efeitos adversos , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Tempo , Falha de TratamentoRESUMO
OBJECTIVE: The aim of this study was to assess the effect of clean intermittent self-catheterization (CISC) on stricture recurrence. MATERIALS AND METHODS: The incidence of stricture recurrence was assessed retrospectively in a group of 126 new patients treated endoscopically for urethral stricture in a general urological setting between 1994 and 2001, of whom 31 performed twice-weekly CISC and 95 did not. Stricture recurrence was defined as recurrent symptomatic stricture requiring further operative intervention following initial intervention. The mean follow-up available was 25 months (range 1-132 months). RESULTS: Of the 126 patients assessed, 60 (47.6%) developed recurrent stricture and required an average of 3.13 endoscopic retreatments each during the follow-up period. There was no significant difference (chi-squared p = 0.46) between the number of stricture recurrences in those performing CISC (13-41.9%) and those not performing CISC (47-49.5%). CONCLUSION: CISC does not appear to prevent medium-term stricture recurrence.
Assuntos
Cateterismo Uretral Intermitente/métodos , Estreitamento Uretral/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Endoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios/métodos , Recidiva , Reoperação , Estudos Retrospectivos , Estreitamento Uretral/cirurgia , Procedimentos Cirúrgicos Urológicos , Adulto JovemRESUMO
Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. Here we sequence the genomes or exomes of 31 pRCCs, and in four tumours, multi-region sequencing is undertaken. We identify BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together with at least eight other possible drivers. However, only ~10% of tumours harbour detectable pathogenic changes in any one driver gene, and where present, the mutations are often predicted to be present within cancer sub-clones. We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour. By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution. The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches.
Assuntos
Carcinoma de Células Renais/genética , Cromossomos/ultraestrutura , Neoplasias Renais/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/química , Mapeamento Cromossômico , Variações do Número de Cópias de DNA , Exoma , Éxons , Feminino , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Filogenia , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
BACKGROUND: Live donors are an increasingly important source of kidneys for transplantation in Australia. The aim of this study was to compare the rate and severity of rejection between patients receiving kidney transplants from live versus cadaveric donors. METHODS: A retrospective analysis was undertaken of all patients receiving live-donor (n=109) and cadaveric-donor (n=389) renal transplants at our institution between April 1, 1994, and March 31, 2000. Follow-up was completed on all patients until graft loss, death, or May 31, 2001. RESULTS: The baseline characteristics of the live-donor and cadaveric groups were similar, except for recipient age (mean+/-SD, 36.3+/-15.6 vs. 44.5+/-14.4 years, respectively; P<0.001); donor age (46.1+/-11.3 vs. 36.1+/-16.4 years, P<0.001); pretransplant dialysis duration (1.36+/-2.1 vs. 3.4+/-4.4 years, P<0.001); and the proportions of patients receiving first allografts (95% vs. 88%, respectively; P<0.05), antibody induction (8% vs. 20%, P<0.01), and mycophenolate mofetil (MMF) (60% vs. 37%, P<0.001). Acute rejection was observed in 48 (44%) live-donor and 108 (28%) cadaveric transplants (P=0.001). Cadaveric donor type was independently predictive of less acute rejection both on logistic regression (adjusted odds ratio [AOR], 0.47; 95% confidence interval [CI], 0.30-0.73; P=0.001) and multivariate Cox proportional hazards model analysis (hazard ratio, 0.49; 95% CI, 0.34-0.69; P<0.001). Patients receiving cadaveric-donor transplants were also significantly less likely to receive antibody therapy for rejection (univariate, 18% vs. 9%; P=0.006; multivariate AOR, 0.45; 95% CI, -0.25-0.82; P<0.01), independent of recipient age, gender, race, transplant number, human leukocyte antigen mismatch, sensitization, induction therapy, delayed graft function, MMF use, tacrolimus or cyclosporine A use, sirolimus-everolimus use, year of transplant, donor age, or dialysis duration. However, donor type did not independently influence graft survival, immunologic graft survival, or patient survival. CONCLUSIONS: Live-donor kidney transplant recipients had a higher rate and severity of rejection and a shorter rejection-free period than cadaveric renal transplant recipients. Further consideration of the reasons for this difference and the use of alternative immunosuppressive strategies for live-donor transplants are recommended.