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PURPOSE OF REVIEW: This review paper is intended to show that changes in body composition are key in the pathogenesis of bone fragility amongst patients with breast and prostate cancer receiving hormone deprivation therapies (HDTs) and that the mechanism is based on the development of alterations in bone quality rather than in bone quantity. RECENT FINDINGS: Preclinical and clinical data suggest a tight connection amongst bone, adipose and muscular tissues by means of several soluble mediators, potentially leading to (1) bone resorption and bone quality deterioration in sarcopenic obese subjects, (2) bone mineral deposition in healthy trained subjects. Cancer patients treated with HDTs frequently fall into the first condition, named osteosarcopenic obesity. Current clinical guidelines for the prevention of treatment-induced osteoporosis focus on bone mineral density (BMD) as a main predictive factor for fracture risk; however, the pathophysiology underlying HDT-induced bone fragility differs from that of primary and postmenopausal osteoporosis, suggesting a prevalent role for bone quality alterations. Focusing on available data from clinical trials, in our review we suggest osteosarcopenic obesity as a common target for the prevention and treatment of HDTs-related metabolic and skeletal complications, beyond a BMD-centred approach.
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PURPOSE: To retrospectively review our 20 year experience of multidisciplinary management of non-metastatic ductal prostate cancer (dPC), a rare but aggressive histological subtype of prostate cancer whose optimal therapeutic approach is still controversial. METHODS: Histologically confirmed dPC patients undergoing primary, curative treatment [radical prostatectomy (RP), external beam radiotherapy (EBRT), and androgen deprivation therapy (ADT)] were included, and percentage of ductal and acinar pattern within prostate samples were derived. Survival outcomes were assessed using the subdistribution hazard ratio (SHR) and Fine-and-Gray model. RESULTS: From January 1997 to December 2016, 81 non-metastatic dPC fitted selection criteria. Compared to surgery alone, SHR for progression-free survival and cancer-specific mortality were 2.8 (95% CI 0.6-13.3) and 1.3 (95% CI 0.1-16.2) for exclusive EBRT, 2.7 (95% CI 0.6-13.0) and 6.5 (95% CI 0.6-69.8) for adjuvant EBRT, 4.9 (95% CI 0.7-35.5) and 5.8 (95% CI 0.5-65.6) for salvage EBRT post-prostatectomy recurrence, and 3.2 (95% CI 0.7-14.0) and 3.9 (95% CI 0.3-44.1) for primary ADT (P = 0.558; P = 0.181), respectively. Comparing multimodal treatment and monotherapy confirmed the above trends. Local recurrence more typically occurred in pure dPC patients, mixed histology more frequently produced metastatic spread (29.6% relapse in total, P = 0.026). CONCLUSION: Albeit some limitations affected the study, our findings support the role of local treatment to achieve better disease control and improve quality of life. Different behavior, with typical local growth in pure dPC, higher distant metastatization in the mixed form, might influence treatment response. Given its poor prognosis, we recommend multidisciplinary management of dPC.
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Adenocarcinoma/terapia , Carcinoma Ductal/terapia , Equipe de Assistência ao Paciente/tendências , Neoplasias da Próstata/terapia , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Oncologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , UrologiaRESUMO
BACKGROUND: The administration of abiraterone acetate (abiraterone) leads to an adrenocorticotropic hormone (ACTH)-driven increase in mineralocorticoid hormones, requiring glucocorticoid supplementation that may stimulate the growth of prostate cancer (PCa). Amiloride is a drug that selectively reduces the aldosterone-sensitive Na+/K+ exchange and could be effective in the management of mineralocorticoid excess syndrome (MCES). METHODS: The efficacy of amiloride + hydrochlorothiazide (HCT) in the clinical management of abiraterone-induced MCES was assessed in 5 consecutive patients with castration-resistant PCa (CRPC). Then, using the in vitro experimental model of PCa cell lines, the possible effects of drugs usually used in the clinical management of CRPC patients on PCa cell viability were investigated. RESULTS: Amiloride/HCT led to a complete disappearance of all clinical and biochemical signs of abiraterone-induced MCES in the 5 treated patients. The in vitro study showed that abiraterone treatment significantly decreased cell viability of both androgen receptor (AR)-expressing VCaP (vertebral-cancer of the prostate) and LNCaP (lymph node carcinoma of the prostate) cells, with no effect on AR-negative PC-3 cells. Prednisolone, spironolactone, and eplerenone increased LNCaP cell viability, while amiloride reduced it. The non-steroid aldosterone antagonist PF-03882845 did not modify PCa cell viability. CONCLUSIONS: The combination of amiloride/HCT was effective in the management of abiraterone-induced MCES. Amiloride did not negatively interfere with the abiraterone inhibition of PCa cell viability in vitro.
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Amilorida/farmacologia , Androstenos/farmacologia , Antineoplásicos/farmacologia , Síndrome de Excesso Aparente de Minerolocorticoides/induzido quimicamente , Síndrome de Excesso Aparente de Minerolocorticoides/tratamento farmacológico , Mineralocorticoides/metabolismo , Androgênios/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Combinação de Medicamentos , Humanos , Hidroclorotiazida/farmacologia , Masculino , Síndrome de Excesso Aparente de Minerolocorticoides/metabolismo , Neoplasias da Próstata/tratamento farmacológicoRESUMO
Idiopathic intracranial hypertension is a variety of intracranial hypertension that is extremely rare in men. Obesity and hypogonadism are the most important predictive factors. Etiological hypotheses include increased central venous pressure, and various hormonal and metabolic changes commonly found in obese patients. We described the case of an obese man with prostate cancer who showed a consistent bodyweight increase during treatment with taxanes and prednisone. He was hospitalized because of a severe loss of vision as a consequence of idiopathic intracranial hypertension. A complete symptom remission was obtained after 3 weeks of anti-edema therapies (steroids, acetazolamide). Castration-resistant prostate cancer is a risk factor for idiopathic intracranial hypertension. Long-term androgen deprivation therapy, bodyweight increase, and fluid retention during chronic steroid administration and taxane chemotherapy might favor the disease onset. This severe complication has a good outcome, and should be suspected in the presence of symptoms and signs of intracranial hypertension.
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Adenocarcinoma/complicações , Neoplasias da Próstata/complicações , Pseudotumor Cerebral/etiologia , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Immune checkpoint inhibitors (ICIs)-based combinations have improved survival outcomes of advanced renal cell carcinoma (RCC) patients and are currently recommended as first-line treatment options. Rheumatoid arthritis (RA) is a systemic autoimmune disease (AD) of unknown etiology characterized by a chronic inflammatory process involving joints and extra-articular organs. Patients with AD are usually excluded from large randomized clinical trials investigating immunotherapeutic drugs. Therefore, little is known about clinical outcomes of patients with a history of RA treated with ICIs in real-world practice. In the present study, we report the clinical outcome of an advanced RCC patient with a history of RA treated with pembrolizumab in combination with axitinib. The patient experienced serious immune-related adverse events (irAEs) and achieved pathological complete response following only one ICI administration. Our case report shows that ICI-based combinations can be administered efficaciously in advanced RCC patients with a history of AD. However, a close monitoring of these patients is required, given the risk of irAEs and clinical exacerbations of symptoms associated with the preexisting AD. Moreover, prospective clinical data are needed to assess the hypothesis of a correlation between the onset of irAEs and AD flares and responses and survival outcomes to ICIs.
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BACKGROUND: Most patients with testicular germ cell tumors (GCTs) are treated with cisplatin (CP)-based chemotherapy. However, some of them may develop CP resistance and therefore represent a clinical challenge. Cyclin-dependent kinase 5 (CDK5) is involved in chemotherapy resistance in different types of cancer. Here, we investigated the possible role of CDK5 and other CDKs targeted by dinaciclib in nonseminoma cell models (both CP-sensitive and CP-resistant), evaluating the potential of the CDK inhibitor dinaciclib as a single/combined agent for the treatment of advanced/metastatic testicular cancer (TC). METHODS: The effects of dinaciclib and CP on sensitive and resistant NT2/D1 and NCCIT cell viability and proliferation were evaluated using MTT assays and direct count methods. Flow cytometry cell-cycle analysis was performed. The protein expression was assessed via Western blotting. The in vivo experiments were conducted in zebrafish embryos xenografted with TC cells. RESULTS: Among all the CDKs analyzed, CDK5 protein expression was significantly higher in CP-resistant models. Dinaciclib reduced the cell viability and proliferation in each cell model, inducing changes in cell-cycle distribution. In drug combination experiments, dinaciclib enhances the CP effect both in vitro and in the zebrafish model. CONCLUSIONS: Dinaciclib, when combined with CP, could be useful for improving nonseminoma TC response to CP.
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Cisplatino , Óxidos N-Cíclicos , Indolizinas , Neoplasias Embrionárias de Células Germinativas , Compostos de Piridínio , Neoplasias Testiculares , Masculino , Animais , Humanos , Cisplatino/farmacologia , Peixe-Zebra , Proliferação de Células , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Background: Among its extragonadal effects, follicle-stimulating hormone (FSH) has an impact on body composition and bone metabolism. Since androgen deprivation therapy (ADT) has a profound impact on circulating FSH concentrations, this hormone could potentially be implicated in the changes of fat body mass (FBM), lean body mass (LBM), and bone fragility induced by ADT. The objective of this study is to correlate FSH serum levels with body composition parameters, bone mineral density (BMD), and bone turnover markers at baseline conditions and after 12 months of ADT. Methods: Twenty-nine consecutive non-metastatic prostate cancer (PC) patients were enrolled from 2017 to 2019 in a phase IV study. All patients underwent administration of the luteinizing hormone-releasing hormone antagonist degarelix. FBM, LBM, and BMD were evaluated by dual-energy x-ray absorptiometry at baseline and after 12 months of ADT. FSH, alkaline phosphatase, and C-terminal telopeptide of type I collagen were assessed at baseline and after 6 and 12 months. For outcome measurements and statistical analysis, t-test or sign test and Pearson or Spearman tests for continuous variables were used when indicated. Results: At baseline conditions, a weak, non-significant, direct relationship was found between FSH serum levels and FBM at arms (r = 0.36) and legs (r = 0.33). Conversely, a stronger correlation was observed between FSH and total FBM (r = 0.52, p = 0.006), fat mass at arms (r = 0.54, p = 0.004), and fat mass at trunk (r = 0.45, p = 0.018) assessed after 12 months. On the other hand, an inverse relationship between serum FSH and appendicular lean mass index/FBM ratio was observed (r = -0.64, p = 0.001). This is an ancillary study of a prospective trial and this is the main limitation. Conclusions: FSH serum levels after ADT could have an impact on body composition, in particular on FBM. Therefore, FSH could be a promising marker to monitor the risk of sarcopenic obesity and to guide the clinicians in the tailored evaluation of body composition in PC patients undergoing ADT. Funding: This research was partially funded by Ferring Pharmaceuticals. The funder had no role in design and conduct of the study, collection, management, analysis, and interpretation of the data and in preparation, review, or approval of the manuscript. Clinical trial number: clinicalTrials.gov NCT03202381, EudraCT Number 2016-004210-10.
Treatments given to cancer patients can cause negative side effects. For example, a treatment known as androgen deprivation therapy which is used to reduce male sex hormone levels in prostate cancer patients can lead to increased body fat percentage and decreased bone density. These adverse effects can have further negative impacts on patient health, such as increasing the risk of cardiovascular disease and fractures from falls from standing height or less, respectively. Understanding how androgen deprivation therapy contributes to these negative side effects may help clinicians better manage care and outcomes for patients with prostate cancer. Follicle stimulating hormone (or FSH for short) has roles in male and female reproduction but has also been linked to changes in body composition. For example, elevated FSH levels are associated with higher total fat body mass in post-menopausal women. While androgen deprivation therapy is known to alter FSH blood levels, the impact of this change in prostate cancer patients was not well understood. To investigate the effect of androgen deprivation therapy on FSH levels and body composition, Bergamini et al. used X-ray technology to measure total fat body mass in prostate cancer patients before and after undergoing 12 months of androgen deprivation therapy. The findings showed that patient FSH blood levels significantly decreased after 12 months of treatment. Higher FSH blood levels strongly correlated with increased total fat body mass after 12 months of treatment. The findings of this clinical trial suggest that FSH blood levels impact the body composition of patients undergoing androgen deprivation therapy. As a result, FSH blood levels may be a suitable biomarker for identifying patients that are more likely to develop obesity and are therefore at greater risk of complications such as cardiovascular disease.
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Antagonistas de Androgênios , Composição Corporal , Densidade Óssea , Hormônio Foliculoestimulante , Neoplasias da Próstata , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Absorciometria de Fóton , Antagonistas de Androgênios/uso terapêutico , Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Hormônio Foliculoestimulante/sangue , Oligopeptídeos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/sangueRESUMO
BACKGROUND/AIM: Single-agent tyrosine kinase inhibitors are still prescribed as first-line treatment to a relevant subgroup of patients with metastatic renal cell carcinoma (mRCC). These agents are known to cause disfunction of many endocrine glands (e.g., thyroid). In this two-step trial, we aimed to assess gonadal function among male patients with mRCC treated with sunitinib. PATIENTS AND METHODS: We enrolled a first cross-sectional cohort of pre-treated (>6 months) patients and a subsequent cohort of treatment-naïve patients who were prospectively followed-up. All patients were screened for hypogonadism and received a Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire at study entry and after 6 months of therapy. Patients who were candidates for testosterone replacement therapy (TRT) also received a FACT-G questionnaire at baseline and 3 months after supplementation. RESULTS: Among the 30 enrolled patients, the prevalence of hypogonadism was found to be higher in those receiving sunitinib for a longer period (27.3% at baseline, 41.7% in the first 6 months, and 68.4% after 9 months of therapy). The testosterone level of patients correlated with quality of life (R=0.32). A total of six patients received TRT, with a significant improvement in their global quality of life after the first 3 months of treatment. CONCLUSION: An increasing prevalence of hypogonadism was seen among male patients who received long-term treatment with sunitinib. TRT was associated with relevant improvements in quality of life. These findings corroborate similar published observations and encourage the assessment of gonadal function in male patients with mRCC under treatment with sunitinib.
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Carcinoma de Células Renais , Gônadas , Neoplasias Renais , Sunitinibe , Humanos , Masculino , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Estudos Transversais , Gônadas/efeitos dos fármacos , Gônadas/fisiopatologia , Hipogonadismo/epidemiologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Qualidade de Vida , Sunitinibe/efeitos adversos , Testosterona/análiseRESUMO
PURPOSE: Whether or not androgen receptor (AR) axis could still be targetable in castration resistant prostate cancer (CRPC) patients with disease progression to next generation hormonal agents (NGHAs) is a controversial issue. RESULTS: Serum testosterone in CRPC patients has a positive prognostic role and increasing testosterone levels after androgen deprivation therapy (ADT) withdrawal or testosterone supplementation, as part of a bipolar androgen therapy (BAT) strategy, has been shown to potentially restore sensitivity to previous lines of NGHAs. CONCLUSION: These data suggest that maintenance of ADT in CRPC patients receiving further lines of treatment, as recommended by current international guidelines, could be questionable. Conversely, testosterone supplementation aimed to re-sensitize CRPC to further hormonal manipulation is a strategy worth to be explored in future clinical trials.
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Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Antagonistas de Androgênios/uso terapêutico , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos , Testosterona/uso terapêuticoRESUMO
The development of a neuroendocrine phenotype as a mechanism of resistance to hormonal treatment is observed in up to 20% of advanced prostate cancer patients. High grade neuroendocrine prostate cancer (NEPC) is associated to poor prognosis and the therapeutic armamentarium is restricted to platinum-based chemotherapy. Prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET)/computed tomography (CT) imaging has recently emerged as a potential new standard for the staging of prostate cancer and PSMA-based radioligand therapy (RLT) as a therapeutic option in advanced metastatic castration resistant prostate cancer (mCRPC). PSMA-based theranostic is not currently applied in the staging and treatment of NEPC since PSMA expression on neuroendocrine differentiated cells was shown to be lost. In this case series, we present 3 consecutive mCRPC patients with histologically proven high grade neuroendocrine differentiation who underwent PSMA-PET/CT and surprisingly showed high tracer uptake. This observation stimulates further research on the use of PSMA-based theranostic in the management of NEPC.
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CONTEXT: As patients are now living with prostate cancer for longer, the long-term impact of hormonal treatment on bone health is an increasingly debated subject. OBJECTIVE: To characterize the changes in bone mineral density (BMD) and bone turnover markers after degarelix administration in prostate cancer patients without bone metastases. To explore the predictive role of body composition on treatment induced bone loss. METHODS: BMD and body composition (lean body mass, fat body mass, and appendicular mass index [ALMI]) were assessed by dual X-ray absorptiometry on study entry and after 12 months of degarelix therapy. Alkaline phosphate (ALP) and C-terminal telopeptide of type I collagen (CTX) were assessed at baseline, and 6 and 12 months. RESULTS: Twenty-nine patients entered the study. Degarelix administration was associated with a significant decrease in BMD after 12 months (2.4% reduction from baseline at lumbar spine). Serum CTX and ALP increased significantly (median increase from baseline 99% and 19.3%, respectively). An inverse correlation was observed between ALMI and CTX, but not ALP, at both baseline (Pearson r = -0.62, Pâ <â .0001) and month 12 (Pearson r = -0.41, Pâ =â .032). Moreover, a significant inverse correlation between changes in ALMI and CTX at 12 months (Pearson r = -0.43, Pâ =â .019) and a direct relationship between changes of ALMI and ALP (Pearson r = 0.44, Pâ =â .016) during degarelix therapy were observed. CONCLUSION: Degarelix administration is associated with a significant decrease in BMD and increase in bone turnover markers. ALMI is a promising predictor of bone loss in prostate cancer patients receiving androgen deprivation therapy, and ALMI changes during therapy are associated with bone turnover derangement favoring bone quality alterations.
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Doenças Ósseas Metabólicas , Neoplasias Ósseas , Neoplasias da Próstata , Masculino , Animais , Humanos , Densidade Óssea , Antagonistas de Androgênios/farmacologia , Neoplasias da Próstata/complicações , Neoplasias da Próstata/tratamento farmacológico , Absorciometria de Fóton , Vértebras Lombares/diagnóstico por imagem , Neoplasias Ósseas/tratamento farmacológico , Remodelação ÓsseaRESUMO
BACKGROUND: Luteinizing hormone-releasing hormone (LHRH)-agonists in prostate cancer (PCa) patients induce sarcopenic obesity. The effect of LHRH-antagonist on body composition has never been explored. We evaluated changes in fat (FBM) and lean body mass (LBM) in PCa patients undergoing Degarelix. METHODS: This is a single-center prospective study, enrolling 29 non-metastatic PCa patients eligible to LHRH-antagonist from 2017 to 2019. All patients received monthly subcutaneous injection of Degarelix for 12 months. Changes in FBM and LBM between baseline and 12-month Degarelix, as measured by dual-energy x-ray absorptiometry, were the co-primary endpoints. Secondary endpoints were changes in serum lipids, glucose profile and follicle-stimulating hormone (FSH). Appendicular lean mass index (ALMI) and ALMI/FBM ratio were assessed as post-hoc analyses. Linear mixed models with random intercept tested for estimated least squared means differences (EMD). RESULTS: FBM significantly increased after 12 months (EMD +2920.7, +13.8%, p < 0.001), whereas LBM remained stable (EMD -187.1, -0.3%, p = 0.8). No differences occurred in lipid profile. Glycated hemoglobin significantly increased and serum FSH significantly decreased. A significant inverse relationship was found between serum FSH and ALMI/FBM ratio after 12 month (r = -0.44, p = 0.02). CONCLUSIONS: The BLADE study prospectively evaluated changes in body composition after LHRH-antagonist. LHRH-antagonist therapy is associated to an increased risk of obesity and diabetes, but lean body mass and serum lipids are not affected. This may represent an additional evidence supporting the reduced cardiovascular risk associated with LHRH-antagonist. The role of FSH in influencing sarcopenic obesity in PCa after androgen deprivation deserves to be further explored.
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Composição Corporal , Neoplasias Ósseas , Lipídeos/sangue , Oligopeptídeos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Idoso , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Taxa de SobrevidaRESUMO
BACKGROUND: Cisplatin-based chemotherapy is the mainstay of pharmacological treatment of testicular germ cell tumors (TGCTs) that, together with early diagnosis, surgery, and/or radiotherapy, has dramatically improved the prognosis. However, under the pressure of such pharmacological therapy (both classical cytotoxic drugs and targeted therapy), cancer cells may develop resistance. Thus, combination therapy that may include cytotoxic drugs and targeted therapy could offer an advantage to curing cancers. Here, we investigated the in vitro and in vivo antitumor activity of cisplatin, as a single-agent or in combination with palbociclib. PATIENTS AND METHODS: The cell viability of Ntera-2/cl.D1 (NT2/D1) and 833K after exposure to palbociclib and/or cisplatin was evaluated by MTT dye reduction assay and by ATPLite Luminescence Assay. Gene and protein expression was evaluated by quantitative reverse transcription polymerase chain reaction and by western blot. Flow cytometric cell-cycle analysis was performed, as well. The in vivo experiments were conducted on NT2/D1 xenografts in AB zebrafish embryos exposed to the drugs. RESULTS: Palbociclib and cisplatin decreased TGCT cell viability both in vitro and in vivo. This effect was additive when cells were exposed to the drug combination. In the NT2/D1 cell lines, the drug combination also exerted a positive effect with regard to delaying cell recovery after the toxic insult. In the combination experiments, cisplatin-induced cell accumulation in G2/M was predominant compared with the palbociclib effect. CONCLUSIONS: These results could provide the rationale for developing further studies to improve the pharmacological treatment of TGCTs, but they must be demonstrated in a dedicated clinical trial.
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Antineoplásicos , Neoplasias Testiculares , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Quinase 4 Dependente de Ciclina , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas , Piperazinas , Piridinas , Neoplasias Testiculares/tratamento farmacológico , Peixe-ZebraRESUMO
BACKGROUND: This study was designed to demonstrate the non-inferiority (NI) in overall survival (OS) of suspension of androgen deprivation therapy (ADT) versus maintenance and intermittent versus continuous docetaxel administration in metastatic castration-resistant prostate cancer (mCRPC) patients. PATIENTS AND METHODS: mCRPC patients were randomised to first-line docetaxel with maintenance or suspension of ADT. Patients attaining a prostate-specific antigen (PSA) response after four chemotherapy cycles underwent second randomisation to receive continuous or intermittent docetaxel therapy. Six hundred patients were to be randomised to achieve 80% statistical power to demonstrate an NI hazard ratio (HR) of 1.25 of interruption versus maintenance of ADT. RESULTS: The trial was prematurely closed when 198 participants were randomised. OS was similar in patients who continued (N = 96) versus those who interrupted (n = 102) ADT during docetaxel therapy (HR 0.98, 95% confidence interval [CI] 0.72-1.33] and those on a continuous (N = 35) versus an intermittent (N = 42) docetaxel schedule (HR 0.86, 95% CI 0.55-1.43). No difference in radiological progression-free survival, PSA response, or toxicity was observed between the study arms. The actual NI hazard margins of OS in Arms A and B patients were 1.33 and 1.43, respectively. CONCLUSIONS: This trial enrolled one-third of the planned patients; this main weakness dramatically limits the interpretation of the results. ADT discontinuation and switching to an intermittent schedule did not seem to affect docetaxel efficacy. The absence of testosterone recovery in the majority of patients could have been a contributory factor. In men with mCRPC, ADT discontinuation should only be done with regular biochemical and clinical monitoring, with the option of quickly restarting ADT at disease progression.
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Antagonistas de Androgênios/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Antagonistas de Androgênios/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Docetaxel/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Análise de SobrevidaRESUMO
BACKGROUND: Pre-clinical data suggest that docetaxel and enzalutamide interfere with androgen receptor translocation and signalling. The aim of this study is to assess the efficacy of their concurrent administration in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). METHODS: In this open-label, randomised, phase II trial, previously untreated mCRPC patients were randomised 1:1 to receive eight 21-d courses of docetaxel 75 mg/m2, oral prednisone 5 mg twice daily and oral enzalutamide 160 mg/d (arm DE), or the same treatment without enzalutamide (arm D). The primary end-point was the percentage of patients without investigator-assessed disease progression 6 months after the first docetaxel administration. RESULTS: The 246 eligible patients were randomly assigned to receive docetaxel, prednisone and enzalutamide (n = 120) or docetaxel and prednisone (n = 126). The 6-month progression rate was 12.5% (95% confidence interval [CI] 8.1-20.6) in arm DE and 27.8% (95% CI 22.8-39.4) in arm D (chi-squared test 10.01; P = 0.002). The most frequent grade III-IV adverse events were fatigue (12.5% in arm DE versus 5.6% in arm D), febrile neutropenia (9.3% versus 4.0%) and neutropenia (7.6% versus 5.6%). CONCLUSIONS: The combination of enzalutamide and docetaxel appears to be more clinically beneficial than docetaxel alone in previously untreated mCRPC patients, although serious adverse events were more frequent. Our findings suggest that first-line treatment with this combination could lead to an additional clinical benefit when prompt and prolonged disease control is simultaneously required. Clearly, these results should be considered cautiously because of the study's phase II design and the absence of an overall survival benefit. TRIAL REGISTRATION NUMBERS: EudraCT 2014-000175-43 - NCT02453009.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/uso terapêutico , Docetaxel/uso terapêutico , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Docetaxel/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/farmacologiaRESUMO
We evaluated the advantages and the reliability of novel protocols for the enrichment of tumor extracellular vesicles (EVs), enabling a blood-based test for the noninvasive parallel profiling of multiple androgen receptor (AR) gene alterations. Three clinically relevant AR variants related to response/resistance to standard-of-care treatments (AR-V7 transcript, AR T878A point mutation and AR gene amplification) were evaluated by digital PCR in 15 samples from patients affected by Castration-Resistant Prostate Cancer (CRPC). Plasma was processed to obtain circulating RNA and DNA using protocols based on tumor EVs enrichment through immuno-affinity and peptide-affinity compared to generic extraction kits. Our results showed that immuno-affinity enrichment prior to RNA extraction clearly outperforms the generic isolation method in the detection of AR-V7, also allowing for a distinction between responder (R) and non-responder (NR) patients. The T878A mutation was detected, overall, in nine out of 15 samples and no approach alone was able to reveal mutations in all harboring samples, showing that the employed methods complement each other. AR amplification was detected in the majority of CRPC samples analysed using either cell-free DNA (cfDNA) or exosome isolation kits (80%). We demonstrated that selective isolation of a subset of circulating exosomes enriched for tumor origin, rather than analysis of total plasma exosomes, or total plasma nucleic acids, increases sensitivity and specificity for the detection of specific alterations.
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Patients with cancer are at a higher risk of developing serious disease-related complications in case of contracting SARS-CoV-2. Oncology units should implement all possible preventive measures to reduce the risk of viral transmission by healthcare professionals (HCPs) to patients. We conducted a surveillance for SARS-CoV-2 infection among the staff members of the Medical Oncology Unit of ASST Spedali Civili in Brescia, one of the Italian areas most affected by the SARS-CoV-2 pandemic. The aim of this study was to demonstrate whether the recommended preventive measures, promptly implemented by the unit, have been effective in reducing the spread of the virus among the HCPs. Between February 24 and May 19, 2020, SARS-CoV-2 infection was detected in 10 out of 76 healthy HCPs (13%). Six of them developed a symptomatic disease, leading to home quarantine, and four remained asymptomatic. The infection was revealed when a serology test was performed on all staff members of the unit. In seven HCPs, in which it was possible to trace the person-to-person infection, the contagion occurred as a result of unprotected contacts or partially protected with surgical masks. In particular, four asymptomatic HCPs did not stop working, but a widespread outbreak in the unit was avoided. Adherence to the recommended preventive strategies, in particular, wearing of surgical masks by both the HCPs and the patients, is effective in reducing and preventing the viral spread.
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BACKGROUND: No compelling evidence is available about surveillance and follow-up of patients with testicular germ cell tumour (TGCT). METHODS: In the light of the best clinical evidence, the Italian Germ cell cancer Group (IGG) and the Associazione Italiana di Oncologia Medica (AIOM) set up a multidisciplinary national consensus conference, involving 42 leading experts and 3 TGCT survivors. A minimum of 50% of votes was required in order to achieve a consensus recommendation on 29 questions. RESULTS: Recommendations have been summarized in three tables, divided by stage I seminoma, stage I nonseminoma and the advanced disease, which may be useful for clinicians to appropriately choose the clinical investigation and its timing during the surveillance and follow-up of TGCT patients based on an accurate estimation of their risk of disease relapse. CONCLUSIONS: The IGG-AIOM consensus recommendations may help clinicians to choose appropriate clinical investigations for the surveillance and follow-up of TGCT patients.