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Registrative trials recommended the use of upfront chemotherapy in high-volume metastatic prostate cancer. We reported survival outcomes of patients with high-volume mCRPC treated with ARTA in a chemo-naïve setting compared to patients treated with chemotherapy as first-line from a longitudinal real-life multicenter series. We retrospectively collected data on mCRPC patients treated at six centers. The dataset was queried for high-volume disease (defined as more than 6 bone lesions or bulky nodes ≥ 5 cm). We compared the main clinical features of chemo-naïve versus chemo-treated patients. The Mann-Whitney U test and Chi-squared test were used to compare continuous and categorial variables, respectively. The Kaplan-Meier method was used to compare differences in terms of progression-free survival (PFS), cancer specific survival (CSS) and overall survival (OS) in an upfront ARTA or chemo-treated setting. Survival probabilities were computed at 12, 24, 48, and 60 months. Out of 216 patients, 88 cases with high-volume disease were selected. Sixty-nine patients (78.4%) received upfront ARTA, while 19 patients received chemotherapy as the first-line treatment option. Forty-eight patients received Abiraterone (AA), 21 patients received Enzalutamide (EZ) as the first-line treatment. The ARTA population was older (p = 0.007) and less likely to receive further lines of treatment (p = 0.001) than the chemo-treated cohort. The five-year PFS, CSS and OS were 60%, 73.3%, and 72.9%, respectively. Overall, 28 patients (31.8%) shifted after their first-line therapy to a second-line therapy: EZ was prescribed in 17 cases, AA in seven cases and radiometabolic therapy in four patients. Sixteen cases (18.2%) developed significant progression and were treated with chemotherapy. At Kaplan-Meyer analysis PFS, CSS and OS were comparable for upfront ARTA vs chemo-treated patients (log rank p = 0.10, p = 0.64 and p = 0.36, respectively). We reported comparable survival probabilities in a real-life series of high-volume mCRPC patients who either received upfront ARTA or chemotherapy. Patients primarily treated with chemotherapy were younger and more likely to receive further treatment lines than the upfront ARTA cohort. Our data support the use of novel antiandrogens as first line treatment regardless tumor burden, delaying the beginning of a more toxic chemotherapy in case of significant disease progression.
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The introduction of first-line combinations had improved the outcomes for metastatic renal cell carcinoma (mRCC) compared to sunitinib. However, some patients either have inherent resistance or develop resistance as a result of the treatment. Depending on the kind of therapy employed, many factors underlie resistance to systemic therapy. Angiogenesis and the tumor immune microenvironment (TIME), nevertheless, are inextricably linked. Although angiogenesis and the manipulation of the tumor microenvironment are linked to hypoxia, which emerges as a hallmark of renal cell carcinoma (RCC) pathogenesis, it is only one of the potential elements involved in the distinctive intra- and inter-tumor heterogeneity of RCC that is still dynamic. We may be able to more correctly predict therapy response and comprehend the mechanisms underlying primary or acquired resistance by integrating tumor genetic and immunological markers. In order to provide tools for patient selection and to generate hypotheses for the development of new strategies to overcome resistance, we reviewed the most recent research on the mechanisms of primary and acquired resistance to immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) that target the vascular endothelial growth factor receptor (VEGFR).We can choose patients' treatments and cancer preventive strategies using an evolutionary approach thanks to the few evolutionary trajectories that characterize ccRCC.
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Objective: This study aims to estimate the incidence of Vestibular neuritis (VN) in three different districts in Italy, its epidemiological features, and the prevalence of comorbidities associated with it. Methods: An observational prospective study of 198 patients referred to ENT departments in Siena, Grosseto, and Cuneo was carried out over a 2-year period. Each patient underwent a complete otoneurologic examination in the first 48 h from the onset of symptoms and a brain MRI in the early stages of the disease. The follow-up lasted for 1 year. Results: The total VN incidence rate of the three municipalities was 48.497 (95% CI: 48.395-48.598) and its standardized value was 53.564 (95% CI: 53.463-53.666). The total VN incidence rate for the whole sample (municipality and district of the three centers) was 18.218 (95% CI: 18.164-18.272), and its standardized value was 20.185 (95% CI: 20.129-20.241). A significant difference was highlighted between patients living in the city compared to those living in the surrounding area (p < 0.000), this may be due to the ease of reaching the otoneurological referral center. Conclusion: The total incidence rate for the three municipalities was 48.497. This result is higher than previously reported studies.
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C6O4 is a water soluble perfluoroether carboxylic acid ammonium salt used as surfactant in the synthesis of fluoropolymers. Available experimental data in rats exposed by the oral route indicate it is eliminated in urine. Previous studies with various linear perfluorocarboxylic acids have suggested that these compounds are substrates of renal membrane transporters in rats and humans, and that the interaction with basal and apical membrane transporters can influence the elimination kinetic by these organisms and explain, in part, the observed differences in the respective half-lives. In particular, apical transporters may contribute to the reuptake of these exogenous compounds from the tubule lumen. The present study was designed to investigate the uptake of C6O4 in two renal cell lines transiently transfected with the human apical membrane transporters, organic anion transporter 4 (OAT4), and urate transporter 1 (URAT1). The uptake of the linear perfluorohexanoic acid (PFC6) was evaluated in parallel. While the uptake of the conjugated steroid estrone-3-sulfate (E3S), a known substrate for renal transporters, and of PFC6 was clearly observed in both cell types transfected with either OAT4 or URAT1, no significant uptake of C6O4 was measured under the same test conditions. The results of the transporter's functionality measured in vitro were consistent with molecular docking simulations. Both outward and inward models of the transporters showed a reduced interaction between C6O4 and URAT1 or OAT4. In contrast, more stable interactions were predicted for PFC6 and PFOA, as well as for the E3S substrate, as shown by the respective docking scores reflecting the binding strength and by the poses assumed in the transporter channels. Altogether, the in vitro and in silico modeling results showed a low reuptake potential and limited interactions of C6O4 molecule with two human apical membrane transporters, contrasting with the more efficient reuptake of PFC6 from the tubule lumen. These results suggest reabsorption from the proximal tubule by apical renal transporters is not likely to interfere with the elimination pathway of C6O4 in humans.
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Transportadores de Ânions Orgânicos , Animais , Transporte Biológico , Humanos , Rim/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Simulação de Acoplamento Molecular , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , RatosRESUMO
The recent approval of immune checkpoint inhibitor (ICI)-based combinations has redefined the first-line standard of care of metastatic renal cell carcinoma (mRCC) patients. Although the undisputed advantage of these combinations, most patients progressed, requiring subsequent therapies. The change of first-line therapy inevitably led to modification of the all mRCC treatment algorithm; to date, the most appropriate second-line options remain still unclear. The aim of our review was to provide a useful summary of the available evidence in order to overcome the doubts about treatment sequences. Retrospectively, the efficacy of second-line VEGFR-TKIs seems to be greater after failure of a dual ICIs combination rather than after ICIs plus VEGFR-TKIs, nevertheless prospective data of second-line TKIs are limited. Moreover, ICI re-challenge could be an option but, again, most data derived from retrospective series emphasizing the identification of predictive factors of response to select mRCC patients that could benefit from this strategy. Novel molecules and different ICI-based combinations are under evaluation with the aim of implementing the second-line setting. In particular, belzutifan, ciforadenant (CPI-444), and talazoparib achieved encouraging objective response rates (ORR) in phase I/II trials. Phase III trials comparing these new molecules with the standard of care are currently ongoing. The first-line regimen, and the type and duration of response emerged as crucial factors that could influence the efficacy of second-line therapy. Prognostic models that integrate clinical features and molecular biomarkers with a predictive value are warranted to guide clinicians in the decision-making process with the ultimate goal of offering to the patients the most effective therapy in a personalized, precision medicine-based, therapeutic strategy.
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Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Prognóstico , Estudos Prospectivos , Estudos RetrospectivosRESUMO
BACKGROUND/AIM: Recent evidence suggests potential synergistic antitumor effects of the combination of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors with the oral hypoglycemic agent metformin. The aim of this study was to investigate the safety and activity of metformin combined with nivolumab in diabetic cancer patients. PATIENTS AND METHODS: Patients with advanced melanoma, renal cell carcinoma or lung cancer receiving nivolumab with concurrent diabetes treated with metformin were retrospectively collected. The primary endpoint was the safety of nivolumab plus metformin combination. RESULTS: We collected 40 patients with solid tumors who received metformin for concomitant diabetes and nivolumab as anticancer therapy in four Italian Hospitals. The concomitant use of nivolumab and metformin was well tolerated; adverse events (AEs) of any grade occurred in 75% of patients (mainly fatigue, pruritus, rash, and asthenia). Grade 3 AEs occurred only in 20% of cases; no grade 4 AEs were observed. A statistically significant correlation was found between higher doses of metformin (>1,000 mg daily) and longer progression-free survival (p=0.021), overall survival (p=0.037) and higher overall response rate. CONCLUSION: The combination of nivolumab and metformin was safe and might have an antitumor activity, supporting further investigations on the synergistic antitumor effect of this combination.
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Antígeno B7-H1/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Metformina/uso terapêutico , Neoplasias/tratamento farmacológico , Nivolumabe/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Inibidores de Checkpoint Imunológico/efeitos adversos , Itália , Masculino , Metformina/efeitos adversos , Neoplasias/diagnóstico , Neoplasias/imunologia , Neoplasias/mortalidade , Nivolumabe/efeitos adversos , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de TempoRESUMO
BACKGROUND: The 2021 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium represents an unmissable event for oncologists who deal with renal cell carcinoma (RCC). AIM AND RESULTS: This article describes the main acquisitions of RCC management, including the advent of a new combo (pembrolizumab+lenvatinib) as first-line therapy, the confirmation of an OS advantage of ICI plus VEGFR-TKI combinations over sunitinib at longer follow-up, the persistent benefit from these combinations in particular subgroups (clear cell mRCC tumors with sarcomatoid differentiation), and possible new approaches in subsequent lines of therapy (including the HIF-2α inhibitor belzutifan). CONCLUSIONS: This 2021 ASCO Genitourinary Cancer Symposium laid the foundations for further knowledge development necessary for an increasingly personalized management of mRCC.
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Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Urogenitais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Urogenitais/terapiaRESUMO
BACKGROUND: Prostate cancer (PC) is a heterogeneous disease that requires a personalized treatment approach for proper patient management. AIM: We analyzed a selected overview of the most important news recently presented at the 2021 ASCO genitourinary cancer symposium. RESULTS: In particular, we focused on the identification of predictive biomarkers as potential targets for therapy. Molecular signatures of increased T cell activity, proliferation, and hormone dependence were associated with greater probability of response to apalutamide in non-metastatic CRPC. Pathogenic variants of DDR genes mutations detected with circulating tumor DNA (ctDNA) analysis, which had a high concordance with tumor tissue analysis, might represent a useful way for selecting mutated patients for poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors therapy. Loss of PTEN could be a target for ipatasertib (a pan-AKT inhibitor) associated with abiraterone in mCRPC patients. CONCLUSIONS: The 2021 ASCO Genitourinary Cancers Symposium significantly contributed to the complex research goal of intimately understanding PC carcinogenesis with the ultimate aim of improving patient outcomes.
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DNA Tumoral Circulante , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Neoplasias Urogenitais , DNA Tumoral Circulante/genética , Humanos , Masculino , Poli(ADP-Ribose) Polimerases , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias Urogenitais/genética , Neoplasias Urogenitais/terapiaRESUMO
Introduction: Prostate cancer (PCa) is one of the most common adult malignancies worldwide, and a major leading cause of cancer-related death in men in Western societies. In the last years, the prognosis of advanced PCa patients has been impressively improved thanks to the development of different therapeutic agents, including taxanes (docetaxel and cabazitaxel), second-generation anti-hormonal agents (abiraterone and enzalutamide), and the radiopharmaceutical Radium-223. However, great efforts are still needed to properly select the most appropriate treatment for each single patient.Areas covered: Several prognostic or predictive biomarkers have been studied, none of which has an established validated role in daily clinical practice. This paper analyzed the major biomarkers (including PSA, androgen receptor (AR) splice variants, ßIII-tubulin, ALP, circulating tumor cells, and DNA repair genes) with a potential prognostic and/or predictive role in advanced PCa patients.Expert commentary: Surrogate biomarkers - measurable, reproducible, closely associated with tumor behavior and linked to relevant clinical outcomes - are urgently needed to improve PCa patient management.
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Biomarcadores Tumorais , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/terapia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Tomada de Decisão Clínica , Terapia Combinada , Gerenciamento Clínico , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Estadiamento de Neoplasias , Células Neoplásicas Circulantes , Células-Tronco Neoplásicas , Medicina de Precisão/métodos , Neoplasias da Próstata/etiologia , Resultado do TratamentoRESUMO
The aim of this study was to assess the natural course of positional down-beating nystagmus (pDBN) and vertigo in patients with no evidence of central nervous system involvement and of presumed peripheral origin. Fifty-three patients with pDBN had a complete otoneurological examination. All subjects, apart from three (excluded from the study), showed no additional neurological signs and normal brain imaging. Patients were randomly assigned to two groups: with or without treatment with exercise. Patients were seen again after 24 h, and then weekly for up to 6 months. Forty-seven patients (94%) showed pDBN in the straight head-hanging position and in a Dix-Hallpike position. A torsional component was detected in 17 patients (34%). The mean latency and duration of pDBN was 4.7 ± 5 s and 40.1 ± 22 s, respectively. After 2 weeks, only 12 patients (24%) still had pDBN and all but one patient had recovered by 1 month. Twenty patients (40%) were diagnosed with a typical posterior canal benign paroxysmal positional vertigo (PC BPPV) before or after pDBN. This study assessed for the first time the natural course of presumed peripheral pDBN, which was characterized by a spontaneous remission in 24 patients in the first week and in 49 patients within 4 weeks. pDBN is much more common than previously suggested, with about the same frequency as lateral canal BPPV. Furthermore, the clinical characteristics of pDBN have been highlighted, as well as its possible relationship to PC BPPV.
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Nistagmo Patológico/reabilitação , Vertigem/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Vertigem Posicional Paroxística Benigna , Terapia por Exercício , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nistagmo Patológico/complicaçõesRESUMO
We evaluated the incidence and characteristics of hyperventilation-induced nystagmus (HVN) in 49 patients with gadolinium-enhanced magnetic resonance imaging evidence of vestibular schwannoma and 53 patients with idiopathic unilateral sensorineural hearing loss and normal radiological findings. The sensitivity and specificity of the hyperventilation test were compared with other audio-vestibular diagnostic tests (bedside examination of eye movements, caloric test, auditory brainstem responses) in the two groups of patients. The hyperventilation test scored the highest diagnostic efficiency (sensitivity 65.3 %; specificity 98.1 %) of the four tests in the differential diagnosis of vestibular schwannoma and idiopathic unilateral sensorineural hearing loss. Small tumors with a normal caloric response or caloric paresis were associated with ipsilateral HVN and larger tumors and severe caloric deficits with contralateral HVN. These results confirm that the hyperventilation test is a useful diagnostic test for predicting vestibular schwannoma in patients with unilateral sensorineural hearing loss.
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Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Unilateral/diagnóstico , Hiperventilação/fisiopatologia , Neuroma Acústico/diagnóstico , Nistagmo Patológico/fisiopatologia , Adulto , Idoso , Diagnóstico Diferencial , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Perda Auditiva Neurossensorial/fisiopatologia , Perda Auditiva Unilateral/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroma Acústico/fisiopatologia , Sensibilidade e Especificidade , Testes de Função VestibularRESUMO
We developed the head impulse testing device (HITD) based on an inertial sensing system allowing to investigate the functional performance of the rotational vestibulo-ocular reflex (VOR) by testing its gaze stabilization ability, independently from the subject's visual acuity, in response to head impulses at different head angular accelerations ranging from 2000 to 7000 deg/s(2). HITD was initially tested on 22 normal subjects, and a method to compare the results from a single subject (patient) with those from controls was set up. As a pilot study, we tested the HITD in 39 dizzy patients suffering, non-acutely, from different kinds of vestibular disorders. The results obtained with the HITD were comparable with those from the clinical head impulse test (HIT), but an higher number of abnormalities was detectable by HITD in the central vestibular disorders group. The HITD appears to be a promising tool for detecting abnormal VOR performance while providing information on the functional performance of the rotational VOR, and can provide a valuable assistance to the clinical evaluation of patients with vestibular disorders.