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Bats are distinctive among mammals due to their ability to fly, use laryngeal echolocation, and tolerate viruses. However, there are currently no reliable cellular models for studying bat biology or their response to viral infections. Here, we created induced pluripotent stem cells (iPSCs) from two species of bats: the wild greater horseshoe bat (Rhinolophus ferrumequinum) and the greater mouse-eared bat (Myotis myotis). The iPSCs from both bat species showed similar characteristics and had a gene expression profile resembling that of cells attacked by viruses. They also had a high number of endogenous viral sequences, particularly retroviruses. These results suggest that bats have evolved mechanisms to tolerate a large load of viral sequences and may have a more intertwined relationship with viruses than previously thought. Further study of bat iPSCs and their differentiated progeny will provide insights into bat biology, virus host relationships, and the molecular basis of bats' special traits.
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Quirópteros , Células-Tronco Pluripotentes , Viroses , Vírus , Animais , Vírus/genética , Transcriptoma , FilogeniaRESUMO
BACKGROUND: The TheraP study reported improved prostate-specific antigen responses with lutetium-177 [177Lu]Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer progressing after docetaxel. In this Article, we report the secondary outcome of overall survival with mature follow-up, and an updated imaging biomarker analysis. We also report the outcomes of participants excluded due to ineligibility on gallium-68 [68Ga]Ga-PSMA-11 and 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) PET-CT. METHODS: TheraP was an open-label, randomised phase 2 trial at 11 centres in Australia. Eligible participants had metastatic castration-resistant prostate cancer progressing after docetaxel, and PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG that showed prostate-specific membrane antigen (PSMA)-positive disease and no sites of metastatic disease with discordant 2-[18F]FDG-positive and PSMA-negative findings. Participants were randomly assigned (1:1) to treatment with [177Lu]Lu-PSMA-617 (every 6 weeks for a maximum of six cycles; starting at 8·5 GBq, decreasing by 0.5 GBq to 6·0 GBq for the sixth cycle) versus cabazitaxel (20 mg/m2 every 3 weeks, maximum of ten cycles). Overall survival was analysed by intention-to-treat and summarised as restricted mean survival time (RMST) to account for non-proportional hazards, with a 36-month restriction time corresponding to median follow-up. This trial is registered with ClinicalTrials.gov, NCT03392428, and is complete. FINDINGS: 291 men were registered from Feb 6, 2018, to Sept 3, 2019; after study imaging, 200 were eligible and randomly assigned to treatment with [177Lu]Lu-PSMA-617 (n=99) or cabazitaxel (n=101). After completing study treatment, 20 (20%) participants assigned to cabazitaxel and 32 (32%) assigned to [177Lu]Lu-PSMA-617 were subsequently treated with the alternative regimen. After a median follow-up of 35·7 months (IQR 31·1 to 39·2), 77 (78%) participants had died in the [177Lu]Lu-PSMA-617 group and 70 (69%) participants had died in the cabazitaxel group. Overall survival was similar among those assigned to [177Lu]Lu-PSMA-617 versus those assigned to cabazitaxel (RMST 19·1 months [95% CI 16·9 to 21·4] vs 19·6 months [17·4 to 21·8]; difference -0·5 months [95% CI -3·7 to 2·7]; p=0·77). No additional safety signals were identified with the longer follow-up in this analysis. 80 (27%) of 291 men who were registered after initial eligibility screening were excluded after [68Ga]Ga-PSMA-11 and 2-[18F]FDG PET. In the 61 of these men with follow-up available, RMST was 11·0 months (95% CI 9·0 to 13·1). INTERPRETATION: These results support the use of [177Lu]Lu-PSMA-617 as an alternative to cabazitaxel for PSMA-positive metastatic castration-resistant prostate cancer progressing after docetaxel. We did not find evidence that overall survival differed between the randomised groups. Median overall survival was shorter for men who were excluded because of low PSMA expression or 2-[18F]FDG-discordant disease. FUNDING: Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, It's a Bloke Thing, CAN4CANCER, and The Distinguished Gentleman's Ride.
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Radioisótopos de Gálio , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Resultado do Tratamento , Docetaxel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18 , Austrália , Antígeno Prostático EspecíficoRESUMO
The prevalence of mitotically heritable clonal random monoallelic expression of autosomal genes (aRME) remains controversial. Specifically, presence of clonal aRME is well supported in vitro but remains elusive in vivo. Here, we provide critical insights into this matter and discuss whether prevalent clonal aRME is natural or artifactual.
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Alelos , Cromossomos/genética , Evolução Clonal/genética , Mitose/genética , Regulação da Expressão Gênica/genética , HumanosRESUMO
BACKGROUND: Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing. FINDINGS: Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9-30·2) for the talazoparib group and 24·6 months (14·4-30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months-not reached) for talazoparib plus enzalutamide and 21·9 months (16·6-25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51-0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3-4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group. INTERPRETATION: Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations. FUNDING: Pfizer.
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Anemia , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Adolescente , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos , Antagonistas de Androgênios/uso terapêutico , Anemia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Método Duplo-CegoRESUMO
Poly(ADP-ribose) polymerase inhibitors in combination with androgen-receptor signaling inhibitors are a promising therapeutic option for patients with metastatic castration-sensitive prostate cancer (mCSPC) and homologous recombination repair (HRR) gene alterations. Here, we describe the design and rationale of the multinational, phase III, TALAPRO-3 study comparing talazoparib plus enzalutamide versus placebo plus enzalutamide in patients with mCSPC and HRR gene alterations. The primary end point is investigator-assessed radiographic progression-free survival (rPFS) per RECIST 1.1 in soft tissue, or per PCWG3 criteria in bone. The TALAPRO-3 study will demonstrate whether the addition of talazoparib can improve the efficacy of enzalutamide as assessed by rPFS in patients with mCSPC and HRR gene alterations undergoing androgen deprivation therapy. Clinical Trial Registration:NCT04821622 (ClinicalTrials.gov) Registry Name: Study of Talazoparib With Enzalutamide in Men With DDR Gene Mutated mCSPC. Date of Registration: 29 March 2021.
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Benzamidas , Feniltioidantoína , Ftalazinas , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Antagonistas de Androgênios/uso terapêutico , Androgênios , Nitrilas/uso terapêutico , Castração , Ensaios Clínicos Fase III como AssuntoRESUMO
WHAT IS THIS SUMMARY ABOUT?: This summary is about the ongoing research study called TALAPRO-3. This study is testing the use of two medicines called talazoparib and enzalutamide. The two medicines are being used together as a treatment for patients with a type of cancer called metastatic castration-sensitive prostate cancer and changes in specific DNA repair genes within their tumors. The study began in May 2021, and includes 599 patients from 27 countries. WHAT IS METASTATIC CASTRATION-SENSITIVE PROSTATE CANCER?: Metastatic castration-sensitive prostate cancer is known as mCSPC for short. It is cancer that has started in the prostate and spread to other body parts. The prostate is a gland below the bladder and helps make semen (the liquid that contains sperm). Castration-sensitive means that the cancer responds to treatments that lower testosterone in the blood. WHICH MEDICINES ARE BEING TESTED?: In this study, some patients will take talazoparib plus enzalutamide while others will take a placebo plus enzalutamide. Talazoparib and enzalutamide are two different cancer medicines. Talazoparib is not currently used to treat patients with mCSPC. Enzalutamide is used to treat patients with prostate cancer. Talazoparib plus enzalutamide is being compared with a placebo plus enzalutamide to see if patients live longer without their cancer getting worse, or them dying, when taking talazoparib plus enzalutamide or when taking a placebo plus enzalutamide. WHAT ARE THE AIMS OF THE TALAPRO-3 STUDY?: This study aims to find out if treatment with talazoparib plus enzalutamide increases the length of time the patients in the study live without their cancer getting worse, or them dying, compared with treatment with a placebo plus enzalutamide. The study will also measure how long the patients in the study live, the number and types of side effects they have, their general health and quality of life, and whether there are changes in how patients report their pain.Clinical Trial Registration: NCT03395197 (TALAPRO-2) (ClinicalTrials.gov).
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WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from the TALAPRO-2 research study (also known as a clinical trial). The TALAPRO-2 study tested the combination of two medicines called talazoparib plus enzalutamide. This combination of medicines was used as the first treatment for adult patients with metastatic castration-resistant prostate cancer. The combination of talazoparib plus enzalutamide was compared with a placebo plus enzalutamide. WHAT IS METASTATIC CASTRATION-RESISTANT PROSTATE CANCER?: Metastatic castration-resistant prostate cancer is a type of cancer that starts in the prostate and has spread to other parts of the body. Castration-resistant means that the cancer continues to grow even when testosterone levels in the blood are reduced to very low levels. Taking medicines to lower testosterone levels in the blood is a standard treatment for men with advanced prostate cancer. WHAT ARE THE AIMS OF THE TALAPRO-2 TRIAL?: TALAPRO-2 looked at if combining talazoparib plus enzalutamide would increase the length of time patients lived before their cancer got worse or they died compared with a placebo plus enzalutamide. Researchers looked at how treatment affected the size and number of tumors and the length of time before patients needed to change to a new cancer medicine. Researchers also looked at any side effects patients had during the study. WHAT ARE THE KEY TAKEAWAYS?: A total of 805 patients with metastatic castration-resistant prostate cancer took part in the study. Compared with patients who took a placebo plus enzalutamide, the group of patients who took talazoparib plus enzalutamide had a 37% reduced risk of their cancer getting worse or dying. Some patients had tumors that at the start of the study could be measured with scans. Sixty-two percent of patients who took talazoparib plus enzalutamide had their tumors decrease or shrink to the point that they could no longer be seen on scans versus 44% of patients who took a placebo plus enzalutamide. Patients who took talazoparib plus enzalutamide were more likely to have a longer time before they needed to change to a new cancer medicine. The most common side effects of talazoparib plus enzalutamide were low levels of red blood cells (66% of patients) and neutrophils (36% of patients), and excessive tiredness or exhaustion (34% of patients).Clinical Trial Registration: NCT03395197 (TALAPRO-2) (ClinicalTrials.gov).
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Kariavattom Campus Postmenopausal osteoporosis (PMO) is an old age disorder associated with estrogen deficiency, which reduces bone mass and makes bones more prone to fracture. The present study was proposed to evaluate the invivo osteogenic efficiency of Pterospermum rubiginosum methanolic bark extract (PRME) in the PMO model. Molecular docking studies on transcription factor NFATC1 showed excellent interactions with phytochemical ligands with the lowest binding energies. Female Sprague Dawley (SD) rats (n=24) were divided into four groups, (n=6 each) sham control (Group I) and osteoporotic control (Group II) groups treated with saline, PRME (50â mg/kg/day) and alendronate (10â mg/kg/day) treated with Group III and Group IV (n=6) respectively. The serum tartrate-resistant acid phosphatase 5b and cathepsin-K also exhibited a significant rise after PRME treatment 12.33±2.30â mU/ml and 427.68±46.97â pg/ml, respectively. DEXA results exhibited a remarkable increase in total bone mineral content and density values in PRME-treated animals (0.175±0.002â g/cm2) and (7.95±0.23â g) when compared to osteoporotic control (0.163±0.004â g/cm2) and (6.83±0.34 g). Long-term toxicity study revealed that PRME is non-toxic, up to 100â mg/kg bodyweight for 6â months. Our findings suggest PRME protects osteoporotic SD rats from PMO damage resulting from estrogen deficiency by regulating bone remodelling markers and upregulating BMD indices.
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Osteoporose Pós-Menopausa , Feminino , Humanos , Ratos , Animais , Osteoporose Pós-Menopausa/tratamento farmacológico , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley , Remodelação Óssea , Estrogênios , BiomarcadoresRESUMO
BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood. Type I PPB is a purely cystic lesion that has a microscopic population of primitive small cells with or without rhabdomyoblastic features and may progress to type II or III PPB, whereas type Ir lacks primitive small cells. METHODS: Children with suspected PPB were enrolled in the International PPB/DICER1 Registry. Pathology was centrally reviewed, and follow-up was ascertained annually. RESULTS: Between 2006 and 2022, 205 children had centrally reviewed type I or Ir PPB; 39% of children with type I and 5% of children with type Ir PPB received chemotherapy. Outcomes were favorable, although 11 children (nine with type I and two with type Ir PPB) experienced progression to type II/III (n = 8) or regrowth of type I PPB at the surgical site (n = 3), none of whom received chemotherapy before progression. Age and cyst size in combination were more suitable than either factor alone in predicting whether a particular lesion was type I or Ir PPB. CONCLUSIONS: For young children with type I PPB, outcomes are favorable, but complete resection is indicated because of the risk for progression. Chemotherapy may be useful in a subset of children at increased risk for recurrence/progression. Efforts to risk stratify children with type I PPB to optimize outcomes while reducing treatment-related side effects are underway.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias Pulmonares , Blastoma Pulmonar , Criança , Humanos , Pré-Escolar , Blastoma Pulmonar/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Sistema de Registros , Ribonuclease III , RNA Helicases DEAD-boxRESUMO
The landscape of advanced prostate cancer treatment has evolved tremendously in past decades. The treatment paradigm has shifted from androgen deprivation therapy (ADT) alone to doublet combinations comprising ADT with docetaxel or an androgen receptor inhibitor, and now triplet therapy involving all 3 classes of agents. Robust clinical data has demonstrated survival benefits with this strategy of upfront treatment intensification. Subgroup analysis has alluded to the importance of tailoring treatment according to metastatic disease burden. However, defining the volume of disease is becoming increasingly controversial due to the advent of next generation molecular imaging. Several trials testing established agents in the castrate-resistant setting are now underway in metastatic hormone sensitive prostate cancer patients. As the treatment milieu is enriched earlier in the disease trajectory, future studies should elucidate biomarkers to further define specific patient populations who will benefit most from treatment intensification and/or de-escalation, with what agents and for what duration.
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Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/patologia , Antagonistas de Androgênios/uso terapêutico , Docetaxel/uso terapêutico , Hormônios/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Previously, results from the TheraP trial showed that treatment with lutetium-177 [177Lu]Lu-PSMA-617 improved frequency of prostate-specific antigen (PSA) response rate and progression-free survival compared with cabazitaxel in men with metastatic castration-resistant prostate cancer. In this study, we aimed to analyse gallium-68 [68Ga]Ga-PSMA-11 PET (PSMA-PET) and 2-[18F]fluoro-2-deoxy-D-glucose PET (FDG-PET) imaging parameters as predictive and prognostic biomarkers in this patient population. METHODS: TheraP was a multicentre, open-label, randomised phase 2 trial that recruited men with metastatic castration-resistant prostate cancer after treatment with docetaxel who were suitable for cabazitaxel from 11 hospitals in Australia. Participants were required to be 18 years old or older; have adequate haematological, renal, and liver function; and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned (1:1) using a centralised system using minimisation with a random component and that stratified patients by disease burden, previous treatment with enzalutamide or abiraterone, and study site. Patients were either given cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles) or [177Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles). The primary study endpoint, analysed previously, was PSA response rate. The prespecified tertiary study endpoint was association between total tumour quantitative parameters on PSMA-PET, FDG-PET, and baseline characteristics with clinical outcomes. A SUVmean of 10 or higher on PSMA-PET was evaluated as a predictive biomarker for response to [177Lu]Lu-PSMA-617 versus cabazitaxel. A metabolic tumour volume (MTV) of 200 mL or higher on FDG-PET was tested as a prognostic biomarker. Both cutoff points were prespecified. The analysis was intention-to-treat, using logistic regression. This trial is registered with ClinicalTrials.gov, NCT03392428. FINDINGS: 200 patients were randomly assigned between Feb 6, 2018, and Sept 3, 2019. 101 men were assigned to the cabazitaxel group and 99 were assigned to the [177Lu]Lu-PSMA-617 group. The median follow-up at data cutoff of July 20, 2020, was 18·4 months (IQR 12·8-21·8). 35 (35%) of 99 men who were assigned [177Lu]Lu-PSMA-617 and 30 (30%) of 101 men who were assigned cabazitaxel had high PSMA uptake (SUVmean of ≥10). Odds of PSA response to [177Lu]Lu-PSMA-617 versus cabazitaxel were significantly higher for men with SUVmean of 10 or higher compared with those with SUVmean of less than 10 (odds ratio [OR] 12·19 [95% CI 3·42-58·76] vs 2·22 [1·11-4·51]; padj=0·039 for treatment-by-SUVmean interaction). PSA response rate for [177Lu]Lu-PSMA-617 compared with cabazitaxel was 32 (91% [95% CI 76-98]) of 35 men versus 14 (47% [29-65]) of 30 men in patients with SUVmean of 10 or higher, and 33 (52% [39-64]) of 64 men versus 23 (32% [22-45]) of 71 men in those with SUVmean of less than 10. High-volume disease on FDG-PET (MTV ≥200 mL) was seen in 30 (30%) of 99 men who were assigned [177Lu]Lu-PSMA-617 and 30 (30%) of 101 men who were assigned cabazitaxel. PSA response rate for both treatment groups combined for FDG-PET MTV of 200 mL or higher versus FDG-PET MTV of less than 200 mL was 23 (38% [95% CI 26-52]) of 60 men versus 79 (56% [48-65]) of 140 men (OR 0·44, 95% CI 0·23-0·84; padj=0·035). INTERPRETATION: In men with metastatic castration-resistant prostate cancer, PSMA-PET SUVmean was predictive of higher likelihood of favourable response to [177Lu]Lu-PSMA-617 than cabazitaxel, which provides guidance for optimal [177Lu]Lu-PSMA-617 use. High FDG-PET MTV was associated with lower responses regardless of randomly assigned treatment, warranting further research for treatment intensification. A strength of this analysis is the validation of pre-specified cutpoints within a multicentre, randomised, controlled trial. Quantitative PET parameters used, however, require specialised software and are not yet routinely available in most clinics. FUNDING: Prostate Cancer Foundation of Australia, Endocyte (a Novartis Company), Australian Nuclear Science and Technology Organisation, Movember Foundation, It's a Bloke Thing, CAN4CANCER, The Distinguished Gentleman's Ride.
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Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Adolescente , Adulto , Antígeno Prostático Específico/uso terapêutico , Fluordesoxiglucose F18 , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Prognóstico , Austrália , Resultado do TratamentoRESUMO
Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of our study, investigating safety, pharmacokinetics, pharmacodynamics and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer, estrogen receptor-positive breast cancer and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment-related AEs (any grade) were thrombocytopenia (64%), nausea (43%) and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Antitumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted.
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Benzodiazepinas/uso terapêutico , Neoplasias/tratamento farmacológico , Proteínas Nucleares/metabolismo , Neoplasias Testiculares/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Benzodiazepinas/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/antagonistas & inibidores , Receptores de Superfície Celular/antagonistas & inibidores , Adulto JovemRESUMO
BACKGROUND & AIMS: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS. METHODS: We tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8). RESULTS: Molecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (â¼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes. CONCLUSIONS: Our study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms. LAY SUMMARY: We molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.
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Carcinoma Hepatocelular , Hepatoblastoma , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Criança , Aberrações Cromossômicas , Hepatoblastoma/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Mutação , Adulto JovemRESUMO
BACKGROUND: Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers ß radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. METHODS: We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0-2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. FINDINGS: Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16-42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9-37]; p=0·0016). Grade 3-4 adverse events occurred in 32 (33%) of 98 men in the [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [177Lu]Lu-PSMA-617. INTERPRETATION: [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. FUNDING: Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.
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Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Lutécio/uso terapêutico , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Radioisótopos/uso terapêutico , Taxoides/uso terapêutico , Administração Intravenosa , Idoso , Antígenos de Superfície/genética , Glutamato Carboxipeptidase II/genética , Humanos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Antígeno Prostático Específico/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/radioterapia , Resultado do TratamentoRESUMO
BACKGROUND: Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC. METHODS: We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models. RESULTS: The 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59-3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies. CONCLUSIONS: Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Biomarcadores Tumorais/genética , Docetaxel/uso terapêutico , Feminino , Humanos , Lipidômica , Lipídeos , Masculino , Fosfatidilinositol 3-Quinases/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/metabolismo , Esfingolipídeos/uso terapêuticoRESUMO
Early detection and management of prostate cancer has evolved over the past decade, with a focus now on harm minimisation and reducing overdiagnosis and overtreatment, given the proven improvements in survival from randomised controlled trials. Multiparametric magnetic resonance imaging (mpMRI) is now an important aspect of the diagnostic pathway in prostate cancer, improving the detection of clinically significant prostate cancer, enabling accurate localisation of appropriate sites to biopsy, and reducing unnecessary biopsies in most patients with normal magnetic resonance imaging scans. Biopsies are now performed transperineally, substantially reducing the risk of post-procedure sepsis. Australian-led research has shown that prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has superior accuracy in the staging of prostate cancer than conventional imaging (CT and whole-body bone scan). Localised prostate cancer that is low risk (International Society for Urological Pathology [ISUP] grade 1, Gleason score 3 + 3 = 6; and ISUP grade group 2, Gleason score 3 + 4 = 7 with less than 10% pattern 4) can be offered active surveillance, reducing harms from overtreatment. Prostatectomy and definitive radiation remain the gold standard for localised intermediate and high risk disease. However, focal therapy is an emerging experimental treatment modality in Australia in carefully selected patients. The management of advanced prostate cancer treatment has evolved to now include several novel agents both in the metastatic hormone-sensitive and castration-resistant disease settings. Multimodal therapy with androgen deprivation therapy, additional systemic therapy and radiotherapy are often recommended. PSMA-based radioligand therapy has emerged as a treatment option for metastatic castration-resistant prostate cancer and is currently being evaluated in earlier disease states.
Assuntos
Próstata , Neoplasias da Próstata , Masculino , Humanos , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/terapia , Neoplasias da Próstata/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Antagonistas de Androgênios , Androgênios , AustráliaRESUMO
BACKGROUND: Docetaxel has emerged as a standard-of-care for metastatic hormone-sensitive prostate cancer (mHSPC). Uptake of docetaxel for mHSPC in Australia has not previously been reported. AIMS: To investigate the real-world uptake of docetaxel in mHSPC and to identify predictors of utilisation of docetaxel in mHSPC. METHODS: Men diagnosed from June 2014 to December 2018 and enrolled in the Prostate Cancer Outcomes Registry-Victoria (PCOR-Vic) were included. Data collected include demographics, diagnosis method and institution, staging investigations and treatments within 12 months of diagnosis. Wilcoxon rank-sum, Chi-squared and trend tests were used to identify predictors of docetaxel utilisation. All predictors were entered as covariates simultaneously into a multivariable logistic regression model. Statistical significance was set at 0.05 (two sided). RESULTS: In all, 1014 men with mHSPC were analysed, 25% of whom received docetaxel with androgen deprivation therapy. Uptake of docetaxel increased from 20% in 2014 to 33% in 2018. Predictors of higher usage of docetaxel were younger age and treatment in a private hospital, with both remaining significant on multivariable analysis. Notably, the proportion of men aged <70 years receiving docetaxel increased from 54% in 2014-2015 to 64% in 2016-2018, while in men aged ≥70 years the comparative figures were 15% and 22% respectively. CONCLUSIONS: Although docetaxel was not used in the majority of cases, there was a clear increase in docetaxel uptake, especially in younger men following publication of the CHAARTED and STAMPEDE trials. Identifying barriers to real-world implementation of pivotal clinical trial data is critical to improving outcomes in mHSPC.
Assuntos
Antagonistas de Androgênios , Neoplasias da Próstata , Antagonistas de Androgênios/uso terapêutico , Androgênios , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel/uso terapêutico , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/epidemiologia , Resultado do Tratamento , VitóriaRESUMO
The C-N cross-coupling of (hetero)aryl (pseudo)halides with NH substrates employing nickel catalysts and organic amine bases represents an emergent strategy for the sustainable synthesis of (hetero)anilines. However, unlike protocols that rely on photoredox/electrochemical/reductant methods within NiI/III cycles, the reaction steps that comprise a putative Ni0/II C-N cross-coupling cycle for a thermally promoted catalyst system using organic amine base have not been elucidated. Here we disclose an efficient new nickel-catalyzed protocol for the C-N cross-coupling of amides and 2'-(pseudo)halide-substituted acetophenones, for the first time where the (pseudo)halide is chloride or sulfonate, which makes use of the commercial bisphosphine ligand PAd2-DalPhos (L4) in combination with an organic amine base/halide scavenger, leading to 4-quinolones. Room-temperature stoichiometric experiments involving isolated Ni0, I, and II species support a Ni0/II pathway, where the combined action of DBU/NaTFA allows for room-temperature amide cross-couplings.
Assuntos
Aminas , Níquel , 4-Quinolonas , Amidas , Aminação , CatáliseRESUMO
BACKGROUND: The androgen receptor (AR) pathway-associated gene nuclear receptor coactivator 2 (NCOA2) has an established oncogenic role in early prostate cancer and likewise is a driver of metastatic disease and castration-resistant prostate cancer. However, its significance as a biomarker in metastatic castration-resistant prostate cancer (mCRPC), both alone and in conjunction with co-occurring AR alterations using a liquid biopsy approach has not been investigated. METHODS: Ninety-one patients were included in this study, (n = 68 receiving an androgen receptor pathway inhibitor and n = 23 receiving taxane chemotherapy). Up to 30 ml of peripheral blood was collected before commencing treatment from each patient. Plasma cell-free DNA, along with a matched germline sample, underwent targeted next-generation sequencing using a validated, highly sensitive in-house prostate cancer panel. Variants in AR and NCOA2 were identified and correlated with clinical outcomes. RESULTS: Plasma AR and NCOA2 aberrations were identified in 35% and 13% of the cohort, respectively, whilst 8% had concurrent AR and NCOA2 alterations. NCOA2 copy number gain and any NCOA2 aberration predicted for lower prostate-specific antigen (PSA) response rates. Likewise, median overall survival was shorter for NCOA2 gain (10.1 vs. 18.3 months; p = .004), remaining significant after adjusting for covariates including circulating tumor DNA fraction and tumor suppressor gene alterations. Importantly, dual AR and NCOA2 aberrations were also associated with inferior outcomes, including no PSA responses in patients treated with AR pathway inhibitors (0% vs. 64%; p = .02). CONCLUSIONS: These data highlight the importance of identifying multiple markers of AR pathway modulation in mCRPC and represent the first instance of the assessment of plasma NCOA2 status as a prognostic biomarker for standard-of-care therapies. Further assessment is warranted to determine if NCOA2 aberrations are a marker of primary resistance to AR pathway inhibitors.
Assuntos
Coativador 2 de Receptor Nuclear/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Receptores Androgênicos/sangue , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Taxa de Sobrevida , Taxoides/uso terapêuticoRESUMO
BACKGROUND: Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival. METHODS: We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years. RESULTS: A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively. CONCLUSIONS: The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132 ; EudraCT number, 2007-002402-21 .).