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1.
Cell ; 173(3): 611-623.e17, 2018 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-29656891

RESUMO

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Progressão da Doença , Neoplasias Renais/genética , Neoplasias Renais/patologia , Mutação , Regiões 5' não Traduzidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 5 , Feminino , Dosagem de Genes , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Telomerase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética
2.
Cell ; 173(3): 595-610.e11, 2018 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-29656894

RESUMO

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Biomarcadores Tumorais , Cromossomos , Evolução Clonal , Progressão da Doença , Evolução Molecular , Feminino , Heterogeneidade Genética , Variação Genética , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Mutação , Metástase Neoplásica , Fenótipo , Filogenia , Prognóstico , Estudos Prospectivos , Análise de Sequência de DNA
3.
J Vasc Interv Radiol ; 34(8): 1291-1302.e1, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36977432

RESUMO

The discovery of increasing numbers of actionable molecular and gene targets for cancer treatment has driven the demand for tissue sampling for next-generation sequencing (NGS). Requirements for sequencing can be very specific, and inadequate sampling leads to delays in management and decision making. It is important that interventional radiologists are aware of NGS technologies and their common applications and be cognizant of the factors that contribute to successful sample sequencing. This review summarizes the fundamentals of cancer tissue collection and processing for NGS. It elaborates on sequencing technologies and their applications with the aim of providing readers with a working understanding that can enhance their clinical practice. It then describes imaging, tumor, biopsy, and sample collection factors that improve the chances of NGS success. Finally, it discusses future practice, highlighting the problem of undersampling in both clinical and research settings and the opportunities within interventional radiology to address this.


Assuntos
Neoplasias , Humanos , Neoplasias/genética , Biópsia , Sequenciamento de Nucleotídeos em Larga Escala/métodos
4.
Eur Radiol ; 32(7): 4647-4656, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35092476

RESUMO

OBJECTIVES: To evaluate whether multiparametric bone MRI (mpBMRI) utilising a combination of DWI signal, ADC and relative fat-fraction (rFF) can identify bone metastases, which provide high diagnostic biopsy yield and next-generation genomic sequencing (NGS) feasibility. METHODS: A total of 150 CT-guided bone biopsies performed by interventional radiologists (3/2013 to 2/2021) at our centre were reviewed. In 43 patients, contemporaneous DWI and rFF images, calculated from 2-point T1w Dixon MRI, were available. For each biopsied lesion, a region of interest (ROI) was delineated on ADC and rFF images and the following MRI parameters were recorded: visual classification of DWI signal intensity (SI), mean, median, 10th and 90th centile ADC and rFF values. Non-parametric tests were used to compare values between tumour positive/negative biopsies and feasible/non-feasible NGS, with p-values < 0.05 deemed significant. RESULTS: The mpBMRI combination high DWI signal, mean ADC < 1100 µm2/s and mean rFF < 20% identified tumour-positive biopsies with 82% sensitivity, 80% specificity, a positive predictive value (PPV) of 93% (p = 0.001) and NGS feasibility with 91% sensitivity, 78% specificity and 91% PPV (p < 0.001). The single MRI parameters DWI signal, ADC and rFF failed to distinguish between tumour-positive and tumour-negative biopsies (each p > 0.082). In NGS feasible biopsies, mean and 90th centile rFF were significantly smaller (each p < 0.041). Single ADC parameters did not show significant difference regarding NGS feasibility (each p > 0.292). CONCLUSIONS: MpBMRI utilising the combination of DWI signal, ADC and rFF can identify active bone metastases, which provide biopsy tissue with high diagnostic yield and NGS feasibility. KEY POINTS: • Multiparametric bone MRI with diffusion-weighted and relative fat-fraction images helps to identify active bone metastases suitable for CT-guided biopsy. • Target lesions for CT-guided bone biopsies in cancer patients can be chosen with greater confidence. • CT-guided bone biopsy success rates, especially yielding sufficient viable tissue for advanced molecular tissue analyses, can be improved.


Assuntos
Neoplasias Ósseas , Imagem de Difusão por Ressonância Magnética , Biópsia , Neoplasias Ósseas/secundário , Imagem de Difusão por Ressonância Magnética/métodos , Estudos de Viabilidade , Humanos , Biópsia Guiada por Imagem , Imageamento por Ressonância Magnética/métodos , Tomografia Computadorizada por Raios X
5.
Eur Radiol ; 32(10): 6820-6829, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35881184

RESUMO

OBJECTIVES: Investigate the laboratory, imaging and procedural factors that are associated with a tumour-positive and/or NGS-feasible CT-guided sclerotic bone lesion biopsy result in cancer patients. METHODS: In total, 113 CT-guided bone biopsies performed in cancer patients by an interventional radiologist in one institution were retrospectively reviewed. Sixty-five sclerotic bone biopsies were eventually included and routine blood parameters and tumour marker levels were recorded. Non-contrast (NC) biopsy CTs (65), contrast-enhanced CTs (24), and PET/CTs (22) performed within four weeks of biopsy were reviewed; lesion location, diameter, lesion-to-cortex distance, and NC-CT appearance (dense-sclerosis versus mild-sclerosis) were noted. Mean NC-CT, CE-CT HU, and PET SUVmax were derived from biopsy tract and lesion segmentations. Needle diameter, tract length, and number of samples were noted. Comparisons between tumour-positive/negative and next-generation sequencing (NGS)-feasible/non-feasible biopsies determined significant (p < 0.05) laboratory, imaging, and procedural parameter differences. RESULTS: Seventy-four percent of biopsies were tumour-positive. NGS was feasible in 22/30 prostate cancer patients (73%). Neither laboratory blood parameters, PET/CT availability, size, nor lesion-to-cortex distance affected diagnostic yield or NGS feasibility (p > 0.298). Eighty-seven percent of mildly sclerotic bone (mean 244 HU) biopsies were positive compared with 56% in dense sclerosis (622 HU, p = 0.005) and NC-CT lesion HU was significantly lower in positive biopsies (p = 0.003). A 610 HU threshold yielded 89% PPV for tumour-positive biopsies and a 370 HU threshold 94% PPV for NGS-feasible biopsies. FDG-PET and procedural parameters were non-significant factors (each p > 0.055). CONCLUSION: In cancer patients with sclerotic bone disease, targeting areas of predominantly mild sclerosis in lower CT-attenuation lesions can improve tumour tissue yield and NGS feasibility. KEY POINTS: • Areas of predominantly mild sclerosis should be preferred to areas of predominantly dense sclerosis for CT-guided bone biopsies in cancer patients. • Among sclerotic bone lesions in prostate cancer patients, lesions with a mean HU below 370 should be preferred as biopsy targets to improve NGS feasibility. • Laboratory parameters and procedure related factors may have little implications for CT-guided sclerotic bone biopsy success.


Assuntos
Doenças Ósseas , Neoplasias Ósseas , Doenças das Cartilagens , Neoplasias da Próstata , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Humanos , Biópsia Guiada por Imagem/métodos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Esclerose , Tomografia Computadorizada por Raios X/métodos
6.
Ann Surg ; 274(6): e1093-e1098, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31850986

RESUMO

OBJECTIVE: To analyze whether the route of preoperative biopsy influences oncological outcome in GIST patients. SUMMARY OF BACKGROUND DATA: Preoperative biopsies are widely used for diagnosing GIST. Little is known about the risk of tumor seeding after different routes of biopsy. METHODS: Patients who underwent resection of a primary GIST between 1996 and 2014 were identified from 2 databases from 2 tertiary referral centers. Survival data were obtained using the Kaplan-Meier method. Possible confounders were identified using Cox regression analysis. The primary endpoint was local recurrence free survival (RFS) and the secondary endpoint was DSS. RESULTS: A total of 228 patients were included, with a median age of 62 years (range 17-86) and a median follow-up time of 53 months (range 1-204). From these patients, 42 patients did not have a biopsy (18%), 70 underwent a transcutaneous biopsy (31%), and 116 a transluminal biopsy (51%). A total of 42 patients (19.0%) had a local and/or distant recurrence. From the 70 patients with a transcutaneous biopsy, only 1 patient developed a needle tract recurrence (1.4%). Local RFS and DSS were both significantly shorter in the transcutaneous biopsy group on univariate analysis compared to the other groups; however, in multivariate analysis the route of biopsy did not influence local RFS (P = 0.128) or DSS (P = 0.096). CONCLUSIONS: Transluminal or transcutaneous biopsies for diagnosing GIST do not significantly alter the risk of local recurrent disease or DSS in multivariate Cox regressions. The risk of needle tract seeding after transcutaneous biopsy was low.


Assuntos
Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/cirurgia , Inoculação de Neoplasia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Fatores de Risco , Taxa de Sobrevida
7.
Eur Radiol ; 30(12): 6702-6708, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32666317

RESUMO

OBJECTIVES: Percutaneous liver biopsy (PLB) poses specific challenges in oncological patients such as bleeding and tumour seeding. This study's aim was to compare a coaxial (C-PLB) and non-coaxial (NC-PLB) biopsy technique in terms of diagnostic yield, safety and seeding risk of image-guided PLB techniques in an oncological setting. METHODS: Local research committee approval was obtained for this single-site retrospective study. Patients who underwent a PLB between November 2011 and December 2017 were consecutively included. Medical records were reviewed to determine diagnostic yield and complications. Follow-up imaging was re-reviewed for seeding, defined as visible tumour deposits along the PLB track. Mann-Whitney U and chi-squared tests were performed to investigate differences between biopsy techniques in sample number, complications and seeding rate. RESULTS: In total, 741 patients (62 ± 13 years, 378 women) underwent 932 PLB (C-PLB 72.9% (679/932); NC-PLB 27.1% (253/932)). More tissue cores (p < 0.001) were obtained with C-PLB (median 4 cores; range 1-12) compared with NC-PLB (2 cores; range 1-4) and diagnostic yield was similar for both techniques (C-PLB 92.6% (629/679); NC-PLB 92.5% (234/253); p = 0.940). Complication rate (9.3%; 87/932) using C-PLB (8.2% (56/679)) was lower compared with NC-PLB (12.3% (31/253); p = 0.024). Major complications were uncommon (C-PLB 2.7% (18/679); NC-PLB 2.8% (7/253)); bleeding developed in 1.2% (11/932; C-PLB 1.2% (8/679); NC-PLB 1.2% (3/253)). Seeding was a rare event, occurring significantly less in C-PLB cases (C-PLB 1.3% (7/544); NC-PLB 3.1% (6/197); p = 0.021). CONCLUSIONS: C-PLB allows for high diagnostic tissue yield with a lower complication and seeding rate than a NC-PLB and should be the preferred method in an oncological setting. KEY POINTS: • A coaxial percutaneous liver biopsy achieves a significant higher number of cores and fewer complications than a non-coaxial biopsy technique. • The risk of tumour seeding is very low and is significantly lower using the coaxial biopsy technique. • In this study, a larger number of cores (median = 4) could be safely acquired using the coaxial technique, providing sufficient material for advanced molecular analysis.


Assuntos
Procedimentos Cirúrgicos do Sistema Digestório , Biópsia Guiada por Imagem , Biópsia por Agulha , Feminino , Humanos , Fígado/diagnóstico por imagem , Estudos Retrospectivos
8.
Curr Treat Options Oncol ; 21(7): 55, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32462367

RESUMO

OPINION STATEMENT: The treatment of advanced GIST is rapidly evolving with the development of novel molecular compounds such as avapritinib and ripretinib, but also promising results have been achieved with cabozantinib in a phase II trial. The availability of over five lines of treatment for patients with advanced GIST is likely to completely shift the current second-line and third-line treatment options, and will also potentially enable a personalised approach to treatment. Imatinib will most likely remain as the first-line treatment of choice for the vast majority of GIST patients. However, for GIST patients with tumours harbouring a D842V mutation in PDGFRA exon 18, avapritinib has shown efficacy and will become first-line therapy for this molecular subgroup. For second- and third-line treatment, results are awaited of a number of clinical trials. However, second-line and further treatment could potentially be tailored depending on secondary mutations found in imatinib-resistant GISTs. As secondary resistance to TKIs remains the biggest challenge in the treatment of GIST and despite negative results with alternating regimens in phase II, combination treatments should be further evaluated to tackle this issue. Moreover, the favourable safety profiles observed with avapritinib and ripretinib suggest that combination treatments are feasible, for instance, combining two TKIs or a TKI with drugs targeting downstream signalling pathways, such as PI3K inhibitors or MEK inhibitors. Finally, in line with further personalisation of treatment in GIST, a multidisciplinary approach is essential, and local treatment options, such as RFA, resection in case of unifocal progression, and radiotherapy, should be considered.


Assuntos
Tumores do Estroma Gastrointestinal/terapia , Tomada de Decisão Clínica , Ensaios Clínicos como Assunto , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Gerenciamento Clínico , Suscetibilidade a Doenças , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/etiologia , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Retratamento , Resultado do Tratamento
9.
Gastroenterology ; 154(4): 1066-1079.e5, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29113809

RESUMO

BACKGROUND & AIMS: Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small-molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors. METHODS: We performed a high-throughput screen of 484 small-molecule compounds to identify those that reduced viability of 6 human CCA cell lines. We tested the effects of HSP90 inhibitors on cells with disruption of the MIR21 gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of MIR21. We obtained CCA biopsies from patients, cultured them as organoids (patient-derived organoids). We assessed their architecture, mutation and gene expression patterns, response to compounds in culture, and when grown as subcutaneous xenograft tumors in mice. RESULTS: Cells with IDH1 and PBRM1 mutations had the highest level of sensitivity to histone deacetylase inhibitors. HSP90 inhibitors were effective in all cell lines, irrespective of mutations. Sensitivity of cells to HSP90 inhibitors correlated inversely with baseline level of MIR21. Disruption of MIR21 increased cell sensitivity to HSP90 inhibitors. CCA cells that expressed transgenic MIR21 were more resistant to HSP90 inhibitors than cells transfected with control vectors; inactivation of MIR21 in these cells restored sensitivity to these agents. MIR21 was shown to target the DnaJ heat shock protein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of patient-derived organoids to HSP90 inhibitors, in culture and when grown as xenograft tumors in mice, depended on expression of miRNA21. CONCLUSIONS: miRNA21 appears to mediate resistance of CCA cells to HSP90 inhibitors by reducing levels of DNAJB5. HSP90 inhibitors might be developed for the treatment of CCA and miRNA21 might be a marker of sensitivity to these agents.


Assuntos
Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , MicroRNAs/metabolismo , Animais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Proteínas de Ligação a DNA , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Isocitrato Desidrogenase/genética , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/genética , Mutação , Proteínas Nucleares/genética , Organoides , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Fatores de Transcrição/genética , Transfecção , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Gut ; 67(8): 1484-1492, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-28790159

RESUMO

OBJECTIVE: Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection. DESIGN: Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies. RESULTS: Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07-1.04), p=0.06). CONCLUSIONS: Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Biomarcadores/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico por imagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
13.
Radiol Imaging Cancer ; 6(2): e230077, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38363197

RESUMO

Rectal tumors extending beyond the total mesorectal excision (TME) plane (beyond-TME) require particular multidisciplinary expertise and oncologic considerations when planning treatment. Imaging is used at all stages of the pathway, such as local tumor staging/restaging, creating an imaging-based "roadmap" to plan surgery for optimal tumor clearance, identifying treatment-related complications, which may be suitable for radiology-guided intervention, and to detect recurrent or metastatic disease, which may be suitable for radiology-guided ablative therapies. Beyond-TME and exenterative surgery have gained acceptance as potentially curative procedures for advanced tumors. Understanding the role, techniques, and pitfalls of current imaging techniques is important for both radiologists involved in the treatment of these patients and general radiologists who may encounter patients undergoing surveillance or patients presenting with surgical complications or intercurrent abdominal pathology. This review aims to outline the current and emerging roles of imaging in patients with beyond-TME and recurrent rectal malignancy, focusing on practical tips for image interpretation and surgical planning in the beyond-TME setting. Keywords: Abdomen/GI, Rectum, Oncology © RSNA, 2024.


Assuntos
Adenocarcinoma , Neoplasias Retais , Humanos , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/cirurgia , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/cirurgia , Neoplasias Retais/patologia , Reto/patologia , Reto/cirurgia , Imagem Multimodal
14.
Clin Cancer Res ; 30(10): 2140-2159, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38376926

RESUMO

PURPOSE: The multi-kinase inhibitor (mKi) regorafenib has demonstrated efficacy in chemorefractory patients with metastatic colorectal cancer (mCRC). However, lack of predictive biomarkers and concerns over significant toxicities hamper the use of regorafenib in clinical practice. EXPERIMENTAL DESIGN: Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemorefractory patients with mCRC treated with regorafenib in a phase II clinical trial (PROSPECT-R n = 40; NCT03010722) and in a multicentric validation cohort (n = 241). Tissue biopsies collected at baseline, after 2 months and at progression in the PROSPECT-R trial were used to establish patient-derived organoids (PDO) and for molecular analyses. MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform and results were validated by digital-droplet PCR and/or ISH in paired liquid and tissue biopsies. PDOs co-cultures and PDO-xenotransplants were generated for functional analyses. RESULTS: Large-scale microRNA expression analysis in longitudinal matched liquid and tissue biopsies from the PROSPECT-R trial identified MIR652-3p as a biomarker of clinical benefit to regorafenib. These findings were confirmed in an independent validation cohort and in a "control" group of 100 patients treated with lonsurf. Using ex vivo co-culture assays paired with single-cell RNA-sequencing of PDO established pre- and post-treatment, we modeled regorafenib response observed in vivo and in patients, and showed that MIR652-3p controls resistance to regorafenib by impairing regorafenib-induced lethal autophagy and by orchestrating the switch from neo-angiogenesis to vessel co-option. CONCLUSIONS: Our results identify MIR652-3p as a potential biomarker and as a driver of cell and non-cell-autonomous mechanisms of resistance to regorafenib.


Assuntos
Biomarcadores Tumorais , MicroRNA Circulante , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Compostos de Fenilureia , Piridinas , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/sangue , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Piridinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Animais , Feminino , Estudos Prospectivos , Masculino , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Idoso , Biópsia Líquida/métodos , Pessoa de Meia-Idade , Linhagem Celular Tumoral , MicroRNAs/genética , MicroRNAs/sangue
15.
Biomedicines ; 11(4)2023 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-37189680

RESUMO

The management of hepatocellular carcinoma (HCC) remains complex and will continue to rely on the multidisciplinary input of hepatologists, surgeons, radiologists, oncologists and radiotherapists. With the appropriate staging of patients and selection of suitable treatments, the outcomes for HCC are improving. Surgical treatments encompassing both liver resection and orthotopic liver transplantation (OLT) are the definitive curative-intent options. However, patient suitability, as well as organ availability, pose essential limitations. Consequently, non-surgical options, such as ablative techniques, play an increasingly important role, especially in small HCCs, where overall and disease-free survival can be comparable to surgical resection. Ablative techniques are globally recommended in recognised classification systems, showing increasingly promising results. Recent technical refinements, as well as the emerging use of robotic assistance, may expand the treatment paradigm to achieve improved oncological results. At present, in very early stage and early stage unresectable disease, percutaneous thermal ablation is considered the treatment of choice. Owing to their different features, various ablative techniques, including radiofrequency ablation, microwave ablation, cryotherapy ablation and irreversible electroporation, have been shown to confer different comparative advantages and applicability. We herein review the role of available ablative techniques in the current complex multidisciplinary management of HCC, with a main focus on the indications and outcomes, and discuss future perspectives.

16.
Cancer Imaging ; 23(1): 121, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38102655

RESUMO

BACKGROUND: Bone biopsies in metastatic castrate-resistant prostate cancer (mCRPC) patients can be challenging. This study's objective was to prospectively validate a multiparametric bone MRI (mpBMRI) algorithm to facilitate target lesion selection in mCRPC patients with sclerotic bone disease for subsequent CT-guided bone biopsies. METHODS: 20 CT-guided bone biopsies were prospectively performed between 02/2021 and 11/2021 in 17 mCRPC patients with only sclerotic bone disease. Biopsy targets were selected based on MRI, including diffusion-weighted (DWI) and T1-weighted VIBE Dixon MR images, allowing for calculation of the apparent diffusion coefficient (ADC) and the relative fat-fraction (rFF), respectively. Bone marrow with high DWI signal, ADC < 1100 µm2/s and rFF < 20% was the preferred biopsy target. Tumor content and NGS-feasibility was assessed by a pathologist. Prognostic routine laboratory blood parameters, target lesion size, biopsy tract length, visual CT density, means of HU, ADC and rFF were compared between successful and unsuccessful biopsies (p < 0.05 = significant). RESULTS: Overall, 17/20 (85%) biopsies were tumor-positive and next-generation genomic sequencing (NGS) was feasible in 13/18 (72%) evaluated samples. Neither laboratory parameters, diameter, tract length nor visual CT density grading showed significant differences between a positive versus negative or NGS feasible versus non-feasible biopsy results (each p > 0.137). Lesion mean HU was 387 ± 187 HU in NGS feasible and 493 ± 218 HU in non-feasible biopsies (p = 0.521). For targets fulfilling all MRI selection algorithm criteria, 13/14 (93%) biopsies were tumor-positive and 10/12 (83%) provided NGS adequate tissue. CONCLUSIONS: Multiparametric bone MRI can facilitate target lesion selection for subsequent CT-guided bone biopsy in mCPRC patients with sclerotic metastases. TRIAL REGISTRATION: Committee for Clinical Research of the Royal Marsden Hospital registration number SE1220.


Assuntos
Doenças Ósseas , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Biópsia Guiada por Imagem , Tomografia Computadorizada por Raios X , Imageamento por Ressonância Magnética/métodos
17.
Int J Comput Assist Radiol Surg ; 18(10): 1819-1828, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37072657

RESUMO

PURPOSE: Radiofrequency ablation (RFA) is a curative treatment option for small lung metastases, which conventionally involves multiple freehand manipulations until the treating electrode is satisfactorily positioned. Stereotactic and robotic guidance has been gaining popularity for liver ablation, although has not been established in lung ablation. The purpose of this study is to determine the feasibility, safety, and accuracy of robotic RFA for pulmonary metastases, and compare procedures with a conventional freehand cohort. METHODS: A single center study with prospective robotic cohort, and retrospective freehand cohort. RFA was performed under general anesthesia using high frequency jet ventilation and CT guidance. Main outcomes were (i) feasibility/technical success (ii) safety using Common Terminology Criteria for Adverse Events (iii) targeting accuracy (iv) number of needle manipulations for satisfactory ablation. Robotic and freehand cohorts were compared using Mann-Whitney U tests for continuous variables, and Fisher's exact for categorical variables. RESULTS: Thirty-nine patients (mean age 65 ± 13 years, 20 men) underwent ablation of 44 pulmonary metastases at single specialist cancer center between July 2019 and August 2022. 20 consecutive participants underwent robotic ablation, and 20 consecutive patients underwent freehand ablation. All 20/20 (100%) robotic procedures were technically successful, and none were converted to freehand procedures. There were 6/20 (30%) adverse events in the robotic cohort, and 15/20 (75%) in the freehand cohort (P = 0.01). Robotic placement was highly accurate with 6 mm tip-to-target distance (range 0-14 mm) despite out-of-plane approaches, with fewer manipulations than freehand placement (median 0 vs. 4.5 manipulations, P < 0.001 and 7/22, 32% vs. 22/22, 100%, P < 0.001). CONCLUSIONS: Robotic radiofrequency ablation of pulmonary metastases with general anesthesia and high frequency jet ventilation is feasible and safe. Targeting accuracy is high, and fewer needle/electrode manipulations are required to achieve a satisfactory position for ablation than freehand placement, with early indications of reduced complications.


Assuntos
Ablação por Cateter , Neoplasias Pulmonares , Ablação por Radiofrequência , Procedimentos Cirúrgicos Robóticos , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Estudos de Coortes , Estudos Prospectivos , Ablação por Cateter/métodos , Tomografia Computadorizada por Raios X/métodos , Neoplasias Pulmonares/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
18.
Br J Radiol ; 95(1134): 20220217, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35290098

RESUMO

OBJECTIVE: A commercially available CT-guided robot offers enhanced abilities in planning, targeting, and confirming accurate needle placement. In this short communication, we describe our first UK experience of robotic interventional oncology procedures. METHODS: We describe the device, discuss installation, operation, and report upon needle insertion success, accuracy (path deviation; PD and tip deviation; TD), number of adjustments, complications, and procedural success. RESULTS: Nine patients (seven males), median age 66 years (range 43-79) were consented for biopsy or ablation between March and April 2021. Needle placement in biopsy was more accurate than ablation (median 1 vs 11 mm PD and 1 vs 20 mm TD) and required fewer adjustments (median 0 vs 5). No complications arose, and all procedures were successful (diagnostic material obtained or complete ablation at follow-up). CONCLUSION: Short procedure times and very high levels of accuracy were readily achieved with biopsy procedures, although tumour ablation was less accurate which likely reflects higher procedural complexity. ADVANCES IN KNOWLEDGE: Achieving highly accurate robotic biopsy with is feasible within a very short time span. Further work is required to maximise the potential of robotic guidance in tumour ablation procedures, which is likely due to higher complexity giving a longer learning curve.


Assuntos
Procedimentos Cirúrgicos Robóticos , Robótica , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Agulhas , Procedimentos Cirúrgicos Robóticos/métodos , Tomografia Computadorizada por Raios X/métodos , Reino Unido
19.
Eur Radiol Exp ; 6(1): 55, 2022 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-36411379

RESUMO

BACKGROUND: Magnetic resonance imaging (MRI) can be used to target tumour components in biopsy procedures, while the ability to precisely correlate histology and MRI signal is crucial for imaging biomarker validation. Robotic MRI/computed tomography (CT) fusion biopsy offers the potential for this without in-gantry biopsy, although requires development. METHODS: Test-retest T1 and T2 relaxation times, attenuation (Hounsfield units, HU), and biopsy core quality were prospectively assessed (January-December 2021) in a range of gelatin, agar, and mixed gelatin/agar solutions of differing concentrations on days 1 and 8 after manufacture. Suitable materials were chosen, and four biopsy phantoms were constructed with twelve spherical 1-3-cm diameter targets visible on MRI, but not on CT. A technical pipeline was developed, and intraoperator and interoperator reliability was tested in four operators performing a total of 96 biopsies. Statistical analysis included T1, T2, and HU repeatability using Bland-Altman analysis, Dice similarity coefficient (DSC), and intraoperator and interoperator reliability. RESULTS: T1, T2, and HU repeatability had 95% limits-of-agreement of 8.3%, 3.4%, and 17.9%, respectively. The phantom was highly reproducible, with DSC of 0.93 versus 0.92 for scanning the same or two different phantoms, respectively. Hit rate was 100% (96/96 targets), and all operators performed robotic biopsies using a single volumetric acquisition. The fastest procedure time was 32 min for all 12 targets. CONCLUSIONS: A reproducible biopsy phantom was developed, validated, and used to test robotic MRI/CT-fusion biopsy. The technique was highly accurate, reliable, and achievable in clinically acceptable timescales meaning it is suitable for clinical application.


Assuntos
Gelatina , Procedimentos Cirúrgicos Robóticos , Reprodutibilidade dos Testes , Ágar , Biópsia Guiada por Imagem , Imageamento por Ressonância Magnética/métodos , Tomografia Computadorizada por Raios X/métodos
20.
Anticancer Res ; 41(10): 5089-5096, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593459

RESUMO

BACKGROUND/AIM: Distinguishing true oligometastatic disease from early polymetastatic disease is vital in patients with soft tissue sarcoma as contemporary treatment strategies differ significantly. Clinical factors such as tumour biology, organ involved, number of lesions, and patient fitness influence clinical decisions. PATIENTS AND METHODS: A retrospective search of a prospective database identified patients with new distant relapse, treated between 2009 and 2012. RESULTS: A total of 223 patients were included, and oligometastases were diagnosed in 81 (36%) patients, which were pulmonary in just over half of cases. These were treated with local therapy in 66 of 89 cases, and 7 patients received subsequent treatment for additional oligometastases. Metastasectomy was the most common treatment modality. A total of 16/66 patients (24%) underwent active surveillance for >6 months prior to local therapy. CONCLUSION: Patients with oligometastatic disease can experience durable disease control with timely multimodality treatment approaches for evolving metastatic disease, where disease biology allows.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Metastasectomia/mortalidade , Sarcoma/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Sarcoma/patologia , Sarcoma/terapia , Taxa de Sobrevida , Adulto Jovem
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