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1.
Annu Rev Med ; 73: 267-278, 2022 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-34606324

RESUMO

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third leading cause of cancer-related death worldwide. Single-agent anti-PD-1 immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in early-phase trials, a finding that was not confirmed in phase III studies. The combination of atezolizumab (an anti-PD-L1 ICI) with bevacizumab (an anti-VEGF antibody) was approved as first-line therapy in 2020, however, with significant improvement in response rate, progression-free survival, and overall survival in comparison with the previous standard of care, sorafenib. Numerous ongoing clinical trials are assessing ICIs in combination with each other or with targeted agents, and also in earlier stages with local therapies. This review summarizes the latest concepts in the use of ICIs for the management of HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Anticorpos Monoclonais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Imunoterapia , Neoplasias Hepáticas/tratamento farmacológico , Intervalo Livre de Progressão
2.
Curr Treat Options Oncol ; 22(4): 33, 2021 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-33641042

RESUMO

OPINION STATEMENT: Malignant peripheral nerve sheath tumors (MPNSTs) are rare mesenchymal neoplasms that represent a profound therapeutic challenge due to their high proclivity for recurrence and metastasis and relatively poor response to systemic therapy regimens. While our understanding of the pathophysiology of MPNST is growing, including loss of the tumor suppressor gene neurofibromin and subsequent activation of the Ras pathway, targeted therapy to modify the poor prognosis seen in MPNST patients has thus far been without success. Correspondingly, MPNST patients are treated as per soft tissue sarcoma treatment algorithms with anthracycline-based therapy as the front-line therapy of choice for patients with unresectable, locally advanced, or metastatic MPNST. Beyond first-line anthracycline-based therapy, other standard cytotoxic chemotherapy agents used in advanced MPNST include the alkylating agent ifosfamide and the topoisomerase II inhibitor etoposide. Notably, soft tissue sarcoma regimens are used in MPNST despite distinct systemic therapy sensitivity and prognosis. This is particularly notable for neurofibromatosis type 1 (NF1)-associated MPNST, which is associated with poorer response to systemic therapy and prognosis than sporadic MPNST. As such, NF1-associated MPNST is a particular area in need of novel therapeutic strategies. Given the lack of benefit in the targeting of unique aspects of MPNST disease biology thus far, pre-clinical studies to identify novel rational therapies are critical to inform future clinical trials.


Assuntos
Neoplasias de Bainha Neural/diagnóstico , Neoplasias de Bainha Neural/terapia , Biomarcadores Tumorais , Tomada de Decisão Clínica , Terapia Combinada , Gerenciamento Clínico , Suscetibilidade a Doenças , Predisposição Genética para Doença , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias de Bainha Neural/etiologia , Neoplasias de Bainha Neural/mortalidade , Prognóstico , Resultado do Tratamento
3.
Urol Int ; 104(3-4): 330-332, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31896110

RESUMO

We report a rare case of Budd-Chiari syndrome (BCS) as a postoperative complication after bilateral nephrectomy in a kidney transplant recipient with polycystic liver and kidneys. Contrast-enhanced computed tomography of the abdomen showed a narrowed inferior vena cava, compressed by the polycystic liver that moved downwards after nephrectomy. A stenting angioplasty was performed, resulting in remarkable clinical improvement. This case highlights the need for careful evaluation of polycystic kidneys and their anatomic relationship with the liver before nephrectomy, as well as for considering BCS as a differential diagnosis in similar cases.


Assuntos
Síndrome de Budd-Chiari/etiologia , Transplante de Rim , Nefrectomia/efeitos adversos , Doenças Renais Policísticas/cirurgia , Complicações Pós-Operatórias/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Nefrectomia/métodos
4.
Oncologist ; 23(11): 1282-1288, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30120166

RESUMO

BACKGROUND: Patients with metastatic breast cancer with bone-only metastases (BOM) are a unique patient population without consensus regarding high-risk characteristics, which we sought to establish. METHODS: We identified 1,445 patients with BOM followed for at least 6 months at MD Anderson Cancer Center from January 1, 1997, to December 31, 2015. RESULTS: Seventy-one percent (n = 936) of the 1,325 patients with BOM with available pain characterization were symptomatic at time of BOM diagnosis. Pain was more common in patients with lytic compared with blastic or sclerotic metastases (odds ratio [OR], 1.79; 95% confidence interval [CI,] 1.26-2.53) and multiple versus single bone metastases (OR, 1.37; 95% CI, 1.03-1.83). Poorer overall survival (OS) was also noted in patients with multiple bone metastases (median OS, 4.80 years; 95% CI, 4.49-5.07) compared with single bone metastasis (median OS, 7.54 years; 95% CI, 6.28-10.10) and in patients with metastases in both the axial and appendicular skeleton (median OS, 4.58 years; 95% CI, 4.23-4.96) compared with appendicular-only (median OS, 6.78 years; 95% CI, 5.26-7.96) or axial-only metastases (median OS, 5.62 years; 95% CI, 4.81-6.69). Black/non-Hispanic patients had poorer outcomes, and patients aged 40-49 years at time of breast cancer diagnosis had significantly better OS compared with both younger and older patient groups. CONCLUSION: Overall, several risk features for decreased OS were identified, including multiple bone metastases and both axial and appendicular skeleton involvement. Multiple bone metastases and lytic bone metastases were associated with increased pain. IMPLICATIONS FOR PRACTICE: Patients with metastatic breast cancer and bone-only metastases (BOM) represent a poorly characterized patient subset. The ability to identify unique patient characteristics at time of BOM diagnosis associated with increased morbidity or mortality would allow for recognition of patients who would benefit from more aggressive therapy. In this study, the largest sample of patients with BOM thus far reported is characterized, highlighting several higher-risk BOM groups, including those with multiple bone metastases and bone metastases in both the axial and appendicular skeleton at time of BOM diagnosis. In addition to tailoring current practices for these high-risk patients, ongoing studies of these patients are indicated.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/mortalidade , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Análise de Sobrevida , Adulto Jovem
5.
Lancet Reg Health Am ; 30: 100671, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38259252

RESUMO

As a developing region, Latin America faces unique cancer control and prevention challenges, which are intensified when considering rare cancers, including sarcomas. Sarcomas are a group of malignancies that arise in the connective tissues of the body-such as muscle, fat, nerves, blood vessels, and bones-accounting for a diverse range of tumours that, although rare, require specialized attention. Sarcoma care and research in Latin America require a comprehensive approach that includes deeper epidemiologic knowledge, diagnostic capacity building, access to innovative treatments, increased patient advocacy, and strengthening of clinical research capacity. This article will review current challenges and opportunities for treating patients with sarcoma in Latin America and outline a pathway toward improvement for regional collaborative groups.

6.
Clin Cancer Res ; 29(2): 401-409, 2023 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-36288393

RESUMO

PURPOSE: Recently, the Connective Tissue Oncology Society published consensus guidelines for recognizing ultrarare sarcomas (URS), defined as sarcomas with an incidence ≤1 per 1,000,000. We assessed the outcomes of 56 patients with soft tissue, and 21 with bone sarcomas, enrolled in Phase 1 trials. EXPERIMENTAL DESIGN: In this Sarcoma-Matched Biomarker Analysis (SAMBA-102 study), we reviewed records from patients on Phase 1 trials at the University of Texas MD Anderson Cancer Center between January 2013 and June 2021. RESULTS: Among 587 sarcomas, 106 (18.1%) were classified as URS. Fifty (47%) were male, and the median age was 44.3 years (range, 19-82). The most common subtypes were alveolar soft part sarcoma (ASPS), chordoma, dedifferentiated chondrosarcoma, and sclerosing epithelioid fibrosarcoma. Compared with common sarcomas, median OS was similar 16.1 months [95% confidence interval (CI), 13.6-17.5] versus 16.1 (95% CI, 8.2-24.0) in URS (P = 0.359). Objective response to treatment was higher in URS 13.2% (n = 14/106) compared with common sarcomas 6.9% (n = 33/481; P = 0.029). Median OS for those treated on matched trials was 27.3 months (95% CI, 1.9-52.7) compared with 13.4 months (95% CI, 6.3-20.6) for those not treated on matched trials (P = 0.291). Eight of 33 (24%) molecularly matched treatments resulted in an objective response, whereas 6 of 73 unmatched treatments (8.2%) resulted in an objective response (P = 0.024). Clinical benefit rate was 36.4% (12/33) in matched trials versus 26.0% (19/73) in unmatched trials (P = 0.279). CONCLUSIONS: The results demonstrate the benefit of genomic selection in Phase 1 trials to help identify molecular subsets likely to benefit from targeted therapy.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Sarcoma Alveolar de Partes Moles , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Genômica , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Sarcoma Alveolar de Partes Moles/genética
7.
Front Oncol ; 12: 1079909, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36741731

RESUMO

Background: The development of novel therapies for patients with sarcoma is challenging due to the rarity and diversity of these mesenchymal neoplasms. Hence, histology-agnostic approvals can be of particular interest for the treatment of patients with soft tissue and bone sarcoma. Methods: We queried the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database Cohort v12.0-Public to investigate the prevalence of currently Food and Drug Administration (FDA)-approved and other potentially actionable histology-agnostic alterations in patients with soft tissue and bone sarcoma. Targets were identified by a literature review by the authors. Results are presented for each cohort identified in the GENIE database, namely: (1) soft tissue sarcoma (STS), (2) gastrointestinal stromal tumor (GIST), (3) bone sarcoma, (4) uterine sarcoma, and (5) breast sarcoma. Results: We identified 7,512 samples of 6,955 patients with sarcoma in the AAACR GENIE database v12.0-Public. Molecular alterations that could lead to the clinical use of a currently approved histology-agnostic therapy were identified in 2.1% of sarcomas (2.6% STS, 1.3% GIST, 1.4% bone, 2.7% uterine, and 0% breast). In addition, 2.9% of patients could be eligible for future histology-agnostic approvals. These specific mutations, fusions, and amplifications occurred in multiple histotypes in all cohorts. Discussion: Exploring a public large-scale genomic database, we identified that 5% of patients with sarcoma could be eligible for current histology-agnostic FDA-approved drugs or future potential histology-agnostic indications. These actionable alterations were present in a wide variety of histologies in soft tissue and bone sarcomas, highlighting that next-generation sequencing can be considered for patients with advanced sarcoma to guide treatment strategies.

8.
Cancer J ; 28(6): 462-468, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36383909

RESUMO

ABSTRACT: Antibody-drug conjugates (ADCs) deliver effective medications to tumor cells that express specific antigens, maximizing efficacy and reducing adverse effects. Because ado-trastuzumab emtansine was approved in 2013, 5 ADCs received US Food and Drug Administration approval for solid tumor treatment. Technical advancements in the development of each component of ADCs allowed novel monoclonal antibodies, linkers, and payloads to increase drug transport to malignant cells and drug activity even in cancers with heterogeneous antigen expression. In addition, several ADCs are in development using new molecular targets expressed across a broad range of histologies to allow the use of ADC biomarker-driven therapy irrespective of the primary tumor site. This suggests that the future efficacy of ADCs in multiple histologies may be similar to other classes of drugs that are considered histology-agnostic therapies nowadays. This review focuses on novel ADCs for the treatment of solid tumors, including topics such as their structure and mechanism of action, the latest indications of already US Food and Drug Administration-approved ADCs, and the outlook for new promising ADCs under development for the treatment of tumors of various histologies.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Preparações Farmacêuticas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ado-Trastuzumab Emtansina/uso terapêutico , Neoplasias/tratamento farmacológico
9.
J Clin Oncol ; 40(30): 3520-3528, 2022 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-35537102

RESUMO

Advances in biology and immunology have elucidated genetic and immunologic origins of cancer. Innovations in sequencing technologies revealed that distinct cancer histologies shared common genetic and immune phenotypic traits. Pharmacologic developments made it possible to target these alterations, yielding novel classes of targeted agents whose therapeutic potential span multiple tumor types. Basket trials, one type of master protocol, emerged as a tool for evaluating biomarker-targeted therapies among multiple tumor histologies. Conventionally conducted within the phase II setting and designed to estimate high and durable objective responses, basket trials pose challenges to statistical design and interpretation of results. This article reviews basket trials implemented in oncology studies and discusses issues related to their statistical design and analysis.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Humanos , Oncologia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Projetos de Pesquisa
10.
Front Oncol ; 12: 860453, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35444941

RESUMO

Although a relatively uncommon tumor, cholangiocarcinoma is on the rise globally. Of note, most patients are diagnosed with metastatic disease, and the prognosis is poor with cytotoxic chemotherapy. Strategies targeting specific genomic alterations have demonstrated promising activity in recent years and could represent a new therapeutic avenue for these patients. In this review, we will address the biology and clinical results of FGFR inhibition in intrahepatic cholangiocarcinoma, highlighting limitations associated with treatment and discussing the use of circulating tumor DNA to detect mechanisms of resistance.

11.
Trends Cancer ; 8(2): 135-144, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34887213

RESUMO

Tissue-agnostic drug development is a major step forward in offering treatment options for rare tumors. Sarcomas are heterogeneous rare malignancies with more than 100 subtypes. Recent failure of Phase III trials, nonbiomarker-driven clinical trials, and rarity hamper developmental therapeutics in sarcomas. Since a 'one-size-fits-all' approach continues to be the standard of care, tissue-agnostic approvals assume significance in sarcomas. In this review, we focus on the clinical evidence of recent drug approvals for neurotrophic tyrosine receptor kinase (NTRK) fusion, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) phenotype, and tumor mutation burden-high (TMB-H) status in the context of sarcomas, and the future landscape of tissue-agnostic targets, such as rearranged during transfection (RET), fibroblast growth factor receptor (FGFR), and neuregulin-1 (NRG1).


Assuntos
Sarcoma , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Fusão Gênica , Humanos , Instabilidade de Microssatélites , Receptores Proteína Tirosina Quinases/genética , Sarcoma/diagnóstico , Sarcoma/tratamento farmacológico , Sarcoma/genética
12.
Curr Probl Cancer ; 45(5): 100794, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34656365

RESUMO

Recent failure of phase 3 trials and paucity of druggable oncogenic drivers hamper developmental therapeutics in sarcomas. Antibody-based therapeutics, like antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR)-based therapeutics, have emerged as promising strategies for anticancer drug delivery. The efficacy of these novel therapies is highly dependent on expression of the antibody target. We used RNA sequencing data from Cancer Genome Atlas (TCGA) to analyze expression of target antigens in sarcoma subtypes including dedifferentiated liposarcoma (DDLPS; n = 50), uterine leiomyosarcoma (ULMS; n = 27), leiomyosarcoma (STLMS; n = 53), undifferentiated pleomorphic sarcoma (UPS; n = 44), myxofibrosarcoma (MFS; n = 17), synovial sarcoma (SS; n = 10), and malignant peripheral nerve sheath tumor (MPNST; n = 5). We searched published literature and clinicaltrial.gov for ADC targets, bispecific antibodies, immunotoxins, radioimmunoconjugates, SPEAR T-cells, and CAR's that are in clinical trials. CD70 expression was significantly higher in DDLPS, UPS, and MFS than SS and STLMS. CDH3 expression was greater in LMS and ULMS than UPS (P < 0.001), MFS (P < 0.001), and DDLPS (P < 0.001). ERBB2 expression was low; however, it was overexpressed in MPNST when compared with UPS (P < 0.001), and MFS (P < 0.01). GPNMB was highly expressed in most sarcomas, with the exception of SS. LRRC15 also appeared to be a relevant target, especially in UPS. MSLN expression was relatively low except in SS and MPNST. PDGFRA was also highly expressed in most sarcomas with the exception of ULMS and STLMS. TNFRSF8 seems to be most appropriate in DDLPS, as well as MFS. AXL was expressed especially in MFS and STLMS. Sarcoma subtypes express multiple target genes relevant for ADCs, SPEAR T-cells and CAR's, warranting further clinical validation and evaluation.


Assuntos
Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/uso terapêutico , Sarcoma/tratamento farmacológico , Adulto , Genoma , Humanos , Análise de Sequência de RNA
13.
Am Soc Clin Oncol Educ Book ; 41: e133-e144, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34061563

RESUMO

Misgivings have been raised about the operating characteristics of the canonical 3+3 dose-escalation phase I clinical trial design. Yet, the traditional 3+3 design is still the most commonly used. Although it has been implied that adhering to this design is due to a stubborn reluctance to adopt change despite other designs performing better in hypothetical computer-generated simulation models, the continued adherence to 3+3 dose-escalation phase I strategies is more likely because these designs perform the best in the real world, pinpointing the correct dose and important side effects with an acceptable degree of precision. Beyond statistical simulations, there are little data to refute the supposed shortcomings ascribed to the 3+3 method. Even so, to address the unique nuances of gene- and immune-targeted compounds, a variety of inventive phase 1 trial designs have been suggested. Strategies for developing these therapies have launched first-in-human studies devised to acquire a breadth of patient data that far exceed the size of a typical phase I design and blur the distinction between dose selection and efficacy evaluation. Recent phase I trials of promising cancer therapies assessed objective tumor response and durability at various doses and schedules as well as incorporated multiple expansion cohorts spanning a variety of histology or biomarker-defined tumor subtypes, sometimes resulting in U.S. Food and Drug Administration approval after phase I. This article reviews recent innovations in phase I design from the perspective of multiple stakeholders and provides recommendations for future trials.


Assuntos
Ensaios Clínicos como Assunto , Neoplasias , Simulação por Computador , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Projetos de Pesquisa
14.
Oncotarget ; 12(8): 756-766, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33889299

RESUMO

BACKGROUND: Sorafenib was the first systemic therapy approved for the treatment of Child-Turcotte-Pugh (CTP) class A patients with advanced hepatocellular carcinoma (HCC). However, there are no biomarkers to predict survival and treatment outcomes and guide HCC systemic therapy. Type 1 insulin-like growth factor (IGF-1)/CTP composite score has emerged as a potential hepatic reserve assessment tool. Our study investigated the association of the IGF/CTP score with overall survival (OS) and progression-free survival (PFS) of HCC patients treated with sorafenib. MATERIALS AND METHODS: In this prospective study, patients with HCC were treated with sorafenib and followed up until progression/death. We calculated the IGF/CTP score and used the Kaplan-Meier method and log-rank test to estimate and compare the time-to-event outcomes between patient subgroups. RESULTS: 171 patients were included, 116 of whom were CTP class A. Median PFS for IGF/CTP score AA and AB patients were 6.88 and 4.28 months, respectively (p = 0.1359). Median OS for IGF/CTP score AA and AB patients were 14.54 and 7.60 months, respectively (p = 0.1378). The PFS and OS was superior in AA patients, but the difference was not significant, likely due to the sample size. However, there was a significant difference in early OS and PFS curves between AA and AB (p = 0.0383 and p = 0.0099), respectively. CONCLUSIONS: In CTP class A patients, IGF/CTP score B was associated with shorter PFS and OS, however, study was underpowered to reach statistical significance. If validated in larger cohorts, IGF/CTP score may serve as stratification tool in clinical trials, a hepatic reserve assessment tool for HCC outcomes prediction and to assist in therapy decisions.

15.
Nat Rev Clin Oncol ; 17(9): 555-568, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32528101

RESUMO

With advances in tumour biology and immunology that continue to refine our understanding of cancer, therapies are now being developed to treat cancers on the basis of specific molecular alterations and markers of immune phenotypes that transcend specific tumour histologies. With the landmark approvals of pembrolizumab for the treatment of patients whose tumours have high microsatellite instability and larotrectinib and entrectinib for those harbouring NTRK fusions, a regulatory pathway has been created to facilitate the approval of histology-agnostic indications. Negative results presented in the past few years, however, highlight the intrinsic complexities faced by drug developers pursuing histology-agnostic therapeutic agents. When patient selection and statistical analysis involve multiple potentially heterogeneous histologies, guidance is needed to navigate the challenges posed by trial design. Additionally, as new therapeutic agents are tested and post-approval data become available, the regulatory framework for acting on these data requires further optimization. In this Review, we summarize the development and testing of approved histology-agnostic therapeutic agents and present data on other agents currently under development. Finally, we discuss the challenges intrinsic to histology-agnostic drug development in oncology, including biological, regulatory, design and statistical considerations.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Desenvolvimento de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Biomarcadores Tumorais/imunologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Medicina de Precisão
16.
Oncotarget ; 11(13): 1186-1201, 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32284794

RESUMO

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)- and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.

17.
Oral Oncol ; 101: 104523, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31864957

RESUMO

OBJECTIVES: Prior reports have demonstrated a potential enhancement in overall response rate (ORR) to chemotherapy after exposure to immunotherapy. The goal of this study was to evaluate the ORR and survival to chemotherapy and/or targeted therapy in head and neck squamous cell carcinoma (HNSCC) patients who progressed on immune checkpoint inhibitors (ICI). MATERIALS AND METHODS: We retrospectively collected clinical and pathologic data from patients with recurrent/metastatic HNSCC who progressed on ICI and subsequently received chemotherapy or targeted therapy. ORR was assessed by RECIST version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: A total of 43 patients met criteria for inclusion. The majority were male (91%) and former smokers (60%). Most patients received ICI as first-line (58.14%); the vast majority was platinum exposed (90.7%). The ORR to ICI was 21%. The ORR to systemic therapy before ICI was 47%, and the ORR after ICI failure was 42%. After progression on ICI, the median PFS and OS on the subsequent line of therapy were 4.2 and 8.4 months respectively. CONCLUSION: In our cohort of recurrent/metastatic HNSCC patients, the ORR and OS to systemic therapy after progression on ICI were higher than historical controls for second-line or beyond. Further investigations are warranted to better characterize optimal sequencing and combination strategies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Feminino , Humanos , Masculino , Metástase Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Retratamento , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Análise de Sobrevida , Falha de Tratamento , Resultado do Tratamento
18.
Cancer Immunol Res ; 7(9): 1390-1395, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31289040

RESUMO

In hepatocellular carcinoma (HCC), surgical resection is associated with high recurrence rate, and no effective adjuvant therapy currently exists. We initiated a pilot randomized trial of perioperative immunotherapy with nivolumab and ipilimumab for resectable HCC. Here, we provide an illustrative report of a case that achieved a complete response and report immunologic correlates of this complete pathologic response to perioperative immunotherapy. Clinical response was correlated with an increase in CD8+ T-cell infiltration, with an increase in two effector T-cell clusters. This study is ongoing, and the final results may contribute to a paradigm shift in the perioperative treatment of HCC, leading to the incorporation of immunotherapy in the curative setting.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Cuidados Pré-Operatórios , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/imunologia , Terapia Combinada , Feminino , Humanos , Imuno-Histoquímica , Imunofenotipagem , Neoplasias Hepáticas/diagnóstico , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Estadiamento de Neoplasias , Tomografia Computadorizada por Raios X , Resultado do Tratamento
19.
J Immunother Cancer ; 7(1): 329, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779702

RESUMO

BACKGROUND: Currently, there are no imaging predictors of immunotherapy outcome in hepatocellular carcinoma (HCC). The study aim was to determine if stiffness changes measured by magnetic resonance elastography (MRE) can be a predictor of immunotherapy response in patients with advanced HCC. MATERIALS AND METHODS: This was a prospective study of 15 patients with biopsy proven-advanced HCC treated with Pembrolizumab. All patients had liver MRE and liver biopsy at baseline and at 6 weeks of therapy. Change in HCC stiffness on MRE was compared with overall survival (OS), time to disease progression (TTP), and number of intratumoral CD3+ T lymphocytes. Analysis was performed using descriptive statistics and Spearman correlation (R); p-value < 0.05 was considered statistically significant. RESULTS: Nine patients were evaluable. Median age was 71 years (range, 54-78). Etiology of liver disease was HCV (n = 4), HBV (n = 1) and NASH (n = 4). Median OS and TTP were 44 weeks and 13 weeks, respectively. Average baseline HCC stiffness and change in HCC stiffness were 5.0 kPa and 0.12 kPa, respectively. In contrast, average non-tumor liver stiffness was 3.2 kPa, and did not significantly change at 6 weeks (p = 0.42). Average size of measured tumor and change in size were 4 cm and - 0.32 cm, respectively. Change in HCC stiffness at 6 weeks correlated significantly with OS (R = 0.81), and TTP (R = 0.88,p < 0.01). Abundance of intratumoral T lymphocytes on tumor biopsy correlated significantly with HCC stiffness (R = 0.79,p = 0.007). CONCLUSION: Our pilot MRE data suggests early change in tumor stiffness may be an indicator of immunotherapy response in patients with advanced HCC.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Técnicas de Imagem por Elasticidade , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Idoso , Biomarcadores , Biópsia , Carcinoma Hepatocelular/terapia , Feminino , Humanos , Imunoterapia , Neoplasias Hepáticas/terapia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Resultado do Tratamento , Microambiente Tumoral
20.
Clin Cancer Res ; 25(20): 6107-6118, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31363003

RESUMO

PURPOSE: Molecular profiling has been used to select patients for targeted therapy and determine prognosis. Noninvasive strategies are critical to hepatocellular carcinoma (HCC) given the challenge of obtaining liver tissue biopsies. EXPERIMENTAL DESIGN: We analyzed blood samples from 206 patients with HCC using comprehensive genomic testing (Guardant Health) of circulating tumor DNA (ctDNA). RESULTS: A total of 153/206 (74.3%) were men; median age, 62 years (range, 18-91 years). A total of 181/206 patients had ≥1 alteration. The total number of alterations was 680 (nonunique); median number of alterations/patient was three (range, 1-13); median mutant allele frequency (% cfDNA), 0.49% (range, 0.06%-55.03%). TP53 was the common altered gene [>120 alterations (non-unique)] followed by EGFR, MET, ARID1A, MYC, NF1, BRAF, and ERBB2 [20-38 alterations (nonunique)/gene]. Of the patients with alterations, 56.9% (103/181) had ≥1 actionable alterations, most commonly in MYC, EGFR, ERBB2, BRAF, CCNE1, MET, PIK3CA, ARID1A, CDK6, and KRAS. In these genes, amplifications occurred more frequently than mutations. Hepatitis B (HBV)-positive patients were more likely to have ERBB2 alterations, 35.7% (5/14) versus 8.8% HBV-negative (P = 0.04). CONCLUSIONS: This study represents the first large-scale analysis of blood-derived ctDNA in HCC in United States. The genomic distinction based on HCC risk factors and the high percentage of potentially actionable genomic alterations suggests potential clinical utility for this technology.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , DNA Tumoral Circulante/genética , Testes Genéticos/métodos , Neoplasias Hepáticas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/terapia , DNA Tumoral Circulante/sangue , Tomada de Decisão Clínica/métodos , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Seleção de Pacientes , Prognóstico , Estados Unidos , Adulto Jovem
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