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1.
Glob Health Sci Pract ; 11(Suppl 2)2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38110201

RESUMO

We describe the responsive feedback (RF) approach experience of a nongovernmental organization, Girls Health Champions (now known as Adolescent Health Champions [AHC]), that undertakes peer education interventions in Mumbai, India, schools to improve gender equality and health outcomes for adolescents aged 13-19 years. AHC used the RF approach at the onset of the COVID-19 pandemic in light of uncertainties stemming from school closures and the negative impact of the lockdown on adolescents' physical and mental health. Using an RF approach, AHC was able to: (1) understand pandemic-specific challenges faced by adolescents; (2) overhaul its theory of change; (3) pilot new modes of intervention delivery; (4) design a curriculum for parents/guardians and a COVID-19 module; (5) design an AHC mobile app; (6) develop a new, more gender-inclusive name and visual identity; (7) change the overall structure, adolescent-friendly nature, and agility of the organization; (8) and help clarify future directions taken by the organization. Overall, use of the RF approach had significant positive impacts on AHC as an organization, such as changes in organizational culture, deeper stakeholder engagement, and innovation, and was instrumental in AHC's growth, development, and pandemic response. This article outlines the steps of the process, from initial informal stakeholder consultations to the eventual formalization of the RF approach into the everyday working of AHC through the creation of a youth advisory board. We discuss challenges, such as time and resource constraints encountered; strategies for dealing with such challenges; and general key findings and learnings from this experience that could be beneficial to other youth- and community-serving organizations.


Assuntos
Saúde do Adolescente , COVID-19 , Feminino , Adolescente , Humanos , Pandemias , Retroalimentação , COVID-19/prevenção & controle , Controle de Doenças Transmissíveis
2.
Cells ; 12(20)2023 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-37887279

RESUMO

To rapidly assess healthy tissue toxicities induced by new anti-cancer therapies (i.e., radiation alone or in combination with drugs), there is a critical need for relevant and easy-to-use models. Consistent with the ethical desire to reduce the use of animals in medical research, we propose to monitor lung toxicity using an ex vivo model. Briefly, freshly prepared organotypic lung slices from mice were irradiated, with or without being previously exposed to chemotherapy, and treatment toxicity was evaluated by analysis of cell division and viability of the slices. When exposed to different doses of radiation, this ex vivo model showed a dose-dependent decrease in cell division and viability. Interestingly, monitoring cell division was sensitive enough to detect a sparing effect induced by FLASH radiotherapy as well as the effect of combined treatment. Altogether, the organotypic lung slices can be used as a screening platform to rapidly determine in a quantitative manner the level of lung toxicity induced by different treatments alone or in combination with chemotherapy while drastically reducing the number of animals. Translated to human lung samples, this ex vivo assay could serve as an innovative method to investigate patients' sensitivity to radiation and drugs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Camundongos , Animais , Pulmão , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia Combinada , Divisão Celular
3.
Adv Radiat Oncol ; 8(6): 101291, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37457823

RESUMO

Hypofractionated radiotherapy schedules provide higher per-fraction radiation doses delivered in fewer fractions than conventional schedules. This novel delivery method is supported by a large body of clinical trial evidence across various cancer sites in both curative and palliative settings. Hypofractionation is associated with benefits such as lower costs, improved patient access and increased treatment precision, which has led to its inclusion in various treatment guidelines. Despite this, utilization is not uniform across cancer sites and geographic regions due to reasons such as reimbursement models, nuances in healthcare systems, and professional culture. Key factors to ensure patients benefit from access to high quality radiotherapy include publishing clinical evidence, cross-country collaboration to fill knowledge gaps, reviewing reimbursement models, and improving patient advocacy in treatment decision-making.

4.
Cardiovasc Intervent Radiol ; 46(9): 1276-1282, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37337060

RESUMO

Knee osteoarthritis is a leading cause of chronic disability and economic burden. In many patients who are not surgical candidates, existing treatment options are insufficient. Clinical evidence for a new treatment approach, genicular artery embolisation (GAE), is currently limited to single arm cohort, or small population randomised studies. This trial will investigate the use of a permanent embolic agent for embolisation of abnormal genicular arterial vasculature to reduce pain in patients with mild to moderate knee osteoarthritis. Up to 110 participants, 45 years or older, with knee pain for ≥ 3 months resistant to conservative treatment will be randomised (1:1) to GAE or a sham procedure. The treatment group will receive embolisation using 100-micron Embozene™ microspheres (Varian, a Siemens Healthineers Company) (investigational use for this indication in the UK), and the sham group will receive 0.9% saline in an otherwise identical procedure. Patients will be followed for 24 months. At 6 months, sham participants will be offered crossover to GAE. The primary endpoint is change of 4 Knee Injury and OA Outcome Score subscales (KOOS4) at 6 months post-randomisation. The study will also evaluate quality of life, health economics, imaging findings, and psychosocial pain outcomes. The primary manuscript will be submitted for publication after all participants complete 6 months of follow-up. The trial is expected to run for 3.5 years. Trial Registration: ClinicalTrials.gov, Identifier: NCT05423587.


Assuntos
Osteoartrite do Joelho , Humanos , Artérias , Método Duplo-Cego , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/terapia , Dor , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Pessoa de Meia-Idade
5.
JAMA Oncol ; 9(1): 62-69, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36273324

RESUMO

Importance: To our knowledge, there have been no clinical trials of ultra-high-dose-rate radiotherapy delivered at more than 40 Gy/sec, known as FLASH therapy, nor first-in-human use of proton FLASH. Objectives: To assess the clinical workflow feasibility and treatment-related toxic effects of FLASH and pain relief at the treatment sites. Design, Setting, and Participants: In the FAST-01 nonrandomized trial, participants treated at Cincinnati Children's/UC Health Proton Therapy Center underwent palliative FLASH radiotherapy to extremity bone metastases. Patients 18 years and older with 1 to 3 painful extremity bone metastases and life expectancies of 2 months or more were eligible. Patients were excluded if they had foot, hand, and wrist metastases; metastases locally treated in the 2 weeks prior; metal implants in the treatment field; known enhanced tissue radiosensitivity; and implanted devices at risk of malfunction with radiotherapy. One of 11 patients who consented was excluded based on eligibility. The end points were evaluated at 3 months posttreatment, and patients were followed up through death or loss to follow-up for toxic effects and pain assessments. Of the 10 included patients, 2 died after the 2-month follow-up but before the 3-month follow-up; 8 participants completed the 3-month evaluation. Data were collected from November 3, 2020, to January 28, 2022, and analyzed from January 28, 2022, to September 1, 2022. Interventions: Bone metastases were treated on a FLASH-enabled (≥40 Gy/sec) proton radiotherapy system using a single-transmission proton beam. This is consistent with standard of care using the same prescription (8 Gy in a single fraction) but on a conventional-dose-rate (approximately 0.03 Gy/sec) photon radiotherapy system. Main Outcome and Measures: Main outcomes included patient time on the treatment couch, device-related treatment delays, adverse events related to FLASH, patient-reported pain scores, and analgesic use. Results: A total of 10 patients (age range, 27-81 years [median age, 63 years]; 5 [50%] male) underwent FLASH radiotherapy at 12 metastatic sites. There were no FLASH-related technical issues or delays. The average (range) time on the treatment couch was 18.9 (11-33) minutes per patient and 15.8 (11-22) minutes per treatment site. Median (range) follow-up was 4.8 (2.3-13.0) months. Adverse events were mild and consistent with conventional radiotherapy. Transient pain flares occurred in 4 of the 12 treated sites (33%). In 8 of the 12 sites (67%) patients reported pain relief, and in 6 of the 12 sites (50%) patients reported a complete response (no pain). Conclusions and Relevance: In this nonrandomized trial, clinical workflow metrics, treatment efficacy, and safety data demonstrated that ultra-high-dose-rate proton FLASH radiotherapy was clinically feasible. The treatment efficacy and the profile of adverse events were comparable with those of standard-of-care radiotherapy. These findings support the further exploration of FLASH radiotherapy in patients with cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT04592887.


Assuntos
Neoplasias Ósseas , Prótons , Criança , Humanos , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Dor/etiologia , Cuidados Paliativos , Resultado do Tratamento
6.
JMIR Res Protoc ; 12: e41812, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36206189

RESUMO

BACKGROUND: In preclinical studies, FLASH therapy, in which radiation delivered at ultrahigh dose rates of ≥40 Gy per second, has been shown to cause less injury to normal tissues than radiotherapy delivered at conventional dose rates. This paper describes the protocol for the first-in-human clinical investigation of proton FLASH therapy. OBJECTIVE: FAST-01 is a prospective, single-center trial designed to assess the workflow feasibility, toxicity, and efficacy of FLASH therapy for the treatment of painful bone metastases in the extremities. METHODS: Following informed consent, 10 subjects aged ≥18 years with up to 3 painful bone metastases in the extremities (excluding the feet, hands, and wrists) will be enrolled. A treatment field selected from a predefined library of plans with fixed field sizes (from 7.5 cm × 7.5 cm up to 7.5 cm × 20 cm) will be used for treatment. Subjects will receive 8 Gy of radiation in a single fraction-a well-established palliative regimen evaluated in prior investigations using conventional dose rate photon radiotherapy. A FLASH-enabled Varian ProBeam proton therapy unit will be used to deliver treatment to the target volume at a dose rate of ≥40 Gy per second, using the plateau (transmission) portion of the proton beam. After treatment, subjects will be assessed for pain response as well as any adverse effects of FLASH radiation. The primary end points include assessing the workflow feasibility and toxicity of FLASH treatment. The secondary end point is pain response at the treated site(s), as measured by patient-reported pain scores, the use of pain medication, and any flare in bone pain after treatment. The results will be compared to those reported historically for conventional dose rate photon radiotherapy, using the same radiation dose and fractionation. RESULTS: FAST-01 opened to enrollment on November 3, 2020. Initial results are expected to be published in 2022. CONCLUSIONS: The results of this investigation will contribute to further developing and optimizing the FLASH-enabled ProBeam proton therapy system workflow. The pain response and toxicity data acquired in our study will provide a greater understanding of FLASH treatment effects on tumor responses and normal tissue toxicities, and they will inform future FLASH trial designs. TRIAL REGISTRATION: : ClinicalTrials.gov NCT04592887; http://clinicaltrials.gov/ct2/show/NCT04592887. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41812.

7.
Radiother Oncol ; 175: 197-202, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35868604

RESUMO

The physico-chemical and biological response to conventional and UHDR electron and proton beams was investigated, along with conventional photons. The temporal structure and nature of the beam affected both, with electron beam at ≥1400 Gy/s and proton beam at 0.1 and 1260 Gy/s found to be isoefficient at sparing zebrafish embryos.


Assuntos
Terapia com Prótons , Peixe-Zebra , Animais , Elétrons , Prótons , Peróxido de Hidrogênio , Dosagem Radioterapêutica
8.
J Vasc Interv Radiol ; 33(9): 1034-1044.e29, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35526675

RESUMO

PURPOSE: To assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemoembolization (TACE) in patients with resectable liver malignancies. MATERIALS AND METHODS: The VEROnA clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years and had resectable hepatocellular carcinoma (HCC) (Child-Pugh A) or metastatic colorectal cancer (mCRC). Patients received 1 mL of BTG-002814 transarterially (containing 100 mg of vandetanib) 7-21 days prior to surgery. The primary objectives were to establish the safety and tolerability of BTG-002814 and determine the concentrations of vandetanib and the N-desmethyl vandetanib metabolite in the plasma and resected liver after treatment. Biomarker studies included circulating proangiogenic factors, perfusion computed tomography, and dynamic contrast-enhanced magnetic resonance imaging. RESULTS: Eight patients were enrolled: 2 with HCC and 6 with mCRC. There was 1 grade 3 adverse event (AE) before surgery and 18 after surgery; 6 AEs were deemed to be related to BTG-002814. Surgical resection was not delayed. Vandetanib was present in the plasma of all patients 12 days after treatment, with a mean maximum concentration of 24.3 ng/mL (standard deviation ± 13.94 ng/mL), and in resected liver tissue up to 32 days after treatment (441-404,000 ng/g). The median percentage of tumor necrosis was 92.5% (range, 5%-100%). There were no significant changes in perfusion imaging parameters after TACE. CONCLUSIONS: BTG-002814 has an acceptable safety profile in patients before surgery. The presence of vandetanib in the tumor specimens up to 32 days after treatment suggests sustained anticancer activity, while the low vandetanib levels in the plasma suggest minimal release into the systemic circulation. Further evaluation of this TACE combination is warranted in dose-finding and efficacy studies.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Adolescente , Adulto , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/efeitos adversos , Quimioembolização Terapêutica/métodos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Piperidinas , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinas/efeitos adversos , Resultado do Tratamento
10.
Br J Radiol ; 95(1130): 20210594, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34762499

RESUMO

OBJECTIVE: To determine the feasibility of using radiopaque (RO) beads as direct tumour surrogates for image-guided radiotherapy (IGRT) in patients with liver tumours after transarterial chemoembolisation (TACE). METHODS: A novel vandetanib-eluting RO bead was delivered via TACE as part of a first-in-human clinical trial in patients with either hepatocellular carcinoma or liver metastases from colorectal cancer. Following TACE, patients underwent simulated radiotherapy imaging with four-dimensional computed tomography (4D-CT) and cone-beam CT (CBCT) imaging. RO beads were contoured using automated thresholding, and feasibility of matching between the simulated radiotherapy planning dataset (AVE-IP image from 4D data) and CBCT scans assessed. Additional kV, MV, helical CT and CBCT images of RO beads were obtained using an in-house phantom. Stability of RO bead position was assessed by comparing 4D-CT imaging to CT scans taken 6-20 days following TACE. RESULTS: Eight patients were treated and 4D-CT and CBCT images acquired. RO beads were visible on 4D-CT and CBCT images in all cases and matching successfully performed. Differences in centre of mass of RO beads between CBCT and simulated radiotherapy planning scans (AVE-IP dataset) were 2.0 mm mediolaterally, 1.7 mm anteroposteriorally and 3.5 mm craniocaudally. RO beads in the phantom were visible on all imaging modalities assessed. RO bead position remained stable up to 29 days post TACE. CONCLUSION: RO beads are visible on IGRT imaging modalities, showing minimal artefact. They can be used for on-set matching with CBCT and remain stable over time. ADVANCES IN KNOWLEDGE: The role of RO beads as fiducial markers for stereotactic liver radiotherapy is feasible and warrants further exploration as a combination therapy approach.


Assuntos
Carcinoma Hepatocelular/radioterapia , Embolização Terapêutica/métodos , Marcadores Fiduciais , Neoplasias Hepáticas/radioterapia , Radiocirurgia/métodos , Radioterapia Guiada por Imagem/métodos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Neoplasias Colorretais/patologia , Tomografia Computadorizada de Feixe Cônico , Estudos de Viabilidade , Tomografia Computadorizada Quadridimensional , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Microesferas , Imagens de Fantasmas , Projetos Piloto
12.
Diagn Interv Radiol ; 27(5): 677-683, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34318754

RESUMO

Colorectal cancer liver metastases (CRLMs) are common. Treating CRLMs with thermal ablation can prolong survival, but compared to lesions smaller than 3 cm, local control rates and overall survival are relatively worse with larger, intermediate (3-5 cm) lesions. Local recurrence rates range between 1.7%-20.2% and 6.7%-68.9% for CRLMs less than 3 cm and greater than 3 cm, respectively. Worse outcomes are also present when ablating intermediate size hepatocellular carcinoma (HCC) and there are some pathological similarities with CRLMs, namely the presence of micrometastatic disease. Combining ablation with transarterial chemoembolization is more effective in treating intermediate-size HCC than ablation alone. A meta-analysis of robust randomized controlled trials demonstrated long-term improved survival with combination therapy compared to ablation alone (odds ratio at 1, 3 and 5 years of 2.74, 2.77 and 5.23, respectively). There is, however, minimal evidence for combination therapy in CRLMs, limited to a handful of studies that are predominantly retrospective and have heterogeneous inclusion criteria. Given the difficulty in successfully treating intermediate CRLMs, the strong evidence for combination therapy in intermediate HCC and potential pathological similarities, formal evaluation of combination treatment in CRLM is merited. This review highlights existing evidence for treatment of intermediate-size liver lesions and highlights where trials in CRLMs should focus.


Assuntos
Carcinoma Hepatocelular , Ablação por Cateter , Quimioembolização Terapêutica , Neoplasias Colorretais , Neoplasias Hepáticas , Carcinoma Hepatocelular/terapia , Humanos , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia , Estudos Retrospectivos , Resultado do Tratamento
13.
Eur J Cancer ; 153: 153-161, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34157617

RESUMO

AIM: This is the first randomised study to evaluate toxicity and survival outcomes of two neoadjuvant chemoradiotherapy (CRT) regimens for patients with localised oesophageal adenocarcinoma (OAC) or gastro-oesophageal junction (GOJ) adenocarcinoma. The initial results showed comparable toxicity between regimens and pathological complete response (pCR) rate favouring CarPacRT. Herein, we report survival, progression patterns, and long-term toxicity after a median follow-up of 40.7 months. METHODS: NeoSCOPE was an open-label, UK multicentre, randomised, phase II trial. Eighty-five patients with resectable OAC or GOJ adenocarcinoma, ≥cT3 and/or ≥cN1 (TNM v7), suitable for neoadjuvant CRT, were recruited between October 2013 and February 2015. Patients were randomised to OxCapRT (oxaliplatin 85 mg/m2 on Days 1, 15, and 29; capecitabine 625 mg/m2 orally twice daily on days of radiotherapy [RT]) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m2 on Days 1, 8, 15, 22, and 29). RT dose was 45 Gy/25 fractions/5 weeks. Both arms received induction chemotherapy (two cycles oxaliplatin 130 mg/m2 on Day 1, capecitabine 625 mg/m2 orally twice daily on Days 1-21) before CRT. Surgery was performed 6-8 weeks after CRT. The primary end-point was pCR. Secondary end-points were toxicity, progression-free survival (PFS), overall survival (OS), and patterns of progression. RESULTS: Eighty-five patients were recruited from 17 UK centres. The median OS was 41.7 months (95% confidence interval [CI] 19.6 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable hazard ratio [HR] = 0.48, 95% CIs: 0.24-0.95, P = 0.035). The median PFS was 32.6 months (95% CIs: 17.1 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable HR = 0.54, 95% CIs: 0.29-1.01, P = 0.053). In both arms, the distant progression was twice as common as locoregional progression. CONCLUSIONS: OS and PFS favoured neoadjuvant CarPacRT over OxCapRT. Distant was more common than locoregional progression; therefore, priority should be given to optimising the systemic treatment component. CLINICAL TRIAL INFORMATION: EudraCT Number: 2012-000640-10; ClinicalTrials.gov: NCT01843829.


Assuntos
Adenocarcinoma/tratamento farmacológico , Capecitabina/uso terapêutico , Carboplatina/uso terapêutico , Quimiorradioterapia Adjuvante/métodos , Neoplasias Esofágicas/tratamento farmacológico , Oxaliplatina/uso terapêutico , Paclitaxel/uso terapêutico , Idoso , Capecitabina/farmacologia , Carboplatina/farmacologia , Feminino , Humanos , Masculino , Oxaliplatina/farmacologia , Paclitaxel/farmacologia
14.
Cancers (Basel) ; 13(5)2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33804336

RESUMO

Ultra-high dose rate radiation has been reported to produce a more favorable toxicity and tumor control profile compared to conventional dose rates that are used for patient treatment. So far, the so-called FLASH effect has been validated for electron, photon and scattered proton beam, but not yet for proton pencil beam scanning (PBS). Because PBS is the state-of-the-art delivery modality for proton therapy and constitutes a wide and growing installation base, we determined the benefit of FLASH PBS on skin and soft tissue toxicity. Using a pencil beam scanning nozzle and the plateau region of a 250 MeV proton beam, a uniform physical dose of 35 Gy (toxicity study) or 15 Gy (tumor control study) was delivered to the right hind leg of mice at various dose rates: Sham, Conventional (Conv, 1 Gy/s), Flash60 (57 Gy/s) and Flash115 (115 Gy/s). Acute radiation effects were quantified by measurements of plasma and skin levels of TGF-ß1 and skin toxicity scoring. Delayed irradiation response was defined by hind leg contracture as a surrogate of irradiation-induced skin and soft tissue toxicity and by plasma levels of 13 different cytokines (CXCL1, CXCL10, Eotaxin, IL1-beta, IL-6, MCP-1, Mip1alpha, TNF-alpha, TNF-beta, VEGF, G-CSF, GM-CSF and TGF- ß1). Plasma and skin levels of TGF-ß1, skin toxicity and leg contracture were all significantly decreased in FLASH compared to Conv groups of mice. FLASH and Conv PBS had similar efficacy with regards to growth control of MOC1 and MOC2 head and neck cancer cells transplanted into syngeneic, immunocompetent mice. These results demonstrate consistent delivery of FLASH PBS radiation from 1 to 115 Gy/s in a clinical gantry. Radiation response following delivery of 35 Gy indicates potential benefits of FLASH versus conventional PBS that are related to skin and soft tissue toxicity.

15.
Anticancer Drugs ; 32(9): 897-908, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33929994

RESUMO

Vandetanib-eluting radiopaque beads (VERB) have been developed for use in transarterial chemoembolization of liver tumours, with the goal of combining embolization with local delivery of antiangiogenic therapy. The objective of this study was to investigate how embolization-induced hypoxia may affect antitumoural activity of vandetanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), in the context of hepatocellular carcinoma (HCC) treatment. We studied the effect of vandetanib on proliferation, cell cycle and apoptosis of HCC cells, in hypoxic conditions, as well as the direct effects of the beads on 3D HCC spheroids. Vandetanib suppressed proliferation and induced apoptosis of HCC cells in vitro and was equipotent in hypoxic and normoxic conditions. High degrees of apoptosis were observed among cell lines in which vandetanib suppressed ERK1/2 phosphorylation and upregulated the proapoptotic protein Bim, but this did not appear essential for vandetanib-induced cell death in all cell lines. Vandetanib also suppressed the hypoxia-induced secretion of VEGF from HCC cells and inhibited proliferation of endothelial cells. Incubation of tumour spheroids with VERB led to sustained growth inhibition equivalent to the effect of free drug. We conclude that vandetanib has both antiangiogenic and direct anticancer activity against HCC cells even in hypoxic conditions, warranting the further evaluation of VERB as novel anticancer agents.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Hipóxia/induzido quimicamente , Neoplasias Hepáticas/terapia , Piperidinas/farmacologia , Quinazolinas/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
17.
Ann Palliat Med ; 10(5): 5988-6001, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32921074

RESUMO

In the United States of America, almost 150,000 people are estimated to be diagnosed with colorectal cancer in 2020 and up to 35% of those are expected to present with oligometastatic disease. The term 'oligometastasis' was first used in 1995, however surgical literature describing liver resection for colorectal cancer dates back to the 1940s. Five-year survival rates of up to 42% with surgery alone for solitary lesions are reported. Modern trials have demonstrated median overall survival rates of over 80 months for patients with colorectal liver metastases treated with perioperative chemotherapy. Colorectal liver metastases have accordingly been described as 'proof of concept' for the oligometastatic theory.


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Colorretais/terapia , Humanos , Neoplasias Hepáticas/terapia , Resultado do Tratamento
18.
Cancers (Basel) ; 12(7)2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32668592

RESUMO

Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential. To explore the benefit of combined vandetanib and radiotherapy treatment for HCC, we studied outcomes following combined treatment in pre-clinical models. METHODS: Vandetanib and radiation treatment were combined in HCC cell lines grown in vitro and in vivo. In addition to 2D migration and clonogenic assays, the combination was studied in 3D spheroids and a syngeneic mouse model of HCC. RESULTS: Vandetanib IC 50 s were measured in 20 cell lines and the drug was found to significantly enhance radiation cell kill and to inhibit both cell migration and invasion in vitro. In vivo, combination therapy significantly reduced cancer growth and improved overall survival, an effect that persisted for the duration of vandetanib treatment. CONCLUSION: In 2D and 3D studies in vitro and in a syngeneic model in vivo, the combination of vandetanib plus radiotherapy was more efficacious than either treatment alone. This new combination therapy for HCC merits evaluation in clinical trials.

19.
Ann Glob Health ; 86(1): 57, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32566485

RESUMO

Background: India's 120 million adolescent girls often have limited opportunities to receive health education, as health-related content in school curricula can be minimal, and the few existing external interventions for this demographic rarely cover multiple topics. Objectives: This study conducted a program evaluation of Girls Health Champions, a school-based peer education intervention in Mumbai, India that educates girls about leading causes of adolescent morbidity and mortality, including nutrition, mental health, and sexual & reproductive health. Methods: Female participants ages 12 to 16 in the eighth, ninth, and tenth standards were recruited at five participating schools in Mumbai, India to learn a multi-topic health curriculum from their peers, with a subset of ninth standard participants in each school trained as the peer educators. Using a quasi-experimental design, participant survey data was collected three times during the 2016-2017 academic year: at baseline, immediately following the peer-led education sessions, and five months following these sessions. Outcomes of interest included change in knowledge levels and health attitudes following the intervention, as well as retention at mid-year. An additional outcome was the change in self-reported leadership skills of peer educators before and after participating. Findings: Compared to baseline, participants demonstrated statistically significant increases in knowledge levels (+48%, p < 0.001) and positive shifts in health-related attitudes (+42%, p < 0.001). These changes were maintained at mid-year (+29% for knowledge levels, p < 0.001; +37% for attitudes, p < 0.001). Findings were consistent when data was stratified by standard and peer educator status (peer educators versus non-peer educators). Peer educators also demonstrated a statistically significant increase in their interest in health promotion. Conclusions: This study demonstrates the effectiveness of the peer education delivery model and finds school-based, peer-led programs covering a range of adolescent health topics can significantly increase knowledge and shift attitudes of program participants. Such benefits can accrue to both peer educators and non-peer educator program participants.


Assuntos
Saúde do Adolescente , Currículo , Educação em Saúde , Conhecimentos, Atitudes e Prática em Saúde , Saúde Mental , Grupo Associado , Saúde Reprodutiva , Serviços de Saúde Escolar , Adolescente , Anemia , Criança , Feminino , Violência de Gênero , Promoção da Saúde , Humanos , Índia , Desnutrição , Menstruação , Avaliação de Programas e Projetos de Saúde , Educação Sexual , Capacitação de Professores
20.
J Nucl Med ; 61(11): 1658-1664, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32358093

RESUMO

The purpose of this study was to establish the dose-response relationship of selective internal radiation therapy (SIRT) in patients with metastatic colorectal cancer (mCRC), when informed by radiobiological sensitivity parameters derived from mCRC cell lines exposed to 90Y. Methods: Twenty-three mCRC patients with liver metastases refractory to chemotherapy were included. 90Y bremsstrahlung SPECT images were transformed into dose maps assuming the local dose deposition method. Baseline and follow-up CT scans were segmented to derive liver and tumor volumes. Mean, median, and D70 (minimum dose to 70% of tumor volume) values determined from dose maps were correlated with change in tumor volume and volumetric RECIST response using linear and logistic regression, respectively. Radiosensitivity parameters determined by clonogenic assays of mCRC cell lines HT-29 and DLD-1 after exposure to 90Y or external beam radiotherapy (EBRT; 6 MV photons) were used in biologically effective dose (BED) calculations. Results: Mean administered radioactivity was 1,469 ± 428 MBq (range, 847-2,185 MBq), achieving a mean absorbed radiation dose to tumor of 35.5 ± 9.4 Gy and mean normal liver dose of 26.4 ± 6.8 Gy. A 1.0 Gy increase in mean, median, and D70 absorbed dose was associated with a reduction in tumor volume of 1.8%, 1.8%, and 1.5%, respectively, and an increased probability of a volumetric RECIST response (odds ratio, 1.09, 1.09, and 1.10, respectively). Threshold mean, median and D70 doses for response were 48.3, 48.8, and 41.8 Gy, respectively. EBRT-equivalent BEDs for 90Y are up to 50% smaller than those calculated by applying protraction-corrected radiobiological parameters derived from EBRT alone. Conclusion: Dosimetric studies have assumed equivalence between 90Y SIRT and EBRT, leading to inflation of BED for SIRT and possible undertreatment. Radiobiological parameters for 90Y were applied to a BED model, providing a calculation method that has the potential to improve assessment of tumor control.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundário , Radioisótopos de Ítrio/uso terapêutico , Idoso , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Radiobiologia , Dosagem Radioterapêutica , Tomografia Computadorizada de Emissão de Fóton Único
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