RESUMO
After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or preeclampsia (PE). Placental growth factor (PlGF) is a known contributing factor for pathological angiogenesis but the mechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine angiogenesis by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signaling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signaling. Taken together, perturbed PlGF-NFAT5-SGK1 signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs-endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE.
Assuntos
Endométrio , Neovascularização Patológica , Fator de Crescimento Placentário , Pré-Eclâmpsia , Proteínas Serina-Treonina Quinases , Fatores de Transcrição , Feminino , Humanos , Gravidez , Endométrio/metabolismo , Endométrio/irrigação sanguínea , Ensaio de Imunoadsorção Enzimática , Proteínas Imediatamente Precoces/metabolismo , Neovascularização Patológica/metabolismo , Fator de Crescimento Placentário/metabolismo , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Células Estromais/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; PTGS2) both participate in diverse pathologies including cancer progression. However, the biological role of the NFAT5-COX2 signaling pathway in human endometrial cancer has remained elusive. The present study explored whether NFAT5 is expressed in endometrial tumors and if NFAT5 participates in cancer progression. To gain insights into the underlying mechanisms, NFAT5 protein abundance in endometrial cancer tissue was visualized by immunohistochemistry and endometrial cancer cells (Ishikawa and HEC1a) were transfected with NFAT5 or with an empty plasmid. As a result, NFAT5 expression is more abundant in high-grade than in low-grade endometrial cancer tissue. RNA sequencing analysis of NFAT5 overexpression in Ishikawa cells upregulated 37 genes and downregulated 20 genes. Genes affected included cyclooxygenase 2 and hypoxia inducible factor 1α (HIF1A). NFAT5 transfection and/or treatment with HIF-1α stabilizer exerted a strong stimulating effect on HIF-1α promoter activity as well as COX2 expression level and prostaglandin E2 receptor (PGE2) levels. Our findings suggest that activation of NFAT5-HIF-1α-COX2 axis could promote endometrial cancer progression.
Assuntos
Neoplasias do Endométrio , Regulação da Expressão Gênica , Humanos , Feminino , Ciclo-Oxigenase 2/genética , Neoplasias do Endométrio/genética , Fatores de Transcrição NFATC , Transdução de Sinais , Dinoprostona , Fator V , Fatores de TranscriçãoRESUMO
AIM: Hepatocellular carcinoma (HCC) with bile duct invasion (BDI) (BDIHCC) has a poor prognosis. Moreover, due to the paucity of reports, there is no consensus regarding optimal management of this clinical condition yet. The aim of this study was to clarify the efficacy and safety of proton beam therapy (PBT) for BDIHCC. METHODS: Between 2009 and 2018, 15 patients with BDIHCC underwent PBT at our institution. The overall survival (OS), local control (LC), and progression-free survival (PFS) curves were constructed using the Kaplan-Meier method. Toxicities were assessed using the Common Terminology Criteria of Adverse Events version 4.0. RESULTS: The median follow-up time was 23.4 months (range, 7.9-54.3). The median age was 71 years (range, 58-90 years). Many patients were Child A (n = 8, 53.3%) and most had solitary tumors (n = 11, 73.3%). Additionally, most patients had central type BDI (n = 11, 73%). The median tumor size was 4.0 cm (range, 1.5-8.0 cm). The 1-, 2-, and 3-year OS rates were 80.0%, 58.7% and 40.2%, respectively, and the corresponding LC and PFS rates were 93.3%, 93.3%, and 74.7% and 72.7%, 9.7%, and 0.0%, respectively. Acute grade 1/2 dermatitis (n = 7, 46.7%), and grades 2 (n = 1, 6.7%) and 3 (n = 1, 6.7%) cholangitis were observed. Late toxicities such as grade 3 gastric hemorrhage and pleural effusion were observed. No toxicities of grade 4 or higher were observed. CONCLUSIONS: PBT was feasible with tolerable toxicities for the treatment of BDIHCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Terapia com Prótons , Idoso , Humanos , Ductos Biliares , Intervalo Livre de Progressão , Terapia com Prótons/efeitos adversos , Terapia com Prótons/métodos , Pessoa de Meia-Idade , Idoso de 80 Anos ou maisRESUMO
Proton beam therapy and carbon-ion radiotherapy, also known as particle beam therapy, are gaining popularity in cancer care and liver tumor treatment is one of the main areas of interest. Comparative studies are in high demand and the article highlights this. While the data presented in this article are without doubt valuable, we raise concerns about their interpretation.
Assuntos
Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/cirurgia , Pesquisa Comparativa da Efetividade , Hepatectomia , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/cirurgia , Terapia com Prótons , HumanosRESUMO
Charged particle therapy (proton beam therapy and carbon ion therapy) is a form of radiotherapy which has the unique characteristic of superior depth dose distribution, and has been used for the treatment of hepatocellular carcinoma (HCC) in a limited number of patients, especially in Japan. We undertook a systematic review to define the clinical utility of charged particle therapy for patients with HCC. We searched the MEDLINE database from 1983 to June 2016 to identify clinical studies on charged particle therapy for HCC. Primary outcomes of interest were local control, overall survival, and late radiation morbidities. A total of 13 cohorts from 11 papers were selected from an initial dataset of 78 papers. They included a randomized controlled trial comparing proton beam therapy with transarterial chemoembolization, 9 phase I or II trials and 2 retrospective studies. The reported actuarial local control rates ranged from 71.4-95% at 3 years, and the overall survival rates ranged from 25-42.3% at 5 years. Late severe radiation morbidities were uncommon, and a total of 18 patients with grade ≥3 late adverse events were reported among the 787 patients included in this analysis. Charged particle therapy for HCC was associated with good local control with limited probability of severe morbidities. The cost-effectiveness and the distinctive clinical advantages of charged particle therapies should be clarified in order to become a socially accepted treatment modality for HCC.
Assuntos
Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/radioterapia , Terapia com Prótons/métodos , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Ensaios Clínicos como Assunto , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Proton beam therapy (PBT) is a potential new alternative to treatment with photon radiotherapy that may reduce the risk of late toxicity and secondary cancer, especially for pediatric tumors. The goal of this study was to evaluate the long-term benefits of PBT in cancer survivors. A retrospective observational study of pediatric patients who received PBT was performed at four institutions in Japan. Of 343 patients, 62 were followed up for 5 or more years. These patients included 40 males and 22 females, and had a median age of 10 years (range: 0-19 years) at the time of treatment. The irradiation dose ranged from 10.8 to 81.2 GyE (median: 50.4 GyE). The median follow-up period was 8.1 years (5.0-31.2 years). The 5-, 10- and 20-year rates for grade 2 or higher late toxicities were 18%, 35% and 45%, respectively, and those for grade 3 or higher late toxicities were 6%, 17% and 17% respectively. Univariate analysis showed that the irradiated site (head and neck, brain) was significantly associated with late toxicities. No malignant secondary tumors occurred within the irradiated field. The 10- and 20-year cumulative rates for all secondary tumors, malignant secondary tumors, and malignant nonhematologic secondary tumors were 8% and 16%, 5% and 13%, and 3% and 11%, respectively. Our data indicate that PBT has the potential to reduce the risk of late mortality and secondary malignancy. Longer follow-up is needed to confirm the benefits of PBT for pediatric tumors.
Assuntos
Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias/radioterapia , Terapia com Prótons/efeitos adversos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Japão/epidemiologia , Masculino , Dosagem Radioterapêutica , Estudos Retrospectivos , Inquéritos e Questionários , Adulto JovemRESUMO
Long-term efficacy of proton beam therapy (PBT) remains unclear for patients with previously untreated hepatocellular carcinoma (HCC). We aimed to study the long-term outcomes of PBT according to Barcelona Clinic Liver Cancer (BCLC) staging classifications in patients with previously untreated HCC. The major eligibility criteria of this observational study were an Eastern Cooperative Oncology Group performance status (PS) 0-2, Child-Pugh grade A or B, previously untreated HCC covered within an irradiation field, and no massive ascites. A total of 66.0-77.0 GyE was administered in 10-35 fractions. Local tumor control (LTC), defined as no progression in the irradiated field, progression-free survival (PFS), and overall survival (OS) were assessed according to BCLC staging. From 2002 to 2009 at our institution, 129 patients were eligible. The 5-year LTC, PFS, and OS rates were 94%, 28%, and 69% for patients with 0/A stage disease (n = 9/21), 87%, 23%, and 66% for patients with B stage disease (n = 34), and 75%, 9%, and 25% for patients with C stage disease (n = 65), respectively. The 5-year LTC and OS rates of 15 patients with tumor thrombi in major vessels were 90% and 34%, respectively. Multivariate analyses revealed that PS (0 versus 1-2) was a significant prognostic factor for OS. No grade 3 or higher adverse effects were observed. PBT showed favorable long-term efficacies with mild adverse effects in BCLC stage 0 to C, and can be an alternative treatment for localized HCC especially when accompanied with tumor thrombi. This study was registered with UMIN Clinical Trials Registry (UMIN000025342).
Assuntos
Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/radioterapia , Terapia com Prótons/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Terapia com Prótons/efeitos adversos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: We retrospectively elucidated the oncological outcomes, prognostic factors and toxicities of proton beam therapy in trimodal bladder-preserving therapy for muscle-invasive bladder cancer at our institution. METHODS: From 1990 to 2015, 70 patients with cT2-3N0M0 muscle-invasive bladder cancer underwent trimodal bladder-preserving therapy consisting of maximal transurethral resection of the bladder tumor, small pelvis photon irradiation, intra-arterial chemotherapy and proton beam therapy. The overall survival rate, progression-free survival rate, time to progression, predictive factors for progression and toxicities were analyzed. Progression was defined as when muscle-invasive recurrence, distant metastasis or upper urinary tract recurrence was observed. RESULTS: The patients' median age was 65 (range 36-85) years. The median follow-up period was 3.4 (range 0.6-19.5) years. The 5-year cumulative overall survival rate, progression-free survival rate and time to progression rate were 82%, 77%, and 82%, respectively. In univariate and multivariate analyses, tumor multiplicity and tumor size (≥5 cm) were significant and independent factors associated with progression (hazard ratio 3.5, 95% confidence interval 1.1-12; hazard ratio 5.0, 95% confidence interval 1.3-17; P < 0.05 for all). As for toxicity, 26 (18%) patients had grade 3-4 acute hematologic toxicities and 2 (3%) patients had grade 3 late genitourinary toxicity. No patient had to discontinue the treatment due to acute toxicity. CONCLUSIONS: Our bladder-preserving therapy with proton beam therapy was well tolerated and achieved a favorable mortality rate. Tumor multiplicity and tumor size were important risk factors for progression. Our findings indicate that this therapy can be an effective treatment option for selected muscle-invasive bladder cancer patients.
Assuntos
Terapia com Prótons , Neoplasias da Bexiga Urinária/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Intervalo Livre de Doença , Feminino , Doenças Hematológicas/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Recidiva Local de Neoplasia , Prognóstico , Modelos de Riscos Proporcionais , Terapia com Prótons/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/radioterapiaRESUMO
BACKGROUND: Understanding the irradiated area and dose correctly is important for the reirradiation of organs that deform after irradiation, such as the liver. We investigated the spatial registration error using the deformable image registration (DIR) software products MIM Maestro (MIM) and Velocity AI (Velocity). METHODS: Image registration of pretreatment computed tomography (CT) and posttreatment CT was performed in 24 patients with liver tumors. All the patients received proton beam therapy, and the follow-up period was 4-14 (median: 10) months. We performed DIR of the pretreatment CT and compared it with that of the posttreatment CT by calculating the dislocation of metallic markers (implanted close to the tumors). RESULTS: The fiducial registration error was comparable in both products: 0.4-32.9 (9.3 ± 9.9) mm for MIM and 0.5-38.6 (11.0 ± 10.0) mm for Velocity, and correlated with the tumor diameter for MIM (r = 0.69, P = 0.002) and for Velocity (r = 0.68, P = 0.0003). Regarding the enhancement effect, the fiducial registration error was 1.0-24.9 (7.4 ± 7.7) mm for MIM and 0.3-29.6 (8.9 ± 7.2) mm for Velocity, which is shorter than that of plain CT (P = 0.04, for both). CONCLUSIONS: The DIR performance of both MIM and Velocity is comparable with regard to the liver. The fiducial registration error of DIR depends on the tumor diameter. Furthermore, contrast-enhanced CT improves the accuracy of both MIM and Velocity. INSTITUTIONAL REVIEW BOARD APPROVAL: H28-102; July 14, 2016 approved.
Assuntos
Algoritmos , Neoplasias Hepáticas/diagnóstico por imagem , Fígado/diagnóstico por imagem , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Software , Técnica de Subtração , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reconhecimento Automatizado de Padrão/métodos , Intensificação de Imagem Radiográfica/métodos , Radiografia Abdominal/métodos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
To evaluate the safety and efficacy of postoperative proton beam therapy (PBT) combined with nimustine hydrochloride (ACNU) or temozolomide (TMZ) for glioblastoma multiforme (GBM). The subjects were 46 patients with GBM who were treated with high dose (96.6 GyE) PBT. There were 24 males and 22 females, and the median age was 58 years old (range 24-76). The Karnofsky performance status was 60, 70, 80, 90 and 100 in 5, 10, 12, 11 and 8 patients, respectively. Total resection, partial resection, and biopsy were performed for 31, 14 and 1 patients, respectively. Photon beams were delivered to high intensity areas on T2-weighted magnetic resonance imaging (MRI) in the morning (50.4 Gy in 28 fractions). More than 6 h later, PBT was delivered to the enhanced area plus a 10 mm margin in the first half of the protocol (23.1 GyE in 14 fractions) and to the enhanced volume in the second half (23.1 GyE in 14 fraction). Concurrent chemotherapy with ACNU during weeks 1 and 4 or daily TMZ was administered in 23 and 23 patients, respectively. The overall 1 and 2 year survival rates were 82.6 and 47.6 %, respectively. Median survival was 21.1 months (95 % CI 13.1-29.2), with no significant difference in survival between the ACNU and TMZ groups. The patient characteristics were similar in the two groups. Late radiation necrosis occurred in 11 patients (six ACNU, five TMZ), but was controlled by necrotomy and therapy including bevacizumab. PBT concurrent with ACNU or TMZ was tolerable and beneficial for carefully selected patients with GBM.
Assuntos
Antineoplásicos/uso terapêutico , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Nimustina/uso terapêutico , Terapia com Prótons/métodos , Adulto , Idoso , Dacarbazina/uso terapêutico , Feminino , Seguimentos , Glioblastoma/diagnóstico por imagem , Glioblastoma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Temozolomida , Resultado do Tratamento , Adulto JovemRESUMO
The number of patients treated by proton beam therapy in Japan since 2000 has increased; in 2016, 11 proton facilities were available to treat patients. Notably, proton beam therapy is very useful for pediatric cancer; since the pediatric radiation dose to normal tissues should be reduced as much as possible because of the effect of radiation on growth, intellectual development, endocrine organ function and secondary cancer development. Hepatocellular carcinoma is common in Asia, and most of the studies of proton beam therapy for liver cancer have been reported by Japanese investigators. Proton beam therapy is also a standard treatment for nasal and paranasal lesions and lesions at the base of the skull, because the radiation dose to critical organs such as the eyes, optic nerves and central nervous system can be reduced with proton beam therapy. For prostate cancer, comparative studies that address adverse effects, safety, patient quality of life and socioeconomic issues should be performed to determine the appropriate use of proton beam therapy for prostate cancer. Regarding new proton beam therapy applications, experience with proton beam therapy combined with chemotherapy is limited, although favorable outcomes have been recently reported for locally advanced lung cancer, esophageal cancer and pancreatic cancer. Therefore, 'chemoproton' therapy appears to be a very attractive field for further clinical investigations. In conclusion, there are cost issues and considerations regarding national insurance for the use of proton beam therapy in Japan. Further studies and discussions are needed to address the use of proton beam therapy for several types of cancers, and for maintaining the quality of life of patients while retaining a high cure rate.
Assuntos
Neoplasias/radioterapia , Terapia com Prótons/métodos , Institutos de Câncer , Neoplasias Esofágicas/radioterapia , Humanos , Cobertura do Seguro , Japão , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/radioterapia , Masculino , Neoplasias/patologia , Neoplasias Nasais/radioterapia , Neoplasias Pancreáticas/radioterapia , Neoplasias da Próstata/radioterapia , Terapia com Prótons/economia , Terapia com Prótons/instrumentaçãoRESUMO
BACKGROUND AND AIM: Treatment for unresectable intrahepatic cholangiocarcinoma (ICC) has not been established. The aim of the study was to evaluate the outcome of proton beam therapy (PBT) for patients with unresectable ICC. METHODS: Up to 2010, 20 patients (11 males, 9 females, median age 63 years old) with unresectable ICC (two, seven, seven, and four in stages II, IIIA, IIIC, and IV, respectively) were treated with PBT. The largest dimensions of the tumors ranged from 15 to 140 mm (median: 50 mm). The intrahepatic region and lymph nodes received median total proton doses of 72.6 GyE in 22 fractions and 56.1 GyE in 17 fractions, respectively. Four patients received concurrent chemotherapy (tegafur, gimeracil, and oteracil; TS-1) during PBT. Twelve patients were treated curatively, and eight were treated palliatively because tumors were present outside the irradiation field. RESULTS: In the curative group, nine tumors within the irradiated field were controlled in follow-up of 8.6-62.6 months (median: 20.8 months). Median survival rates in the curative and palliative groups were 27.5 and 9.6 months, respectively, and overall 1- and 3-year survival rates were 82% and 38%, and 50% and 0%, respectively. Eight patients survived for > 2 years, and there was no distant metastasis in five of these patients after 2 years. No severe side-effects occurred. CONCLUSIONS: The results suggest that long-term survival can be achieved using PBT for patients with unresectable ICC without distant metastasis. Further studies are required to determine the optimal treatment schedule and best combination of PBT and chemotherapy.
Assuntos
Neoplasias dos Ductos Biliares/radioterapia , Colangiocarcinoma/radioterapia , Terapia com Prótons , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Terapia Combinada , Fracionamento da Dose de Radiação , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ácido Oxônico/administração & dosagem , Terapia com Prótons/mortalidade , Dosagem Radioterapêutica , Taxa de Sobrevida , Tegafur/administração & dosagem , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The aim of this study was to evaluate the efficacy of proton beam therapy for pediatric patients with ependymoma. METHODS: Proton beam therapy was conducted for six patients (three boys and three girls; age, 2-6 years; median, 5 years) with ependymoma. The tumors were WHO grades 2 and 3 in two and four patients, respectively. All patients underwent surgery (subtotal and gross total resection in three patients each) and proton beam therapy at doses of 50.4-61.2 GyE (median, 56.7 GyE). The mean doses to normal brain tissue in proton beam therapy and photon radiotherapy were simulated using the same treatment planning computed tomography images. RESULTS: All patients completed the planned irradiation. The follow-up period was 13-44 months (median, 24.5 months) from completion of proton beam therapy and all patients were alive at the end of this period. Local recurrence in the treatment field occurred in one patient at 4 months after proton beam therapy at 50.4 GyE. Alopecia and mild dermatitis occurred in all patients, but there was no severe toxicity. One patient had a once-off seizure after proton beam therapy and alopecia persisted in another patient for 31 months, but no patients had difficulty with daily life. The simulation showed that proton beam therapy reduces the dose to normal brain tissue by approximately half compared with photon radiotherapy. CONCLUSIONS: Proton beam therapy for pediatric ependymoma is safe, does not have specific toxicities, and can reduce irradiation of normal brain tissue.
Assuntos
Ependimoma/radioterapia , Criança , Pré-Escolar , Ependimoma/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Terapia com Prótons/métodos , Estudos Retrospectivos , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Charged particles such as protons and carbon-ions offer advantageous physical properties to radiation therapy (RT) for the treatment of various cancers when compared with photons, because they exhibit a spread-out Bragg peak, and may be utilized to achieve a desirable dose distribution to the target volume by using specified beam modulation. Interestingly, the cytocidal effect of protons is almost equal to that of photons, because both protons and photons are considered low-linear energy transfer radiations. Hence, proton beam therapy (PBT) is an attractive RT option, especially in the treatment of locally advanced cancers, as irradiation doses can be safely escalated while sparing the surrounding normal tissues, and because PBT may be concurrently combined with chemotherapy for treating such cancers. Recent advances in PBT techniques including a spot scanning method, as well as an increase in the number of particle therapy institutes are anticipated to yield favorable results through future multi-institutional prospective studies. The University of Tsukuba has carried out several studies to validate the effectiveness of PBT for many types of cancers since 1983. Here, we present our findings on the clinical outcomes of PBT for esophageal cancer, non-small cell lung cancer, intrahepatic biliary tract cancer, pancreas cancer, and bladder cancer; future aspects of PBT concurrently combined with chemotherapy for treating locally advanced cancers are also discussed.
Assuntos
Quimiorradioterapia , Neoplasias/radioterapia , Terapia com Prótons , HumanosRESUMO
AIM: Proton beam therapy is safe and more effective than conventional radiation therapy for the local control of nodular hepatocellular carcinoma (HCC). However, evaluating therapeutic response by imaging is not accurate during the early post-irradiation period. Therefore, we examined whether the histopathological study of biopsy specimens obtained at 3 weeks after irradiation can be used to more accurately assess therapeutic response. METHODS: Fifteen HCC lesions from 13 patients were treated with proton beam irradiation. Tissue biopsy samples were obtained using abdominal ultrasound-guided percutaneous fine-needle aspiration from the center of the tumor before, 3 weeks after and 1 year post-proton therapy. The specimens were examined after staining with hematoxylin-eosin (HE) and a MIB-1 antibody. RESULTS: MIB-1 labeling indices (LI) before treatment were 13.0 ± 8.5% (mean ± SD; range, 0.6-27.0), whereas those 3 weeks after proton therapy were significantly reduced to 3.2 ± 2.4% (range, 0.6-8.9) (P < 0.05). Although the tumor size was reduced, we did not observe a reduction in tumor blood flow by dynamic computed tomography or degenerative changes by HE. All lesions that displayed reduced MIB-1 LI at 3 weeks post-proton treatment were ultimately diagnosed as complete response at 1 year after treatment. In contrast, one case with increased MIB-1 LI at 3 weeks had significant tumor size progression at 1 year post-treatment. CONCLUSION: The percutaneous fine-needle aspiration biopsy of HCC is a safe and useful tool that can be used to evaluate the response to proton irradiation. In particular, MIB-1 LI may provide additional information to assess the therapeutic response of HCC during the early post-irradiated period.
RESUMO
Circumscribed choroidal hemangiomas are rare and benign tumors but often have a progressive course and are complicated by retinal detachment and glaucoma. The effectiveness of external radiation for large tumors that are difficult to treat with photodynamic therapy was recently reported; however, few studies have conducted long-term follow-ups. We encountered a case of localized choroidal hemangioma that was treated with proton beam therapy and followed up for 15 years. A 37-year-old man was diagnosed with a 10 × 4 mm circumscribed choroidal hemangioma involving the macular area with retinal detachment. Proton beam therapy was performed at 26.4 Gy relative biological effectiveness (RBE) in 8 fractions. The choroidal hemangioma gradually shrank over three years, and the retinal detachment also improved. A cataract developed on the affected side 11 years after irradiation, and eye coordination issues developed 15 years after irradiation. Glaucoma was not observed during the follow-up period; however, visual acuity did not recover, and the patient developed light perception. Although vision was not preserved, proton beam therapy effectively shrank the tumor and maintained quality of life.
RESUMO
Adenoid cystic carcinoma (ACC) of the trachea is a rare disease that is slow growing and has a risk of distant metastasis. The standard treatment for ACC of the trachea is surgery, but this tumor is often unresectable. In definitive radiotherapy using photons for unresectable ACC of the trachea, it is sometimes difficult to deliver a sufficient dose to the target without exceeding the tolerable dose to the surrounding normal tissues. Here, we report two cases of ACC of the trachea that received a high dose (74 Gy [relative biological effectiveness]) of proton beam therapy and achieved long-term survival.
Assuntos
Carcinoma Adenoide Cístico , Terapia com Prótons , Humanos , Traqueia/patologia , Seguimentos , Carcinoma Adenoide Cístico/radioterapia , Brônquios/patologiaRESUMO
The usefulness of moderately hypofractionated radiotherapy for localized prostate cancer has been extensively reported, but there are limited studies on proton beam therapy (PBT) using similar hypofractionation schedules. The aim of this prospective phase II study is to confirm the safety of a shortened PBT course using 70 Gy relative biological effectiveness (RBE) in 28 fractions. From May 2013 to June 2015, 102 men with localized prostate cancer were enrolled. Androgen deprivation therapy was administered according to risk classification. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 4.0. Of the 100 patients ultimately evaluated, 15 were classified as low risk, 43 as intermediate risk, and 42 as high risk. The median follow-up time of the surviving patients was 96 months (range: 60-119 months). The 5-year cumulative incidences of grade 2 gastrointestinal/genitourinary adverse events were 1% (95% CI: 0.1-6.9) and 4% (95% CI: 1.5-10.3), respectively; no grade ≥ 3 gastrointestinal/genitourinary adverse events were observed. The current study revealed a low incidence of late adverse events in prostate cancer patients treated with moderately hypofractionated PBT of 70 Gy (RBE) in 28 fractions, indicating the safety of this schedule.
Assuntos
Neoplasias da Próstata , Terapia com Prótons , Hipofracionamento da Dose de Radiação , Humanos , Masculino , Neoplasias da Próstata/radioterapia , Terapia com Prótons/efeitos adversos , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento , Idoso de 80 Anos ou mais , Fracionamento da Dose de RadiaçãoRESUMO
Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) has a poor prognosis and is generally not indicated for surgery. Proton beam therapy (PBT) may offer an alternative treatment. In this study, long-term outcomes were examined in 116 patients (median age 66 years, 100 males) with HCC with advanced PVTT (Vp3 or Vp4) who received PBT from April 2008 to March 2018. Of these patients, 63 received PBT as definitive treatment and 53 as palliative treatment. The representative dose was 72.6 Gy (RBE) in 22 fractions. Eight patients died in follow-up, including 72 due to tumor progression. The 5-year overall survival (OS) rate was 18.0% (95% CI 9.8-26.2%) and the 5-year local control (LC) rate was 86.1% (74.9-97.3%). In multivariate analyses, performance status and treatment strategy were significantly associated with OS. The median follow-up period for survivors with definitive treatment was 33.5 (2-129) months, and the 5-year OS rate was 25.1% (12.9-37.3%) in these cases. The median survival time after definitive irradiation was >20 months. The 5-year OS rate was 9.1% (0-19.7%) for palliative irradiation. These results compare favorably with those of other therapies and suggest that PBT is a useful option for cases of HCC with advanced PVTT that cannot undergo surgery, with an expected survival benefit and good local control. Determining the optimal indication for this treatment is a future challenge.
RESUMO
PURPOSE: A prospective multicenter registry study was started May 2016 in Japan to evaluate the efficacy and safety of proton beam therapy (PBT) for hepatocellular carcinoma (HCC). METHODS AND MATERIALS: Patients who received PBT for HCC from May 2016 to June 2018 were registered in the database of the Particle Beam Therapy Committee and Subcommittee of the Japanese Society for Radiation Oncology. Overall survival (OS), progression-free survival (PFS), and local recurrence were evaluated. RESULTS: Of the 755 registered patients, 576 with initial PBT and no duplicate cancer were evaluated. At final follow-up, 322 patients were alive and 254 had died. The median follow-up period for survivors was 39 months (0-58 months). The median OS time of the 576 patients was 48.8 months (95% CI, 42.0-55.6 months) and the 1-, 2-, 3-, and 4-year OS rates were 83.8% (95% CI, 80.5%-86.6%), 68.5% (64.5%-72.2%), 58.2% (53.9%-62.2%), and 50.1% (44.9%-55.0%), respectively. Recurrence was observed in 332 patients, including local recurrence in 45 patients. The median PFS time was 14.7 months (95% CI, 12.4-17.0 months) and the 1-, 2-, 3-, and 4-year PFS rates were 55.2% (95% CI, 51.0%-59.2%), 37.5% (33.5%-41.5%), 30.2% (26.3%-34.2%), and 22.8% (18.5%-27.4%), respectively. The 1-, 2-, 3-, and 4-year OS rates were significantly higher for tumor size <5 versus 5 to 10 cm (P < .001) and <5 versus ≥10 cm (P < .001); Child-Pugh score A/B versus C (P < .001); and distance of the tumor from the gastrointestinal tract <1 versus 1 to 2 cm (P < .008) and <1 versus >2 cm (P < .001). At final follow-up, 27 patients (4.7%) had late adverse events of grade 3 or higher, with liver failure (n = 7), and dermatitis (n = 7) being most common. CONCLUSIONS: This multicenter prospective data registry indicated that PBT for HCC gives good therapeutic effects (3-year local control rate of 90%) with a low risk of severe late adverse events.