RESUMO
This open-label first-in-human study evaluated JPH203, which is a novel selective L-type amino acid transporter 1 inhibitor. We also evaluated the association between the N-acetyltransferase 2 phenotype and outcomes. Japanese patients with advanced solid tumors received daily intravenous JPH203 treatment for 7 days, followed by a 21-day rest period, at escalating doses of 12-85 mg/m2. Dose-limiting toxicities were evaluated during the first cycle using a 3 + 3 design. The study enrolled 17 patients, although grade 3 liver dysfunction was detected in one of six patients receiving 60 mg/m2 and in the first patient to receive 85 mg/m2. Further enrollment was terminated and the maximum tolerated dose was defined as 60 mg/m2. The AUC∞ increased between 12 mg/m2 and 25 mg/m2, although no differences were observed at 25-40 mg/m2. Partial response was observed for one patient with biliary tract cancer (BTC) at the 12 mg/m2 dose, and disease control was achieved by 3 of 6 patients at the 12 mg/m2 and 25 mg/m2 dose levels. Based on these results, we recommend a phase II dose of 25 mg/m2. The disease control rate for BTC was 60%. Two patients with grade 3 liver dysfunction had the rapid N-acetyltransferase 2 phenotype, and disease control was more common for the non-rapid phenotype (50% vs. 12.5%). It appears that JPH203 was well-tolerated and provided promising activity against BTC. The N-acetyltransferase 2 phenotype might help predict the safety and efficacy of JPH203. Clinical trial registration: UMIN000016546.
Assuntos
Antineoplásicos/administração & dosagem , Benzoxazóis/administração & dosagem , Transportador 1 de Aminoácidos Neutros Grandes , Neoplasias/tratamento farmacológico , Tirosina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Aminoácidos/sangue , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Arilamina N-Acetiltransferase/genética , Benzoxazóis/efeitos adversos , Benzoxazóis/sangue , Benzoxazóis/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/genética , Neoplasias/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento , Tirosina/administração & dosagem , Tirosina/efeitos adversos , Tirosina/sangue , Tirosina/farmacocinéticaRESUMO
The aging rate in Japan is the highest in the world, and it is entering a very aging society that has never happened before. The first cause of death is a malignant neoplasm, and opportunities of the treatment for elderly cancer patients are rapidly increasing. The elderly have increased chronic diseases and complications with aging, and the adverse event in medication therapy also increases. Also, the form of medical provision is diversified, home medical care and nursing care are recommended. Therefore, it is important to appreciate the various aspects including psychophysiological, living, social aspects in addition to changes in physical function caused by aging and appropriately evaluate them, for selecting treatment methods in elderly cancer patients. Geriatric assessment(GA)is recommended for this evaluation, and it is expected to contribute to improvement of treatment outcome and quality of life(QOL). In this article, we will outline the role of aged general comprehensive functional evaluation in elderly cancer treatment and the problems of chemotherapy in the elderly.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Humanos , Guias de Prática Clínica como Assunto , Qualidade de Vida , Fatores de Risco , Resultado do TratamentoRESUMO
The number of older adults in Japan is rising, and healthcare for older patients differs from those of younger patients.We have limited available data regarding the outcomes of cancer treatment in this population.In addition, we have few guidelines to address the evaluation and treatment of older cancer patients in Japan.The Japan Agency for Medical Research and Development(AMED)has funded clinical research focusing on elderly cancer patients.We organized the Geriatric Study Committee in Japan Clinical Oncology Group(JCOG)to develop geriatric research policy in this area.This policy includes the (1)definition of a selection policy for the subjects of geriatric research,(2)establishment of standard endpoints and methodological schemes for geriatric research, and(3)recommendations for standard tools of geriatric assessment.We are also developing a curriculum in geriatric oncology for medical doctors and oncology nurses to improve the evidence-based evaluation and treatment of elderly cancer patients.Japanese society is progressing to address the increasing number of elderly patients using a team approach in a broad sense, which consists of cancer professionals, healthcare providers, and government.
Assuntos
Neoplasias/terapia , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisões , Guias como Assunto , Humanos , Assistência TerminalRESUMO
The use of FOLFIRINOX and gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer is currently approved in Japan. Although the efficacies of these regimens were investigated only in patients with metastatic pancreatic cancer, they are also expected to be effective for locally advanced pancreatic cancer. Meanwhile, chemoradiotherapy is recognized as a treatment option for locally advanced pancreatic cancer. S-1 or capecitabine-based chemoradiotherapy is being developed in Japan or in Western countries, respectively. Recently, the concept of induction chemotherapy followed by chemoradiotherapy has been accepted and applied in clinical trials. In the JCOG1106 trial, induction gemcitabine followed by S-1 and concurrent radiotherapy demonstrated promising results. This regimen has been recognized as a very promising one for chemoradiotherapy in Japan. However, the optimal therapy for locally advanced pancreatic cancer remains controversial, especially in terms of which between chemotherapy and chemoradiotherapy is superior.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Neoplasias Pancreáticas/terapia , Humanos , Quimioterapia de Indução , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Secondary trigeminal neuralgia (TN) is caused by identifiable diseases or lesions of the trigeminal nerve root, Gasserian ganglion and/or pons. TN is a neuropathic pain disorder characterized by electric shock-like or stabbing pain in the facial region, which can lead to impaired health-related quality of life. The present case report describes a rare case of secondary TN caused by trigeminal nerve metastases from lung adenocarcinoma, in which opioids provided symptomatic relief. The patient was a 46-year-old man with stage IV lung adenocarcinoma. They were admitted to hospital for the introduction of fifth-line chemotherapy because of previous chemotherapy-refractory disease progression. Electric shock-like or stabbing pain in the left facial area and bilateral auditory disturbances coincided with intracranial peri-brainstem metastases. Facial pain was triggered by mastication, making it difficult for the patient to eat. A fentanyl transdermal patch (25 mcg/h) was initiated following a diagnosis of TN secondary to lung adenocarcinoma metastases on the trigeminal nerves by magnetic resonance imaging. Subsequently, the facial pain improved rapidly. In conclusion, unlike classic and idiopathic TN, which is usually treated with carbamazepine as a first-line drug, oncologic secondary TN can be treated with opioids.
RESUMO
Complex molecular interactions dictate the developmental steps that lead to a mature and functional cornea and lens. Peters anomaly is one subtype of anterior segment dysgenesis especially due to abnormal development of the cornea and lens. MSX2 was recently implicated as a potential gene that is critical for anterior segment development. However, the role of MSX2 within the complex mechanisms of eye development remains elusive. Our present study observed the morphologic changes in conventional Msx2 knockout (KO) mice and found phenotypes consistent with Peters anomaly and microphthalmia seen in humans. The role of Msx2 in cornea and lens development was further investigated using IHC, in situ hybridization, and quantification of proliferative and apoptotic lens cells. Loss of Msx2 down-regulated FoxE3 expression and up-regulated Prox1 and crystallin expression in the lens. The FoxE3 and Prox1 malfunction and precocious Prox1 and crystallin expression contribute to a disturbed lens cell cycle in lens vesicles and eventually to cornea-lentoid adhesions and microphthalmia in Msx2 KO mice. The observed changes in the expression of FoxE3 suggest that Msx2 is an important contributor in controlling transcription of target genes critical for early eye development. These results provide the first direct genetic evidence of the involvement of MSX2 in Peters anomaly and the distinct function of MSX2 in regulating the growth and development of lens vesicles.
Assuntos
Segmento Anterior do Olho/anormalidades , Opacidade da Córnea/genética , Anormalidades do Olho/genética , Fatores de Transcrição Forkhead/biossíntese , Proteínas de Homeodomínio/genética , Animais , Segmento Anterior do Olho/embriologia , Segmento Anterior do Olho/metabolismo , Segmento Anterior do Olho/patologia , Córnea/anormalidades , Córnea/embriologia , Opacidade da Córnea/embriologia , Opacidade da Córnea/metabolismo , Opacidade da Córnea/patologia , Cristalinas/biossíntese , Cristalinas/genética , Regulação para Baixo/genética , Anormalidades do Olho/embriologia , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Fatores de Transcrição Forkhead/genética , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/fisiologia , Cristalino/anormalidades , Cristalino/embriologia , Cristalino/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microftalmia/embriologia , Microftalmia/genética , Microftalmia/metabolismo , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genética , Regulação para Cima/genéticaRESUMO
BACKGROUND AND OBJECTIVES: Irinotecan (CPT-11) is metabolized to an active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterase (CES). SN-38 is then converted to the inactive metabolite SN-38 glucuronide (SN-38G) by glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphisms in UGT1A1 have been associated with altered SN-38 pharmacokinetics, which increase the risk of toxicity in patients. CPT-11 is also converted to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC) by cytochrome P450 3A (CYP3A), and this route also affects the plasma concentration of SN-38. We evaluated the activities of UGT1A1, CYP3A, and CES and the factors affecting the pharmacokinetics of plasma SN-38 in patients with UGT1A1 gene polymorphisms. METHODS: Three male patients aged 56, 65, and 49 years were recruited for the analysis. All patients had pancreatic cancer, received FOLFIRINOX, and had UGT1A1*6/*6 (patients 1 and 3) or *6/*28 (patient 2) genetic polymorphisms. The rate constants for evaluating the enzyme activity were determined from the measured plasma concentration of CPT-11 and its metabolites using a two-compartment model by WinNonlin. RESULTS: The area under the plasma concentration-time curve (AUC) of SN-38 was patient 1 > patient 2 > patient 3. The rate constants obtained from the model analysis indicated the respective enzyme activities of UGT1A1 (k57), CYP3A (k13 + k19), and CES (k15). The order of values for UGT1A1 activity was patient 2 > patient 3 > patient 1. Since UGT1A1 activity was low in patient 1 with a high AUC of SN-38, it can be said that the increase in plasma concentration was due to a decrease in UGT1A1 activity. Conversely, the order of values for CYP3A and CES activities was patient 3 > patient 1 > patient 2 and patient 2 > patient 1 > patient 3, respectively. Patient 3 had the lowest AUC of SN-38, caused by a lower level of CES activity and increased CYP3A activity. CONCLUSION: In this study, we indicated that the plasma AUC of SN-38 and AUC ratio of SN-38G/SN-38 may depend on changes in the activities of CYP3A, CES, and UGT1A1. Using pharmacokinetic analysis, it is possible to directly evaluate enzyme activity and consider what kind of enzyme variation causes the increase in the AUC of SN-38.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Glucuronosiltransferase/genética , Irinotecano/farmacocinética , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Área Sob a Curva , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Carboxilesterase/metabolismo , Citocromo P-450 CYP3A/metabolismo , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Glucuronídeos/farmacocinética , Glucuronosiltransferase/metabolismo , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Leucovorina/farmacocinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Oxaliplatina/administração & dosagem , Oxaliplatina/farmacocinética , Polimorfismo GenéticoRESUMO
PURPOSE: Signaling by members of the TGFß superfamily of molecules is essential for embryonic development and homeostasis. Smad4, a key intracellular mediator in TGFß signaling, forms transcriptional activator complexes with Activin-, BMP-, and TGFß-restricted Smad proteins. However, the functional role of Smad4 in controlling different visual system compartments has not been fully investigated. METHODS: Using the Pax6 promoter-driven Cre transgenic, smad4 was conditionally inactivated in the lens, cornea and ectoderm of the eyelids. Standard histological and molecular analytical approaches were employed to reveal morphological and cellular changes. RESULTS: Inactivation of Smad4 in the lens led to microphthalmia and cataract formation in addition to the persistent adhesion of the retina to the lens and the iris to the cornea. Inactivation of Smad4 from the ectoderm of the eyelid and cornea caused disruption to eyelid fusion and proper development of the corneal epithelium and corneal stroma. CONCLUSIONS: Smad4 is required for the development and maintenance of the lens in addition to the proper development of the cornea, eyelids, and retina.
Assuntos
Catarata/genética , Anormalidades do Olho/genética , Cristalino/anormalidades , Proteína Smad4/genética , Actinas/metabolismo , Animais , Apoptose , Proliferação de Células , Pálpebras/metabolismo , Pálpebras/fisiologia , Cristalino/embriologia , Cristalino/metabolismo , Camundongos , Camundongos Transgênicos , Mutação , Proteína Smad4/metabolismo , alfa-Cristalinas/biossíntese , beta-Cristalinas/biossínteseRESUMO
Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent complication in patients receiving anticancer chemotherapy, but no effective treatment is yet available. Objective: To evaluate the efficacy and safety of a tramadol/acetaminophen combination tablets for CIPN. Design: This is a single-arm phase II study of tramadol/acetaminophen. Setting/subjects: Eligible patients had received oxaliplatin, paclitaxel, or nab-paclitaxel, and were experiencing CIPN. The patients were given one tablet (37.5 mg tramadol plus 325 mg acetaminophen) twice a day for 7 days, then four times a day for 21 days. Measurements: The primary endpoint was the numerical rating scale of neuropathic pain. Other endpoints included the potential of CYP2D6 genetic variants to effective response or toxicity. Results: Of the 34 patients enrolled, 23 completed the protocol treatment. The mean neuropathic pain score decreased insignificantly from 5.53 at baseline to 5.00 at 28 days (95% confidence interval -0.21 to 1.43; p = 0.139). However, 13 of the 23 (56.5%) patients who completed the protocol treatment showed improvement of the neuropathic pain score by at least 1 point. No severe adverse events were observed. Tramadol/acetaminophen may be more effective in patients with the intermediate metabolizer phenotype of the CYP2D6 single nucleotide polymorphisms (SNPs) although at the cost of increased toxicity. Conclusions: Although tramadol/acetaminophen tablets did not reduce neuropathic pain to a statistically significant degree, the neuropathic pain severity reduced in more than a half of the patients.
RESUMO
BACKGROUND/AIM: Amino acids are among the most important nutrients for supplying energy and building protein blocks in cancers. L-type amino acid transporter (LAT) 1 is known to play a critical role in cancer growth. We have completed the first-in-human phase I study using the LAT1-specific inhibitor JPH203. PATIENTS AND METHODS: We evaluated plasma free amino acids (PFAAs), body mass index (BMI), and efficacy of JPH203 in patients enrolled in the phase I study. RESULTS: LAT1-substrate PFAAs and branched chain amino acids (BCAAs) were higher in patients with biliary tract cancer (BTC) than in those with other cancers. High inhibition of uptake of LAT1-substrate PFAAs was associated with survival. BMI of more than the median was associated with disease control and survival. BCAAs tended to be associated with BMI. CONCLUSION: BCAAs and BMI are useful predictors of the efficacy of JPH203, which shows promising activity against BTC.
Assuntos
Transportador 1 de Aminoácidos Neutros Grandes , Neoplasias , Benzoxazóis , Biomarcadores , Humanos , Transportador 1 de Aminoácidos Neutros Grandes/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Tirosina/análogos & derivadosRESUMO
BACKGROUND: No standard second-line chemotherapy has been yet established for gemcitabine-refractory biliary tract cancer (BTC). PATIENTS AND METHODS: We conducted multivariable Cox regression analysis to examine the prognostic factors for overall survival (OS) in patients who had received gemcitabine-based treatment. RESULTS: Forty-six patients received second-line chemotherapy. The median serum carbohydrate antigen 19-9 (CA 19-9) value was 487 U/ml. The modified Glasgow prognostic score (mGPS) was: 0 (n=24), 1 (n=10), or 2 (n=10). The second-line chemotherapy included: S-1 in 20 patients, gemcitabine-based in 20, and tyrosine kinase inhibitors in five. The median OS was 8.3 months, and the median progression-free survival was 3.0 months. Multivariate analysis identified serum CA 19-9 ≥500 U/ml, mGPS ≥1, and presence of liver metastasis as significant prognostic factors for OS. CONCLUSION: Second-line chemotherapy for gemcitabine-refractory BTC remains inadequate. Randomized trials with appropriate stratification criteria are required.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno CA-19-9/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Combinação de Medicamentos , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Ácido Oxônico/administração & dosagem , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Estudos Retrospectivos , Tegafur/administração & dosagem , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND/AIM: Vascular endothelial growth factor receptor (VEGFR) has been identified as a treatment target for biliary tract cancer (BTC) and axitinib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3. This study was conducted as a preliminary evaluation of the safety and efficacy of axitinib for patients with advanced BTC. PATIENTS AND METHODS: Patients refractory to gemcitabine-based regimens were administered axitinib at the dose of 5 mg twice daily. RESULTS: Five patients (3 male and 2 female) with a median age of 68 years were enrolled. Although 3 patients developed treatment-related grade 3/4 adverse events (AEs), none of these patients required discontinuation of the protocol treatment due to the AEs. Partial response (PR) was achieved in 1 patient, with a 67% reduction. The response was classified as stable disease (SD) in 3 patients and as progressive disease (PD) in 1 patient. Overall survival (OS) and progression-free survival (PFS) ranged from 2.0 to 19.9 months and 1.5 to 7.4 months, respectively. CONCLUSION: This preliminary study suggested that axitinib is well-tolerated and might exert promising activity in patients with BTC.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Axitinibe , Neoplasias do Sistema Biliar/diagnóstico por imagem , Neoplasias do Sistema Biliar/patologia , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imidazóis/efeitos adversos , Indazóis/efeitos adversos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , GencitabinaRESUMO
BACKGROUND: Gemcitabine (GEM) plus cisplatin (CDDP) chemotherapy has been used worldwide as the standard first-line treatment for advanced biliary tract cancer (BTC). A phase II trial has also suggested promising activity of GEM plus S-1 chemotherapy against advanced BTC. The aim of this study was to evaluate the efficacy and safety of GEM plus S-1 chemotherapy in patients with advanced BTC. PATIENTS AND METHODS: The eligibility criteria were as follows: histologically-proven BTC, unresectable or recurrent disease, ECOG performance status (PS) 0-1 regardless of previous treatment. Gemcitabine was administered intravenously at the dose of 1,000 mg/m2 over 30 min on days 1 and 8, and S-1 was administered orally at doses of 60/80/100 mg/day based on the BSA, from day 1 to day 14, every 3 weeks. The primary endpoint was the response rate according to RECIST, ver. 1.1, and the secondary endpoints were the frequency/severity of toxicities, progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 38 patients were enrolled between August 2008 and November 2011. There were 19 men and 19 women, with a median age of 66 years (range=44-81 years). Seven patients had a previous history of first-line or adjuvant chemotherapy after surgery. The PS was 0 and 1 in 30 and 7 patients, respectively. The treatment response was classified as partial response in 6 patients (15.8%) and as stable disease in 18 patients (47.4%). The median PFS and OS were 5.8 and 15.9 months, respectively. The toxicity was generally mild, and the most common grade 3/4 toxicities were leukopenia (31.6%), neutropenia (36.8%), nausea/vomiting (2.6%), and diarrhea (2.6%). There was one treatment-related death due to interstitial pneumonia. CONCLUSION: Our study revealed that gemcitabine plus S-1 chemotherapy was well-tolerated and exhibited favorable antitumor activity in patients with advanced BTC.