RESUMO
Recent studies have shown that transmembrane-type tight junction proteins are upregulated in various cancers compared with their levels in normal tissues and are involved in cancer progression, suggesting that they are potential therapeutic targets. Here, we demonstrated the expression profile and a novel role of junctional adhesion molecule-A (JAM-A) in breast cancer. Immunohistochemistry of surgical specimens showed that JAM-A was highly expressed from carcinoma in situ lesions, as in other adenocarcinomas, with higher expression in invasive carcinomas. High expression of JAM-A contributed to malignant aspects such as lymph node metastasis and lymphatic involvement positivity. In breast cancer cells, JAM-A expression status affects malignant potentials including proliferation and migration. Multilayered proteomics revealed that JAM-A interacts with the amino acid transporter LAT1 in breast cancer cells. JAM-A regulates the expression of LAT1 and interacts with it on the whole cell membrane, leading to enhanced amino acid uptake to promote tumor growth. Double high expression of JAM-A and LAT1 predicts poor prognosis in patients with breast cancer. Of note, an antibody against an extracellular domain of JAM-A suppressed the proliferation of breast cancer cells. Our findings indicate the possibility of JAM-A-targeted therapy ideally combined with LAT1-targeted therapy as a new therapeutic strategy against breast cancer.
RESUMO
Eribulin inhibits microtubule polymerization and improves the overall survival of patients with recurrent metastatic breast cancer. A subgroup analysis revealed a low neutrophil to lymphocyte ratio (NLR) (<3) to be a prognostic factor of eribulin treatment. We thus hypothesized that eribulin might be related to the immune response for breast cancer cells and we analyzed the effects of eribulin on the immune system. Immunohistochemical staining revealed that human leukocyte antigen (HLA) class I expression was increased in clinical samples after eribulin treatment. In vitro assays revealed that eribulin treatment increased HLA class I expression in breast cancer line cells. RNA-sequencing demonstrated that eribulin treatment increased the expression of the NOD-like family CARD domain-containing 5 (NLRC5), a master regulator of HLA class I expression. Eribulin treatment increased the NY-ESO-1-specific T-cell receptor (TCR) transduced T (TCR-T) cell response for New York oesophageal squamous cell carcinoma 1 (NY-ESO-1) overexpressed breast cancer cells. The eribulin and TCR-T combined therapy model revealed that eribulin and immunotherapy using TCR-T cells has a synergistic effect. In summary, eribulin increases the expression of HLA class 1 via HLA class 1 transactivatior NLRC5 and eribulin combination with immunotherapy can be effective for the treatment of breast cancer.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Proteínas NLR , Domínio de Ativação e Recrutamento de Caspases , Recidiva Local de Neoplasia , Receptores de Antígenos de Linfócitos T/metabolismo , Antígenos de Neoplasias , Antígenos HLA , Peptídeos e Proteínas de Sinalização Intracelular/metabolismoRESUMO
BACKGROUND: In clinical practice, drains had been routinely used for reducing seroma formation after breast surgery. However, an optimal timing to remove drains does not identify yet. METHODS: This study aimed to compare the clinical outcome, such as seroma formation, surgical site infection (SSI), and a length of hospital stay between early removal and late removal. A systematic review was performed using PubMed, MEDLINE, and the Cochrane Library. Breast cancer patients who received surgery using drains were eligible. Those parameters were compared between early vs late removal. RESULTS: Eleven studies included in this meta-analysis. Seroma formation in the early removal group was significantly higher than the one in the late removal group (RR = 1.58: 95%CI [1.25-2.01], P = 0.0001), meanwhile no significant difference was found among the groups for SSI (RR = 0.82: 95%CI [0.51-1.31], P= 0.40). A length of hospital stay in the early removal group was also significantly shorter than late removal (RR -3.31: 95%CI [-5.13-1.49], P = 0.0004). CONCLUSIONS: Seroma formation was significantly higher in patients who had early drain removal. Conversely, SSI incidence was low, and early removal did not increase SSI incidence. In conclusion, early drain removal has no proved clinical benefit in these settings besides reduction of hospital stays.
Assuntos
Neoplasias da Mama , Drenagem , Neoplasias da Mama/cirurgia , Drenagem/efeitos adversos , Feminino , Humanos , Tempo de Internação , Mastectomia/efeitos adversos , Seroma/epidemiologia , Seroma/etiologia , Seroma/prevenção & controle , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/prevenção & controleRESUMO
PURPOSE: The newly introduced erector spinae plane block (ESPB) has given anesthesiologists an alternative regional anesthetic technique for thoracic analgesia. Although ESPB and retrolaminar block (RLB) have similar puncture sites, no clinical study comparing ESPB and RLB has been reported. The aim of this study was to compare ESPB and RLB in terms of analgesic efficacy in the context of multimodal analgesia following breast surgery. METHODS: Fifty female patients undergoing breast surgery under general anesthesia were randomly allocated to receive either ultrasound-guided ESPB or RLB with 20 mL of 0.375% levobupivacaine for postoperative analgesia. The primary outcome was analgesic efficacy in terms of time to first postoperative rescue analgesic after the block procedure. The secondary outcomes were consumption of remifentanil during anesthesia, pain intensity at rest for 24 h postoperatively, and occurrence of postoperative nausea and vomiting (PONV). RESULTS: After excluding five patients, 45 patients (22 and 23 patients in the ESPB and RLB group, respectively) were analyzed. Median time until the first postoperative rescue analgesic after the block procedure in the ESPB group was not significantly longer than that in the RLB group (8.6 [range 2.7-24] vs. 4.8 [3.0-24] h; P = 0.83). There was no significant difference in the consumption of remifentanil during anesthesia, pain intensity at rest for 24 h postoperatively, and occurrence of PONV between the two groups. CONCLUSION: ESPB is equivalent, and not superior, to RLB for postoperative analgesia after breast surgery when 20 mL of 0.375% levobupivacaine is injected at the fourth thoracic vertebra.
Assuntos
Analgesia , Neoplasias da Mama , Bloqueio Nervoso , Feminino , Humanos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Músculos ParaespinaisRESUMO
The prognosis of advanced pancreatic adenocarcinoma is still extremely poor. This study sought to determine the efficacy of, and immunological response to, peptide vaccination therapy in patients with this disease. In this multicenter randomized phase II study, patients with advanced pancreatic adenocarcinoma after gemcitabine and/or tegafur/gimeracil/oteracil were randomly assigned to 3 groups that each received a 2-step treatment course. In Step 1, the groups received treatments of: (i) survivin 2B peptide (SVN-2B) plus interferon-ß (IFNß); (ii) SVN-2B only; or (iii) placebo until the patients show progression. In Step 2, all patients who consented to participate received 4 treatments with SVN-2B plus IFNß. The primary endpoint was progression-free survival (PFS) after initiation of Step 1 treatment. Secondary endpoints included immunological effects assessed by analysis of PBMCs after Step 1. Eighty-three patients were randomly assigned to receive SVN-2B plus IFNß (n = 30), SVN-2B (n = 34), or placebo (n = 19). No significant improvement in PFS was observed. Survivin 2B-specific CTLs were found to be increased in the SVN-2B plus IFNß group by tetramer assay. Among patients who participated in Step 2, those who had received SVN-2B plus IFNß in Step 1 showed better overall survival compared with those who had received placebo in Step 1. Patients vaccinated with SVN-2B plus IFNß did not have improved PFS, but showed significant immunological reaction after vaccination. Subgroup analysis suggested that a longer SVN-2B plus IFNß vaccination protocol might confer survival benefit. (Clinical trial registration number: UMIN 000012146).
Assuntos
Adenocarcinoma/tratamento farmacológico , Vacinas Anticâncer/uso terapêutico , Interferon beta/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Peptídeos/uso terapêutico , Survivina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Vacinação/métodos , Vacinas de Subunidades Antigênicas/uso terapêutico , Gencitabina , Neoplasias PancreáticasRESUMO
BACKGROUND: We examined the expression of nonhomologous end-joining (NHEJ) proteins by breast cancer cells in patients with or without ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy. We also investigated whether there was a difference of NHEJ-related protein expression by tumor cells between two types of IBTR, i.e., true recurrence (TR) with regrowth from the tumor bed or development of a new primary tumor (NP). PATIENTS AND METHODS: The original cohort comprised 560 breast cancer patients who received breast-conserving therapy between February 1995 and March 2006, including 520 patients without IBTR and 40 patients with IBTR. Propensity score matching was employed to select 40 trios (120 patients) consisting of 1 patient with IBTR and 2 patients without IBTR. Immunohistochemical examination of proteins related to NHEJ was performed in surgical specimens. RESULTS: The 40 patients with IBTR included 22 patients who developed TR and 18 who had NP. The 15-year overall survival rate was 85.9% for patients with NP and 95.5% for those with TR, while it was 96.5% for patients without IBTR. Patients with high XRCC4 expression in tumor cells had significantly higher IBTR rates than those with low XRCC4 expression (Pâ¯< 0.001). The frequency of TR was significantly higher in patients with high expression of XRCC4 than in those with low XRCC4 expression (pâ¯< 0.001). XRCC4 expression by tumor cells was not significantly related to development of NP. CONCLUSION: IBTR due to TR may be related to low radiosensitivity of tumor cells, possibly related to high XRCC4 expression.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Carcinoma Ductal/genética , Carcinoma Lobular/genética , Proteínas de Ligação a DNA/genética , Mastectomia Segmentar , Recidiva Local de Neoplasia/genética , Adulto , Idoso , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Ductal/mortalidade , Carcinoma Ductal/patologia , Carcinoma Lobular/mortalidade , Carcinoma Lobular/patologia , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/mortalidade , Segunda Neoplasia Primária/patologia , Prognóstico , Pontuação de Propensão , Taxa de SobrevidaRESUMO
A 62-year-old woman who underwent surgery to treat pancreatic cancer provided written, informed consent to undergo adjuvant therapy with gemcitabine, tegafur, and uracil. However, this was stopped after only 14 days due to Grade 4 neutropenia. She was then started on vaccine therapy with Survivin 2B peptide (SVN-2B) including IFA and INF-α. Although metastatic lung tumors were identified and resected at 82 months after surgery, the patient has remained free of new or relapsed disease for 12 years thereafter. Tetramer and ELISPOT assays revealed the continuous circulation of SVN-2B-restricted cytotoxic T-lymphocytes (CTLs) in her peripheral blood, and CTL clones had specific activity for SVN-2B at 12 years after surgery. The adverse effects of the peptide vaccination were tolerable and comprised low-grade headache, nausea, and fatigue. A prognosis beyond 10 years in the face of pancreatic cancer with distant metastasis is extremely rare. This experience might indicate the value of cancer vaccination therapy.
Assuntos
Vacinas Anticâncer/uso terapêutico , Proteínas Inibidoras de Apoptose/imunologia , Neoplasias Pancreáticas/mortalidade , Linfócitos T Citotóxicos/imunologia , Vacinas Anticâncer/imunologia , Feminino , Humanos , Imunização , Pessoa de Meia-Idade , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Prognóstico , Survivina , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/uso terapêuticoRESUMO
To establish an effective cancer immunotherapy, it is crucial that cancer cells present a cancer-specific antigen in a hypoxic area, a hallmark of the tumor microenvironment. Here, we show the impact of hypoxia on MHC class I antigen presentation in vitro and in vivo in murine tumors. Activation of antigen-specific CTLs by tumor cells that had been pre-incubated under a condition of hypoxia was enhanced compared with that by tumor cells pre-incubated under a condition of normoxia. Cell surface expression of MHC class I-peptide complex on the tumor cells was increased under a condition of hypoxia, thereby leading to higher susceptibility to specific CTLs. We show that the hypoxia-inducible ER-resident oxidase ERO1-α plays an important role in the hypoxia-induced augmentation of MHC class I-peptide complex expression. ERO1-α facilitated oxidative folding of MHC class I heavy chains, thereby resulting in the augmentation of cell surface expression of MHC class I-peptide complex under hypoxic conditions. These results suggest that since the expression of MHC class I-peptide complex is augmented in a hypoxic tumor microenvironment, strategies for inhibiting the function of regulatory T cells and myeloid-derived suppressor cells and/or immunotherapy with immune checkpoint inhibitors are promising for improving cancer immunotherapy.
Assuntos
Glicoproteínas/metabolismo , Hipóxia/imunologia , Imunoterapia/métodos , Melanoma/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Apresentação de Antígeno , Modelos Animais de Doenças , Feminino , Antígenos H-2/metabolismo , Humanos , Hipóxia/terapia , Melanoma/terapia , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oxirredução , Oxirredutases , Dobramento de Proteína , Linfócitos T Citotóxicos/transplante , Microambiente TumoralRESUMO
Colorectal carcinoma (CRC) is one of the most frequently diagnosed cancers and the leading cause of cancer-related death for both men and women. Recent studies have revealed that a small sub-population of cancer cells, termed cancer stem-like cells (CSCs)/cancer-initiating cells (CICs), are endowed with tumor-initiating ability, self-renewal ability and differentiation ability. CSCs/CICs are resistant to current therapies including chemotherapy and radiotherapy. Thus, CSCs/CICs are responsible for recurrence and metastasis, and eradication of CSCs/CICs is essential to cure cancer. In this study, we isolated CR-CSCs/CICs as sphere-cultured cells and found that a product derived from LY6/PLAUR domain containing 3 (LYPD3) is preferentially expressed in CSCs/CICs. Gene overexpression and gene knockdown experiments revealed that LYPD3 has a role in the maintenance of CR-CSCs/CICs. The findings provide a novel molecular insight into CR-CSCs/CICs.
Assuntos
Moléculas de Adesão Celular/genética , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas/metabolismo , Esferoides Celulares/metabolismo , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Família Aldeído Desidrogenase 1 , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Células HCT116 , Células HT29 , Humanos , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Células-Tronco Neoplásicas/patologia , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Retinal Desidrogenase , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Transdução de Sinais , Esferoides Celulares/patologiaRESUMO
Colorectal cancer (CRC) is one of the most common malignancy, and the prognosis is not still satisfactory due to treatment resistance, recurrence and distant metastasis. Cancer stem cells (CSCs)/cancer-initiating cells (CICs) is endowed with higher tumor-initiating ability, self-renewal ability and differentiation ability, and CSCs/CICs are resistant to treatments. Thus, CSCs/CICs are thought to be responsible for recurrence and distant metastasis, and eradication of CSCs/CICs is essential to cure CRCs. However, the molecular mechanisms of CSCs/CICs are remain unknown, and we aimed to elucidate molecular aspects of CR-CSCs/CICs in this study. We screened the transcriptome data of primary human CR-CSCs/CICs that we previously established, and found that LEM domain containing 1 (LEMD1) is preferentially expressed in CR-CSCs/CICs. LEMD1 belongs to cancer-testis (CT) antigen, and has five transcript variants (variant 1 [V1] - variant 5 [V5]). We found that LEMD1 V1, V2 and V3 is expressed in testis and CR-CSCs/CICs, whereas LEMD1 V4 and V5 is ubiquitously expressed. LEMD1 gene knockdown experiments using siRNAs and gene overexpression experiments revealed that LEMD1 has a role in the maintenance of CR-CSCs/CICs. These observations indicate that CR-CSC/CIC-specific LEMD1 variants are reasonable target of CR-CSC/CIC-targeted therapy.
Assuntos
Neoplasias Colorretais/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Neoplasias Colorretais/patologia , Feminino , Células HCT116 , Células HT29 , Humanos , Masculino , Células-Tronco Neoplásicas/patologia , Isoformas de Proteínas/genética , Interferência de RNA , Splicing de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esferoides Celulares/metabolismo , Testículo/metabolismoRESUMO
ERO1-α is an oxidizing enzyme that exists in the endoplasmic reticulum and is induced under hypoxia. It reoxidizes the reduced form of protein disulfide isomerase that has oxidized target proteins. We found that ERO1-α is overexpressed in a variety of tumor types. MHC class I H chain (HC) has two disulfide bonds in the α2 and α3 domains. MHC class I HC folding is linked to the assembly of MHC class I molecules because only fully disulfide-bonded class I HCs efficiently assemble with ß2-microglobulin. In this study, we show that ERO1-α associates with protein disulfide isomerase, calnexin, and immature MHC class I before being incorporated into the TAP-1-associated peptide-loading complex. Importantly, ERO1-α regulates the redox state as well as cell surface expression of MHC class I, leading to alteration of susceptibility by CD8(+) T cells. Similarly, the ERO1-α expression within cancer cells was associated with the expression level of MHC class I in colon cancer tissues. Thus, the cancer-associated ERO1-α regulates the expression of the MHC class I molecule via oxidative folding.
Assuntos
Apresentação de Antígeno/imunologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Antígenos de Histocompatibilidade Classe I/biossíntese , Glicoproteínas de Membrana/metabolismo , Oxirredutases/metabolismo , Western Blotting , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imuno-Histoquímica , Imunoprecipitação , Glicoproteínas de Membrana/imunologia , Oxirredução , Oxirredutases/imunologia , Dobramento de Proteína , Estrutura Terciária de Proteína , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: Endoplasmic reticulum disulfide oxidase 1-α (ERO1-α) is an oxidase that exists in the endoplasmic reticulum and has a role in the formation of disulfide bonds of secreted proteins and cell-surface proteins. Recently, we reported that ERO1-α is present in high levels in various types of tumours, and that ERO1-α is a novel factor of poor prognosis. However, how ERO1-α affects a tumour in vivo and why patients who have a tumour with a high expression level of ERO1-α have a poor prognosis are still unknown. Therefore, to clarify the mechanism, we investigated the effect of ERO1-α on a tumour from the point of view of angiogenesis. METHODS: The effect of ERO1-α on tumour growth and angiogenesis was analysed by using non-obese diabetic-severe combined immunodeficient mice. The production of vascular endothelial growth factor (VEGF) in MDA-MB-231 cells with ERO1-α- overexpression or with ERO1-α knockdown was measured. The role of ERO1-α on VEGF expression was investigated. In triple-negative breast cancer cases, the relationship between expression of ERO1-α and angiogenesis was analysed. RESULTS: We found that the expression of ERO1-α promoted tumour growth in a mouse study and angiogenesis. The effects of ERO1-α on angiogenesis were mediated via oxidative protein folding of VEGF and enhancement of VEGF mRNA expression by using MDA-MB-231. In triple-negative breast cancer cases, the expression of ERO1-α related to the number of the blood vessel. Furthermore, we found that ERO1-α was a poor prognosis factor in triple-negative breast cancer. CONCLUSIONS: Our study has established a novel link between expression of ERO1-α and secretion of VEGF, providing new evidence for the effectiveness of ERO1-α-targeted therapy in patients with ERO1-α-expressed cancer.
Assuntos
Regulação Neoplásica da Expressão Gênica , Glicoproteínas de Membrana/fisiologia , Proteínas de Neoplasias/fisiologia , Neovascularização Patológica/enzimologia , Oxirredutases/fisiologia , Dobramento de Proteína , Neoplasias de Mama Triplo Negativas/enzimologia , Fator A de Crescimento do Endotélio Vascular/biossíntese , Animais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Dissulfetos/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Oxirredução , Oxirredutases/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease, and disease activity is associated with serum IFN-α level. Plasmacytoid dendritic cells (pDCs) sense microbial as well as self-nucleic acids by TLRs 7 and 9 and produce a large amount of IFN-α. Here, we show that heat shock protein 90 (Hsp90) associates with and delivers TLR7/9 from the ER to early endosomes for ligand recognition. Inhibition of Hsp90 by various approaches including the use of Hsp90 inhibitor, a geldanamycin derivative, suppressed the Hsp90 association with TLR7/9, which resulted in inhibition of IFN-α production, leading to improvement of SLE symptoms in mice. Notably, we observed that serum Hsp90 is clearly increased in patients with active SLE compared with that in patients with inactive disease. Furthermore, we demonstrated that serum Hsp90 detected in SLE patients binds to self-DNA and/or anti-DNA Ab, thus leading to stimulation of pDCs to produce IFN-α. Our data demonstrate that Hsp90 plays a crucial role in the pathogenesis of SLE and that an Hsp90 inhibitor will therefore provide a new therapeutic approach to SLE and other nucleic acid-related autoimmune diseases.
Assuntos
Autoantígenos/imunologia , Proteínas de Choque Térmico HSP90/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Ácidos Nucleicos/imunologia , Receptor 7 Toll-Like/imunologia , Receptor Toll-Like 9/imunologia , Animais , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Western Blotting , Células Dendríticas/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Humanos , Imunoprecipitação , Interferon-alfa/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Endogâmicos MRL lpr , Microscopia ConfocalRESUMO
Pancreatic tumors are chemoresistant and malignant, and there are very few therapeutic options for pancreatic cancer, as the disease is normally diagnosed at an advanced stage. Although attempts have been made to develop vaccine therapies for pancreatic cancer for a couple of decades, none of the resultant protocols or regimens have succeeded in improving the clinical outcomes of patients. We herein review vaccines tested within the past few years, including peptide, biological and multiple vaccines, and describe the three sets of criteria used to evaluate the therapeutic activity of vaccines in solid tumors.
Assuntos
Vacinas Anticâncer/uso terapêutico , Carcinoma Ductal Pancreático/terapia , Neoplasias Pancreáticas/terapia , Vacinas Bacterianas , Antígeno Carcinoembrionário , Ensaios Clínicos como Assunto , Vírus da Varíola das Aves Domésticas , Gastrinas , Genes ras/genética , Proteínas de Choque Térmico , Proteínas Inibidoras de Apoptose , Cinesinas , Listeria monocytogenes , Mucina-1 , Mutação , Peptídeos , Survivina , Telomerase , Vacinas Atenuadas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Vacinas Virais , Proteínas WT1RESUMO
The presentation of an exogenous antigen in a major histocompatibility complex class-I- restricted fashion to CD8(+) T cells is called cross-presentation. Heat shock proteins (HSPs) such as Hsp70, gp96, and Hsp90 have been shown to elicit efficient CTL responses by cross-presentation through an as-yet entirely unknown mechanism. Hsp90 is the most abundant cytosolic HSP and is known to act as a molecular chaperone. We have shown that a tumor antigen peptide complexed with Hsp90 could be cross-presented by dendritic cells (DCs) through an endosomal pathway in a murine system. However, it has not been determined whether human DCs also cross-present an Hsp90-peptide complex and induce peptide-specific CTLs. In this study, we found that an Hsp90-cancer antigen peptide complex was efficiently cross-presented by human monocyte-derived DCs and induced peptide-specific CTLs. Furthermore, we observed that the internalized Hsp90-peptide complex was strictly sorted to the Rab5(+), EEA1(+) static early endosome and the Hsp90-chaperoned peptide was processed and bound to MHC class I molecules through an endosome-recycling pathway. Our data indicate that targeting of the antigen to a "static" early endosome by Hsp90 is essential for efficient cross-presentation.
Assuntos
Apresentação Cruzada , Células Dendríticas/imunologia , Endossomos/metabolismo , Proteínas de Choque Térmico HSP90/fisiologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Humanos , Proteínas Inibidoras de Apoptose/imunologia , Fragmentos de Peptídeos/imunologia , Transporte Proteico , Survivina , Linfócitos T Citotóxicos/imunologiaRESUMO
PURPOSE: The Multinational Association of Supportive Care in Cancer (MASCC) developed the MASCC antiemesis tool (MAT) as a tool for chemotherapy-induced nausea and vomiting (CINV) assessment and subsequently published its Japanese version in 2010. We evaluated the validity of CINV assessment in outpatients using the Japanese version of MAT. METHODS: Patients administered highly or moderately emetogenic chemotherapy in the outpatient chemotherapy unit of our hospital were included in the study. The study was designed as a prospective two-period crossover observational study to evaluate the correlation between the daily patient diary and the Japanese version of MAT in terms of CINV onset. We examined with a focus on reliability of the Japanese version of MAT particularly in the description of the delayed phase of nausea and vomiting. RESULTS: Patient descriptions of CINV onset in a total of 116 cycles in 58 patients (two cycles/patient) were analyzed. The CINV incidence indicated by the patient diary was similar to that by the Japanese version of MAT. The concordance rate between the two tools in the same patients was 86.2 % for CINV onset in the delayed phase. The nausea score was also similar between the two tools regarding the mean and variance, showing a strong correlation with a correlation coefficient of 0.71. CONCLUSIONS: The results of the study showed that the Japanese version of MAT is a highly reliable tool for CINV assessment, indicating that it is valid for assessing CINV in outpatients.
Assuntos
Antieméticos/uso terapêutico , Náusea/diagnóstico , Neoplasias/tratamento farmacológico , Inquéritos e Questionários , Vômito/diagnóstico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Estudos Cross-Over , Feminino , Hospitais , Humanos , Incidência , Japão , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Pacientes Ambulatoriais , Estudos Prospectivos , Reprodutibilidade dos Testes , Vômito/induzido quimicamente , Vômito/tratamento farmacológicoRESUMO
BACKGROUND: The objective of the present clinical study is to determine the maximum tolerated dose (MTD)/recommended dose (RD) of combination therapy with nanoparticle albumin-bound paclitaxel (nab-PTX) and cyclophosphamide (CPA) in patients with metastatic or recurrent breast cancer. METHODS: nab-PTX and CPA were administered on the first day of each 21-day treatment cycle. The dose of CPA was fixed at 600 mg/m(2), while the dose of nab-PTX was increased from 180 mg/m(2) (Level 1) to 220 mg/m(2) (Level 2) and then to 260 mg/m(2) (Level 3). RESULTS: A total of 11 patients from two institutions were enrolled in the present study. At Level 3, a dose-limiting toxicity (DLT) was observed in 1 patient. Considering treatment continuity and the risk of adverse events in Cycle 2 and thereafter at this level, further subject enrollment at Level 3 was discontinued after two patients had been enrolled. Since the doses used at Level 3 were considered the MTD of nab-PTX and CPA and the doses used at Level 2 were considered the RD of nab-PTX and CPA, three additional subjects were enrolled at Level 2. No DLTs were observed at Level 2. CONCLUSION: The RD of combination therapy with nab-PTX and CPA was 220 mg/m(2) and 600 mg/m(2), respectively, in patients with metastatic or recurrent breast cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso , Paclitaxel Ligado a Albumina/administração & dosagem , Neoplasias da Mama/patologia , Neoplasias da Mama/secundário , Ciclofosfamida/administração & dosagem , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , NanopartículasRESUMO
According to the Japanese Breast Cancer Society national breast cancer registration, 71.8%of breast cancer cases reported in 2004 and 79.8% of cases reported in 2010 were estrogen receptor(ER)positive. The frequency of ER-positive breast cancer is increasing annually in Japan. Many clinical trials have proven that adjuvant hormonal treatment affects both progression- free survival and overall survival in ER-positive breast cancer cases. However, some clinical questions remain, including those regarding the definition of preoperative hormonal treatment, appropriate dosage period, and therapeutic drug choice. In January 2013, we conducted a questionnaire survey of 53 medical doctors engaged in breast cancer treatment at 15 Japanese Breast Cancer Society-authorized facilities in Hokkaido. This survey included 6 clinical questions about preoperative hormonal treatment, 5 clinical questions about postoperative hormonal treatment for premenopausal breast cancer, and 4 clinical questions about postoperative hormonal treatment for postmenopausal breast cancer. We obtained replies from 35 medical doctors at 27 facilities. The response rate was 66%. We accumulated and analyzed these data. The discussion of questionnaire results in the medical administration field facilitates the sharing of information regarding differences in the approaches of different facilities to breast cancer patients. As a result, standardization of the breast cancer medical treatment system in this area has been accomplished.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptores de Estrogênio/análise , Neoplasias da Mama/química , Quimioterapia Adjuvante , Terapia de Reposição de Estrogênios , Feminino , Humanos , Japão , Menopausa , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: Time is crucial for patients with metastatic breast cancer (MBC), and clinicians are expected to determine the optimal timing for best supportive care (BSC) transition but no evident marker has been established. We recently revealed that absolute lymphocyte count (ALC) was a prognostic marker for patients with MBC. Thus, we investigated whether ALC could be an indicator of the best timing for the BSC transition. METHODS: 101 patients with MBC were retrospectively investigated, and the relationship between clinicopathological factors, including ALC, and the duration of the last treatment was analysed. RESULTS: Mean ALC significantly gradually decreased during the last three systemic treatments towards BSC transition. Patients of younger age, with special histology type, hormone receptor-positive tumours and low ALC at the start of the last treatment had significantly shorter time-to-treatment-termination (TTT) for the last treatment. When ALC was classified into low and high, the mean TTT of the last treatment in the ALC-low group was significantly shorter (16.4 weeks) compared with that in the ALC-high group (30.2 weeks; p=0.004). CONCLUSIONS: Our data suggest that ALC values, which decrease as MBC progresses, could serve as a potential indicator for determining the optimal timing of BSC transition.
RESUMO
BACKGROUND/AIM: Various biomarkers are utilized in the field of breast cancer. Human lymphocyte antigen (HLA) class I molecules have a critical role in cancer immune surveillance. Therefore, this study aimed to assess the HLA class I expression and analyze the correlation with clinicopathologic factors in breast cancer. PATIENTS AND METHODS: We investigated the clinical pathology archives of 150 consecutive patients with breast cancer who underwent a curative operation at the Sapporo Medical University, Japan, from January 2012 to December 2014. Immunohistochemical staining was used to evaluate HLA class I expression and CD8-positive T cell infiltration. The Pearson χ2 test was used to assess HLA class I expression level and clinicopathological parameters. The Kaplan-Meier method was used to evaluate survival and the log-rank test to analyze the differences between survival curves. RESULTS: Patients with dull/negative HLA class I had significantly poor disease-free survival (DFS) compared with those with positive HLA class I (p=0.0073). Univariate analyses revealed that pT, pN, positive lymphatic invasion, and dull/negative HLA class I were significantly associated with DFS. Multivariate analyses revealed dull/negative HLA class I as an independent poor prognostic factor (hazard ratio=2.75, 95% confidence interval=1.30-5.80, p=0.008). CONCLUSION: HLA class I expression level may have a very sensitive prognostic effect on patients with breast cancer.