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1.
Pharmacogenet Genomics ; 32(4): 144-151, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35383711

RESUMO

OBJECTIVE: Prostacyclin infusion for pulmonary arterial hypertension (PAH) is an effective therapy with varied dosing requirements and clinical response. The major aim of this study was to determine new biologically-based predictors of prostacyclin treatment response heterogeneity. METHODS: Ninety-eight patients with hemodynamically defined PAH at two academic medical centers volunteered for registry studies. A stable dose of treprostinil was the quantitative phenotype for the genome-wide association study (GWAS). Candidate genes with the largest effect sizes and strongest statistical associations were further characterized with in silico and in-vitro assays to confirm mechanistic hypotheses. The clinical significance of these candidate predictors was assessed for mechanistically consistent physiologic effects in an independent cohort of patients. RESULTS: GWAS identified three loci for association with P < 10-6. All three loci had clinically significant effect sizes. Specific single-nucleotide polymorphisms (SNPs) at two of the loci: rs11078738 in phosphoribosylformylglycinamidine synthase and rs10023113 in CAMK2D encoded sequence changes with clear predicted consequences. Production of the primary mediator of prostacyclin-induced vasodilation, cyclic AMP, was reduced in human cell lines by the missense variant rs11078738 (p.L621P). Located in the promoter of CAMK2D, the allele of rs10023113 associated with a higher treprostinil dose has higher ventricular transcription of CAMK2δ. At initial diagnostic catheterization in a separate cohort of patients, the same allele of rs10023113 was associated with elevated right mean atrial and ventricular diastolic pressures. CONCLUSIONS: The quantitative phenotype of stable treprostinil dose identified two gene loci associated with pharmacodynamic response and right ventricular function in PAH worth further investigation.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Anti-Hipertensivos , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Estudo de Associação Genômica Ampla , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/genética
2.
Int J Dent ; 2022: 9299602, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35464103

RESUMO

Background: Denosumab, a human monoclonal antibody against receptor activator of nuclear factor-kappa B ligand (RANKL), is a novel bone antiresorptive agent used in patients with osteoporosis or metastatic bone cancer. Denosumab-related osteonecrosis of the jaw (DRONJ) has been recently reported in patients using denosumab. However, the mechanisms of DRONJ are not fully understood. Appropriate pathogenic mechanisms of DRONJ have yet to be established. Therefore, we investigated the pathogenesis of DRONJ in mice. Methods: Anti-mouse RANKL monoclonal antibody and melphalan were performed to create a mouse model of DRONJ-like lesions in female C57BL/6J mice. We examined the development of DRONJ-like lesions and immune function. Results: We showed that administration of anti-mouse RANKL monoclonal antibody and melphalan caused DRONJ-like lesions that recapitulated major clinical manifestations of the human disease, including the characteristic features of an open alveolar socket and exposed necrotic bone. In the analysis using a mouse model of DRONJ-like lesion, it was revealed that anti-mouse RANKL monoclonal antibody and melphalan suppress autoimmune regulator (AIRE) expression in the thymus and imbalanced T cell populations. Conclusion: This study suggests evidence of an immunity-based mechanism of DRONJ-like disease. This work may contribute to a better understanding of the pathogenesis of human DRONJ.

3.
J Clin Biochem Nutr ; 70(2): 108-116, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35400823

RESUMO

Metabolic alteration is increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types, and metabolically targeted therapies could become important strategies for reducing fibrosis. In present study, target enzymes that are involved in changes in phospholipid metabolism during fibroblast-to-myofibroblast transition induced by transforming growth factor beta 1 (TGF-ß1) were examined. Different amounts of phospholipids were found in the 2 groups. In response to TGF-ß1 stimulation, 17 lipids decreased and 17 increased. The latter included the phospholipids phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylethanolamine (PE). Furthermore, among the rate-limiting enzymes that regulate these phospholipids, phosphatidylserine decarboxylase (PISD), which controls conversion of PS to PE and is localized in mitochondria, decreased in response to TGF-ß1. Knockdown of PISD alone without TGF-ß1 stimulation increased expression of α-smooth muscle actin mRNA and production of total collagen. Taken together, these results indicate that PISD is involved in the mechanism of fibrogenesis by regulating phospholipid metabolism.

4.
Thorac Cancer ; 13(9): 1342-1348, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35318811

RESUMO

BACKGROUND: We conducted a phase II study of carboplatin plus nab-paclitaxel for the treatment of small cell lung cancer (SCLC) after the failure of a prior standard chemotherapy containing platinum, etoposide, irinotecan, and amrubicin if indicated. Patients with interstitial pneumonia complications were included in the study. METHODS: Patients received 100 mg/m2 of nab-paclitaxel weekly (on days 1, 8, and 15) and an AUC 5 of carboplatin on day 1. The study treatment was repeated every 3 weeks until disease progression or the appearance of unacceptable toxicities. The primary endpoint was the objective response rate. RESULTS: A total of 21 patients were enrolled, all of whom were eligible for inclusion in the analysis. Twelve patients had pre-existing interstitial pneumonia. The overall response rate was 19.0% (90% confidence interval [CI]: 6.8%-38.4%). The lower limit of the 90% CI for the response rate did not exceed the prespecified threshold value of 10%. Among the 12 patients with pre-existing interstitial pneumonia, the response rate was 25%. The median progression-free survival time was 2.5 months (95% CI: 1.5-3.4 months), and the median survival time was 5.1 months (95% CI: 2.1-8.1 months). Two patients developed interstitial lung disease; both of these patients had pre-existing interstitial pneumonia. One of the patients died from interstitial lung disease. CONCLUSION: Combination chemotherapy with carboplatin plus nab-paclitaxel for recurrent SCLC had a modest activity, although the primary study endpoint was not met. Further investigation of this regimen for patients with recurrent SCLC and interstitial pneumonia is warranted.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Doenças Pulmonares Intersticiais , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/tratamento farmacológico , Recidiva Local de Neoplasia/complicações , Recidiva Local de Neoplasia/tratamento farmacológico , Paclitaxel , Carcinoma de Pequenas Células do Pulmão/complicações , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico
5.
JMA J ; 5(1): 1-8, 2022 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-35224254

RESUMO

I introduce here what we have been and are doing in the Cross-ministerial Strategic Innovation Promotion Program (SIP) "Innovative AI Hospital System" project supported by the Japanese government. This SIP program began in April 2018 as 1 of 12 SIP projects that aim to establish "Society 5.0" in various scientific areas. This AI hospital program is the only one related to the health and medical care field, in which we are attempting to construct a big medical database, to implement many artificial intelligence (AI) tools in hospital systems, and to make the medical care system more effective along with reduction of workload of medical workers. To maintain or improve the quality of the health and medical care system, it is indispensable to share various updated and useful information among healthcare workers as well as the general population. We have been challenging to establish the digitalized medical care system in various aspects. I describe here where we are and the future perspective of the AI-based digital medicine.

7.
Cancer Sci ; 2022 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-35201661

RESUMO

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) significantly improve progression-free survival and have become the standard therapy for estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer patients. Treatment surveillance by radiological imaging has some limitations in detection and repeated biopsy genomic profiling is not clinically feasible. Serial circulating tumor DNA (ctDNA) analysis may provide insights into treatment response. Here we performed serial ctDNA analysis (n = 178) on 33 patients. Serial ctDNA analysis identified disease progression with sensitivity of 75% and specificity of 92%. In eight of 12 patients (61%) responding to CDK4/6i who eventually developed progressive disease, serial sampling every 3 or 6 months captured the initial rise of ctDNA with an average lead time of 3 months. In three of eight patients that did not respond to CDK4/6i (progressive disease at first radiological assessment, 3 months), biweekly sequencing within the first cycle of CDK4/6i treatment (1 month) detected sustained ctDNA levels (≥0.2% variant allele frequency), with lead time of 2 months. Serial ctDNA analysis tracked RECIST response, including clinically challenging scenarios (bone metastases or small-sized target lesions), as well as detecting acquired genetic alterations linked to CDK4/6i resistance in the G1 to S transition phase. Circulating tumor DNA analysis was more sensitive than carcinoembryonic antigen or cancer antigen 15-3 serum tumor markers at monitoring tumor response to CDK4/6i treatment. Our findings indicated the possible clinical utility of serial ctDNA analysis for earlier progressive disease detection and real-time monitoring of CDK4/6i response.

8.
J Hum Genet ; 2022 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-35110673

RESUMO

Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) was first reported in China in December 2019, various variants have been identified in different areas of the world such as United Kingdom (alpha), South Africa (beta and omicron), Brazil (gamma), and India (delta). Some of SARS-CoV-2 variants, each of which is characterized by a unique mutation(s) in spike protein, are concerned due to their high infectivity and the capability to escape from neutralizing antibodies elicited by vaccinations. To identify peptide epitopes that are derived from SARS-CoV-2 viral proteins and possibly induce CD8+ T cell immunity, we investigated SARS-CoV-2-derived peptides that are likely to bind to major histocompatibility complex (MHC) class I molecules. We identified a total of 15 peptides that bind to human leukocyte antigen (HLA)-A*24:02, HLA-A*02:01, or HLA-A*02:06, and possibly induce cytotoxic T lymphocytes (CTLs); thirteen of them corresponded to ORF1ab polyprotein, one peptide to spike protein and the remaining one to membrane glycoprotein. CD8+ T cells that recognize these peptides were detected in peripheral blood samples in three individuals recovered from COVID-19 as well as non-infected individuals. Since most of these peptides are commonly conserved among other coronaviruses including SARS-CoV and/or MERS-CoV, these might be useful to maintain T cell responses to coronaviruses that are pandemic at present and will become the future threat. We could define pairs of TRA and TRB sequences of nine CTL clones that recognize SARS-CoV-2-derived peptides. We might use these SARS-CoV-2-derived peptide-reactive TCR sequences for investigating the history of SARS-CoV-2 infection.

9.
Gastric Cancer ; 25(3): 515-526, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34997450

RESUMO

BACKGROUND: The role of tumor-stroma interactions in tumor immune microenvironment (TME) is attracting attention. We have previously reported that cancer-associated fibroblasts (CAFs) contribute to the progression of peritoneal metastasis (PM) in gastric cancer (GC), and M2 macrophages and mast cells also contribute to TME of PM. To elucidate the role of CAFs in TME, we established an immunocompetent mouse PM model with fibrosis, which reflects clinical features of TME. However, the involvement of CAFs in the immunosuppressive microenvironment remains unclear. In this study, we investigated the efficacy of Tranilast at modifying this immune tolerance by suppressing CAFs. METHODS: The interaction between mouse myofibroblast cell line LmcMF and mouse GC cell line YTN16 on M2 macrophage migration was investigated, and the inhibitory effect of Tranilast was examined in vitro. Using C57BL/6J mouse PM model established using YTN16 with co-inoculation of LmcMF, TME of resected PM treated with or without Tranilast was analyzed by immunohistochemistry. RESULTS: The addition of YTN16 cell-conditioned medium to LmcMF cells enhanced CXCL12 expression and stimulated M2 macrophage migration, whereas Tranilast inhibited the migration ability of M2 macrophages by suppressing CXCL12 secretion from LmcMF. In PM model, Tranilast inhibited tumor growth and fibrosis, M2 macrophage, and mast cell infiltration and significantly promoted CD8 + lymphocyte infiltration into the tumor, leading to apoptosis of cancer cells by an immune response. CONCLUSION: Tranilast improved the immunosuppressive microenvironment by inhibiting CAF function in a mouse PM model. Tranilast is thus a promising candidate for the treatment of PM.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Peritoneais , Neoplasias Gástricas , Animais , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Proliferação de Células , Fibroblastos/patologia , Fibrose , Humanos , Macrófagos/patologia , Mastócitos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Peritoneais/metabolismo , Neoplasias Gástricas/patologia , Microambiente Tumoral , ortoaminobenzoatos
10.
Ann Surg ; 275(1): e155-e162, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33055588

RESUMO

OBJECTIVES: To elucidate the efficacy of adjuvant vaccine monotherapy using 3 Human Leukocyte Antigen (HLA)-A∗24-restricted tumor-specific peptide antigens for ESCC, upregulated lung cancer 10, cell division cycle associated 1, and KH domain-containing protein overexpressed in cancer 1. SUMMARY OF BACKGROUND DATA: ESCC patients with pathologically positive nodes (pN(+)) have a high risk for postoperative recurrence, despite curative resection after preoperative therapy. Subclinical micrometastases are an appropriate target for cancer vaccine. METHODS: This is a non-randomized prospective phase II clinical trial (UMIN000003557). ESCC patients curatively resected after preoperative therapy with pN(+) were allocated into the control and vaccine groups (CG and VG) according to the HLA-A status. One mg each of three epitope peptides was postoperatively injected 10 times weekly followed by 10 times biweekly to the VG. The primary and secondary endpoints were relapse-free survival (RFS) and esophageal cancer-specific survival (ECSS), respectively. RESULTS: Thirty were in the CG and 33 in the VG. No significant difference was observed in RFS between the CG and VG (5-year RFS: 32.5% vs 45.3%), but the recurrence rate significantly decreased with the number of peptides which induced antigen-specific cytotoxic T lymphocytes. The VG showed a significantly higher 5-year ECSS than the CG (60.0% vs 32.4%, P = 0.045) and this difference was more prominent in patients with CD8+ and programmed death-ligand 1 double negative tumor (68.0% vs 17.7%, P = 0.010). CONCLUSIONS: Our cancer peptide vaccine might improve the survival of ESCC patients, which is warranted to be verified in the phase III randomized controlled study.


Assuntos
Vacinas Anticâncer/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Esofagectomia , Imunoterapia Ativa/métodos , Linfonodos/patologia , Cuidados Pré-Operatórios/métodos , Microambiente Tumoral/imunologia , Adulto , Idoso , Antígenos de Neoplasias/imunologia , Intervalo Livre de Doença , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/secundário , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias/métodos , Estudos Prospectivos
11.
Curr Med Res Opin ; 38(3): 417-426, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34918590

RESUMO

OBJECTIVE: Prostate cancer is a common malignancy and patients may progress to castration-resistant prostate cancer (CRPC). Among patients with CRPC, fatigue is a common symptom associated with current treatments. The aim of this real-world study was to describe patient-reported fatigue in Japanese patients treated with androgen receptor-axis-targeted therapies for CRPC. METHODS: Data of this observational study were collected in a quantitative phase for the description of patient-reported fatigue, and a qualitative phase for elicitation of fatigue perception and barriers to reporting fatigue. RESULTS: In the quantitative phase (N = 22), fatigue was investigated in two formats: symptoms report and Brief Fatigue Inventory (BFI). In the report of the symptoms, 12 patients reported tiredness, and four moderate-to-severe tiredness during treatment. In the BFI, all patients reported fatigue; eight reported moderate-to-severe fatigue. The most affected BFI domain was mood: five patients reporting moderate-to-severe impact. In interviews (qualitative phase; N = 8), diverse patient experience on fatigue was observed, including apathetic feelings, affected speed and distance during the walk, negative impact on profession, housework, or driving, reduced outgoing activity, and difficulty in enjoying time with grandchildren or travel. Five out of eight patients communicated fatigue to their physicians but received diverse reactions. CONCLUSION: Patient interviews highlighted the impact of fatigue on patients' lives and difficulties in communicating fatigue to physicians. Fatigue frequency after medication may need to be monitored and its burden is considered to provide treatment that meets the needs, wishes, and circumstances of each patient. Further research is needed to elucidate how fatigue affects patients' lives, and underscore patient-physician communication difficulties.


Assuntos
Médicos , Neoplasias de Próstata Resistentes à Castração , Comunicação , Fadiga/epidemiologia , Fadiga/etiologia , Humanos , Japão , Masculino , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
12.
Cancer Sci ; 113(2): 721-732, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34935247

RESUMO

Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12-18 months. Frizzled homolog 10 (FZD10) is overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of ß-radioimmunotherapy (RIT) with the 90 Y-labeled anti-FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α-RIT with OTSA101 labeled with the α-emitter 225 Ac. Competitive inhibition and cell binding assays showed that specific binding of 225 Ac-labeled OTSA101 to SYO-1 synovial sarcoma cells was comparable to that of the imaging agent 111 In-labeled OTSA101. Biodistribution studies showed high uptake in SYO-1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of 225 Ac-labeled OTSA101 for tumors was 7.8 Bd higher than that of 90 Y-labeled OTSA101. 90 Y- and 225 Ac-labeled OTSA101 decreased tumor volume and prolonged survival. 225 Ac-labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. 225 Ac-labeled OTSA101 induced a larger amount of necrosis and apoptosis than 90 Y-labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment-related mortality or obvious toxicity, except for temporary body weight loss, was observed. 225 Ac-labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO-1. RIT with 225 Ac-labeled OTSA101 is a promising therapeutic option for synovial sarcoma.


Assuntos
Actínio/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Receptores Frizzled/antagonistas & inibidores , Sarcoma Sinovial/radioterapia , Actínio/química , Actínio/farmacocinética , Partículas alfa/uso terapêutico , Animais , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacocinética , Linhagem Celular Tumoral , Receptores Frizzled/imunologia , Receptores Frizzled/metabolismo , Humanos , Camundongos , Radioimunoterapia , Dosagem Radioterapêutica , Indução de Remissão , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patologia , Distribuição Tecidual/efeitos da radiação , Carga Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto , Radioisótopos de Ítrio/química , Radioisótopos de Ítrio/farmacocinética , Radioisótopos de Ítrio/uso terapêutico
13.
Nat Genet ; 53(10): 1415-1424, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34594039

RESUMO

Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (ntotal = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Sistema ABO de Grupos Sanguíneos/genética , Bancos de Espécimes Biológicos , Loci Gênicos , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Humanos , Complexo Principal de Histocompatibilidade/genética , Metanálise como Assunto , Mutação/genética , Fenótipo
14.
Chembiochem ; 22(24): 3406-3409, 2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34605137

RESUMO

Conformationally constrained peptides hold promise as molecular tools in chemical biology and as a new modality in drug discovery. The construction and screening of a target-focused library could be a promising approach for the generation of de novo ligands or inhibitors against target proteins. Here, we have prepared a protein kinase-focused library by chemically modifying helix-loop-helix (HLH) peptides displayed on phage and subsequently tethered to adenosine. The library was screened against aurora kinase A (AurA). The selected HLH peptide Bip-3 retained the α-helical structure and bound to AurA with a KD value of 13.7 µM. Bip-3 and the adenosine-tethered peptide Bip-3-Adc provided IC50 values of 103 µM and 7.7 µM, respectively, suggesting that Bip-3-Adc bivalently inhibited AurA. In addition, the selectivity of Bip-3-Adc to several protein kinases was tested, and was highest against AurA. These results demonstrate that chemical modification can enable the construction of a kinase-focused library of phage-displayed HLH peptides.


Assuntos
Aurora Quinase A/metabolismo , Peptídeos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Humanos , Biblioteca de Peptídeos , Peptídeos/química , Conformação Proteica , Inibidores de Proteínas Quinases/química
15.
Cancers (Basel) ; 13(19)2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34638288

RESUMO

In the field of colorectal cancer (CRC) treatment, diagnostic modalities and chemotherapy regimens have progressed remarkably in the last two decades. However, it is still difficult to identify minimal residual disease (MRD) necessary for early detection of recurrence/relapse of tumors and to select and provide appropriate drugs timely before a tumor becomes multi-drug-resistant and more aggressive. We consider the leveraging of in-depth genomic profiles of tumors as a significant breakthrough to further improve the overall prognosis of CRC patients. With the recent technological advances in methodologies and bioinformatics, the genomic profiles can be analyzed profoundly without delay by blood-based tests-'liquid biopsies'. From a clinical point of view, a minimally-invasive liquid biopsy is thought to be a promising method and can be implemented in routine clinical settings in order to meet unmet clinical needs. In this review, we highlighted clinical usefulness of liquid biopsies in the clinical management of CRC patients, including cancer screening, detection of MRD, selection of appropriate molecular-targeted drugs, monitoring of the treatment responsiveness, and very early detection of recurrence/relapse of the disease. In addition, we addressed a possibility of adoptive T cell therapies and a future personalized immunotherapy based on tumor genome information.

16.
Immunol Invest ; : 1-17, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34486463

RESUMO

Although immune checkpoint inhibitors (ICIs) have emerged as new therapeutic options for refractory cancer, they are only effective in select patients. Tumor antigen-pulsed dendritic cell (DC) vaccine therapy activates tumor-specific cytotoxic T lymphocytes, making it an important immunotherapeutic strategy. Salivary ductal carcinoma (SDC) carries a poor prognosis, including poor long-term survival after metastasis or recurrence. In this study, we reported a case of refractory metastatic SDC that was treated with a tumor lysate-pulsed DC vaccine followed by a single injection of low-dose nivolumab, and a durable complete response was achieved. We retrospectively analyzed the immunological factors that contributed to these long-lasting clinical effects. First, we performed neoantigen analysis using resected metastatic tumor specimens obtained before treatment. We found that the tumor had 256 non-synonymous mutations and 669 class I high-affinity binding neoantigen peptides. Using synthetic neoantigen peptides and ELISpot analysis, we found that peripheral blood mononuclear leukocytes cryopreserved before treatment contained pre-existing neoantigen-specific T cells, and the cells obtained after treatment exhibited greater reactivity to neoantigens than those obtained before treatment. Our results collectively suggest that the rapid and long-lasting effect of this combination therapy in our patient may have resulted from the presence of pre-existing neoantigen-specific T cells and stimulation and expansion of those cells following tumor lysate-pulsed DC vaccine and ICI therapy.

18.
Cancer Biol Med ; 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34369137

RESUMO

With the significant advances in cancer genomics using next-generation sequencing technologies, genomic and molecular profiling-based precision medicine is used as a part of routine clinical test for guiding and selecting the most appropriate treatments for individual cancer patients. Although many molecular-targeted therapies for a number of actionable genomic alterations have been developed, the clinical application of such information is still limited to a small proportion of cancer patients. In this review, we summarize the current status of personalized drug selection based on genomic and molecular profiling and highlight the challenges how we can further utilize the individual genomic information. Cancer immunotherapies, including immune checkpoint inhibitors, would be one of the potential approaches to apply the results of genomic sequencing most effectively. Highly cancer-specific antigens derived from somatic mutations, the so-called neoantigens, occurring in individual cancers have been in focus recently. Cancer immunotherapies, which target neoantigens, could lead to a precise treatment for cancer patients, despite the challenge in accurately predicting neoantigens that can induce cytotoxic T cells in individual patients. Precise prediction of neoantigens should accelerate the development of personalized immunotherapy including cancer vaccines and T-cell receptor-engineered T-cell therapy for a broader range of cancer patients.

19.
Mol Clin Oncol ; 15(3): 172, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34276991

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancer types. Activating oncogenic KRAS mutations are commonly observed in PDAC; however, oncogenic KRAS amplification is rarely observed, and its significance in prognosis and resistance to therapy remains poorly characterized. The present report describes the case of a 52-year-old male patient diagnosed with advanced PDAC with liver metastasis. The patient received modified FOLFIRINOX (mFFX) therapy to which the patient became intolerant with a strong inflammatory response. Subsequent treatment with gemcitabine plus nab-paclitaxel failed to control the disease. Targeted genetic analysis revealed KRAS G12D and TP53 R248Q mutations in the primary tumor and liver metastases. Analysis of circulating tumor DNA (ctDNA) before the first line of treatment confirmed these genetic findings and revealed a >4-fold amplification of the mutant KRAS G12D not detected in the primary tumor. Additionally, subsequent analysis confirmed a 5-fold amplification of the KRAS G12D allele in liver metastasis. Consecutive monitoring of ctDNA revealed an initial decrease in the tumor burden 2 weeks after the first cycle of mFFX. However, coinciding with treatment intolerance, a sharp increase in tumor mutational levels and KRAS G12D amplification was observed 1 month later. The patient died 70 days after treatment initiation. Overall, amplification of oncogenic KRAS G12D was not only associated with an aggressive phenotype, but also supported cancer resistance to chemotherapy. Importantly, this case suggests that plasma detection of KRAS G12D amplification is feasible in the clinical routine and constitutes a powerful tool for assessing tumor aggressiveness.

20.
Anticancer Res ; 41(8): 4101-4115, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281881

RESUMO

BACKGROUND/AIM: Neoantigens are tumor-specific antigens that emerge due to gene mutations in tumor cells, and are highly antigenic epitopes that escape central immune tolerance in the thymus, making cancer vaccine therapy a desirable option. PATIENTS AND METHODS: Tumor neoantigens were predicted in 17 patients with advanced cancer. They were resistant to the standard treatment regime, and their synthetic peptides were pulsed to the patient's monocyte-derived dendritic cells (DCs), and administered to the patient's lymph nodes via ultrasound. RESULTS: Some patients showed sustained tumor shrinkage after this treatment, while some did not respond, showing no ELISpot reaction. Although the number of mutations and the predicted neoantigen epitopes differed between patients, the clinical effect depended more on the presence or absence of an immune response after vaccination rather than the number of neoantigens. CONCLUSION: Intranodal neoantigen peptide-pulsed DC vaccine administration therapy has clinical and immunological efficacy and safety.


Assuntos
Antígenos de Neoplasias/administração & dosagem , Vacinas Anticâncer/uso terapêutico , Células Dendríticas , Neoplasias/terapia , Peptídeos/administração & dosagem , Adulto , Idoso , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
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