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PURPOSE: The concept of non-mass abnormalities of the breast has been employed in Japan for approximately 20 years. Although B-mode findings are classified as non-mass abnormalities, the usefulness of adding color Doppler ultrasonography (US) and strain elastography to B-mode US is unclear. Therefore, we conducted a multicenter study (JABTS BC-07) to establish the diagnostic criteria for breast US, including color Doppler and elastography, for non-mass abnormalities of the breast and verify their diagnostic usefulness. METHODS: We registered US images of non-mass abnormalities of the breast and their clinical and histopathological data from 13 institutions (202 malignant and 183 benign non-mass lesions). Furthermore, we evaluated the centralized image interpretation usefulness of the diagnostic criteria for B-mode and color Doppler US, as well as the sensitivity and specificity when color Doppler US and elastography were added to B-mode US. RESULTS: Echogenic foci in the mammary gland (odds ratio 3.45, 95% confidence interval [CI] 1.92-6.19, p < 0.0001) and the configuration of internal solid components of the ducts (odds ratio 0.056, 95% CI 0.005-0.591, p < 0.0165) significantly differentiated benign and malignant non-mass abnormalities. The sensitivity of B-mode alone (83.7%) was significantly improved by adding color Doppler US (93.1%) (p = 0.0004); however, adding color Doppler US and elastography to B-mode US made no significant difference in either sensitivity or specificity. CONCLUSION: Although adding color Doppler US and elastography to B-mode US improved sensitivity, the diagnostic significance was limited. Therefore, a comprehensive diagnostic method comprising mammography and magnetic resonance imaging is warranted.
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PURPOSE: This study was designed to investigate the prognostic significance of artificial intelligence (AI)-based quantification of myxoid stroma in patients undergoing esophageal squamous cell carcinoma (ESCC) surgery after neoadjuvant chemotherapy (NAC) and to verify its significance in an independent validation cohort from another hospital. METHODS: We evaluated two datasets of patients with pathological stage II or III ESCC who underwent surgery after NAC. Cohort 1 consisted of 85 patients who underwent R0 surgery for the primary tumor after NAC. Cohort 2, the validation cohort, consisted of 80 patients who received same treatments in another hospital. AI-based myxoid stroma was evaluated in resected specimens, and its area was categorized by using the receiver operating characteristic curve for overall survival (OS) of cohort 1. RESULTS: The F1 scores, which are the degree of agreement between the automatically detected myxoid stroma and manual annotations, were 0.83 and 0.79 for cohorts 1 and 2. The myxoid stroma-high group had a significantly poorer prognosis than the myxoid stroma-low group in terms of OS, disease-specific survival (DSS), and recurrence-free survival (RFS) in cohort 1. Comparable results were observed in cohort 2, where OS, DSS, and RFS were significantly affected by myxoid stroma. Multivariate analysis for RFS revealed that AI-determined myxoid stroma-high was one of the independent prognostic factors in cohort 1 (hazard ratio [HR] 1.97, p = 0.037) and cohort 2 (HR 4.45, p < 0.001). CONCLUSIONS: AI-determined myxoid stroma may be a novel and useful prognostic factor for patients with pathological stage II or III ESCC after NAC.
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Aprendizado Profundo , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Terapia Neoadjuvante , Humanos , Feminino , Terapia Neoadjuvante/mortalidade , Masculino , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/terapia , Pessoa de Meia-Idade , Taxa de Sobrevida , Prognóstico , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/cirurgia , Carcinoma de Células Escamosas do Esôfago/terapia , Seguimentos , Idoso , Esofagectomia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Retrospectivos , Quimioterapia Adjuvante , Células Estromais/patologiaRESUMO
Background: Drug-induced pneumonia, especially immune-related adverse events, can sometimes be fatal, and it is crucial to seize the signs for early treatment. A clinical trial (ATTRACTION-4) reported no cases of grade 4 or 5 pneumonia or interstitial lung disease associated with nivolumab plus S-1 and oxaliplatin. However, we encountered two cases of fatal pneumonia induced by this regimen. Case Description: The two patients were in their 70s, male and diagnosed gastric cancer with peritoneal dissemination. The patient of case 1 underwent surgery and adjuvant chemotherapy nine years before. The patient of case 2 was diagnosed unresectable 6 months before and chemo naïve. Both patients received nivolumab plus S-1 and oxaliplatin for the dissemination. The onset of both cases occurred after the fifth dose of the regimen, and the responses to corticosteroids were transient and limited. Computed tomography showed bilateral consolidation and ground-glass opacities, seemingly similar to an organizing pneumonia pattern. Acute and organizing stages of diffuse alveolar damage were detected histopathologically. Despite showing notable antitumor effects, both patients had indications of interstitial pneumonitis before admission, such as elevation of C-reactive protein (CRP) and Krebs von den Lungen-6 (KL-6) levels and slight lung opacity or respiratory symptoms approximately 10 days before admission. Conclusions: Patients undergoing nivolumab plus S-1 and oxaliplatin should be closely followed up with imaging, evaluation of symptom including oxygen saturation, and serological marker analysis such as lactate dehydrogenase, CRP, and KL-6. Early detection of pneumonia leads to adequate cessation of chemotherapy and early treatment, and this can prevent severe adverse events.
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We investigated humoral immune responses in 222 unvaccinated Japanese people after recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in 2021. Anti-spike-protein IgG antibody levels and neutralizing antibody titers were measured in serum samples obtained within 20-180 days after diagnosis. The geometric mean of antibody titers was 1555 ELU/mL (95% confidence interval (CI) = 1257-1923), and the neutralizing activity (50% inhibitory dilution) was 253 (95% CI = 204-313). The antibody titer and neutralizing activity both increased with increasing disease severity, and both values were approximately fourfold higher for hospitalized patients than for non-hospitalized patients. However, these differences were smaller in older patients. The humoral immune response, which increased with increasing disease severity, gradually decreased over time after SARS-CoV-2 infection. Most patients with mild or moderate symptoms sustained neutralizing activity for up to 180 days after the infection; the decay of the neutralizing activity in the asymptomatic patients was rather faster than in the other groups. Around 11.7% (26/222) of patients had very low neutralizing activity, and half of these were aged in their 20s. Our study's results show the importance of measuring the neutralizing activity to confirm the immune status and to estimate the timing of vaccines.
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COVID-19 , Imunidade Humoral , Idoso , Humanos , COVID-19/imunologia , População do Leste Asiático , Gravidade do Paciente , Japão , Anticorpos Antivirais , Anticorpos NeutralizantesRESUMO
Ultrasound images of ductal carcinoma in situ (DCIS) show a wide range of variations from mass to non-mass lesions. This article describes the characteristics of ultrasound images of DCIS based on the BC-02 study conducted by The Japanese Association of Breast and Thyroid Sonology (JABTS). In the BC-02 study, ultrasound images of 705 DCIS cases were classified by imaging findings. The results showed that non-mass abnormalities accounted for 60% of all lesions and masses for 40%. Looking at each subclassification, hypoechoic areas in the mammary gland were the most common (50% of the total), followed by solid masses (31%), mixed masses (9%), and abnormalities of the ducts (8%). These four classifications accounted for 98% of the total. Echogenic foci without a hypoechoic area, architectural distortion, and clustered microcysts were very rare, accounting for about 1% of the total. The ultrasound images of DCIS were characterized by a wide range of variations from masses to non-masses abnormalities, with hypoechoic areas in the mammary gland being the most common, followed by solid masses.
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Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Feminino , Humanos , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/patologia , Ultrassonografia Mamária/métodos , Ultrassonografia , Mama/diagnóstico por imagem , Glândula Tireoide/patologia , Neoplasias da Mama/diagnóstico por imagemRESUMO
It is possible to appropriately diagnose non-mass abnormalities by elucidating ultrasound non-mass abnormality findings and sharing the concept. If non-mass abnormalities can be diagnosed early, the number of curable cases could increase, leading to fewer breast cancer deaths. The Japan Society of Ultrasonics in Medicine (JSUM) Terminology/Diagnostic Criteria Committee has classified non-mass abnormalities into five subtypes: hypoechoic area in the mammary gland, abnormalities of the ducts, architectural distortion, multiple small cysts, and echogenic foci without a hypoechoic area. We herein define the findings for each of these subtypes and present a summary of the JSUM guidelines on non-mass abnormalities of the breast generated based on those findings.
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Neoplasias da Mama , Ultrassom , Feminino , Humanos , Ultrassonografia Mamária , Japão , Mama/diagnóstico por imagem , Neoplasias da Mama/diagnóstico por imagemRESUMO
Regorafenib is a standard salvage line therapy used for advanced colorectal cancer (CRC). Recently, trifluridine/tipiracil (TFTD) plus bevacizumab also showed promising efficacy as a salvage line therapy for advanced CRC. However, the efficacy and safety of regorafenib for patients with advanced CRC who have previously received TFTD plus bevacizumab is unclear. We retrospectively collected clinicopathologic data from patients with advanced CRC who received regorafenib after TFTD plus bevacizumab in multiple institutions between April 2017 and June 2020.Thirty-four advanced CRC patients who received regorafenib were analyzed. The median age was 66.5 (range 43-81 years), 11 patients were male, and all had an ECOG performance status(PS) of 0 or 1. Twenty-two patients had left-sided tumors, 18 patients had RAS mutants, and 1 patient had a BRAF V600E mutation. The response rate was 0%, and the disease control rate was 31%. The median progression-free survival was 70 days (95% CI: 56-91), and the overall survival was 233 days (95% CI: 188-324). Treatment was discontinued in 32 patients, and 28 (82%) discontinued treatment due to progressive disease. The major grade 3 and4 toxicities were proteinurea (29%), hypertension (26%), hand-foot syndrome(15%), and platelet decrease (6%). Regorafenib after TFTD plus bevacizumab showed efficacy similar to that of the previous study, and no new adverse events were observed.
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Neoplasias Colorretais , Trifluridina , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Bevacizumab/efeitos adversos , Estudos Retrospectivos , Trifluridina/uso terapêutico , Uracila/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Timina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Compostos de Fenilureia/efeitos adversos , Pirrolidinas/uso terapêutico , Combinação de MedicamentosRESUMO
Essential oils are liquid extracts of various plants with potential health benefits and are often used in aromatherapy. Contact allergy, including skin irritation, is a well-known side effects of these extracts. A Japanese woman visited our emergency department complaining of dyspnea, cough, and fever. Two weeks earlier, she had started aromatherapy using a humidifier and essential oil. Based on clinical and imaging findings, and the results of bronchoalveolar lavage, we diagnosed acute eosinophilic pneumonia due to inhalation of essential oil. Her symptoms resolved after steroid therapy. This case makes the clinicians aware the possibility of acute eosinophilic pneumonia induced by aromatherapy using essential oil.
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BACKGROUND/AIM: The usefulness of angiogenesis inhibitors as second-line treatment after the progression of anti-epidermal growth factor receptor antibody drug-containing regimens for RAS wild-type metastatic colorectal cancer (mCRC) has not been fully investigated. Therefore, we conducted a phase II study to verify the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab (SIRB regimen) as second-line treatment for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC. PATIENTS AND METHODS: Patients with mCRC who had previously received oxaliplatin and cetuximab-containing regimen were eligible for this study. Patients were infused with bevacizumab 7.5 mg/kg and irinotecan 150 mg/m2 intravenously on day 1, whereas S-1 80 mg/m2 was administered orally twice daily until day 15, followed by a 7-day drug holiday period. The primary end point was 6-month progression-free survival (PFS) rate. RESULTS: In total, 17 patients were enrolled in this study. The 6-month PFS rate was 64.7% [95% confidence interval (CI)=41.99-87.43], median PFS was 10.1 months (95%CI=4.11-17.28), and median overall survival was 21.8 months (95%CI=9.79-37.91). The response rate was 23.5% (95%CI=6.81-49.90%). Grade ≥3 adverse events were observed in 10% of patients, and included leukopenia [3 (17.6%)], neutropenia [5 (29.4%)], anorexia [2 (11.8%)], diarrhea [2 (11.8%)], and hypertension [3 (17.6%)]. No treatment-related deaths or febrile neutropenia were observed. CONCLUSION: The SIRB regimen might be a promising second-line treatment option for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC in terms of efficacy and safety.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Camptotecina , Cetuximab , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Fatores Imunológicos/uso terapêutico , Irinotecano/uso terapêutico , Oxaliplatina/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Retais/tratamento farmacológicoRESUMO
Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage-driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia-induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA-induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L-norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR-knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia-exposed mice. Conclusions Increased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.
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Pulmão , Hipertensão Arterial Pulmonar , Ácido Úrico , Animais , Pulmão/metabolismo , Camundongos , Hipertensão Arterial Pulmonar/patologia , Ratos , Ácido Úrico/metabolismoRESUMO
BACKGROUND: Regorafenib and trifluridine/tipiracil are standard third-line chemotherapies for colorectal cancer patients, but their efficacy is limited. Anti-epidermal growth factor receptor antibody rechallenge has been reported to be promising for patients who have obtained clinical benefit from first-line cetuximab-based chemotherapy. Moreover, panitumumab showed non-inferior efficacy to cetuximab. OBJECTIVE: This study assessed the efficacy and safety of third-line panitumumab rechallenge in patients with metastatic KRAS exon 2 wild-type metastatic colorectal cancer who obtained clinical benefit from first-line panitumumab-based chemotherapy. PATIENTS AND METHODS: This was a prospective, multicenter, phase II trial conducted from October 2013 to August 2017. Major eligibility criteria included KRAS exon 2 wild-type and achievement of complete response, partial response, or continued stable disease for at least 6 months in first-line panitumumab-based therapy. Irinotecan plus panitumumab treatment was continued until disease progression or unacceptable toxicity was observed. The primary endpoint was the 3-month progression-free survival (PFS) rate. RESULTS: Twenty-five patients were enrolled in this study. Their median age was 66.5 years, and the 3-month PFS rate was 50.0% (95% confidence interval 30.0-70.0). The median PFS and overall survival were 3.1 months and 8.9 months, respectively. The response rate and disease control rate were 8.3% and 50.0%, respectively. Common grade 3/4 adverse events were acneiform rash (17%), hypomagnesemia (13%), and dry skin (13%). No treatment-related deaths occurred. CONCLUSION: Irinotecan plus panitumumab rechallenge is a promising third-line treatment regimen in patients with metastatic wild-type KRAS colorectal cancer. CLINICAL TRIAL IDENTIFICATION: UMIN000015916.
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Neoplasias do Colo , Neoplasias Colorretais , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/patologia , Humanos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Estudos Multicêntricos como Assunto , Panitumumabe/farmacologia , Panitumumabe/uso terapêutico , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
BACKGROUND: We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting. METHODS: We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out. RESULTS: We enrolled 230 patients (anthracycline, n = 115; S-1, n = 115). Median overall survival was 30.1 months (95% CI 24.9-35.8) with the S-1 group and 33.7 months (95% CI 25.5-36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80-1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90-1.25); P non-inferiority = 0.0062). CONCLUSIONS: S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. CLINICAL TRIAL REGISTRATION: The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011.
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Antraciclinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácido Oxônico/administração & dosagem , Taxoides/administração & dosagem , Tegafur/administração & dosagem , Adulto , Idoso , Antraciclinas/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/genética , Combinação de Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Ácido Oxônico/farmacologia , Receptor ErbB-2/genética , Análise de Sobrevida , Taxoides/farmacologia , Tegafur/farmacologia , Resultado do Tratamento , Adulto JovemRESUMO
The usefulness of color Doppler ultrasound (CD) in distinguishing between benign and malignant breast lesions remains controversial. Our prior study, the Japan Association of Breast and Thyroid Sonology (JABTS) BC-04 study (malignant: 839, benign: 569), found CD was useful in breast cancer diagnosis, and we developed CD diagnostic criteria. The first aim of the current study (the CD-CONFIRM study) was to evaluate the usefulness of the CD diagnostic criteria. The second aim was to evaluate the relationship between CD and elastography. We evaluated ultrasound images of breast masses from 13 institutions (malignant: 639, benign: 712). While the sensitivity of B-mode alone was very high and was not significantly improved with CD, the specificity was significantly improved with CD (61.2%-69.2%, p < 0.0001). Furthermore, the specificity of the combination of B-mode and CD improved significantly with the addition of elastography (72.8%-79.0%, p < 0.0001). This study found that the CD criteria are useful, and CD and elastography are independent.
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Neoplasias da Mama , Técnicas de Imagem por Elasticidade , Mama/diagnóstico por imagem , Neoplasias da Mama/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Sensibilidade e Especificidade , Ultrassonografia MamáriaRESUMO
LESSONS LEARNED: Three-month adjuvant capecitabine plus oxaliplatin in combination (CAPOX) appeared to reduce recurrence, with mild toxicity in postcurative resection of colorectal cancer liver metastases (CLM). Recurrence in patients who underwent the 3-month adjuvant CAPOX after resection of CLM was most commonly at extrahepatic sites. BACKGROUND: The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable colorectal cancer liver metastases (CLM) is still unclear. We evaluated the feasibility of 3-month adjuvant treatment with capecitabine plus oxaliplatin in combination (CAPOX) for postcurative resection of CLM. METHODS: Patients received one cycle of capecitabine followed by four cycles of CAPOX as adjuvant chemotherapy after curative resection of CLM. Oral capecitabine was given as 1,000 mg/m2 twice daily for 2 weeks in a 3-week cycle, and CAPOX consisted of oral capecitabine plus oxaliplatin 130 mg/m2 on day 1 in a 3-week cycle. Primary endpoint was the completion rate of adjuvant chemotherapy. Secondary endpoints included recurrence-free survival (RFS), overall survival (OS), dose intensity, and safety. RESULTS: Twenty-eight patients were enrolled. Median age was 69.5 years, 54% of patients had synchronous metastases, and 29% were bilobar. Mean number of lesions resected was two, and mean size of the largest lesion was 31 mm. Among patients, 20 (71.4%; 95% confidence interval, 53.6%-89.3%) completed the protocol treatment and met its primary endpoint. The most common grade 3 or higher toxicity was neutropenia (29%). Five-year recurrence-free survival and overall survival were 65.2% and 87.2%, respectively. CONCLUSION: Three-month adjuvant treatment with CAPOX is tolerable and might be a promising strategy for postcurative resection of CLM.
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Neoplasias Colorretais , Neoplasias Hepáticas , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/uso terapêutico , Quimioterapia Adjuvante , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Fluoruracila/efeitos adversos , Hepatectomia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/tratamento farmacológico , Oxaliplatina/uso terapêuticoRESUMO
Background Recent accumulating evidence suggests that toll-like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases. However, its role in pulmonary hypertension remains uncertain. We hypothesized that TLR9 is involved in the development of pulmonary hypertension. Methods and Results A rat model of monocrotaline-induced pulmonary hypertension was used to investigate the effects of TLR9 on hemodynamic parameters, vascular remodeling, and survival. Monocrotaline-exposed rats significantly showed increases in plasma levels of mitochondrial DNA markers, which are recognized by TLR9, TLR9 activation in the lung, and interleukin-6 mRNA level in the lung on day 14 after monocrotaline injection. Meanwhile, monocrotaline-exposed rats showed elevated right ventricular systolic pressure, total pulmonary vascular resistance index and vascular remodeling, together with macrophage accumulation on day 21. In the preventive protocol, administration (days -3 to 21 after monocrotaline injection) of selective (E6446) or nonselective TLR9 inhibitor (chloroquine) significantly ameliorated the elevations of right ventricular systolic pressure and total pulmonary vascular resistance index as well as vascular remodeling and macrophage accumulation on day 21. These inhibitors also significantly reduced NF-κB activation and interleukin-6 mRNA levels to a similar extent. In the short-term reversal protocol, E646 treatment (days 14-17 after monocrotaline injection) almost normalized NF-κB activation and interleukin-6 mRNA level, and reduced macrophage accumulation. In the prolonged reversal protocol, E6446 treatment (days 14-24 after monocrotaline injection) reversed total pulmonary vascular resistance index and vascular remodeling, and improved survival in monocrotaline-exposed rats. Conclusions TLR9 is involved in the development of pulmonary hypertension concomitant via activation of the NF-κBâIL-6 pathway. Inhibition of TLR9 may be a novel therapeutic strategy for pulmonary hypertension.
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Cloroquina/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Monocrotalina/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Receptor Toll-Like 9/antagonistas & inibidores , Animais , Antirreumáticos/farmacologia , Modelos Animais de Doenças , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Masculino , Artéria Pulmonar/fisiopatologia , Ratos , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacosRESUMO
INTRODUCTION: The previous randomized phase 3 trial (SELECT BC) showed that S-1 as a first-line chemotherapy for metastatic breast cancer (MBC) is non-inferior to taxane with respect to overall survival. This study aimed to identify the usefulness of metabolism-related genes as predictive biomarkers for the response to S-1 compared with taxane using tumor tissue samples from the previous trial.â¯â¯ PATIENTS AND METHODS: In this SELECT BC-EURECA study, 147 patients with human epidermal growth factor 2 (HER2)-negative MBC who received either S-1 or taxane were evaluated. Formalin-fixed paraffin-embedded specimens were collected, and 14 genes involved in the pyrimidine metabolic pathway, estrogen receptor, progesterone receptor, HER2, Ki67, and beta-tubulin were measured using reverse transcription polymerase chain reaction in microdissected tumor specimens. The expression of each gene was categorized as low, intermediate, and high by tertile values.â¯â¯ RESULTS: Interaction tests to identify biomarkers for the response to S-1 compared with taxane, revealed the following as the top 3 biomarkers: RRM1 (P value = 0.24), GGH (P value = 0.25), and MTHFR (P value = 0.28). In the S-1 group, lower GGH and higher MTHFR expression were significantly correlated with better time to treatment failure. In the taxane group, there was no gene that was identified as a significant indicator of treatment failure. CONCLUSION: This biomarker analysis from SELECT BC did not identify any predictive biomarkers for the response to S-1 compared with taxane. Future studies with larger sample size and information on not only mRNA, but also protein and DNA for broad functional analyses are needed.
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Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Ácido Oxônico/uso terapêutico , Tegafur/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Combinação de Medicamentos , Feminino , Nível de Saúde , Humanos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismoRESUMO
PURPOSE: Breast ultrasound has been widely used as an essential examination for diagnosing breast cancer. However, standardized diagnostic criteria are as yet lacking. This study aimed to develop a simple diagnostic flowchart for beginners learning breast ultrasonography. The diagnostic flowchart was developed based on the recall criteria widely used in Japan. METHODS: We conducted a multicenter study to examine recall criteria usefulness in the diagnostic phase of breast disease. Women with ultrasound-visible breast masses who underwent B-mode breast ultrasound examination were recruited from 22 hospitals in Japan between September 2009 and January 2010. B-mode images were evaluated by members of the centralized image interpretation committee. We developed the new diagnostic flowchart based on the results. The usefulness of the diagnostic flowchart was assessed by employing datasets from the current study and another study which we conducted (BC-04 study). RESULTS: We evaluated 1045 solid masses (malignant: 495, benign: 550). Multivariate analysis showed that shape, margin, echogenic halo, interruption of the mammary gland interface, and depth width ratio were significant findings for distinguishing between benign and malignant masses. We modified the recall criteria and developed our novel diagnostic flowchart using these findings. The sensitivity and specificity of the new flowchart (current study: 0.97, 0.45; BC-04 study dataset: 0.95, 0.45) were similar to those of experts (current study: 0.96, 0.54; BC-04 study dataset: 0.98, 0.38). CONCLUSION: We developed a simple diagnostic flowchart for breast ultrasound. This flowchart is anticipated to be applicable to educating beginners learning breast ultrasound.
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Neoplasias da Mama/diagnóstico por imagem , Ultrassonografia Mamária/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/patologia , Feminino , Humanos , Japão , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Sensibilidade e Especificidade , Sociedades MédicasRESUMO
BACKGROUND: Regorafenib or trifluridine/tipiracil as third-line treatment have limited efficacy in metastatic colorectal cancer (mCRC). METHODS: This Phase 2 trial evaluated the efficacy and safety of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type mCRC patients who achieved clinical benefit with first-line cetuximab-containing therapy. The primary endpoint was 3-month progression-free survival (PFS) rate. A sample size was calculated; 30 patients with a 3-month PFS rate of 45% deemed promising and 15% unacceptable. Patients with greater and less than the cut-off value of cetuximab-free intervals (CFIs) were classified into the long and short CFI groups, respectively, in subgroup analyses. RESULTS: Among 34 eligible patients who received treatment at least once, 3-month PFS rate was 44.1% (95% confidence interval, 27.4-60.8%). The median PFS and overall survival (OS) were 2.4 and 8.2 months, respectively. The response and disease control rates were 2.9 and 55.9%, respectively. PFS and OS were significantly longer in the long- than in the short CFI group. CONCLUSIONS: Irinotecan plus cetuximab rechallenge as third-line treatment for KRAS wild-type mCRC was safe and had promising activity, especially in those with a long CFI, warranting further investigation in a Phase 3 randomised trial. CLINICAL TRIAL REGISTRATION: UMIN000010638.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Irinotecano/administração & dosagem , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cetuximab/efeitos adversos , Quimioterapia Adjuvante , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Humanos , Irinotecano/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas Proto-Oncogênicas p21(ras)/genética , Terapia de Salvação , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Nivolumab has changed the treatment of advanced gastric cancer (AGC). Nivolumab shows better outcomes compared to best supportive care among AGC patients who received at least two prior regimens. However, there are no reliable data regarding AGC patients with poor performance status (PS) who received nivolumab. We investigated the efficacy and safety of nivolumab among AGC patients with poor PS. METHODS: We retrospectively collected clinicopathologic data from patients with AGC who underwent nivolumab monotherapy at our institution from October 2017 to June 2019. RESULTS: Forty-nine AGC patients who received nivolumab were assessed. Twenty-seven patients had PS 0 or 1 (Good group) and 22 had PS 2 or 3 (Poor group). The median progression-free survival and overall survival durations were 2.0 and 6.0 months in the Good group, respectively, and 1.2 and 2.8 months in the Poor group, respectively. The overall survival was significantly shorter in the Poor group (6.0 vs 2.8 months, p = 0.0255). The disease control rates were 23 and 9% in the Good and Poor groups, respectively. Thirty-three percent of patients experienced immune-related adverse events in the Good group, and 18% in the Poor group. CONCLUSION: Nivolumab is feasible but insufficient as third- or later-line treatment for AGC patients with poor PS.