Abstract
Tumor endothelial cells (TEC) lining tumor blood vessels actively contribute to tumor progression and metastasis. In addition to tumor cells, TEC may develop drug resistance during cancer ...treatment, allowing the tumor cells to survive chemotherapy and metastasize. We previously reported that TECs resist paclitaxel treatment via upregulation of ABCB1. However, whether TEC phenotypes are altered by anticancer drugs remains to be clarified. Here, we show that ABCB1 expression increases after chemotherapy in urothelial carcinoma cases. The ratio of ABCB1-positive TEC before and after first-line chemotherapy in urothelial carcinoma tissues (n = 66) was analyzed by ABCB1 and CD31 immunostaining. In 42 cases (64%), this ratio increased after first-line chemotherapy. Chemotherapy elevated ABCB1 expression in endothelial cells by increasing tumor IL8 secretion. In clinical cases, ABCB1 expression in TEC correlated with IL8 expression in tumor cells after first-line chemotherapy, leading to poor prognosis. In vivo, the ABCB1 inhibitor combined with paclitaxel reduced tumor growth and metastasis compared with paclitaxel alone. Chemotherapy is suggested to cause inflammatory changes in tumors, inducing ABCB1 expression in TEC and conferring drug resistance. Overall, these findings indicate that TEC can survive during chemotherapy and provide a gateway for cancer metastasis. Targeting ABCB1 in TEC represents a novel strategy to overcome cancer drug resistance.
Significance:
These findings show that inhibition of ABCB1 in tumor endothelial cells may improve clinical outcome, where ABCB1 expression contributes to drug resistance and metastasis following first-line chemotherapy.
IgG4-related disease is a poorly understood immune disorder. Its features include tumour-like swelling of involved organs, lymphoplasmacytic infiltrate with IgG4 positive plasma cells. IgG4-related ...lung disease can manifest radiologically as various types of pulmonary abnormalities, including mass-like lesions and pleural effusion, and it may mimic malignant disease.
A 76-year-old man was found to have a 4-mm ground glass opacity in the left lower lobe of the lung on follow-up chest CT after surgery for colon carcinoma. This lesion gradually became consolidated and enlarged to 9 mm over about three years. We performed a video-assisted left basal segmentectomy for the purposes of both diagnosis and treatment. Pathological examination revealed lymphoplasmacytic infiltration, mainly with IgG4-positive plasma cells.
A major characteristic of IgG4-related lung disease is multiple, small, bilateral, lung nodules and solid nodules reportedly being detected in almost all patients. However, solitary nodules are rare, being present in only 14 %. Moreover, this case shows extremely rare radiological findings in which a ground-glass opacity had gradually morphed into a solid nodule. It is difficult to differentiate IgG4-related lung nodules from other lung diseases, such as primary or metastatic lung tumours, standard interstitial pneumonia, organizing pneumonia.
We have here presented a rare case of IgG4-related lung disease with a 3-year course, including detailed radiological findings. Surgery is very useful for both diagnosis and treatment of a small, solitary, deeply located, pulmonary nodule of IgG4-related lung disease.
•A rare solitary lung nodule of IgG-4 related disease, minicking primary lung carcinoma or metastatic lung tumor, was slowly growing after for colon cancer.•IgG4-related lung disease is very important to include in the differential diagnosis of a ground glass opacity or a solitary lung nodule.•Surgery is very useful for both diagnosis and treatment of a solitary lung nodule of IgG-4 related lung disease.
New molecular targeted agents are needed for patients with non-small-cell lung cancer (NSCLC) who progress while receiving erlotinib, gefitinib, or both. Afatinib, an oral irreversible ErbB family ...blocker, has preclinical activity in epidermal growth factor receptor (EGFR ErbB1) mutant models with EGFR-activating mutations, including T790M.
This was a Japanese single-arm phase II trial conducted in patients with stage IIIB to IV pulmonary adenocarcinoma who progressed after ≥ 12 weeks of prior erlotinib and/or gefitinib. Patients received afatinib 50 mg per day. The primary end point was objective response rate (complete response or partial response) by independent review. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.
Of 62 treated patients, 45 (72.6%) were EGFR mutation positive in their primary tumor according to local and/or central laboratory analyses. Fifty-one patients (82.3%) fulfilled the criteria of acquired resistance to erlotinib and/or gefitinib. Of 61 evaluable patients, five (8.2%; 95% CI, 2.7% to 18.1%) had a confirmed objective response rate (partial response). Median PFS was 4.4 months (95% CI, 2.8 to 4.6 months), and median OS was 19.0 months (95% CI, 14.9 months to not achieved). Two patients had acquired T790M mutations: L858R + T790M, and deletion in exon 19 + T790M; they had stable disease for 9 months and 1 month, respectively. The most common afatinib-related adverse events (AEs) were diarrhea (100%) and rash/acne (91.9%). Treatment-related AEs leading to afatinib discontinuation were experienced by 18 patients (29%), of whom four also had progressive disease.
Afatinib demonstrated modest but noteworthy efficacy in patients with NSCLC who had received third- or fourth-line treatment and who progressed while receiving erlotinib and/or gefitinib, including those with acquired resistance to erlotinib, gefitinib, or both.
Summary Background Currently, crizotinib is the only drug that has been approved for treatment of ALK -rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of ...CH5424802, a potent, selective, and orally available ALK inhibitor. Methods In this multicentre, single-arm, open-label, phase 1–2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK -rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-101264. Findings Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20–300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93·5%, 95% CI 82·1–98·6) including two complete responses (4·3%, 0·5–14·8) and 41 partial responses (89·1%, 76·4–96·4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment. Interpretation CH5424802 is well tolerated and highly active in patients with advanced ALK -rearranged NSCLC. Funding Chugai Pharmaceutical Co, Ltd.
In LUX‐Lung 3, afatinib significantly improved progression‐free survival (PFS) versus cisplatin/pemetrexed in EGFR mutation‐positive lung adenocarcinoma patients and overall survival (OS) in Del19 ...patients. Preplanned analyses in Japanese patients from LUX‐Lung 3 were performed. Patients were randomized 2:1 to afatinib or cisplatin/pemetrexed, stratified by mutation type (Del19/L858R/Other). Primary endpoint was PFS (independent review). Secondary endpoints included OS, objective response, and safety. Median PFS (data cut‐off: February 2012) for afatinib versus cisplatin/pemetrexed was 13.8 vs 6.9 months (hazard ratio HR, 0.38; 95% confidence interval CI, 0.20–0.70; P = 0.0014) in all Japanese patients (N = 83), with more pronounced improvements in those with common mutations (Del19/L858R; HR, 0.28; 95% CI, 0.15–0.52; P < 0.0001) and Del19 mutations (HR, 0.16; 95% CI, 0.06–0.39; P < 0.0001). PFS was also improved in L858R patients (HR, 0.50; 95% CI, 0.20–1.25; P = 0.1309). Median OS (data cut‐off: November 2013) with afatinib versus cisplatin/pemetrexed was 46.9 vs 35.8 months (HR, 0.75; 95% CI, 0.40–1.43; P = 0.3791) in all Japanese patients, with greater benefit in patients with common mutations (HR, 0.57; 95% CI, 0.29–1.12; P = 0.0966) and Del19 mutations (HR, 0.34; 95% CI, 0.13–0.87; P = 0.0181); OS was not significantly different in L858R patients (HR, 1.13; 95% CI, 0.40–3.21; P = 0.8212). Following study treatment discontinuation, most patients (93.5%) received subsequent anticancer therapy. The most common treatment‐related adverse events were diarrhea, rash/acne, nail effects and stomatitis with afatinib and nausea, decreased appetite, neutropenia, and leukopenia with cisplatin/pemetrexed. Afatinib significantly improved PFS versus cisplatin/pemetrexed in Japanese EGFR mutation‐positive lung adenocarcinoma patients and OS in Del19 but not L858R patients (www.clinicaltrials.gov; NCT00949650).
In subgroup analyses of LUX‐Lung 3, afatinib significantly improved progression‐free survival versus cisplatin/pemetrexed in Japanese patients with EGFR mutation‐positive lung adenocarcinoma. Overall survival was significantly improved with afatinib in Japanese patients with Del19 mutation, while overall survival in Japanese patients with L858R mutation was similar between treatment arms.
Early repolarization pattern is a common ECG finding characterized by J-point elevation and QRS notching or slurring in the inferior and/or lateral leads, yet little is known about its incidence and ...long-term prognosis in Asian populations.
We reviewed all the ECG records of the 5976 atomic-bomb survivors who were examined at least once during our biennial health examination in Nagasaki, Japan, between July 1958 and December 2004. We defined early repolarization pattern as ≥0.1-mV elevation of the J point or ST segment, with notching or slurring in at least 2 inferior and/or lateral leads. We assessed unexpected, cardiac, and all-cause death risk by Cox analysis. We identified 1429 early repolarization pattern cases (779 incident cases) during follow-up, yielding a positive rate of 23.9% and an incidence rate of 715 per 100 000 person-years. Early repolarization pattern had an elevated risk of unexpected death (hazard ratio, 1.83; 95% confidence interval, 1.12 to 2.97; P=0.02) and a decreased risk of cardiac (hazard ratio, 0.75; 95% confidence interval, 0.60 to 0.93; P<0.01) and all-cause (hazard ratio, 0.85; 95% confidence interval, 0.78 to 0.93; P<0.01) death. In addition, both slurring and notching were related to higher risk of unexpected death (hazard ratio, 2.09; 95% confidence interval, 1.06 to 4.12; P=0.03), as was early repolarization pattern manifestation in both inferior and lateral leads (hazard ratio, 2.50; 95% confidence interval, 1.29 to 4.83; P<0.01).
Early repolarization pattern is associated with an elevated risk of unexpected death and a decreased risk of cardiac and all-cause death. Specific early repolarization pattern morphologies and location are associated with an adverse prognosis.
► Caspase-1 deficiency reduced the atherosclerosis in Apoe−/− mice fed the Western diet. ► Caspase-1 deficiency reduced vascular inflammation in Apoe−/− mice fed the Western diet. ► Calcium crystals ...activate caspase-1 and release IL-1β and IL-1α in macrophages. ► IL-1β release by calcium crystals was caspase-1-dependent. ► IL-1 α release by calcium crystals was caspase-1-independent.
Recent investigations have suggested that the inflammasome plays a role in the development of vascular inflammation and atherosclerosis; however, its precise role remains controversial. We produced double-deficient mice for apolipoprotien E (Apoe) and caspase-1 (Casp1), a key component molecule of the inflammasome, and investigated the effect of caspase-1 deficiency on vascular inflammation and atherosclerosis.
Atherosclerotic plaque areas in whole aortas and aortic root of Western diet (WD)-fed Apoe−/−Casp1−/− mice were significantly reduced compared to those in Apoe−/− mice. The amount of macrophages and vascular smooth muscle cells in the plaques was also reduced in Apoe−/−Casp1−/− mice. No significant differences in plasma lipid profiles and body weight change were observed between these mice. Expression of interleukin (IL)-1β in the plaques as well as plasma levels of IL-1β, IL-1α, IL-6, CCL2, and TNF-α, in Apoe−/−Casp1−/− mice were lower than those in Apoe−/− mice. In vitro experiments showed that calcium phosphate crystals induced caspase-1 activation and secretion of IL-1β and IL-1α in macrophages.
Our findings suggest that caspase-1 plays a critical role in vascular inflammation and atherosclerosis, and that modulation of caspase-1 could be a potential target for prevention and treatment of atherosclerosis.
Thrombosis is a well‐known cardiovascular disease (CVD) complication that has caused death in many patients with cancer. Oral bacteria have been reported to contribute to systemic diseases, including ...CVDs, and tumor metastasis. However, whether oral bacteria‐induced thrombosis induces tumor metastasis remains poorly understood. In this study, the cariogenic oral bacterium Streptococcus mutans was used to examine thrombosis in vitro and in vivo. Investigation of tumor metastasis to the lungs was undertaken by intravenous S. mutans implantation using a murine breast cancer metastasis model. The results indicated that platelet activation, aggregation, and coagulation were significantly altered in S. mutans‐stimulated endothelial cells (ECs), with elevated neutrophil migration, thereby inducing thrombosis formation. Streptococcus mutans stimulation significantly enhances platelet and tumor cell adhesion to the inflamed ECs. Furthermore, S. mutans‐induced pulmonary thrombosis promotes breast cancer cell metastasis to the lungs in vivo, which can be reduced by using aspirin, an antiplatelet drug. Our findings indicate that oral bacteria promote tumor metastasis through thrombosis formation. Oral health management is important to prevent CVDs, tumor metastasis, and their associated death.
The cariogenic oral bacterium Streptococcus mutans promotes platelet and coagulation pathway activation in endothelial cells to induces thrombosis. Streptococcus mutans‐induced pulmonary thrombosis promotes breast cancer cell metastasis to the lungs. Thrombosis is a well‐known cardiovascular disease complication that has caused death in many patients with cancer. Our findings indicate that oral health management is important to prevent cardiovascular disease, tumor metastasis, and their associated death.
Purpose Alectinib is an anaplastic lymphoma kinase (ALK) -specific kinase inhibitor that seems to be effective against non-small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary ...analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor-naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment.
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