Clinicopathological differences between EGFR mutated and EGFR wild-type lung adenocarcinoma with papillary predominant pattern.

OBJECTIVES: We aimed to reveal the clinicopathological differences between epidermal growth factor receptor (EGFR)-mutated and wild-type (WT) lung adenocarcinoma (LUAD) focusing on the predominant subtype. METHODS: This study included 352 with EGFR mutation and 370 with WT patients in consecutive stage I LUAD classified by the predominant subtype, and their clinicopathological characteristics and prognosis were analyzed. Using the Cancer Genome Atlas Program (TCGA) cohort, we analyzed differences in gene expression between EGFR mutation and WT groups. Furthermore, we performed immunohistochemical evaluations for 46 with EGFR mutation and 47 with WT patients in consecutive stage I papillary predominant adenocarcinoma (PPA). RESULTS: Compared to the PPA with WT [n = 115], those with EGFR mutation [n = 99] exhibited smaller invasive size (p = 0.03) and less frequent vessel invasion (p < 0.01). However, PPA with EGFR mutation showed significantly worse 5-ys recurrence-free survival (RFS) rates compared to those with WT (70.6 % versus 83.3 %, p = 0.03). Contrarily, no significant differences were observed in other predominant subtypes. In the TCGA cohort, PPA with EGFR mutation tended to show higher expression of galectin-3, which is associated with tumor metastasis and resistance to anoikis, compared to those with WT (p = 0.06). Immunohistochemical evaluation revealed that galectin-3 expression was significantly higher in PPA with EGFR mutation than in those with WT (p < 0.01). CONCLUSIONS: The prognosis of PPA with EGFR mutation proved to be less favorable compared to that with WT, and galectin-3 is highly expressed in EGFR-mutated PPA.

Salvage extended surgery after immune-checkpoint inhibitor treatment for advanced non-small cell lung cancer.

PURPOSE: We evaluated the surgical outcomes of salvage extended surgery after definitive medical treatment with an immune-checkpoint inhibitor (ICI) for locally advanced or unresectable non-small-cell lung cancer (NSCLC). METHODS: The subjects of this single-center retrospective analysis were 14 patients who underwent salvage surgery after ICI treatment between May, 2017 and April, 2023 at our institute. We reviewed the comprehensive surgical outcomes, including operative procedures, intraoperative findings, and postoperative morbidities. Overall survival (OS) was calculated using a Kaplan-Meier estimation. RESULTS: The initial clinical stage before medical treatment (c-stage) was stage III in eight patients, stage IV in five patients, and one patient had postoperative lung cancer recurrence. The indications for surgery were as follows: local control for relapse or residual tumor in ten patients and discontinuation of systemic therapy because of treatment-related complications in four patients. The surgical modes were segmentectomy (n = 1), lobectomy (n = 4), bilobectomy (n = 3), pneumonectomy (n = 6), and bronchoplasty (n = 7). Grade 3 or higher postoperative morbidities were observed in six patients, including only one case of 90-day mortality. CONCLUSIONS: Our series demonstrated that the surgical outcome of salvage extended surgery after ICI therapy may be positive with careful selection of the procedure and indication.

Stepwise progression of invasive mucinous adenocarcinoma based on radiological and biological characteristics.

INTRODUCTION: Invasive mucinous lung adenocarcinoma (IMA) has unique radiological findings and pathological characteristics. IMA is classified into solitary and pneumonic types; however, it is unclear whether these are biologically identical. METHODS: A single-center retrospective analysis was performed for 70 IMA patients (solitary type [n = 38] and pneumonic type [n = 32]) who underwent pulmonary resection between January 2010 and December 2018. We compared clinical and biological characteristics between the two types. RESULTS: The frequencies of genetic alternations such as EGFR, KRAS, BRAF, GNAS, ERBB2, TP53, NRG1, and MET were not different. Immunohistochemically, expression of MUC1 was significantly more common in the pneumonic type (5.0% versus 20.0%, p = 0.01) and diffuse MUC6 positive in the solitary type (39.0% versus 13.0%, p = 0.02). We further classified solitary types into those with or without ground-glass opacity (GGO) and pneumonic types into those with or without crazy-paving appearance (CPA), and evaluated their surgical outcomes. Five-year overall survival and relapse free survival rates were 95.8%/86.6%, 64.3%/70.7%, 74.6%/68.9%, and 50.0%/28.6% in patients with solitary type with GGO, solitary type without GGO, pneumonic type without CPA, and pneumonic type with CPA, respectively. CONCLUSIONS: There were no differences in genetic alternations; however, mucin expression pattern was different. Surgical outcomes were different according to the presence of GGO in the solitary type and the presence of CPA in the pneumonic type. These findings suggested a stepwise progression from solitary to pneumonic IMA.

A Versatile and Efficient Strategy to Discrete Conjugated Oligomers.

An efficient and scalable strategy to prepare libraries of discrete conjugated oligomers (D = 1.0) using the combination of controlled polymerization and automated flash chromatography is reported. From this two-step process, a series of discrete conjugated materials from dimers to tetradecamers could be isolated in high yield with excellent structural control. Facile and scalable access to monodisperse libraries of different conjugated oligomers opens pathways to designer mixtures with precise composition and monomer sequence, allowing exquisite control over their physical, optical, and electronic properties.

Controlled Synthesis of Poly(p-phenylene) Using a Zincate Complex, t Bu4 ZnLi2.

Well-defined poly(2,5-dihexyloxyphenylene-1,4-diyl) (PPP) is successfully synthesized by the Negishi catalyst-transfer polycondensation (NCTP) using dilithium tetra(tert-butyl)zincate (t Bu4 ZnLi2 ). The obtained PPP possesses the number-averaged molecular weight (Mn ) values in the range of 2100-22 000 and the molar-mass dispersity (ÐM ) values in the range of 1.09-1.23. In addition, block copolymers containing PPP and poly(3-hexylthiophene) (P3HT) segments (PPP-b-P3HT) are synthesized to confirm the feasibility of chain extension between the different monomers based on NCTP.

Nonstoichiometric Stille Coupling Polycondensation for Synthesizing Naphthalene-Diimide-Based π-Conjugated Polymers.

A nonstoichiometric Stille coupling polycondensation was first succeeded between 2,5-bis(trimethylstannyl)thiophene (1) and 4,9-dibromo-2,7-bis(2-decyltetradecyl)benzo[lmn][3,8]-phenanthroline-1,3,6,8-tetraone (2) with ratios ranging from 1:1 to 1:10. The model reaction using 2-(tributylstannyl)thiophene (3) and 4,9-dibromo-2,7-bis(2-hexyl)benzo[lmn][3,8]-phenanthroline-1,3,6,8-tetraone (4) at a 1:1 molar ratio in the presence of catalytic Pd2(dba)3/P(o-tolyl)3 indicated that the rate constant of the second substitution reaction (k2) is 15 times higher than that of the first one (k1). It was found that the selective intramolecular catalyst transfer was promoted by the naphthalene-diimide (NDI) skeleton. The results also provided a new one-pot symmetrical end-functionalization method to synthesize an NDI-based n-type polymer with NDI groups at both α,ω-chain ends.

Successful treatment of severe amiodarone pulmonary toxicity with polymyxin B-immobilized fiber column direct hemoperfusion.

Amiodarone pulmonary toxicity (APT) is the most serious side effect of amiodarone. Although severe APT, such as ARDS, is rare, mortality of severe APT is high. Polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) is a medical device that reduces blood endotoxin levels in sepsis. Recent reports have shown that PMX-DHP improves oxygenation in patients with acute exacerbation of idiopathic pulmonary fibrosis and drug-induced severe interstitial pneumonia. Here, we present a case study of a patient with severe APT treated with PMX-DHP with complete recovery. The patient rapidly developed respiratory failure and required mechanical ventilation. Despite corticosteroid pulse therapy, no clinical improvement was noted. PMX-DHP was then started, and severe respiratory failure improved with reduction of serum levels of amiodarone and its metabolite monodesethylamiodarone. The patient was weaned from mechanical ventilation and has done well without recurrence. To our knowledge, this is the first reported case of PMX-DHP therapy for severe APT. We speculate that PMX-DHP could be a new treatment strategy for severe APT.

Purification-Free and Protection-Free Synthesis of Regioregular Poly(3-hexylthiophene) and Poly(3-(6-hydroxyhexyl)thiophene) Using a Zincate Complex of tBu4ZnLi2.

The controlled synthesis of head-to-tail regioregular poly(3-hexylthiophene) (P3HT) using a dianion-type zincate complex, tBu4ZnLi2, is described. The molecular weights of P3HTs could be increased up to 30 kDa by increasing the feed ratio of the monomer to Ni catalyst while maintaining a low polydispersity (PDI < 1.2) and a high regioregularity (>97%, when Mn > 10 kDa). Surprisingly, this new system can be used in as-received THF as well as in THF containing protic impurities, such as isopropanol, methanol, and even 1000 ppm water. In addition, the direct synthesis of poly[3-(6-hydroxyhexyl)thiophene] (P3HHT) could be performed without protection based on the developed system.

Galectin-9 attenuates acute lung injury by expanding CD14- plasmacytoid dendritic cell-like macrophages.

RATIONALE: Galectin (Gal)-9 plays a crucial role in the modulation of innate and adaptive immunity. OBJECTIVES: To investigate whether Gal-9 plays a role in a murine acute lung injury (ALI) model. METHODS: C57BL/6 mice were pretreated with Gal-9 by subcutaneous injection 24 and 48 hours before intranasal LPS inoculation. MEASUREMENTS AND MAIN RESULTS: Gal-9 suppressed pathological changes of ALI induced by LPS. Gal-9 reduced levels of proinflammatory cytokines and chemokines, such as tumor necrosis factor (TNF)-α, IL-1ß, IL-6, and keratinocyte-derived cytokine; decreased neutrophils; and increased IL-10 and CD11b(+)Gr-1(+) macrophages in the bronchoalveolar lavage fluid of ALI mice. In Gal-9-deficient mice, pathological changes of ALI were exaggerated, and the number of neutrophils and the TNF-α level were increased. CD11b(+)Gr-1(+) cells were increased in the spleen of both Gal-9-treated and phosphate-buffered saline (PBS)-treated ALI mice, but only Gal-9 increased the ability of CCR2-expressing macrophages to migrate toward monocyte chemoattractant protein-1. Transfer of CD11b(+)Gr-1(+) macrophages obtained from Gal-9-treated mice ameliorated ALI. CD11b(+)Gr-1(+) macrophages obtained from Gal-9-treated but not PBS-treated mice suppressed TNF-α and keratinocyte-derived cytokine production from LPS-stimulated macrophages, and down-regulated Toll-like receptor-4 (TLR4) and TLR2 expression on thioglycollate-elicited macrophages. Fluorescence-activated cell-sorting analysis revealed that CD14 is negligible on CD11b(+)Gr-1(+) macrophages obtained from Gal-9-treated mice, although those from both groups resembled plasmacytoid dendritic cells (pDCs). Gal-9 down-regulated CD14 on pDC-like macrophages from PBS-treated mice independently of Gal-9/Tim-3 (T-cell immunoglobulin- and mucin domain-containing molecule-3) interaction, resulting in the acquisition of suppressive function, suggesting that the loss of CD14 by Gal-9 is critical for the suppression of pDC-like macrophages. CONCLUSIONS: Gal-9 attenuates ALI by expanding CD14(-)CD11b(+)Gr-1(+) pDC-like macrophages by preferentially suppressing macrophage functions to release proinflammatory cytokines through TLR4 and TLR2 down-regulation.

[A case of stage IIIB pulmonary pleomorphic carcinoma that responded well to chemoradiotherapy and surgery].

A 44-year-old man was admitted because he had a mass in the right upper lung field showing high uptake of FDG-PET. Although he had already received video-assisted thoracic surgery to remove the mass in another hospital, the procedure had been unsuccessful because of severe adhesion to the superior vena cava. The pathological diagnosis of a specimen obtained in surgery was pleomorphic carcinoma, clinical stage IIIb (c-T4N2M0). We performed concurrent chemoradiotherapy consisting of systemic chemotherapy twice with both cisplatin and vinorelbine, and radiation therapy (60Gy). The tumor size reduced by 46% immediately after chemoradiotherapy. Because there was still no evidence of distant metastasis, we performed a right upper lobectomy and resection of the superior vena cava to remove the tumor completely. We did not detect any microscopic cancer cells in the surgical specimens and the pathological diagnosis was complete response (CR). It is thought that chemotherapy and radiotherapy are ineffective for pulmonary pleomorphic carcinoma. However, in this case, concurrent chemoradiotherapy with surgical therapy was highly effective and no recurrence has been observed 13 months after surgery.

[Successful treatment of pleurodesis for seemingly intractable pleural effusion in pleural amyloidosis with rheumatoid arthritis].

We report a case of secondary amyloidosis with pleural involvement in a patient with rheumatoid arthritis. A 77-year-old man had received a diagnosis of rheumatoid arthritis 10 years previously. Bilateral pleural effusion of unknown etiology was noted 2 years prior to admission. A biopsy of the left pleura by video-assisted thoracic surgery did not reveal any evidence of the cause of his pleural effusion. The histological findings revealed chronic inflammation of the pleura on a hematoxylin-eosin (HE) stain, but treatment with an increased dose of corticosteroid did not improve his effusion. Right pneumothorax then developed. Based on the histological findings of a Congo red stain, the diagnosis was changed to pleural amyloidosis. An initial attempt at pleurodesis with OK-432 and a pleural patch with the patient's own blood was attempted but was not successful. Subsequently, pleurodesis with OK-432 and the patient's own blood improved his pleural effusion and pneumothorax. Pleural involvement in amyloidosis is extremely rare and is difficult to treat.

CD8 and CD103 are highly expressed in asthmatic bronchial intraepithelial lymphocytes.

BACKGROUND: Although characteristics of intraepithelial lymphocytes (IELs) in mucosal immunity have been well defined in the intestine, bronchial IELs have been little investigated. Recently, we showed that bronchial IELs have a distinct function that partly resembles that of intestinal IELs; however, surface antigen expression of bronchial IELs and the relationship of that expression to airway disease have not been studied. METHODS: We analyzed phenotypic profiles of human bronchial IELs and lamina propria lymphocytes (LPLs) by double-staining immunohistochemistry using full-thickness bronchial specimens (10 nonasthmatic controls and 7 asthmatics) from lung resections. RESULTS: In controls, the percentage of CD4+ cells was lower, and the percentage of CD8+ cells was higher in IELs compared to LPLs (CD4: median 50.0% in IELs vs. 65.9% in LPLs, p = 0.01; CD8: 50.9% in IELs vs. 34.4% in LPLs, p = 0.007). The percentage of cells positive for CD103 (αE-integrin) was higher in IELs than that in LPLs (median 60.1% in IELs vs. 16.9% in LPLs; p < 0.001). In IELs from asthmatics, these characteristics were particularly significant (CD4: median 26.2%, p = 0.008; CD8: 79.8%, p = 0.007; CD103: 76.2%, p = 0.019; all compared with IELs from nonasthmatics). CONCLUSIONS: These results suggest that human bronchial IELs have roles distinct from subsets of other lymphocytes, and that CD8+ cells and CD103+ cells have potentially important functions in the bronchial epithelium.

[Case of osteosarcoma of the pulmonary artery].

A 49-year-old man was admitted to our hospital for an expanding tumor in the pulmonary artery. He had visited a previous hospital complaining of dyspnea on effort and had syncope 4 months before admission, and pulmonary embolism was diagnosed because enhanced chest CT showed filling defects, with calcification in the pulmonary trunk and left pulmonary artery. Despite thrombolytic and anticoagulant therapy, the filling defects grew and expanded into the extravascular portion. Additionally, CT showed multiple pulmonary nodules and a small calcified nodule in a right-sided back muscle also appeared. At our hospital, FDG-PET showed abnormal uptake in each lesion shown on CT. We then performed a CT-guided needle biopsy of the nodule of the back muscle, which was pathologically diagnosed as osteosarcoma. He was finally given a diagnosis of osteosarcoma of the pulmonary artery. We administered cisplatin and doxorubicin with partial inhibitory effect on tumor growth. Osteosarcoma of the pulmonary artery is extremely rare, and its diagnosis is difficult before surgery or autopsy. To the best of our knowledge there have been no reports of chemotherapy for osteosarcoma of the pulmonary artery.

Phase II study of carboplatin-paclitaxel combination chemotherapy in elderly patients with advanced non-small cell lung cancer.

BACKGROUND: More than 30% of cases of non-small cell lung cancer (NSCLC) arise in patients aged > or =70 years. The efficacy and safety of carboplatin-paclitaxel combination chemotherapy in elderly patients with advanced NSCLC were evaluated in a phase II trial. METHODS: Twenty-five patients aged > or =70 years (median, 76; range, 70-83) with chemotherapy-naive advanced NSCLC were enrolled between January 2001 and July 2003. Additional criteria included the presence of measurable lesions, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients received carboplatin at an area under the curve of 5 mg/ml/min and paclitaxel at 180 mg/m(2) on the first day of consecutive 3 week periods. RESULTS: The patients included four with stage IIIB, 19 with stage IV and two with recurrent disease. The median number of treatment cycles was three (range, 1-4). One complete response and six partial responses, yielding an objective response rate of 28%, were obtained. The median survival time was 12.3 months and the 1-year survival rate was 52%. Hematological toxicities of grade 3 or 4 included leukopenia (40%), neutropenia (68%) and anemia (4%). Non-hematological toxicities of grade 3 included arthralgia-myalgia (16%) and neuropathy (12%). The objective response rate for patients aged > or =75 years (n = 15) was 26%, and no evidence of excessive toxicity in these patients was apparent compared with those aged <75 years. CONCLUSION: The combination carboplatin-paclitaxel at these doses is a feasible treatment option with a favorable toxicity profile for fit elderly patients with advanced NSCLC.

T cells of atopic asthmatics preferentially infiltrate into human bronchial xenografts in SCID mice.

T cells play an important role in the pathogenesis of bronchial asthma. However, it is not completely known how circulating lymphocytes infiltrate into the airways of asthmatic patients. Because SCID mice are unable to reject xenogenic transplants, many xenotransplant models using various human tissues have been developed. Therefore, to examine the interaction between bronchi and T lymphocytes of asthma, it may be possible to use the human bronchial xenograft and PBMC xenograft in SCID mice. We transplanted human bronchi into the subcutaneum of SCID mice and i.p. injected PBMCs that were obtained from patients with atopic asthma, atopic dermatitis and rheumatoid arthritis, and normal subjects (asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice). There was no difference in the percentage of CD3-, CD4-, CD8-, CD25-, CD45RO-, CD103-, and cutaneous lymphocyte Ag-positive cells in PBMCs among the patients with asthma, dermatitis, rheumatoid arthritis, and normal subjects, and CD3-positive cells in peripheral blood of asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice. The number of CD3-, CD4-, and CD8-positive cells in the xenografts of asthmatic huPBMC-SCID mice was higher than those of dermatitis, rheumatic, and normal huPBMC-SCID mice. IL-4 mRNA and IL-5 mRNA were significantly higher in the xenografts of asthmatic huPBMC-SCID mice than those in the xenografts of normal huPBMC-SCID mice, but there were no significant differences in the expressions of IL-2 mRNA or IFN-gamma mRNA between them. These findings suggest that T cells, especially Th2-type T cells, of asthmatics preferentially infiltrate into the human bronchi.

Association of galectin-9 with eosinophil apoptosis.

BACKGROUND: There is no information whether galectin-9 (a novel eosinophil chemoattractant) was associated with pathogenesis of eosinophilic disorders. METHODS: We assessed the expression of galectin-9 with imunostaining and in situ hybridization both in the lesion of angiolymphoid hyperplasia with eosinophilia, and peripheral blood eosinophils of eosinophilic patients (E-Eos) in comparison with those of normal volunteers (N-Eos). Regulation of expression of galectin-9 on eosinophils and the effect of galectin-9 on apoptosis of eosinophil were also evaluated. RESULTS: Many eosinophils infiltrating the site were positive for galectin-9. Surface and intracellular immunoreactive galectin-9 was more evident in E-Eos than N-Eos. When eosinophils were cultured with IL-5 in vitro, the surface galectin-9 expression of E-Eos was significantly downregulated, although that of N-Eos was not affected. Treatment of eosinophils with dexamethasone or anti-Fas antibody significantly upregulated the surface galectin-9 expression of E-Eos. In contrast, dexamethasone partially downregulated the surface galectin-9 of N-Eos, although anti-Fas antibody failed to affect on the surface galectin-9 expression. We also found that recombinant galectin-9 significantly suppressed apoptosis of E-Eos (p = 0.0431), whereas it apparently enhanced apoptosis of N-Eos (p = 0.0173). Furthermore, dexamethasone-induced apoptosis of N-Eos was significantly suppressed by galectin-9 (p = 0.0431), whereas galectin-9 failed to induce significant change in dexamethasone-induced apoptosis of E-Eos. In contrast, apoptosis induced by anti-Fas antibody in both N-Eos (p = 0.0431) and E-Eos (p = 0.0431) was enhanced by galectin-9. CONCLUSIONS: These findings suggested that galectin-9 was produced by eosinophils, and galectin-9 showed heterogeneous effects and kinetics to eosinophils, and this factor might be one of crucial factors in eosinophilic inflammation.