Alveolar adenoma and coexisting atypical adenomatous hyperplasia: a case report and literature review.

Alveolar adenoma is a rare tumour of the lung. It is typically found in asymptomatic adults as a peripheral or subplerual nodule on imaging examination. Microscopically, the tumour is composed of admixture of epithelial and mesenchymal component in variable sized cystic or alveolar structures. The tumour shows a benign nature. There have been no reported recurrences or metastases. Malignant transformation of alveolar adenoma and coexisting with lung carcinoma have been rarely described. In this article, we report a case of an alveolar adenoma and coexisting atypical adenomatous hyperplasia. This case, contributing to the limited numbers of cases described to date, illustrates the importance of awareness on the possibility of alveolar adenoma being associated with lung carcinoma and its precursor lesions especially when diagnosed by small biopsy specimens.

Novel light delivery method for performing transbronchial photodynamic therapy ablation to treat peripheral lung cancer: A pilot study.

BACKGROUND: Photodynamic therapy involves using a photosensitizer with l illumination and is recommended for treating early, centrally located lung cancers, but it is not a standard treatment for peripheral lung tumor.. We previously proposed a novel light delivery method, in which lipiodol is perfused into the bronchial tree to increase the scope of illumination via the fiber effect. Herein, we attempted this novel technique under electromagnetic bronchoscope guidance in a hybrid operation room where lipiodol facilitated light diffusion, and evaluated the effectiveness and feasibility of this technique for peripheral lung cancers. METHODS: This phase 0 pilot study included three patients with peripheral lung cancers (primary tumors ≤20-mm diameter). The photodynamic therapy was administered using Porfimer sodium as the photosensitizer, and an electromagnetic navigation bronchoscope in a hybrid operating room to guide the catheter to the tumor. This facilitated lipiodol infusion to encase the tumor and permit the transbronchial photodynamic therapy ablation. RESULTS: Administering 630 nm 200 J/cm (400mW/500sec) energy through a 3-cm cylindrical diffusing laser fiber was safe; no significant acute complications were observed. Although the treatment outcome was unsatisfactory due to the low light dose, tumor pathology in one case revealed tumor necrosis, with no significant damage to the surrounding lung tissue. CONCLUSIONS: Novel light delivery transbronchial photodynamic therapy ablation for peripheral lung tumors is feasible and safe. Additional clinical trials may help determine the best illumination plan and light dose through multiple deliveries from multiple angles.

Bronchoscopic light delivery method for peripheral lung cancer photodynamic therapy.

BACKGROUND: Trans-bronchoscope treatment for early stage small peripheral lung cancer, such as photodynamic therapy (PDT), has been investigated. However, despite the efficacy of PDT, light delivery issues limit its application. A method of administering mineral oil with a high refractive index (RI) was previously proposed to enhance light delivery in branched or bent anatomic structures. Lipiodol has a high RI and an exhaustive history of use as a contrast medium for bronchography. We aimed to determine whether the use of lipiodol, like mineral oil, could enhance the illumination effect and therapeutic range of PDT for peripheral lung tumors. METHODS: We injected lipiodol into a pig lung model, guided by a bronchoscope under fluorescent surveillance, to simulate future treatment in humans, and then illuminated with PDT laser fiber to the lipiodol-infused lung to test the technique feasibility in a pig orally administered 20 mg/kg of 5-aminolevulinicc acid (5-ALA) 2 hours before treatment. We also attempted to determine the maximal tolerable light dose in this pilot study for the future studies in human. RESULTS: We successfully injected lipiodol into peripheral lungs by this technique. The pig could tolerate up to a total of 40 mL of lipiodol and 800 J of red light, without severe acute fetal injury in a non-cancerous lung. CONCLUSIONS: The technique of injecting lipiodol using bronchoscopy under fluorescent guidance was feasible in a pig model. We can apply the guide sheath through bronchoscopy under fluoroscope inspection. Lipiodol can be used as a light diffuser for the peripheral lung tumor PDT model. No severe lethal acute lung injury was caused by this PDT model under careful manipulation. Additional studies evaluating the dose correlation of the photosensitizer and light are needed.

Suppressing migration and invasion of H1299 lung cancer cells by honokiol through disrupting expression of an HDAC6-mediated matrix metalloproteinase 9.

Metastasis is the crucial mechanism to cause high mortality in lung cancer. Degradation of extracellular matrix (ECM) by proteolytic enzymes, especially matrix metalloproteinases (MMPs), is a key process for promoting cancer cell migration and invasion. Therefore, targeting MMPs might be a strategy for lung cancer metastasis suppression. Honokiol, a biological active component of Magnolia officinalis, has been indicated to suppress lung cancer tumorigenesis through epigenetic regulation. However, the regulation of MMPs-mediated migration and invasion by honokiol through epigenetic regulation in lung cancer is still a mystery. In the present study, the migration and invasion ability of H1299 lung cancer was suppressed by noncytotoxic concentrations of honokiol treatment. The proteolytic activity of MMP-9, rather than MMP-2, was inhibited in honokiol-treated H1299 cells. Honokiol-inhibited MMP-9 expression was through promoting MMP-9 protein degradation rather than suppressing transcription mechanism. Furthermore, the expression of specific histone deacetylases 6 (HDAC6) substrate, acetyl-α-tubulin, was accumulated after honokiol incubation. The disassociation of MMP-9 with hyper-acetylated heat shock protein 90 (Hsp90) was observed resulting in MMP-9 degradation after honokiol treatment. Meanwhile, honokiol-suppressed MMP-9 expression and invasion ability of H1299 lung cancer cells was rescued by HDAC6 overexpression. Accordingly, the results suggested that the suppression of migration and invasion activities by honokiol was through inhibiting HDAC6-mediated Hsp90/MMP-9 interaction and followed by MMP-9 degradation in lung cancer.

Shikonin Inhibited Migration and Invasion of Human Lung Cancer Cells via Suppression of c-Met-Mediated Epithelial-to-Mesenchymal Transition.

Epithelial-to-mesenchymal transition (EMT) is a major process to regulate cell migration and invasion. Inhibition of epidermal growth factor receptor (EGFR)-mediated EMT by tyrosine kinase inhibitors (TKIs) is a strategy to prevent lung cancer invasion. However, drug resistance is emerged and accelerated invasion through other signaling bypassing EGFR after TKIs therapy. c-Met signaling pathway is highly activated in EGFR-mutated lung cancer cells. Targeting c-Met signaling pathway may be a strategy to suppress EGFR-independent migration and invasion for lung cancer therapy. Therefore, we examined the anti-migration and anti-invasion abilities of shikonin, an active compound from Lithospermum erythrorhizon, in highly and ligand-induced c-Met activation lung cancer cells. Our results revealed that cell viability and cell cycle progression did not change under 1 µM of shikoinin treatment in highly c-Met expressive HCC827 lung cancer cells. Endogenous c-Met activation was dose-dependently inhibited and the migration and invasion activity of HCC827 cells were suppressed by shikonin treatment. Induction of E-cadherin expression and inhibition of vimentin, slug, and snail expression by shikonin was through c-Met-mediated PI3K/Akt and ERK signaling suppression. Furthermore, hepatocyte growth factor (HGF)-induced migration, invasion and EMT marker change were reversed by shikonin in low c-Met expressive A549 lung cancer cells. Inhibition of HGF-induced c-Met, PI3K/Akt and MEK/ERK activation were observed in shikonin-treated cells. Co-treatment of PI3K/Akt inhibitor or ERK inhibitor with shikonin enhanced shikonin-reversed HGF-regulated EMT marker expression. Taken together, the results suggested that the anti-migration and anti-invasion activities of shikonin was through c-Met inhibition and following by EMT suppression in lung cancer. J. Cell. Biochem. 118: 4639-4651, 2017. © 2017 Wiley Periodicals, Inc.

Low-fluence rate, long duration photodynamic therapy in glioma mouse model using organic light emitting diode (OLED).

BACKGROUND: The treatment of gliomas poses significant clinical challenges due to resistance to chemo and radiation therapy, and treatment side effects. Metronomic photodynamic therapy (mPDT), which involves long treatment time with low fluence rate and multiple or continuous photosensitizer administrations, has potential in treating gliomas without threatening the quality of life and has been demonstrated in rats and rabbits. mPDT in small animals such as mouse is not yet shown due to lack of lightweight illumination device for long periods of time. METHODS: We presented low fluence rate (3mW/cm(2)) and long duration (3.7h) PDT treatment in a nude mouse model of human glioblastoma by using organic light emitting diode (OLED) with single dose of 5-aminolevulinic acid (ALA) administration as photosensitizer. Tumor volume was measured using bioluminescent imaging and the animal survival time was recorded. Additionally, we have performed limited PDT dosimetric measurements of PpIX fluorescence, tumor oxygenation and hemoglobin concentration in 3 PDT mice. RESULTS: For animals with similar pre- and immediate post-light tumor volume, the averaged total survival time of PDT mice is 40.5±9.2 days that are significantly longer than the control mice (26.0±2.0 days). The post-light survival time of PDT mice is 14.3±5.9 days that are marginally longer than the control group (8.0±0.0 days). In the dosimetric measurement, good maintenance of PpIX fluorescence in one PDT mouse has relatively improved survival time, compared with the other two PDT mice (i.e., 24 days versus 16 and 17 days). CONCLUSIONS: This pilot study demonstrated the feasibility of low-fluence rate and long treatment time of ALA-PDT using OLED without anesthetization of animals. The response of PDT treated animals with similar pre- and post-light tumor volume is encouraging to show a longer survival time than the controls. The dosimetric indices such as photosensitizer fluorescence and tissue oxygenation would help understand the possible treatment barriers for further improvement of treatment plans.

Upfront gefitinib/erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer: a mono-institutional experience.

BACKGROUND: Upfront tyrosine kinase inhibitor (TKI) has proved effective for selective advanced lung cancer patients in Taiwan. We hypothesized that early integration of radiotherapy during TKI treatment would decrease the chance of drug resistance and prolong progression-free survival (PFS). METHODS: This study included 25 patients with stage IIIb or IV non-squamous cell, non-small cell lung cancer (NSqCLC) who responded to upfront TKI treatment. Multi-target radiotherapy was administered during the TKI treatment course. Tomotherapy comprising a hypofractionated schedule with a dose of 40-50 Gy in 16-20 fractions was used for individual metastatic lesions. RESULTS: The patients' median follow-up duration was 30 months (range, 9-62 months). Of the 23 patients who had stage IV disease, 9 had oligometastases (≤5 gross target volumes) and 14 were in the more advanced stages of the disease. Twelve patients received more than 1 cycle of radiotherapy (median, 3; range, 2-6) with TKI being the only systemic treatment before they were salvaged with chemotherapy. The overall response rate after radiotherapy was 84.0%, and the median PFS was 16 months. The 3-year overall survival rate was 62.5% (95% confidence interval [CI], 39.1-85.8%). Toxicities were generally tolerated but it is necessary to prevent radiation-induced pneumonitis. CONCLUSION: We showed that combined first-line TKI therapy and early multi-target radiotherapy are very effective in selected patients that respond to TKI, when the status of mutations in the epidermal growth factor receptor (EGFR) are not known before the treatment. Our data may aid expansion of the effectiveness of TKI treatment through radiotherapy in Asian patients with stage IV NSqCLC.

Metachronous adenocarcinoma occurring at an esophageal colon graft.

Subtotal esophagectomy and reconstruction with colonic interposition grafting is the usual surgical treatment for benign esophageal stricture and malignant esophageal cancer. While short-term complications are frequently reported, long-term complications are rare. Herein, we report a 57-year-old male, with a previous caustic injury to the esophagus who underwent subtotal esophagectomy and right colon grafting at age 18. He underwent left hemicolectomy for obstructive colon cancer at the splenic flexure at age 55, followed by resection of the interposed colon graft due to adenocarcinoma at age 57.