Pneumothorax as a rare presentation of bronchial schwannoma.

Tracheobronchial schwannomas are rare diseases. Common signs and symptoms of this tumor include cough, wheezing, and dyspnea. In contrast, pneumothorax is an exceptional presentation. This study reports the first case of bronchial schwannoma presenting with pneumothorax. A 79-year-old woman was diagnosed with pneumothorax by chest radiography. Chest computed tomography unexpectedly revealed a tumor occluding the right main bronchus. Following the pathological diagnosis of bronchial schwannoma, the patient underwent thoracoscopic tumor enucleation. The airway lumens are consequently secured postoperatively. We reviewed the literature and discussed the mechanisms and treatment options for bronchial benign tumor-associated pneumothorax. Pneumothorax should be aware of a rare presentation of non-malignant tracheobronchial tumors.

Outcome of patients with lung cancer and severe psychiatric disorder admitted to a medical psychiatric unit.

The purpose of the present study was to evaluate the clinical profiles and treatment outcomes of patients with lung cancer admitted to the Medical Psychiatric Unit (MPU), which is built for patients with physical and severe psychiatric disorders. All medical records of patients with lung cancer admitted to the MPU of Tachikawa hospital were reviewed. The clinical outcomes of these patients were retrospectively evaluated between January 2010 and December 2016. A total of 24 patients in the MPU were histologically or cytologically diagnosed with primary lung cancer. Of these, 20 patients had schizophrenia, and 4 patients had a mood disorder. There were 15 patients who were diagnosed using bronchoscopy. The histology indicated adenocarcinoma, squamous cell carcinoma and non-small-cell lung cancer-not otherwise specified were in 11, 8, and 1 patient, respectively, while small-cell lung cancer was indicated in 4 patients. Surgery, chemoradiotherapy, radiotherapy, chemotherapy was performed in 13, 4, 2, 1 and 4 patients, respectively. The median survival time was 76.7 months for patients who underwent surgery, while it was 14.4 months for those who underwent chemoradiotherapy. In the MPU, patients with lung cancer and severe psychiatric disorders could be safely diagnosed, and patients with early-stage lung cancer exhibited long-term survival.

A Histologically Complete Response to Immunotherapy Using Pembrolizumab in a Patient with Giant Cell Carcinoma of the Lung: An Additional Report and Literature Review.

We previously reported a case of giant cell carcinoma in the lung, in which the use of antiprogrammed death 1 (PD-1) immunotherapy resulted in substantial tumor reduction. In the present study, we describe an additional clinical course. A 69-year-old woman was diagnosed with giant cell carcinoma of the lung in clinical stage IVB (T2bN0M1c, BRA). The tumor expressed programmed death ligand 1 (PD-L1) in a high proportion. The patient received stereotactic radiotherapy for two sites of small brain metastases, followed by immunotherapy using anti-PD-1 antibodies (pembrolizumab). The treatment exerted a substantial tumor reduction through four cycles. However, treatment was withdrawn due to renal dysfunction. The primary lung tumor continued to regress for an additional four months without any further therapy, resulting in a clinical stage of T1aN0M0. Salvage thoracic surgery was then performed to remove the tumor residue in the lung. Microscopic examination of the sample revealed no residual cancer. The patient was free from recurrence at 16 months post surgery. We then comprehensively reviewed lung sarcomatoid carcinoma cases in the literature, in which anti-PD-1 antibodies were implemented. The current literature and our own findings suggest sarcomatoid carcinomas express high levels of tumoral PD-L1 and can be effectively treated with anti-PD-1 antibodies.

Pulmonary sclerosing pneumocytoma demonstrating intratumoral hematoma.

Pulmonary sclerosing pneumocytoma (PSP) is a rare benign neoplasm of the lung that shows a slow growing pattern. Corresponding contrast-enhancements on chest computed tomography (CT) vary widely in both patterns and degrees. However, gross intratumoral radiolucencies, attributable to cyst formation, necrosis, or intratumoral hematoma, were rarely reported in PSP cases. We herein report on a case involving a 61-year-old Japanese women with PSP demonstrating CT-defined intratumoral radiolucency. A chest CT scan revealed a solitary and well-circumscribed nodule that showed a substantial growth over a 7-year period. The tumor was composed of a solid portion visualized with contrast-enhancement and a central radiolucency on a chest CT scan. A positron emission tomography scan revealed high uptake of fluorodeoxyglucose on the solid portion of the tumor, but the radiolucent portion showed negative uptake. The examination of a tumor specimen obtained by a percutaneous core needle biopsy aided in determining a pathological diagnosis of PSP, and the patient subsequently received a right lower lobectomy of the lung. The portion of central radiolucency on the CT scan corresponding to the surgical specimen was pathologically proven to be gross hematoma.

Invasive mucinous adenocarcinoma of the lung presenting as a large, thin-walled cyst: A case report and literature review.

Invasive mucinous adenocarcinoma (IMA), formerly referred to as mucinous bronchioloalveolar carcinoma, is a rare variant form of invasive adenocarcinoma and is radiologically characterized by dense pneumonic consolidation, ground-glass opacity and nodules. By contrast, large, thin-walled cysts are rare. We herein report the case of a 75-year-old man with IMA presenting as a large, irregularly shaped cystic lesion. The histological diagnosis was based on specimens obtained during a bronchoscopy. The patient underwent lobectomy followed by anticancer chemotherapy for residual intrapulmonary metastases. Of note, the small metastatic nodules transformed into cystic lesions with thin walls and fused, forming a large, multiloculated cystic lesion. Typical pneumonic consolidation appeared in the pericystic parenchyma later during the clinical course. The available literature on this rare radiological manifestation was also reviewed and discussed. Clinicians should be aware of thin-walled cystic lesions as they may be an unusual radiological finding in IMA.

Usefulness of immunohistochemical studies in diagnosing metachronous gallbladder and small intestinal metastases from lung cancer with gastrointestinal hemorrhage: a case report.

Isolated metachronous gastrointestinal metastases from advanced-stage lung cancer are rarely diagnosed on the basis of symptoms and resected. In this report, we present a case of resectable metachronous gallbladder and small intestinal metastases of lung cancer. An 86-year-old woman was treated for lung cancer with resection of the right inferior lobe. Five months after the surgery, she was re-admitted because of melena and anemia. Ultrasonography showed a gallbladder tumor with gastrointestinal hemorrhage, and laparoscopic-assisted cholecystectomy was subsequently performed. However, 2 months after this event, the patient presented again with melena and anemia and was diagnosed with a small intestinal tumor. Therefore, laparoscopic-assisted partial resection of the small intestine was performed. Immunohistochemical staining for thyroid transcription factor-1 and cytokeratin 7 confirmed that the two resected tumors were metachronous metastases of the primary lung cancer. The patient died of liver metastases 5 months after the last surgery. Our experience with this case suggests that surgical resection might not be curative but palliative for patients with isolated gallbladder and small intestinal metastases diagnosed on the basis of melena that is resistant to conservative treatment.

MicroRNA-196a is a putative diagnostic biomarker and therapeutic target for laryngeal cancer.

BACKGROUND: MicroRNA (miRNA) is an emerging subclass of small non-coding RNAs that regulates gene expression and has a pivotal role for many physiological processes including cancer development. Recent reports revealed the role of miRNAs as ideal biomarkers and therapeutic targets due to their tissue- or disease-specific nature. Head and neck cancer (HNC) is a major cause of cancer-related mortality and morbidity, and laryngeal cancer has the highest incidence in it. However, the molecular mechanisms involved in laryngeal cancer development remain to be known and highly sensitive biomarkers and novel promising therapy is necessary. METHODOLOGY/PRINCIPAL FINDINGS: To explore laryngeal cancer-specific miRNAs, RNA from 5 laryngeal surgical specimens including cancer and non-cancer tissues were hybridized to microarray carrying 723 human miRNAs. The resultant differentially expressed miRNAs were further tested by using quantitative real time PCR (qRT-PCR) on 43 laryngeal tissue samples including cancers, noncancerous counterparts, benign diseases and precancerous dysplasias. Significant expressional differences between matched pairs were reproduced in miR-133b, miR-455-5p, and miR-196a, among which miR-196a being the most promising cancer biomarker as validated by qRT-PCR analyses on additional 84 tissue samples. Deep sequencing analysis revealed both quantitative and qualitative deviation of miR-196a isomiR expression in laryngeal cancer. In situ hybridization confirmed laryngeal cancer-specific expression of miR-196a in both cancer and cancer stroma cells. Finally, inhibition of miR-196a counteracted cancer cell proliferation in both laryngeal cancer-derived cells and mouse xenograft model. CONCLUSIONS/SIGNIFICANCE: Our study provided the possibilities that miR-196a might be very useful in diagnosing and treating laryngeal cancer.

Tumor suppressor 101F6 and ascorbate synergistically and selectively inhibit non-small cell lung cancer growth by caspase-independent apoptosis and autophagy.

101F6 is a candidate tumor suppressor gene harbored on chromosome 3p21.3, a region with frequent and early allele loss and genetic alterations in many human cancers. We previously showed that enforced expression of wild-type 101F6 by adenoviral vector-mediated gene transfer significantly inhibited tumor cell growth in 3p21.3-deficient non-small cell lung cancer (NSCLC) cells in vitro and in vivo. The molecular mechanism of 101F6-mediated tumor suppression is largely unknown. A computer-aided structural and functional model predicts the 101F6 protein to be a member of the cytochrome b561 protein family that is involved in the regeneration of the antioxidant ascorbate. 101F6 protein is expressed in normal lung bronchial epithelial cells and fibroblasts but is lost in most lung cancers. Treatment with 101F6 nanoparticle-mediated gene transfer in combination with a subpharmacologic dose (200-500 micromol/L) of ascorbate synergistically and selectively inhibited lung cancer cell growth in vitro. Systemic injection of 101F6 nanoparticles plus the i.p. injection of ascorbate synergistically inhibited both tumor formation and growth in human NSCLC H322 orthotopic lung cancer mouse models (P<0.001). Furthermore, exogenous expression of 101F6 enhanced intracellular uptake of ascorbate, leading to an accumulation of cytotoxic H(2)O(2) and a synergistic killing of tumor cells through caspase-independent apoptotic and autophagic pathways. The antitumor synergism showed by the combination treatment with systemic administration of 101F6 nanoparticles and ascorbate on lung cancer offers an attractive therapeutic strategy for future clinical trials in cancer prevention and treatment.

Eupalmerin acetate, a novel anticancer agent from Caribbean gorgonian octocorals, induces apoptosis in malignant glioma cells via the c-Jun NH2-terminal kinase pathway.

The marine ecosystem is a vast but largely untapped resource for potential naturally based medicines. We tested 15 compounds derived from organisms found in the Caribbean Sea (14 gorgonian octocoral-derived compounds and one sponge-derived compound) for their anticancer effects on human malignant glioma U87-MG and U373-MG cells. Eupalmerin acetate (EPA) was chosen as the lead compound based on its longer-term stability and greater cytotoxicity than those of the other compounds we tested in these cell types. EPA induced G(2)-M cell cycle arrest and apoptosis via the mitochondrial pathway; it translocated Bax from the cytoplasm to the mitochondria and dissipated the mitochondrial transmembrane potential in both cell types. EPA was found to increase phosphorylated c-Jun NH(2)-terminal kinase (JNK) by >50% in both U87-MG and U373-MG cells. A specific JNK inhibitor, SP600125, inhibited EPA-induced apoptosis, confirming the involvement of the JNK pathway in EPA-induced apoptotic cell death. Furthermore, 7 days of daily intratumoral injections of EPA significantly suppressed the growth of s.c. malignant glioma xenografts (P < 0.01, on day 19). These results indicate that EPA is therapeutically effective against malignant glioma cells in vitro and in vivo and that it, or a similar marine-based compound, may hold promise as a clinical anticancer agent.

Autophagic cell death of malignant glioma cells induced by a conditionally replicating adenovirus.

BACKGROUND: Conditionally replicating adenoviruses (CRAds) can be engineered to replicate selectively in cancer cells and cause cancer-specific cell lysis; thus they are considered a promising cancer therapy. METHODS: To elucidate the mechanisms by which CRAds induce cancer-specific cell death, we infected normal human fibroblasts (MRC5, telomerase negative), human malignant glioma (U373-MG and U87-MG), human cervical cancer (HeLa), and human prostate cancer (PC3) cells (all telomerase positive) with CRAds regulated by the human telomerase reverse transcriptase promoter (hTERT-Ad) or control nonreplicating adenoviruses (Ad-GFP). Nonapoptotic autophagy was assessed in Ad-GFP- and hTERT-Ad-infected cells by examining cell morphology, the development of acidic vesicular organelles, and the conversion of microtubule-associated protein 1 light chain 3 from the cytoplasmic form to the autophagosome membrane form; signaling via mammalian target of rapamycin (mTOR), an autophagy-associated molecule, was monitored by western blot analysis. We also compared the growth of subcutaneous gliomas in nude mice that were treated by intratumoral injection with Ad-GFP or hTERT-Ad. Survival of athymic mice carrying intracranial gliomas treated by intratumoral injection with Ad-GFP or hTERT-Ad was compared by using the Kaplan-Meier method and the Cox-Mantel log-rank analysis. All statistical tests were two-sided. RESULTS: hTERT-Ad induced tumor-specific autophagic cell death in tumor cells and in subcutaneous gliomas. hTERT-Ad-induced autophagy was associated with hTERT-Ad infection kinetics. The mTOR signaling pathway was suppressed in tumor cells and in subcutaneous gliomas treated with hTERT-Ad compared with GFP-Ad or no treatment as shown by reduced phosphorylation of mTOR's downstream target p70S6 kinase (p70S6K). hTERT-Ad treatment of mice (n = 7) slowed growth of subcutaneous gliomas (mean tumor volume = 39 mm3, 95% confidence interval [CI] = 23 to 54 mm3) compared with GFP-Ad treatment (n = 7) (mean tumor volume = 200 mm3, 95% CI = 149 to 251 mm3) at day 7 (volume difference = 161 mm3, 95% CI = 126 to 197 mm3; P < .001). Mice carrying intracranial tumors that were treated with three intratumoral injections of hTERT-Ad survived longer (53 days) than after treatment with GFP-Ad (29 days) (seven mice per group, difference = 24 days, 95% CI = 20 to 28 days; P < .001). CONCLUSIONS: hTERT-Ad may kill telomerase-positive cancer cells by inducing autophagic cell death.

Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status.

Replacement of the p53 tumor suppressor gene is a rational approach to the management of malignant gliomas because p53 is frequently mutated or inactivated in these cancers. Major weaknesses of this approach are that malignant gliomas are mixtures of cells with wild-type and mutant p53, and that tumor cells exhibiting wildtype p53 are resistant to p53 gene transfer. An effective alternative is needed to overcome these difficulties. p53-upregulated modulator of apoptosis (PUMA) was identified as a p53-inducible proapoptotic molecule. Our purpose was to elucidate a role for PUMA in p53 gene therapy and to investigate whether PUMA is an efficient substitute for p53 in cancer therapy. We demonstrated that PUMA was upregulated in mutant p53 malignant glioma cells (U373-MG and T98G) undergoing apoptosis but was not upregulated in apoptosis-resistant wild-type p53 malignant glioma cells (U87-MG and D54) after adenoviral transfer of p53. Overexpression of PUMA resulted in massive apoptosis associated with mitochondrial damage and caspase-3 activation in all tumor cells tested. Use of the human telomerase reverse transcriptase (hTERT) promoter system induced apoptosis only in malignant glioma cells with telomerase activity, while sparing normal cells lacking telomerase. The ability of PUMA to induce apoptosis was greater than that of caspase-6 or caspase-8 transfer, using the same system. Moreover, exogenous expression of PUMA under the hTERT promoter system significantly suppressed the growth of subcutaneous U87-MG tumors in nude mice and did not induce apoptosis in surrounding nontumor tissues. These results indicate that PUMA, which is regulated under a tumor-specific expression system such as the hTERT promoter, may be better than p53 as a therapeutic tool for malignant gliomas.

Does the lobectomy plus lymph node dissection still remain a standard surgical procedure for patients with cT1N0M0 adenocarcinoma of the lung?

OBJECTIVES: Controversies still exists regarding treatment for cT1N0M0 adenocarcinoma of the lung. The following topics need to be answered: 1) Should all patients undergo lobectomy plus lymph node dissection? and 2) Is there poor-prognostic subgroup that may need adjuvant therapy? METHODS: Between 1990 and 1999, 141 patients with cT1N0M0 adenocarcinoma of the lung underwent lobectomy plus lymph node dissection. Fifteen clinicopathological characteristics of the entire population were investigated with regard to survival. Forty-seven samples, which were possible to reexamine among 68 patients with small adenocarcinoma 2 cm or less in greatest dimension, were assessed according to Noguchi's classification. RESULTS: Nine of fifteen clinicopathological variables were significant in indicating poor prognostic factors in univariate analysis: gender, differentiation, p-T status, p-N status, pm, lymphatic invasion, vascular invasion, pleural invasion, and serum carcinoembryonic antigen (CEA) level. The p-N status and high serum CEA level were independent predictive variables in multivariate analysis. A five-year survival rate for patients with Noguchi's type A and B was 100%. However, six (8.8%) of 68 patients with small adenocarcinoma had lymph node involvement and four patients (5.9%) had pulmonary metastasis. CONCLUSIONS: It is inappropriate and inadequate to omit lobectomy or lymph node dissection only on the basis of tumor size. Therefore, it seems reasonable to conclude that lobectomy plus lymph node dissection still remains as a standard surgical procedure to treat cT1N0M0 adenocarcinoma of the lung. We must continue to search for new deciding factors in order to choose candidates for limited operation among patients with cT1N0M0 adenocarcinoma of the lung.

Analysis of angiogenic profiles by estimation of tumor blood flow with colored dye extraction microspheres after antiangiogenic therapy.

No study has directly estimated tumor blood flow after antiangiogenic therapy. Using dye extraction colored microspheres, we estimated blood flow in a rat LY80 tumor model before and after antiangiogenic therapy with TNP-470. Dyed microspheres were infused into the tumor-bearing rats. The dye was extracted and its concentration was quantified by spectrophotometry. Tumor blood flow corrected for wet weight (ml. min(-1)g(-1)) was calculated as follows (AU = absorbency units): (blood flow to tumor) = (AU per gram of tumor) x (reference withdrawal rate)/(AU per gram of reference blood). Tumor tissues with or without TNP-470 were also examined histologically. Tumor blood flow 1 week after transplantation could be predicted by the simple regression equation. In the groups treated with TNP-470, this simple regression equation shifted to the left, despite virtually no difference in the results of pathological examination. In LY80 tumors 2 weeks after transplantation, blood flow in tumors treated with TNP-470 was higher than without TNP-470. This technique can be used to obtain information about the angiogenic status within tumor before and after antiangiogenic therapy. These angiogenic profiles may provide important clues to optimal antiangiogenic therapy, combinations of antiangiogenic treatment and cytotoxic therapy, and schedules for combination therapy.

Oxygenation of hypoxic region in solid tumor by administration of human serum albumin incorporating synthetic hemes.

Recombinant human serum albumin incorporating synthetic heme (rHSA-FeP) was tested for its ability to increase O(2) tension in the hypoxia of the solid tumor rat model. By the direct administration of the rHSA-FeP solution (10 mL/kg) via the aorta descendens to the ascites hepatoma LY80 tumor on the right femur, the O(2) tension of the hypoxic region immediately increased to 3.45 +/- 1.43 Torr, which corresponds to a 2.4-fold increase compared to that of the baseline value. These high O(2) levels continued for 300 s after the infusion. The rHSA-FeP solution can be utilized not only as a red blood cell substitute but also as an O(2)-carrying medicine for the effective reoxygenation of the hypoxia solid tumor.