Toshihiro Shiozawa

Differences in the prognostic implications of vascular invasion between lung adenocarcinoma and squamous cell carcinoma.

OBJECTIVES Vascular invasion (VI) has been accepted as a universally important prognostic factor for patients with lung carcinoma. However, the clinical significance of VI in each of the histological subtypes has been unclear. The aim of the present study was to investigate differences in the clinicopathological implications of VI between adenocarcinoma and squamous cell carcinoma. METHOD A total of 336 patients were evaluated, of whom 81 were diagnosed as having peripheral-type squamous cell carcinoma, and 255 as having adenocarcinoma. RESULT Among the 336 patients, the five-year survival rates for those who were VI-positive and VI-negative were 38.4% and 76.3%, respectively, the difference being significant (p<0.0001). Multivariate analysis identified VI as an independent prognostic factor (hazard ratio: 1.86). Although the difference in cancer-free survival between VI-positive and -negative patients was statistically significant for adenocarcinoma (p<0.0001), it was not significant for squamous cell carcinoma (p=0.086). For adenocarcinoma, the difference between the survival curves for VI-positive and -negative patients was significant for the subtypes with a predominant lepidic (p<0.0001), papillary (p=0.0026), and acinar (p=0.0060) component, whereas that for the predominantly solid subtype was not significant (p=0.58). Squamous cell carcinomas were then divided into two groups on the basis of the diameter of vessels that had been invaded by the cancer cells: large-vessel invasion (LVI; 1000 μm or more) and small-vessel invasion (SVI; less than 1000 μm). Although there was no difference in the survival curves between the LVI and SVI groups, the LVI group showed a significantly higher incidence of cavity formation and distant metastasis. CONCLUSION We conclude that VI is a useful prognostic indicator in lung carcinoma, although the clinical implications of VI differ between adenocarcinoma and squamous cell carcinoma.

Stratifin accelerates progression of lung adenocarcinoma at an early stage

BackgroundsAdenocarcinoma in situ (AIS) of the lung has an extremely favorable prognosis. However, early but invasive adenocarcinoma (eIA) sometimes has a fatal outcome. We had previously compared the expression profiles of AIS with those of eIA showing lymph node metastasis or a fatal outcome, and found that stratifin (SFN, 14-3-3 sigma) was a differentially expressed gene related to cell proliferation. Here, we performed an in vivo study to clarify the role of SFN in initiation and progression of lung adenocarcinoma.FindingsSuppression of SFN expression in A549 (a human lung adenocarcinoma cell line) by siSFN significantly reduced cell proliferation activity and the S-phase subpopulation. In vivo, tumor development or metastasis to the lung was reduced in shSFN-transfected A549 cells. Moreover, we generated SFN-transgenic mice (Tg-SPC-SFN+/−) showing lung-specific expression of human SFN under the control of a tissue-specific enhancer, the SPC promoter. We found that Tg-SPC-SFN+/− mice developed lung tumors at a significantly higher rate than control mice after administration of chemical carcinogen, NNK. Interestingly, several Tg-SPC-SFN+/− mice developed tumors without NNK. These tumor cells showed high hSFN expression.ConclusionThese results suggest that SFN facilitates lung tumor development and progression. SFN appears to be a novel oncogene with potential as a therapeutic target.

DNMT3a expression pattern and its prognostic value in lung adenocarcinoma.

OBJECTIVES DNA methyltransferases (DNMTs) are an important part of the methylation pathway that is highly correlated with the pathophysiology of cancers. Several studies have reported overexpression of DNMTs in human lung cancer, but none have compared the expression pattern to pathological features. In this study, we clarified the association of DNMT3a expression pattern with pathological features and prognosis of lung adenocarcinoma. MATERIALS AND METHODS 135 cases of surgically resected lung adenocarcinoma specimens were used for DNMT3a immunohistochemistry (IHC). IHC score was determined by counting the number of positive nuclei. The ROC curve was drawn to determine the best cut-off point of the score; this was set at 57.5. Western blot also implemented and confirmed the specificity of the antibody. Correlations between expression pattern and clinicopathological features and prognosis were analyzed using chi-squared method and Cox proportional hazards model respectively. RESULT Seventy-nine of the 135 cases (58.5%) showed strong positive reactivity to anti-DNMT3a. In terms of histological subtypes, among invasive lung adenocarcinomas 41 out of 53 lepidic adenocarcinomas (77%) were strongly positive, while among the other histological subtypes only 23 out of 66 cases (34.8%) showed a positive reaction. Among non-invasive lung adenocarcinomas 15 out of 16 cases (93.8%) were strongly positive. The level of DNMT3a expression was associated with patient outcome, and patients with weak expression of DNMT3a had a poorer outcome than those with strong expression. Multivariate analysis also indicated that DNMT3a is an independent prognostic marker in lung adenocarcinoma. CONCLUSION Our results indicate that DNMT3a expression in lung adenocarcinoma is associated with the histologically non-invasive type and lepidic subtype, and a favorable prognosis. We also showed that DNMT3a expression is an independent prognostic marker in lung adenocarcinoma. Since lack of DNMT3a is thought to facilitate tumor progression, DNMT3a might be clinically applicable as an indicator of favorable prognosis.

Dimethylarginine dimethylaminohydrolase 2 promotes tumor angiogenesis in lung adenocarcinoma.

Although embryonal proteins have been used as tumor marker, most are not useful for detection of early malignancy. In the present study, we developed mouse monoclonal antibodies against fetal lung of miniature swine, and screened them to find an embryonal protein that is produced at the early stage of malignancy, focusing on lung adenocarcinoma. We found an antibody clone that specifically stained stroma of lung adenocarcinoma. LC-MS/MS identified the protein recognized by this clone as dimethylarginine dimethylaminohydrolase 2 (DDAH2), an enzyme known for antiatherosclerotic activity. DDAH2 was found to be expressed in fibroblasts of stroma of malignancies, with higher expression in minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma than in adenocarcinoma in situ (AIS). Moreover, tumors with high stromal expression of DDAH2 had a poorer prognosis than those without. In vitro analysis showed that DDAH2 increases expression of endothelial nitric oxide synthase (eNOS), inducing proliferation and capillary-like tube formation of vascular endothelial cells. In resected human tissues, eNOS also showed higher expression in invasive adenocarcinoma than in AIS and normal lung, similarly to DDAH2. Our data indicate that expression of DDAH2 is associated with invasiveness of lung adenocarcinoma via tumor angiogenesis. DDAH2 expression might be a prognostic factor in lung adenocarcinoma.

Characteristics of clinical N0 metastatic non-small cell lung cancer.

OBJECTIVES Non-small cell lung cancer (NSCLC) patients who have clinically no mediastinal lymph node metastasis but have distant metastasis are occasionally found in clinical practice. Such clinical N0 metastatic NSCLC may be a different subtype from the clinical N1-3 patients with regional lymph node metastasis. The aim of this study was to evaluate the prognosis, clinical features, and incidence of clinical N0 NSCLC patients with metastasis. METHODS All metastatic NSCLC patients (n=761) diagnosed at our hospitals from April 1999 to August 2012 were retrospectively analyzed. They were divided into two groups: N0 and N1-3. Staging was recorded according to the UICC 7th edition of the TNM classification. Differences between the two groups were analyzed using a Chi-square test. Prognostic factors were analyzed by the Kaplan-Meier method and Cox proportional hazards analysis. A probability value less than 0.05 was considered to be significant. RESULTS A total of 761 patients with NSCLC were registered. 124 patients (16.3%) were N0 and 637 (83.7%) were N1-3. There were no differences between the two groups in age, sex, smoking history, performance status, and histological type. The ratio of adrenal gland metastasis was low in the N0 group (N0 7.3%, N1-3 13.4%, p=0.002). Median survival time was longer in the N0 group (N0 11.9 months vs N1-3 7.2 months, p<0.001). N0 was an independent favorable prognostic factor. CONCLUSION Metastatic NSCLC patients with clinical N0 had a favorable prognosis and a lower ratio of adrenal gland metastasis than those with clinical N1-3. Our results suggest that a certain type of adrenal metastasis may result from direct lymphatic spread from a primary lung tumor. About one sixth of metastatic NSCLC cases are clinical N0. Therefore, clinical evaluations for detecting metastasis are important even in clinical N0 patients.

A case study of bofutsushosan‑induced pulmonary injury in a patient: Case report

Bofutsushosan, a herbal (traditional Kampo) medicine, is administered to obese patients in North-East Asia. Bofutsushosan has been reported to exert various anti-obesity effects by stimulating the adipose tissue. The present study describes the case of a patient who developed a severe pulmonary injury that was potentially associated with bofutsushosan therapy. A 52-year-old woman was admitted to Mito Medical Center, University of Tsukuba, Mito Kyodo General Hospital (Mito, Japan) due to progressive dyspnea. Two months previously, bofutsushosan had been newly prescribed for her obesity. Bilateral ground-glass opacities and progressive respiratory deterioration suggested respiratory failure due to a therapeutic agent-induced lung injury. With discontinuation of bofutsushosan and the administration of a corticosteroid, an improvement in her respiratory condition was achieved, although sequelae remained in certain areas of the lungs. Resumption of other therapeutic agents did not reinduce the lung injury. Therefore, a diagnosis of bofutsushosan-induced lung injury was made. Although bofutsushosan-induced lung injury is particularly rare, clinicians should consider it when bofutsushosan is used.

Ossification and increased bone mineral density with zoledronic acid in a patient with lung adenocarcinoma: A case report

Cases of ossification and increased bone mineral density (BMD) at sites of bone metastasis following zoledronic acid (ZA) treatment have not been reported. The current study presents the case of a 65-year-old patient with lung adenocarcinoma and bone metastases in the lumbar vertebrae and femurs. Ossification and an increase in BMD at the metastatic sites was achieved following treatment with ZA and irradiation of the bone metastatic sites. The patient was able to maintain a normal lifestyle for over two years, despite the bone metastases. Therefore, as treatment with ZA was demonstrated to improve patient quality of life, physicians should consider this treatment strategy, particularly for the treatment of metastasis in weight-bearing bones.

Rechallenge with First-Line Platinum Chemotherapy for Sensitive-Relapsed Small-Cell Lung Cancer

Background: Sensitive-relapsed small-cell lung cancer (SCLC) is thought to be sensitive to chemotherapy; therefore, second-line chemotherapy is recommended. Although platinum rechallenge is performed in the second-line chemotherapy for sensitive-relapsed SCLC, it remains unclear whether such a strategy is effective. Methods: We retrospectively analyzed the outcome of rechallenge chemotherapy for sensitive-relapsed SCLC. The endpoints of this study were progression-free survival from the time of relapse (PFS-Re) and overall survival from the time of relapse (OS-Re). We also compared the toxicity profile of rechallenge chemotherapy to that of first-line chemotherapy. Results: Of the 133 SCLC patients who received first-line treatment, 20 patients satisfied the definition of sensitive relapse and received rechallenge chemotherapy. Combined carboplatin and etoposide was the most commonly used rechallenge regimen, and 17 (85%) received it at a reduced dose due to hematological toxicity during the first-line treatment. Median PFS-Re and OS-Re were 4.5 months (95% CI: 3.5–5.4) and 10.5 months (95% CI: 7.9–13.0), respectively. There was no association between dose adjustment and survival. The frequency of hematologic toxicity tended to be lower with rechallenge than first-line treatment. The incidence of grade 3 febrile neutropenia decreased from 40% in first-line treatment to 15% in rechallenge. Conclusion: Platinum rechallenge could be a useful second-line option for sensitive-relapsed SCLC, having favorable efficacy and safety. Dose adjustment at rechallenge based on the toxicity profile during the first-line chemotherapy could reduce toxicity without weakening efficacy.

Bronchoscopy in diagnosis of haemoptysis

www.journals.viamedica.pl Address for correspondence: Hiroaki Satoh, MD, PhD, Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba, Miya-machi 3-2-7, Mito, Ibaraki, 310-0015, Japan, Tel: +81-29-231-2371, e-mail: hirosato@md.tsukuba.ac.jp DOI: 10.5603/ARM.2018.0016 Received: 16.03.2018 Copyright

Sole metastatic pulmonary nodules from breast cancer simulating primary lung adenocarcinoma: Two case reports

The characteristic radiological signs of primary lung adenocarcinoma include notching, lobulation, spicular formation, pleural indentation and a bronchus leading to the nodule (bronchus sign). However, metastatic tumors rarely display such characteristics. We herein present two cases of breast cancer with sole metastatic pulmonary tumors recurring ~20 years after surgery for breast cancer. These patients exhibited radiographic signs specific to primary lung adenocarcinoma. Pulmonary metastatic nodular lesions occur through hematogenous spread; therefore, obtaining pathological specimens by transbronchial biopsy may be challenging. In our patients, however, obtaining pathological specimens by transbronchial biopsy was feasible and it ultimately confirmed the diagnosis of lung metastasis from previously treated breast cancer. To the best of our knowledge, no similar cases are reported in the English medical literature. Therefore, metastatic breast cancer may exhibit the characteristic radiological signs of pulmonary lung adenocarcinoma and, although rare, pulmonary metastasis from breast cancer should be considered even in the presence of irregularly shaped pulmonary nodule(s) following long-term disease-free survival.