Regional Mediastinal Lymph Nodes Research Articles

The Response, Outcome and Toxicity of Aggressive Palliative Thoracic Radiotherapy for Metastatic Non-Small Cell Lung Cancer Patients with Controlled Extrathoracic Diseases.

Background and PurposeFor metastatic non-small cell lung cancer (NSCLC) patients with controlled extrathoracic disease after systemic treatment, stable or progressive primary lung lesions may cause respiratory symptoms and increase comorbidities. In the present study, we sought to investigate whether aggressive palliative thoracic radiotherapy (RT) can enhance local control and improve the survival for this subgroup of patients.Materials and MethodsBetween March 2006 and December 2014, 56 patients with metastatic NSCLC who had responsive or stable extrathoracic diseases after chemotherapy and/or molecular targets, and received thoracic RT for stable and progressive primary lung lesions were included. RT with a median dose of 55 Gy (range, 40–62 Gy) was administered in 1.8–2.5 Gy fractions to primary lung tumor and regional mediastinal lymph nodes using modern RT technique. Overall survival (OS) from diagnosis, and locoregional progression-free survival (LRPFS), and survival calculated from radiotherapy (OS-RT) were estimated using the Kaplan-Meier method.ResultsThere were 37 men and 19 women with a median age of 60 years at diagnosis. The median interval from the diagnosis of metastatic disease to thoracic RT was 8 months. Following thoracic RT, 26 patients (46%) achieved complete or partial response (overall response rate, ORR). Patients with squamous cell carcinoma or poorly-differentiated carcinoma had a higher ORR than those with adenocarcinoma (63% vs. 34%, P = 0.034). EGFR mutations was closely associated with a better ORR (45% vs. 29%, P = 0.284). At a median follow-up time of 44 months, the median OS, LRPFS after RT, and OS-RT were 50 months, 15 months, and 18 months.ConclusionRadical palliative throractic RT is safe and might be beneficial for primary lung lesions of metastatic NSCLC patients with controlled extrathoracic diseases.

Infection-induced type I interferons activate CD11b on B-1 cells for subsequent lymph node accumulation.

Innate-like B-1a lymphocytes rapidly redistribute to regional mediastinal lymph nodes (MedLNs) during influenza infection to generate protective IgM. Here we demonstrate that influenza infection-induced type I interferons directly stimulate body cavity B-1 cells and are a necessary signal required for B-1 cell accumulation in MedLNs. Vascular mimetic flow chamber studies show that type I interferons increase ligand-mediated B-1 cell adhesion under shear stress by inducing high-affinity conformation shifts of surface-expressed integrins. In vivo trafficking experiments identify CD11b as the non-redundant, interferon-activated integrin required for B-1 cell accumulation in MedLNs. Thus, CD11b on B-1 cells senses infection-induced innate signals and facilitates their rapid sequester into secondary lymphoid tissues, thereby regulating the accumulation of polyreactive IgM producers at sites of infection.

Aspirin reduces lung cancer metastasis to regional lymph nodes

BackgroundLung cancer is the main cause of cancer-related death worldwide. The high mortality is probably attributable to early metastasis; however, the mechanism underlying metastasis to regional lymph nodes is still unknown. Cyclooxygenase (COX)-derived prostaglandin E2 (PGE2) induces tumor growth and metastasis and is associated with a poor prognosis. The present study investigated the effect of an authentic COX inhibitor, aspirin, on regional lymph node metastasis during the development of lung cancer in mice. MethodsAn orthotopic intrapulmonary implantation model based on male C57BL/6 (6–8-weeks-old) mice was used. The lungs were injected with a solution containing Lewis lung carcinoma (LLC) cells overexpressing green fluorescent protein (GFP) and BD Matrigel®. The effect of aspirin on mediastinal lymph node metastasis of LCC cells from the primary injection sites was then examined. ResultsThe implantation process took approximately 30 s per mouse and operative mortality was 10%. Single pulmonary nodules developed at the implanted site in 95% of animals, and regional mediastinal lymph node metastasis was observed at 14 days post-LLC-GFP cell injection in all mice that formed a primary lung tumor. The mean survival time of mice injected with LLC-GFP cells was 15±3 days (range, 12–22 days). Histopathological analysis revealed that no metastatic tumors developed in the regional mediastinal lymph nodes by Day 10–12 post-LLC-GFP cell injection and no metastasis to distant organs or distant lymph nodes was observed by Day 21 post-injection. Oral administration of aspirin (100mg/kg, twice a day) after LLC-GFP cell injection inhibited metastasis to the regional lymph nodes, with no significant suppression of primary tumor growth in the lungs. Aspirin treatment led to a significant reduction in mortality (P<0.0001). ConclusionsThe present lymph node metastasis model is useful for evaluating the efficacy of agents that inhibit tumor metastasis to the regional lymph nodes. Aspirin reduced the metastasis of LLC-GFP cells injection to the regional lymph nodes, with a significant reduction in mortality. These findings suggested that COX inhibitors have potential for preventing lymph node metastasis.

Research for mediastinal lymph node desection style of stage Ib upper lobe non-small cell lung cancer

背景与目的淋巴转移是肺癌最主要的转移途径，也是影响肺癌患者预后的主要因素之一。现有的研究显示上叶肺癌较之中、下叶肺癌更易发生区域性纵隔淋巴结转移。本研究回顾分析Ib期上叶非小细胞肺癌（non-small cell lung cancer, NSCLC）纵隔淋巴结清扫方式的选择及影响预后的相关因素。方法147例行肺上叶完全性切除术的NSCLC患者，其中左肺上叶71例，右肺上叶76例。术后病理均为Ib期（T2aN0M0）。术中共清扫淋巴结925枚，其中纵隔淋巴结491枚（上纵隔组266枚，下纵隔组225枚）。采用Kaplan-Meier乘积法和Log-rank检验对患者进行单因素生存分析，采用Cox回归模型进行多因素生存分析。结果① 单因素及多因素分析均显示：年龄、肿瘤直径及上纵隔淋巴结清扫站数是影响患者预后的重要因素；②对于Ib期右肺上叶NSCLC，#4组淋巴结与预后存在统计学意义（P=0.021），而对于Ib期左肺上叶NSCLC，#5组淋巴结与预后存在统计学意义（P=0.024）。结论对于Ib期上叶NSCLC而言，年龄、肿瘤直径及上纵隔淋巴结清扫站数是影响患者预后的重要因素；对于此类患者，采用肺叶特异性系统性淋巴结清扫或许是更为高效的手术方式。

縦隔リンパ節部位のCT読影基準のための縦隔内構造物の位置関係の検討

目的．CT画像上で，縦隔内構造物の位置関係を観察し，各リンパ節領域の画像上の位置関係について検討すること．対象と方法．2005年4月上旬から2005年9月中旬までの期間に大阪大学医学部附属病院にて結節とびまん性肺疾患の疑いで胸部CTが施行された201例と，2005年5月中旬から2005年8月中旬までの期間に国立がんセンター中央病院にて肺癌の術前に胸部CTが施行された7例について，縦隔内構造物の位置関係を解析した．リンパ節領域分けの指標には，肺癌取扱い規約（第6版）を用いた．結果．隣接する2つのアキシャル方向の基準スライスを比較した場合，左腕頭静脈と気管正中線の交点（79％）と大動脈弓上縁（21％），奇静脈弓上縁（61％）と大動脈弓下縁（39％），奇静脈弓上縁（96％）と左主肺動脈上縁（4％），右主肺動脈上縁（70％）と気管分岐部（30％）の4組で上下関係に個体差が生じ（カッコ内は頭側となるスライスの割合），これにより＃2～＃4，＃6のリンパ節領域の境界面に差異が現れ，各リンパ節領域の画像上の位置関係が異なることがわかった．結論．縦隔内構造物の位置関係には個体差が存在し，これにより＃2～＃4，＃6の各リンパ節領域の境界面は変化する．したがって，縦隔リンパ節の正確な診断・治療，及び三次元的なリンパ節領域分け表示のためには，これらの位置関係を考慮する必要がある．

Limited mediastinal lymph node dissection for non-small cell lung cancer according to intraoperative histologic examinations

Although radioisotopic procedures are commonly used to detect sentinel lymph nodes in breast cancer surgery, these procedures are often problematic and not necessarily suitable for lung cancer surgery. Our previous study revealed that the mediastinal sentinel lymph node, defined as the regional mediastinal lymph node, consisted of nodes 2, 3, or 4 in right upper lobe cancers; 3, 7, or 8 in right lower lobe cancers; 4, 5, or 7 in left upper lobe cancers; and 4, 7, or 8 in left lower lobe cancers. On the basis of these findings, we pathologically investigated one representative lymph node at each of the 3 levels dissected during surgical intervention in 69 patients with non-small cell lung cancer from September 1993 through December 2002. Fifty-eight patients with lung cancer underwent lobectomies with limited mediastinal lymph node dissection according to this strategy. Mediastinal lymph node recurrence was observed in only one patient during 41 +/- 25 months (maximum, 98 months) of follow-up. The cancer-specific 5-year survivals were 96.6% in patients with pathologic stage IA disease (n = 31) and 67.4% in patients with stage IB disease (n = 16). These results suggested that limited mediastinal lymph node dissection is applicable to patients with non-small cell lung cancer whose regional mediastinal lymph nodes are not metastatic.

Radiotherapy for medically inoperable non-small cell lung cancer at clinical stage I and II.

We reviewed the records of 36 patients with medically inoperable stage I-II non-small cell lung carcinoma who were treated with radiotherapy. The median dose to the target was 60 Gy with conventional fractionation. Fifteen patients were treated without elective irradiation fields, while the remaining 21 were treated with extended fields including elective mediastinal regional lymph nodes. The overall survival rates at three and five years were 32.3% and 18.8%, the cause-specific survival rates were 40.9% and 27.3%, and the local control rates were 31.7% and 23.8%, respectively. In multivariate analysis the radiation dose had a marginally significant influence on the cause-specific survival, while tumor size had a significant influence on the local control rate. Only one patient had relapse in the regional mediastinal lymph nodes as the only site of metastasis. We conclude that the dose used in the present study is inadequate and recommend that further efforts be made to improve local control by dose escalation within a small target volume.

Progressive increase of CD4+/CD45RC− lymphocytes after allograft rat lung transplantation: A marker of acute rejection

Background: Acute rejection remains one the most serious problems in lung transplantation. Although biopsy has been used for assessing the dysfunction of grafts, it is difficult to determine rejection at an early stage. Lymphocyte infiltration and activation play an important role in acute rejection of transplanted organs, and the dynamic change of lymphocyte subpopulations might be a marker to determine graft rejection after lung transplantation. Methods: A rat lung transplant model was used. Graft-infiltrating lymphocytes in lung tissues were examined by means of histology, and isolated cells were analyzed by means of flow cytometry. Phenotypes of lymphocytes in the regional and remote lymph nodes, spleen, peripheral blood, and bronchoalveolar lavage fluid were also measured by means of flow cytometry. Results: After allograft transplantation, increased lymphocytes were seen in allografts but not in isografts. In allografts the percentage of T cells increased from day 1 to day 5, whereas that of B cells was decreased. The CD4+/CD8+ ratio decreased in allografts. The proportion of CD4+/CD45RC− cells increased in the allografts, which was mainly due to the increase of CD45RC− cells in the total CD4+ cells. Similar changes were found in regional mediastinal lymph nodes but not in the mesenteric lymph nodes, spleen, or peripheral blood. Thus this is a specific response to lung allografts. Importantly, CD45RC− cells were significantly increased in the bronchoalveolar lavage fluid. Conclusion: Significant change of lymphocyte subpopulations is a sign of lymphocyte activation. Increased CD4+/CD45RC− cells in lung allografts could be an early marker of acute rejection, which can be examined by means of lung lavage and flow cytometry.J Thorac Cardiovasc Surg 2002;124:675-83

TGF-beta-producing CD4+ mediastinal lymph node cells obtained from mice tracheally tolerized to ovalbumin (OVA) suppress both Th1- and Th2-induced cutaneous inflammatory responses to OVA by different mechanisms.

Advances in the treatment of allergic disorders require elucidation of the autoregulatory immune systems induced in averting detrimental inflammatory responses against invading foreign Ags. We previously reported that excessive Ags intruding through the airway mucosa induce a subset of regulatory CD4+ T cells secreting TGF-beta in the regional mediastinal lymph nodes (MLNs), which inhibits Th2 cells and subsequent eosinophilic inflammation in the trachea. In the present experiments we examined whether and in what mechanisms TGF-beta-secreting CD4+ T cells in the MLNs regulate Th cell-mediated skin inflammation using a previously established murine model. Th1 or Th2 cells injected s.c. into ear lobes of naive mice induced swelling, whereas the concomitant local injection of MLN cells suppressed the inflammation. The suppressor activities of MLN cells were markedly neutralized by anti-TGF-beta mAb and were mimicked by rTGF-beta. The MLN cell- and rTGF-beta-induced inhibition was reversed by anti-IL-10 mAb significantly in Th1-induced inflammation and only partially in Th2-induced inflammation. rIL-10 reduced Th-induced ear swelling, although higher doses of rIL-10 were required in Th2-induced one. Thus, allergen-specific TGF-beta-producing CD4+ T cells induced in the respiratory tract controlled cutaneous inflammatory responses by Th1 or Th2 cells either directly by TGF-beta or indirectly through IL-10 induction. From a clinical standpoint, these observations might explain the mechanism of spontaneous regression in some patients with atopic dermatitis, which exhibits both Th1- and Th2-mediated skin inflammation in response to airborne protein Ags.

Quantitative analysis of the influenza virus-specific CD4+ T cell memory in the absence of B cells and Ig.

The role of B lymphocytes and their Ig product in the development and maintenance of virus-specific CD4+ T cells has been analyzed in mice homozygous for disruption of the Ig mu gene (mu MT). These mice lack mature B220+ B cells and do not secrete Ig, but generate normal CD8+ cytotoxic T lymphocyte responses and have no difficulty clearing the HKx31 influenza A virus from the infected respiratory tract. Sequential limiting dilution analysis of virus-specific CD4+ T cells established that the frequencies of IL-2-producing T helper cell precursors in the draining lymph nodes and/or spleen from 7 days to 6 mo after infection were essentially similar in mu MT and C57BL/6 (B6) mice. Ag presentation and processing mechanisms involving Ig or B cells are apparently not required to generate virus-specific T helper cell precursors, and Ag-Ig complexes on follicular dendritic cells are not essential for the persistence of virus-specific CD4+ T cell memory. The main difference was that the spleens of the mu MT mice were much smaller than those of the B6 controls, and greater numbers of CD4+ T cells were found consistently in the regional mediastinal lymph nodes. This could be the result of abnormal expression of the lymph node homing receptor (CD62L) on the mu MT CD4+ T cells. However, the profiles of CD62L expression over the long term were comparable for both total and virus-specific CD4+ T cells from the two groups. The diminished role of the mu MT spleen is thus more likely to reflect the absence of germinal centers and/or Ig rather than a disruption of CD62L-mediated T cell trafficking.

Administration of anti-IFN-gamma antibody to beta 2-microglobulin-deficient mice delays influenza virus clearance but does not switch the response to a T helper cell 2 phenotype.

Treatment of mice that were homozygous for a beta 2-microglobulin gene disruption with a mAb that was specific for IFN-gamma delayed clearance of an influenza A virus from the respiratory tract for at least 3 days, whereas administration of an anti-IL-4 mAb had no effect. However, all mice survived and eventually cleared the virus. The anti-IFN-gamma significantly decreased both the level of class II MHC glycoprotein expression and the numbers of CD4+ lymphocytes in the inflammatory populations recovered by bronchoalveolar lavage of the pneumonic lung, whereas the total cell counts remained the same. These differences were not apparent for the regional mediastinal lymph nodes, although the frequency of lymph node B cells producing virus-specific Ab of the IgG2a subclass was greatly reduced. However, neither the anti-IFN-gamma nor anti-IL-4 treatments drastically altered the cytokine production profiles detected for freshly isolated lymphocytes by the using single cell ELISPOT assay or by ELISA of culture supernatants after in vitro restimulation with virus. Thus, neutralization of secreted IFN-gamma during the course of an influenza-specific response in beta 2-microglobulin-deficient mice that lack CD8+ T cells delays virus clearance and modifies the character of the host response, but does not cause the CD4+ subset to switch to a Th2 cytokine profile.

Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma.

We studied a multimodality approach using extrapleural pneumonectomy, chemotherapy, and radiotherapy in patients with malignant pleural mesothelioma. From 1980 to 1992, 52 selected patients, underwent treatment. Median age was 53 years (range, 33 to 69). Initial patient evaluation was performed by a multimodality team. Pathologic diagnosis was reviewed and confirmed before therapy. Patients with no medical contraindication and potentially resectable mesothelioma on computed tomography (CT) (magnetic resonance imaging [MRI] when it became available) received extrapleural pneumonectomy, cyclophosphamide, doxorubicin, and cisplatin (CAP) chemotherapy, and radiotherapy. Perioperative morbidity and mortality rates were 17% and 5.8%, respectively. The overall median survival duration is 16 months (range, 1 month to 8 years). The 32 patients with epithelial histologic variant had 1-, 2-, and 3-year survival rates of 77%, 50%, and 42%, respectively. Patients with mixed and sarcomatous cell disease had 1- and 2-year survival rates of 45% and 7.5%; no patient lived longer than 25 months (P < .01). At resection, positive regional mediastinal lymph nodes were found in 13. Positive lymph nodes were associated with poorer survival than were negative nodes (P < .01). Patients with epithelial variant and negative mediastinal lymph nodes had a survival rate of 45% at 5 years. Multimodality therapy including extrapleural pneumonectomy has acceptable morbidity and mortality for selected patients. Prolonged survival occurred in patients with epithelial histologic variant and negative mediastinal lymph nodes. These data provide a rationale for a revised staging system for malignant pleural mesothelioma; furthermore, they permit stratification of patients into groups likely to benefit from aggressive multimodality treatment.

Influenza virus RNA in the lung and lymphoid tissue of immunologically intact and CD4-depleted mice

The distribution and clearance of viral RNA (vRNA) and mRNA has been analysed for the acute and recovery stages of the pneumonia induced by intranasal infection of C57BL/6J mice with H3N2 influenza A viruses. Amplification of viral genomic material by the polymerase chain reaction showed that the influenza haemagglutinin (HA) gene was eliminated from the lungs of immunologically intact mice by day 14 post-infection, whereas in vitro depletion of the CD4+ T cells delayed clearance by at most 4 days. Viral RNA encoding the HA gene was first demonstrated in the regional mediastinal lymph nodes at 48 h, and continued to be present until day 6 or day 10 after infection of the intact and CD4-depleted mice, respectively. Evidence for the presence of vRNA in the thymus, but not in the mesenteric lymph nodes or the spleen, was found in some situations. Otherwise, the distribution and clearance of vRNA was as would be predicted from earlier studies using virus isolation procedures to monitor localization patterns, and shows a lack of long-term persistence of the influenza virus genome.