Management of Progressive Pulmonary Nodules Found during and outside of CT Lung Cancer Screening Studies.

Although the effectiveness of screening for lung cancer remains controversial, it is a fact that most lung cancers are diagnosed at an advanced stage outside of lung cancer screening programs. In 2013, the U.S. Preventive Services Task Force revised its lung cancer screening recommendation, now supporting lung cancer screening by low-dose computed tomography in patients at high risk. This is also endorsed by many major medical societies and advocacy group stakeholders, albeit with different eligibility criteria. In Europe, population-based lung cancer screening has so far not been recommended or implemented, as some important issues remain unresolved. Among them is the open question of how enlarging pulmonary nodules detected in lung cancer screening should be managed. This article comprises two parts: a review of the current lung cancer screening approaches and the potential therapeutic options for enlarging pulmonary nodules, followed by a meeting report including consensus statements of an interdisciplinary expert panel that discussed the potential of the different therapeutic options.

Perspectives of novel imaging techniques for staging, therapy response assessment, and monitoring of surveillance in lung cancer: summary of the Dresden 2013 Post WCLC-IASLC State-of-the-Art Imaging Workshop.

Modern imaging techniques that can provide functional information on tumor vascularization, metabolic activity, or cellularity have seen significant improvements over the past decade. However, most of these techniques are currently not broadly utilized neither in clinical trials nor in clinical routine, although there is a large agreement on the fact that conventional approaches for therapy response assessment such as Response Evaluation Criteria in Solid Tumors or World Health Organization criteria-that exclusively focus on the change in tumor size-are of less value for response assessment in modern thoracic oncology. The aim of this article comprises two parts: a short review of the most promising state-of-the-art imaging techniques that have the potential to play a larger role in thoracic oncology within the near future followed by a meeting report including recommendations of an interdisciplinary expert panel that discussed the potential of the different techniques during the Dresden 2013 Post World Congress of Lung Cancer (WCLC)--International Association for the Study of Lung Cancer (IASLC) meeting. It is intended to provide a comprehensive summary about ongoing trends and future perspectives on functional imaging in thoracic oncology.

Cervical and retrosternal approach to the left thoracic cavity using a flexible endoscope.

OBJECTIVES: Mediastinoscopy remains the gold standard for surgical exploration of the mediastinum. The use of this approach to access the left thoracic cavity could be complicated by vascular or neurological lesion. The aim of this experimental work was to describe a new approach to the left thoracic cavity through a cervical incision and retrosternal space using a flexible endoscope as a unique instrument. METHODS: We conducted an experimental work on 12 refrigerated and non-embalmed cadavers. Through a cervical incision, we dissected the retrosternal space to the level of Louis angle and then opened the left mediastinal pleura. We introduced the flexible endoscope through this pleural window into the left thoracic cavity. We defined three distances between the borders of the endoscope entry point, the phrenic nerve and the mammary artery: Distance 1: between the medial edge of the endoscope entrance point and the medial edge of the left mammary artery, Distance 2: between the top of the endoscope entrance point and the penetration of phrenic nerve in the left thoracic cavity and Distance 3: between the lateral edge of the entrance point of the endoscope and the medial edge of the phrenic nerve. To measure these distances, we performed a left postero-lateral thoracotomy. RESULTS: Procedure was successfully executed in 10 of the 12 studied subjects. The mean distances 1, 2 and 3 were 17.1 (range 2-40), 39.5 (17-80) and 19.1 mm (10-40), respectively. The minimal Distance 1 was in two subjects 0.2 and 0.5 mm. CONCLUSIONS: This approach avoids the para-aortic and supra-aortic zone; this access could be less dangerous than already described access techniques. Despite the limits of our work on cadavers, and the two failures in the application of the access, the mean distances we calculated show the potential safety of our approach concerning the phrenic nerve and the mammary artery. An experimental protocol on living animals is currently underway with the aim of confirming the safety of our approach.

10-year long-term survival (LTS) of induction chemotherapy with three cycles cisplatin/paclitaxel followed by concurrent chemoradiation cisplatin/etoposide/45 Gy (1.5 Gy bid) plus surgery in locally advanced non-small-cell lung cancer (NSCLC)-a multicenter phase-II trial (CISTAXOL).

BACKGROUND: Induction chemoradiotherapy plus surgery remains an option to study in IIIA(N2) and selected IIIB NSCLC. Here we report ten-year long-term survival of a prospective multicenter German-French phase-II trial with trimodality. PATIENTS AND METHODS: Mediastinoscopically proven IIIA(N2)/selected IIIB NSCLC received three cycles cisplatin (50 mg/m(2) day 1+8) and paclitaxel (175 mg/m(2)d1) qd 22. Concurrent CTx/RTx followed: 45 Gy (1.5 Gy bid) with cisplatin 50 mg/m(2) day 2+9 and etoposide 100 mg/m(2) d 4-6. Surgery was planned three to five weeks after RTx. If evaluated inoperable/irresectable at the end of RTx, definitive RTx-boost (20 Gy; 2 Gy qd) followed. Here we report 10-year-LTS for this cohort. RESULTS: All 64 patients were accrued 3/99 to 2/02. Patients characteristics: IIIA(N2)/IIIB 25/39; m/f 48/16; adeno/squamous/large-cell/adenosquamous/NOS 15/26/18/3/2; age: median 52.5 (range 33-69). 36 operated: R0 32/36 (89%); pCR 16/36 (44%). 10-year-LTS%; all 26.0; IIIA(N2) 37.1; IIIB 17.9; relevant prognostic factors (exploratory): pretreatment - histopathology (squamous/adeno) - age (<50/≥50) - Charlson-CI: 1/>1 - BMI (≥25/<25) - pack years smoking (≥10/<10); treatment-dependent - R0/no-R0. CONCLUSIONS: This regimen achieves substantial LTS. Interestingly, adenocarcinomas, older patients, unfavorable comorbidity scores, higher BMI and light smokers demonstrate poor long-term outcome even with aggressive trimodality. This dataset defines the rationale for our ongoing randomized trial with surgery after induction therapy in IIIA(N2)/selected IIIB (ESPATÜ).

Diaphragm pacing after bilateral implantation of intradiaphragmatic phrenic stimulation electrodes through a transmediastinal endoscopic minimally invasive approach: pilot animal data.

OBJECTIVES: Phrenic nerve stimulation for diaphragm pacing allows patients with central respiratory paralysis to be weaned from mechanical ventilation. Two procedures are available, either intrathoracic (bilateral thoracotomy) or intradiaphragmatic (four ports laparoscopy). The present experimental work assesses the feasibility, safety and efficacy of a trans-mediastinal implantation of intradiaphragmatic phenic nerve stimulation electrodes using a flexible gastroscope through a cervical incision. METHODS: We operated on nine ewes. After selective bronchial intubation, we dissected the latero-tracheal space and opened both mediastinal pleura. We then introduced a flexible gastroscope into the pleural cavities, in a sequential manner. The phrenic nerves were located and followed up to the diaphragm dome. Electrodes loaded within a long, pliable needle were introduced through the adjacent intercostal space and implanted in each hemidiaphragm, at a 'tendinous' location (as close as possible to the entry of the nerve in the central tendon), and at a more lateral 'muscular' location. Postoperatively, the animals were ventilated using bilateral phrenic nerve stimulation. After euthanasia, abdominal verification of the electrodes position was performed through a laparotomy. RESULTS: The mediastinal and pleural parts of the procedure were uneventful. The insertion of electrodes was associated with transdiaphragmatic puncture and small abdominal haematomas in the first two animals studied. After a slight modification of the insertion technique, this was not observed anymore. Phrenic nerve stimulation produced efficient ventilation, with tidal volumes significantly higher when delivered at the tendinous site than at the muscular site. CONCLUSIONS: The trans-mediastinal implantation of intradiaphragmatic phrenic nerve stimulation electrodes is feasible, appears reasonably safe, and allows efficient ventilation.

Minimally invasive trans-mediastinal endoscopic approach to insert phrenic stimulation electrodes in the human diaphragm: a preliminary description in cadavers.

OBJECTIVE: Diaphragm pacing by phrenic nerve (PN) stimulation is currently used for patients with central respiratory paralysis to be weaned from mechanical ventilation. Electrodes are inserted either through bilateral thoracotomy or through four ports laparoscopy. The aim of this experimental work is to demonstrate the feasibility of trans-mediastinal bilateral implantation of PN electrodes using a flexible gastroscope introduced through a cervical incision in human cadavers. METHODS: Ten refrigerated and non-embalmed cadavers were used. The gastroscope was introduced through a cervical incision into the latero-tracheal space and then subsequently into both pleura by opening the mediastinal pleura. After identification of the PN, electrodes were introduced through an intercostal space to the desired diaphragmatic location using a long, pliable needle with the electrode loaded in its lumen. RESULTS: Results are described for each hemi-diaphragm not for an anatomic subject. Mediastinal exploration and introduction of the video gastroscope into the pleural cavities proved easy in all subjects. Pleural adherences were present in five hemi-diaphragms. The central tendon of both hemi-diaphragms could be identified unambiguously in all the subjects. Identification of the entry point of the phrenic nerve into the diaphragm was straightforward in 10 hemi-diaphragms. In the remaining 10, this proved more difficult because of mediastinal fat or lung parenchyma. Introduction of the electrode-holding needles through the intercostal space and their insertion close to the phrenic nerve entry point was also easy. Withdrawal of the needle from the diaphragm and 'capture' of the hook were successful on the first attempt in 14 hemi-diaphragms, but failed in six others in whom a second attempt was necessary. CONCLUSION: Trans-mediastinal implantation of PN stimulation electrodes is possible using a flexible endoscope. This application of endoscopic surgery could allow a minimally invasive placement of PN electrodes in patients with central respiratory paralysis, for example, at the time of tracheostomy.

Release of metal particles from needles used for transbronchial needle aspiration.

BACKGROUND: Although mediastinoscopy is still the gold standard for diagnosis of mediastinal lymphadenopathy, minimally invasive procedures have been developed: transbronchial needle aspiration (TBNA) using a flexible bronchoscope (conventional TBNA) or linear echoendoscope (endobronchial ultrasound [EBUS]) allowing real-time guided lymph node aspiration. The observation of contamination of samples by foreign particles led us to determine the frequency and the nature of this material and to identify its origin. METHODS: From June 2007 to November 2008, 141 consecutive patients underwent conventional TBNA (n = 84) or EBUS-guided TBNA (EBUS-TBNA) (n = 57). All cytologic samples were reviewed in blinded fashion, and contamination was assessed semiquantitatively. Mineral analysis using a transmission electron microscope equipped with an energy dispersive x-ray spectrometer was performed on the solution obtained after rinsing unused needles and on four samples of calf thymuses punctured with EBUS needles. RESULTS: Foreign material, different from anthracosis, was identified in samples obtained with five different batches of needles, only from EBUS-TBNA (P < .0001). The contamination score was correlated to the number of passes (P = .035). Mineral analyses of the rinsing solutions from conventional TBNA needles were negative, whereas metal alloys of iron, titanium, nickel, and chromium were released with EBUS needles. The same contamination was identified in three of the four punctured calf thymuses. CONCLUSIONS: Dedicated EBUS-TBNA needles are able to release metal particles, probably by friction between the stylet and the needle, with a potential risk to inject particles into nodes. The long-term consequences are unknown, but the need for safety measures should be evaluated.

Consensus for EGFR mutation testing in non-small cell lung cancer: results from a European workshop.

INTRODUCTION: Activating somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have recently been characterized in a subset of patients with advanced non-small cell lung cancer (NSCLC). Patients harboring these mutations in their tumors show excellent response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The EGFR-TKI gefitinib has been approved in Europe for the treatment of adult patients with locally advanced or metastatic NSCLC with activating mutations of the EGFR TK. Because EGFR mutation testing is not yet well established across Europe, biomarker-directed therapy only slowly emerges for the subset of NSCLC patients most likely to benefit: those with EGFR mutations. METHODS: The "EGFR testing in NSCLC: from biology to clinical practice" International Association for the Study of Lung Cancer-European Thoracic Oncology Platform multidisciplinary workshop aimed at facilitating the implementation of EGFR mutation testing. Recommendations for high-quality EGFR mutation testing were formulated based on the opinion of the workshop expert group. RESULTS: Co-operation and communication flow between the various disciplines was considered to be of most importance. Participants agreed that the decision to request EGFR mutation testing should be made by the treating physician, and results should be available within 7 working days. There was agreement on the importance of appropriate sampling techniques and the necessity for the standardization of tumor specimen handling including fixation. Although there was no consensus on which laboratory test should be preferred for clinical decision making, all stressed the importance of standardization and validation of these tests. CONCLUSION: The recommendations of the workshop will help implement EGFR mutation testing in Europe and, thereby, optimize the use of EGFR-TKIs in clinical practice.

Cervical incision thoracic endoscopic surgery: a minimally invasive endoscopic approach in thoracic surgery.

Cervical incision thoracic surgery has recently been described. Currently, there is a move to increase the role of flexible endoscopy in surgery. The use of a flexible endoscope through a natural orifice into the thoracic cavity still remains ethically doubtful. The authors present a surgical experimental study using a flexible endoscope through a cervical incision for the exploration of both the mediastinum and the thoracic cavity in a cadaver. An experimental work on 10 refrigerated and non-embalmed cadavers was initiated. We used a unique device - a standard double-channel flexible video gastroscope. Through a small cervical incision, we performed simultaneous exploration of the mediastinum and both pleural cavities. Identification and biopsies of mediastinal lymph nodes at levels 2R, 4R, 7 and 4L were easy to perform in all subjects. In eight cadavers, we performed an assessment of bilateral pleural cavities and multiple pleural biopsies as well as bilateral thoracic sympathectomy. A chest tube was placed in the thoracic cavity at the end of all pleural procedures. The potential advantages of this approach are simultaneous exploration of the mediastinum and pleura and the performance of several thoracic interventions through a small cervical incision. The flexible endoscope could become a surgical tool for thoracic surgery.

Is neoadjuvant chemoradiotherapy a feasible strategy for stage IIIA-N2 non-small cell lung cancer? Mature results of the randomized IFCT-0101 phase II trial.

Locally advanced non-small cell lung cancers share a risk of both local and systemic recurrence and justifies a therapeutic strategy combining focal and systemic treatment. In resectable stage IIIA-N2 tumors, peri-operative chemotherapy significantly increases survival rates. Chemoradiotherapy, which is the standard treatment of non-resectable locally advanced tumors, may have a role as an induction treatment to reduce locoregional recurrence rates. In the present phase II trial, we aimed at comparing standard induction chemotherapy (arm A: cisplatin and gemcitabine) with 2 different regimens of induction chemoradiotherapy (total dose: 46 Gy) including third-generation cytotoxic agents (arm B: cisplatin and vinorelbine; arm C: carboplatin and paclitaxel) in patients with resectable stage IIIA-N2 NSCLC, using feasibility of the whole strategy, including surgery, as a primary endpoint. A total of 46 patients were included. Response rate was significantly higher after induction chemoradiotherapy vs. chemotherapy (87% vs. 57%, p=0.049). A total of 44 patients underwent operation. The feasibility rate of the proposed therapeutic strategy was 89% for the whole cohort, 93% in arm A (induction chemotherapy with cisplatin and gemcitabine), 88% in arm B (induction chemoradiotherapy with cisplatin and vinorelbine), and 87% in arm C (induction chemoradiotherapy with carboplatin and paclitaxel) (p=0.857). Overall median, 1-year, and 3-year survival were 30 months, 87%, and 43%, respectively. Induction chemoradiotherapy with modern treatment regimens is highly feasible and may show promises in the current and future developments of multimodal therapeutic strategies in locally advanced NSCLC.

Isolated rib metastases from renal cell carcinoma.

Osseous metastases of renal cell carcinoma (RCC) are the second most frequent location after lung metastases. They rarely present as isolated location. When isolated, resection may offer five-year survival rates of 30-60%. The purpose of the current study is to focus on a particular subset, the isolated rib metastases (IRM). The files of six patients who underwent radical resection for IRM were reviewed. All had previous radical nephrectomy for clear-cell renal cancer. The mean age of these six men was 55.3 years. Preoperative evaluation included in all patients a conventional chest radiograph and thoracic computed tomography (CT) scanning. Chest wall resections were wide and curative. The mean disease-free interval (DFI) after renal cancer treatment was 25 months. There was no postoperative death. Two patients had synchronous disease. One of them developed two recurrences operated on by large resections. They survived for 77 and 81 months. The overall five and ten-year survival rates were respectively, 83 and 66.7%. IRM of RCC are rare and remain not well-known. Surgical wide resection is a safe and effective treatment.

Long-term results of the international adjuvant lung cancer trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer.

PURPOSE Based on 5-year or shorter-term follow-up data in recent randomized trials, adjuvant cisplatin-based chemotherapy is now generally recommended after complete surgical resection for patients with non-small-cell lung cancer (NSCLC). We evaluated the results of the International Adjuvant Lung Cancer Trial study with three additional years of follow-up. PATIENTS AND METHODS Patients with completely resected NSCLC were randomly assigned to three or four cycles of cisplatin-based chemotherapy or to observation. Cox models were used to evaluate treatment effect according to follow-up duration. Results The trial included 1,867 patients with a median follow-up of 7.5 years. Results showed a beneficial effect of adjuvant chemotherapy on overall survival (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.02; P = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there was a significant difference between the results of overall survival before and after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P = .006 for interaction. Similar results were observed for disease-free survival. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06). CONCLUSION These results confirm the significant efficacy of adjuvant chemotherapy at 5 years. The difference in results beyond 5 years of follow-up underscores the need for the long-term follow-up of other adjuvant lung cancer trials and for a better identification of patients deriving long-term benefit from adjuvant chemotherapy.

Surgical lung resection for severe hemoptysis.

BACKGROUND: The role of surgical lung resection in the management of severe hemoptysis has evolved after advances in interventional radiology. We sought to describe the indications for surgical lung resection in such patients and to identify predictive factors of postoperative complications. METHODS: This study is a retrospective analysis (May 1995 to July 2006) of consecutive patients referred to the intensive care unit of a tertiary hospital for severe hemoptysis who underwent surgical lung resection. RESULTS: Among 813 patients referred for severe hemoptysis, 111 underwent surgical lung resection. Interventional radiology had been first attempted in 87 patients (78%); 68 underwent surgery because of a failed procedure (n = 28) or bleeding persistence or recurrence within 72 hours despite a completed procedure (n = 40); 19 patients underwent surgery after bleeding control. The remaining 24 patients (22%) were directly referred to the surgeon (5 for emergency surgery). Overall, surgery was performed in emergency (n = 48), scheduled after bleeding control (n = 48), or planned after discharge (n = 15). The main indications for surgery were mycetoma, cancer, bronchiectasis, and active tuberculosis. Surgery for mycetoma (odds ratio, 9.4; 95% confidence interval, 2.8 to 32), emergency surgery (odds ratio, 5.3; 95% confidence interval, 1.8 to 16), and pneumonectomy (odds ratio, 4.7; 95% confidence interval, 1.2 to 18) independently predicted complications. Fifteen patients died in the intensive care unit, of whom 14 underwent emergency surgery. Chronic alcoholism (odds ratio, 4.6; 95% confidence interval, 1.1 to 19), the need for mechanical ventilation or vasoactive drugs on admission (odds ratio, 8.2; 95% confidence interval, 1.9 to 35), and blood transfusion before surgery (odds ratio, 8; 95% confidence interval, 1.5 to 42) predicted mortality. CONCLUSIONS: Attempting at controlling bleeding with first-line nonsurgical approaches appears necessary to optimize the operative conditions and improve outcome of patients with severe hemoptysis.

Nonseminomatous germ cell tumors: assessing the need for postchemotherapy contralateral pulmonary resection in patients with ipsilateral complete necrosis.

OBJECTIVES: Our objective was to explore the pathologic components of residual masses after primary chemotherapy in patients with metastatic nonseminomatous germ cell tumors. METHODS: A multicenter retrospective study was conducted of 71 patients with thoracic residual masses (39 patients had bilateral lung metastasis) after first-line cisplatin-based chemotherapy for disseminated nonseminomatous germ cell tumors. Among the 71 patients, 52 also had a retroperitoneal lymph node dissection. RESULTS: Pathologic findings in postchemotherapy residual masses included complete necrosis, teratoma, and viable cancer in 31%, 55%, and 14% of patients, respectively. Discordant pathologic findings were evidenced between retroperitoneal lymph node and thoracic (lung or mediastinal lymph nodes) residual masses in 27% of patients. When a bilateral pulmonary resection was performed, only 2 (5%) of 39 patients had discordant histologic findings between the two lungs. Among patients who had necrosis only in residual masses from their first lung (n = 20), 19 (95%) also had necrosis only in contralateral lesions. A single patient had necrosis only in the first lung and some teratoma in the contralateral lung. CONCLUSIONS: This report shows a high rate (95%) of pathologic concordance between the two lungs. Avoiding contralateral lung surgery could therefore be considered when complete necrosis is found in the first lung after induction chemotherapy for nonseminomatous germ cell tumor.

Cisplatin-based three drugs combination (NIP) as induction and adjuvant treatment in locally advanced non-small cell lung cancer: final results.

INTRODUCTION: This phase III trial was conducted in non-small cell lung cancer patients with locally advanced stage II B (only T3N0) III A and III B (only T4 N0). Primary endpoint was 2-year survival; secondary were toxicity, disease-free survival, and overall survival. METHODS: After three cycles of vinorelbine (N) 25 mg/m2 on days 1 and 5, ifosfamide/mesna (I) 3 g/m2 on day 1, cisplatin (P) (NIP), patients were treated by surgery and within 45 days were randomized to two additional cycles of NIP versus observation. RESULTS: Median tumor diameter was 5.5 cm (1.2-10.6). Overall, 155 of 156 patients received chemotherapy: 133 (85%) men, median age: 59 years (35-75). Sixty-five percentage of patients were stage III A, 28% II B, and 7% III B. The study has been closed prematurely because of the low inclusion rate. After three cycles of induction in 143 assessable patients, 82 reported an objective response (57.3%) (95% CI: 48.8-65.6), with 3.5% complete response and 53.8% partial response. Relative dose intensity during neoadjuvant NIP (%) was 97, 98, and 98.5 for vinorelbine, ifosfamide/mesna, and cisplatin, respectively. Tolerance: G3 to 4 neutropenia in 3% of patients and G3 to 4 anemia in 4%; nonhematological toxicities included G3 nausea/vomiting in 11%, G3 anorexia and G3 to 4 infection in 6.5%, G3 asthenia in 10% and G3 to 4 alopecia in 25.5%. After a median of 32 days after NIP, 107 patients (69%) underwent operation with complete resection (R0) in 74% (79 of 107 patients). Downstaging (N2 to N0) after surgery was 29%. Operative mortality rate was 2.8%. Twenty-one days (median) after surgery, 79 patients were randomized to adjuvant NIP (47%) or control (53%). Tolerance of adjuvant NIP: 12.5% G3 to 4 nausea/vomiting, 19% G3 alopecia, 6% G3 infection, and G3 asthenia. Overall median survival 32.3 versus 31.8 months in the observation and NIP arms, respectively. CONCLUSIONS: NIP allows 74% of R0 with no surgery delay. The few number of randomized patients did not allow to conclude on the efficacy of adjuvant chemotherapy.

Surgery for bronchioloalveolar carcinoma and "very early" adenocarcinoma: an evolving standard of care?

Lobectomy and mediastinal lymph node dissection is the standard surgical management of early stage non-small cell lung cancer (NSCLC) because more limited resections have been associated with a higher risk of local recurrence. Nevertheless, recent lung cancer screening studies have led to the detection of an increasing number of "very early" NSCLC (defined as less than 2 cm in size) and of good-prognosis histologic subtypes, bronchioloalveolar carcinoma (BAC), and adenocarcinoma (AC), mixed subtypes that are potentially appropriate for sublobar resection. The precise indications for sublobar resection remain unclear and are the subject of ongoing clinical trials, but it seems that very early, peripherally located, node-negative AC of a predominantly BAC pattern may be adequately treated in this manner. Multifocal AC and BAC, either synchronous or metachronous, are also effectively treated by complete resection, using limited resections whenever possible. The pneumonic form of BAC, the rarest variant of this disease spectrum, continues to have a poor prognosis despite complete resection. Very limited experience suggests that lung transplantation leads to prolonged survival in highly selected patients with this histologic subtype. To improve our management of very early AC, much more information is needed about the molecular abnormalities of AC and their relationship to clinical outcomes.

NK cells infiltrating a MHC class I-deficient lung adenocarcinoma display impaired cytotoxic activity toward autologous tumor cells associated with altered NK cell-triggering receptors.

NK cells are able to discriminate between normal cells and cells that have lost MHC class I (MHC-I) molecule expression as a result of tumor transformation. This function is the outcome of the capacity of inhibitory NK receptors to block cytotoxicity upon interaction with their MHC-I ligands expressed on target cells. To investigate the role of human NK cells and their various receptors in the control of MHC-I-deficient tumors, we have isolated several NK cell clones from lymphocytes infiltrating an adenocarcinoma lacking beta2-microglobulin expression. Unexpectedly, although these clones expressed NKG2D and mediated a strong cytolytic activity toward K562, Daudi and allogeneic MHC-class I+ carcinoma cells, they were unable to lyse the autologous MHC-I- tumor cell line. This defect was associated with alterations in the expression of natural cytotoxicity receptor (NCR) by NK cells and the NKG2D ligands, MHC-I-related chain A, MHC-I-related chain B, and UL16 binding protein 1, and the ICAM-1 by tumor cells. In contrast, the carcinoma cell line was partially sensitive to allogeneic healthy donor NK cells expressing high levels of NCR. Indeed, this lysis was inhibited by anti-NCR and anti-NKG2D mAbs, suggesting that both receptors are required for the induced killing. The present study indicates that the MHC-I-deficient lung adenocarcinoma had developed mechanisms of escape from the innate immune response based on down-regulation of NCR and ligands required for target cell recognition.