Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: a potential issue for anti-PD-L1 therapeutic strategies.

BACKGROUND: High expression of programmed death ligand-1 (PD-L1) on tumor cells (TC) and/or on tumor-infiltrating immune cells (IC) is associated with a high response rate in patients with advanced nonsmall-cell lung cancer (NSCLC) treated with PD-L1 inhibitors. The use of a PD-L1 immunohistochemical (IHC) test in determining the responsiveness to immunotherapy has raised the question of the reliability and reproducibility of its evaluation in lung biopsies compared with corresponding resected surgical specimens. PATIENTS AND METHODS: PD-L1 expression in TC and IC was assessed in 160 patients with operable NSCLC on both whole surgical tissue sections and matched lung biopsies, by using a highly sensitive SP142 IHC assay. The specimens were scored as TC 0-3 and IC 0-3 based on increasing PD-L1 expression. RESULTS: PD-L1 expression was frequently discordant between surgical resected and matched biopsy specimens (the overall discordance rate = 48%; 95% confidence interval 4.64-13.24) and κ value was equal to 0.218 (poor agreement). In all cases, the biopsy specimens underestimated the PD-L1 status observed on the whole tissue sample. PD-L1-positive IC tumors were more common than PD-L1-positive TC tumors on resected specimens. The discrepancies were mainly related to the lack of a PD-L1-positive IC component in matched biopsies. CONCLUSIONS: Our results indicate relatively poor association of the PD-L1 expression in TC and IC between lung biopsies and corresponding resected tumors. Although these results need to be further validated in larger cohorts, they indicate that the daily routine evaluation of the PD-L1 expression in diagnostic biopsies can be misleading in defining the sensitivity to treatment with PD-L1 targeted therapy.

Clinical value of circulating endothelial cells and of soluble CD146 levels in patients undergoing surgery for non-small cell lung cancer.

BACKGROUND: Previous studies indicate that endothelial injury, as demonstrated by the presence of circulating endothelial cells (CECs), may predict clinical outcome in cancer patients. In addition, soluble CD146 (sCD146) may reflect activation of angiogenesis. However, no study has investigated their combined clinical value in patients undergoing resection for non-small cell lung cancer (NSCLC). METHODS: Data were collected from preoperative blood samples from 74 patients who underwent resection for NSCLC. Circulating endothelial cells were defined, using the CellSearch Assay, as CD146+CD105+CD45-DAPI+. In parallel, sCD146 was quantified using an ELISA immunoassay. These experiments were also performed on a group of 20 patients with small-cell lung cancer, 60 healthy individuals and 23 patients with chronic obstructive pulmonary disease. RESULTS: The CEC count and the plasma level of sCD146 were significantly higher in NSCLC patients than in the sub-groups of controls (P<0.001). Moreover, an increased CEC count was associated with higher levels of sCD146 (P=0.010). Both high CEC count and high sCD146 plasma level at baseline significantly correlated with shorter progression-free survival (P<0.001, respectively) and overall survival (P=0.005; P=0.009) of NSCLC patients. CONCLUSIONS: The present study provides supportive evidence to show that both a high CEC count and a high sCD146 level at baseline correlate with poor prognosis and may be useful for the prediction of clinical outcome in patients undergoing surgery for NSCLC.

Cisplatin-docetaxel induction plus concurrent 3-D conformal radiotherapy and weekly chemotherapy for locally advanced non-small cell lung cancer patients: a phase II trial.

Concurrent chemoradiotherapy (CHRT) is the standard of care for unresectable locally advanced stage III non-small cell lung cancer. However, the optimal combination remains unclear. The aim of this study was to evaluate the efficacy of 2 induction chemotherapy cycles (days 1 and 22) with docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) followed by concurrent chemotherapy (weekly docetaxel-cisplatin, 20 mg/m(2)) and 3-D conformal radiotherapy for 6 weeks (66 Gy/5 fractions per week/2 Gy per fraction). The primary endpoint was the response rate. Secondary objectives were toxicity, time to progression, and overall survival. Forty-four patients were included and 40 were eligible. The mean age was 60.5 years (range 40.7-72.1), and 75% had stage IIIB disease. Six patients underwent complete R0 resection including 2 pathologic complete responses after a planned intermediate evaluation. Thirty-three patients completed CHRT. The objective response rate was 65% (95% CI 50.2-79.8). Grade 3-4 hematologic and digestive toxicities were observed mainly during the induction phase. Grade 3 esophagitis (5%) was experienced during CHRT. With a median follow-up of 38.7 months, the median progression-free survival was 28.3 months (95% CI 11.0-35.0) and the median survival rate was 31.4 months. Cisplatin-docetaxel induction followed by concurrent 3-D conformal radiotherapy and weekly chemotherapy is a feasible protocol associated with a promising response rate and acceptable toxicity.

Morphological analysis of circulating tumour cells in patients undergoing surgery for non-small cell lung carcinoma using the isolation by size of epithelial tumour cell (ISET) method.

BACKGROUND AND OBJECTIVE: Recurrence rates after surgery for non-small cell lung cancer (NSCLC) range from 25 to 50% and 5-year survival is only 60-70%. Because no biomarkers are predictive of recurrence or the onset of metastasis, pathological TNM (pTNM) staging is currently the best prognostic factor. Consequently, the preoperative detection of circulating tumour cells (CTCs) might be useful in tailoring therapy. The aim of this study was to characterize morphologically any circulating non-haematological cells (CNHCs) in patients undergoing surgery for NSCLC using the isolation by size of epithelial tumour cell (ISET) method. METHODS: Of 299 blood samples tested, 250 were from patients with resectable NSCLC and 59 from healthy controls. The presence of CNHCs was assessed blindly and independently by 10 cytopathologists on May-Grünwald-Giemsa stained filters and the cells classified into three groups: (i) malignant cells, (ii) uncertain malignant cells, and (iii) benign cells. We assessed interobserver agreement using Kappa (κ) analysis as the measure of agreement. RESULTS: A total of 123 out of 250 (49%) patients showed CNHCs corresponding to malignant, uncertain malignant and benign cells, in 102/250 (41%), 15/250 (6%) and 6/250 (2%) cases, respectively. No CNHCs were detected in the blood of healthy subjects. Interobserver diagnostic variability was absent for CNHCs, low for malignant cells and limited for uncertain malignant and benign cells. CONCLUSION: Identification of CTCs in resectable NSCLC patients, using ISET technology and according to cytopathological criteria of malignancy, appears to be a new and promising field of cytopathology with potential relevance to lung oncology.

[Sodium valproate-induced pleural effusion: When it changes sides!] / Pleurésie induite par le valproate de sodium : quand ça change de côté !

INTRODUCTION: Pleural fluid effusion is a possible harmful effect of sodium valproate. It most often consists in polynuclear eosinophilic pleurisy and occurs within months of treatment initiation. CASE REPORT: We report on a case of sodium valproate-induced pleural effusion occurring more than 12years after initiation of treatment. The original formula was variegated and not eosinophilic. The patient exhibited contralateral recurrence with continued treatment. Once treatment was discontinued, there was no recurrence during three-year follow-up. CONCLUSION: Sodium valproate-induced pleural effusion can present an atypical polymorphous picture leading to erroneous diagnoses.

[Thoracic endometriosis and lymphangioleiomyomatosis: Coincidence or hormonal rational?] / Endométriose thoracique et lymphangioléïmyomatose : coïncidence ou rationnel hormonal?

INTRODUCTION: Lymphagioleiomyomatosis (LAM) and endometriosis are two diseases that occur in young women. The main thoracic complication of both diseases is pneumothorax. CASE REPORT: We describe the case of a 45-year-old woman who presented with a right-sided pneumothorax. The clinical context and the perioperative findings were suggestive of thoracic endometriosis, while the histology of the pulmonary biopsy and the evolution of her case were in favour of LAM. This presentation indicates the coexistence of the two diseases, which has never previously been described in the literature. The case raises the question as to whether it should be policy to systematically undertake a pulmonary biopsy in cases of thoracic endometriosis. CONCLUSIONS: LAM and endometriosis are both diseases under hormonal influence. To date, we do not know if there is any direct link between the two diseases or if the presentation that we describe here occurred by chance.

High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognostic in patients with non-small cell lung cancer.

BACKGROUND: Carbonic anhydrase IX (CAIX) is an enzyme upregulated by hypoxia during tumour development and progression. This study was conducted to assess if the expression of CAIX in tumour tissue and/or plasma can be a prognostic factor in patients with non-small cell lung cancer (NSCLC). METHODS: Tissue microarrays containing 555 NSCLC tissue samples were generated for quantification of CAIX expression. The plasma level of CAIX was determined by ELISA in 209 of these NSCLC patients and in 58 healthy individuals. The CAIX tissue immunostaining and plasma levels were correlated with clinicopathological factors and patient outcome. RESULTS: CAIX tissue overexpression correlated with shorter overall survival (OS) (P=0.05) and disease-specific survival (DSS) of patients (P=0.002). The CAIX plasma level was significantly higher in patients with NSCLC than in healthy individuals (P<0.001). A high level of CAIX in the plasma of patients was associated with shorter OS (P<0.001) and DSS (P<0.001), mostly in early stage I+II NSCLC. Multivariate Cox analyses revealed that high CAIX tissue expression (P=0.002) was a factor of poor prognosis in patients with resectable NSCLC. In addition, a high CAIX plasma level was an independent variable predicting poor OS (P<0.001) in patients with NSCLC. CONCLUSION: High expression of CAIX in tumour tissue is a predictor of worse survival, and a high CAIX plasma level is an independent prognostic biomarker in patients with NSCLC, in particular in early-stage I+II carcinomas.

Tracheal obstruction due to tumour: use of veno-venous extracorporeal membrane oxygenation during rigid bronchoscopy.

Tracheal tumour is rare but can lead to upper airway obstruction and acute respiratory distress. Its management includes surgical resection, radiotherapy or interventional bronchoscopy. Ventilation or difficulties with tracheal intubation can occur during the peri-operative course resulting in serious adverse consequences. We report the case of an 83-year-old man with an obstructive tracheal chondrosarcoma resected by rigid bronchoscopy undergoing veno-venous extracorporeal membrane oxygenation. Such support should be considered when the patient's airway patency cannot be ensured by conventional methods.

[Thoracic surgery: the major surgical procedures]. / Chirurgie thoracique: les grandes opérations.

The most frequent thoracic surgeries are performed for the treatment of primary lung cancer and pleural mesothelioma. For lung cancer, the standard procedures are pneumonectomy and lobectomy with associated mediastinal lymphadenectomy. In order to avoid pneumonectomy, extended lobectomy with sleeve bronchoplasty and/or angioplasty can be done. When adjacent organs are involved, extended resections are accepted (chest wall, vena cava...). For small lesions (<2 cm) without lymph nodes involvement and for patients with limited respiratory function, segmentectomy is an option (results under evaluation). For the treatment of pleural mesothelioma, the accepted oncologic resection is extra-pleural pneumonectomy extended to the diaphragm and pericardium. This surgical indication requires careful evaluation of tumour staging and patient's capacities. The morbidity and mortality of these resections require comprehensive follow-up (clinical, biological (including blood gases) and radiological).

[Feasibility and efficacy of cyberknife radiotherapy for lung cancer: early results]. / Analyse de la toxicité précoce des traitements par Cyberknife des cancers pulmonaires et résultats préliminaires.

PURPOSE: High-dose robotic stereotactic irradiation can be achieved with high precision using the CyberknifeM system equipped with the Synchrony respiratory tracking device. Cyberknife irradiation can overcome some limitations of conventional radiotherapy including errors due to breathing motion and patient setup. High dose levels are of interest for tumours that have shown a dose-response relationship including lung tumours. We reviewed the treatments and outcomes for the first French patients with lung tumours treated at the Cyberknife centre of Nice. PATIENTS AND METHODS: Thirty four patients were treated between November 2006 and November 2007 at the Cyberknife centre of Nice, Centre Lacassagne, France. Thirty had untreated primary lung cancer, 4 had colorectal metastasis to the lung. We evaluated the feasibility and reliability of fiducial placement, toxicity and early outcomes. Objective tumour response was assessed on thoracic CT scan every three months. RESULTS: There was no grade 3-4 toxicity. Toxicity (11%) mainly consisted of grade 1-2 asthenia. Crude overall tumour response rate was 96% for all assessable patients and 91% at 3 and 6 months, respectively. The use of one fiducial ensured minimal toxicity (no grade III pneumothorax) while allowing reliable tumour tracking as shown by the low infield failure rate (no geographic miss). Diagnostic procedure was performed during fiducial placement when required. CONCLUSION: Early toxicity and tumour control rates from this population suggest that the use of a unique fiducial for a Cyberknife treatment was safe and effective for the treatment of selected primary and secondary lung tumours. This strategy is corroborated by similar control rates in the literature. Longer follow-up are awaited.

[Paraneoplastic limbic encephalitis with positive anti-RI antibodies and mediastinal seminoma]. / Encéphalite limbique paranéoplasique avec anticorps anti-RI et séminome médiastinal.

We report the case of a 49-year-old man who was admitted for progressive behaviorial disorders with frontal elements. There was no sensorial nor motor deficiency. Clinical examination revealed android obesity, cutaneous and mucous paleness, pubic and axillary depilation and gynecomastia. Encephalic MRI found a lesion of the left amygdalian region with high T2 intensity and low T1 intensity associated with gadolinium-enhancement. Cerebrospinal fluid analysis showed a lymphocytic meningitis. Panhypopituitarism was found on the endocrine investigations. Anti-RI antibodies were positive, leading to the diagnosis of paraneoplastic limbic encephalitis. The CT-scan showed a node of the lower part of the thymic area. Surgical resection revealed an ectopic mediastinal seminoma. The evolution consisted of paraneoplastic fever and crossed-syndrome with right hemiparesia and left common oculomotor nerve paralysis. Treatment was completed by two cycles of carboplatin, corticosteroids and substitutive opotherapy. Paraneoplastic fever disappeared, but behavioral disorders and palsy remain unchanged. The patient died two years later in a bedridden state. This case of paraneoplastic limbic encephalitis associated with positive anti-RI antibodies and mediastinal seminoma is exceptional and has not to our knowledge been described in the literature. Cancers usually associated with anti-RI antibody are breast and lung cancer. Paraneoplastic limbic encephalitis is not the classical clinical presentation, which usually is brainstem encephalitis. Hypothalamic involvement, uncommon in paraneoplastic limbic encephalitis is mainly associated with positive antineuronal anti-Ma2 antibodies. Finally, the gadolinium enhancement on encephalic MRI is unusual in paraneoplastic limbic encephalitis.

Classic biphasic pulmonary blastoma: A case report and review of the literature.

Pulmonary blastomas represent about 0.5% of primary pulmonary malignancies. The prognosis is poor. Standard treatment consists of surgical excision. There are no published series on which to judge the efficacy of chemotherapy or radiation therapy. We describe an unusual case of classic biphasic pulmonary blastoma (CBPC), with long-term survival despite numerous and varied cancer-related events and review the literature. Our 71-year-old Caucasian woman presented with history of blood in sputum in 2009. Right lower lobectomy yielded a diagnosis of sarcomatoid carcinoma (pneumoblastoma). Unusually, our patient is still alive 7 years after initial surgery, despite metastatic first relapse after 2 years. Metastatic progression was confirmed histologically on three separate occasions during the disease course. The patient received a combination of cisplatin (or carboplatin) and etoposide on three separate occasions. Molecular biology studies of CBPC are needed to identify effective treatments, and a patient registry should be created.

[Evolution of pain during respiratory rehabilitation after major lung resection]. / Évolution de la douleur en soins de suites et rééducation après résection pulmonaire majeure.

INTRODUCTION: Lung resection for cancer is the cause of significant postoperative pain. The aim of this study was to determine whether pulmonary rehabilitation could induce a resurgence of pain. METHODS: In 2014 and 2015, pulmonary rehabilitation was offered to all patients referred to our institution after lung resection for cancer. Patients were assessed at entry and departure for nociceptive pain, neuropathic pain (DN4), for quality of life using questionnaire EORTC QlQ-C30 and for anxiety and depression (HAD questionnaire). Pain was studied before and after the sessions of cycloergometer, gym and massages. RESULTS: During the period, 99 patients were admitted to our institution following lung resection for cancer. Medians changed during pulmonary rehabilitation from 3 to 1 for nociceptive pain (p<0.001), 3 to 3 for DN4 (NS), 50 to 67 for the quality of life score (p<0.001), 7 to 5 for the anxiety (p<0.001) and 5 to 3 for depression (p<0.0001). Pain remained stable during the sessions of cycloergometer and gym, and decreased during massage. Patients undergoing thoracotomy or video-assisted thoracic surgery evolved identically. CONCLUSION: Postoperative pulmonary rehabilitation after lung resection for cancer was not harmful. It was associated with a decrease in nociceptive pain and was without effect on neuropathic pain.

["Therapeutic" pleural surgery]. / La chirurgie pleurale "thérapeutique".

Renewed interest in carcinological pleura surgery for the treatment of mesothelioma has resulted from an increased incidence of the tumor and also better control of postoperative mortality for an operation with a dramatic reputation. Techniques include pleurectomy, pleurodecrotication and wide pleuropneumectomy. To achive isolated resection of the parietal pleura or a combined resection of the parietal and visceral pleura with more or less wide resection of the diaphragm and pericardium. Indications depend on the tumor extension and the patient's status. Mortality, particularly for wide pleuropneumectomy is no well controlled by well-trained teams and is to the order of 5%. The rate of local recurrence is to the order of 10% and can warrant use of local treatments such as intrathoracic hyperthermic chemotherapy. Median survival for operated mesothelioma is 19 months with a 46% five-year survival for the tumors with the best prognosis. At the present time, radical surgical resection is the basis of local treatment for pleural mesothelioma.

[Impact of pulmonary rehabilitation after lung resection for cancer on patients' level of anxiety and depression]. / Impact de la réhabilitation respiratoire sur l'anxiété et la dépression après chirurgie thoracique pour cancer.

INTRODUCTION: Pulmonary rehabilitation (PR) for patients undergoing lung resection for cancer remains controversial. We studied the effects of PR, its impact on quality of life and the level of anxiety and depression. METHODS: In 2011 and 2012, PR was offered to all patients referred to our institution after lung resection for cancer. Patients were evaluated between admission and discharge by a 6 minutes walking test (6MWD), a Visual Analogue Pain Intensity Scale, a quality of life questionnaire (EORTC QLQ C30) and by the Hospital Anxiety and Depression Scale (HAD). The same questionnaires were mailed 6 months after completing PR. RESULTS: Between early 2011 and late 2012, 133 patients were admitted to our institution following lung resection for cancer. Of these, 59 (44%) patients completed PR and returned their questionnaires 6 months after discharge. During PR of these 59 patients, the mean quality of life score increased from 56.3 to 65.9 (P<0.05), the median anxiety score decreased from 5.5 to 4 (P<0.05) and that of depression from 3 to 2 (P<0.05). At 6 months post-discharge, the mean quality of life score remained stable at 66.3 (P=0.8), the median anxiety score reverted to 6 (P<0.05) and the median depression score reverted to 4.5 (P<0.05). CONCLUSION: This observational study during PR, showed that quality of life and the levels of anxiety and depression were improved at the end of the course. After returning home, the average quality of life score remained stable but the level of anxiety and depression increased.

Management of pleural effusion of cirrhotic origin.

STUDY OBJECTIVE: To determine the indications and limitations of surgical videothoracoscopy for management of pleural effusion, an infrequent and often recurring complication of cirrhotic ascites whose pathogenesis involves direct passage of ascitic fluid into the pleural space through minute defects in the diaphragm. DESIGN/SETTING/PATIENTS/INTERVENTIONS: Eight cirrhotic patients with ascites and recurrent pleural effusion underwent surgical videothoracoscopy to localize and close any diaphragmatic defects and to achieve pleurodesis by application of talc. MEASUREMENTS AND RESULTS: Diaphragmatic defects were localized and closed in six patients; postoperative mean volume and duration of drainage were, respectively, 0.408 +/- 0.157 mL and 7.6 +/- 1.75 days. None of these six patients developed recurrent pleural effusion (follow-up, 7 to 36 months). In the 2 patients in whom no defect was found, drainage had to be maintained for 15 days and 18 days (drainage volumes, 3 and 4 L). At hospital discharge, both patients had a stable recurrent effusion occupying the lower third of the cavity. CONCLUSIONS: Utilization of videothoracoscopy appears particularly indicated for these fragile patients when medical therapy fails. The procedure's efficacy is immediate and durable once defects are identified and closed. If the technique proves unsuccessful, it does not hinder subsequent use of other methods.

Combined video-assisted mediastinoscopy and video-assisted thoracoscopy in the management of lung cancer.

BACKGROUND: This study seeks to assess the safety and usefulness of combined video-assisted mediastinoscopy and video-assisted thoracoscopy in the management of patients with lung cancer. METHODS: Ten consecutive patients with lung neoplasms were evaluated. Indications for this combined approach included inconclusive findings from imaging techniques concerning locoregional extension and resectability; possible involvement of different structures not accessible to a single procedure; and failure to obtain histologic diagnosis by a single technique. RESULTS; Histologic diagnosis was obtained in 6 patients without preoperative histologic typing. In 3 patients, in contrast with preoperative imaging studies, combined thoracoscopy and mediastinoscopy showed the resectability of the primary tumor and the absence of metastatic mediastinal lymph nodes. These findings were confirmed at thoracotomy. In 3 other patients prevascular lymph nodes metastases were found. They underwent neoadjuvant chemotherapy; at subsequent operation, a complete resection was possible. In the remaining four cases combined exploration proved definitive contraindications for operation (recognition of oat-cell carcinoma, n = 2; T4 status, n = 1; T3N2, n = 1). CONCLUSIONS: Combined video-assisted mediastinoscopy and video-assisted thoracoscopy seems to be a safe and useful tool in the management of selected patients with lung neoplasms. Both the extent of primary tumor and the possible intrathoracic spread may be exhaustively evaluated. In patients with left lung cancer a complete exploration of the aortopulmonary window is possible.

Intrathoracic migration of Kirschner pins.

We report two cases of intrathoracic migration of Kirschner pins used for the treatment of sternoclavicular joint dislocation. The migration was asymptomatic in both cases. Treatment involved median sternotomy in one patient and video-assisted thoracoscopy in the other. A favorable outcome was observed in both patients. The reports confirm the potential dangers related to management of sternoclavicular joint dislocation with metallic fixation devices.

Lemierre's syndrome with bilateral empyema thoracis.

A 31-year-old patient is described with thrombophlebitis of the right jugular vein, and anerobic septicemia (Lemierre's syndrome). Multiple pulmonary abscesses and bilateral fibrinopurulent empyema were also present. Treatment included intravenous antibiotics, heparin, and video-assisted thoracoscopic debridement of pleural cavities. A favorable outcome was observed.

Nephrobronchial fistula secondary to xantogranulomatous pyelonephritis.

We report a case of staghorn nephrolithiasis that evolved into xanthogranulomatous pyelonephritis with perinephric abscess, nephrobronchial fistula, and lung abscess. The patient was an intravenous drug abuser who tested positive for human immunodeficiency virus, without evidence of acquired immunodeficiency syndrome. He presented with a 2-month history of untreated repeated episodes of left flank pain and hyperpyrexia. Treatment involved left nephrectomy, debridement of abscess, tube drainage, and intravenous antibiotics. The patient illustrates the need to consider untreated nephrolitiasis as a predisposing factor for pulmonary complications.