Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer.

Metastatic small cell lung cancer (SCLC) is not curable. While SCLC is initially sensitive to chemotherapy, remissions are short-lived. The relapse is induced by chemotherapy-selected tumor stem cells, which express the AC133 epitope of the CD133 stem cell marker. We studied the effectiveness of AC133-specific CAR T cells post-chemotherapy using human primary SCLC and an orthotopic xenograft mouse model. AC133-specific CAR T cells migrated to SCLC tumor lesions, reduced the tumor burden, and prolonged survival in a humanized orthotopic SCLC model, but were not able to entirely eliminate tumors. We identified CD73 and PD-L1 as immune-escape mechanisms and combined PD-1-inhibition and CD73-inhibition with CAR T cell treatment. This triple-immunotherapy induced cures in 25% of the mice, without signs of graft-versus-host disease or bone marrow failure. AC133+ cancer stem cells and PD-L1+CD73+ myeloid cells were detectable in primary human SCLC tissues, suggesting that patients may benefit from the triple-immunotherapy. We conclude that the combination of AC133-specific CAR T cells, anti-PD-1-antibody and CD73-inhibitor specifically eliminates chemo-resistant tumor stem cells, overcomes SCLC-mediated T cell inhibition, and might induce long-term complete remission in an otherwise incurable disease.

Retraction notice to "Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer" [Canc. Lett. 520 (2021) 385-399].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Following the publication of the above article, the Editor was notified that an error occurred in which all images were published with incorrect versions. The Editor has taken the decision that the manuscript is no longer acceptable in its current form, nor with a corrigendum, as the extensive changes to the figures and publication would lead to ambiguity for our readers. We have therefore made the decision to retract this manuscript from Cancer Letters with the possibility of resubmission and republication of the manuscript in its corrected form after peer review.

High diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of adolescent pulmonary tuberculosis.

BACKGROUND: The microbiological diagnosis of pulmonary tuberculosis (Tb) in a pediatric population is hampered by both low pathogen burden and noncompliance with sputum sampling. Although endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been found useful for the evaluation of mediastinal pathologies in adults, for children, sparse data are available. Here, we have evaluated EBUS-TBNA as a diagnostic procedure in children and adolescents with suspected pulmonary Tb. METHODS: In this retrospective analysis, we reviewed the charts of unaccompanied refugee minors (URM) who were admitted between January 2016 and July 2018 and who, during their initial medical screening upon arrival in Germany, were found to have abnormal radiological pulmonary and mediastinal findings and/or immunological results indicative of Tb. For each patient, basic sociodemographic data, clinical features and data on diagnostic procedures performed were assessed. These included imaging, immunodiagnostic tests and microbiological data derived from sputum, bronchoalveolar lavage, EBUS-TBNA, bronchoscopy and pleural fluid sampling. All patients who underwent invasive sampling procedures were included in the study. RESULTS: Out of 42 URM with suspected Tb, 34 fulfilled the study's inclusion criteria. Ages ranged from 14 to 17 years. All were of African origin, with 70.0% coming from Somalia, Eritrea and Ethiopia. Among the 21 patients for whom EBUS-TBNA was performed, the diagnostic yield was high: 66.7% positive results (MTb detected either by acid-fast stain, culture or PCR in 4.8, 42.9 and 61.9% of samples, respectively). Multidrug-resistant MTb was found in two patients from Somalia. No complications were associated with the procedure. Overall, pulmonary Tb was diagnosed in 29 patients (85.3%), miliary Tb in two patients (5.9%) and latent Tb in three patients (8.8%). CONCLUSIONS: EBUS-TBNA is a sensitive and safe method with high diagnostic yield in the evaluation of pediatric patients with mediastinal pathology and suspected Tb.

RETRACTED: Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Following the publication of the above article, the Editor was notified that an error occurred in which all images were published with incorrect versions. The Editor has taken the decision that the manuscript is no longer acceptable in its current form, nor with a corrigendum, as the extensive changes to the figures and publication would lead to ambiguity for our readers. We have therefore made the decision to retract this manuscript from Cancer Letters with the possibility of resubmission and republication of the manuscript in its corrected form after peer review.

Mucinous cystadenocarcinoma arising from mucinous cystadenoma of the lung: case report and review of the literature.

Mucinous cystadenoma is a benign tumor commonly found in the pancreas, the ovaries or the appendix. Only very few cases of these tumors originating from the lungs have been reported worldwide, with even less cases describing malignant transformation. We present the case of a 58-year-old woman with a history of recurrent pulmonary infections who underwent left upper lobectomy for lung abscess and was initially diagnosed with pulmonary mucinous cystadenoma (PMCA). Upon thorough immunohistochemical workup, especially due to carcinoembryonic antigen (CEA) positivity, intramucinous singlet cells were eventually diagnostic for invasive carcinoma, in this case a mucinous cystadenocarcinoma arising from a PCMA. PMCA is a rare benign tumor whose potential for malignant transformation has not yet been fully understood. Due to the low number of cases further studies are needed to evaluate if there is a benefit of complete oncologic resection, provided the general condition of the patient allows it. A review of the currently available literature serves to better understand the clinical, radiological and histological features of this rare tumor.

Local Concentrations of CC-Chemokine-Ligand 18 Correlate with Tumor Size in Non-small Cell Lung Cancer and Are Elevated in Lymph Node-positive Disease.

BACKGROUND: The tumor microenvironment plays a critical role in tumor growth and spreading. Tumor-associated macrophages (TAM) make up a large proportion of the tumor mass and are one of the main producers of CC-chemokine ligand 18 (CCL18), which is believed to carry out important functions in the immunological interactions that promote tumor progression. MATERIALS AND METHODS: Cytokines/chemokines were measured in bronchoalveolar lavage (BAL) from the tumor site and serum before and after resection in patients with proven non-small cell lung cancer (NSCLC). RESULTS: CCL18 concentrations in BAL positively correlated with the radiologically determined tumor volume (r=0.72, p=0.0003) in NSCLC. In addition, tumors with lymph-node metastasis exhibited significantly higher CCL18 concentrations in BAL (p=0.049) than those without. Serum CCL18 concentrations did not differ significantly before and after tumor resection. CONCLUSION: The increased release of CCL18 with greater tumor size is most likely due to the accompanied growth of leukocyte infiltrate. With previous findings taken into account, this could be one factor contributing to tumor invasiveness and particularly lymphatic spread in patients with larger tumors.

Altered purinergic signaling in the tumor associated immunologic microenvironment in metastasized non-small-cell lung cancer.

OBJECTIVES: Purines are well-known as intracellular sources for energy but they also act as extracellular signaling molecules. In the recent years, there has been a growing interest in the therapeutic potential of purinergic signaling for cancer treatment. This is the first study to analyze lung purine levels and purinergic receptors in non-small-cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: In this prospective clinical trial we enrolled 26 patients with NSCLC and 21 patients with chronic obstructive pulmonary disease (COPD) without signs of malignancy. The purine concentrations were analyzed in bronchoalveolar lavage fluid (BALF) using fluorescent/luminescent assays. Expression of purinergic receptors and ectonucleotidases were analyzed using real time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Patients with NSCLC have significantly lower ATP and ADP concentrations in BALF than patients with COPD (p=0.006 and p=0.009). Expression of the ectonucleotidase CD39 is significantly higher in BAL cells from cancer patients compared to COPD (p=0.001) as well as in metastasized tumors compared to non-metastasized tumors (p=0.009). Receptor-analysis revealed a higher expression of P2X4 (p=0.03), P2X7 (p=0.001) and P2Y1 (p=0.003) in BAL cells of tumors with distant metastasis. CONCLUSION: Our data suggests a role for CD39 in lung cancer tumor microenvironment, influencing tumor invasiveness and metastasization. Potentially the increased degradation of ATP and ADP leads to a subversion of their anti-neoplastic effects. Furthermore P2Y1, P2X4 and P2X7 receptors are upregulated in BAL cells in metastatic disease. Our findings might facilitate the identification of new therapeutic targets for cancer immunotherapy.

mRNA and miRNA analyses in cytologically positive endobronchial ultrasound-guided transbronchial needle aspiration: implications for molecular staging in lung cancer patients.

BACKGROUND: Lung cancer is highly aggressive and tends to metastasize early. Therefore, accurate mediastinal staging is important for therapeutic decision making. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as a minimally invasive procedure for mediastinal lymph node sampling and cancer staging. Classical EBUS-TBNA cytology has been combined with molecular staging techniques to improve sensitivity and specificity. This study aimed to assess mRNA integrity in samples acquired by EBUS-TBNA in the clinics. As proof-of-principle experiments, we also investigated whether stable miRNA could be detected in these samples. METHODS: Integrity of mRNA isolated from tumor-positive EBUS-TBNA samples was assessed by calculating the RNA integrity number (RIN). In addition, 4 microRNAs were investigated (miRNA 21, miRNA 155, miRNA 200c, and miRNA 34a) because their relation to lung cancer has been documented recently. A group of patients with benign mediastinal lymphadenopathy served as a control. RESULTS: mRNA isolated from EBUS-TBNA samples was nearly completely degraded if handled under clinical conditions (RIN <5). Intact miRNA was detected in all samples, with no nonspecific amplification in negative control samples. miRNA 21 and miRNA 200c levels were significantly higher in tumor-positive than in control samples (miRNA 21: median, 325,678 [range, 34,822-583,502] vs. 801,430 (range, 17,013-5,362,145]; P < .05; miRNA 200c: median, 9,198 [range, 610-211,121] vs. 42,870 [range, 0-926,252]; P < .05). CONCLUSIONS: Under clinical conditions, mRNA detection is likely unsuitable for improving sensitivity of EBUS-TBNA-facilitated cancer staging. In contrast, detection of miRNA combined with EBUS-TBNA cytology may improve staging sensitivity.

Implementation and effectiveness of a hospital smoking cessation service in Germany.

OBJECTIVE: Hospitalized smokers are often highly motivated to quit and receptive to assistance. There are few published accounts of hospital-based smoking cessation programmes implemented outside of a trial setting, particularly outside North America. We describe the implementation and effectiveness of a dedicated smoking cessation service in Freiburg, Germany. METHODS: Measures of implementation (e.g. number of patients referred and consenting to participate, receipt of post-discharge support) and effectiveness are presented. RESULTS: In the first 2 years of the service, 1432 patients were referred. Over half (55.3%) of counselled smokers agreed to participate. Sustained abstinence for 6 months was achieved by 28.0% (missing cases coded as smokers), whereas 7-day point prevalence rates were between 30 and 35% at 3, 6 and 12 months. Those who received 4+ post-discharge calls were more likely to achieve sustained abstinence, as were older smokers, those with higher self-efficacy, and cardiovascular patients. CONCLUSION: Hospitalized patients in Germany are receptive to the offer of bedside counselling and to phone support post-discharge, and success rates are comparable to those achieved in other countries. PRACTICE IMPLICATIONS: The findings argue strongly for the routine identification of smokers upon hospital admission, and the availability of cessation support both during hospitalization and following discharge.

Changes in lung function after surgery for mesothelioma.

BACKGROUND: The effect of pleurectomy/decortication or extrapleural pleuropneumonectomy on pulmonary function has not yet been evaluated. The aim of this study was to determine the parameters of pulmonary function before and after pleurectomy/decortication or extrapleural pleuropneumonectomy. METHODS: We conducted a review of 48 patients with unilateral malignant pleural mesothelioma who underwent pleurectomy/decortication or extrapleural pleuropneumonectomy. Data including medical history, histology, survival, and pre- and postoperative pulmonary function were extracted from the medical database of the University Medical Center Freiburg, or sought by telephone interview with the general practitioner or patients. RESULTS: 25 patients underwent extrapleural pleuropneumonectomy and 23 had pleurectomy/decortication. Pulmonary function was not significantly reduced in the pleurectomy/decortication group postoperatively. In the extrapleural pleuropneumonectomy group, the median preoperative total lung capacity of 4.8 L (77.7%) differed significantly from the postoperative total lung capacity of 3.5 L (55.3%; p <0.0006). The median vital capacity was significantly reduced from 2.8 L (77.7%) preoperatively to 1.8 L (47.6%) postoperatively (p <0.0002). Other parameters were also highly significantly reduced after extrapleural pleuropneumonectomy. CONCLUSIONS: Pleurectomy/decortication preserved good pulmonary function, whereas extrapleural pleuropneumonectomy significantly reduced pulmonary function, which may lead to dyspnea and influence the quality of life of these patients.

Morbidity and mortality in patients with usual interstitial pneumonia (UIP) pattern undergoing surgery for lung biopsy.

BACKGROUND: Previous studies revealed that surgical lung biopsy in usual interstitial pneumonia (UIP) patients is accompanied with higher morbidity and mortality. The aim of this retrospective analysis was to assess morbidity and mortality of patients with suspected UIP undergoing surgical lung biopsy. METHODS: We conducted a retrospective study of 45 patients with suspected UIP pattern undergoing surgical biopsy for diffuse pulmonary infiltrates in our department. Data concerning medical history, histology, and survival status were extracted from the medical database of the University Medical Center Freiburg. RESULTS: UIP was diagnosed by experienced pneumo-pathologists according to the criteria of American Thoracic Society/European Respiratory Society (ATS/ERS) consensus classification. Due to adhesions the surgeon decided in two patients to perform wedge resection via open surgery. In 43 patients lung biopsy was performed via Video-assisted thoracoscopy (VATS). No intraoperative complications were observed. Postoperative complications consisted of bradyarrhythmia (n = 1), gastrointestinal bleeding (n = 1), bacterial pneumonia (n = 1), candida pneumonia (n = 1) and acute exacerbation (n = 1). There was no 30-day mortality, but one patient was lost in follow-up and therefore censored. The intraoperative placed thoracic drain was removed at the first postoperative day in most cases (mean day of removal 1.9, ±2.6). The mean length of hospital stay was 8.1 days (±6.8). CONCLUSIONS: We conclude that surgical biopsy can be safely performed in patients with suspected UIP.

MAGE qPCR improves the sensitivity and accuracy of EBUS-TBNA for the detection of lymphatic cancer spread.

INTRODUCTION: Microscopic examination of histologic slides or cytologic specimens of mediastinal lymph node samples obtained by diagnostic mediastinoscopy or endobronchial ultrasound-guided fine-needle aspiration (EBUS-TBNA) is routinely used for the staging of lung cancer patients. Therefore, we explored whether the detection of tumor-associated mRNA in lymph node samples from patients with suspected lung cancer adds diagnostic accuracy to conventional histopathological staging. METHODS: We examined 202 lymph nodes obtained by EBUS-TBNA or mediastinoscopy from 89 patients with lung cancer. Lymph node samples from patients with nonmalignant disease were available as controls (60 samples from 31 patients). Real-time quantitative mRNA analysis was performed for melanoma antigen-A genes (MAGE-A 1-6, MAGE-A 12) using a LightCycler 480 instrument. RESULTS: MAGE transcript levels in control and cancer patients differed widely, and the 95% confidence interval served to define the threshold between negative and positive samples. MAGE 1 to 6 transcripts were detected in 35 of 122 (28.7%) lymph nodes obtained by EBUS-TBNA and 16 of 80 (20.0%) lymph nodes obtained by mediastinoscopy. MAGE 12 transcripts were detected in 10 of 122 (8.2%) lymph nodes obtained by EBUS-TBNA and 9 of 80 (11.3%) lymph nodes obtained by mediastinoscopy. Although the accuracy of histopathological diagnosis after EBUS-TBNA and mediastinoscopy was 69.6% and 84.1%, respectively, it increased to 81.2% and 86.4%, respectively, when combined with MAGE-quantitative polymerase chain reaction. CONCLUSIONS: The combination of EBUS-TBNA and MAGE-quantitative polymerase chain reaction increases the accuracy of tumor cell detection to the level seen with mediastinoscopy.