Transbronchial cryobiopsy in unexplained, severe ARDS: a single center retrospective case series.

BACKGROUND: Acute respiratory distress syndrome (ARDS) deptics an acute form of lung infjury with often severe respiratory impairment that requires invasive mechanical ventilation. Since ARDS can be caused by several distinct etiologies, correct characterization is desired and frequently challenging. Surgical lung biopsy was previously reported to be of additive value. We describe our institutional experience using transbronchial cryobiopsy (TBCB) for further characterization of severe and unexplained ARDS cases. CASE PRESENTATION: We retrospectively collected data of TBCB in patients with unexplained ARDS, whether with or without ECMO-support. Between 2019 and 2020 TBCB was performed in eight patients. Decision for the intervention was decided in multidisciplinary discussion. Five patients were treated with ECMO. The median duration of invasive ventilation before TBCB was 24 days. TBCB was performed in one segment, that was prophylactically occluded by Watanabe spigot or swab after the procedure. Histology results and their contribution to further therapeutic decisions were analyzed. Histology revealed five diffuses alveolar damage, one acute fibrinoid organizing pneumonia, one cryptogenic organizing pneumonia and one lung cancer. All results contributed to the decision of further management. While no pneumothorax or severe endobronchial bleeding occurred, two delayed hematothoraces needed surgical treatment. No patients died due to TBCB. CONCLUSION: TBCB is feasible in ARDS even during ECMO treatment. Histologic results can play a significant role in therapeutic and ethic discussion to guide the patients' care. Side effects should be considered and monitored.

Endoscopic Lung Volume Reduction with One-Way Valves in Patients with Severe Chronic Obstructive Pulmonary Disease with Hypercapnia.

BACKGROUND: Robust clinical evidence on the efficacy and safety of endoscopic lung volume reduction (ELVR) with one-way valves in patients with severe lung emphysema with chronic hypercapnic respiratory failure is lacking. OBJECTIVE: The aim of this study was to compare patient characteristics, clinical outcome measures, and incidences of adverse events between patients with severe COPD undergoing ELVR with one-way valves and with either a partial pressure of carbon dioxide (pCO2) of ≤45 mm Hg or with pCO2 >45 mm Hg. METHODS: This was a multicentre prospective study of patients with severe lung disease who were evaluated based on lung function, exercise capacity (6-min walk test [6-MWT]), and quality-of-life tests. RESULTS: Patients with pCO2 ≤45 mm Hg (n = 157) and pCO2 >45 mm Hg (n = 40) showed similar baseline characteristics. Patients with pCO2 ≤45 mm Hg demonstrated a significant increase in forced expiratory volume in 1 s (p < 0.001), a significant decrease in residual volume (RV) (p < 0.001), and significant improvements in the quality of life and 6-MWT at the 3-month follow-up. Patients with pCO2 >45 mm Hg had significant improvements in RV only (p < 0.05). There was a significant decrease in pCO2 between baseline and follow-up in hypercapnic patients, relative to the decrease in patients with pCO2 ≤45 mm Hg (p = 0.008). Patients who were more hypercapnic at baseline showed a greater reduction in pCO2 after valve placement (r = -0.38, p < 0.001). Pneumothorax was the most common adverse event in both groups. CONCLUSIONS: ELVR with one-way valves seems clinically beneficial with a remarkably good safety profile for patients with chronic hypercapnic respiratory failure.

Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis.

BACKGROUND: Among patients meeting diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH), there is an emerging lung phenotype characterised by a low diffusion capacity for carbon monoxide (DLCO) and a smoking history. The present study aimed at a detailed characterisation of these patients. METHODS: We analysed data from two European pulmonary hypertension registries, COMPERA (launched in 2007) and ASPIRE (from 2001 onwards), to identify patients diagnosed with IPAH and a lung phenotype defined by a DLCO of less than 45% predicted and a smoking history. We compared patient characteristics, response to therapy, and survival of these patients to patients with classical IPAH (defined by the absence of cardiopulmonary comorbidities and a DLCO of 45% or more predicted) and patients with pulmonary hypertension due to lung disease (group 3 pulmonary hypertension). FINDINGS: The analysis included 128 (COMPERA) and 185 (ASPIRE) patients with classical IPAH, 268 (COMPERA) and 139 (ASPIRE) patients with IPAH and a lung phenotype, and 910 (COMPERA) and 375 (ASPIRE) patients with pulmonary hypertension due to lung disease. Most patients with IPAH and a lung phenotype had normal or near normal spirometry, a severe reduction in DLCO, with the majority having no or a mild degree of parenchymal lung involvement on chest computed tomography. Patients with IPAH and a lung phenotype (median age, 72 years [IQR 65-78] in COMPERA and 71 years [65-76] in ASPIRE) and patients with group 3 pulmonary hypertension (median age 71 years [65-77] in COMPERA and 69 years [63-74] in ASPIRE) were older than those with classical IPAH (median age, 45 years [32-60] in COMPERA and 52 years [38-64] in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries). While 99 (77%) patients in COMPERA and 133 (72%) patients in ASPIRE with classical IPAH were female, there was a lower proportion of female patients in the IPAH and a lung phenotype cohort (95 [35%] COMPERA; 75 [54%] ASPIRE), which was similar to group 3 pulmonary hypertension (336 [37%] COMPERA; 148 [39%] ASPIRE]). Response to pulmonary arterial hypertension therapies at first follow-up was available from COMPERA. Improvements in WHO functional class were observed in 54% of patients with classical IPAH, 26% of patients with IPAH with a lung phenotype, and 22% of patients with group 3 pulmonary hypertension (p<0·0001 for classical IPAH vs IPAH and a lung phenotype, and p=0·194 for IPAH and a lung phenotype vs group 3 pulmonary hypertension); median improvements in 6 min walking distance were 63 m, 25 m, and 23 m for these cohorts respectively (p=0·0015 for classical IPAH vs IPAH and a lung phenotype, and p=0·64 for IPAH and a lung phenotype vs group 3 pulmonary hypertension), and median reductions in N-terminal-pro-brain-natriuretic-peptide were 58%, 27%, and 16% respectively (p=0·0043 for classical IPAH vs IPAH and a lung phenotype, and p=0·14 for IPAH and a lung phenotype vs group 3 pulmonary hypertension). In both registries, survival of patients with IPAH and a lung phenotype (1 year, 89% in COMPERA and 79% in ASPIRE; 5 years, 31% in COMPERA and 21% in ASPIRE) and group 3 pulmonary hypertension (1 year, 78% in COMPERA and 64% in ASPIRE; 5 years, 26% in COMPERA and 18% in ASPIRE) was worse than survival of patients with classical IPAH (1 year, 95% in COMPERA and 98% in ASPIRE; 5 years, 84% in COMPERA and 80% in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries). INTERPRETATION: A cohort of patients meeting diagnostic criteria for IPAH with a distinct, presumably smoking-related form of pulmonary hypertension accompanied by a low DLCO, resemble patients with pulmonary hypertension due to lung disease rather than classical IPAH. These observations have pathogenetic, diagnostic, and therapeutic implications, which require further exploration. FUNDING: COMPERA is funded by unrestricted grants from Acceleron, Bayer, GlaxoSmithKline, Janssen, and OMT. The ASPIRE Registry is supported by Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Linear Endobronchial Ultrasound in the Era of Personalized Lung Cancer Diagnostics-A Technical Review.

Major advances in molecular profiling for available targeted treatments and immunotherapy for lung cancer have significantly increased the complexity of tissue-based diagnostics. Endobronchial ultrasound-guided transbronchial needle aspirations (EBUS-TBNA) are commonly performed for diagnostic biopsies and lymph node staging. EBUS-TBNA has increasingly become one of the main sources of tumor cells for molecular analyses. As a result, there is a growing need for high quality EBUS-TBNA samples with adequate cellularity. This has increased the technical demands of the procedure and has created additional challenges, many of which are not addressed in the current EBUS guidelines. This review provides an overview of current evidence on the technical aspects of EBUS-TBNA in light of comprehensive sample processing for personalized lung cancer management. These include sonographic lymph node characterization, optimal needle choice, suction biopsy technique, and the role of rapid on-site evaluation. Attention to these technical details will be important to maximize the throughput of EBUS-TBNA biopsies for molecular testing.

DNA methylation of PTGER4 in peripheral blood plasma helps to distinguish between lung cancer, benign pulmonary nodules and chronic obstructive pulmonary disease patients.

BACKGROUND/INTRODUCTION: In contrast to patients who present with advanced stage lung cancer and associated poor prognosis, patients with early-stage lung cancer may be candidates for curative treatments. The results of the NELSON lung cancer screening trial are expected to stimulate the development and implementation of a lung cancer screening strategy in most countries. Widespread use of chest computed tomography scans will also result in the detection of solitary pulmonary nodules. Because reliable biomarkers to distinguish between malignant and benign lesions are lacking, tissue-based histopathological diagnostics remain the gold standard. In this study, we aimed to establish a test to assess the predictive ability of DNA hypermethylation of SHOX2 and PTGER4 in plasma to discriminate between patients with 1.) lung cancer, 2.) benign lesions, and 3.) patients with chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: We retrospectively analysed SHOX2 and PTGER4 methylation in 121 prospectively collected plasma samples of patients with lung cancer (group 1A), benign lesions (group 1B), and COPD without nodules (group 2). RESULTS: PTGER4 DNA hypermethylation was more frequently observed in patients with lung cancer than in controls (p = 0.0004). Results remained significant after correction for tumour volume, smoking status, age, and eligibility for the NELSON trial. CONCLUSIONS: Detection of methylated PTGER4 in plasma DNA may serve as a biomarker to support clinical decision-making in patients with pulmonary lesions at lung cancer screening in high-risk populations. Further exploration in prospective studies is warranted.

Joint Statement of the German Respiratory Society and German Society of Thoracic Surgery in Cooperation with the German Radiological Society: Structural Prerequisites of Centres for Interventional Treatment of Emphysema.

Interventional treatment of emphysema offers a wide range of surgical and endoscopic options for patients with advanced disease. Multidisciplinary collaboration of pulmonology, thoracic surgery, and imaging disciplines in patient selection, therapy, and follow-up ensures treatment quality. The present joint statement describes the required structural and quality prerequisites of treatment centres. This is a translation of the German article "Positionspapier der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin und der Deutschen Gesellschaft für Thoraxchirurgie in Kooperation mit der Deutschen Röntgengesellschaft: Strukturvoraussetzungen von Zentren für die interventionelle Emphysemtherapie" Pneumologie. 2020;74:17-23.

Durvalumab after definitive chemoradiotherapy in locally advanced NSCLC: Data of the German EAP.

Following the PACIFIC trial, durvalumab has been approved by the European Medicines Agency (EMA) for consolidation of locally advanced PD-L1-positive NSCLC after chemoradiotherapy (CRT). Patients were treated with durvalumab in the EAP from 22.11.2017 to 15.10.2018 allowing analysis of its efficacy and safety. 211 patients were registered by 90 German centres. Data were collected retrospectively by questionnaire and queries. 56 centres reported data on 126 patients who actually received at least one cycle of durvalumab. In contrast to the PACIFIC-trial population, some patients with oligometastatic disease and a history of autoimmune disease are included in the EAP population. Information on PD-L1 status was obtained for 111 patients. Baseline data include age, gender, ECOG, stage (IASLC 8th ed.), and smoking history. Treatment data include mode of chemoradiotherapy, used chemotherapy agent, and duration of durvalumab therapy. Adverse evants were documented according to CTAEC 5.0. Data were analysed for progression-free survival (PFS), overall survival (OS), and adverse events (AE). The results were published in Lung Cancer [1].

Capability of processed EEG parameters to monitor conscious sedation in endoscopy is similar to general anaesthesia.

BACKGROUND: Reliable and safe sedation is a prerequisite for endoscopic interventions. The current standard is rather safe, yet, an objective device to measure sedation depth is missing. To date, anaesthesia monitors based on processed electroencephalogram (EEG) have not been utilised in conscious sedation. OBJECTIVE: To investigate EEG parameters to differentiate consciousness in endoscopic propofol sedation. METHODS: In total, 171 patients aged 21-83 years (ASA I-III) undergoing gastrointestinal and bronchial endoscopy were enrolled. Standard monitoring and a frontotemporal two-channel EEG were recorded. The state of consciousness was identified by repeated requests to squeeze the investigator's hand. RESULTS: In total, 1132 state-of-consciousness (SOC) transitions were recorded in procedures ranging from 5 to 69 min. Thirty-four EEG parameters from the frequency domain, time-frequency domain and complexity measures were calculated. Area under the curve ranged from 0.51 to 0.82 with complexity and optimised frequency domain parameters yielding the best results. CONCLUSION: Prediction of the SOC with processed EEG parameters is feasible, and the results for sedation in endoscopic procedures are similar to those reported from general anaesthesia. These results are insufficient for a clinical application, but prediction capability may be increased with optimisation and modelling.

Crown-Cut Endobronchial Ultrasound Guided Transbronchial Aspiration Needle: First Real-World Experiences.

Advancements in personalized medicine have increased the demand for quantity and preservation of tissue architecture of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples. These demands may be addressed by the SonoTip TopGain® needle, which has a 3-point crown-cut design that contrasts with the standard single bevel design of the ViziShot 2®. The objective was to compare the SonoTip TopGain® and ViziShot 2® needles by considering biopsy sample characteristics, diagnostic accuracy, and patient safety. The primary endpoint of the study was the number of high-power fields (HPFs) in the center of the formalin-fixed paraffin-embedded cell block per sample. The lymph node with the highest probability for malignant infiltration based on size and sonographic appearance was chosen as the target lymph node for 20 patients. The same lymph node in each patient was sampled using both the ViziShot 2® and SonoTip TopGain® needles. The samples were measured, sliced, and analyzed by a pathologist. Sixteen patients were biopsied with both needles. Four patients could not be biopsied with the SonoTip TopGain® needle since it could not penetrate cartilage or be repositioned to bypass cartilage. HPFs and sample dimensions were significantly greater in the patients where sampling with the SonoTip TopGain® needle was possible (p = 0.007 and p = 0.005, respectively). Diagnostic accuracy and safety profiles were comparable. Significantly more material can be sampled using the SonoTip TopGain® needle when cartilage penetration can be avoided. This improves the yield for molecular workup in the era of personalized medicine.

Durvalumab after definitive chemoradiotherapy in locally advanced unresectable non-small cell lung cancer (NSCLC): Real-world data on survival and safety from the German expanded-access program (EAP).

BACKGROUND: Following the PACIFIC trial, durvalumab has been approved by the European Medicines Agency (EMA) for consolidation of locally advanced PD-L1-positive NSCLC after chemoradiotherapy (CRT). Patients were treated with durvalumab in the EAP from 22.11.2017 to 15.10.2018 allowing analysis of its efficacy and safety. METHODS: Data from 56 centres were analysed for adverse events (AE), progression-free survival (PFS), overall survival (OS). RESULTS: 126 patients actually received at least 1 cycle durvalumab. Compared to the PACIFIC trial, the EAP population had more advanced stage and included "oligometastatic" stage IV patients and patients with autoimmune disease. PFS (20.1 months) and OS (not reached) were similar in the EAP and the PACIFIC trial. 42.9 % completed 12 months of durvalumab without deaths during FU. Stage IV patients (n = 7) had encouraging OS (not reached at 27 months). Autoimmune disease did not affect survival. PFS and OS were similar in PD-L1-negative patients (n = 32) and PD-L1-positive patients (n = 79). CONCLUSIONS: Survival in the EAP was comparable to the PACIFIC trial. Selected stage IV patients and patients with autoimmune disease may benefit from durvalumab consolidation and should be included in future immuno-oncological trials. PD-L1 did not predict survival challenging the exclusion of PD-L1-negative patients from durvalumab consolidation. In summary, durvalumab consolidation is safe and effective in a European real-world setting.

[Challenges of the COVID-19 pandemic in gastrointestinal endoscopy: expectations and implementation of recommendations]. / Gastrointestinale Endoskopie in Zeiten der COVID-19-Pandemie: Umsetzung von Empfehlungen und Erwartungen für die Zukunft.

INTRODUCTION: The COVID-19 pandemic represents a major challenge for health care systems worldwide. Recent data suggests an increased risk for personnel of gastrointestinal (GI) endoscopy units for SARS-CoV-2 infections. Several societies have provided recommendations for the current situation, but their feasibility is unclear and real-world data on preparedness of endoscopy units are lacking. AIMS & METHODS: A web-based survey among German GI-endoscopy heads was conducted from April 1 to April 7, 2020. It comprised 33 questions based on the ESGE (European Society of Gastrointestinal Endoscopy) recommendations and was distributed electronically by the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS). RESULTS: Of 551 completed surveys, 202 (37 %) endoscopy units cancelled less than 40 % of their procedures. Small-volume units (< 4000 procedures/year) cancelled significantly less procedures than high-volume units (> 4000). Complete spatial separation of high-risk patients was possible in only 17 %. Most units systematically identified patients at risk (91 %) and used risk adapted personal protective equipment (PPE, 85 %). For the future, shortages in PPE (83 %), staff (69 %) and relevant financial losses (80 %) were expected. CONCLUSIONS: Recommendations on structural measures were only partially fulfilled and cancellations of procedures were heterogeneous. Clear definitions of indications to perform endoscopies during such a pandemic are needed. Further, structural recommendations should be adapted and strategies to compensate financial losses need to be developed.

Integration of Bronchoscopic Transesophageal Ultrasound Examination of the Left Adrenal Gland into Routine Lung Cancer Staging Workup: A Prospective Trial.

BACKGROUND: Endobronchial ultrasound (EBUS) with transbronchial needle aspiration increases the diagnostic yield of lung cancer staging. The left adrenal gland (LAG) is a common site for lung cancer metastasis. The modality of transesophageal examination with an EBUS bronchoscope (EUS-B) routinely for LAG has not been assessed. OBJECTIVE: The aim of this study was to prospectively assess if evaluation and tissue sampling of the LAG could routinely be implemented in an EBUS procedure. METHODS: Patients referred for EBUS between March and August 2017 had assessment of the LAG via EUS-B. Fine-needle aspiration (FNA) was performed in cases with a suspicious LAG. The detection rate, procedure time, and learning curve of four experienced EBUS-bronchoscopists was assessed, plus the diagnostic accuracy and complication rate of FNA. RESULTS: In total, 313 consecutive patients were included. The overall LAG detection rate was 87.5%. After the initial learning curve, the detection rate for all four bronchoscopists was >93%. The detection rate did not correlate with any patient characteristics. EUS-B-FNA revealed nine LAG metastases, with a sensitivity, specificity, and accuracy of 75%, 100%, and 99%, respectively. The mean EUS-B operation time was 194.4 s, with 594.8 s for FNA. There were no FNA-associated complications. CONCLUSIONS: Evaluation of the LAG with EUS-B could routinely be included in an EBUS procedure if necessary. A high detection rate can be achieved after an initial learning period. FNA of the LAG was feasible and safe. EUS-B of the LAG could be integrated into the usual EBUS/EUS-B procedure in lung cancer staging workup.

Bronchial Thermoplasty Including the Middle Lobe Bronchus Significantly Improves Lung Function and Quality of Life in Patients Suffering from Severe Asthma.

PURPOSE: Bronchial Thermoplasty (BT) is indicated in patients suffering from severe and symptomatic bronchial asthma despite maximal medical therapy. However, treatment of the right middle lobe (RML) bronchus is currently not recommended. The aim of this study was to investigate the safety and efficacy of BT if the RML bronchus is included. METHODS: BT was performed in 17 consecutive patients, quality of life and pulmonary function were characterized before and 90 days after BT completion. Furthermore, we performed a clean-up bronchoscopy following every BT. This study was approved by the IRB of the University of Essen (No. 17-7356 BO) and registered as a retrospective observational study at the German Clinical Trials Registry (No. DRKS 00011550). RESULTS: The median baseline values of FEV1 and Asthma Questionnaire of Life Quality (AQLQ) were 1.33 l (0.91; 1.73) and 3.01 (2.76; 3.61), respectively, and significantly improved 90 days after treatment with FEV 1 at 1.75 l (p-value 0.002) and AQLQ 3.8 (p-value < 0.05). Also the amount of oral corticosteroid necessity decreased significantly. No severe adverse events occurred due to the procedure. Clean-up bronchoscopies-when performed-revealed significant fibrinous exudation after every BT procedure. CONCLUSION: BT including the RML bronchus is feasible. Functionally limited patients with severe asthma could potentially profit. Due to the relevant fibrinous exudation, BT should be followed by clean-up bronchoscopy, not only after RML treatment.

A Prospective, Randomized Trial for the Comparison of 19-G and 22-G Endobronchial Ultrasound-Guided Transbronchial Aspiration Needles; Introducing a Novel End Point of Sample Weight Corrected for Blood Content.

BACKGROUND: The use of 22- or 21-gauge (G) endobronchial ultrasound (EBUS) needles are recommended for lung cancer diagnosis and staging. Performance of detailed molecular workup and programmed death ligand 1 (PD-L1) staining in lung cancer patients increases the demand for tissue. The aim of this prospective, randomized two-center trial was to compare 19-G and 22-G EBUS needles regarding tissue quality, diagnostic yield, feasibility, safety, performance, and blood content. PATIENTS AND METHODS: Patients with a computed tomography scan indicative of lung cancer with mediastinal or hilar lymph node metastases were prospectively enrolled and randomized for the use of either a 19-G or a 22-G EBUS needle. A blood content score from 0 to 2 was applied. Samples were weighed, tumor cells were counted per slide, and complications and final diagnoses were documented. RESULTS: We enrolled 107 patients (53 [49.5%] in the 19-G group/54 [50.5%] in the 22-G group) and samples were weighed immediately after performing EBUS. Samples obtained with a 19-G needle contained significantly more tissue (P = .0119). Non-small-cell lung cancer-infiltrated EBUS samples contained significantly more tumor cells when sampled with a 19-G needle (P = .0312). The diagnostic yield was equally adequate in both groups. Four moderate EBUS-related bleedings occurred (2 per group), hemostasis was rapidly achieved in all cases. Further complications did not occur. CONCLUSION: Endobronchial ultrasound-guided transbronchial needle aspirations with a 19-G needle contain significantly more tissue and tumor cells per slide with a safety profile similar to 22-G needles. Further research is needed to investigate the relevance of this finding in terms of molecular analyses and PD-L1 staining.

Endobronchial Ultrasound (EBUS) - Update 2017.

Endobronchial ultrasound (EBUS) has revolutionized the diagnosis of lung cancer over the last decade. This minimally invasive diagnostic method has also become increasingly important in the case of other diseases such as sarcoidosis, thereby helping to avoid unnecessary diagnostic interventions. This review article provides an update regarding EBUS and discusses current and future developments of this method.

Bronchoscopic Lung Volume Reduction with Endobronchial Valves in Low-FEV1 Patients.

BACKGROUND: Bronchoscopic lung volume reduction (BLVR) with valves has been shown to improve lung function, exercise capacity, and quality of life in patients with emphysema, but only few patients with forced expiratory volume in 1 s (FEV1) ≤20% predicted have been included in former studies. Although the procedure can be performed safely, pneumothorax is a frequent complication, which can be critical for these very severely diseased patients. OBJECTIVES: The aim of the study was to assess the safety of BLVR in patients with a very advanced stage of emphysema, as indicated by FEV1 ≤20% predicted. PATIENTS AND METHODS: Patients in whom BLVR was performed between January 2013 and August 2015 were included in this analysis if their baseline predicted FEV1 was ≤20%. BLVR, performed only if collateral ventilation was absent, achieved complete occlusion of the target lobe. All patients were closely monitored and were not discharged before the fourth day after BLVR. RESULTS: Twenty patients with FEV1 ≤20% predicted were included in the analysis. Lung volume reduction was achieved in 65% of the cases. Pneumothorax occurred in 4 cases (20%). No patient died. Lung function and exercise tolerance improved after 1 and 3 months, respectively. CONCLUSIONS: BLVR with valves can be safely performed in patients with FEV1 ≤20% predicted when close postprocedural monitoring is provided. Improvement in lung function and exercise capacity can be achieved.

Sequential X-irradiation induced acquired resistance to oxaliplatin but increased sensitivity to cisplatin in two human teratoma cell lines in vitro.

UNLABELLED: Cisplatin (CDDP) and oxaliplatin (OXA-P) are potential therapeutic drugs in the treatment of testicular cancer. However, the emergence of drug resistance has been documented not only in patients after chemotherapy but also subsequently to fractionated X-irradiation. Specific radiation-induced biochemical alterations may play a role in the observed resistance. Since irradiation influences the cellular responses to chemotherapy, this study investigated changes in the expression of key proteins in the regulation of DNA repair and apoptosis subsequent to sequential irradiation. MATERIALS AND METHODS: Logarithmically growing human teratocarcinoma cell lines 2101 EP and H 12.1 were irradiated (10 fractions of 4 Gy in vitro) to establish the sub-lines 2101 EP/DXR-10 and H 12.1/DXR-10. Radiosensitivity was assayed using a clonogenic survival assay. Drug response was assayed using a sulforhodamine B assay. Expression of p53, PARP, hMSH2 and Fas was detected by Western blotting. RESULTS: Both DXR-10 sub-lines showed a significant increase in sensitivity towards CDDP as compared to their parental cell line, however, there was a concomitant increase in resistance against OXA-P. No significant changes in radiosensitivity between parental and DXR-10 cell lines were observed. In addition, there was an up-regulation of PARP, p53, hMSH2 and Fas in the DXR-10 sub-lines, implicating induced damage tolerance and repair mechanisms following irradiation. CONCLUSION: These results suggest that radiation preceding chemotherapy might induce resistance to subsequent chemotherapy with oxaliplatin but not to cisplatin. This is a novel observation and, if confirmed, particularly in other tumor types, may have clinical implications.