Osimertinib-induced DNA resistance mutations in cerebrospinal fluid of EGFR mutated NSCLC patients developing leptomeningeal metastases: ORA-LM study.

BACKGROUND: Diagnosis and treatment of leptomeningeal metastases (LM) in epidermal growth factor receptor mutation positive (EGFRm+) NSCLC is challenging. We aimed to identify resistance mechanisms (RM) to osimertinib in cerebrospinal fluid (CSF) and plasma. METHODS: EGFRm+ patients with new or progressive LM during osimertinib were enrolled. NGS Ampliseq was performed on DNA isolated from CSF. Patients were prescribed osimertinib dose escalation (DE, 160mg QD) following lumbar puncture. Clinical and radiological response was evaluated four weeks after osimertinib DE. RESULTS: Twenty-eight patients were included. The driver mutation was identified in 93% of CSF samples (n=26). Seven (27%) harbored ≥1 RM. Twenty-five patients (89%) were prescribed osimertinib DE. Four weeks afterwards, symptoms improved in five patients, stabilized in nine and worsened in eleven patients. Twenty-one (84%) patients underwent MR imaging. Four showed radiological improvement, fourteen stabilization, and three worsening. CONCLUSIONS: In 27% of patients an RM was found in CSF ctDNA, none of which are targetable at time of writing, and clinical efficacy of osimertinib DE seems limited. There is much to gain in diagnostic as well as therapeutic strategies in EGFRm+ NSCLC LM.

Observer variation of 2-deoxy-2-[F-18]fluoro-D-glucose-positron emission tomography in mediastinal staging of non-small cell lung cancer as a function of experience, and its potential clinical impact.

PURPOSE: To test the extent of variation among nuclear medicine physicians with respect to staging non-small cell lung cancer with positron emission tomography (PET). PROCEDURES: Two groups of nuclear medicine physicians with different levels of PET experience reviewed 30 PET scans. They were requested to identify and localize suspicious mediastinal lymph nodes (MLN) using standardized algorithms. Results were compared between the two groups, between individuals, and with expert reading. RESULTS: Overall we found good interobserver agreement (kappa 0.65). Experience with PET translated into a better ability to localize MLN stations (68% vs. 51%, respectively), and experienced readers appeared to be more familiar with translating PET readings into clinically useful statements. CONCLUSIONS: Although our results suggest that clinical experience with PET increases observers' ability to read and interpret results from PET adequately, there is room for improvement. Experience with PET does not necessarily improve the accuracy of image interpretation.

Cardiac function and position more than 5 years after pneumonectomy.

BACKGROUND: Pneumonectomy not only reduces the pulmonary vascular bed but also changes the position of the heart and large vessels, which may affect the function of the heart. We investigated long-term effects of pneumonectomy on right ventricular (RV) and left ventricular (LV) function and whether this function is influenced by the side of pneumonectomy or the migration of the heart to its new position. METHODS: In 15 patients who underwent pneumonectomy and survived for more than 5 years, we evaluated by dynamic magnetic resonance imaging the function of the RV and LV and the position of the heart within the thorax. RESULTS: Long-term effect of pneumonectomy on the position of the heart is characterized by a lateral shift after right-sided pneumonectomy and rotation of the heart after left-sided pneumonectomy. Postoperatively, heart rate was high (p = 0.006) and stroke volume was low (p = 0.001), compared with the reference values, indicating impaired cardiac function. Patients after right-sided pneumonectomy had an abnormal low RV end-diastolic volume of 99 +/- 29 mL together with a normal LV function. No signs of RV hypertrophy were found. In left-sided pneumonectomy patients, RV volumes were normal whereas LV ejection fraction was abnormally low. CONCLUSIONS: The long-term effects of pneumonectomy on the position of the heart are characterized by a lateral shift in patients after right-sided pneumonectomy and rotation of the heart in patients after left-sided pneumonectomy. Overall, cardiac function in long-term survivors after pneumonectomy is compromised, and might be explained by the altered position of the heart.

Influence of introduction of positron emission tomography on adherence to mediastinal staging protocols and performance of mediastinoscopy.

PURPOSE: In this study, we investigated the impact of implementation of [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) in daily practice on adherence to mediastinal staging protocols and performance of mediastinoscopy in non-small-cell lung cancer (NSCLC) patients who are possible candidates for surgical resection. Institutional review board approval was obtained. PATIENTS AND METHODS: From a nonuniversity teaching hospital and three surrounding community hospitals in Eindhoven, the Netherlands, we studied data from 143 patients with NSCLC who underwent mediastinoscopy and/or thoracotomy in three consecutive periods (1, 0 to 9 months; 2, 10 to 18 months; and 3, 19 to 31 months) after introduction of PET. Mediastinoscopy was indicated in case of enlarged and/or PET-positive nodes. Adherence to these surgical mediastinal staging guidelines and the performance of PET and mediastinoscopy were investigated and compared between the three periods and with our previous study before introduction of PET. RESULTS AND CONCLUSION: Guidelines for indicating mediastinoscopy were adequately followed in significantly more instances after introduction of PET (80%), compared with the period before PET (66%). Optimal yield (lymph node stations 4, right and left, and 7) of mediastinoscopy (in 27% of patients) was not significantly different from the period before PET (39% of patients). Compared with the historical data, the percentage of positive mediastinoscopies increased from 15.5 to 17.6 (not significant). We found no significant differences between the three consecutive periods with regard to adequacy of indicating and performance of mediastinoscopy. After introduction of PET, adherence to staging guidelines with respect to mediastinoscopy improved. Although fewer mediastinoscopies had an optimal yield, more proved to be positive for metastases. Nevertheless, when a mediastinoscopy is indicated, surgeons must be encouraged to reach an optimal yield because PET positive nodes might be false negative. This occurred in 5% to 6% of all patients.

Surgical mediastinal staging in daily practice.

STUDY OBJECTIVES: An adequately staged mediastinum remains obligatory in patients with NSCLC prior to surgery. In this study, we investigated the accuracy of preoperative surgical mediastinal staging procedures in four hospitals. SETTING: Non-university teaching hospital and three surrounding community hospitals in Eindhoven, The Netherlands. PATIENTS, MEASUREMENTS AND RESULTS: Patients with NSCLC who underwent mediastinoscopy and/or thoracotomy, between 1993 and 1999. Adherence to guidelines for indicating and performing mediastinoscopy were investigated and compared in four hospitals. Guidelines for indicating mediastinoscopy were adequately followed in two-thirds of cases. Mediastinoscopy was performed according to gold standards in 40% of cases. The hospital with the smallest number of evaluated patients scored the worst. Postoperatively, 17% of patients appeared to have "unforeseen N2-3 disease". In approximately 18% of these "upstaged" patients, thoracotomy could have been prevented, if guidelines had been followed adequately. CONCLUSIONS: In clinical practice the adherence to staging guidelines with respect to mediastinoscopy is insufficient in one-third of patients. Furthermore, mediastinoscopy was performed according to gold standards in 40% of patients.

Actual and predicted postoperative changes in lung function after pneumonectomy: a retrospective analysis.

STUDY OBJECTIVES: Little is known about long-term effects of pneumonectomy on lung function and exercise tolerance. We evaluated the long-term validity of two formulas frequently used to predict postoperative lung function, as well as trends in postoperative lung function and late postoperative exercise capacity. SETTING: Nonuniversity teaching hospital of Eindhoven, the Netherlands. PATIENTS: Patients who underwent pneumonectomy between 1993 and 1998 and survived for > 1 year after the operation. MEASUREMENTS AND RESULTS: Lung function and exercise test data of 32 patients were analyzed. Postoperative FVC and FEV1 according to Kristersson/Olsen (split function of resected lung) and Juhl and Frost (number of segments to be resected) were calculated and compared with observed values measured in the third postoperative year. Calculated values correlated well with observed values, whereas Kristersson/Olsen appeared to be more accurate than Juhl and Frost. When considering trends in FEV1, we found a mean decline of 44 mL/yr; only three patients (12%) showed a rapid decline of > 100 mL/yr. Of 14 patients (44%), postoperative maximal exercise capacity was impaired due to ventilatory limitation. CONCLUSIONS: The Kristersson/Olsen formula was more accurate in predicting postoperative lung function in the third postoperative year in pneumonectomy patients. Although the annual decline in FEV1 in these patients is almost the same as in healthy patients without COPD, pneumonectomy has serious implications on exercise capacity in many patients.