Systematic and combined endosonographic staging of lung cancer (SCORE study).

Guidelines recommend endosonography for mediastinal nodal staging in patients with resectable nonsmall cell lung cancer (NSCLC). We hypothesise that a systematic endobronchial ultrasound (EBUS) evaluation combined with an oesophageal investigation using the same EBUS bronchoscope (EUS-B) improves mediastinal nodal staging versus the current practice of targeted positron emission tomography (PET)-computed tomography (CT)-guided EBUS staging alone.A prospective, multicentre, international study (NCT02014324) was conducted in consecutive patients with (suspected) resectable NSCLC. After PET-CT, patients underwent systematic EBUS and EUS-B. Node(s) suspicious on CT, PET, EBUS and/or EUS-B imaging and station 4R, 4L and 7 (short axis ≥8 mm) were sampled. For patients without N2/N3 disease determined on endosonography, surgical-pathological staging was the reference standard.229 patients were included in this study. The prevalence of N2/N3 disease was 103 out of 229 patients (45%). A PET-CT-guided targeted approach by EBUS identified 75 patients with N2/N3 disease (sensitivity 73%, 95% CI 63-81%; negative predictive value (NPV) 81%, 95% CI 74-87%). Four additional patients with N2/N3 disease were found by systematic EBUS (sensitivity 77%, 95% CI 67-84%; NPV 84%, 95% CI 76-89%) and five more by EUS-B (84 patients total; sensitivity 82%, 95% CI 72-88%; NPV 87%, 95% CI 80-91%). Additional clinical relevant staging information was obtained in 23 out of 229 patients (10%).Systematic EBUS followed by EUS-B increased sensitivity for the detection of N2/N3 disease by 9% compared to PET-CT-targeted EBUS alone.

Ultrasound-Guided Tissue Core Biopsies in Supraclavicular Lymph Nodes in Patients with Suspected Thoracic Malignancies.

BACKGROUND: Supraclavicular (SC) lymph node metastases are important in the analysis of thoracic malignancies for staging as well as for diagnosing purposes. Ultrasound (US) guidance visualises lesions very precisely, enabling tissue biopsies in real-time mode. OBJECTIVES: To report on the diagnostic qualities of SC tissue core biopsies (TCB). METHODS: A retrospective database analysis was performed in TCB performed under US guidance in SC nodes in patients suspected of having a thoracic malignancy. Clinical characteristics and results of diagnostic evaluations were analysed. RESULTS: Between October 2008 and October 2014, 67 sessions for TCB in 65 patients were performed. The diagnostic accuracy of TCB for all diagnoses is 90%, with a sensitivity of 89%. For malignant diagnoses, the sensitivity of US-guided TCB is 93%. In 20 patients, molecular analysis for EGFR and KRAS was performed, with a diagnostic success rate of 95%. One patient suffered a moderate haemorrhage after TCB. CONCLUSION: TCB of SC nodes in the analysis of suspected thoracic malignancy is safe and has a high diagnostic accuracy in determining tumour subtype as well as molecular analysis.

The Identification of Stenotrophomonas maltophilia Contamination in Ultrasound Endoscopes and Reproduction of Decontamination Failure by Deliberate Soiling Tests.

BACKGROUND: An outbreak of Stenotrophomonas maltophilia was observed in the cultures of bronchial aspirations. After systematic culturing of the scopes and reprocessing the equipment, it turned out to be a pseudo-outbreak caused by a failure of the disinfector to sterilize ultrasound scopes, subsequently resulting in cross infection of the bronchoscopes via the connecting tubes in the dryer. OBJECTIVES: To support the above-mentioned findings and to show how different variables influence the decontamination process. METHODS: The ultrasound scopes were deliberately contaminated with test soil and subsequently disinfected with peracetic acid (PAA), glutaraldehyde (GA) and hot water. Cultures were taken immediately after disinfection and after 4 days in the drying cabinet. RESULTS: After disinfection with PAA, persistent contamination was observed in the endobronchial ultrasound scope, and after disinfection with PAA and prolonged storage in the drying cabinet, contamination of the endoscopic ultrasound scope persisted. All ultrasound scopes were effectively disinfected with GA. CONCLUSION: It is concluded that disinfection with PAA fails to decontaminate the small channels of the ultrasound scopes. Prolonged storage in humid conditions seems to enhance the outgrowth of microorganisms. By reassignment of all endoscopes to fixed locations in the drying cabinet, by using disposable connector tubes for the balloon channels, and by using GA instead of PAA, the reprocessing procedure in our hospital was corrected effectively.

Percutaneous ultrasonography as imaging modality and sampling guide for pulmonologists.

Ultrasound (US) imaging is gradually progressing into common practice in contemporary pulmonology. Its main applications are to determine the presence and amount of pleural effusions and to guide subsequent treatment interventions. Guidelines recommend the use of US for these indications. Training programs are organized and competency levels are formulated. Image guidance with US to obtain specimens for pathologic and/or microbiological analysis is less extensively practiced by pulmonologists but it is an important tool for tumour staging and diagnosing diseases. Lung tumours in contact with the pleural surface, pleural thickenings, mediastinal tumours and chest wall tumours are conceivable indications for pulmonologists to approach with the help of US visualization. Moreover, sampling of chest disease-related extrathoracal lesions may also be regarded as the working field of the pulmonologist. For example, supraclavicular and axillar lymph node metastasis, and also soft tissue and bone metastases, are lesions encountered during dissemination tests. US-guided biopsy provides not only a diagnosis, but also gives information on the stage of disease in sometimes inaccessible primary lesions. US-guided sampling increases diagnostic efficacy and safety and enables very precise performance of fine-needle aspirations as well as tissue core biopsies.

Osimertinib and palbociclib in an EGFR-mutated NSCLC with primary CDK4 amplification after progression under osimertinib.

Precision cancer medicine has changed the treatment paradigm of patients with non-small cell lung cancer (NSCLC) with specific molecular aberrations. A major challenge is management of the resistance that tumor cells eventually develop against targeted therapies, either through primary or acquired resistance mechanisms. We report a 61 year-old male patient with metastatic NSCLC harboring an EGFR exon 19 deletion, a PIK3CA mutation, and CDK4 amplification. After an initial partial response to osimertinib as mono-therapy (third-generation EGFR tyrosine kinase inhibitor), the patient had progression of disease after 4 months of treatment and was referred for combined osimertinib and palbociclib (CDK4/6 inhibitor) treatment. Though complicated by transient pneumonitis, the patient has an ongoing partial response for > 10 months and has experienced clinical improvement on this treatment regimen. As amplification of CDK4 occurs in ~ 10% of treatment-naïve patients with EGFR-mutated NSCLC, the successful treatment of our patient with osimertinib and palbociclib may be highly relevant for future patients with NSCLC.

The determination of pleurodesis using sonography after surgical pleurectomy for pneumothorax: a pilot study.

The aim of this study is to evaluate feasibility of monitoring the process of pleurodesis after surgical pleurectomy with thoracic ultrasound. Repetitive measurements with thoracic ultrasound after surgical pleurectomy could provide information on the extent and development speed of pleurodesis. We conducted a prospective single-center cohort study. Adult patients who required surgical pleurectomy after pneumothorax were eligible. Participants had daily thoracic ultrasound examination until discharge to determine lung sliding [present (0 point), questionable (1 point), or absent (2 points)], and pleural thickening [normal (0 point), questionable (1 point), or present (2 points)]. Thoracic ultrasound was performed in six regions, the sum of all scores was divided by the number of regions. Fourteen patients were enrolled. Thoracic ultrasound on day 1-4 was 0.25±0.26, 0.39±0.48, 0.84±0.49, 1.12±0.56 for mean lung sliding, and 1.0±0.56, 1.17±0.48, 1.44±0.44, 1.54±0.34 for mean pleural thickening. Lung sliding and pleural thickening increased significantly between day 1 and day 4 (P=0.002 and P=0.023, respectively). One (7%) and 3 (21%) patients reached the maximum achievable grade for lung sliding and pleural thickening, respectively. Thoracic ultrasound grades tended to be lower in three patients with recurrent pneumothorax, although this was not statistically significant. This study shows a significant increase in thoracic ultrasound grading for pleurodesis lung sliding and pleural thickening during the first postoperative days after surgical pleurectomy, probably attributable to progressing pleurodesis. Only a minority of patients reached complete pleurodesis before discharge despite complete surgical pleurodesis (SP). The results of this study may guide future research regarding optimal timing of chest tube removal.

Robot-assisted thoracic surgery for stages IIB-IVA non-small cell lung cancer: retrospective study of feasibility and outcome.

Robot-assisted thoracic surgery (RATS) for higher stages non-small cell lung carcinoma (NSCLC) remains controversial. This study reports the feasibility of RATS in patients with stages IIB-IVA NSCLC. A single-institute, retrospective study was conducted with patients undergoing RATS for stages IIB-IVA NSCLC, from January 2015 until January 2020. Unforeseen N2 disease was excluded. Data were collected from the Dutch Lung Cancer Audit database. Conversion rate, radical (R0) resection rate, local recurrence rate and complications were analyzed, as were risk factors for conversion. RATS was performed in 95 patients with NSCLC clinical or pathological stages IIB (N = 51), IIIA (N = 39), IIIB (N = 2) and IVA (N = 3). 10.5% had received neoadjuvant chemoradiotherapy. Pathological staging was T3 in 33.7% and T4 in 34.7%. RATS was completed in 77.9% with a radical resection rate of 94.8%. Lobectomy was performed in 67.4% of the total resections. Conversion was for strategic (18.9%) and emergency (3.2%) reasons. Pneumonectomy (p = 0.001), squamous cell carcinoma (p < 0.001), additional resection of adjacent structures (p = 0.025) and neoadjuvant chemoradiation (p = 0.017) were independent risk factors for conversion. Major post-operative complications occurred in ten patients (10.5%) including an in-hospital mortality of 2.1% (n = 2). Median recurrence-free survival was estimated at 39.4 months (CI 16.4-62.5). Two- and 5-year recurrence-free survival rates were 53.8% and 36.7%, respectively. This study concludes that RATS is safe and feasible in higher staged NSCLC tumors after exclusion of unforeseen N2 disease. It brings new perspective on the potential of RATS in higher stages, dealing with larger and more invasive tumors.

Percutaneous ultrasound-guided biopsies in the evaluation of thoracic tumours after PET-CT: a prospective diagnostic study.

BACKGROUND: Lesions detected by positron emission tomography-computed tomography (PET-CT) during the analysis of thoracic tumours are often impalpable at physical examination, and subsequent ultrasound (US) may aid in finding these lesions for pathologic evaluation. OBJECTIVES: The success rate of percutaneous US-guided biopsies of palpable and non-palpable lesions and the impact on tumour stage were studied prospectively. METHODS: Lesions, significant for diagnosis and disease stage, with metabolic activity on PET-CT and presumed appropriate for percutaneous approach under US guidance were selected for cytologic aspiration or tissue core biopsies. RESULTS: In 127 patients, 134 lesions (subdivided into 24 local thoracic, 74 supraclavicular and 36 distant metastatic lesions) were biopsied percutaneously under US guidance. Malignancy, benign disease and inadequate biopsies were found in 80% (106/134), 14% (19/134) and 7% (9/134), respectively. In 55% (56/102) of patients, biopsies confirmed the disease stage. Fifty-one percent (18/35) of distant lesions and 54% (43/68) of supraclavicular lesions were impalpable on physical examination. CONCLUSIONS: US-guided biopsies in patients with suspected thoracic malignancy on PET-CT provide an excellent tool for obtaining a pathological diagnosis, leading to a definitive disease stage in over half of the patients.

High Yield of Chest X-ray in the Follow-Up of Colorectal Cancer.

PURPOSE: Worldwide, colorectal carcinoma (CRC) has a high incidence and a substantial cancer-related mortality. The recurrence risk is 30-50% and lung metastases are common. Treatment of lung metastases with stereotactic ablative radiotherapy (SABR) or metastasectomy may increase survival. The best modality for thoracic screening in the follow-up, however, remains controversial. In this study, we aimed to unravel the additional value of routine chest X-ray (CXR) for detecting lung metastases during the follow-up of CRC patients treated with curative surgery. METHODS: Between 2013 and 2017, 668 CRC patients were treated with curative intent, of whom 633 patients were included in follow-up, which consisted of CXR, serum Carcino-Embryonic Antigen (CEA) and ultrasound of the liver. Patients who developed lung metastases, diagnosed with CXR and characterised by a normal concomitant serum CEA level, were identified. Number, size and treatment of lung metastases were described. RESULTS: Thirty-four (5.4%) patients developed lung metastases. Seventeen (50%) were detected by CXR without pathological CEA levels. Eleven (65%) of these patients were treated with curative intent, whereas 21% of patients with lung metastases and elevated CEA levels were treated with curative intent (p = 0.049). Higher numbers of lung metastases were associated with a lower chance of curative treatment. CONCLUSIONS: More than 50% of patients with lung metastases on CXR in the follow-up would not have been detected with CEA-triggered imaging only. In addition, patients with colorectal lung metastases without elevated CEA levels were often suitable for curative treatment and, therefore, CXR seems to have additional value within the follow-up of CRC.

Investigation of the added value of CT-based radiomics in predicting the development of brain metastases in patients with radically treated stage III NSCLC.

Introduction: Despite radical intent therapy for patients with stage III non-small-cell lung cancer (NSCLC), cumulative incidence of brain metastases (BM) reaches 30%. Current risk stratification methods fail to accurately identify these patients. As radiomics features have been shown to have predictive value, this study aims to develop a model combining clinical risk factors with radiomics features for BM development in patients with radically treated stage III NSCLC. Methods: Retrospective analysis of two prospective multicentre studies. Inclusion criteria: adequately staged [18F-fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG-PET-CT), contrast-enhanced chest CT, contrast-enhanced brain magnetic resonance imaging/CT] and radically treated stage III NSCLC, exclusion criteria: second primary within 2 years of NSCLC diagnosis and prior prophylactic cranial irradiation. Primary endpoint was BM development any time during follow-up (FU). CT-based radiomics features (N = 530) were extracted from the primary lung tumour on 18-FDG-PET-CT images, and a list of clinical features (N = 8) was collected. Univariate feature selection based on the area under the curve (AUC) of the receiver operating characteristic was performed to identify relevant features. Generalized linear models were trained using the selected features, and multivariate predictive performance was assessed through the AUC. Results: In total, 219 patients were eligible for analysis. Median FU was 59.4 months for the training cohort and 67.3 months for the validation cohort; 21 (15%) and 17 (22%) patients developed BM in the training and validation cohort, respectively. Two relevant clinical features (age and adenocarcinoma histology) and four relevant radiomics features were identified as predictive. The clinical model yielded the highest AUC value of 0.71 (95% CI: 0.58-0.84), better than radiomics or a combination of clinical parameters and radiomics (both an AUC of 0.62, 95% CIs of 0.47-076 and 0.48-0.76, respectively). Conclusion: CT-based radiomics features of primary NSCLC in the current setup could not improve on a model based on clinical predictors (age and adenocarcinoma histology) of BM development in radically treated stage III NSCLC patients.

Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer.

Introduction: Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods: Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0-3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2-16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results: Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2-18.8) for CPE and 10.3 months (95% CI 7.1-15.5; hazard ratio (HR) 0.62, 95% CI 0.25-1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07-0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8-61.9 months) for CPE compared to 17.2 months (95% CI 11.5-45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22-1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion: Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity.

Ambulant treatment with a digital chest tube for prolonged air leak is safe and effective.

BACKGROUND: Outpatient or ambulatory treatment for prolonged air leak (PAL) has been reported previously in various studies. Evidence regarding efficiency and safety is nevertheless poor. This report describes the experience of 10 years ambulatory care with a digital chest drain system monitored by specialized nurses in our centre. The aim of the study is to give further insights in the effectiveness and safety of this treatment. METHODS: Retrospective data of 10 years ambulatory care for PAL were examined. One hundred and forty patients with PAL after pneumothorax or pulmonary surgery were included. RESULTS: A total of 140 patients with PAL were included. Treatment was successful in 112 patients (80.0%). Hospital readmission was necessary in 33 patients (23.6%) and 28 (20.0%) of them received additional treatment. Additional treatment consisted of video-assisted thoracoscopic surgery (VATS) in 19 patients (13.6%), new chest tube placement in 8 patients (5.7%) and pleurodesis (with talc slurry) in 1 patient (0.7%). Minor complications occurred in 10 patients (7.1%), major complications requiring readmission occurred in 14 patients (10.0%). CONCLUSIONS: Ambulatory treatment of PAL with a digital monitoring device resulted in a high success rate with a limited complication rate.

Quality assessment of robot assisted thoracic surgical resection of non-small cell lung cancer: nodal upstaging and mediastinal recurrence.

BACKGROUND: Robot assisted thoracic surgery (RATS) is the minimally invasive surgical technique of choice for treatment of patients with non-small cell lung cancer (NSCLC), at the Isala Hospital. The aim of this study is to compare clinical and pathological staging results and mediastinal recurrence after RATS for anatomical resections of lung cancer as surrogate markers for quality of mediastinal lymph node dissection (MLND). METHODS: This single institute retrospective study was conducted in patients who underwent RATS for NSCLC. Excluded were patients with a history of concurrent malignant disease, with other previous neoplasms, with small cell lung cancer (SCLC) and patients in whom the robotic technique was converted to thoracotomy, prior to lymph node dissection. Data were obtained from the hospital database. The difference between clinical and pathological staging was expressed as upstaging and downstaging. Computed Tomography scanning was used for follow-up, and diagnosis of mediastinal recurrence. RESULTS: From November 2011 to May 2016, 227 patients underwent RATS at Isala Hospital Zwolle, the Netherlands. Of those, 130 (mean age, 69.5±9.3 years) met the eligibility criteria. Preoperative mediastinal lymph node staging was done by endoscopic ultrasound/endobronchial ultrasound, by positron emission tomography (PET) or mediastinoscopy. In 14 patients (10.8%) unforeseen N2 disease was found, 6 patients (4.6%) were upstaged from cN0 to pN2 and 8 patients (6.2%) were upstaged from cN1 to pN2. Mediastinal recurrence was detected in 7 patients (5.4%) during a median follow-up of 54 months (range, 1.5-102 months). CONCLUSIONS: In patients with NSCLC, who underwent anatomical resection by means of RATS, an unforeseen N2 disease rate of 10.8% was demonstrated and a mediastinal recurrence rate of 5.4%. It is concluded that robotic surgery provides an accurate lymph node dissection.

Clinical Value of EGFR Copy Number Gain Determined by Amplicon-Based Targeted Next Generation Sequencing in Patients with EGFR-Mutated NSCLC.

BACKGROUND: The clinical relevance of epidermal growth factor receptor (EGFR) copy number gain in patients with EGFR mutated advanced non-small cell lung cancer on first-line tyrosine kinase inhibitor treatment has not been fully elucidated. OBJECTIVE: We aimed to estimate EGFR copy number gain using amplicon-based next generation sequencing data and explored its prognostic value. PATIENTS AND METHODS: Next generation sequencing data were obtained for 1566 patients with non-small cell lung cancer. EGFR copy number gain was defined based on an increase in EGFR read counts relative to internal reference amplicons and normal controls in combination with a modified z-score ≥ 3.5. Clinical follow-up data were available for 60 patients treated with first-line EGFR-tyrosine kinase inhibitors. RESULTS: Specificity and sensitivity of next generation sequencing-based EGFR copy number estimations were above 90%. EGFR copy number gain was observed in 27.9% of EGFR mutant cases and in 7.4% of EGFR wild-type cases. EGFR gain was not associated with progression-free survival but showed a significant effect on overall survival with an adjusted hazard ratio of 3.14 (95% confidence interval 1.46-6.78, p = 0.003). Besides EGFR copy number gain, osimertinib in second or subsequent lines of treatment and the presence of T790M at relapse revealed significant effects in a multivariate analysis with adjusted hazard ratio of 0.43 (95% confidence interval 0.20-0.91, p = 0.028) and 0.24 (95% confidence interval 0.1-0.59, p = 0.001), respectively. CONCLUSIONS: Pre-treatment EGFR copy number gain determined by amplicon-based next generation sequencing data predicts worse overall survival in EGFR-mutated patients treated with first-line EGFR-tyrosine kinase inhibitors. T790M at relapse and subsequent treatment with osimertinib predict longer overall survival.

Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial.

BACKGROUND: Almost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy. METHODS: We did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0-2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m2 on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847. FINDINGS: Between March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36·5 months (95% CI 34·2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6·2 months [95% CI 4·6-8·7]) than in the supportive care group (3·2 months [2·8-4·1]; hazard ratio [HR] 0·48 [95% CI 0·33-0·71]; p=0·0002). The benefit was confirmed by masked independent central review (HR 0·49 [0·33-0·72]; p=0·0002). Grade 3-4 adverse events occurred in 33 (52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection. INTERPRETATION: Switch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma. FUNDING: Dutch Cancer Society (Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding) and Stichting NVALT studies.

Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response.

BACKGROUND: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) compared to best supportive care (BSC) in malignant mesothelioma. Whether these effects are paralleled by changes in circulating immune cell subsets is currently unknown. These analyses could offer improved mechanistic insights into the effects of gemcitabine on the host and guide development of effective combination therapies in mesothelioma. METHODS: We stained peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) at baseline and 3 weeks following start of gemcitabine or BSC treatment in a subgroup of mesothelioma patients included in the NVALT19-trial. In total, 24 paired samples including both MDSCs and PBMCs were included. We performed multicolour flow-cytometry to assess co-inhibitory and-stimulatory receptor- and cytokine expression and matched these parameters with PFS and OS. FINDINGS: Gemcitabine treatment was significantly associated with an increased NK-cell- and decreased T-regulatory cell proliferation whereas the opposite occurred in control patients. Furthermore, myeloid-derived suppressor cells (MDSCs) frequencies were lower in gemcitabine-treated patients and this correlated with increased T-cell proliferation following treatment. Whereas gemcitabine variably altered co-inhibitory receptor expression, co-stimulatory molecules including ICOS, CD28 and HLA-DR were uniformly increased across CD4+ T-helper, CD8+ T- and NK-cells. Although preliminary in nature, the increase in NK-cell proliferation and PD-1 expression in T cells following gemcitabine treatment was associated with improved PFS and OS. INTERPRETATION: Gemcitabine treatment was associated with widespread effects on circulating immune cells of mesothelioma patients with responding patients displaying increased NK-cell and PD-1 + T-cell proliferation. These exploratory data provide a platform for future on treatment-biomarker development and novel combination treatment strategies.

Relevance and Effectiveness of Molecular Tumor Board Recommendations for Patients With Non-Small-Cell Lung Cancer With Rare or Complex Mutational Profiles.

PURPOSE: Molecular tumor boards (MTBs) provide physicians with a treatment recommendation for complex tumor-specific genomic alterations. National and international consensus to reach a recommendation is lacking. In this article, we analyze the effectiveness of an MTB decision-making methodology for patients with non-small-cell lung cancer (NSCLC) with rare or complex mutational profiles as implemented in the University Medical Center Groningen (UMCG). METHODS: The UMCG-MTB comprises (pulmonary) oncologists, pathologists, clinical scientists in molecular pathology, and structural biologists. Recommendations are based on reported actionability of variants and molecular interpretation of pathways affected by the variant and supported by molecular modeling. A retrospective analysis of 110 NSCLC cases (representing 106 patients) with suggested treatment of complex genomic alterations and corresponding treatment outcomes for targeted therapy was performed. RESULTS: The MTB recommended targeted therapy for 59 of 110 NSCLC cases with complex molecular profiles: 24 within a clinical trial, 15 in accordance with guidelines (on label) and 20 off label. All but 16 recommendations involved patients with an EGFR or ALK mutation. Treatment outcome was analyzed for patients with available follow-up (10 on label and 16 off label). Adherence to the MTB recommendation (21 of 26; 81%) resulted in an objective response rate of 67% (14 of 21), with a median progression-free survival of 6.3 months (interquartile range, 3.2-10.6 months) and an overall survival of 10.4 months (interquartile range, 6.3-14.6 months). CONCLUSION: Targeted therapy recommendations resulting from the UMCG-MTB workflow for complex molecular profiles were highly adhered to and resulted in a positive clinical response in the majority of patients with metastatic NSCLC.

Direct costs associated with the disease management of patients with unresectable advanced non-small-cell lung cancer in The Netherlands.

INTRODUCTION: Disease management and costs of treatment of patients with unresectable advanced non-small-cell lung cancer (NSCLC) in The Netherlands are not well known. METHODS: A retrospective medical chart review was performed by collecting data from the time of diagnosis until the time of death or the end of the evaluation period. In addition to the demographic data, information was collected on the overall management of the patient. Hospital resource utilisation data collected included number of outpatient specialist visits, number and length of hospitalisation, type and number of diagnostic and laboratory procedures, type and number of radiotherapy cycles and detailed information on chemotherapy. To evaluate the economic impact of second-line treatment, a distinction was made between patients who received only best supportive care (BSC, group A) and those who received chemotherapy as a second-line treatment in addition to BSC (group B). The study was performed from the hospital perspective and reports on 2005 costs. RESULTS: Of 102 patients, 74 belonged to group A and 28 to group B. Patient management included a multidisciplinary approach, the extent of which depended on symptoms of the disease and presence of metastases. The average total treatment cost per patient per year of unresectable advanced NSCLC in The Netherlands was euro32,840 in group A and euro31,187 in group B. In both groups, hospitalisation was the major cost driver. In group B second-line chemotherapy was the second largest contributor of the costs. In spite of the difference in numbers of treatment lines provided to patients in groups A and B the total average costs per patient per year were comparable. Overall, the management of unresectable advanced NSCLC appeared to conform with current guidelines in The Netherlands. CONCLUSION: These patients show high medical resource consumption, with hospitalisation being the main cost driver in both groups. As economic arguments are becoming increasingly important in medical decision making on both national and local levels, this information is relevant for both policy makers and specialists. These data can also be used in future research to evaluate the economic impact of new therapies in NSCLC, especially of those that aim to treat patients in an outpatient setting.

[Pseudoprogression in immune therapy]. / Pseudoprogressie bij immuuntherapie.

Immune therapy is increasingly used as an effective treatment for various types of cancer. The response of tumours to immune therapy is different from conventional chemotherapy. In about 10% of patients, pseudoprogression may occur. This is a phenomenon where disease progression initially appears on imaging due to inflammation, but response is seen with repeated imaging. Pseudoprogression is often accompanied by a good clinical status. We describe a 63-year-old woman with metastasized melanoma, a 53-year-old woman with metastasized lung cancer and a 77-year-old woman with metastasized renal cancer who all developed pseudoprogression upon treatment with immune therapy. Premature discontinuation of treatment should be prevented when suspecting pseudoprogression and care should be taken to avoid burdening patients with bad news. Imaging should be repeated after a minimum interval of four weeks if pseudoprogression is suspected. When in doubt, a biopsy may be performed.

[Immunotherapy for cancer: from medical breakthrough to application in daily practice]. / Immuuntherapie voor kanker.

Immunotherapy induces a response against cancer by activating the immune system. Examples are therapies with checkpoint inhibitors, oncolytic viruses and chimeric antigen receptor T-cells (CAR T-cells). These therapies have, due to their rapid development, found their way to daily practice. For some patients with metastatic disease immunotherapy has led to significant long-term survival. Currently, there is a shift in the treatment with checkpoint inhibitors towards the (neo)adjuvant setting. Treatments with CAR T-cells seem particularly effective in haematological malignancies. Oncolytic viruses are used in the treatment for melanoma, but presently only on a limited scale. Only a limited number of patients benefit from immunotherapy. There remain many challenges for the future, most importantly the optimal use of treatment, recognition and treatment of side effects, determining the optimal duration of treatment and the increasing healthcare costs.