Short-term outpatient follow-up of COVID-19 patients: A multidisciplinary approach.

BACKGROUND: Short-term follow-up of COVID-19 patients reveals pulmonary dysfunction, myocardial damage and severe psychological distress. Little is known of the burden of these sequelae, and there are no clear recommendations for follow-up of COVID-19 patients.In this multi-disciplinary evaluation, cardiopulmonary function and psychological impairment after hospitalization for COVID-19 are mapped. METHODS: We evaluated patients at our outpatient clinic 6 weeks after discharge. Cardiopulmonary function was measured by echocardiography, 24-hours ECG monitoring and pulmonary function testing. Psychological adjustment was measured using questionnaires and semi-structured clinical interviews. A comparison was made between patients admitted to the general ward and Intensive care unit (ICU), and between patients with a high versus low functional status. FINDINGS: Eighty-one patients were included of whom 34 (41%) had been admitted to the ICU. New York Heart Association class II-III was present in 62% of the patients. Left ventricular function was normal in 78% of patients. ICU patients had a lower diffusion capacity (mean difference 12,5% P = 0.01), lower forced expiratory volume in one second and forced vital capacity (mean difference 14.9%; P<0.001; 15.4%; P<0.001; respectively). Risk of depression, anxiety and PTSD were 17%, 5% and 10% respectively and similar for both ICU and non-ICU patients. INTERPRETATION: Overall, most patients suffered from functional limitations. Dyspnea on exertion was most frequently reported, possibly related to decreased DLCOc. This could be caused by pulmonary fibrosis, which should be investigated in long-term follow-up. In addition, mechanical ventilation, deconditioning, or pulmonary embolism may play an important role.

ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib.

OBJECTIVE: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. MATERIALS AND METHODS: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. RESULTS: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010. CONCLUSION: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.

Non-classic EGFR mutations in a cohort of Dutch EGFR-mutated NSCLC patients and outcomes following EGFR-TKI treatment.

BACKGROUND: Data on non-small-cell lung cancer (NSCLC) patients with non-classic epidermal growth factor receptor (EGFR) mutations are scarce, especially in non-Asian populations. The purpose of this study was to evaluate prevalence, clinical characteristics and outcome on EGFR-TKI treatment according to type of EGFR mutation in a Dutch cohort of NSCLC patients. METHODS: We retrospectively evaluated a cohort of 240 EGFR-mutated NSCLC patients. Data on demographics, clinical and tumour-related features, EGFR-TKI treatment and clinical outcome were collected and compared between patients with classic EGFR mutations, EGFR exon 20 insertions and other uncommon EGFR mutations. RESULTS: Classic EGFR mutations were detected in 186 patients (77.5%) and non-classic EGFR mutations in 54 patients (22.5%); 23 patients with an exon 20 insertion (9.6%) and 31 patients with an uncommon EGFR mutation (12.9%). Median progression-free survival (PFS) and overall survival (OS) on EGFR-TKI treatment were 2.9 and 9.7 months, respectively, for patients with an EGFR exon 20 insertion, and 6.4 and 20.2 months, respectively, for patients with an uncommon EGFR mutation. Patients with a double uncommon EGFR mutation that included G719X/L861Q/S768I had longer PFS and OS on EGFR-TKI treatment compared with patients with a single G719X/L861Q/S768I EGFR mutation (both P=0.02). CONCLUSIONS: In our Dutch cohort, prevalence and genotype distribution of non-classic EGFR mutations were in accordance with previously reported data. The PFS and OS on EGFR-TKI treatment in patients with an uncommon EGFR mutation were shorter compared with patients with classic EGFR mutations, but varied among different uncommon EGFR mutations.

Risk of spontaneous pneumothorax due to air travel and diving in patients with Birt-Hogg-Dubé syndrome.

BACKGROUND AND OBJECTIVES: Birt-Hogg-Dubé syndrome is an autosomal dominant disorder characterized by skin fibrofolliculomas, lung cysts, spontaneous pneumothorax and renal cell cancer due to germline folliculin (FLCN) mutations (Menko et al. in Lancet Oncol 10(12):1199-1206, 2009). The aim of this study was to evaluate the incidence of spontaneous pneumothorax in patients with BHD during or shortly after air travel and diving. METHODS: A questionnaire was sent to a cohort of 190 BHD patients and the medical files of these patients were evaluated. The diagnosis of BHD was confirmed by FLCN mutations analysis in all patients. We assessed how many spontaneous pneumothoraces (SP) occurred within 1 month after air travel or diving. RESULTS: In total 158 (83.2 %) patients returned the completed questionnaire. A total of 145 patients had a history of air travel. Sixty-one of them had a history of SP (42.1 %), with a mean of 2.48 episodes (range 1-10). Twenty-four (35.8 %) patients had a history of pneumothorax on both sides. Thirteen patients developed SP < 1 month after air travel (9.0 %) and two patients developed a SP < 1 month after diving (3.7 %). We found in this population of BHD patients a pneumothorax risk of 0.63 % per flight and a risk of 0.33 % per episode of diving. Symptoms possible related to SP were perceived in 30 patients (20.7 %) after air travel, respectively in ten patients (18.5 %) after diving. CONCLUSION: Based on the results presented in this retrospective study, exposure of BHD patients to considerable changes in atmospheric pressure associated with flying and diving may be related to an increased risk for developing a symptomatic pneumothorax. Symptoms reported during or shortly after flying and diving might be related to the early phase of pneumothorax. An individualized advice should be given, taking also into account patients' preferences and needs.

Single organ metastatic disease and local disease status, prognostic factors for overall survival in stage IV non-small cell lung cancer: Results from a population-based study.

PURPOSE: To analyse the prognostic impact on overall survival (OS) of single versus multiple organ metastases, organ affected, and local disease status in a population based stage IV non-small cell lung cancer (NSCLC) cohort. METHODS: In this observational study, data were analysed of all histologically confirmed stage IV NSCLC patients diagnosed between 1 January 2006 and 31 December 2012 registered in the Netherlands Cancer Registry. Location of metastases before treatment was registered. Multivariable survival analyses [age, gender, histology, M-status, local disease status, number of involved organs, actual organ affected] were performed for all patients and for an (18)fluorodeoxyglucose-positron emission tomography ((18)FDG-PET)-staged subgroup. RESULTS: 11,094 patients were selected: 60% male, mean age 65 years, 73% adenocarcinoma. Median OS for 1 (N = 5676), 2 (N = 3280), and ⩾ 3 (N = 2138) metastatically affected organs was 6.7, 4.3, 2.8 months, respectively (p < 0.001). Hazard ratio (HR) for 2 versus 1 organ(s) was 1.33 (p < 0.001), for ⩾ 3 versus 1 organ(s) 1.91 (p < 0.001). Results were confirmed in the (18)FDG-PET-staged cohort (N = 1517): patients with single organ versus 2 and ⩾ 3 organ metastases had higher OS (8.6, 5.7, 3.8 months, HR 1.40 and 2.17, respectively, p < 0.001). In single organ metastases, OS for low versus high TN-status was 8.5 versus 6.5 months [HR 1.40 (p < 0 .001)]. (18)FDG-PET-staged single organ metastases patients with low TN-status had a superior OS than those with high TN-status (11.6 versus 8.2 months, HR 1.62, p < 0.001). CONCLUSION: Patients with single organ metastases stage IV NSCLC have a favourable prognosis, especially in combination with low TN status. They have to be regarded as a separate subgroup of stage IV disease.

DNA hypermethylation analysis in sputum for the diagnosis of lung cancer: training validation set approach.

BACKGROUND: Lung cancer has the highest mortality of all cancers. The aim of this study was to examine DNA hypermethylation in sputum and validate its diagnostic accuracy for lung cancer. METHODS: DNA hypermethylation of RASSF1A, APC, cytoglobin, 3OST2, PRDM14, FAM19A4 and PHACTR3 was analysed in sputum samples from symptomatic lung cancer patients and controls (learning set: 73 cases, 86 controls; validation set: 159 cases, 154 controls) by quantitative methylation-specific PCR. Three statistical models were used: (i) cutoff based on Youden's J index, (ii) cutoff based on fixed specificity per marker of 96% and (iii) risk classification of post-test probabilities. RESULTS: In the learning set, approach (i) showed that RASSF1A was best able to distinguish cases from controls (sensitivity 42.5%, specificity 96.5%). RASSF1A, 3OST2 and PRDM14 combined demonstrated a sensitivity of 82.2% with a specificity of 66.3%. Approach (ii) yielded a combination rule of RASSF1A, 3OST2 and PHACTR3 (sensitivity 67.1%, specificity 89.5%). The risk model (approach iii) distributed the cases over all risk categories. All methods displayed similar and consistent results in the validation set. CONCLUSIONS: Our findings underscore the impact of DNA methylation markers in symptomatic lung cancer diagnosis. RASSF1A is validated as diagnostic marker in lung cancer.

Bilateral renal tumour as indicator for birt-hogg-dubé syndrome.

Birt-Hogg-Dubé (BHD) syndrome is a cancer disorder caused by a pathogenic FLCN mutation characterized by fibrofolliculomas, lung cysts, pneumothorax, benign renal cyst, and renal cell carcinoma (RCC). In this case we describe a patient with bilateral renal tumour and a positive familial history for pneumothorax and renal cancer. Based on this clinical presentation, the patient was suspected for BHD syndrome, which was confirmed after molecular testing. We discuss the importance of recognizing this autosomal dominant cancer disorder when a patient is presented at the urologist with a positive family history of chromophobe renal cell cancer or a positive familial history for renal cell cancer and pneumothorax.

Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients.

AIM: Non-small cell lung cancer (NSCLC)-patients with an epidermal growth factor receptor (EGFR)-mutation have median progression-free survival (PFS) of 12 months on tyrosine kinase inhibitors (TKIs). Resistance is mediated by the EGFR T790M-mutation in the majority of patients. Longitudinal follow-up data are lacking. We retrospectively evaluated EGFR-mutated NSCLC-patients who were rebiopsied after TKI-treatment. A subgroup was sequentially rebiopsied along the course of the disease. PATIENTS AND METHODS: Advanced EGFR-mutated NSCLC-patients who had both a pre-TKI biopsy and post-TKI biopsy available were included. Information on treatments and (re)biopsies was collected chronologically. Primary endpoint was the incidence of the T790M-mutation. RESULTS: Sixty-six patients fulfilled the inclusion criteria. In first post-TKI biopsies, T790M-mutation was detected in 34 patients (52%) of patients. Twenty-seven patients had subsequent post-TKI rebiopsies with mutation analysis available; in 10 patients (37%) the T790M-status in subsequent post-TKI rebiopsies was not consistent with the T790M-status of the first post-TKI biopsy. Progression free survival (PFS) on TKI-treatment was 12.0 months. Objective response rate on TKI-treatment was 81%. Patients developing T790M-mutation at post-TKI biopsy had longer median PFS compared to T790M-negative patients (14.2 versus 11.1 months respectively (P=0.034)) and longer overall survival (45.9 months versus 29.8 months respectively (P=0.213)). Transformation to SCLC was detected in 1 patient (2%). CONCLUSION: Incidence of T790M-mutation at first post-TKI biopsy in this cohort of EGFR-mutated NSCLC-patients was 52%. Detection of T790M-mutation was not consistent over time; some patients who were T790M-positive at first post-TKI biopsy became T790M-negative in later post-TKI rebiopsies and vice versa. T790M-positive patients showed longer PFS than T790M-negative patients. Whether the low incidence of transformation to SCLC is justifying post-TKI rebiopsy in EGFR-mutated NSCLC-patients with acquired TKI-resistance in regular clinical practice is debatable.

Lung cysts as indicator for Birt-Hogg-Dubé syndrome.

In this case, we describe a patient with a history of recurrent pneumothorax. Based on CT-thorax and histopathology of the lung tissue, the Birt-Hogg-Dubé syndrome was suspected and confirmed after genetic testing. Recognizing this syndrome by pulmonologists and radiologists is very important, because the risk on developing of renal cell cancer is high.

Exhaled molecular profiles in the assessment of cystic fibrosis and primary ciliary dyskinesia.

BACKGROUND: Early diagnosis and monitoring of disease activity are essential in cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). We aimed to establish exhaled molecular profiles as the first step in assessing the potential of breath analysis. METHODS: Exhaled breath was analyzed by electronic nose in 25 children with CF, 25 with PCD and 23 controls. Principle component reduction and canonical discriminant analysis were used to construct internally cross-validated ROC curves. RESULTS: CF and PCD patients had significantly different breath profiles when compared to healthy controls (CF: sensitivity 84%, specificity 65%; PCD: sensitivity 88%, specificity 52%) and from each other (sensitivity 84%, specificity 60%). Patients with and without exacerbations had significantly different breath profiles (CF: sensitivity 89%, specificity 56%; PCD: sensitivity 100%, specificity 90%). CONCLUSION: Exhaled molecular profiles significantly differ between patients with CF, PCD and controls. The eNose may have potential in disease monitoring based on the influence of exacerbations on the VOC-profile.

Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD. METHODS: In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families. RESULTS: Among 14 FLCN mutation carriers who developed renal cancer 7 were <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6-26%) and 29% (95% minimal confidence interval: 9-49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas. CONCLUSION: We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.

1st ESMO Consensus Conference in lung cancer; Lugano 2010: small-cell lung cancer.

The 1st ESMO Consensus Conference on lung cancer was held in Lugano, Switzerland on 21st and 22nd May 2010 with the participation of a multidisciplinary panel of leading professionals in pathology and molecular diagnostics and medical, surgical and radiation oncology. Before the conference, the expert panel prepared clinically relevant questions concerning five areas as follows: early and locally advanced non-small-cell lung cancer (NSCLC), first-line metastatic NSCLC, second-/third-line NSCLC, NSCLC pathology and molecular testing, and small-cell lung cancer (SCLC) to be addressed through discussion at the Consensus Conference. All relevant scientific literature for each question was reviewed in advance. During the Consensus Conference, the panel developed recommendations for each specific question. The consensus agreement in SCLC is reported in this article. The recommendations detailed here are based on an expert consensus after careful review of published data. All participants have approved this final update.

Retreatment with erlotinib: Regain of TKI sensitivity following a drug holiday for patients with NSCLC who initially responded to EGFR-TKI treatment.

BACKGROUND: Tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are approved as treatment of non-small-cell lung cancer (NSCLC). Despite an initially impressive response to EGFR-TKIs, patients with an activating EGFR mutation invariably relapse. For these patients few treatment options are available after additional progression during or after chemotherapy. The aim of this study is to examine the effect of retreatment with an EGFR-TKI after a drug holiday. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 14 patients with stage IV NSCLC who progressed after long-term disease control with EGFR-TKI, who were subsequently treated with standard chemotherapy and at renewed progression retreated with EGFR-TKI. RESULTS: Fourteen patients (five male, nine female, median age 55 years (39-70 years) received retreatment with erlotinib. The median interval from the discontinuation of EGFR-TKI to the 2nd episode was 9.5 months (3-36 months). Before starting retreatment 36% (n=5) had a T790M mutation. Retreatment resulted in 36% (n=5) partial response, 50% stable disease (n=7) and 14% progressive disease (n=2). Among patients with a T790M mutation this number was two, one and two, respectively. Seven patients are still on therapy without signs of progression. Median follow up is 9 months (1.5-16+months) and median PFS is 6.5 months (1-16+months). CONCLUSION: Our findings suggest that retreatment with erlotinib is an option for patients with NSCLC who initially benefited from previous EGFR-TKI treatment and progressed after standard cytotoxic chemotherapy.

Iron deficiency is common in idiopathic pulmonary arterial hypertension.

The aims of this study were to assess the prevalence of iron deficiency in idiopathic pulmonary arterial hypertension (IPAH) and investigate whether oral iron supplementation has effects in iron-deficient patients. Iron parameters were measure for all IPAH patients attending our centre (VU University Medical Center, Amsterdam, the Netherlands) between May 2009 and February 2010. Iron data were related to clinical parameters, including 6-min walking distance (6MWD), and haemodynamic parameters measured during right heart catheterisation. In a subset of iron-deficient patients, the uptake of iron from the bowel was studied after administering oral iron for 4 weeks. Iron deficiency was found in 30 (43%) out of 70 patients. 6MWD was reduced in iron-deficient patients compared with iron-sufficient patients (mean±sd 390±138 versus 460±143 m; p<0.05) irrespective of the existence of anaemia. In a subset of 18 patients that received oral iron, ferritin levels were significantly increased, although eight patients only slightly increased their iron storage. This study shows that iron deficiency is frequently present in IPAH and is associated with a lower exercise capacity. The small response to oral iron in 44% of the treated patients suggests impaired iron absorption in these patients.

Outcomes of concurrent chemoradiotherapy in patients with stage III non-small-cell lung cancer and significant comorbidity.

BACKGROUND: published trials of concurrent chemoradiotherapy (CCRT) in stage III non-small-cell lung cancer (NSCLC) generally excluded patients with significant comorbidity. We evaluated outcomes in patients who were selected by using radiation planning parameters and were considered, despite comorbidity, fit enough to receive cisplatin-based chemotherapy. PATIENTS AND METHODS: from 2003 to 2008, 89 patients with stage III NSCLC fit to receive cisplatin-based chemotherapy and a V(20) <42% underwent CCRT at one center outside clinical trials. Most received one cycle of cisplatin-gemcitabine, followed by two to three cycles of cisplatin-etoposide concurrent with involved-field thoracic radiotherapy between 46 and 66 Gy. RESULTS: median age was 64 years; performance status (PS) of zero, one or two in 20/64/5 patients; one or more comorbidities in 41.6%; 14% were treated previously for NSCLC. Median V(20) was 26.6% (range 4%-39.4%). Grade III esophagitis and pneumonitis occurred in 28.1% and 7.9% of patients, respectively, while 4.5% died during treatment. Median overall survival was 18.2 months [95% confidence interval (CI) 13.1-23.3 months]. Independent prognostic factors for overall survival were PS (0 versus ≥ 1, P = 0.041) and planning target volume (P = 0.022). CONCLUSIONS: patients with significant comorbidity who are fit to undergo cisplatin-based CCRT achieve median survivals similar to that reported in phase III trials and with relatively few late toxic effects.

The arterial load in pulmonary hypertension.

The anatomical differences between the pulmonary and systemic arterial system are the main cause of the difference in distribution of compliance. In the pulmonary arterial system compliance is distributed over the entire arterial system, and stands at the basis of the constancy of the RC-time. This distribution depends on the number of peripheral vessels, which is ∼8-10 times more in the pulmonary system than the systemic tree. In the systemic arterial tree the compliance is mainly located in the aorta (80% of total compliance in thoracic-abdominal aorta). The constant RC-time in the pulmonary bed results in proportionality of systolic and diastolic pressure with mean pressure and, in turn, in the constant ratio of oscillatory and mean power.

Fasudil reduces monocrotaline-induced pulmonary arterial hypertension: comparison with bosentan and sildenafil.

Pulmonary arterial hypertension (PAH) still cannot be cured, warranting the search for novel treatments. Fasudil (a Rho kinase inhibitor) was compared with bosentan (an endothelin receptor blocker) and sildenafil (a phosphodiesterase 5 inhibitor), with emphasis on right ventricular (RV) function, in a reversal rat model of monocrotaline (MCT)-induced PAH. In addition, the effects of combining bosentan or sildenafil with fasudil were studied. MCT (40 mg·kg body weight(-1)) induced clear PAH in male Wistar rats (n = 9). After 28 days, echocardiography, RV catheterisation and histochemistry showed that cardiac frequency, stroke volume and RV contractility had deteriorated, accompanied by RV dilatation and hypertrophy, and marked pulmonary arterial wall thickening. Mean pulmonary arterial pressure and pulmonary vascular resistance increased significantly compared to healthy rats (n = 9). After 14 days, MCT-treated rats received a 14-day oral treatment with bosentan, sildenafil, fasudil or a combination of fasudil with either bosentan or sildenafil (all n = 9). All treatments preserved cardiac frequency, stroke volume and RV contractility, and reduced pulmonary vascular resistance and RV dilatation. Fasudil lowered RV systolic pressure and mean pulmonary arterial pressure significantly, by reducing pulmonary arterial remodelling, which reduced RV hypertrophy. Combining bosentan or sildenafil with fasudil had no synergistic effect. Fasudil significantly improved PAH, to a greater degree than did bosentan and sildenafil.