[Cystic fibrosis in childhood and adulthood]. / Mukoviszidose im Kindes- und im Erwachsenenalter.

BACKGROUND: Cystic fibrosis (CF, or mucoviscidosis) is one of the rare diseases with a fatal course and with the highest prevalence. Formerly known as a purely childhood disease, this multisystemic disease follows an autosomal recessive inheritance pattern and results in a malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, leading to the production of viscous secretions. The prognosis and outcome of CF are determined by the severity of the involvement of the lungs. Other typically affected organs include the pancreas, liver and intestines. OBJECTIVE: This article reviews the clinical presentation and evolution of CF with a focus on the new era of the highly effective CFTR modulator treatment. MATERIAL AND METHODS: An overview of the current state of knowledge on the care for CF patients is presented. RESULTS AND DISCUSSION: The introduction of the CF newborn screening, the increased understanding of the disease and the development of novel treatment options have substantially increased the quality of life and life expectancy of people with CF. As a result, more than half of CF patients in Germany are now older than 18 years of age and the complications of a chronic disease as well as organ damage due to the intensive treatment are gaining in importance. The highly effective CFTR modulator treatment results in a significant improvement in CFTR function, lung function, body mass index and quality of life and is available to approximately 90% of patients in Germany, based on the genotype. Nevertheless, further research including the development of causal treatment, e.g., gene therapy, targeting the underlying defect in the remaining 10% of CF patients, is urgently needed. Even in adult patients, CF with a mild course or a CFTR-related disease should be considered, e.g., in cases of bronchiectasis and/or recurrent abdominal complaints.

Elexacaftor/tezacaftor/ivacaftor improves nasal nitric oxide in patients with cystic fibrosis.

BACKGROUND: In health, nitric oxide (NO) shows high concentrations in the upper airways, while nasal NO (nNO) is significantly lower in patients with sinonasal inflammation, such as people with cystic fibrosis (PwCF). In PwCF treated with elexacaftor/tezacaftor/ivacaftor (ETI; PwCF-ETI), clinical improvement of sinonasal symptoms and inflammation was observed. We therefore hypothesised that ETI may increase nNO in PwCF. METHODS: 25 PwCF-ETI underwent nNO measurement at baseline and after 3 to 24 months of ETI treatment. NNO was measured using velum closure (VC) techniques in cooperative patients and tidal breathing (TB) for all patients. As controls, 7 CF patients not eligible for ETI (PwCF-non ETI) and 32 healthy controls (HC) were also repeatedly investigated. RESULTS: In PwCF-ETI, sinonasal symptoms, lung function parameters and sweat chloride levels improved from baseline to follow-up whereas there was no change in PwCF-non ETI and HC. NNO increased from a median (IQR) value at baseline to follow-up from 348.2 (274.4) ppb to 779.6 (364.7) ppb for VC (P < 0.001) and from 198.2 (107.0) ppb to 408.3 (236.1) ppb for TB (P < 0.001). At follow-up, PwCF-ETI reached nNO values in the normal range. In PwCF-non ETI as well as HC, nNO did not change between baseline and follow-up. CONCLUSIONS: In PwCF-ETI, the nNO values significantly increased after several months of ETI treatment in comparison to baseline and reached values in the normal range. This suggests that nNO is a potential non-invasive biomarker to examine sinonasal inflammatory disease in PwCF and supports the observation of clinical improvement in these patients.

Risk of pneumothorax in Birt-Hogg-Dubé syndrome during pregnancy and birth.

Birt-Hogg-Dubé syndrome (BHDS) is a genetic disorder characterized by fibrofolliculomas, renal cell cancer and lung cysts. Patients are at risk to develop pneumothorax but the magnitude of this risk during pregnancy is unknown. Information was obtained from 46 women with BHDS that had at least one pregnancy (BHDS-with preg), 18 female BHDS relatives without pregnancies (BHDS-no preg) and 25 non-BHDS female relatives with at least one pregnancy (noBHDS-with preg). In total, 77 pneumothoraces occurred in the BHDS-with preg group (mean 1.7/patient) and 11 in the BHDS-no preg group. Comparison of patient years for the first two groups showed pneumothorax incidence rates of 0.054 and 0.016, respectively. The incidence rate difference was significant [0.038 (CI 0.02-0.057), value of p-value 0.0001]. This difference is not caused by an increased number of patients with pneumothorax but by an increased number of pneumothoraces per patient. Pregnancy in BHDS therefore might be a risk factor for multiple pneumothoraces.

Effects of elexacaftor/tezacaftor/ivacaftor therapy on mental health of patients with cystic fibrosis.

Introduction: The CFTR modulator drug elexacaftor/tezacaftor/ivacaftor (ETI) was shown to improve CFTR function and clinical symptoms in patients with cystic fibrosis (CF) with at least one F508del allele. Recently, some case reports suggested potential side effects of ETI on mental health with an increase in depressive symptoms and even suicide attempts in patients with CF. However, the general effects of this triple combination therapy on the mental health status of patients with CF remain largely unknown. Methods: We, therefore, performed a prospective, observational study in a real-life setting and investigated the relationship between initiation of ETI therapy and changes in mental health in adult patients with CF. We assessed Cystic Fibrosis Questionnaire-Revised (CFQ-R), Patient Health Questionnaire-9 (PHQ-9), Beck's Depression Inventory - Fast Screen (BDI-FS) and Generalized Anxiety Disorder 7-item Scale (GAD-7) at baseline and 8-16 weeks after initiation of ETI. Results: In total, 70 adult patients with CF with at least one F508del allele and a median age of 27.9 years were recruited. After initiation of ETI, the CFQ-R respiratory domain score improved by 27.9 (IQR 5.6 to 47.2; p < 0.001). The PHQ-9 score of depressive symptoms decreased by 1.0 (IQR -3.0 to 0.3; p < 0.05) with an increase of 16.9% in the group with a minimal score after initiation of ETI and a decrease in the groups of mild (-11.3%) or moderate (-5.7%) scores compared to baseline. The BDI-FS score of depressive symptoms decreased from 1.0 (IQR 0.0-2.0) at baseline to 0.0 (IQR 0.0 to 2.0; p < 0.05) after initiation of ETI. The group with a minimal BDI-FS score increased by 8.0% after initiation of ETI, whereas the groups with mild (-4.9%), moderate (-1.6%) or severe (-1.6%) scores decreased compared to baseline. The GAD-7 score of anxiety symptoms did not change after initiation of ETI compared to baseline (0.0; IQR -2.0. to 0.0; p = 0.112). Conclusion: Initiation of ETI improves symptoms of depression in adult patients with CF with at least one F508del allele. However, symptoms of anxiety do not change after short-term therapy with ETI.

The impact of the COVID-19 pandemic on processes, resource use and cost in palliative care.

BACKGROUND: The COVID-19 pandemic impacts on working routines and workload of palliative care (PC) teams but information is lacking how resource use and associated hospital costs for PC changed at patient-level during the pandemic. We aim to describe differences in patient characteristics, care processes and resource use in specialist PC (PC unit and PC advisory team) in a university hospital before and during the first pandemic year. METHODS: Retrospective, cross-sectional study using routine data of all patients cared for in a PC unit and a PC advisory team during 10-12/2019 and 10-12/2020. Data included patient characteristics (age, sex, cancer/non-cancer, symptom/problem burden using Integrated Palliative Care Outcome Scale (IPOS)), information on care episode, and labour time calculated in care minutes. Cost calculation with combined top-down bottom-up approach with hospital's cost data from 2019. Descriptive statistics and comparisons between groups using parametric and non-parametric tests. RESULTS: Inclusion of 55/76 patient episodes in 2019/2020 from the PC unit and 135/120 episodes from the PC advisory team, respectively. IPOS scores were lower in 2020 (PCU: 2.0 points; PC advisory team: 3.0 points). The number of completed assessments differed considerably between years (PCU: episode beginning 30.9%/54.0% in 2019/2020; PC advisory team: 47.4%/40.0%). Care episodes were by one day shorter in 2020 in the PC advisory team. Only slight non-significant differences were observed regarding total minutes/day and patient (PCU: 150.0/141.1 min., PC advisory team: 54.2/66.9 min.). Staff minutes showed a significant decrease in minutes spent in direct contact with relatives (PCU: 13.9/7.3 min/day in 2019/2020, PC advisory team: 5.0/3.5 min/day). Costs per patient/day decreased significantly in 2020 compared to 2019 on the PCU (1075 Euro/944 Euro for 2019/2020) and increased significantly for the PC advisory team (161 Euro/200 Euro for 2019/2020). Overhead costs accounted for more than two thirds of total costs. Direct patient cost differed only slightly (PCU: 134.7 Euro/131.1 Euro in 2019/2020, PC advisory team: 54.4 Euro/57.3 Euro). CONCLUSIONS: The pandemic partially impacted on daily work routines, especially on time spent with relatives and palliative care problem assessments. Care processes and quality of care might vary and have different outcomes during a crisis such as the COVID-19 pandemic. Direct costs per patient/day were comparable, regardless of the pandemic.

Outcome of lung transplant recipients infected with SARS-CoV-2/Omicron/B.1.1.529: a Nationwide German study.

PURPOSE: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is currently the major threat for immunocompromised individuals. The course of COVID-19 in lung transplant recipients in the Omicron era remains unknown. The aim of the study was to assess outcome and associated factors in lung transplant recipients in a German-wide multicenter approach. METHODS: All affected individuals from January 1st to March 20th, 2022 from 8 German centers during the Omicron wave were collected. Baseline characteristics and antiviral measures were associated with outcome. RESULTS: Of 218 patients with PCR-proven SARS-CoV-2 infection 166 patients (76%) received any early (< 7 days) antiviral therapy median 2 (interquartile range 1-4) days after symptom onset. Most patients received sotrovimab (57%), followed by remdesivir (21%) and molnupiravir (21%). An early combination therapy was applied in 45 patients (21%). Thirty-four patients (16%) developed a severe or critical disease severity according to the WHO scale. In total, 14 patients (6.4%) died subsequently associated with COVID-19. Neither vaccination and antibody status, nor applied treatments were associated with outcome. Only age and glomerular filtration rate < 30 ml/min/1.73m2 were independent risk factors for a severe or critical COVID-19. CONCLUSION: COVID-19 due to Omicron remains an important threat for lung transplant recipients. In particular, elderly patients and patients with impaired kidney function are at risk for worse outcome. Prophylaxis and therapy in highly immunocompromised individuals need further improvement.

Cost-Effectiveness of a Specialized Breathlessness Service Versus Usual Care for Patients With Advanced Diseases.

OBJECTIVES: The Munich Breathlessness Service (MBS) significantly improved control of breathlessness measured by the Chronic Respiratory Questionnaire (CRQ) Mastery in a randomized controlled fast track trial with waitlist group design spanning 8 weeks in Germany. This study aimed to assess the within-trial cost-effectiveness of MBS from a societal perspective. METHODS: Data included generic (5-level version of EQ-5D) health-related quality of life and disease-specific CRQ Mastery. Quality-adjusted life years (QALYs) were calculated based on 5-level version of EQ-5D utilities valued with German time trade-off. Direct medical costs and productivity loss were calculated based on standardized unit costs. Incremental cost-effectiveness ratios (ICER) and cost-effectiveness-acceptance curves were calculated using adjusted mean differences (AMD) in costs (gamma-distributed model) and both effect parameters (Gaussian-distributed model) and performing 1000 simultaneous bootstrap replications. Potential gender differences were investigated in stratified analyses. RESULTS: Between March 2014 and April 2019, 183 eligible patients were enrolled. MBS intervention demonstrated significantly better effects regarding generic (AMD of QALY gains of 0.004, 95% confidence interval [CI] 0.0003 to 0.008) and disease-specific health-related quality of life at nonsignificantly higher costs (AMD of €605 [95% CI -1109 to 2550]). At the end of the intervention, the ICER was €152 433/QALY (95% CI -453 545 to 1 625 903) and €1548/CRQ Mastery point (95% CI -3093 to 10 168). Intervention costs were on average €357 (SD = 132). Gender-specific analyses displayed dominance for MBS in males and higher effects coupled with significantly higher costs in females. CONCLUSIONS: Our results show a high ICER for MBS. Considering dominance for MBS in males, implementing MBS on approval within the German health care system should be considered.

Delayed diagnosis of Birt-Hogg-Dubé syndrome might be aggravated by gender bias.

Background: Birt-Hogg-Dubé syndrome is a rare genetic tumor syndrome characterized by renal cell cancer, lung bullae, pneumothorax, and fibrofolliculoma. Patients with such orphan tumor disorders are at risk of not receiving a timely diagnosis. In the present, gender-sensitive study, we analyzed the delay between onset of symptoms and diagnosis of Birt-Hogg-Dubé syndrome. Methods: Clinical data of 158 patients from 91 unrelated families were collected. FLCN mutation testing was performed in index patients and family members. Findings: The occurrence of the first symptom (fibrofolliculoma, pneumothorax or renal cell cancer) was rarely followed by a timely diagnosis of Birt-Hogg-Dubé syndrome and did so significantly less often in female (1.3%) compared to male (11.4%) patients (chi-square 6.83, p-value 0.009). Only 17 out of 39 renal cell cancers (7/17 female, 10/22 male patients) were promptly recognized as a symptom of Birt-Hogg-Dubé syndrome. Patients in which renal cell cancer was initially not recognized as a symptom of Birt-Hogg-Dubé syndrome waited 9.7 years (females SD 9.2, range 1-29) and 8.8 years (males, SD 4.1, range 2-11) for their diagnosis, respectively. Four (three female, one male) patients developed renal cell cancer twice before the genetic tumor syndrome was diagnosed. The delay between fibrofolliculoma or pneumothorax as a first symptom and diagnosis of Birt-Hogg-Dubé syndrome was considerable but not significantly different between females and males (18.1/17.19 versus 16.1/18.92 years). Furthermore, 73 patients were only diagnosed due to family history (delay 15.1 years in females and 17.4 years in males). Interpretation: The delay between onset of symptoms and diagnosis of Birt-Hogg-Dubé syndrome can be substantial and gender-dependent, causing considerable health risks for patients and their families. It is therefore important to create more awareness of Birt-Hogg-Dubé syndrome and resolve gender biases in diagnostic work-up. Funding: None declared.

Consequences of the COVID-19 pandemic on lung cancer care and patient health in a German lung cancer center: results from a cross-sectional questionnaire.

BACKGROUND: The novel coronavirus SARS-CoV-2 has caused a global COVID-19 pandemic, leading to worldwide changes in public health measures. In addition to changes in the public sector (lockdowns, contact restrictions), hospitals modified care to minimize risk of infection and to mobilize resources for COVID-19 patients. Our study aimed to assess the impact of these measures on access to care and behaviour of patients with thoracic malignancies. METHODS: Thoracic oncology patients were surveyed in October 2020 using paper-based questionnaires to assess access to ambulatory care services and tumor-directed therapy during the COVID-19 pandemic. Additionally, behaviour regarding social distancing and wearing of face masks were assessed, as well as COVID-19 exposure, testing and vaccination. Results are presented as absolute and relative frequencies for categorical variables and means with standard deviation for numerical variables. We used t-test, and ANOVA to compare differences in metric variables and Chi2-test to compare proportions between groups. RESULTS: 93 of 245 (38%) patients surveyed completed the questionnaire. Respiration therapy and physical therapy were unavailable for 57% to 70% of patients during March/April. Appointments for tumor-directed therapy, tumor imaging, and follow-up care were postponed or cancelled for 18.9%, 13.6%, and 14.8% of patients, respectively. Patients reported their general health as mostly unaffected. The majority of patients surveyed did not report reducing their contacts with family. The majority reduced contact with friends. Most patients wore community masks, although a significant proportion reported respiratory difficulties during prolonged mask-wearing. 74 patients (80%) reported willingness to be vaccinated against SARS-CoV-2. CONCLUSIONS: This survey provides insights into the patient experience during the second wave of the COVID-19 pandemic in Munich, Germany. Most patients reported no negative changes to cancer treatments or general health; however, allied health services were greatly impacted. Patients reported gaps in social distancing, but were prepared to wear community masks. The willingness to get vaccinated against SARS-CoV-2 was high. This information is not only of high relevance to policy makers, but also to health care providers.

Lymphocytes and sinus histiocytosis in tumor and matched lymph nodes as predictors of survival in non-small-cell lung cancer.

Aim: To analyze immune cell populations in non-small-cell lung cancer (NSCLC) tumors and matched tumor-bearing and non-tumor-bearing lymph nodes (ntbLNs) to predict prognosis. Patients & methods: 71 patients with long-term disease-free survival and 80 patients with relapse within 3 years were included in this study. We used Cox regression to identify factors associated with overall survival (OS) and progression-free survival (PFS). Results: Sinus histiocytosis and tumor-infiltrating lymphocyte density in the tumor were positively associated with PFS and OS. CD4 expression in node 1 (hazard ratio = 0.72; p = 0.02) and node 2 (hazard ratio = 0.91; p = 0.04) ntbLNs were positively correlated with OS and PFS, respectively. Discussion: Immunological markers in ntbLNs could be used to predict survival in NSCLC.

Lay abstract Aim: We analyzed populations of immune cells in non-small-cell lung cancer (NSCLC). In addition, we also investigated lymph nodes from the same patient that contained or did not contain cancer cells. Patients & methods: We included 71 patients whose cancer did not return within 3 years and 80 patients whose cancer did return within 3 years after they underwent surgery to remove their tumors. We used various statistical methods to identify factors that can predict survival. Results: Sinus histiocytosis (a widening of ducts in the lymph nodes due to an increased number of certain cells) and the density of tumor-infiltrating lymphocytes (immune cells that enter the tumor to destroy it) can predict how long patients can survive after surgery or if their tumor will come back quickly. Discussion: Looking at immune cells can help physicians decide which patients need increased follow-up care due to an increased risk for their tumors to return.

Osimertinib rechallenge under steroid protection following osimertinib-induced pneumonitis: three case studies.

Osimertinib is a third-generation tyrosine kinase inhibitor that became the preferred first-line treatment option for metastatic non-small cell lung cancer with sensitizing epidermal growth factor receptor mutations. Drug-induced pneumonitis is known to occur with osimertinib. In case of severe pneumonitis, discontinuation of treatment and therapy with corticosteroids is recommended, and a treatment switch is usually performed. We herein report the treatment course in three patients who were rechallenged with osimertinib under steroid protection following an osimertinib-induced pneumonitis. All our patients were initially re-exposed to a lower dose of osimertinib. Two patients were successfully rechallenged under prednisolone protection. The third patient, who was initially retreated with osimertinib without steroid protection, suffered from a recurrent pneumonitis, and was later rechallenged successfully under steroid protection. Our case series indicates that rechallenge with osimertinib following recovery from osimertinib-induced pneumonitis allows a successful rechallenge in individual cases when alternative treatment options are lacking. Concomitant steroids appear to protect against flares of pneumonitis during rechallenge.

Colorectal cancer risk in families with Birt-Hogg-Dubé syndrome increased.

OBJECTIVE: Birt-Hogg-Dubé syndrome (BHDS) is an inherited tumour syndrome characterised by three major symptoms: lung cysts with spontaneous pneumothorax, fibrofolliculoma and renal cell cancer. The first family with this syndrome was described in 1975 and one of its members presented with adenomatous colon polyps and colorectal cancer. Since then, it has been a matter of debate whether colorectal cancer is indeed part of the BHDS spectrum and if regular screening should be recommended. DESIGN: We analysed the frequency of colorectal cancer in a large sample of BHDS families. Clinical data were available from 256 BHDS patients (male 130, female 126) belonging to 83 unrelated families. For controls, 83 index patients who attended our outpatient clinic for non-malignancy-related genetic counselling and their family members (total of 519 controls) were used. RESULTS: The patients with BHDS showed a moderately but significantly increased rate of colorectal cancer (5.1% versus 1.5%, p-value .0068). Unexpectedly, 35% of patients with colorectal cancer corresponding to eight of 82 BHDS families fulfilled the revised Bethesda criteria for HNPCC, either because colorectal cancer occurred before age 50 years or because three family members were affected by colorectal cancer. Apart from colorectal cancer, no other HNPCC-associated tumours occurred within the Bethesda criteria-positive families, an observation that argues against a concurrence of BHDS and HNPCC in these families. CONCLUSION: The results suggest that BHDS is associated with early-onset colorectal cancer, a hypothesis that might have a marked impact on preventive screening recommendations.

Effectiveness of a specialised breathlessness service for patients with advanced disease in Germany: a pragmatic fast-track randomised controlled trial (BreathEase).

BACKGROUND: The effectiveness of the Munich Breathlessness Service (MBS), integrating palliative care, respiratory medicine and physiotherapy, was tested in the BreathEase trial in patients with chronic breathlessness in advanced disease and their carers. METHODS: BreathEase was a single-blinded randomised controlled fast-track trial. The MBS was attended for 5-6 weeks; the control group started the MBS after 8 weeks of standard care. Randomisation was stratified by cancer and the presence of a carer. Primary outcomes were patients' mastery of breathlessness (Chronic Respiratory Disease Questionnaire (CRQ) Mastery), quality of life (CRQ QoL), symptom burden (Integrated Palliative care Outcome Scale (IPOS)) and carer burden (Zarit Burden Interview (ZBI)). Intention-to-treat (ITT) analyses were conducted with hierarchical testing. Effectiveness was investigated by linear regression on change scores, adjusting for baseline scores and stratification variables. Missing values were handled with multiple imputation. RESULTS: 92 patients were randomised to the intervention group and 91 patients were randomised to the control group. Before the follow-up assessment after 8 weeks (T1), 17 and five patients dropped out from the intervention and control groups, respectively. Significant improvements in CRQ Mastery of 0.367 (95% CI 0.065-0.669) and CRQ QoL of 0.226 (95% CI 0.012-0.440) score units at T1 in favour of the intervention group were seen in the ITT analyses (n=183), but not in IPOS. Exploratory testing showed nonsignificant improvements in ZBI. CONCLUSIONS: These findings demonstrate positive effects of the MBS in reducing burden caused by chronic breathlessness in advanced illness across a wide range of patients. Further evaluation in subgroups of patients and with a longitudinal perspective is needed.

Response to Checkpoint Inhibition in Non-Small Cell Lung Cancer with Molecular Driver Alterations.

AIMS: Non-small cell lung cancer (NSCLC) patients with EGFR mutations do not respond well to checkpoint inhibitors. However, little is known about the activity of immunotherapy in NSCLC with other driver mutations. The increasing use of next-generation sequencing (NGS) leads to molecular findings that face the clinician with problems while choosing the best treatment. This study aims at analyzing response of NSCLC with driver mutations to immunotherapy. PATIENTS AND METHODS: We retrospectively included 84 NSCLC patients diagnosed and treated at 2 German tertiary-care lung cancer centers using NGS and treatment with immunotherapy. Response to immunotherapy was analyzed in correlation to molecular findings. RESULTS: 51 patients harbored at least 1 driver mutation. PIK3CA, EGFR, and STK11 mutations did not respond to immunotherapy. KRAS, TP53, and MET exon 14 skipping mutations responded well. One patient with NF-1 mutation showed durable response. CONCLUSIONS: Molecular testing may be of use in guiding treatment decision making in NSCLC.

Genetic Risk Factors for Spontaneous Pneumothorax in Birt-Hogg-Dubé Syndrome.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a genetic tumor syndrome characterized by lung cysts, spontaneous pneumothorax, fibrofolliculomas, and renal cell cancer. Because of its rarity and clinical heterogeneity, much is still unknown regarding the course of the disease and individual risk assessment. Therefore, we studied nonenvironmental risk factors for pneumothorax in a large sample of patients with BHDS. METHODS: Clinical data were available from 197 patients with BHDS (male patients, 103; female patients, 94) belonging to 63 unrelated families. The FLCN coding region including adjacent intronic sequences was analyzed by PCR and subsequent Sanger sequencing as well as by multiplex ligation-dependent probe amplification. Statistical analyses were performed, using adequate methods to account for familial clustering. RESULTS: Patients who had only a single spontaneous pneumothorax were significantly older at the time of occurrence than those with multiple pneumothoraces (mean, 38.93 vs 29.74 years; P value, .010). The risk for three or more pneumothoraces drastically increased after the second event. Significantly increased pneumothorax risks were found for mutations c.1300G>C (59%) and c.250-2A>G (77%), compared with FLCN hotspot mutation c.1285dup (37% risk) (P value, .02). CONCLUSIONS: We observed significant differences for the spontaneous pneumothorax risk regarding both age and sex in patients with BHDS. Furthermore, two FLCN mutations were identified that are associated with significantly increased pneumothorax risk. Thus, formerly unknown individual predictors have been identified that provide improved risk stratification for patients with BHDS.

Excellent platinum dependent response to chemotherapy after relapse under TKI treatment in NSCLC with sensitizing EGFR mutations and no detectable resistance mutations: three case studies.

First-line tyrosine-kinase inhibitor (TKI) treatment is the current standard for patients with metastasized non-small cell lung cancer (NSCLC) and sensitizing epidermal growth factor receptor (EGFR) mutations. Despite good initial responses, patients treated with TKIs relapse after an average of 12 months. About half of them develop known resistance mechanisms and therefore are qualified for further targeted therapies. However, many patients still have to be treated with standard chemotherapeutic regimens. In this case series we describe three patients with similar progression patterns under TKI treatment in the absence of treatable resistance mechanisms and excellent platinum dependent response to chemotherapy and review the current literature focusing on effectiveness of standard chemotherapy in this cohort.

Late-onset severe pneumonitis under osimertinib.

Pneumonitis is a rare and possibly life threatening side effect of TKI-treatment. We present a patient with adenocarcinoma of the lung harboring an uncommon EGFR Exon 21 mutation treated with osimertinib as second-line therapy. After nine months of treatment, the patient developed progressing shortness of breath and night sweats. A severe late-onset predominantly eosinophilic pneumonitis was diagnosed, osimertinib treatment was discontinued and immunosuppressive treatment was initiated. This case report highlights late-onset pneumonitis as a side effect of third-generation TKI-treatment and possible options for subsequent tumor treatment.