A new large pantherine and a sabre-toothed cat (Mammalia, Carnivora, Felidae) from the late Miocene hominoid-bearing Khorat sand pits, Nakhon Ratchasima Province, northeastern Thailand.

We describe two large predators from the hominoid-bearing Khorat sand pits, Nakhon Ratchasima Province, northeastern Thailand: a new genus of pantherine, Pachypanthera n. gen., represented by partial mandible and maxilla and an indeterminate sabre-toothed cat, represented by a fragment of upper canine. The morphological characters of Pachypanthera n. gen., notably the large and powerful canine, the great robustness of the mandibular body, the very deep fossa for the m. masseter, the zigzag HSB enamel pattern, indicate bone-cracking capacities. The genus is unique among Felidae as it has one of the most powerful and robust mandibles ever found. Moreover, it may be the oldest known pantherine, as other Asian pantherines are dated back to the early Pliocene. The taxa we report here are the only carnivorans known from the late Miocene of Thailand. Although the material is rather scarce, it brings new insights to the evolutionary history of Neogene mammals of Southeast Asia, in a geographic place which is partly "terra incognita."

International Tailored Chemotherapy Adjuvant (ITACA) trial, a phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy versus standard adjuvant chemotherapy in completely resected stage II-IIIA non-small-cell lung cancer.

BACKGROUND: Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor. PATIENTS AND METHODS: Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS). RESULTS: Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T. CONCLUSION: In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.

[Clinical Course of Typical and Atypical Carcinoids (bpNET): Evaluation of PneuNET Register Berlin Data for the Identification of Indicators for Prognosis Determination and Therapy Planning]. / Klinischer Verlauf typischer und atypischer Karzinoide (bpNET) ­ Auswertung von Registerdaten des PneuNET-Registers Berlin zur Identifikation von Indikatoren zur Prognosebestimmung und Therapieplanung.

AIM: Retrospective analysis of data from PneuNET registry to evaluate clinical follow up of patients with typical and atypical bronchopulmonary carcinoid (bpNET). METHOD: Three lung cancer centres in Berlin included patients in the registry between 2007 and 2016. Inclusion criteria were: diagnosis of typical or atypical carcinoid, age > 18 years, follow-up for not less than 2 years. Frequency, gender, functional status, smoking status, localisation of the tumour, biomarker, diagnostic and therapeutic procedures and follow-up were evaluated. RESULTS: Since 01. 01. 2007, 187 patients with bronchopulmonary carcinoid had been included in the registry. The ratio between TC and AC was 8:2. The median age was 65.4 years and 64 % of patients were women. 10.7 % of patients had pulmonary symptoms, 2 patients a carcinoid syndrome, no patient was detected with MEN-1-syndrome. 87.7 % of patients had undergone surgery, 69.5 % as lobectomy with systematic lymphadenectomy. Only 10 % of patients were diagnosed with Stage IV disease, with atypical carcinoid predominating Systemic therapies included chemotherapy, everolimus and somatostatin analogues. CONCLUSION: Bronchopulmonary carcinoids are well differentiated tumours of the lung. The early stage diagnosis offers the possibility of local therapy with excellent prognosis. We have improved systemic treatment options with mTOR-inhibitor everolimus and somatostatin analogues also in advanced stage of the disease. Because of the rareness of this heterogenous group of tumours, it is meaningful to collect data systematically in order to have a standardised algorithm of diagnostic procedures and therapy assessment.

[Diagnostics and Treatment of Cardiac Sarcoidosis - Consensus Paper of the German Respiratory Society (DGP) and the German Cardiac Society (DGK)]. / Diagnostik und Therapie der kardialen Sarkoidose.

Sarcoidosis is a multisystemic granulomatous disorder which affects the respiratory system in the majority of the cases. Symptomatic cardiac manifestations are found in less than 10 % of the affected cohorts and show a large heterogeneity based on the ethnic background. Cardiac sarcoidosis is not only found in patients with rhythmogenic heart disease, such as atrial and ventricular fibrillation but also in all phenotypes of cardiomyopathy. The overall morbidity and mortality caused by cardiac sarcoidosis in Germany remains unclear and large prospective international observational studies.underline the importance of this disease entity. This consensus paper on diagnostic and therapeutic algorithms for cardiac sarcoidosis is based on a current literature search and forms an expert opinion statement under the auspices of the German Respiratory Society and the German Cardiac Society. The rationale of this statement is to provide algorithms to facilitate clinical decision-making based on the individual case situation.

[Responsibilities of Weaning Centers during the COVID-19 Pandemic Outbreak - Recommendations for the Assignment of ICU Capacities in COVID-19 Patients as shown by the Berlin-Brandenburg POST-SAVE-Model]. / Aufgaben der Weaning-Zentren im Pandemiefall COVID-19.

The enormous increase in patients with severe respiratory distress due to the COVID-19 pandemic outbreak requires a systematic approach to optimize ventilated patient at risk flow. A standardised algorithm called "SAVE" was developed to distribute patients with COVID-19 respiratory distress syndrome requiring invasive ventilation. This program is established by now in Berlin. An instrumental bottleneck of this approach is the vacant slot assignment in the intensive care unit to guarantee constant patient flow. The transfer of the patients after acute care treatment is needed urgently to facilitate the weaning process. In a next step we developed a triage algorithm to identify patients at SAVE intensive care units with potential to wean and transfer to weaning institutions - we called POST SAVE. This manuscript highlights the algorithms including the use of a standardised digital evaluation tool, the use of trained navigators to facilitate the communication between SAVE intensive care units and weaning institutions and the establishment of a prospective data registry for patient assignment and reevaluation of the weaning potential in the future.

[Monitoring of None-invasive Ventilated Patients in a Home Care Setting]. / Prospektive Untersuchung der außerklinischen Versorgung und Therapiekontrolle bei nichtinvasiv heimbeatmeten Patienten.

There is a paucity of data about the at home monitoring and the outpatient setting and care of patients with non-invasive ventilation. We here show, in a prospective study, that both standardized outpatient care visits as well as quality of life monitoring at home are safe and feasible. Monitoring and managing the quality of care at home did not lead to an increase of non-elective hospitalisations or deterioration of respiratory disease burden.

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer.

Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders. Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4-5.6) versus 10.3 months (95% CI: 8.6-12.0), P < 0.001; OS 15.0 months (95% CI: 5.0-24.9) versus 50.0 months (95% CI: 22.9-77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3-4.1) versus 6.2 months (95% CI: 1.8-10.5), P = 0.021; OS 2.0 months (95% CI: 0.0-4.6) versus 9.0 months (95% CI: 6.1-11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9-7.2) versus 14.0 months (95% CI: 8.0-20.1), P < 0.001; OS 17.0 months (95% CI: 6.7-27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1-10.7) versus 9.9 months (95% CI: 6.4-13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001). Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.

[Longterm Homecare Augmentation Program in Alpha-1-Antitrypsin Deficient Patients]. / Langzeit-Augmentationstherapie von Patienten mit Alpha-1-Antitrypsin-Mangel in der häuslichen Pflege.

BACKGROUND: Augmentation with human alpha-1 proteinase inhibitor is the only specific treatment for Alpha-1-Antitrypsin Deficiency (AATD), a rare genetic disease with symptoms of progressive COPD. OBJECTIVES: A prospective long-term exploration of outcomes during the "Alpha-1-Mobile" home care AAT augmentation program in seven advanced-stage patients. METHODS: Patients received weekly i. v. AAT augmentation and COPD therapy. Symptoms, lung function, health status, quality-of-life aspects, and safety were documented continuously. Outcomes during six years of home care augmentation therapy were observed and evaluated on an inter- and intraindividual basis. FEV1 profiles were compared to pre-program data. RESULTS: The seven patients had a mean age of 56.7 (40-68) years and had previously received augmentation for 8.8 (1-19) years. Compared to the three-year preprogram period, functional decline of FEV1 (ΔFEV1 0.47 L vs 0.17 L) slowed. Mean QoL scores showed seasonal fluctuations in the first three years of observation, and then stabilized. All blood samples tested exceeded the protective threshold of 50 mg/dL with a dose of 60 mg AAT/kg/week. Less than one exacerbation-related hospitalization occurred per patient-year. No adverse events of related to augmentation therapy were observed. CONCLUSIONS: Home care with i. v. augmentation therapy by medical professionals contributes to optimum care through consistent treatment and close health-status monitoring in our collective. Exacerbation-related hospitalizations were largely avoided. "Alpha-1-Mobile" was well accepted, practical, and safe.

Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial.

BACKGROUND: Large-cell neuroendocrine carcinoma of the lung (LCNEC) is a rare disease with poor prognosis and limited treatment options. Neuroendocrine tumors frequently show overactivation of the mTOR pathway. Based on the good activity of the mTOR inhibitor everolimus in different types of neuroendocrine tumors and the results of a previous phase I trial, we evaluated the efficacy and safety of everolimus in combination with carboplatin and paclitaxel as upfront treatment for patients with advanced LCNEC. PATIENTS AND METHODS: In this prospective, multicenter phase II trial chemotherapy-naive patients with stage IV LCNEC received 5 mg everolimus daily combined with paclitaxel 175 mg/m2 and carboplatin AUC 5 every 3 weeks for a maximum of four cycles followed by maintenance everolimus 5 mg daily until progression. Efficacy parameters were determined based on central radiologic assessment. RESULTS: Forty-nine patients with a mean age of 62 ±9 years and a predominance of male (71%) smokers (98%) were enrolled in 10 German centers. The overall response rate was 45% (95% confidence interval [CI] 31%-60%), the disease control rate 74% (CI 59%-85%), the median progression-free survival 4.4 (CI 3.2-6) months and the median overall survival 9.9 (CI 6.9-11.7) months. The progression-free survival rate at 3 months (primary end point) was 76% (CI 64%-88%) according to Kaplan-Meier. Grade-3/4 toxicities occurred in 51% of patients and mainly consisted of general physical health deterioration (8%), cytopenias (24%), infections (10%) and gastrointestinal problems (8%). Typical everolimus-related adverse events, like stomatitis, rash and ocular problems occurred only in a minority of patients (<15%) and were exclusively of grade 1-2. CONCLUSION: Everolimus in combination with carboplatin and paclitaxel is an effective and well-tolerated first-line treatment for patients with metastatic LCNEC. REGISTERED CLINICAL TRIAL NUMBERS: EudraCT number 2010-022273-34, NCT01317615.

[Sporadic Lymphangioleiomyomatosis (sLAM) and Tuberous Sclerosis Complex (TSC) - Pulmonary Manifestations]. / Sporadische Lymphangioleiomyomatose (sLAM) und Tuberöse-Sklerose-Komplex (TSC) ­ Pulmonale Manifestationen.

Lymphangioleiomyomatosis (LAM) is a rare multi-system disorder affecting predominantly women of childbearing age. The disease entity is divided in sporadic LAM (sLAM) and LAM associated with tuberous sclerosis complex (TSC). In up to 50 % of female TSC-patients pulmonary involvement (TSC-LAM) can be found, with first clinical symptoms usually starting between 25 and 30 years of age. Progressive deterioration of lung function of 3 - 11 % of diffusion capacity per year has been described, that's why all female TSC patients should be screened for LAM (pulmonary function testing, 6-minute walk test, high-resolution chest CT scan). MTOR inhibitors such as Everolimus or Sirolimus are implemented in the treatment of TSC/LAM and found to control disease burden. Screening for all organ manifestations in TSC is recommended and allows to improve prognosis and to prevent complications in TSC.

Atherosclerotic Vessel Changes in Sarcoidosis.

Sarcoidosis is a systemic granulomatous disease. Atherosclerosis is a chronic inflammatory vessel disease. The aim of our present study was to investigate whether sarcoidosis could be associated with increased risk of atherosclerotic vessel changes. Angiological analysis and blood tests were performed in 71 sarcoidosis patients and 12 matched controls in this prospective cross-sectional study. Specifically, angiological measurements comprised ankle brachial index (ABI), central pulse wave velocity (cPWV), pulse wave index (PWI), and duplex sonography of central and peripheral arteries. Sarcoidosis activity markers (angiotensin converting enzyme, soluble interleukin-2 receptor) and cardiovascular risk parameters such as cholesterol, lipoprotein(a), C-reactive protein, interleukin 6, fibrinogen, d-dimer, and blood count were analyzed in blood. We found no relevant differences in ABI, cPWV, and plaque burden between the sarcoidosis and control groups (1.10 ± 0.02 vs. 1.10 ± 0.02, 6.7 ± 0.5 vs. 6.1 ± 1.2, 53.7 % vs. 54.5 %, respectively). However, PWI was significantly higher in sarcoidosis patients (146.2 ± 6.8) compared with controls (104.9 ± 8.8), irrespectively of the activity of sarcoidosis and immunosuppressive medication. Except for increased lipoprotein(a) and d-dimer in sarcoidosis, the remaining cardiovascular markers were similar in both groups. We conclude that sarcoidosis is associated with increased pulse wave index, which may indicate an early stage of atherosclerosis.

[Models of communication to integrate early palliative care in thoracic oncology]. / Kommunikationsmodell zur frühen Integration der Palliativmedizin in der thorakalen Onkologie.

The recent development in optimising palliative care standards in thoracic oncology is associated with an increased demand in specialized communication skills. Standardised and integrated assessments of the palliative care need of the patient is met by limited health care resources. The model of communication described in this article emphasizes the need to structure palliative distress assessment of the patient. Communication pathways are shown as a platform to evaluate and support patient and caregivers. Standards to establish algorithms of communication in palliative care will improve the very important interaction between patient and caregivers.

[New therapeutic approaches to pulmonary embolism: trials' results and significance of direct oral anticoagulants]. / Neue Therapieoptionen zur Behandlung der Lungenembolie: Studienlage und Stellenwert der direkten oralen Antikoagulantien.

Venous thromboembolisms (VTE) are frequently encountered emergencies that sometimes run a fatal course. Diagnostic and therapeutic strategies in patients with suspected pulmonary embolism (PE) are based on the presence of shock and hypotension. Oral anticoagulation is recommended for at least three months, extended anticoagulation should be considered for patients with unprovoked PE and low bleeding risk. As an alternative to vitamin K antagonists, direct oral anticoagulants are recommended. The present review discusses the mode of action, current data, and the status of rivaroxaban, dabigatran, apixaban and edoxaban in the treatment of PE - taking into account the new guidelines of the European Society of Cardiology and their clinical implementation.

[Position Paper: Significance of the Forced Vital Capacity in Idiopathic Pulmonary Fibrosis]. / Positionspapier zur Bedeutung der forcierten Vitalkapazität für Patienten mit idiopathischer Lungenfibrose (IPF).

Spirometry is a highly standardized method which allows to measure the forced vital capacity (FVC) with high precision and reproducibility. In patients with IPF FVC is directly linked to the disease process which is characterized by scaring of alveoli and shrinkage of the lungs. Consequently, there is ample evidence form clinical studies that the decline of FVC over time is consistently associated with mortality in IPF. As for the first time effective drugs for the treatment of IPF are available it becomes obvious that in studies which could demonstrate that the drug reduces FVC decline, a numerical effect on mortality was also observed, while in one study where a significant effect on FVC decline was missed, there was also no change in mortality. Based on these studies FVC decline is a validated surrogate of mortality in IPF. It is concluded that FVC decline is not only accepted as an endpoint of clinical treatment trials in IPF but is also valid as a patient related outcome parameter which should be considered for the assessment of the efficacy of an IPF drug.

[Malignant pleural mesothelioma: new aspects of medical therapy]. / Neue Aspekte der medikamentösen Therapie des malignen Pleuramesothelioms.

Malignant pleural mesothelioma, a typical long-term consequence of exposure to asbestos, represents a therapeutic challenge. In the early stages of the disease, trimodal therapy combining surgery, radiation and chemotherapy is used as standard care. In advanced stages, the combination of cisplatin and pemetrexed has been approved as first-line therapy, but there is a lack of randomised controlled drug trials for second-line treatment. Monotherapy with pemetrexed, vinorelbine or gemcitabine may provide some survival benefit compared to treatment aiming at symptom control only. Immunotherapy seems to be a promising new concept. The so-called frustrated phagocytosis, with continuing antigen presentation leading to persisting local inflammation and antigen tolerance, can be interrupted by blocking the T-cell surface protein CTLA-4. The monoclonal antibodies ipilimumab and tremelimumab that block CTLA-4 can stimulate immune response and thus increase the number of tumor-infiltrating lymphocytes. Clinical studies exploring this avenue of treatment are being awaited with great excitement.

[Anti-angiogenic strategy: therapy optimization of non-squamous non-small cell lung carcinoma]. / Antiangiogenes Wirkprinzip--Konzepte der Therapieoptimierung des nicht-squamösen nicht-kleinzelligen Lungenkarzinoms.

Anti-angiogenic treatment with anti-VEGF compounds plays a central role in the therapy of non-squamous non-small cell lung cancer (NSCLC). However, biometric analysis of overall survival of the established treatment options reveals several limitations of efficacy in unselected patient cohorts. Furthermore, there are no established predictive biomarkers to help select patients who might benefit from this treatment option. This review focuses on underlying principles of action of tumor-related angiogenesis and presents new treatment options that may contribute to improved overall survival.

[Cardiac sarcoidosis: diagnostic and therapeutic algorithms]. / Diagnostik und Therapie der kardialen Sarkoidose.

Sarcoidosis is a multisystemic granulomatous disorder which affects the respiratory system in the majority of the cases. Cardiac manifestations are found in up to 10 % of the affected cohort and show a large heterogeneity based on the ethnic background. Cardiac sarcoidosis are not only found in patients with rhythmogenic heart disease such as atrial and ventricular fibrillation but also in all phenotypes of cardiomyopathies. The overall morbidity and mortality caused by cardiac sarcoidois in Germany is unclear and no large prospective international studies are published on this topic. This consensus paper on diagnostic and therapeutic algorithms in cardiac sarcoidosis is based on a current literature search and forms a expert opinion statement under the hospices of the "Deutsche Gesellschaft für Pneumologie" and "Deutsche Gesellschaft für Kardiologie". It is the rationale of this statement to offer algorithms to facilitate clinical decision-making based on the individual case.

Treatment of advanced BP-NETS with lanreotide autogel/depot vs placebo: the phase III SPINET study.

Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical carcinoids and atypical carcinoids (TCs and ACs)). SPINET (EudraCT: 2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) vs placebo plus BSC, with an optional open-label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression-free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n = 51 (TCs, n = 29; ACs, n = 22); placebo, n = 26 (TCs, n = 16; ACs, n = 10)). Median (95% CI) PFS during double-blind and open-label phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable (NC)) months in TCs, and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN vs 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients' quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR-positive TCs and ACs and suggests clinical benefit in TCs.

Overall survival and central nervous system activity of crizotinib in ROS1-rearranged lung cancer-final results of the EUCROSS trial.

BACKGROUND: In 2019, we reported the first efficacy and safety analysis of EUCROSS, a phase II trial investigating crizotinib in ROS1 fusion-positive lung cancer. At that time, overall survival (OS) was immature and the effect of crizotinib on intracranial disease control remained unclear. Here, we present the final analysis of OS, systemic and intracranial activity, and the impact of co-occurring aberrations. MATERIALS AND METHODS: EUCROSS was a prospective, single-arm, phase II trial. The primary endpoint was best overall response rate (ORR) using RECIST 1.1. Secondary and exploratory endpoints were progression-free survival (PFS), OS, and efficacy in pre-defined subgroups. RESULTS: Median OS of the intention-to-treat population (N = 34) was 54.8 months [95% confidence interval (CI) 20.3 months-not reached (NR); median follow-up 81.4 months] and median all-cause PFS of the response-evaluable population (N = 30) was 19.4 months (95% CI 10.1-32.2 months). Time on treatment was significantly correlated with OS (R = 0.82; P < 0.0001). Patients with co-occurring TP53 aberrations (28%) had a significantly shorter OS [hazard ratio (HR) 11; 95% CI 2.0-56.0; P = 0.006] and all-cause PFS (HR 4.2; 95% CI 1.2-15; P = 0.025). Patients with central nervous system (CNS) involvement at baseline (N = 6; 20%) had a numerically shorter median OS and all-cause PFS. Median intracranial PFS was 32.2 months (95% CI 23.7 months-NR) and the rate of isolated CNS progression was 24%. CONCLUSIONS: Our final analysis proves the efficacy of crizotinib in ROS1-positive lung cancer, but also highlights the devastating impact of TP53 mutations on survival and treatment efficacy. Additionally, our data show that CNS disease control is durable and the risk of CNS progression while on crizotinib treatment is low.