Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM).

BACKGROUND: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date. PATIENTS AND METHODS: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions). RESULTS: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1. CONCLUSIONS: Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations.

Reprinted article "Realistic expectations for patients with stent-graft treatment of abdominal aortic aneurysms. Results of a European multicentre registry".

OBJECTIVE: The outcomes for patients after endovascular treatment of abdominal aortic aneurysm (AAA) are determined primarily by the endpoints of death and endoleaks, the latter representing continued risk of rupture. The data of a multicentre registry were analysed with regard to the early outcome of stent-graft procedures for AAA and the complications associated with this treatment. In addition, the results during follow-up were analysed by determining mortality and endoleak development as separate endpoints and as a combined endpoint defined as endoleak-free survival. SETTING: 38 European institutions of Vascular Surgery collaborating in a multicentre registry project. PATIENTS AND METHODS: 899 patients with AAA underwent between May 1994 and March 1998 elective endovascular repair (818 men and 81 women; mean age 69 years). 80 (8.9%) of the patients had medical conditions that excluded them from open repair. 818 (91%) of patients had a bifurcated device, 63 (7%) had a straight tube graft, and only 18 (2%) had an aorto-uni-iliac device. Clinical examination and contrast-enhanced computed tomography was performed at fixed follow-up intervals to assess increase or decrease of the maximum transverse diameter (MTD). Endoleaks observed at follow-up were discriminated into persistent endoleak and temporary endoleak. The latter is defined as single time observed endoleaks or with two or more negative imaging studies between observed endoleaks. Life-table analyses were used to calculate the rates of freedom-from-endoleak (no endoleak at any time), freedom-from-persistent endoleak (no persistent endoleak), patient survival, and persistent-endoleak-free-survival. RESULTS: The median follow-up of this patient series was 6.2 months. The ratio between observed and expected follow-up data was 82% for the overall follow-up period. However, at 18 months of follow-up this rate was only 45%. The number of patients followed during this period was sufficient to allow statistically meaningful assessment. The MTD in patients with temporary endoleaks demonstrated a significant decrease at 6 to 12 months compared to preoperative values (mean 57 and 53 respectively, p = 0.004). In patients with persistent endoleaks there was no change between the preoperative and 6-month MTD (mean 57 and 60 mm respectively). At 6 and 18 months freedom-from-endoleak was 83% and 74% and freedom-from-persistent endoleak was 93% and 90%, respectively. The 18-month cumulative patient survival was 88% and the main outcome measure, the persistent endoleak-free-survival was 79%. CONCLUSIONS: The MTD decreases in patients with temporary endoleak, but not in patients with persistent endoleak. Therefore, the use of the rate of freedom-from-persistent endoleak, reflecting absence of persisting endoleaks to estimate the prognosis with regard to the AAA, is justified. Determining persistent endoleak-free survival appears a rational approach to provide a realistic outlook for patients with stent-grafted AAA. The observed 18-month endoleak-free survival reflects a satisfactory mid-term result.

Validation of the chronic venous insufficiency quality of life questionnaire in Dutch patients treated for varicose veins.

BACKGROUND: The Chronic Venous Insufficiency Quality of Life Questionnaire (CIVIQ) is a disease-specific instrument to measure the impact of chronic venous insufficiency (CVI) on patients' lives. The objective of this study is to test the psychometric properties of the CIVIQ, and to validate the use of the questionnaire translated into the Dutch language. METHODS: A standardised questionnaire, including CIVIQ and Short Form (36) Health Survey (SF-36), was obtained before and 1 month after treatment to all new patients with varicose veins. The feasibility was tested by missing responses and response distribution. CIVIQ scores were compared to the SF-36 scores and between different levels of severity of varicose veins. The CIVIQ's reliability was assessed using Cronbach's alpha and test-retest reliability. The structure was studied using factor analysis. The scores before and after therapy were compared to assess responsiveness. RESULTS: There was a response rate of 93.5%. None of 20 items missed < 10% of responses, but three showed ceiling effect. The CIVIQ correlated well with the physical and moderately with the mental MCS of the SF-36, suggesting a good construct validity of the CIVIQ. The median CIVIQ scores increased significantly with the severity of varicose veins. The CIVIQ showed an excellent internal consistency and an excellent test-retest reliability. The CIVIQ score decreased in 76% of patients after treatment. The results were in accordance with the Norman's rule and showed a median effect size. CONCLUSION: This study confirms the feasibility, validity, reliability and responsiveness of the CIVIQ in patients with varicose veins. The psychometric properties of the Dutch CIVIQ were comparable to the original French version.

Patient-specific AAA wall stress analysis: 99-percentile versus peak stress.

OBJECTIVE: Biomechanically, rupture of an Abdominal Aortic Aneurysm (AAA) occurs when the stress acting on the wall due to the blood pressure, exceeds the strength of the wall. Peak wall stress estimations, based on CT reconstruction, may be prone to observer variation. This study focuses on the robustness and reproducibility of AAA wall stress assessment and the relation with geometrical features of the AAA. METHODS: The AAAs of twenty patients were reconstructed by three operators. Both the peak and 99-percentile stress were used for intra- and inter-operator variability using the intraclass correlation coefficient (ICC). A regression analysis was performed to relate the stress parameters with the maximum diameter. Outliers were analyzed by their geometrical characteristics. RESULTS: The intra-operator ICC was 0.73-0.79 for the peak stress and 0.94 for the 99-percentile stress. The inter-operator ICC was 0.71 for the peak stress and 0.95 for the 99-percentile stress. A significant linear relation with the diameter was found only for the 99-percentile stress. CONCLUSIONS: The 99-percentile stress is more reproducible than peak wall stress. A significant relation between wall stress and diameter was found. Other geometrical features had no statistical relation with high stress.

[Endarterectomy is a good treatment option in patients with asymptomatic carotid stenosis]. / Endarteriëctomie goede behandeloptie bij patiënten met een asymptomatische carotisstenose.

Among patients with substantial carotid artery stenosis without neurological symptoms, the benefit of carotid endarterectomy had been unclear until this issue was addressed in two randomised trials. The incidence of stroke during follow-up was reduced by approximately one-half after endarterectomy. In appropriate patients, endarterectomy ofa significant asymptomatic carotid stenosis is certainly a treatment option.

Vascular laboratory criteria for the management of peripheral vascular disease of the lower extremities.

From experience gained in over 4,500 vascular laboratory procedures, segmental Pulse Volume Recorder (PVR) tracings, systolic pressure measurements, and other noninvasive laboratory techniques have been found extremely useful in the management of patients with arteriosclerotic peripheral vascular disease. Both PVR recordings and limb pressures were found to be important and are used in complementary fashion. Although arteriography is essential in defining structural lesions and in establishing graftability, noninvasive vascular studies provide an inexpensive, accurate, reproducible method for assessing functional significance of arterial disease. These studies contribute to the diagnosis, definition of severity, and establishment of an objective baseline prior to medical or surgical therapy. Because they may be used in a repetitive manner, they are extremely useful in establishing success of a given therapy and in the long-term follow-up of patients. Based upon our experience, laboratory criteria have been developed which allow accurate identification of ischemic rest pain, aid in predicting healing of foot lesions or below-knee amputations, and quantitate the functional disability of claudication.

Does endovascular aortic aneurysm repair justify a reduced cardiology work-up?

Endovascular repair of abdominal aortic aneurysms (EVAR) has been introduced as an alternative to open surgery with the purpose of reducing operative risk and improving survival. Since cardiac co-morbidity is a major risk factor for both the operative procedure and long-term survival, it seems worthwhile to compare the cardiac implication of the 2 procedures. If EVAR would indeed afford a cardioprotective effect, this could have clinical consequences. Preoperative cardiology work-up could be reduced and more high-risk patients could be treated. A review of the literature has been made focusing on studies that examined cardiology work-up and cardiac risk profile of EVAR and open surgery. Most literature data suggest that cardiac risk is indeed reduced with EVAR, since hemodynamic alterations are less severe, episodes of anaemia are less frequent, plasma catecholamine levels are lower and general anaesthesia can be avoided. There is no level I or II evidence that immediate or late cardiac complications are indeed reduced with EVAR. At present, there are not enough literature data on the cardiac implications of EVAR to justify a reduced preoperative cardiology work-up. Even if conclusive evidence was available that EVAR reduces operative cardiac risk, the value of preoperative cardiac screening and myocardial revascularisation would remain unchanged: the purpose of cardiology work-up is not only to reduce operative risk but also to improve long-term survival.

The multicenter experience with a third-generation endovascular device for abdominal aortic aneurysm repair. A report from the EUROSTAR database.

AIM: The purpose of this study was to evaluate the effect of the preoperative diameter of abdominal aortic aneurysms (AAA) upon the midterm outcome obtained by endovascular AAA repair, using a third-generation endovascular device, the Excluder bifurcated endoprosthesis (W. L. Gore & Associates, Inc. Sunnyvale, CA, USA). METHODS: The data of 676 patients, who had undergone endovascular aneurysm repair (EVAR) were analysed. Patients were enrolled over a 6-year period to April 2004 in the EUROSTAR database. Outcomes were compared between 2 groups defined by the preoperative diameter of the aneurysm: group A (n=300), smaller than 5.5 cm; group B (n=376), 5.5 cm or larger. Patient characteristics, details of aorto-iliac anatomy, operative procedure and postoperative complications in the 2 patient groups were compared. Outcome events included aneurysm-related death, overall death, conversion, and late rupture of the aneurysm. Life table analyses and log rank tests were used to compare outcome in the study groups. Multivariate Cox models were used to determine whether baseline and follow-up variables were independently associated with adverse outcomes. RESULTS: Patients in group B were significantly older than patients in group A (73 years vs 71 years respectively; p=0.006), and more frequently were at higher operative risk (ASA-classification >3; 44% vs 59%; p<0.0001). Anatomic differences included a higher incidence of aorto-iliac angulation, a wider and shorter infrarenal neck in group B. Risk factors that were more frequently observed in group B included hypertension, carotid disease and pulmonary disorders. Additional operative events including device migration occurred more frequently in group B (0% vs 2%; p=0.03). Device-related (type I and III combined) endoleaks were more frequently observed at completion arteriography in group B compared to group A (2% vs 4%; p=n.s.). Thirty-day mortality was comparable between the 2 study groups. However, the overall death rate after 3 years of follow-up was significantly higher in patients with larger aneurysms, group B (4% vs 14%; p=0.0025). Similarly, aneurysm-related death was significantly higher in group B (after 3 years 0.3% vs 3%; p=0.02). Aneurysm growth after EVAR was modest low in both study groups (after 2 years 6% vs 8%; non-significant). There was no correlation between growth of the sac and aneurysm-related death. CONCLUSIONS: The midterm outcome after endovascular repair by Excluder devices was satisfactory in patients with small and large AAAs. A higher rate in all-cause deaths and aneurysm-related deaths in patients with larger aneurysms was observed. Post-EVAR aneurysm growth was observed in a small percentage of patients but this did not contribute to aneurysm-related death.

Endoleaks during follow-up after endovascular repair of abdominal aortic aneurysm. Are they all dangerous?

AIM: Development of endovascular abdominal aortic aneurysm repair (EVAR) has been accompanied by previously unencoutered complications. The most challenging but least understood of these complications is incomplete seal of the endovascular graft (endoleak), a phenomenon which has a variety of causes. An important consequence of endoleakage may be persistent pressurisation of the aneurysm sac, which may ultimately lead to post-EVAR rupture. METHODS: Data of 110 European centers were recorded in a central database (EUROSTAR). Patient, anatomic characteristics and operative and device details were correlated with the occurrence of different types of endoleaks. Outcome events during follow-up, notably expansion of the aneurysm, incidence of conversion to open repair and post-EVAR rupture were assessed in the different categories of endoleaks and in a group of patients without any endoleak. RESULTS: Type I and III endoleak were associated with an increased frequency of open conversions or risk of rupture of the aneurysm. Device-related endoleaks also correlated with an increased need for secondary interventions. These types of endoleak need to be treated without delay, and when no other possibilities are present, an open conversion to avert the risk of rupture should be considered. Endoleaks type II do not pose an indication for urgent treatment. However, they may not be harmless, as there was a frequent association with enlargement of aneurysm and reinterventions. CONCLUSION: Our findings suggest that more frequent surveillance examinations are indicated than in patients without collateral endoleak. The indication for intervention is primarily dictated by documented expansion of the aneurysm.

[Endovascular therapy of aneurysms of the abdominal aorta: report of 4,291 patients of the Eurostar Register]. / Endovaskuläre Therapie von Aneurysmen der Bauchaorta: Bericht über 4291 Patienten des Eurostar-Registers.

BACKGROUND: The Eurostar project is a multicentred database of the outcome of endovascular repair of infra-renal aortic aneurysms. From 1996 to March, 2002, 113 European centres of vascular surgery have contributed. The purpose of this article is to review the medium term (up to 7 years) results of endovascular aneurysm repair as reported to Eurostar. PATIENTS AND METHODS: Patients intended for endovascular aneurysm repair were notified to the Eurostar Data Registry Centre before treatment in order to eliminate bias due to selective reporting. The following data was collected on all patients: (1) their demographic details and the anatomical characteristics of their aneurysms, (2) details of the endovascular device used, (3) procedural complications and the immediate outcome, (4) results of contrast enhanced CT imaging at 1, 3, 6, 12, 18 and 24 months after operation and at yearly intervals thereafter, (5) all adverse events. Life table analysis was performed to determine the cumulative rates of: (1) death from all causes, (2) secondary intervention. RESULTS: By March 2002, pre- and postoperative data of 4291 patients had been registered. The median duration of follow-up was 12 mo (range 0-96). Successful deployment was achieved in 97.8% of the patients with a perioperative (30 day) mortality of 2.4%. Early conversion to open repair occurred in 1.3%. Late rupture of the aneurysm occurred in 35 patients. The significant factors were endoleaks, graft migration and kinking. Late conversion to open repair occurred at an annual rate of approximately 2%. Risk factors (indications) for late conversion were endoleaks, graft migration and kinking. CONCLUSIONS: Endovascular repair of infra-renal aortic aneurysms using the first and second-generation devices that predominated in this study is associated with a risk of early or late failure of 3% per year, based upon an analysis of observed primary endpoints of rupture and conversion.

The diagnosis and treatment of acute aortic occlusions.

Acute occlusion of the abdominal aorta is infrequently observed. The clinical presentation may vary from acute limb ischaemia, neurologic symptoms of the lower extremities, abdominal symptoms and acute hypertension. This clinical picture is caused by embolic occlusion or, more often, by acute thrombosis. Pre-existing atherosclerosis combined with a low flow state because of poor cardiac performance is a relatively frequent cause of acute aortic occlusion. Hyper-coagulability is observed as well in association with abdominal arteria thrombosis. The management of this condition includes immediate heparinization and measures to improve the cardiac condition. Although operative treatment by thromboembolectomy, aortofemoral bypass or axillofemoral bypass is still most commonly used management, the present treatment of choice probable consists of thrombolytic therapy and mechanical rheolytic thrombectomy followed by stent placement at severely diseased arterial segments. This latter method is associated with a lower mortality than operative therapy in this high risk patient group.

Development time, oviposition activity and onset of diapause in Culex tarsalis, Culex restuans and Culiseta inornata in southern Manitoba.

Development times and survival of immatures and reproductive diapause of adult females of Culex tarsalis, Cx. restuans and Culiseta inornata were investigated from hatching to adult emergence at 15, 20 and 25 degrees C in the laboratory and at natural temperatures and photoperiods in southern Manitoba. Based on patterns of oviposition in artificial pools operated from mid-April to the end of September and development time of the immature stages, 3 generations of Cx. tarsalis, Cx. restuans and Cs. inornata were possible in 1980 and 1981. In 1981, 70% of field-reared Cx. tarsalis females emerging in mid-August were in diapause. Field-reared Cx. restuans and Cs. inornata entered reproductive diapause 2-3 weeks later than Cx. tarsalis.

[Results of bypass surgery for imperiled leg]. / Resultaten van bypass-operaties wegens bedreigd been.

Femoropopliteal and crural bypass operations are performed frequently, but the results of operations for intermittent claudication and severe ischaemia are often reported jointly. However, the importance of the latter category for the quality of life is of a different order, so that its results should be studied separately. In a period of over eight years 199 bypass operation were performed. The cumulative proportion of preserved legs after three years was 82% for femoropopliteal and 68% for femorocrural transplantations. Factors such as presence of gangrene, diabetes mellitus and a systolic ankle blood pressure below 40 mm Hg were associated with a significantly smaller proportion of saved legs. The five-year survival rate for the group of patients as a whole was 42%, far lower than the 79% that applies to a comparable group of healthy persons. Cardiopathy was the main cause of death. Even if the number of remaining years of life is less, saving the leg by a bypass operation performed in time should be considered of major importance.

[Endovascular abdominal aortic aneurysm repair. First experiences regarding 20 patients in Eindhoven]. / Endovasculaire behandeling van een aneurysma aortae abdominalis. Eerste ervaringen met 20 patiënten in Eindhoven.

OBJECTIVE: Evaluation of the early results of endovascular abdominal aortic aneurysm (AAA) repair. DESIGN: Prospective cohort study. SETTING: Catharina Hospital, Eindhoven, the Netherlands. METHODS: Operative results and complications following endovascular AAA repair in 20 consecutive patients were surveyed. The early results consisted of the procedural outcome and the events during a mean follow-up of 6.6 months (range: 1-12 months). Nine patients had a considerably increased operation risk (American Society of Anesthesiology (ASA) class III of IV). Criteria for success were absence of endoleak and of further expansion of the aneurysm. RESULTS: Three of the nine patients in bad general shape suffered an episode of cardiac failure after the operation. In the other patients there were no serious systemic complications. No patient died. Sixteen patients (80%) had a successful immediate AAA exclusion. In two patients a second endovascular procedure was required to seal an endoleak. In one patient the procedure was converted to an open reconstruction because of a persistent endoleak, while in another patient a small midgraft endoleak was treated conservatively. Ultimately 18 patients (90%) had a successful endovascular AAA repair. CONCLUSION: Endovascular AAA repair is feasible with a high success rate and a low complication rate. This method is expected to gain an important place in future AAA repair. Longer follow-up is needed to study late complications, among which occurrence of early and late endoleaks is the most important.