Diagnostic and therapeutic delays in lung cancer during the COVID-19 pandemic: a single center experience at a German Cancer center.

BACKGROUND: The COVID-19 pandemic has had negative drawbacks on the healthcare system worldwide and on individuals other than those directly affected by the virus. Delays in cancer therapy and diagnosis have been reported in the literature. We hypothesized similar effects on patients with lung cancer at our center. METHODS: We retrospectively analyzed data of patients referred to our center with newly diagnosed lung cancer from 2018 to 2022. We considered distribution of UICC Stages and time from case presentation in our multidisciplinary tumor board or from therapeutic indication from treating physician to therapy initiation (surgery, systemic therapies and radiation) to define delays in diagnosis and treatment. RESULTS: 1020 patients with newly diagnosed lung cancer were referred to our center from 2018 to 2022, with a median of 206 cases yearly (range: 200-208). Cases with Stage IV in 2020-2022 were significantly higher than in 2018-2019 (57% vs. 46%, p = 0,001). 228 operative resections took place between 2018 and 2022, 100 from January 2018 to February 2020 and 128 from March 2020 to December 2022. Median time from presentation in our tumor board to resection was also significantly longer after the beginning of the pandemic than before (22 days vs. 15,5 days, p = 0,013). No significant delays were observed for administration of systemic treatment and initiation of radiation. CONCLUSIONS: During the pandemic higher disease stages were reported for patients with lung cancer, yet there were no clinically relevant delays in treatment. In the context of the post-covid era new diagnostic strategies are necessary to facilitate early diagnosis of lung cancer. Despite the pandemic, for patients with suspicious symptoms prompt access to healthcare facilities is essential for early diagnosis.

Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011.

BACKGROUND: Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients. METHODS: Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival. RESULTS: The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97-0.97), sex (OR 1.18, 95% CI 1.11-1.25), date of diagnosis (OR 1.05, 95% CI 1.04-1.06), 'diagnosis during screening' (OR 3.24, 95% CI 2.50-4.19) and place of residence (OR 1.23, 95% CI 1.16-1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8-83.9%). CONCLUSIONS: No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008.

Hypertension in the first blood pressure reading and the risk of cardiovascular disease mortality in the general population: findings from the prospective KORA study.

BACKGROUND: The risk of cardiovascular disease (CVD) mortality in individuals with an alerting reaction, assessed by hypertension in the first blood pressure (BP) reading but normal BP in further readings, remains unknown in the general population. METHODS AND RESULTS: In a sample of 11 146 adults (51.5% men and 48.5% women) with a mean age of 47.1 years (SD ±â€Š12.3) from a German population-based cohort, we analyzed risk factors and CVD mortality risk associated with an alerting reaction. An alerting reaction was prevalent in 10.2% of the population and associated with sociodemographic, lifestyle, and somatic CVD risk factors. Within a mean follow-up period of 22.7 years (SD ±â€Š7.05 years; max: 32 years; 253 201 person years), 1420 (12.7%) CVD mortality cases were observed. The CVD mortality rate associated with an alerting reaction was significantly higher than in normotension (64 vs. 32 cases/10 000 person-years), but lower than hypertension (118 cases/10 000 person-years). Correspondingly, the alerting reaction was associated with a 23% higher hazard ratio of CVD mortality than normal blood pressure [hazard ratio 1.23 (95% confidence interval 1.02-1.49), P  = 0.04]. However, adjustment for antihypertensive medication use attenuated this association [1.19 (0.99-1.44), P  = 0.06]. CONCLUSION: The results may warrant monitoring of an alerting reaction as a preventive measure of CVD mortality in untreated individuals with elevated first BP readings, as well as optimized treatment in treated individuals.

NGS-Guided Precision Oncology in Breast Cancer and Gynecological Tumors-A Retrospective Molecular Tumor Board Analysis.

Background: Precision oncology treatments are being applied more commonly in breast and gynecological oncology through the implementation of Molecular Tumor Boards (MTBs), but real-world clinical outcome data remain limited. Methods: A retrospective analysis was conducted in patients with breast cancer (BC) and gynecological malignancies referred to our center's MTB from 2018 to 2023. The analysis covered patient characteristics, next-generation sequencing (NGS) results, MTB recommendations, therapy received, and clinical outcomes. Results: Sixty-three patients (77.8%) had metastatic disease, and forty-four patients (54.3%) had previously undergone three or more lines of systemic treatment. Personalized treatment recommendations were provided to 50 patients (63.3%), while 29 (36.7%) had no actionable target. Ultimately, 23 patients (29.1%) underwent molecular-matched treatment (MMT). Commonly altered genes in patients with pan-gyn tumors (BC and gynecological malignancies) included TP53 (n = 42/81, 51.9%), PIK3CA (n = 18/81, 22.2%), BRCA1/2 (n = 10/81, 12.3%), and ARID1A (n = 9/81, 11.1%). Patients treated with MMT showed significantly prolonged progression-free survival (median PFS 5.5 vs. 3.5 months, p = 0.0014). Of all patients who underwent molecular profiling, 13.6% experienced a major clinical benefit (PFSr ≥ 1.3 and PR/SD ≥ 6 months) through precision oncology. Conclusions: NGS-guided precision oncology demonstrated improved clinical outcomes in a subgroup of patients with gynecological and breast cancers.

[High blood pressure in women - gender-specific features]. / Hoher Blutdruck bei Frauen ­ geschlechtsspezifische Besonderheiten.

Arterial hypertension, particularly elevated systolic blood pressure, is the most common risk factor for cardio- and cerebrovascular morbidity and mortality in women as it is in men. Blood pressure regulation and the development of sustained hypertension differ by sex. There are still few data on the question of whether the current normal values can apply equally to men and women and on the question of a different effect and dosage of antihypertensive drugs in women.

The EffecTs of Amlodipine and other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases (TREAT-SVDs) trial: Study protocol for a randomised crossover trial.

Background: Hypertension is the leading modifiable risk factor for cerebral small vessel diseases (SVDs). Yet, it is unknown whether antihypertensive drug classes differentially affect microvascular function in SVDs. Aims: To test whether amlodipine has a beneficial effect on microvascular function when compared to either losartan or atenolol, and whether losartan has a beneficial effect when compared to atenolol in patients with symptomatic SVDs. Design: TREAT-SVDs is an investigator-led, prospective, open-label, randomised crossover trial with blinded endpoint assessment (PROBE design) conducted at five study sites across Europe. Patients aged 18 years or older with symptomatic SVD who have an indication for antihypertensive treatment and are suffering from either sporadic SVD and a history of lacunar stroke or vascular cognitive impairment (group A) or CADASIL (group B) are randomly allocated 1:1:1 to one of three sequences of antihypertensive treatment. Patients stop their regular antihypertensive medication for a 2-week run-in period followed by 4-week periods of monotherapy with amlodipine, losartan and atenolol in random order as open-label medication in standard dose. Outcomes: The primary outcome measure is cerebrovascular reactivity (CVR) as determined by blood oxygen level dependent brain MRI signal response to hypercapnic challenge with change in CVR in normal appearing white matter as primary endpoint. Secondary outcome measures are mean systolic blood pressure (BP) and BP variability (BPv). Discussion: TREAT-SVDs will provide insights into the effects of different antihypertensive drugs on CVR, BP, and BPv in patients with symptomatic sporadic and hereditary SVDs. Funding: European Union's Horizon 2020 programme. Trial registration: NCT03082014.

Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial.

BACKGROUND: Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. METHODS: We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated. FINDINGS: Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10-4%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10-4%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10-4%/mm Hg [19·6; -45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10-4%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10-4%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10-4%/mm Hg [27·5; -77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10-4%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10-4%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake. INTERPRETATION: 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research. FUNDING: EU Horizon 2020 programme.

Cardiovascular mortality risk in young adults with isolated systolic hypertension: findings from population-based MONICA/KORA cohort study.

The clinical significance of isolated systolic hypertension in young adults (ISHY) remains a topic of debate due to evidence ISHY could be a spurious condition resulting from exageratted pulse pressure amplification in "young tall men with elastic arteries". Hence, we aimed to investigate whether ISHY is associated with an increased risk of cardivascular (CVD) mortality in a sample of 5597 young adults (49.8% men, 50.2% women) between 25 and 45 years old from the prospective population-based MONICA/KORA cohort. ISHY was prevalent in 5.2% of the population, affecting mostly men (73.1%), and associated with increased smoking, obesity, and hypercholesterolemia in comparison to participants with normal blood pressure (BP). Within a follow-up period of 25.3 years (SD ± 5.2; 141,768 person-years), 133(2.4%) CVD mortality cases were observed. Participants with ISHY had a hazard ratio (HR) of 1.89(1.01-3.53, p < 0.05) times higher risk of CVD mortality than participants with normal BP, even following adjustment for CVD risk factors. However, adjustment for antihypertensive medication (HR 0.46; 0.26-0.81, p < 0.001) and increasing height (HR 0.96; 0.93-0.99, p < 0.05) revealed independently protective effects against CVD mortality, suggesting that although ISHY is associated with an increased risk of CVD mortality, the protective effects of increasing height or antihypertensive medication should be considered in treatment rationale.

Digital preventive measures for arterial hypertension (DiPaH) - a mixed-methods study protocol for health services research.

Introduction: Digital health measures promise to further improve the quality of cardiovascular care but have not yet been widely implemented in routine care. The research project Digital preventive measures for arterial hypertension (DiPaH) will systematically identify structural and individual factors in different stakeholders that influence the use of digital preventive measures in patients with arterial hypertension in Germany. Special focus is given to remote and sparsely populated areas, the age-specific impact, as well as influence of digital health literacy. Methods and analysis: The DiPaH project is an exploratory cross-sectional study with a mixed-methods design, in which written surveys and interviews with patients and physicians will be conducted. In addition, secondary data from a health insurance company will be analyzed. In module 1, individuals from the database of the health insurance company with confirmed arterial hypertension will be interviewed (1,600 questionnaires, 30 interviews). Module 2 includes users of digital prevention offers and apps (400 questionnaires, 40 interviews) and in module 3, family physicians and cardiologists will be interviewed (400 questionnaires, 40 interviews). In a final module, the overall results will be analyzed and recommendations for interventions in clinical care will be derived. Discussion: The DiPaH project will contribute to a patient-oriented and demand-based improvement of arterial hypertension prevention services in health care. Challenges and barriers will be analyzed and the respective target groups identified based on their prevention needs and social characteristics to enable a patient-centered implementation of digital prevention of arterial hypertension and cardiovascular services in general, and finally to improve cardiovascular outcomes. Clinical trial registration: https://drks.de/search/de/trial/DRKS00029761, identifier DRKS00029761.

Combined Focused Next-Generation Sequencing Assays to Guide Precision Oncology in Solid Tumors: A Retrospective Analysis from an Institutional Molecular Tumor Board.

BACKGROUND: Increasing knowledge of cancer biology and an expanding spectrum of molecularly targeted therapies provide the basis for precision oncology. Despite extensive gene diagnostics, previous reports indicate that less than 10% of patients benefit from this concept. METHODS: We retrospectively analyzed all patients referred to our center's Molecular Tumor Board (MTB) from 2018 to 2021. Molecular testing by next-generation sequencing (NGS) included a 67-gene panel for the detection of short-sequence variants and copy-number alterations, a 53- or 137-gene fusion panel and an ultra-low-coverage whole-genome sequencing for the detection of additional copy-number alterations outside the panel's target regions. Immunohistochemistry for microsatellite instability and PD-L1 expression complemented NGS. RESULTS: A total of 109 patients were referred to the MTB. In all, 78 patients received therapeutic proposals (70 based on NGS) and 33 were treated accordingly. Evaluable patients treated with MTB-recommended therapy (n = 30) had significantly longer progression-free survival than patients treated with other therapies (n = 17) (4.3 vs. 1.9 months, p = 0.0094). Seven patients treated with off-label regimens experienced major clinical benefits. CONCLUSION: The combined focused sequencing assays detected targetable alterations in the majority of patients. Patient benefits appeared to lie in the same range as with large-scale sequencing approaches.

[The taller the longer? - Body height and life expectancy]. / Je größer, umso länger?

The importance of height for mortality and life expectancy is a matter of controversy. The data on this in different countries vary depending on ethnicity, socio-economic and other factors such as age at the time of the study. Current German data show a positive correlation in younger cohorts in men with hypertension. Vascular factors such as the length of the aorta and its elasticity or stiffness seem to play an important role. A recent Dutch study shows a negative correlation between height and life expectancy in older women. Gender-specific differences in hemodynamics depending on body size or aortic length play a decisive role alongside age at the time of the examination.

[Vascular ophthalmopathies - an interdisciplinary task]. / Vaskuläre Ophthalmopathien ­ eine interdisziplinäre Aufgabe.

Retinal microvascular function is highly depending on macrovascular circulation and especially on blood pressure variability and nocturnal blood pressure. The eyes are more subject to central hemodynamics compared to peripheral pressures. Pulse wave analysis is essential here and can reveal masked aortic hypertension. Morphological and functional changes of retinal vessels are detected today in high resolution by digital imaging techniques. Early hypertensive changes can be visualized best by laser scanning multi-color devices, and the vessel diameters (AV-Ratio) are measured precisely by static vessel analysis. Functional disorders of vascular motility are delineated reproducibly by devices for dynamic vessel analysis. Also functional effects of cardiovascular therapy measures can be judged by these means: micro- meets macrocirculation.

Insufficient reply by Hermida et al. to the critical comments to the MAPEC and HYGIA studies.

The reply of Hermida et al. (2020) to our critical comments on the MAPEC and HYGIA Lemmer and Middeke (2020) studies in this Journal is insufficient and incomplete. Hermida does not address our first and main point on the baseline blood pressure values of 131/77 mmHg over 48 hours comprising 57.4% of the treated hypertensives (according to Table 1 in HYGIA) and consequently 42.6% of the untretated hypertensives! We criticized that in the HYGIA study; both normal and treated patients were included in one group not separated by statistics and without information on the baseline blood pressure values in each subgroup. This basic failure is our key issue of criticism and the basis of unreliability concerning the whole publication. This issue was not picked up in the recent comment of Hermida et al. (2020). They just concentrated on minor points in order to reject our severe criticism.

A commentary on the Spanish hypertension studies MAPEC and HYGIA.

The recently published chronotherapeutic Spanish papers MAPEC and HYGIA proposing that antihypertensive drug treatment should be given at bedtime suffers from obvious deficiencies in study design and are not a valid basis for drug treatment of hypertension.

[Translating Early Vascular Aging into Clinical Practice]. / EVA (Early Vascular Aging) ­ Übersetzung in den klinischen Alltag.

Early Vascular Aging, a concept describing pathophysiologic and clinical aspects of premature arterial stiffness and arteriosclerosis, has attracted attention in recent years. Early diagnosis and intervention is essential for prevention and postponing cardiovascular events.

[Dizziness and Blood Pressure]. / Schwindel und Blutdruck.

Dizziness is most frequently caused by blood pressure dysregulation comprising a broad spectrum from constitutional and orthostatic hypotension to severe conditions like endocrinopathies and neurodegenerative diseases with autonomic dysfunction like in multiple system atrophy.

The PHARAO study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure: a prospective, randomized, controlled prevention trial of the German Hypertension League.

BACKGROUND: The prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure study addresses the issue of whether progression to manifest hypertension in patients with high-normal blood pressure can be prevented with treatment. METHODS: A total of 1008 participants with high-normal office blood pressure were randomized to ramipril treatment group (n = 505) and a control group (n = 503). The patients were followed up for 3 years. Primary endpoint was to prevent or delay the progression to manifest hypertension. Secondary endpoints were reduction in the incidence of cerebrovascular and cardiovascular events, as well as the development of hypertension as defined by ambulatory blood pressure monitoring. FINDINGS: One hundred and fifty-five patients (30.7%) in the ramipril group, and 216 (42.9%) in the control group reached the primary endpoint (relative risk reduction 34.4%, P = 0.0001). Ramipril also proved to be more effective in reducing the incidence of manifest office hypertension in patients with baseline ambulatory blood pressure monitoring high-normal blood pressure. The incidence of cerebrovascular and cardiovascular events showed no statistically significant differences between the two groups. Cough was more frequent in the ramipril group (4.8 vs. 0.4%). INTERPRETATION: There is now good clinical evidence that patients with high-normal blood pressure (prehypertension) are more likely to progress to manifest hypertension than patients with optimal or normal blood pressure. Additional ambulatory blood pressure monitoring seems to be essential to achieve correct diagnosis. Treatment of patients with high-normal office blood pressure with the angiotensin-converting enzyme inhibitor was well tolerated, and significantly reduced the risk of progression to manifest hypertension.

[Arterial hypertension - dosing recommendations at beginning and end of treatment]. / Arterielle Hypertonie - Arzneimittel-Dosierung am Anfang und Ende einer Therapie.

In the treatment of arterial hypertension different dosing strategies like slow dose escalation at the beginning of antihypertensive therapy and gradual dose taper or abrupt withdrawal of drugs may be appropriate. In general treatment should be initiated with a long acting drug at a low dose and doses should only slowly be increased under close blood pressure control. The dose-response curve usually is very flat, whilst adverse effects may rise disproportionately with higher doses. Therefore dose increases to maximal doses are no longer desirable in modern antihypertensive therapy and combinations of two drugs as fixed combinations at low doses should be preferred. Modern antihypertensive drugs can be abruptly and safely withdrawn in most patients. However, a gradual dose taper can be necessary in patients with coronary heart disease treated with cardioselective beta-blockers. Withdrawal is easier and safer under telemetric blood pressure control than self measured blood pressure. The same treatment approach applies to reserve medications like alpha-blockers, centrally acting drugs as clonidine, methyldopa, moxonidine, the vasodilators hydralazine and minoxidil, and other antihypertensives like reserpine and guanethidine. Withdrawal phenomena have to be considered in individual cases and particularly with clonidine after long-term use.