[German S1 Guideline Long-/Post-COVID]. / S1-Leitlinie Long-/Post-COVID.

The German Society of Pneumology initiated 2021 the AWMF S1 guideline Long COVID/Post-COVID. In a broad interdisciplinary approach, this S1 guideline was designed based on the current state of knowledge.The clinical recommendations describe current Long COVID/Post-COVID symptoms, diagnostic approaches, and therapies.In addition to the general and consensus introduction, a subject-specific approach was taken to summarize the current state of knowledge.The guideline has an explicit practical claim and will be developed and adapted by the author team based on the current increase in knowledge.

A record of microplastic in the marine nearshore waters of South Georgia.

The polar plastics research community have recommended the spatial coverage of microplastic investigations in Antarctica and the Southern Ocean be increased. Presented here is a baseline estimate of microplastics in the nearshore waters of South Georgia, the first in situ study of the north-east coast of the island. Our results show that the microplastic concentration in seawater at twelve stations in proximity to King Edward Point Research Station ranged from 1.75 ± 5.17 MP/L (mean ± SD), approximately one order of magnitude higher than similar studies of sea surface waters south of the Polar Front. Levels of microplastics in freshwater (sampled from Gull Lake) and precipitation (collected adjacent to the research station) were 2.67 ± 3.05 MP/L, and 4.67 ± 3.21 MP/L respectively. There was no significant difference in the microplastic concentration between seawater sites, and no significant bilateral relationship between concentration and distance from the research station outlets. We report an average concentration of 1.66 ± 3.00 MP/L in wastewater collected from the research station but overall, the counts of microplastics were too low to attach any statistical significance to the similarity in the microplastic assemblages of seawater and wastewater, or assemblages retrieved from penguin species in the region in other studies. Using a calculation described in contemporary literature we estimate the number of microfibres potentially being released from ships and stations annually in the region but acknowledge that further samples are needed to support the figures generated. More extensive research into microplastic distribution, characteristics, and transport in the region is recommended to fully compute the level of risk which this pollutant represents to the ecosystem health of this remote region.

[Long-term care facilities during the COVID-19 pandemic : Considerations on the way back to normality]. / Langzeitpflegeeinrichtungen in der COVID-19-Pandemie : Überlegungen auf dem Weg zurück in die Normalität.

Long-term care facilities (LTCF) were and are particularly affected by the COVID-19 pandemic. The dimensions of the outbreaks and the high mortality among residents led to massive restrictions in LTCFs, especially in the area of social contacts and activities but also in areas of medical care. With the start of vaccinations and the improved testing options, the situation has now changed and existing restrictions must be evaluated to determine whether they are still appropriate. In an interprofessional and interdisciplinary group of experts, considerations have been formulated on how a way back to normality could look like in LTCFs.

[Medicinal tumor treatment of oropharyngeal cancer]. / Medikamentöse Therapie des Oropharynxkarzinoms.

BACKGROUND: The number of patients suffering from human papillomavirus (HPV)-associated oropharyngeal cancer has increased in recent decades. To date, the role of medical therapy in patients with squamous cell carcinoma of the head and neck region has only been established in the refractory or metastatic setting (r/m HNSCC). OBJECTIVE: What are the current treatment options for patients with r/m HNSCC or r/m oropharyngeal cancer? MATERIALS AND METHODS: A literature search was conducted on systemic treatment of oropharyngeal cancer and r/m HNSCC. RESULTS: There is currently no standard treatment for patients with oropharyngeal cancer in refractory or metastatic stages. Since 2017, immunotherapy with checkpoint inhibitors has become increasingly important in the treatment of r/m HNSCC patients. First-line therapy was recently adapted based on the results of the KEYNOTE-48 (KN048) study. For selected patients with r/m HNSCC, there now exists a chemotherapy-free treatment option. Use of immunotherapy also in earlier stages of HNSCC can be expected in the near future. CONCLUSION: Medical therapy of r/m HNSCC patients is in a period of great change. Treatment is increasingly based on combination therapy with checkpoint inhibitors.

Species-specific impact of microplastics on coral physiology.

There is evidence that microplastic (MP) pollution can negatively influence coral health; however, mechanisms are unknown and most studies have used MP exposure concentrations that are considerably higher than current environmental conditions. Furthermore, whether MP exposure influences coral susceptibility to other stressors such as ocean warming is unknown. Our objective was to determine the physiology response of corals exposed to MP concentrations that have been observed in-situ at ambient and elevated temperature that replicates ocean warming. Here, two sets of short-term experiments were conducted at ambient and elevated temperature, exposing the corals Acroporasp. and Seriatopora hystrix to microspheres and microfibres. Throughout the experiments, gross photosynthesis and net respiration was quantified using a 4-chamber coral respirometer, and photosynthetic yields of photosystem II were measured using Pulse-Amplitude Modulated (PAM) fluorometry. Results indicate the effect of MP exposure is dependent on MP type, coral species, and temperature. MP fibres (but not spheres) reduced photosynthetic capability of Acropora sp., with a 41% decrease in photochemical efficiency at ambient temperature over 12 days. No additional stress response was observed at elevated temperature; photosynthetic performance significantly increased in Seriatopora hystrix exposed to MP spheres. These findings show that a disruption to coral photosynthetic ability can occur at MP concentrations that have been observed in the marine environment and that MP pollution impact on corals remains an important aspect for further research.

[Clarification of dizziness in old age : Interdisciplinary diagnostic process]. / Schwindelabklärung im Alter : Interdisziplinärer diagnostischer Prozess.

The clinical symptom dizziness encompasses a broad range of complaints. The prevalence among older adults is high. Over the course of 1 year 50% of people over 80 years old, 30% of those between 70-80 years old and 20% between 60-70 years old contact a physician as a result of dizziness. The diagnostic process has to be well organized. The medical history and clinical examination are frequently underestimated but in many cases are crucial. Extensive investigations should only be carried out in cases of a firmly suspected diagnosis. A good interdisciplinary cooperation can positively influence the diagnostic process. The awareness of red flags also helps to detect emergency patients with dizziness. This article discusses the differential diagnosis of dizziness in older adults and provides appropriate recommendations for the diagnostic process.

Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML.

This corrects the article DOI: 10.1038/leu.2017.9.

Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants.

Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML.

It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86+pDC frequencies than normal donors (P<0.0024), whereas TFR patients had consistently low CD86+pDC (n=12). This suggested that low CD86+pDC might be predictive of TFR. Indeed, in a prospective analysis of 122 patients discontinuing their TKI within the EURO-SKI trial, the one-year relapse-free survival (RFS) was 30.1% (95% CI 15.6-47.9) for patients with >95 CD86+pDC per 105 lymphocytes, but 70.0% (95% CI 59.3-78.3) for patients with <95 CD86+pDC (hazard ratio (HR) 3.4, 95%-CI: 1.9-6.0; P<0.0001). Moreover, only patients with <95 CD86+pDC derived a significant benefit from longer (>8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1-0.8; P=0.0263). High CD86+pDC counts significantly correlated with leukemia-specific CD8+ T-cell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21-0.92; P=0.0098). Our data demonstrate that CML patients with high CD86+pDC counts have a higher risk of relapse after TKI discontinuation.

Pomalidomide in myeloproliferative neoplasm-associated myelofibrosis.

Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a MPN characterized by bone marrow fibrosis, cytopenias, splenomegaly and constitutional symptoms. Pomalidomide, an immune-modifying drug, is reported to improve anaemia and thrombocytopenia in some patients with MPN-associated myelofibrosis. We designed a phase 2 study of pomalidomide in patients with MPN-associated myelofibrosis and anaemia and/or thrombocytopenia and/or neutropenia. Subjects received pomalidomide 2.0 mg/day in cohort 1 (n=38) or 0.5 mg/day in cohort 2 (n=58). Prednisolone was added if there was no response after 3 months in cohort 1 and based on up-front randomization in cohort 2 if there was no response at 3 or 6 months. Response rates were 39% (95% confidence interval (CI), 26-55%) in cohort 1 and 24% (95% CI, 15-37%) in cohort 2. In a multivariable logistic regression model pomalidomide at 2.0 mg/day (odds ratio (OR), 2.62; 95% CI, 1.00-6.87; P=0.05) and mutated TET2 (OR, 5.07; 95% CI, 1.16-22.17; P=0.03) were significantly associated with responses. Median duration of responses was 13.0 months (range 0.9-52.7). There was no significant difference in response rates or duration in subjects receiving or not receiving prednisolone. Clinical trial MPNSG 01-09 is registered at ClinicalTrials.gov (NCT00949364) and clinicaltrialsregister.eu (EudraCT Number: 2009-010738-23).

[Subgroup Analysis of the Non-interventional REASON Study: PFS and OS According to Age, Smoking History, Gender, and Histology in NSCLC Patients Treated with Gefitinib or Chemotherapy]. / Subgruppenanalyse aus der nicht-interventionellen Beobachtungsstudie REASON: PFS und OS gemäß Alter, Raucherstatus, Geschlecht und histologischem Subtyp unter Verwendung von Gefitinib bzw. chemotherapeutischer Behandlung bei NSCLC-Patienten.

PURPOSE: Assessment of several clinical factors on progression-free (PFS) and overall survival (OS) in NSCLC patients (pts.) (stage IV) with mutated epidermal growth factor receptor (EGFRm+) treated with gefitinib (gef) or with chemotherapy (CT) under real-world conditions. METHODS: 285 EGFRm+ pts. of the non-interventional REASON study treated with gef (n = 206) or CT (n = 79) as first-line therapy or with gef (n = 213) or CT (n = 61) in any line throughout the course of therapy were analyzed according to age, gender, smoking history and histology. RESULTS: Compared with CT, patients treated with gef showed prolongation of PFS and OS in all subgroups. PFS was significantly increased in women and non-smokers. OS was significantly increased in women, non-smokers, (ex)-smokers, patients with adenocarcinoma and elderly patients when treated with gef compared to CT. Female gender turned out to be an independent positive predictive factor for OS in patients treated with gef (HRmale: 1.74, p = 0.0009). CONCLUSION: A clinical benefit of gef was shown for all analyzed clinical subgroups of EGFRm+ pts. This was confirmed for the female gender in a multivariate analysis.

Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label, randomized, controlled phase II study (CERTO).

BACKGROUND: This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. RESULTS: There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvß3 and αvß5 expression was neither a predictive nor a prognostic indicator. CONCLUSIONS: The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment. CLINICAL TRIAL REGISTRATION ID NUMBER: NCT00842712.

OPTN/SRTR 2013 Annual Data Report: heart.

The number of heart transplants performed annually continues to increase gradually, and the number of adult candidates on the waiting list increased by 34.2% from 2003 to 2013. The heart transplant rate among active adult candidates peaked at 149.0 per 100 waitlist years in 2007 and has been declining since then; in 2013, the rate was 87.4 heart transplants per 100 active waitlist years. Increased waiting times do not appear to be correlated with an overall increase in waitlist mortality. Since 2008, the proportion of patients on life support before transplant increased from 53.4% to 65.8% in 2013. Medical urgency categories have become less distinct, with most patients listed in higher urgency categories. Approximately 500 pediatric candidates are added to the waiting list each year; the number of pediatric transplants performed each year increased from 293 in 2003 to 411 in 2013. Patient survival among pediatric recipients continues to improve; 5-year patient survival for transplants performed from 2001 through 2008 was 70% to 80%. Medicare paid for some or all of the care for 42.2% of all heart transplant recipients in 2012.

[Gender-specific aspects of coronary heart disease]. / Geschlechtsspezifische Aspekte bei der koronaren Herzkrankheit.

The total number of deaths from cardiovascular diseases (CVD) is greater for women than for men, although the mean age at manifestation of CVD is about 10 years older. However, the annual number of cases treated for CVD in acute hospital settings in men exceeds that of women by 50 %. Remarkable gender differences exist in terms of morphological and physiological conditions (e.g. mean coronary vessel diameter; ability to adapt to protective exercise-induced myocardial hypertrophy), as well as of the frequency and clinical significance of somatic risk factors (e.g. smoking). Female body weight increases after menopause and the body shape assumes a more android fat distribution. Women report higher levels of unspecific and affective symptoms. They suffer more from anxiety and depression than men; however, the secondary impact on CVD onset may be less pronounced. The post-acute CVD course is more complicated in women, mainly because they are older and suffer more from multi-morbidity. Whilst male CVD patients aim for a rapid recovery, physical fitness and an increased life expectancy, female patients seek relief from everyday challenges, the maintenance of their independence and emotional support.

Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib.

UNLABELLED: Early assessment of response at 3 months of tyrosine kinase inhibitor treatment has become an important tool to predict favorable outcome. We sought to investigate the impact of relative changes of BCR-ABL transcript levels within the initial 3 months of therapy. In order to achieve accurate data for high BCR-ABL levels at diagnosis, beta glucuronidase (GUS) was used as a reference gene. Within the German CML-Study IV, samples of 408 imatinib-treated patients were available in a single laboratory for both times, diagnosis and 3 months on treatment. In total, 301 of these were treatment-naïve at sample collection. RESULTS: (i) with regard to absolute transcript levels at diagnosis, no predictive cutoff could be identified; (ii) at 3 months, an individual reduction of BCR-ABL transcripts to the 0.35-fold of baseline level (0.46-log reduction, that is, roughly half-log) separated best (high risk: 16% of patients, 5-year overall survival (OS) 83% vs 98%, hazard ratio (HR) 6.3, P=0.001); (iii) at 3 months, a 6% BCR-ABL(IS) cutoff derived from BCR-ABL/GUS yielded a good and sensitive discrimination (high risk: 22% of patients, 5-year OS 85% vs 98%, HR 6.1, P=0.002). Patients at risk of disease progression can be identified precisely by the lack of a half-log reduction of BCR-ABL transcripts at 3 months.

Application of the optimized CO-rebreathing method for determination of hemoglobin mass in patients with polycythemia vera.

Determination of red cell volume (RCV) might contribute to establishing the diagnosis of polycythemia vera (PV). A novel simplified method to detect RCV through CO rebreathing is nowadays applied in healthy young individuals but was not tested in a clinical or PV setting. The aim of the present study is to evaluate whether this spirometric approach is applicable in older subjects and contributes to PV diagnosis in a proof-of-concept approach. At first, RCV was determined by the optimized CO-rebreathing method in healthy subjects >50 years of age (n = 81, age 66 ± 9 years). Failure rate and age distribution of subjects who failed with CO rebreathing were analyzed. Then, RCV was measured in male PV patients (n = 7) and compared to healthy male controls (n = 35). RCV values in relation to several anthropometric references (body weight, body surface area (BSA), lean body mass (LBM)) were calculated to determine the sensitivity and specificity of established RCV thresholds when using optimized CO rebreathing. In healthy subjects, test failure rate was 9.9 %, but failure was not associated with age. Sensitivity and specificity (sens/spec) to detect PV was 100 %/83 % using the criteria of the PV study group. Using criteria based on BSA, sens/spec was 14 %/100 %. An arbitrary threshold of 50 ml/kg LBM yielded sens/spec of 100 %/97 %. In conclusion, this proof-of-concept indicates that optimized CO rebreathing is applicable in older subjects and allows determining RCV for the diagnosis of PV. Normalized values for RCV measures obtained from CO rebreathing are needed to grant sufficient sensitivity and/or specificity.

OPTN/SRTR 2012 Annual Data Report: heart.

The number of heart transplants performed annually continues to increase gradually, and the number of adult candidates on the waiting list increased by 25% from 2004 to 2012. The heart transplant rate among active adult candidates peaked at 149 per 100 wait-list years in 2007 and has been declining since; in 2012, the rate was 93 heart transplants per 100 active wait-list years. Increased waiting times do not appear to be correlated with an overall increase in wait-list mortality. Since 2007, the proportion of patients on life support before transplant increased from 48.6% to 62.7% in 2012. Medical urgency categories have become less distinct, with most patients listed in higher urgency categories. Approximately 500 pediatric candidates are added to the waiting list each year; the number of transplants performed each year increased from 274 in 1998 to 372 in 2012. Graft survival in pediatric recipients continues to improve; 5-year graft survival for transplants performed in 2007 was 78.5%. Medicare paid for some or all of the care for nearly 40% of heart transplant recipients in 2010. Heart transplant appears to be more expensive than ventricular assist devices for managing end-stage heart failure, but is more effective and likely more cost-effective.

Gab2 signaling in chronic myeloid leukemia cells confers resistance to multiple Bcr-Abl inhibitors.

Grb2-associated binder 2 (Gab2) serves as a critical amplifier in the signaling network of Bcr-Abl, the driver of chronic myeloid leukemia (CML). Despite the success of tyrosine kinase inhibitors (TKIs) in CML treatment, TKI resistance, caused by mutations in Bcr-Abl or aberrant activity of its network partners, remains a clinical problem. Using inducible expression and knockdown systems, we analyzed the role of Gab2 in Bcr-Abl signaling in human CML cells, especially with respect to TKI sensitivity. We show for the first time that Gab2 signaling protects CML cells from various Bcr-Abl inhibitors (imatinib, nilotinib, dasatinib and GNF-2), whereas Gab2 knockdown or haploinsufficiency leads to increased TKI sensitivity. We dissected the underlying molecular mechanism using various Gab2 mutants and kinase inhibitors and identified the Shp2/Ras/ERK and the PI3K/AKT/mTOR axes as the two critical signaling pathways. Gab2-mediated TKI resistance was associated with persistent phosphorylation of Gab2 Y452, a PI3K recruitment site, and consistent with this finding, the protective effect of Gab2 was completely abolished by the combination of dasatinib with the dual PI3K/mTOR inhibitor NVP-BEZ235. The identification of Gab2 as a novel modulator of TKI sensitivity in CML suggests that Gab2 could be exploited as a biomarker and therapeutic target in TKI-resistant disease.