Extremophiles in a changing world.

Extremophiles and their products have been a major focus of research interest for over 40 years. Through this period, studies of these organisms have contributed hugely to many aspects of the fundamental and applied sciences, and to wider and more philosophical issues such as the origins of life and astrobiology. Our understanding of the cellular adaptations to extreme conditions (such as acid, temperature, pressure and more), of the mechanisms underpinning the stability of macromolecules, and of the subtleties, complexities and limits of fundamental biochemical processes has been informed by research on extremophiles. Extremophiles have also contributed numerous products and processes to the many fields of biotechnology, from diagnostics to bioremediation. Yet, after 40 years of dedicated research, there remains much to be discovered in this field. Fortunately, extremophiles remain an active and vibrant area of research. In the third decade of the twenty-first century, with decreasing global resources and a steadily increasing human population, the world's attention has turned with increasing urgency to issues of sustainability. These global concerns were encapsulated and formalized by the United Nations with the adoption of the 2030 Agenda for Sustainable Development and the presentation of the seventeen Sustainable Development Goals (SDGs) in 2015. In the run-up to 2030, we consider the contributions that extremophiles have made, and will in the future make, to the SDGs.

Long-term survival of breast cancer patients with brain metastases: subanalysis of the BMBC registry.

BACKGROUND: Up to 30% of metastatic breast cancer (BC) patients develop brain metastases (BM). Prognosis of patients with BM is poor and long-term survival is rare. Identification of factors associated with long-term survival is important for improving treatment modalities. PATIENTS AND METHODS: A total of 2889 patients of the national registry for BM in BC (BMBC) were available for this analysis. Long-term survival was defined as overall survival (OS) in the upper third of the failure curve resulting in a cut-off of 15 months. A total of 887 patients were categorized as long-term survivors. RESULTS: Long-term survivors compared to other patients were younger at BC and BM diagnosis (median 48 versus 54 years and 53 versus 59 years), more often had HER2-positive tumors (59.1% versus 36.3%), less frequently luminal-like (29.1% versus 35.7%) or triple-negative breast cancer (TNBC) (11.9% versus 28.1%), showed better Eastern Cooperative Oncology Group (ECOG) performance status (PS) at the time of BM diagnosis (ECOG 0-1, 76.9% versus 51.0%), higher pathological complete remission rates after neoadjuvant chemotherapy (21.6% versus 13.7%) and lower number of BM (n = 1, BM 40.9% versus 25.4%; n = 2-3, BM 26.5% versus 26.7%; n ≥4, BM 32.6% versus 47.9%) (P < 0.001). Long-term survivors had leptomeningeal metastases (10.4% versus 17.5%) and extracranial metastases (ECM, 73.6% versus 82.5%) less frequently, and asymptomatic BM more often at the time of BM diagnosis (26.5% versus 20.1%), (P < 0.001). Median OS in long-term survivors was about two times higher than the cut-off of 15 months: 30.9 months [interquartile range (IQR) 30.3] overall, 33.9 months (IQR 37.1) in HER2-positive, 26.9 months (IQR 22.0) in luminal-like and 26.5 months (IQR 18.2) in TNBC patients. CONCLUSIONS: In our analysis, long-term survival of BC patients with BM was associated with better ECOG PS, younger age, HER2-positive subtype, lower number of BM and less extended visceral metastases. Patients with these clinical features might be more eligible for extended local brain and systemic treatment.

Size distribution and relationship of airborne SARS-CoV-2 RNA to indoor aerosol in hospital ward environments.

Aerosol particles proved to play a key role in airborne transmission of SARS-CoV-2 viruses. Therefore, their size-fractionated collection and analysis is invaluable. However, aerosol sampling in COVID departments is not straightforward, especially in the sub-500-nm size range. In this study, particle number concentrations were measured with high temporal resolution using an optical particle counter, and several 8 h daytime sample sets were collected simultaneously on gelatin filters with cascade impactors in two different hospital wards during both alpha and delta variants of concern periods. Due to the large number (152) of size-fractionated samples, SARS-CoV-2 RNA copies could be statistically analyzed over a wide range of aerosol particle diameters (70-10 µm). Our results revealed that SARS-CoV-2 RNA is most likely to exist in particles with 0.5-4 µm aerodynamic diameter, but also in ultrafine particles. Correlation analysis of particulate matter (PM) and RNA copies highlighted the importance of indoor medical activity. It was found that the daily maximum increment of PM mass concentration correlated the most with the number concentration of SARS-CoV-2 RNA in the corresponding size fractions. Our results suggest that particle resuspension from surrounding surfaces is an important source of SARS-CoV-2 RNA present in the air of hospital rooms.

A multicentre, randomised, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer (DESIREE).

BACKGROUND: Stomatitis is one of the main reasons to discontinue everolimus in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). To decrease stomatitis and subsequently early treatment discontinuations or dose reductions, the DESIREE trial investigated the use of a stepwise dose-escalation schedule of everolimus (EVE esc). PATIENTS AND METHODS: DESIREE is a phase II, multicentre, randomised, double-blind, placebo-controlled trial in patients with HR+/HER2- mBC and progression/relapse after nonsteroidal aromatase inhibitor treatment. Patients were randomised to EVE esc (2.5 mg/day, week 1; 5 mg/day, week 2; 7.5 mg/day, week 3; 10 mg/day, weeks 4-24) or everolimus 10 mg/day (EVE 10mg) for 24 weeks plus exemestane. The primary endpoint was the incidence of stomatitis episodes grade ≥2 within 12 weeks of treatment. The secondary endpoints included toxicity, relative total dose intensity (RTDI) and quality of life (QoL). RESULTS: A total of 160 patients were randomised and 156 started treatment (EVE esc: 80; EVE 10mg: 76). The median age of patients was 64 years (range 33-85), 56.3% patients in the EVE esc arm versus 42.1% in the EVE 10mg arm had liver metastasis (P = 0.081) and 62.5% versus 51.3% received over one metastatic therapy line (P = 0.196). Within 12 weeks, the incidence of stomatitis episodes grade ≥2 was significantly lower in the EVE esc arm compared with the EVE 10mg arm (28.8% versus 46.1%; odds ratio 0.47, 95% confidence interval 0.24-0.92; P = 0.026). Toxicity was in line with the known safety profile without new safety concerns. The median RTDI was 91.1% in the EVE esc arm versus 80.0% in the EVE 10mg arm (P = 0.329). Discontinuation rate in the first 3 weeks was 6.3% versus 15.8%, respectively (P = 0.073). QoL was comparable between the two treatment arms. CONCLUSIONS: A dose-escalation schema of everolimus over 3 weeks can be successfully used to reduce the incidence of high-grade stomatitis in the first 12 weeks of treatment in patients with HR+/HER2- mBC. TRIAL REGISTRATION: ClinicalTrials.govNCT02387099; https://clinicaltrials.gov/ct2/show/NCT02387099.

Characteristics of patients with brain metastases from human epidermal growth factor receptor 2-positive breast cancer: subanalysis of Brain Metastases in Breast Cancer Registry.

BACKGROUND: Up to 40% of patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer develop brain metastases (BMs). Understanding of clinical features of these patients with HER2-positive breast cancer and BMs is vital. PATIENTS AND METHODS: A total of 2948 patients from the Brain Metastases in Breast Cancer registry were available for this analysis, of whom 1311 had primary tumors with the HER2-positive subtype. RESULTS: Patients with HER2-positive breast cancer and BMs were-when compared with HER2-negative patients-slightly younger at the time of breast cancer and BM diagnosis, had a higher pathologic complete response rate after neoadjuvant chemotherapy and a higher tumor grade. Furthermore, extracranial metastases at the time of BM diagnosis were less common in HER2-positive patients, when compared with HER2-negative patients. HER2-positive patients had more often BMs in the posterior fossa, but less commonly leptomeningeal metastases. The median overall survival (OS) in all HER2-positive patients was 13.2 months (95% confidence interval 11.4-14.4). The following factors were associated with shorter OS (multivariate analysis): older age at BM diagnosis [≥60 versus <60 years: hazard ratio (HR) 1.63, P < 0.001], lower Eastern Cooperative Oncology Group status (2-4 versus 0-1: HR 1.59, P < 0.001), higher number of BMs (2-3 versus 1: HR 1.30, P = 0.082; ≥4 versus 1: HR 1.51, P = 0.004; global P = 0.015), BMs in the fossa anterior (HR 1.71, P < 0.001), leptomeningeal metastases (HR 1.63, P = 0.012), symptomatic BMs at diagnosis (HR 1.35, P = 0.033) and extracranial metastases at diagnosis of BMs (HR 1.43, P = 0.020). The application of targeted therapy after the BM diagnosis (HR 0.62, P < 0.001) was associated with longer OS. HER2-positive/hormone receptor-positive patients showed longer OS than HER2-positive/hormone receptor-negative patients (median 14.3 versus 10.9 months; HR 0.86, P = 0.03), but no differences in progression-free survival were seen between both groups. CONCLUSIONS: We identified factors associated with the prognosis of HER2-positive patients with BMs. Further research is needed to understand the factors determining the longer survival of HER2-positive/hormone receptor-positive patients.

Impact of off-label use regulations on patient care in dermatology - a prospective study of cost-coverage applications filed by tertiary dermatology clinics throughout Germany.

BACKGROUND: In dermatology, a medical speciality with a relatively high number of rare diseases, physicians often have to resort to off-label treatment options. To avoid claims, physicians in Germany can file a cost-coverage request (off-label application, OL-A). OBJECTIVES: Our aim was to investigate the extent to which the current regulations affect patient care. MATERIAL AND METHODS: Prospective cohort study among tertiary dermatology clinics throughout Germany, consecutively including OL-As (05/2019-09/2020) and assessing the follow-up correspondence. We modelled regressions to assess factors associated with cost-coverage decisions and the time needed by health insurers to process the OL-As. RESULTS: Thirteen clinics provided data on 121 OL-As, two of which applied for on-label treatments. Of the remaining 119 OL-As, 70 (58.8%) were immediately approved and 44 (37.0%) rejected. Including cases with one or more appeals, 87 of 119 OL-As (73.1%) were finally approved and 26 (21.9%) rejected. There was an association of the final approval rate with (1) the class of medication/treatment, with approval rates being significantly lower for JAK inhibitors than for biologics (OR 0.16, 95%-CI: 0.03-0.82); (2) German state, with approval rates being lower in eastern than in western states (OR 0.30, 95%-CI 0.12-0.76); and (3) cost of the intervention (no linear trend). However, none of these predictors was significant in our multiple logistic regression models. The median health insurer's processing time (first response) was 29 days (IQR 22-38). Our analyses showed no evidence of an association with the predictors we assessed. In cases approved, the median time from the decision to file an OL-A to the actual initiation of the treatment was 65.5 days (IQR 51-92). CONCLUSIONS: Our study points to substantial delays and inequalities in the provision of timely health care for dermatological patients with rare diseases, often involving treatments for which there is no adequate approved therapy.

IVF protocol efficacy in women with expected suboptimal response depending on ovary stimulation mode.

INVESTIGATION OBJECTIVE: IVF protocol efficacy estimation in women with expected suboptimal response depending on ovary stimulation mode. MATERIALS AND TECHNIQUE: A randomized controlled study embracing results of 51 IVF cycle in women with ovary suboptimal response. The suboptimal response prognostic analysis was performed basing on ≤9 oocyte cumulus complexes obtained in previous IVF programs, the presence of no less than 5-9 antral follicles in both oocytes and amount of anti-Mullerian Hormone ≥0,8 ng/mL. In Group I (n = 25), the stimulation was performed by recombinant corifollitropin alfa combined with highly purified urinary gonadotropin, while in Group II (n = 26) it was made by means of recombinant follitropin/lutropin alfa within the protocol of applying gonadotropin-releasing hormone antagonists. RESULTS: The total gonadotropin dose in Group II patients was authentically lower compared to Group I (p˂,01). No statistical difference between the two studied groups was detected concerning the number of obtained oocytes, 2pn zygote, good-quality transferred embryos and clinical pregnancy rate (p>.05). Embryo cryopreservation was performed only for group-II patients. CONCLUSION: Corifollitropin alfa administration combined with highly purified menotropin in IVF cycles for suboptimal responders is quite effective, however, this strategy has no preference over other stimulation modes. The strategy of using recombinant follitropin/lutropin alfa can be promotive to IVF outcomes for suboptimal responders by means of embryo banking. ClinicalTrials.gov Identifier: NCT03177538.

Prognostic relevance of the HER2 status of circulating tumor cells in metastatic breast cancer patients screened for participation in the DETECT study program.

BACKGROUND: Circulating tumor cells (CTCs) have been reported to predict clinical outcome in metastatic breast cancer (MBC). Biology of CTCs may differ from that of the primary tumor and HER2-positive CTCs are found in some patients with HER2-negative tumors. PATIENTS AND METHODS: Patients with HER2-negative MBC were screened for participation in DETECT III and IV trials before the initiation of a new line of therapy. Blood samples were analyzed using CELLSEARCH. CTCs were labeled with an anti-HER2 antibody and classified according to staining intensity (negative, weak, moderate, or strong staining). RESULTS: Screening blood samples were analyzed in 1933 patients with HER2-negative MBC. As many as 1217 out of the 1933 screened patients (63.0%) had ≥1 CTC per 7.5 ml blood; ≥5 CTCs were detected in 735 patients (38.0%; range 1-35 078 CTCs, median 8 CTCs). HER2 status of CTCs was assessed in 1159 CTC-positive patients; ≥1 CTC with strong HER2 staining was found in 174 (15.0%) patients. The proportion of CTCs with strong HER2 staining among all CTCs of an individual patient ranged between 0.06% and 100% (mean 15.8%). Patients with estrogen receptor (ER)- and progesterone receptor (PR)-positive tumors were more likely to harbor ≥1 CTC with strong HER2 staining. CTC status was significantly associated with overall survival (OS). Detection of ≥1 CTC with strong HER2 staining was associated with shorter OS [9.7 (7.1-12.3) versus 16.5 (14.9-18.1) months in patients with CTCs with negative-to-moderate HER2 staining only, P = 0.013]. In multivariate analysis, age, ER status, PR status, Eastern Cooperative Oncology Group performance status, therapy line, and CTC status independently predicted OS. CONCLUSION: CTC detection in patients with HER2-negative disease is a strong prognostic factor. Presence of ≥1 CTC with strong HER2 staining was associated with shorter OS, supporting a biological role of HER2 expression on CTCs.

ViBiBa: Virtual BioBanking for the DETECT multicenter trial program - decentralized storage and processing.

BACKGROUND: Liquid Biopsy (LB) in the form of e.g., circulating tumor cells (CTCs) is a promising non-invasive approach to support current therapeutic cancer management. However, the proof of clinical utility of CTCs in informing therapeutic decision-making for e.g., breast cancer in clinical trials and associated translational research projects is facing the issues of low CTC positivity rates and low CTC numbers - even in the metastasized situation. To compensate for this dilemma, clinical CTC trials are designed as large multicenter endeavors with decentralized sample collection, processing and storage of products, making data management highly important to enable high-quality translational CTC research. AIM: In the DETECT clinical CTC trials we aimed at developing a custom-made, browser-based virtual database to harmonize and organize both decentralized processing and storage of LB specimens and to enable the collection of clinically meaningful LB sample. METHODS: ViBiBa processes data from various sources, harmonizes the data and creates an easily searchable multilayered database. RESULTS: An open-source virtual bio-banking web-application termed ViBiBa was created, which automatically processes data from multiple non-standardized sources. These data are automatically checked and merged into one centralized databank and are providing the opportunity to extract clinically relevant patient cohorts and CTC sample collections. SUMMARY: ViBiBa, which is a highly flexible tool that allows for decentralized sample storage of liquid biopsy specimens, facilitates a solution which promotes collaboration in a user-friendly, federalist and highly structured way. The source code is available under the MIT license from https://vibiba.com or https://github.com/asperciesl/ViBiBa.

Airway obstruction can be better predicted using Global Lung Function Initiative spirometry reference equations in Marfan syndrome.

Marfan syndrome is a genetic disorder of the connective tissue, including involvement of the lungs.Pulmonary function test was performed in 32 asymptomatic adult Marfan patients using European Community for Coal and Steel (ECCS) and Global Lung Function Initiative (GLI) reference values.Using GLI equations for reference, significantly lower lung function values were noted for forced vital capacity (FVC) (87.0 ± 16.6% vs. 97.1 ± 16.9%; P < 0.01) and forced expiratory volume in the first second (FEV1) (79.6 ± 18.9% vs. 88.0 ± 19.1%; P < 0.01) predicted compared to ECCS. Obstructive ventilatory pattern was present in 25% of the cases when calculating with GLI lower limit of normal (LLN), and it was significantly more common in men as compared to women (n = 6, 50% vs. n = 2, 10%; P = 0.03).GLI is more suitable to detect early ventilatory changes including airway obstruction in young patients with special anatomic features, and should be used as a standard way of evaluation in asymptomatic Marfan population.

Magnet dislocation following magnetic resonance imaging in cochlear implant users: Diagnostic pathways and managment.

OBJECTIVES: Although modern cochlear implants (CIs) are approved for magnetic resonance imaging (MRIs) adverse events still occur with unacceptable frequency. Methods: In this retrospective study, magnet displacement due to MRIs was analysed. Relevant factors e.g. symptoms during MRI, diagnostics, surgical intervention following the diagnosis and possible subsequent damage were assessed. RESULTS: 16 patients were enclosed. All patients complained about pain while the scan was conducted. Computed tomography (CT) scans of the temporal bone or X-rays of the skull were performed to confirm diagnosis. Artefacts on CT scans delayed immediate diagnosis in some cases. DISCUSSION: Despite various studies demonstrating the range of adverse events related to CIs following MRI, little information is available on diagnosis and radiologic recognition of magnet dislocation. In patients complaining about pain following an MRI scan an X-ray of the head should be performed immediately. Most adverse events occur in radiological centres without expertise in cochlear implants. CONCLUSION: Comprehensive training of patients, surgeons and radiologists is the most efficient tool to prevent damage to the CI and the patient. X-ray of the skull is suggested to be used as the method of choice in imaging.

Reconstructing tumor history in breast cancer: signatures of mutational processes and response to neoadjuvant chemotherapy⋆.

BACKGROUND: Different endogenous and exogenous mutational processes act over the evolutionary history of a malignant tumor, driven by abnormal DNA editing, mutagens or age-related DNA alterations, among others, to generate the specific mutational landscape of each individual tumor. The signatures of these mutational processes can be identified in large genomic datasets. We investigated the hypothesis that genomic patterns of mutational signatures are associated with the clinical behavior of breast cancer, in particular chemotherapy response and survival, with a particular focus on therapy-resistant disease. PATIENTS AND METHODS: Whole exome sequencing was carried out in 405 pretherapeutic samples from the prospective neoadjuvant multicenter GeparSepto study. We analyzed 11 mutational signatures including biological processes such as APOBEC-mutagenesis, homologous recombination deficiency (HRD), mismatch repair deficiency and also age-related or tobacco-induced alterations. RESULTS: Different subgroups of breast carcinomas were defined mainly by differences in HRD-related and APOBEC-related mutational signatures and significant differences between hormone-receptor (HR)-negative and HR-positive tumors as well as correlations with age, Ki-67 and immunological parameters were observed. We could identify mutational processes that were linked to increased pathological complete response rates to neoadjuvant chemotherapy with high significance. In univariate analyses for HR-positive tumors signatures, S3 (HRD, P < 0.001) and S13 (APOBEC, P = 0.001) as well as exonic mutation rate (P = 0.002) were significantly correlated with increased pathological complete response rates. The signatures S3 (HRD, P = 0.006) and S4 (tobacco, P = 0.011) were prognostic for reduced disease-free survival of patients with chemotherapy-resistant tumors. CONCLUSION: The results of this investigation suggest that the clinical behavior of a tumor, in particular, response to neoadjuvant chemotherapy and disease-free survival of therapy-resistant tumors, could be predicted by the composition of mutational signatures as an indicator of the individual genomic history of a tumor. After additional validations, mutational signatures might be used to identify tumors with an increased response rate to neoadjuvant chemotherapy and to define therapy-resistant subgroups for future therapeutic interventions.

Growth factors in pulmonary arterial hypertension: Focus on preserving right ventricular function.

Pulmonary arterial hypertension (PAH) is a rare and progressive disease, characterized by increased vascular resistance leading to right ventricle (RV) failure. The extent of right ventricular dysfunction crucially influences disease prognosis; however, currently no therapies have specific cardioprotective effects. Besides discussing the pathophysiology of right ventricular adaptation in PAH, this review focuses on the roles of growth factors (GFs) in disease pathomechanism. We also summarize the involvement of GFs in the preservation of cardiomyocyte function, to evaluate their potential as cardioprotective biomarkers and novel therapeutic targets in PAH.

Tumor mutational burden and immune infiltration as independent predictors of response to neoadjuvant immune checkpoint inhibition in early TNBC in GeparNuevo.

BACKGROUND: The predictive value of tumor mutational burden (TMB), alone or in combination with an immune gene expression profile (GEP), for response to neoadjuvant therapy in early triple negative breast cancer (TNBC) is currently not known, either for immune checkpoint blockade (ICB) or conventional chemotherapy. PATIENTS AND METHODS: We obtained both whole exome sequencing and RNA-Seq data from pretreatment samples of 149 TNBC of the recent neoadjuvant ICB trial, GeparNuevo. In a predefined analysis, we assessed the predictive value of TMB and a previously developed immune GEP for pathological complete remission (pCR). RESULTS: Median TMB was 1.52 mut/Mb (range 0.02-7.65) and was significantly higher in patients with pCR (median 1.87 versus 1.39; P = 0.005). In multivariate analysis, odds ratios for pCR per mut/Mb were 2.06 [95% confidence intervals (CI) 1.33-3.20, P = 0.001] among all patients, 1.77 (95% CI 1.00-3.13, P = 0.049) in the durvalumab treatment arm, and 2.82 (95% CI 1.21-6.54, P = 0.016) in the placebo treatment arm, respectively. We also found that both continuous TMB and immune GEP (or tumor infiltrating lymphocytes) independently predicted pCR. When we stratified patients in groups based on the upper tertile of TMB and median GEP, we observed a pCR rate of 82% (95% CI 60% to 95%) in the group with both high TMB and GEP in contrast to only 28% (95% CI 16% to 43%) in the group with both low TMB and GEP. CONCLUSIONS: TMB and immune GEP add independent value for pCR prediction. Our results recommend further analysis of TMB in combination with immune parameters to individually tailor therapies in breast cancer.

Intraabdominal continuous negative pressure therapy for secondary peritonitis: an observational trial in a maximum care center.

Background: Acute secondary peritonitis is afflicted with a high morbidity and mortality. Intensive care therapy, antibiotics and surgical procedures are mandatory. Continuous negative pressure therapy (cNPT) seems to be beneficial but it is unclear which patients will benefit most from this procedures.Methods: We performed a prospective observational trial including all patients that needed to undergo an exploratory laparotomy for the suspicion of acute secondary peritonitis and were treated with cNPT in one year.Results: Thirty nine patients fitted the criteria. Median hospitalization length was 40 days. The vacuum therapy treatment was applied for a median of 4 days. The subgroup analysis between patients, who received the cNPT-dressing for one time (Group A) and patients, in whom the cNPT was continued after first relaparotomy (Group B) showed no differences concerning patients' characteristics. The Mannheimer Peritonitis Index (MPI) during the first operation was significantly correlated with the number of dressing changes (Spearman's rho 0.518, p = .002).Conclusions: Fast acting in acute secondary peritonitis for elimination of the source, abdominal lavage, derivation of the exsudat and interdisciplinary treatment is the treatment of choice. The MPI could be beneficial for the decision process of using cNPT.

Effects of Footbaths with Mustard, Ginger, or Warm Water Only on Objective and Subjective Warmth Distribution in Healthy Subjects: A Randomized Controlled Trial.

OBJECTIVE: To analyze the short-term thermogenic effects of footbaths with warm water alone (WA) versus when combined with medicinal powders. DESIGN: Randomized controlled trial with cross-over. INTERVENTIONS AND OUTCOMES: Seventeen healthy volunteers (mean age 22.1 years, SD = 2.4; 11 female) received three footbaths with WA or WA combined with mustard (MU) or ginger (GI) in a randomized order. Self-perceived warmth (Herdecke warmth perception questionnaire) and actual skin temperatures (thermography) were assessed before (t0), immediately after footbaths (t1), and 10 minutes later (t2). The primary outcome was perceived warmth in the feet. Secondary outcomes were warmth perception in the face, hands and overall, as well as actual skin temperature in the feet, face, and hands. RESULTS: Perceived warmth at the feet (primary outcome) increased significantly (all p's < .001) for MU and GI at t1 as well as for GI at t2 when compared to t0 with high effect sizes. At t2, GI differed significantly from WA (p < .001) and MU (p = .048). With regards to the secondary measures of outcome, no significant effects were seen for perceived warmth at the face or hands. Overall warmth was significantly higher at t1 compared to t0 (p = .01). Thermography assessments of skin temperature at the feet at t1 increased after all conditions (p < .001). No effects were seen in the face. At the hands, temperature decreased at t1 (p = .02) and t2 compared to t0 (p < .001). CONCLUSION: The present study provides preliminary evidence that mustard and ginger increase warmth perception at the feet more than warm water alone, with only the effects for GI enduring at the brief follow-up.

Treatment and outcomes of patients in the Brain Metastases in Breast Cancer Network Registry.

BACKGROUND: Brain metastases (BMs) have a major impact on life expectancy and quality of life for many breast cancer patients. Knowledge about treatment patterns and outcomes is limited. METHODS: We analysed clinical data of 1712 patients diagnosed with BMs from breast cancer between January 2000 and December 2016 at 80 institutions. RESULTS: Median age at diagnosis of BMs was 56 years (22-90 years). About 47.8% (n = 732) of patients had HER2-positive, 21.4% (n = 328) had triple-negative and 30.8% (n = 471) had hormone receptor (HR)-positive, HER2-negative (luminal-like) primary tumours. The proportion of patients with HER2-positive BMs decreased comparing the years 2000-2009 with 2010-2015 (51%-44%), whereas the percentage of patients with luminal-like tumours increased (28%-34%; p = 0.0331). Patients with BMs in the posterior fossa were more often HER2 positive (n = 169/314, 53.8%) than those diagnosed with triple-negative (n = 65/314, 20.7%) or luminal-like primary breast cancer (n = 80/314, 25.5%), (p < 0.0001). Median overall survival (OS) time after development of BMs for the overall cohort was 7.4 months (95% confidence interval [CI]: 6.7-8.0 months). One-year survival rate was 37.7% (95% CI: 35.2-40.1). Patients with HER2-positive tumours had the longest median OS of 11.6 months (95% CI: 10.0-13.4) compared with 5.9 months (95% CI: 5.0-7.2) for patients with luminal-like and 4.6 months (95% CI: 3.9-5.4) for patients with triple-negative tumours. Patients with HER2-positive tumours who received anti-HER2 treatment had longer median OS than those without (17.1 months versus 7.2 months, p < 0.0001). CONCLUSIONS: Prognosis of patients after developing BMs varies significantly according to the subtype. The outcome in this cohort is similarly poor in triple-negative and HR-positive/HER2-negative patients. Our results underline the high medical need for improvement of treatment and prevention strategies for BMs in breast cancer patients.

[Tips and technical issues for performing transoral endoscopic thyroidectomy with vestibular approach (TOETVA): a novel scarless technique for neck surgery]. / Tipps und technische Aspekte zur Durchführung der transoralen endoskopischen Thyreoidektomie mit vestibulärem Zugang (TOETVA): eine neue narbenlose Technik für die Halschirurgie.

BACKGROUND: Nowadays, minimally invasive thyroid and parathyroid gland resections for both benign and malignant tumors are rarely performed. Recently, promising new endoscopic transoral approaches to the anterior neck have been described with good results and few complications. This study describes the first clinical series in Germany using transoral endoscopic thyroidectomy-vestibular approach (TOETVA) and identifies technical issues and solutions. METHODS: The technique is indicated for hemithyroidectomy in patients without pre-existing neck operations. The technical steps consist of a 10 mm incision at the center of the oral vestibule, followed by subplatysmal hydrodissection. A blunt dissector stick is inserted creating a space below the platysma to the anterior neck and the infrahyoid muscles then three trocars are inserted in the vestibular area. After separation of the infrahyoid muscles, the thyroid isthmus is transected. Anatomical structures, such as the superior thyroid artery, parathyroid glands and the recurrent laryngeal nerve can be easily identified with magnification. Intraoperative neuromonitoring is used routinely, adding safety in avoiding nerve damage. RESULTS: An optimal operative field due to subplatysmal dissection enables exposure of the thyroid and parathyroid glands. Several critical steps and suitable solutions were identified in the study. 1 Positioning of the team and technical improvements using the a 4K laparoscopic tower allowing enhanced view of the anatomy especially for dissection of the recurrent laryngeal nerve. 2. Lateral and upper positioning of lateral trocars avoiding mental nerve injury. 3. Initial hydrodissection of the subplatysmal space. 4. Use of one dissector progressively creating the operative space in the anterior cervical region. 5. Using internal-external sutures to retract the infrahyoid muscles. 6. Intraoperative neuromonitoring used routinely through the trocars or percutaneously through a 1 mm incision. 7. Extraction of the specimen through a recovery bag. 8. Drainages are possible, but can be avoided in small operative fields. CONCLUSION: The new TOETVA technique for thyroid surgery is a promising option for selected patients to enable transoral thyroid and parathyroid surgery through the vestibular approach. Further studies in clinical series, especially regarding safety are needed to evaluate the indications of the technique.

Determination of docetaxel in dried blood spots by LC-MS/MS: Method development, validation and clinical application.

In this study, a LC-MS/MS method for the measurement of docetaxel in Dried Blood Spots (DBS) samples was developed and validated. Docetaxel was extracted from 8 mm DBS punch with a mixture of methanol and acetonitrile (9:1, v/v). The chromatographic separation occurred in an Acquity® C18 column (150 × 2.1 mm, 1.7 µm) eluted with a mixture of water and acetonitrile plus 0.1% formic acid (45:55, v/v). Total analytical run time was 7 min. The method was linear from 50 to 3000 ng ml-1. Precision assays showed CV% < 9.8% and accuracy between 99 and 103%, mean recovery was 81%. The method was applied in the determination of the docetaxel in 31 patients, after collection of two paired venous blood and DBS samples, following a limited sampling strategy protocol. The analyte was stable in DBS for 18 days at 25 °C and 9 days at 45 °C. The interval of docetaxel concentrations measured in DBS collected before the end of the infusion was 756-3047 ng ml-1 and 60 ±â€¯10 min after the end of the infusion was 57-331 ng ml-1. AUC values calculated from DBS-derived estimated plasma concentrations (EPC) represented on average 100% of those obtained in plasma samples of 3.1 mgh/l (2.4-4.9 mg h/l). There was a 93% agreement between the classification of patients as within or without the therapeutic range by plasma and EPC AUC. These findings support the clinical use of DBS sampling for routine therapeutic drug monitoring of docetaxel.

[Treated cases of retinopathy of prematurity in Germany : 5-year data from the Retina.net ROP registry]. / Behandelte Frühgeborenenretinopathie in Deutschland : 5-Jahres-Daten des Retina.net ROP-Registers.

BACKGROUND: Retinopathy of prematurity (ROP) is one of the main reasons for childhood blindness. The number of infants requiring treatment, however, is low for individual centers. The Retina.net ROP registry has been founded to allow a joint analysis of treatment patterns and courses post treatment. OBJECTIVE: This paper reports treatment patterns over 5 years. MATERIAL AND METHODS: All infants born between January 2011 and December 2015 who were entered into the treatment registry by one of the 12 participating centers were analyzed. RESULTS: The data of 150 infants (292 eyes) were analyzed and ROP 3+ in zone II was the most prevalent treatment indication. Gestational age and birth weight remained stable over the years. The treatment patterns, however, changed with anti-VEGF treatment (bevacizumab or ranibizumab) accounting for only 10% of treated eyes in 2011 but for 56% and 30% in 2014 and 2015, respectively. Almost all eyes with AP-ROP or zone I disease received anti-VEGF treatment. Zone II disease was predominantly treated with laser photocoagulation. Recurrences were more common and appeared later in the anti-VEGF group compared to the laser group (23%/interval 60 days vs. 17%/interval 23 days). Perioperative complications were evenly distributed across treatment groups. CONCLUSION: The data in this analysis represent about 10-15% of treated infants in Germany. The results provide evidence for an increasing use of anti-VEGF agents for ROP. The data reflect a selection bias for anti-VEGF treatment in eyes with a more aggressive disease. This needs to be considered when interpreting data such as disease recurrence rates. The risk for late recurrences after anti-VEGF treatment is of particular clinical significance.