https://www.mdc-berlin.de/de/veroeffentlichungstypen/clinical- journal-club

Als gemeinsame Einrichtung von MDC und Charité fördert das Experimental and Clinical Research Center die Zusammenarbeit zwischen Grundlagenwissenschaftlern und klinischen Forschern. Hier werden neue Ansätze für Diagnose, Prävention und Therapie von Herz-Kreislauf- und Stoffwechselerkrankungen, Krebs sowie neurologischen Erkrankungen entwickelt und zeitnah am Patienten eingesetzt. Sie sind eingelanden, um uns beizutreten. Bewerben Sie sich! An otherwise healthy 10-year-old girl presented to the primary care clinic with a 10-day history of multiple itchy papules on the soles of her feet and on her toes. The lesions had black dots in the center and were painful. Two weeks earlier, the family had traveled to rural Brazil. During that time, the patient had played in a pigsty without wearing shoes. Sand fleas were removed from multiple lesions. What is the most likely diagnosis?

Coxsackievirus infection

Furuncular myiasis

Foreign body granulomas

Tungiasis

Scabies infestation

Correct! The correct answer is tungiasis. Tungiasis is a skin infestation caused by the sand flea Tunga penetrans, an ectoparasite that is found throughout tropical and subtropical parts of the world. Treatment included flea removal and local wound care. Die Myiasis (nach griechisch μυῖα myia = „Fliege“) oder auch Fliegenmadenkrankheit ist der Befall von Lebewesen mit den Larven (Maden) von Fliegen, welche von dem Gewebe, den Körperflüssigkeiten oder dem Darminhalt des Wirtes leben. Sie ist bei Menschen in Mittel- und Südamerika sowie in Regionen mit tropischen oder subtropischem Klima verbreitet. In der Tiermedizin kommt ein Fliegenmadenbefall auch in Europa häufiger vor. Betroffen sind vor allem stark geschwächte oder anderweitig erkrankte Tiere, die nicht mehr in der Lage sind, sich selbst zu putzen. Die Larven können sich sowohl in der Haut (insbesondere in kleinen Verletzungen) als auch in den Körperöffnungen sowie in offenen Wundenansiedeln. Unzureichende hygienische Bedingungen begünstigen eine Infestation. Parasitäre Fliegenlarven gelangen auf verschiedene Weise unter die Haut: Etwa über schlammige, evtl. mit Exkrementen versetzte Tümpel können die Eier einer Tumba Fly Larva solchen Fliegenart auf die menschliche Haut gelangen. Die schlüpfende Larve gräbt sich dann in das Fleischareal, mit dem sie Kontakt bekommt, ein. Auch über verschmutzte, zum Trocknen aufgehängte Kleidung, auf die die Fliegen ihre Eier gelegt haben, können Letztere mit der Haut in Kontakt kommen. Ein dritter Weg der Kontaktaufnahme ist die Nutzung einer blutsaugenden Fliege als Transportmittel für die Eier. Die eingenistete Larve bleibt für gewöhnlich in der Nähe der Haut und gräbt sich nicht tief ein, da sie atmen muss. Sie nutzt dafür das Loch in der Haut, durch das sie eingedrungen ist. Insecta Tungiasis (also known as nigua, pio and bicho de pie, or pique or sand flea disease) is an inflammatory skin disease caused by infection with the female ectoparasitic Tunga penetrans (also known as chigoe flea, jigger, nigua or sand flea), found in the tropical parts of Africa, the Caribbean, Central and South America, and India. Tunga penetrans is the smallest known flea, measuring 1 mm across. It is also known in Latin America as the nigua and bicho de pie (Spanish) or bicho de pé (Portuguese), literally "foot bug". Tunga penetrans is a member of the genus Tunga, which comprises 13 species. At the third week after penetration and substage 4a, the eggs’ release will have stopped and the lesion will become smaller and more wrinkled. As the flea is near death, fecal and water secretion will stop altogether. Pain, tenderness, and skin inflammation will still be present. Around the 25th day after penetration, the lesion looks like a black crust and the flea’s carcass is removed by host repair mechanisms and the skin begins to heal. With the flea gone, inflammation may still persist for a while. If the patient is not vaccinated, tetanus is often a complication due to secondary infection. Gangrene is another common complication of severe infestation and superinfection. Staphylococcus aureus and Wolbachia endobacteria can be transmitted by the chigoe flea, as well as nearly 150 other different pathogens. For these reasons, the chigoe flea should be removed as soon as possible.

Insecta Krätze,fachsprachlich Skabies, Scabies (von lateinisch sca bere ‚kratzen‘) oder Acarodermatitis, ist eine weitverbreitete, durch die Grab- bzw. Krätzemilbe (vor allem Sarcoptes scabiei) verursachte parasitäre Hautkrankheit des Menschen. Die halbkugelförmigen, 0,3–0,5 Millimeter großen Weibchen der Krätzmilbe bohren sich in die Oberhaut (Epidermis) und legen dort in den Kanälen (caniculi, Milbengänge) Kotballen (Skybala) und ihre Eier ab. Ihre Absonderungen führen zur erheblichen Schädigung der Haut. Die Inkubationszeit beträgt etwa einige Tage bis sechs Wochen. Für befallene Patienten gilt in Deutschland nach § 34 Infektionsschutzgesetz bereits bei Verdacht ein Verbot des Aufenthalts und Arbeitens in Gemeinschaftseinrichtungen. Andere Milbenerkrankungen Arachnida des Menschen werden als Acariasis bezeichnet. Als Entdecker des Zusammenhangs zwischen Milbenbefall und der schon zuvor bekannten Krätze gilt der italienische Arzt Giovanni Cosimo Bonomo im 17. Jahrhundert. Krätze bei Tieren wird umgangssprachlich Räude genannt, wobei hier auch andere Milben vorkommen. Außer den Haarbalgmilben können die meisten dieser Parasiten auch den Menschen als Fehlwirt befallen und eine Pseudokrätze oder Trugräude, medizinisch Pseudoscabies, hervorrufen. Eine multiresistente Tuberkulose, kurz MDR-Tb, ist eine Tuberkulose, die durch Erreger ausgelöst wird, die gegen zwei oder mehr Erstlinien-Tuberkulostatika resistent sind. Das häufig gebrauchte englische Kürzel MDR steht hierbei für "multidrug- resistant“. Zu einer MDR-Tb kommt es durch Tuberkulosebakterien, die zum Beispiel gegen Isoniazid und Rifampicin resistent sind. Sind die Tuberkuloseerreger zusätzlich auch gegen Zweitlinien-Tuberkulostatika resistent, spricht man von einer XDR-Tb. Eine Tuberkulosekranker entwickelt eine MDR-Tb, wenn während der Behandlung die Erstrang- Antituberkulotika falsch dosiert bzw. eingenommen und dadurch unwirksam werden (fehlende Kombinationstherapie). Menschen mit MDR-Tb können infektiös sein und die resistenten Erreger an andere Personen weitergeben. One mechanism is a mutation in the rpoB gene, which encodes the beta subunit of the bacteria's RNA polymerase. In non- resistant TB, rifampin binds the beta subunit of RNA polymerase and disrupt transcription elongation. Mutation in the rpoB gene changes the sequence of amino acids and eventual conformation of the beta subunit. In this case rifampin can no longer bind or prevent transcription, and the bacteria is resistant. Other mutations make the bacterium resistant to other drugs. For example, there are many mutations that confer resistance to isoniazid (INH), including in the genes katG, inhA, ahpC and others. Amino acid replacements in the NADH binding site of InhA apparently result in INH resistance by preventing the inhibition of mycolic acid biosynthesis, which the bacterium uses in its cell wall. Mutations in the katG gene make the enzyme catalase peroxidase unable to convert INH to its biologically active form. Hence, INH is ineffective and the bacteria is resistant. The discovery of new molecular targets is essential to overcome drug resistant problems. A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011. We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority. Participants were eligible for inclusion in the trial if they were 18 years of age or older and had pulmonary tuberculosis (as confirmed by a positive sputum smear or, if coinfected with HIV, a nucleic acid amplification test [GeneXpert, Cepheid]) with evidence of resistance to rifampin. In practice, the management of rifampin- monoresistant tuberculosis and the management of multidrug-resistant tuberculosis are similar. Kaplan–Meier Estimates of the Time to an Unfavorable Outcome and the Time to Death. Panel A shows the Kaplan– Meier estimates of the time to an unfavorable outcome, which was defined by the initiation of two or more drug therapies that were not included in the assigned regimen, treatment extension beyond the permitted duration, death from any cause, a positive culture for Mycobacterium tuberculosis from one of the two most recent specimens, or no visit at 76 weeks or later. In contrast, favorable status at 132 weeks (the primary outcome) was defined by cultures that were negative for M. tuberculosis at 132 weeks after randomization and at a previous occasion during the trial period, with no intervening positive culture or previous unfavorable outcome. Panel B shows the Kaplan–Meier estimates of the time to death. In both panels, insets show the same data on an enlarged y axis. Primary Efficacy Analysis in the Modified Intention-to-Treat and Per-Protocol Populations.

We found that the efficacy of the short regimen (9 to 11 months) that had been studied previously in Bangladesh (modified in the current trial to include high-dose moxifloxacin in place of high-dose gatifloxacin) was noninferior to the long regimen (20 months) that followed the 2011 WHO recommendations. Both regimens resulted in a long-term successful outcome in more than 78% of the participants, with more participants in the short-regimen group having an unfavorable outcome (HIV-adjusted difference, 1.0 percentage point), although this difference could have been 7.5 percentage points in favor of the short regimen or 9.5 percentage points in favor of the long regimen. The Bayesian analysis yielded a probability of 0.83 that this difference would be no more than 5 percentage points. Our final estimate of the difference in efficacy between the two regimens, based on data from 369 participants in the modified intention-to-treat analysis, did not differ notably from the preliminary findings that were based on data from 318 participants (adjusted difference, 2.1 percentage points; 95% CI, −6.9 to 11.2) that we reported at the Union World Conference on Lung Health in October 2017.

After reviewing the results of the STREAM study and of observational studies, the WHO released updated guidelines for multidrug-resistant and rifampin-resistant tuberculosis in December 2018 that continued to include the short regimen as an option for patients “who have not been previously treated for more than one month with second-line medicines used in the shorter MDR [multidrug-resistant] regimen or in whom resistance to fluoroquinolones and second-line injectable agents has been excluded.” Although the results of this trial are encouraging, further research remains essential to find a short, simple regimen for multidrug- resistant tuberculosis that results in efficacy and safety outcomes that are similar to those for drug-susceptible tuberculosis. Volatile Anesthetics versus Total Intravenous Anesthesia for Cardiac Surgery Volatile (inhaled) anesthetic agents have cardioprotective effects, which might improve clinical outcomes in patients undergoing coronary-artery bypass grafting (CABG). We conducted a pragmatic, multicenter, single-blind, controlled trial at 36 centers in 13 countries. Patients scheduled to undergo elective CABG were randomly assigned to an intraoperative anesthetic regimen that included a volatile anesthetic (desflurane, isoflurane, or sevoflurane) or to total intravenous anesthesia. The primary outcome was death from any cause at 1 year. Patients in the volatile anesthetics group received an anesthetic regimen that included desflurane, isoflurane, or sevoflurane. Attending anesthesiologists were instructed to administer volatile anesthetics for as long as possible during surgery, but no specific drug- administration protocol was mandated. The most commonly used intravenous hypnotic agent in the total intravenous anesthesia group was propofol (2355 patients [87.7%]), followed by midazolam (863 patients [32.2%]).

In this pragmatic, multicenter, randomized, single-blind trial involving patients undergoing elective, isolated CABG, intraoperative anesthesia with a volatile anesthetic did not result in a significantly lower number of deaths at 1 year than total intravenous anesthesia. Moreover, the outcomes of death at 30 days, a composite of perioperative nonfatal myocardial infarction at 30 days or death at 30 days, and other major secondary outcomes did not differ significantly between the two groups. Finally, the incidence of adverse events also did not differ significantly between the groups. Several other trial limitations should also be noted. First, our trial was stopped early, which increased the risk of type 2 error for the secondary outcomes. However, there was no trend toward a beneficial effect of volatile anesthetics for these outcomes, and the survival plots were almost identical. Second, we did not mandate postoperative measurement of troponin. Thus, our diagnosis of postoperative myocardial infarction had limited sensitivity. Third, the number of deaths at 1 year in our trial was consistent with that in recent literature but lower than that in the two largest randomized, controlled trials that favored volatile anesthetics. In conclusion, among patients undergoing elective, isolated CABG, an intraoperative anesthetic regimen that included volatile anesthetics did not result in significantly fewer deaths at 30 days or 1 year than a regimen of total intravenous anesthesia. Fulvestrant ist ein neuer Estrogenrezeptor-Antagonist zur Behandlung von postmenopausalen Frauen mit fortgeschrittenem Mammakarzinom. Im Gegensatz zum etablierten Tamoxifen muss Fulvestrant nur einmal monatlich gespritzt werden. Reiner Antagonist Fulvestrant Fulvestrant ist wie Tamoxifen ein Estrogenrezeptor- Antagonist und bindet kompetitiv an den Estrogenrezeptor mit einer dem Estradiol vergleichbaren Affinität. Im Gegensatz zu Tamoxifen blockiert Fulvestrant vollständig die Wirkungen der Estrogene, ohne selbst partiell agonistische (estrogenartige) Eigenschaften zu besitzen. Langfristig sind daraus positive Effekte im Hinblick auf die Inzidenz des Endometriumkarzinoms oder von Thromboembolien zu erwarten. In placebokontrollierten Studien reduzierte Fulvestrant das Estrogenrezeptorprotein in Tumoren. Die Expression des Progesteronrezeptors war ebenfalls signifikant vermindert. Tamoxifen als Standard Tamoxifen gilt bislang wegen der guten Datenlage als Mittel der Wahl zur Behandlung von postmenopausalen Frauen mit hormonsensitivem Mammakarzinom. Der therapeutische Nutzen von Tamoxifen nimmt zwar in den ersten Einnahmejahren mit Dauer der Anwendung zu, jedoch erhöht sich unter anderem die Inzidenz für Endometriumkarzinome und Thromboembolien. Deshalb gelten fünf Jahre als optimale Behandlungsdauer. Anastrozol ist ein Arzneistoff aus der Gruppe der Aromatasehemmer. Er ist in Deutschland zur unterstützenden Behandlung des hormonabhängigen Brustkrebses der Frau nach den Wechseljahren zugelassen. Die Aromatase (auch CYP19A1) ist das Enzym, das in Wirbeltieren die Umsetzung von Testosteron zu Estradiol bzw. von Androstendionzu Estron katalysiert. Die Wirkungen von Anastrozol beruhen auf der Hemmung des Enzyms Aromatase, das die Umwandlung von Androgenen in die Estrogene Estron und Estradiol bestimmt. Durch die Hemmung dieses Enzyms wird der Estrogenspiegel im Blutplasma gesenkt, wodurch den Tumorzellen weniger Hormone für das Wachstum zur Verfügung stehen. Anastrozol hat keine Steroidstruktur und hemmt, im Gegensatz zu etwa Exemestan, die Aromatase reversibel. Des Weiteren hat Anastrozol eine direkte Wirkung auf die Tumorzellen, indem es auch die Aromatase innerhalb der Tumorzellen hemmt. In der Prävention von Brustkrebs wurde Anastrazol erfolgreich bei postmenopausalen Frauen mit hohem Brustkrebsrisiko eingesetzt. In dieser Gruppe kann Anastrozol das Risiko einen Brustkrebs zu entwickeln halbieren. Da Brustkrebs heute aber recht gut behandelbar ist, bleibt fraglich, ob die möglichen Nebenwirkungen wirklich akzeptiert werden sollten. Denn einen Überlebensvorteil bringt die Prävention nicht. Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer

We previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor–positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes. We randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups. Kaplan–Meier Curves for Progression- free Survival, According to Trial Group. Curves are shown for the overall trial population (Panel A) as well as for the subgroup of patients who had not received adjuvant endocrine therapy previously (Panel B).

Kaplan–Meier Curves for Overall Survival, According to Trial Group. Curves are shown for the overall trial population (Panel A) as well as for the subgroup of patients who had not received adjuvant endocrine therapy previously (Panel B). The absolute median prolongation in overall survival of 7.8 months was greater than the prolongation in progression-free survival of 1.5 months owing to late divergence of the progression- free survival curves after the median and early divergence of the overall survival curves before the median. However, the relative benefit with regard to overall survival is similar to the relative benefit in progression-free survival (hazard ratio for disease progression or death, 0.81; hazard ratio for death, 0.82). Postprogression survival was similar in the two groups, which reflects the finding that, despite crossover to fulvestrant in the anastrozole-alone group and the multiple lines of postprogression therapies typically administered in these patients, the progression-free survival benefit of up-front combination therapy resulted in prolonged overall survival. This additional ion therapy with anastrozole plus fulvestrant significantly prolonged, as compared with treatment with anastrozole alone, the primary and secondary end points of progression-free survival (P=0.007) and long-term overall survival (P=0.03) when used as first-line therapy for hormone-receptor– positive metastatic breast cancer in postmenopausal women. Furthermore, sequential therapy with anastrozole and fulvestrant (45% of patients crossed over to fulvestrant alone) did not negate the significance of the long-term overall survival benefit with the combination therapy as compared with anastrozole. Furthermore, this improvement was seen despite the use of a maintenance dose of fulvestrant (after the first-month loading dose) that was lower than the now-standard higher dose (i.e., 250 mg rather than 500 mg per month). The significant benefit with the combination therapy was observed despite longer progression-free survival and overall survival in the anastrozole-alone group than was projected at the start of the trial, with the results in the combination-therapy group even benefit occurred in the absence of clinically significant between-group differences in the incidence of toxic effects of grade 3 to 5 or the discontinuation of treatment, even with long-term follow-up and despite a longer duration of combination therapy. These results of our trial (S0226) are in contrast to the results of two similarly conducted prospective, randomized trials of single- agent aromatase inhibitors as compared with the combination of an aromatase inhibitor plus fulvestrant. Darolutamid, ODM-201 (BAY-1841788) ist ein neuartiger in der Entwicklung befindlicher Hemmstoff des Androgenrezeptors (Androgenrezeptor- Antagonist) mit einer einzigartigen chemischen Struktur, die speziell zur Hemmung des Wachstums von CRPC entwickelt wurde. Darolutamid funktioniert sehr ähnlich zu Enzalutamide hat aber eine kürzere Halbwertszeit. In vorklinischen Studien konnte gezeigt werden, dass Darolutamid in geringem Maße die Blut-Hirn-Schranke überwindet. Der Hemmstoff ODM-201 bindet mit hoher Intensität an den Androgenrezeptor und blockiert die Funktion des Rezeptors, indem er seine zelluläre Funktion hemmt. Die ARAMIS-Studie prüft ODM-201 bei Männern mit kastrationsresistentem Prostatakarzinom, die rasch ansteigende Werte des prostataspezifischen Antigens (PSA), aber noch keine nachweisbaren Metastasen zeigen. Bewertet wird die Wirkung des Medikaments anhand der Zeit bis zum Auftreten von Metastasen. Kastrationsresistente Prostatakarzinom (CRPC) Die Kastration resistentem Prostatakrebs (CRPC) charakterisiert sich durch anhaltende, hohe Androgen- Rezeptor (AR)-Ausprägung und Resistenz gegen herkömmliche Androgen-Rezeptor Inhibitoren. Die Behandlungsmöglichkeiten für Prostatakrebs reichen von der Operation über die Bestrahlung bis hin zur Verabreichung von Hormon-Rezeptorantagonisten – also Substanzen, die die Bildung des männlichen Sexualhormons Testosteron Not a perfume! verhindern oder dessen Wirkung am Zielorgan blockieren. Allerdings wird der Tumor in fast allen Fällen irgendwann resistent gegen die konventionelle Hormontherapie. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer Darolutamide is a structurally unique androgen-receptor antagonist that is under development for the treatment of prostate cancer. We evaluated the efficacy of darolutamide for delaying metastasis and death in men with nonmetastatic, castration-resistant prostate cancer. We conducted a randomized, double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic, castration- resistant prostate cancer and a prostate- specific antigen doubling time of 10 months or less. Patients were randomly assigned in a 2:1 ratio to receive darolutamide (600 mg [two 300-mg tablets] twice daily) or placebo while continuing androgen-deprivation therapy. The primary end point was metastasis-free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks. Darolutamide is an androgen-receptor antagonist with a distinct structure that offers a potential for fewer and less severe toxic effects than apalutamide and enzalutamide because of its low penetration of the blood–brain barrier and low binding affinity for γ-aminobutyric acid type A receptors, as shown in preclinical studies. Kaplan−Meier Estimates and Subgroup Analyses of Metastasis-free Survival (Intention-To-Treat Population). Hazard ratios were based on Cox regression models. The analysis shown in Panel A was stratified according to prostate-specific antigen (PSA) doubling time (≤6 months or >6 months) and the use of osteoclast- targeted therapy at randomization (yes or no). NR denotes not reached. The analyses shown in Panel B, including the analysis of the overall population, were conducted without stratification factors. Gleason scores range from 6 to 10, with higher scores indicating higher- risk cancer. The “rest of the world” geographic region was predominantly made up of European countries (15% of these patients came from non-European countries), and a post hoc analysis of metastasis-free survival in European countries (Austria, Belgium, Germany, Spain, Finland, France, United Kingdom, Italy, Sweden, Portugal, Czech Republic, Estonia, Hungary, Lithuania, Poland, Romania, Russia, Serbia, Turkey, Ukraine, Belarus, Bulgaria, Latvia, and Slovakia) gave a hazard ratio very similar to that for this group. Eastern Cooperative Oncology Group (ECOG) performance status ranges from 0 to 5, with higher scores reflecting greater disability. The 52 patients of African descent could not be included in the analysis according to race or ethnic group because the number of events was too small to allow calculation of a hazard ratio.

Kaplan−Meier Estimates of Overall Survival and Time to PSA Progression. Hazard ratios were based on Cox regression models that were stratified according to PSA doubling time (≤6 months or >6 months) and the use of osteoclast-targeted therapy at randomization (yes or no). The incidence of adverse events was generally similar in the darolutamide and placebo groups; with the exception of fatigue, all adverse events that occurred or worsened during the treatment period that had a frequency of 5% or greater occurred in less than 10% of the patients in either group (Table). Key adverse events that are known to be associated with next-generation androgen-receptor inhibitors, such as fracture, falls, seizures, and weight loss, were analyzed after grouping of synonymous or pathophysiologically related adverse events that occurred or worsened during the treatment period; most showed small or no differences in incidence between the darolutamide group and the placebo group. The incidence of seizures was 0.2% in both groups. Incidences of other adverse events of interest, including hypertension, rash, dizziness, and cognitive disorder, differed only slightly between the darolutamide group and the placebo group. After adjustment for duration of the treatment or observation period, the between-group differences in the incidences of adverse events of interest either decreased or disappeared. Darolutamide is a nonsteroidal androgen-receptor antagonist that is structurally distinct from other androgen-receptor inhibitors, consisting of two pharmacologically active diastereomers. In our trial, darolutamide prolonged metastasis-free survival to 40.4 months, 22 months longer than with placebo. The risk of metastasis or death from any cause was reduced by 59%, and the benefit was consistent across all subgroups, including the subgroup of patients with lower- risk disease. The results for the secondary end point of overall survival also favored darolutamide, although the prespecified alpha split between the primary and the final analysis prevented the significance criteria from being met in this analysis. The results with regard to all secondary end points supported that of the primary end point, and consistent efficacy was observed for metastasis-free, overall, and progression-free survival.

This trial has several strengths. The large size enabled a robust statistical analysis as well as the detection of rare but important safety signals. Patients’ quality of life was assessed in detail with the use of validated instruments to assess different aspects of the effect of treatment, including the BPI scale to measure pain progression. A limitation of the trial is the underrepresentation of patients of African descent (52 in total); therefore, no conclusions can be drawn about efficacy in this group.

In conclusion, metastasis-free survival was significantly longer with darolutamide than with placebo for men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling time of 10 months or less. The results for the secondary and exploratory end points supported the benefits of darolutamide in this clinical context. The safety data indicated no clinically relevant difference between darolutamide and placebo in the incidence of adverse events that occurred during the treatment period, including falls, fractures, seizures, cognitive disorders, and hypertension. Quality-of-life outcomes were similar in the two groups. Changes in Practice among Physicians with Malpractice Claims

Physicians with poor malpractice liability records may pose a risk to patient safety. There are long- standing concerns that such physicians tend to relocate for a fresh start, but little is known about whether, how, and where they continue to practice. We linked an extract of the National Practitioner Data Bank to the Medicare Data on Provider Practice and Specialty data set to create a national cohort of physicians 35 to 65 years of age who practiced during the period from 2008 through 2015. We analyzed associations between the number of paid malpractice claims that physicians accrued and exits from medical practice, changes in clinical volume, geographic relocation, and change in practice-group size. A small group of physicians accounts for a disproportionately large share of all malpractice claims and patient complaints. This maldistribution has long been evident, but studies in the past several years have brought it into sharper focus. For example, our 2016 study of paid malpractice claims over a 10-year period estimated that 1% of physicians accounted for nearly one third of the claims and that 94% of physicians had none. We formed the study cohort by linking extracts of two U.S. data sets: the Medicare Data on Provider Practice and Specialty (MD-PPAS, version 2.2) and the National Practitioner Data Bank (NPDB). Adjusted Odds of Exits from Medical Practice and Adjusted Differences in Clinical Volume. All comparisons are with physicians who had no paid malpractice claims. For exits from medical practice (Panel A), estimates were adjusted for physician sex, age, and specialty; the number of Medicare services billed; year; and state. For clinical volume (Panel B), estimates were adjusted for physician sex, age, and specialty; year; and state. “Medicare services billed” indicates line items billed by the physician for services covered by Medicare. Adjusted Odds of Practice Adjusted Odds of Change in Practice-Group Size. Relocation. “Areas” consist of core- Practice-group sizes were defined according to based statistical areas grouped four categories: solo, small (2 to 10 physicians), according to the population size of medium (11 to 50 physicians), and large (>50 their largest urban cores. physicians). Estimates were adjusted for physician sex, age, and specialty; the number of Medicare services billed; year; and state. This study showed that physicians’ odds of leaving clinical practice increased with the number of paid malpractice claims they accrued. Physicians with multiple claims who continued to practice were more likely than colleagues without claims to switch to smaller practices or solo practice. However, there was no clear association between the number of claims and the propensity to relocate, within or between states. A founding motivation for the NPDB was to restrict the ability of incompetent physicians to move across state lines to put poor track records behind them. Reports abound of such jurisdiction hopping, although evidence is largely anecdotal. Against this backdrop, our null finding is both surprising and reassuring. Our study was not designed to assess the extent to which this result is attributable to the greater availability of information about physicians’ track records made possible by the NPDB, but this seems likely to have played a role. By requiring hospitals to query practitioners’ records before granting them clinical privileges and encouraging physician groups, health plans, and professional societies to do the same, the NPDB has almost certainly increased the difficulty of relocation for physicians with medicolegal problems. Physicians’ claims counts were positively associated with their propensity to switch to smaller practice settings, including solo practice. Shifts to smaller practices may become necessary if a hospital or practice group severs its ties with a claim-prone physician or imposes burdensome remedial actions as a condition of recredentialing. Physicians may also seek a new practice setting if they perceive that their reputation among their colleagues has become tarnished. Finally, our study design and results focused on testing for relative differences among physicians. From a policy perspective, however, the absolute number of some practice changes by high-risk practitioners is important too, regardless of how much that number conforms to or diverges from norms in the medical workforce. Most physicians with multiple claims in our cohort remained in practice and continued to deliver as much care as their colleagues did; 736 of them became solo practitioners and 711 moved to another state. Such activity warrants close attention, especially in light of evidence that the number of paid claims that physicians have accrued is strongly and positively associated with their risks of incurring more. Das Ovarialkarzinom oder Eierstockkrebs ist eine bösartige Erkrankung der Eierstöcke. Es ist in der westlichen Welt nach dem Endometrium- und dem Zervixkarzinom das dritthäufigste Genitalmalignom der Frau und hat eine schlechtere Prognose als jene. Das mittlere Erkrankungsalter beträgt in Deutschland 69 Jahre, wobei auch wesentlich jüngere Frauen, dann häufig in Zusammenhang mit genetischer Prädisposition, erkranken können. Frauen in Deutschland haben ein Lebenszeitrisiko von 1,5 %, an Eierstockkrebs zu erkranken. Die Inzidenz des Ovarialkarzinoms ist in den letzten 20 Jahren deutlich gesunken, wohingegen die Mortalitätsraten sich auf einem etwa konstanten Niveau bewegen. Von 2005 bis 2009 fielen die alters- und bevölkerungskorrigierten Inzidenzraten bundesweit von 13,5 auf 11,5 Neuerkrankungen pro 100.000 weiblichen Einwohnern und Jahr. Die geschätzten Inzidenzraten für das Jahr 2012 lassen 7.200 Neuerkrankungsfälle erwarten, was einer alters- und bevölkerungskorrigierten Inzidenzrate von 11,0 neuen Fällen pro 100.000 weiblichen Einwohnern entspricht. Seröses Zystadenom (30 %) Muzinöses Zystadenom (15 %) Endometrioide Tumoren (5 %) Brenner-Tumor (2 %) Adenomatoidtumor (sehr selten) Zystadenofibrom Mucinous Ovarian Carcinoma Nearly 239,000 new cases of ovarian cancer (and 152,000 associated deaths) are reported worldwide annually, with the highest incidence rates in North America and central and eastern Europe. The most common histologic subtype is high-grade serous ovarian cancer (accounting for 65% of cases). Other histologic subtypes include low-grade serous, endometrioid, clear-cell, and mucinous ovarian cancers, as well as ovarian carcinosarcoma. Mucinous ovarian cancer is a rare tumor, probably accounting for 3% of all epithelial ovarian cancers, and often presents a diagnostic and therapeutic conundrum for oncologists. For decades, the management of mucinous ovarian cancer was based on guidelines developed for serous ovarian cancer. However, experience with mucinous ovarian cancer and an understanding of its biologic features have shown that it is a unique disease requiring unique management. This review highlights the distinguishing features of mucinous ovarian cancer and provides an update on its molecular landscape and surgical and medical management. Stages in the Progression of Mucinous Ovarian Tumors. Mucinous ovarian tumors develop on a continuum from benign epithelium to preinvasive (borderline) carcinoma to mucinous carcinoma. KRAS mutations are an early event, whereas other oncogenic alterations (HER2 amplifications or TP53 mutations) may be acquired later in the course of malignant transformation. Overall Management of Mucinous Ovarian Tumors. The first step in managing a primary mucinous ovarian tumor is to rule out mucinous metastasis to the ovary (a nonovarian primary mucinous cancer) on the basis of a combination of clinical and pathological features. Extensive sampling of these large heterogeneous tumors and review by an expert pathologist are required for accurate diagnosis. Once the diagnosis has been established, both staging and accurate histologic classification guide surgical and medical management. The plus signs in CK7+++, CK20+, and CDX2+ denote the intensity of positive staining on immunohistochemical analysis, with more plus signs indicating higher staining intensity. CT denotes computed tomography, EGD esophagogastroduodenoscopy, LDN lymphadenectomy, and PET positron-emission tomography.

Proposed Individualized Investigational Approach to the Treatment of Metastatic or Relapsed Mucinous Ovarian Carcinoma. For patients with mucinous ovarian carcinoma that has metastasized or relapsed, molecular alterations identified by means of next-generation sequencing can be used to select matched treatments under investigation in clinical trials. FGFR2 denotes fibroblast growth factor receptor 2, HER2 human epidermal growth factor receptor 2, MSI microsatellite instability, PI3K phosphatidylinositol 3-kinase, and TKI tyrosine kinase inhibitor Finally, defects in the mismatch-repair pathway of DNA repair that result in a tumor with microsatellite instability have been detected in 15 to 20% of patients with mucinous ovarian cancer. Given that tumors with microsatellite instability have high mutation burdens and dense immune infiltrates that are characteristic of other tumor types that respond to immune-checkpoint inhibition, enthusiasm is high for testing inhibitors of PD-1 (programmed death 1) or PD-L1 (programmed death ligand 1) in the subset of mucinous ovarian cancers with microsatellite instability.

Important questions remain regarding the management of high-risk, localized mucinous ovarian cancer (stage I infiltrative subtype or stage IC expansile subtype). What are the criteria for selecting patients with high-risk stage I disease for adjuvant treatment? What is an ideal cytotoxic regimen? Will therapy that has some activity against gastrointestinal tumors have meaningful activity against mucinous ovarian cancer? In the future, targeted therapy may be worth testing in patients who have mucinous ovarian cancer with selected genetic alterations such as HER2 mutations or microsatellite instability. The rarity of the tumor mandates international collaboration to evaluate new therapies in a timely fashion.

In line with these questions, the Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup identified four key areas for further research in mucinous ovarian cancer: improvement in the histologic criteria for diagnosis, definition of the optimal surgical and medical approaches to the management of high-risk localized disease, identification of an active cytotoxic regimen, and enrollment of patients in clinical trials of new therapeutics An 18-year-old man presented to the emergency department with generalized tonic–clonic seizures. His parents reported that he had been having pain in the right groin for 1 week. On physical examination, the patient was confused. He had swelling over the right eye and tenderness in the right testis. Magnetic resonance imaging of the head showed numerous well-defined cystic lesions throughout the cerebral cortex (Panel A) and the brain stem and cerebellum (Panel B) that were consistent with neurocysticercosis. Well-defined cysts that contained echogenic nodules were seen on ultrasonography of the eye and the right testis. Western blot analysis and enzyme-linked immunosorbent assay showed positive results for serum cysticercosis IgG antibody. In the context of high cyst burden, treatment with antiparasitic medications can worsen inflammation and cerebral edema, and in the presence of ocular lesions, inflammation can lead to loss of vision. Therefore, antiparasitic medications were not administered in this case. Despite treatment with dexamethasone and antiepileptic medications, the patient died 2 weeks later. A 61-year-old woman presented to the emergency department with acute onset of diffuse abdominal pain and a 1-week history of diarrhea and vomiting. Her medical history included chronic obstructive pulmonary disease, which was being treated with an inhaled glucocorticoid and a long-acting β-agonist. On examination, the abdomen was distended and diffusely tender, with guarding. Computed tomography of the abdomen revealed large amounts of free air (Panel A, arrow) and extraluminal gas in the wall of the small bowel (Panel B, arrow). Emergency laparotomy was performed, and gas-filled, thin-walled, cystlike structures were seen throughout most of the small bowel (Panel C). Examination of the bowel ruled out a perforation, and the bowel was not resected. The pathophysiology of pneumatosis cystoides intestinalis is poorly understood. Cyst rupture can produce pneumoperitoneum and peritoneal irritation. Radiographic findings of pneumoperitoneum and gas within the bowel wall can be associated with a number of conditions, ranging from non–life- threatening causes, as in this case, to surgical emergencies such as ischemic bowel, depending on the clinical scenario. Within 15 months after presentation, the patient returned with a similar episode of abdominal pain, which was treated nonoperatively. At follow-up 2 years after surgery, the patient remained well. Case 10-2019: A 69-Year-Old Man with Progressive Dyspnea Ten years before this evaluation, the patient noticed labored breathing with activity, initially while he was climbing stairs and then while he was walking on level ground. He was evaluated at another hospital with a treadmill stress test and transthoracic echocardiography; the results of both studies were reportedly normal. The dyspnea abated, and the patient was in his usual state of health until 30 months before this evaluation, when fatigue, malaise, sore throat, rhinorrhea, and arthralgias, including arm and chest pain, developed. He sought attention in the emergency department of the other hospital. The hemoglobin level was 13.6 mg per deciliter (reference range, 14.0 to 18.0). Levels of electrolytes and creatinine, results of liver-function tests, and the white-cell and platelet counts were normal.

Initial Imaging Studies of the Chest, Other Hospital. A posteroanterior chest radiograph (Panel A) shows multiple subcentimeter nodular opacities in the upper lobes. Axial images obtained during chest CT (Panels B and C) show diffuse bilateral subpleural reticular opacities without honeycombing or traction bronchiectasis, as well as a mildly enlarged low right paratracheal lymph node (measuring 11 mm in short axis; Panel B, arrowhead). Axial images of the upper, middle, and lower lungs obtained during pulmonary CT angiography (Panels D, E, and F, respectively) show persistent subpleural reticulations with new traction bronchiolectasis (Panel E, arrows) and bilateral lobular areas of air trapping (Panels D and F, arrows). The additional ground-glass opacities may be attributed to low lung volumes. Seventeen months before this evaluation, the patient was seen by his primary care physician at the other hospital for a several-week history of rhinorrhea and a cough that was intermittently productive of green sputum. A radiograph of the sinuses showed opacification of the right frontal sinus but no evidence of sinusitis. Twelve months before this evaluation, the patient reported the insidious onset of exertional dyspnea, which he had first noticed while he was climbing several flights of stairs. The dyspnea had progressed and occurred with less exertion. He had traveled to Denver and felt increased dyspnea at the high altitude. Six months before this evaluation, a nuclear stress test with myocardial perfusion imaging, performed because of several weeks of persistent exertional dyspnea, revealed a small area of distal anterior ischemia. Three months later, transthoracic echocardiography, performed because of ongoing dyspnea, revealed a left ventricular ejection fraction of 70%, mild concentric left ventricular hypertrophy, mild aortic dilatation, and no evidence of valvular disease; the right ventricular systolic pressure could not be estimated. Two weeks before this evaluation, the patient was evaluated by a pulmonologist at the other hospital. Pulmonary-function testing revealed a forced expiratory volume in 1 second

(FEV1) of 2.50 liters (82% of the predicted value), a forced vital capacity (FVC) of 2.90 liters (73% of the predicted value), and a ratio of FEV1 to FVC of 0.86; there was no change with the administration of a bronchodilator. The total lung capacity was 3.92 liters (61% of the predicted value), and the carbon monoxide diffusion capacity (corrected for hemoglobin level) was 45% of the predicted value. Interstitial lung disease In approaching the diagnosis, I start with a simplified division of interstitial lung diseases into three broad categories: intrinsic, including systemic and familial disease; extrinsic, including disease related to exposures such as environmental substances,4 radiation, or drugs; and idiopathic, including idiopathic pulmonary fibrosis and other uncommon diseases that are defined by their histologic patterns. On the basis of the features of this patient’s presentation, I think the most likely diagnosis is connective-tissue disease– associated interstitial lung disease, sarcoidosis, hypersensitivity pneumonitis, or idiopathic pulmonary fibrosis. Connective-Tissue Disease–Associated Interstitial Lung Disease Connective-tissue diseases associated with interstitial lung disease include rheumatoid arthritis, systemic sclerosis, polymyositis, dermatomyositis, and mixed connective-tissue disease. Interstitial lung disease also occurs with ANCA-associated vasculitis, especially when myeloperoxidase antibodies are detected. Sarcoidosis Rarely diagnosed in patients older than 70 years of age, sarcoidosis is characterized by the accumulation of epithelioid granulomas throughout the body. Asymptomatic thoracic lymphadenopathy is a common manifestation of sarcoidosis, but lung fibrosis occurs in less than 20% of patients. Hypersensitivity Pneumonitis Hypersensitivity pneumonitis arises from an aberrant immune response to inhaled antigens. Acute hypersensitivity pneumonitis causes fever and productive cough approximately 4 to 5 hours after exposure, and chronic hypersensitivity pneumonitis causes insidious dyspnea and dry cough that lasts at least 6 months. Idiopathic Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a fatal disease of progressive lung fibrosis. Almost all patients with idiopathic pulmonary fibrosis are older than 50 years of age, and presentation with fibrotic interstitial lung disease at an age above 69 years is highly predictive of this diagnosis. The incidence is increased among smokers. Diagnosis begins with ruling out systemic diseases and exposures associated with lung fibrosis. High-resolution chest CT is then performed to assess for the typical pattern on imaging, which is usual interstitial pneumonia. This patient’s age, symptoms, and history of smoking were consistent with idiopathic pulmonary fibrosis, and he had no clinical or imaging findings that would suggest other diagnoses. His findings on CT were indeterminate for usual interstitial pneumonia, according to the criteria. Subsequent High-Resolution CT Scan, This Hospital. Four months after presentation to this hospital, high-resolution CT was performed. Axial images obtained with the patient in the prone position (Panels A, B, and C) and axial images obtained with the patient in the supine position during the expiratory phase (Panels D, E, and F) show progression of the subpleural reticular opacities in all the lobes, without honeycombing. There is progression of traction bronchiectasis and bronchiolectasis (Panel B, arrows), and there are persistent bilateral lobular areas of air trapping (Panels D and F, arrows). Lung-Biopsy Specimen. Hematoxylin and eosin staining of a lower-lobe specimen was performed. Panel A shows triangular scarring beneath the pleura (arrows), with evidence of normal lung (NL). Panel B shows ectatic, rounded air spaces in the scarring beneath the pleura (P) that are consistent with honeycomb change. Panel C shows honeycomb change with modest inflammation and distorted anatomy, with no evidence of normal lung. Panel D shows two active fibroblastic foci, composed of myxoid collagen with proliferating spindle cells, adjacent to dilated bronchioles. Panel E shows another active fibroblastic focus in a gross lung specimen, abutting ectatic air space, near a normal bronchiole. Panel F shows myxoid metaplasia, with adipocytes replacing interstitium. Until 2014, there were no effective treatments for idiopathic pulmonary fibrosis aside from lung transplantation. A major breakthrough in the management of idiopathic pulmonary fibrosis occurred when the results of two large randomized, controlled trials showed the efficacy of antifibrotic therapies — pirfenidone and nintedanib — in reducing the decline in FVC. Similar to this patient, the patients who were included in these trials had mild-to-moderate disease, as determined by the degree of physiological impairment on pulmonary-function testing. On the basis of currently available evidence, the two medications are considered to be equally efficacious in slowing disease progression, with the choice of specific therapy often depending on patient preference regarding potential side effects. Pirfenidone is a medication used for the treatment of idiopathic pulmonary fibrosis. It works by reducing lung fibrosis through downregulation of the production of growth factors and procollagens I and II. Nintedanib is an oral medication used for the treatment of idiopathic pulmonary fibrosis and along with other medications for some types of non-small-cell lung cancer. It is a small molecule tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet derived growth factor receptor. In this patient, after discussions regarding the side-effect profiles of the two medications, pirfenidone therapy was started, with a dose escalation over a period of 3 weeks to the standard dose of 801 mg three times a day. Ivabradine in Catecholamine-Induced Tachycardia in a Patient with Paraganglioma Paraganglioma-related clinical sequelae result from catecholamine secretion that can cause hypertension, tachyarrhythmia, multiorgan failure, and death. Radiolabeled lutetium-177 (177Lu)–Dotatate (Lutathera) is a systemic therapy administered as a 30-to-60-minute intravenous infusion at a dose of 7.4 GBq (200 mCi) every 8 weeks for four cycles. After binding as a somatostatin analogue to overexpressed somatostatin receptors on a tumor, 177Lu-Dotatate undergoes radioactive decay, releasing beta particles that subsequently lead to cellular disruption; this disruption causes profound catecholamine release. A pharmacologic catecholamine blockade is achieved with α-adrenoceptor and β-adrenoceptor blockers, calcium-channel blockers, or both, with or without a catecholamine synthesis inhibitor, metyrosine. Studies of other medications for catecholamine-induced sinus tachycardia are limited. We report the case of a 54-year-old man with an inoperable metastatic paraganglioma in whom systemic targeted radiotherapy with 177Lu-Dotatate was indicated. He had hypertension and tachycardia that were well controlled with the use of phenoxybenzamine, metoprolol, and metyrosine, and his cardiac status (ejection fraction, 60%) and functional status (New York Heart Association class I) were excellent. Before the initiation of treatment with 177Lu-Dotatate, his plasma norepinephrine level was 20,500 pg per milliliter (normal range, 84 to 794; 121 nmol per liter [normal range, 0.5 to 4.7]), and his plasma epinephrine level was less than 20 pg per milliliter (normal range, 0 to 57; <109 pmol per liter [normal range, 0 to 311.2]). After one cycle of 177Lu-Dotatate, he had hypertension and tachycardia, and he received occasional 5-mg phentolamine intravenous pushes, esmolol at a dose of 200 μg per kilogram of body weight per minute, labetalol at a dose of 2 mg per minute, and diltiazem at a dose of 15 mg per hour to establish circulatory control. Despite adequate medical management, the tachycardia and hypertension became resistant to treatment. As predicted, the norepinephrine level increased, reaching 172,000 pg per milliliter (1020 nmol per liter). Subsequently, systolic heart failure (ejection fraction, 30%) and acute kidney injury developed. Persistent tachycardia despite maximum doses of β- adrenoceptor and calcium-channel blockers, as well as metyrosine, warranted immediate consideration of additional rate-control medications. Ivabradine, which has an excellent safety profile and benefit in patients with heart failure, was administered orally at a dose of 5 mg twice daily. Heart-rate control was achieved with a decrease in the maximal pulse from 143 beats per minute on the day before administration of ivabradine to 92 beats per minute on the third day of ivabradine use. When the dose of ivabradine was tapered to 2.5 mg twice a day, tachycardia developed, and the patient was therefore sent home with instructions to take the drug at a dose of 5 mg twice a day. His cardiac function improved, and the ejection fraction increased to 45%. Because of the patient’s clinical course, subsequent 177Lu-Dotatate cycles were deferred. Sites of Action for Heart-Rate Control in Catecholamine- Induced Tachycardia. As shown in Panel A, heart rate is controlled by the autonomic nervous system, and the sinoatrial (SA) node acts as the pacemaker. Sinus tachycardia that results from elevated levels of catecholamines released from paragangliomas is one of the most prevalent cardiovascular manifestations of these tumors. Norepinephrine, epinephrine, or both are released from sympathetic nerve terminals, the adrenal medulla, or catecholamine-secreting tumors and bind to β1-adrenoceptors, β2-adrenoceptors, or both in the heart. A subsequent cascade results, wherein a β-adrenoceptor coupled with Gs-protein activates adenylate cyclase, which increases cyclic AMP (cAMP) levels and promotes ion-channel permeability, thereby increasing node activity, automaticity, and conduction velocity and leading to sinus tachycardia. AV denotes atrioventricular, DOPA 3,4-dihydroxyphenylalanine, and HCN hyperpolarization-activated, cyclic nucleotide–gated. As shown in Panel B, traditional treatment options for sinus tachycardia include β-adrenoceptor and calcium-channel blockers, which provide negative chronotropic effects on the SA node, depression of the AV node, and decreased conduction velocity and contractility in cardiomyocytes. I As shown in Panel C, a new drug, ivabradine, works by targeting the If current in the SA node through intracellular blockade of the HCN channel, leading to reduced diastolic depolarization of the pacemaker action potential and thus decreasing the heart rate. In this manner, despite β-adrenoceptor activation and cAMP production, an electrical impulse would not be generated because of If current blockade. Ivabradine acts solely on the SA node; therefore, catecholamine effects on the AV node and cardiomyocytes would not be mitigated by this drug. Nevertheless, the regulation of the intrinsic pacemaker in the SA node is paramount in heart-rate control. Mini-gastric bypass/One-anastomosis gastric bypass (MGB-OAGB) is an effective bariatric technique for treating overweight and obesity, controlling and improving excess-weight-related comorbidities.

HCO3 = 24

In Berlin: PA O2 = 150 – PaCO2 x 1,25 = 115 – 54 = A/a Gradient 61 Sättigung wird mit O2 nicht besser!