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A 54-year-old man presented to the oral and maxillofacial clinic with a 2-month history of difficulty chewing his food. He reported a painless brown lesion had grown on his tongue in the center of a white patch that had been present for

• years. Examination of the oral cavity

revealed a well-circumscribed hard mass, measuring 8 mm by 7 mm and surrounded by a white patch on the right side of the tongue. What is the most likely diagnosis? Dermoid cyst Oral candidiasis Lipoma Spindle-cell sarcoma Tongue mucocele An incisional biopsy revealed a high-grade, undifferentiated spindle-cell sarcoma. This is a rare connective-tissue tumor that can grow rapidly. The patient underwent surgery and received adjuvant

• chemotherapy. At follow up 1 year after the completion
• f chemotherapy, he had no evidence of recurrence.

Die Dermoidzyste ist ein Hohlraum, der von Oberhautgewebe ausgekleidet ist. Die Dermoidzyste gehört zu den Teratomen. Sie ist ein Keimzelltumor, ein reifes Teratom, das aus vollkommen verschiedenen Gewebearten besteht. Daher kann es innerhalb der Dermoidzyste zur Ausbildung von Gewebestrukturen wie Muskulatur, Knorpel, kleinen Knochen, Haaren und auch völlig ausgebildeten Zähnen kommen. Obwohl Dermoidzysten überall auftreten können, sind nachstehende Vorkommen vergleichsweise häufig: Eierstock, periorbitale Dermoidzysten, spinale Dermoidzysten, Hoden.

Dermoidzyste im transvaginalen Ultraschall Gewebe mit Zähnen, Haut und Haaren aus einem Teratom des Eierstocks.

Eine Pilzinfektion der Mundhöhle ist eine Erkrankung, die man auf den ersten Blick nicht unbedingt erkennt. Sie ist selten gefährlich, nicht unbedingt schmerzhaft, kann aber sehr unangenehm sein und die Lebensqualität stark beeinträchtigen. Die Infektion wird durch Hefepilze – die sogenannten Candida-Hefen – hervorgerufen, die auf den Schleimhäuten der Mundhöhle siedeln. Daher stammen die Bezeichnungen orale Candidose (Kandidose) oder

• rale Candidiasis. Manchmal wird sie auch „Mundsoor“
• genannt. Der häufigste Erreger ist Candida albicans.

Ein Lipom, auch als gutartige Fettgeschwulst bezeichnet, ist ein gutartiger Tumor der Fettgewebszellen (Adipozyten). Die Lipome des Weichgewebes können in oberflächlich und tieferliegend eingeteilt werden. Die oberflächlichen Lipome treten subkutan auf und haben einen Anteil von 16 bis 50 Prozent an allen Weichteiltumoren. Sie treten meist in der fünften bis siebten Lebensdekade auf. Tiefsitzende Lipome sind mit einem Anteil von 1 bis 2 Prozent wesentlich seltener als oberflächliche. Da tiefsitzende Lipome nur selten klinisch relevant werden und meist nur ein Zufallsbefund einer radiologischen Untersuchung sind, gehen einige Autoren von einer deutlich höheren Prävalenz aus. Tiefsitzende Lipome in den Extremitäten sind meist intra- oder intermuskulär. Sie werden auch oft infiltrierende Lipome genannt. Diese Form von Lipomen tritt meist bei Patienten im Alter zwischen 30 und 60 Jahren im Bereich der unteren Extremitäten (45 Prozent), des Rumpfes (17 Prozent), der Schulter (12 Prozent) und der oberen Extremitäten (10 Prozent) auf. Die Ursachen und die Entstehung von Lipomen sind nach heutigem Wissensstand noch nicht gesichert. Möglicherweise sind sie das Resultat einer abnormalen Entwicklung von primitiven pluripotenten mesenchymalen Zellen, die sich normalerweise in Adipozyten differenzieren.

Weichteilsarkome sind bösartige (maligne) Tumoren (Sarkome), die dem Weichteilgewebe des Körpers entspringen. Sie sind eine relativ seltene Krebsform, bei Kindern und Jugendlichen ist ihr Anteil jedoch relativ groß. Die Therapie hängt von der Art und Klassifizierung des jeweiligen Tumors ab und reicht von

• perativer Entfernung bis zu Bestrahlung und Chemotherapie.

Weichteilsarkome sind relativ seltene Neoplasien. Sie sind mesenchymalen Ursprungs. In den USA stellen sie 0,7 % aller Krebsneuerkrankungen dar. Man findet sie quer durch alle Altersgruppen mit einer überproportionalen Inzidenz im

• Kindesalter. In der Kindheit stellen sie 5–7 % aller

Krebserkrankungen dar. Etwa jedes siebte Sarkom wird bei Kindern unter 15 Jahren diagnostiziert. Weichteilsarkome sind neben den ZNS-Malignomen die zweite große Gruppe von soliden Tumoren in der Pädiatrie, und gehören dort zu den fünfthäufigsten Krebstodesursachen. 40 % aller Krebsneuerkrankungen ereignen sich jenseits des 55.

• Lebensjahrs. Die Inzidenz liegt zurzeit bei etwa 2–3/100.000 pro

Jahr. Rhabdomyosarkome entstehen aus unreifen mesenchymalen

• Zellen. Histologisch findet man Komponenten quergestreifter

Muskulatur. Leiomyosarkome haben histologisch Komponenten von glatter

• Muskulatur. Eine typische Ursprungsstruktur ist die Gebärmutter.

Das Liposarkom ist ein maligner Fettgewebstumor. Es kommt meist in tiefen Weichteilen und im Retroperitoneum vor. Fibrosarkom Malignes Fibröses Histiozytom Synovialsarkom maligne vaskuläre Tumoren (Angiosarkom, malignes Hämangioperizytom u. a.) seltene Formen (alveoläres Weichteilsarkom; Cystosarcoma phylloides der Brust)

Spindelzellsarkom am rechten Hinterbein

An 8-year-old boy was referred for evaluation of a mass in the midline of the ventral surface of the anterior

• tongue. The lesion had fluctuated in size since it was first noted 4 months earlier. He was otherwise

asymptomatic, and his medical history revealed that he habitually bit his tongue. Examination of the tongue revealed a nontender, smooth-walled, translucent, bluish, fluctuant mass of approximately 8 mm in diameter that was resting on an opalescent base. The mass was diagnosed as a mucocele of the salivary glands (glands of Blandin and Nuhn). Commonly found in children, mucoceles develop when a salivary-gland duct is severed and secreted salivary mucin accumulates in the surrounding tissue. Historically, repetitive cheek or lip biting is a finding very commonly associated with this condition. Mucoceles may occur anywhere in the mouth where salivary glands exist, such as the lower lip, buccal mucosa, tongue, or oral floor. When discovered on the retromolar pad, they must be biopsied to distinguish them from mucoepidermoid

• carcinoma. In this case, the mucocele was excised and has not recurred.

Khorana score (Risk of thromboembolism in cancer patients)

Apixaban to Prevent Venous Thromboembolism in Patients with Cancer

Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care

• expenditures. The Khorana score (range, 0 to 6, with

higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis. We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy

• utcome was objectively documented venous

thromboembolism over a follow-up period of 180

• days. The main safety outcome was a major bleeding

episode. The mean age of the patients was 61 years, and the majority of patients (58.2%) were women. The most common types of primary cancer were gynecologic (25.8%), lymphoma (25.3%), and pancreatic (13.6%). A total of 131 patients (22.8%) were using antiplatelet

• r nonsteroidal antiinflammatory therapy. The number
• f patients with solid tumors who had metastatic

disease was 73 in the apixaban group and 67 in the placebo group.

In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P=0.046). The competing-risk analysis that accounted for deaths from causes other than venous thromboembolism

• r bleeding was consistent with the primary analysis (hazard ratio, 0.42; 95% CI, 0.27 to 0.65). The

adjusted odds ratio for venous thromboembolism associated with the use of apixaban as compared with placebo was 0.39 (95% CI, 0.20 to 0.76).

The competing-risk analysis that accounted for deaths from causes other than venous thromboembolism or bleeding was consistent with the primary analysis (hazard ratio, 0.42; 95% CI, 0.27 to 0.65). The adjusted

• dds ratio for venous thromboembolism associated with the use of apixaban as compared with placebo was

0.39 (95% CI, 0.20 to 0.76). During the treatment period, the primary outcome occurred in 3 of 288 patients (1.0%) in the apixaban group and in 20 of 275 patients (7.3%) in the placebo group (hazard ratio, 0.14; 95% CI, 0.05 to 0.42). During the additional 30 days of follow-up after day 180, 1 patient in the apixaban group had deep-vein thrombosis and 1 in the placebo group died from pulmonary embolism.

A total of 3 of the 15 major bleeding episodes were considered to be a clinical emergency, and no bleeding into critical organs was noted. During the treatment period, major bleeding occurred in 6 of 288 patients (2.1%) in the apixaban group and in 3 of 275 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24). Adverse events were reported in 131 patients in the apixaban group and 127 patients in the placebo group; only 1 event in the apixaban group and 2 events in the placebo group were classified as being related to the trial regimen.

The AVERT trial showed that thromboprophylaxis with apixaban resulted in a significantly lower rate of venous thromboembolic complications than placebo among ambulatory patients with cancer who were starting chemotherapy and had a Khorana score of 2 or higher. Venous thromboembolism in patients with cancer who are receiving chemotherapy has a substantial effect on care, including an increase in health care expenditure and a negative effect on quality

• f life. Furthermore, the treatment of venous thromboembolism with therapeutic

anticoagulation is challenging in patients with cancer because it often involves daily injections

• f low-molecular-weight heparin and is associated with a high risk of thrombosis recurrence

and serious bleeding complications. Coexisting conditions that are common in this context, such as thrombocytopenia and renal impairment, as well as the use of concomitant antiplatelet therapy (in 22.8% of our patients), further increase the risk of bleeding among patients with

• cancer. Therefore, prevention of venous thromboembolic complications is important and

clinically relevant. As with all trials of thromboprophylaxis involving patients with cancer, between-trial comparisons can be biased owing to differences in tumor types in patients enrolled in the trial. We had a high proportion of patients with gynecologic, lymphoma, or pancreatic tumors and very few patients with colorectal or prostate cancers. However, this is expected, because these latter tumors are not recognized as posing a high risk of venous thromboembolism according to the Khorana score. Each participating center in Canada provides comprehensive cancer care in their respective region, and patients with all tumor types were assessed for eligibility and enrollment, so we believe that our results are generalizable to a broad spectrum of patients with cancer who received different types of cancer treatment. However, owing to the sample size, we have limited ability to make definitive conclusions about outcomes associated with individual tumor types or individual chemotherapy regimens. Finally, only 5.9% of patients had renal dysfunction as defined by a creatinine clearance of 50 ml or less per minute, so our results may be less applicable to patients with renal dysfunction, who are known to have a higher risk of bleeding than patients with normal renal function.

Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer

Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain. In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk

• f venous thromboembolism), we randomly assigned

patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding. Patients were included if they were 18 years

• f age or older, were ambulatory outpatients with a solid

tumor or lymphoma, had a Khorana score of 2 or higher at baseline, and had an expected survival of more than 6 months with a plan to start a new systemic regimen within 1 week before or after initiating the trial regimen. Patients were excluded if they had a primary brain tumor or known brain metastases, an Eastern Cooperative Oncology Group performance-status score of 3 or more (on a 5-point scale, with higher numbers indicating greater disability), or active bleeding or were at risk for bleeding.

The primary efficacy composite end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P=0.10) in the observation period up to day 180, which was the primary

• analysis. Of the 62 patients who had a primary

end-point event, 24 (39%) did so after the discontinuation of the trial regimen. In the prespecified analysis involving the same population (all the patients who had undergone randomization) with assessment during the intervention period, the primary efficacy end point

• ccurred in 11 of 420 patients (2.6%) in the

rivaroxaban group and 27 of 421 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). In addition to primary end-point events, arterial thromboembolism occurred in 4 of 420 patients (1.0%) in the rivaroxaban group and in 7 of 421 (1.7%) in the placebo group. A prespecified analysis of the composite of the primary end point with the addition of arterial and visceral thromboembolic events in the period up to day 180 showed that the incidence of events was lower in the rivaroxaban group than in the placebo group.

Major bleeding occurred in 8 of 405 patients (2.0%) receiving rivaroxaban and in 4 of 404 (1.0%) receiving placebo (hazard ratio, 1.96; 95% CI, 0.59 to 6.49). Sites of major bleeding included gastrointestinal sites in 8 patients, intraocular sites in 2 patients, and intracranial sites in 2 patients. Clinically relevant nonmajor bleeding occurred in 2.7% of the patients in the rivaroxaban group and in 2.0% of those in the placebo group (hazard ratio, 1.34; 95% CI, 0.54 to 3.32). There was one fatal bleeding event, which occurred in the rivaroxaban group.

We compared the use of rivaroxaban with placebo for primary thromboprophylaxis in ambulatory patients with cancer who were at high risk for venous thromboembolism and were initiating a new systemic cancer

• therapy. The design specified a primary intention-to-treat analysis of the period up to day 180, regardless of

whether events occurred after discontinuation of the trial regimen. Although the primary end point occurred in a lower percentage of patients who had been randomly assigned to the rivaroxaban group in this analysis, the difference was not significant. In a prespecified supportive analysis involving the same population but assessing the more conventional period of during the intervention, we found a difference of 4 percentage points in favor of rivaroxaban over placebo with regard to the primary composite end point of venous thromboembolism and venous thromboembolism–related death.

Direct Oral Anticoagulants for Thromboprophylaxis in Ambulatory Patients with Cancer (N Engl J Med editorial)

In two large, randomized, placebo-controlled trials and a comprehensive meta-analysis, all involving ambulatory patients with different types of metastatic or locally advanced solid cancer who were receiving chemotherapy, low-molecular-weight heparins were associated with an approximately 50% lower risk of symptomatic venous thromboembolism than placebo. The incidence of symptomatic venous thromboembolism in the placebo group and the absolute difference in risk between the trial groups were considered too low to recommend antithrombotic prophylaxis. Several international guidelines suggest that antithrombotic prophylaxis be considered only in high-risk patients. When considered together, the two trials in this issue showed a significant benefit of direct oral anticoagulants for the prevention of venous thromboembolism, with a low incidence of major bleeding. The findings related to bleeding are quite reassuring, given the increase in bleeding observed with apixaban and rivaroxaban in studies on the prophylaxis of venous thromboembolism involving medical patients without cancer. Indeed, when the results of the two studies are combined, the absolute difference in the incidence of symptomatic venous thromboembolism between the active-drug group and the placebo group in the primary intention-to-treat analysis was 2.5 percentage points, which corresponds to a number needed to treat of 40 patients.

Plazomicin is a next-generation aminoglycoside ("neoglycoside") antibacterial derived from sisomicin by appending a hydroxy-aminobutyric acid (HABA) substituent at position 1 and a hydroxyethyl substituent at position 6‘. Plazomicin has been reported to demonstrate in vitro synergistic activity when combined with daptomycin or ceftobiprole versus methicillin- resistant Staphylococcus aureus (MRSA), vancomycin- resistant S. aureus (VRSA) and against Pseudomonas aeruginosa when combined with cefepime, doripenem, imipenem or piperacillin/tazobactam. It also demonstrates potent in vitro activity versus carbapenem-resistant Acinetobacter baumannii. Indicated for complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible microorganism(s): Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae Limited clinical safety and efficacy data are currently available, reserve treatment for use in cUTI patients who have limited or no alternative treatment options 15 mg/kg IV q24hr infused over 30 minutes Duration of therapy should be guided by the severity of infection and the patient’s clinical status for up to 7 days; usual duration 4-7 days. An appropriate oral therapy may be considered after 4-7 days of therapy to complete a total duration of 7-10 days (IV plus oral); maximum duration of therapy for cUTI is 7 days. Die Aminoglykosid-Antibiotika wirken ausgeprägt konzentrationsabhängig stark bakterizid durch Hemmung der Proteinbiosynthese bei sich teilenden und nicht-teilenden Erregern, indem sie an die 30S-Untereinheit der Ribosomen ankoppeln.

Once-Daily Plazomicin for Complicated Urinary Tract Infections

The increasing multidrug resistance among gram- negative uropathogens necessitates new treatments for serious infections. Plazomicin is an aminoglycoside with bactericidal activity against multidrug-resistant (including carbapenem-resistant) Enterobacteriaceae. We randomly assigned 609 patients with complicated urinary tract infections (UTIs), including acute pyelonephritis, in a 1:1 ratio to receive intravenous plazomicin (15 mg per kilogram of body weight once daily) or meropenem (1 g every 8 hours), with optional

• ral step-down therapy after at least 4 days of

intravenous therapy, for a total of 7 to 10 days of

• therapy. The primary objective was to show the

noninferiority of plazomicin to meropenem in the treatment of complicated UTIs, including acute pyelonephritis, with a noninferiority margin of 15 percentage points. The primary end points were composite cure (clinical cure and microbiologic eradication) at day 5 and at the test-of-cure visit (15 to 19 days after initiation of therapy) in the microbiologic modified intention-to-treat population. Plazomicin is an aminoglycoside that is engineered to evade modification by aminoglycoside-modifying enzymes, and it maintains activity in the presence of most mechanisms that lead to resistance in Enterobacteriaceae, including mutations in sites targeted by fluoroquinolones and the production of aminoglycoside-modifying enzymes, extended- spectrum β-lactamases, and carbapenemases.

At day 5, composite cure was observed in 88.0% of the patients (168 of 191 patients) in the plazomicin group and in 91.4% (180 of 197 patients) in the meropenem group (difference, –3.4 percentage points; 95% confidence interval [CI], –10.0 to 3.1). At the test-of-cure visit, composite cure was observed in 81.7% (156 of 191 patients) and 70.1% (138 of 197 patients), respectively (difference, 11.6 percentage points; 95% CI, 2.7 to 20.3). The lower limit of the 95% confidence interval for the between-group difference in the rate of composite cure at the test-of- cure visit exceeded zero.

During the trial, 21 of 300 patients (7.0%) in the plazomicin group and 12 of 297 patients (4.0%) in the meropenem group had an increase in serum creatinine level of 0.5 mg or more per deciliter above the baseline level. Of these, the increase occurred after completion of intravenous therapy in 10 of 300 patients (3.3%) in the plazomicin group and in 3 of 297 patients (1.0%) in the meropenem group; of the 10 patients in the plazomicin group who had serum creatinine increases after completion of intravenous therapy, 9 had had moderate renal impairment at baseline. In general, increases were less than 1.0 mg per deciliter (<80 µmol per liter) from baseline and returned to less than 0.5 mg per deciliter from the baseline value by the last follow-up. Among patients in the plazomicin group, risk factors for an increase in serum creatinine level of 0.5 mg or more per deciliter were moderate renal impairment (14 of 21 patients) and receipt of plazomicin therapy for more than 5 days (12 of 21 patients); 8 of 21 patients had both risk factors. Potentially ototoxic events were identified in 2 patients (1 in each group). Serious adverse events were reported in 1.7% of patients in each treatment group.

In the EPIC trial, plazomicin was noninferior to meropenem in the treatment of patients with complicated UTIs, including acute pyelonephritis, with higher rates of microbiologic eradication and composite cure observed at the test-of-cure visit in the plazomicin group than in the meropenem group. The lower incidence of microbiologic recurrence and clinical relapse in the plazomicin group than in the meropenem group at late follow-up suggests that the greater microbiologic eradication with plazomicin has additional clinical benefit for patients with complicated UTIs, including acute pyelonephritis. This trial assessed possible nephrotoxicity through analyses of adverse events and changes in serum creatinine level as markers of decreased renal function. Because published reports

• f clinical trials of other aminoglycosides do not systematically include analyses of serum

creatinine levels after completion of treatment, an important finding in this trial was that a small number of patients in the plazomicin group had increases in serum creatinine levels approximately 1 week after completion of therapy. The proportion of patients who received oral step-down therapy with levofloxacin despite having a baseline pathogen that was not susceptible to levofloxacin was similar in the two treatment groups, which therefore minimized the possible effect on the test-of-cure results. The majority of these patients received the intravenous trial drug for the prespecified maximum duration. Subgroup analyses showed that composite cure rates were higher among patients who received meropenem plus oral step-down therapy than among patients who received meropenem alone. The rates of composite cure were more consistent in the subgroups of patients who received plazomicin, which suggests that the higher rate of composite cure with plazomicin than with meropenem observed at the test-of-cure visit was not confounded by a switch to oral therapy.

Plazomicin for Infections Caused by Carbapenem-Resistant Enterobacteriaceae

Mortality among patients with infections caused by carbapenem-resistant Enterobacteriaceae (CRE) is high, and such infections have few treatment options. We report results from the Combating Antibiotic-Resistant Enterobacteriaceae trial (CARE; ClinicalTrials.gov number, NCT01970371), a pathogen-focused trial designed according to Food and Drug Administration guidance for the treatment of patients with an unmet medical need. The CARE trial evaluated the efficacy and safety of plazomicin as compared with colistin as part of a combination-therapy regimen for serious CRE infections. This multicenter, randomized, open-label trial was conducted from September 16, 2014, to September 15, 2016. Eligible patients with bloodstream infection or hospital-acquired or ventilator-associated bacterial pneumonia caused by suspected or confirmed CRE were randomly assigned, in a 1:1 ratio, to receive plazomicin (15 mg per kilogram of body weight once daily) or colistin (5 mg colistin base per kilogram per day), in combination with adjunctive meropenem or tigecycline, for 7 to 14 days of therapy. The primary end point was a composite of death from any cause at 28 days or clinically significant disease-related complications in the microbiologic modified intention-to-treat population, which included patients with confirmed CRE infection who received at least one dose of a trial drug. The trial was stopped prematurely because of slow enrollment. Owing to the small sample size, no formal hypothesis testing was performed. Two-sided 95% exact confidence intervals are provided for descriptive purposes.

Needed: Antimicrobial Development

In this issue of the Journal, Wagenlehner et al. and McKinnell et al. report the results of two clinical trials designed to evaluate plazomicin, an aminoglycoside that was developed to target a range of antimicrobial- resistant organisms including carbapenem-resistant Enterobacteriaceae. The trial by Wagenlehner et al., in patients with complicated urinary tract infections (UTIs), achieved full enrollment and was central in evaluating the efficacy and safety profile of plazomicin for the treatment of complicated UTIs. The trial by McKinnell et al. enrolled patients with serious infections (involving the bloodstream or nosocomial pneumonia) caused by carbapenem-resistant Enterobacteriaceae. It was stopped early because of major challenges with enrollment and provides only descriptive statistics of the findings. This drug development program illustrates some of the major challenges inherent in developing a new antibacterial drug: a clinical trial involving patients with a common infection was successfully conducted, although the need for a new drug in UTIs is limited, whereas a clinical trial in patients who have the greatest need of a new therapeutic option had such slow enrollment that the trial was halted after enrollment of only a fraction of the planned number of patients. More than 2000 patients were screened, but only 39 were enrolled. Although consideration of the degree of unmet need and the severity of the infection is important, good-quality information is essential for understanding how a drug performs in treating the targeted infection. There are a number of instances in which a drug performed well in treating one type of infection but was unexpectedly somewhat ineffective in treating another type of infection. Clinically important efficacy deficits may never be detected if we do not have results from well-conducted clinical trials performed in broad populations of patients.

Sacituzumab govitecan-hziy (IMMU-132; Immunomedics) is an antibody–drug conjugate in which SN-38 (an active metabolite of irinotecan) a topoisomerase I inhibitor, is coupled to the humanized antitrophoblast cell- surface antigen 2 (Trop-2) monoclonal antibody hRS7 IgG1κ through the cleavable CL2A linker. Trop-2, a transmembrane calcium signal transducer, is overexpressed in many epithelial cancers, and it stimulates cancer-cell growth.Trop-2 is detected in breast cancer cells, including those in triple-negative breast cancer, and its expression is reported in more than 85% of tumors. On binding to Trop-2, hRS7 (in free or conjugated form) is internalized and delivers SN-38 into the tumor cell. In addition, because of the cleavable linker, SN-38 is released in tumors both intracellularly and in the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the drug in bystander cells to which the conjugate has not bound. Sacituzumab- bound tumor cells are killed by intracellular uptake of SN-38, and adjacent tumor cells are killed by the extracellular release of SN-38. In 2016, sacituzumab govitecan-hziy was assigned a “breakthrough therapy” designation by the Food and Drug Administration (FDA) for the treatment of patients with metastatic triple- negative breast cancer who have received at least two previous therapies for metastatic disease, and, accordingly, the protocol was amended to require further enrollment in a more defined population of patients with metastatic triple-negative breast cancer who had received at least two lines of previous therapy, including previous taxane therapy. Sacituzumab govitecan is an investigational drug that has not been FDA-approved for disease therapy. Immunomedics announced in 2013 that it had received an FDA fast track designation for the compound as a potential treatment for non-small cell lung cancer, small cell lung cancer, and metastatic triple-negative breast

• cancer. Orphan drug status was granted for small cell lung cancer and pancreatic cancer.[4][need quotation to

verify] In in February 2016, Immunomedics announced that sacituzumab govitecan had received an FDA breakthrough therapy designation (a classification designed to expedite the development and review of drugs that are intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition) for the treatment of patients with triple-negative breast cancer who have failed at least two

• ther prior therapies for metastatic disease.

Topoisomerasen sind Enzyme, die für Änderungen der Topologie von DNA-Molekülen verantwortlich sind, welche bei einer Superspiralisierung notwendig sind. Durch die für die Vorgänge Transkription und Replikation notwendige Entspiralisierung der gerade abgelesenen DNA-Abschnitte kommt es in angrenzenden Bereichen der Helix automatisch zum Positiven supercoiling, einer zu starken Verwindung der DNA-Doppelhelix, die mit Torsionskräften einhergeht.

Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer

Standard chemotherapy is associated with low response rates and short progression-free survival among patients with pretreated metastatic triple- negative breast cancer. Sacituzumab govitecan-hziy is an antibody–drug conjugate that combines a humanized monoclonal antibody, which targets the human trophoblast cell-surface antigen 2 (Trop-2), with SN-38, which is conjugated to the antibody by a cleavable linker. Sacituzumab govitecan-hziy enables delivery of high concentrations of SN-38 to tumors. We conducted a phase 1/2 single-group, multicenter trial involving patients with advanced epithelial cancers who received sacituzumab govitecan-hziy intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxic effects. A total of 108 patients received sacituzumab govitecan-hziy at a dose

• f 10 mg per kilogram of body weight after receiving at

least two previous anticancer therapies for metastatic triple-negative breast cancer. The end points included safety; the objective response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), which was assessed locally; the duration of response; the clinical benefit rate (defined as a complete or partial response or stable disease for at least 6 months); progression-free survival; and overall

• survival. Post hoc analyses determined the response

rate and duration, which were assessed by blinded independent central review.

Characteristics

The 108 patients with metastatic triple-negative breast cancer received a mean of 18.7 doses of sacituzumab govitecan-hziy (range, 1 to 102), or 9.6 cycles (range, 1 to 51), with a median duration of exposure of 5.1 months (range, 0.03 to 36.1). A total of 99 patients (92%) received preinfusion medications (acetaminophen, antihistamines, H2 antagonists, glucocorticoids, antiemetics, anxiolytics, and atropine). The most common adverse events were nausea, diarrhea, fatigue, neutropenia, and anemia, and the most common adverse events of grade 3 or higher (>5% incidence) included neutropenia, anemia, and a decreased white-cell count, as outlined. Serious adverse events were reported in 35 patients (32%); the most common (>2% incidence) were febrile neutropenia (in 7% of the patients), vomiting (in 6%), nausea (in 4%), diarrhea (in 3%), and dyspnea (in 3%). Adverse events leading to interruption of treatment

• ccurred in 48 of the 108 patients (44%); the most

common reason was neutropenia. Three patients (3%) discontinued treatment because of adverse events; 2 patients discontinued because of drug-related events, and 1 patient discontinued because of hypertension, which was thought by the investigator not to be drug-

• related. Transient changes in laboratory safety values

that occurred during treatment included decreases in blood-cell counts and alterations in biochemical values, which generally recovered by the end of treatment.

A waterfall plot (A) shows the breadth and depth of responses according to local assessment in 108 patients with metastatic triple-negative breast cancer. The response rate was 33.3% (36 of 108 patients), including complete responses in 3 patients (2.8%). The clinical benefit rate (including stable disease for at least 6 months) was 45.4% (49 of 108 patients). A swimmer plot (B) shows the onset and durability of response in each of the 36 patients who had an

• bjective response. In these patients, the median time

to response was 2.0 months (range, 1.6 to 13.5), and the median duration of response was 7.7 months (95% confidence interval [CI], 4.9 to 10.8). The response rate (34.3% [95% CI, 25.4 to 44.0]) and median duration of response (9.1 months [95% CI, 4.6 to 11.3]) according to blinded independent review were similar to those determined by local assessment At the time of data cutoff (C), 94 patients (87.0%) had disease progression and 77 patients (71.3%) had died. The median progression-free survival was 5.5 months (95% CI, 4.1 to 6.3); the estimated probability of progression-free survival was 41.9% at 6 months and 15.1% at 12 months. The median overall survival was 13.0 months (95% CI, 11.2 to 13.7); the estimated probability of survival was 78.5% at 6 months and 51.3% at 12 months.

To analyze efficacy in relation to the aggressiveness of the clinical course and to address concerns regarding relatively indolent tumor biologic characteristics in the trial population, we compared the duration

• f treatment with sacituzumab govitecan-hziy with that of previous anticancer treatment in the 108 patients

with metastatic triple-negative breast cancer for whom data were available. The median duration of treatment with sacituzumab govitecan-hziy (5.1 months) was approximately twice that with the previous anticancer treatment (2.5 months); this highlights the clinical activity and lack of cross-resistance with this antibody–drug conjugate.

Among patients with metastatic triple-negative breast cancer who had received at least two previous therapies for metastatic disease (median, three) and who received treatment with sacituzumab govitecan- hziy, the response rate was 33.3%, the median duration

• f response was 7.7 months, the median progression-

free survival was 5.5 months, and the median overall survival was 13.0 months. Efficacy was observed in patients who had received taxanes and anthracyclines, suggesting a lack of cross-resistance to previous cytotoxic chemotherapy. The duration of treatment with sacituzumab govitecan-hziy was longer than with the immediate previous antitumor therapy (5.1 months vs. 2.5 months); this provides further evidence of clinical activity in patients with difficult-to-treat metastatic triple- negative breast cancer. Although a subgroup analysis based on the patients’ age, the onset of metastatic disease, the number of previous therapies, or the presence or absence of visceral metastases showed no meaningful differences in outcomes, the small number

• f patients led to wide confidence intervals, and thus

the homogeneity of clinical outcomes observed in these subgroups is weak and should be interpreted with caution. In conclusion, sacituzumab govitecan-hziy (IMMU-132) had efficacy with a 33% response rate in a heavily pretreated population of patients with metastatic triple- negative breast cancer. Diarrhea and myelosuppression were the primary adverse events, and discontinuation rates were low.

Low-Dose Methotrexate for the Prevention of Atherosclerotic Events

Inflammation is causally related to

• atherothrombosis. Treatment with canakinumab, a

monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate

• f cardiovascular events than placebo in a previous

randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar

• benefit. We conducted a randomized, double-blind

trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point.

Cardiovascular death was confirmed in 49 patients in the methotrexate group and in 43 in the placebo group (incidence rate, 0.92 vs. 0.80 per 100 person-years; hazard ratio, 1.14; 95% CI, 0.76 to 1.72). A total of 96 deaths from any cause occurred in the methotrexate group, and 83 occurred in the placebo group (incidence rate, 1.80 vs. 1.55 per 100 person-years; hazard ratio, 1.16; 95% CI, 0.87 to 1.56). We observed no effect modification in subgroup analyses stratified according to type of index event, time since index event, status with respect to diabetes or the metabolic syndrome at the time of enrollment, time spent enrolled in the trial, or levels of baseline high-sensitivity C-reactive protein above or below the trial median (data not shown).

Discussion In this randomized, double-blind, placebo-controlled trial, low-dose methotrexate did not reduce levels of interleukin-1β, interleukin-6, or high-sensitivity C-reactive protein and was not associated with fewer cardiovascular events than placebo among patients with atherosclerosis whose condition was stable but who were at high cardiovascular risk. Methotrexate was associated with modest elevations in liver enzyme levels and reductions in leukocyte counts and hematocrit levels, as well as a higher incidence of non–basal-cell skin cancers than placebo. There was no difference between the groups in all-cause mortality. Because the findings for low-dose methotrexate in CIRT contrast with those for canakinumab in CANTOS, a comparison of these two contemporary trials, which were designed and conducted in parallel, is informative. Both CIRT and CANTOS enrolled patients with atherosclerosis who were in stable condition but at high risk and who received aggressive treatment with lipid- lowering therapies. CANTOS, however, by design, included patients with residual inflammatory risk16 and thus limited enrollment to patients with persistently elevated high-sensitivity C- reactive protein levels; this trial design resulted in a median baseline C-reactive protein level among participants of 4.2 mg per liter (the approximate 90th percentile of the normal distribution). By contrast, CIRT did not screen for C-reactive protein level but instead required participants to have either diabetes or the metabolic syndrome. This trial design resulted in a median high-sensitivity C-reactive protein level of only 1.6 mg per liter at randomization.

Initial Care of the Severely Injured Patient

Hippocrates wrote, “He who would become a surgeon should join an army and follow it.” The rapid advancement of trauma care is often, sadly, firmly linked to warfare. William Mayo, many centuries later, aptly stated, “Medicine is the only victor in war.” The crisis of injury created by war has often led to innovation in trauma care and surgical creativity, and many of our best practices were forced by war into widespread adoption. Others simply evolved into practice through a natural pathway of peer review, publication, and acceptance by the trauma community. Research on the management of severe injury is extremely challenging to conduct, and innovation is often driven by necessity rather than by the scientific

• method. Nevertheless, survival rates after severe injury are higher now than at any point in recorded

history, and recent improvements in care are attributable, in part, to the nearly two decades of war on

• terrorism. In the United States, injury remains the leading cause of death among persons between the

ages of 1 and 44 years, underscoring the fact that trauma is not only a wartime affliction.

Product details of high quality US army black Combat Application Tourniquet outdoor/field medical tactical Tourniquet - intl

Emergency tourniquets (Stauband) are cuff-like devices designed to stop severe traumatic bleeding before or during transport to a care facility. They are wrapped around the limb, proximal to the site of trauma, and tightened until all blood vessels underneath are

• ccluded. The design and construction of emergency

tourniquets allows quick application by first aid responders or the injured persons themselves. Correct use of tourniquet devices have been shown to save lives under austere conditions with comparatively low risk of injury. In field trials, prompt application of emergency tourniquets before the patient goes into shock are associated with higher survival rates than any other scenario where tourniquets were used later

• r not at all. Mechanisms that confer sufficient

mechanical advantage are essential for applying adequate pressure to stop bleeding, particularly on the lower extremities. Pressures that occlude venous but not arterial flow can exacerbate hemorrhage and cause damage to healthy tissue. Tourniquets with wider straps

• r cuffs, especially those with pneumatic actuation in

contrast to mechanical force, distribute pressure more evenly and produce lower pressure gradients. They are therefore more likely to stop bleeding and less likely to cause damage to underlying tissue, in addition to being significantly less painful than tourniquets with narrow straps and bands.

Tourniquets At the beginning of the global war on terror, the death rate from limb exsanguination and junctional wounds was extraordinarily high, despite a 1996 report on military medicine in which the authors recognized the need to use field tourniquets for life-threatening extremity hemorrhage. Improvised tourniquets became commonplace, though largely ineffective. Warfighters (i.e., members of the military who fight in wars) recognized the need for better control of limb hemorrhage at the point of injury, and commercial devices to control limb exsanguination became standard on the battlefield, along with universal training in how to use them. These changes resulted in a demonstrable reduction in deaths from extremity exsanguination. Antifibrinolytic Therapy Although the coagulopathy of trauma is not completely understood, we know that one component is malignant

• hyperfibrinolysis. Fibrinolysis is a normal intravascular process that maintains an appropriate balance with
• thrombosis. After severe injury, a hyperfibrinolytic state develops in some patients, in which thrombus is

endogenously lysed faster than it can be synthesized. This alteration may exacerbate blood loss and contribute to death. Tranexamic acid, a pharmacologic antifibrinolytic agent, has been used for decades to mitigate postpartum hemorrhage. However, its usefulness for the treatment or prevention of hyperfibrinolysis in patients with trauma was not recognized until several years ago. Treatment with tranexamic acid (1 g administered as an intravenous bolus over a period of 10 minutes, followed by a 1-g intravenous infusion over a period of 8 hours, with the first dose given within 3 hours after injury) is simple, and its effect, if given within 3 hours after injury in the most severely injured patients, is substantial. Permissive Hypotension A century ago, Walter Cannon stated that “inaccessible or uncontrolled sources of blood loss should not be treated with intravenous fluids until the time of surgical control.” It took another 76 years to scientifically validate this dictum in a carefully executed study. nfortunately, the strategy of withholding fluid resuscitation until vascular control is achieved was slow to diffuse into routine care; for most of the 20th century, allowing trauma patients to remain hypotensive until surgical intervention violated a major principle of fluid resuscitation with crystalloid solutions. The common practice of administering 2 liters of crystalloid fluid in hypotensive trauma patients worsens coagulopathy and acidosis and should be abandoned. Normotensive patients should receive no fluid resuscitation, whereas hypotensive patients should have fluid resuscitation withheld until systolic blood pressure approaches 80 mm Hg systolic, at which point careful, small-volume boluses of blood or plasma (250 to 500 ml) should be given to maintain systolic blood pressure between 80 and 90 mm Hg.

Walter Bradford Cannon (* 19. Oktober 1871 in Prairie du Chien, Wisconsin; † 1. Oktober 1945 in Franklin, New Hampshire) war ein US-amerikanischer

• Physiologe. 1906 wurde er Nachfolger von Henry

Pickering Bowditch als George Higginson Professor of Physiology an der Harvard University. Diese Professur für Physiologie behielt er bis 1942. Während des Ersten Weltkrieges (ab 1914) diente er als Präsident der American Physiological Society und beschäftigte sich mit dem Traumatischen Schock als Reaktion auf Bedrohung, unter dem viele Soldaten litten. Er prägte den Begriff Fight-or-flight-Response, der die Reaktion von Tieren auf Bedrohung beschreibt, und veröffentlichte zu dem Thema (1915) Bodily Changes in Pain, Hunger, Fear and Rage. Das Konzept der Homöostase (homoestasis) entwickelte er in seinem Buch The Wisdom of the Body (1932). Die Cannon-Bard-Theorie – die Cannon mit seinem Schüler Philip Bard (1898–1977) erarbeitete – besagt, dass ein „Emotionsreiz“ zwei gleichzeitig ablaufende Reaktionen hervorbringt, die physiologische Erregung und die Wahrnehmung der Emotion. Keine der beiden Reaktionen bedingt die andere. Die Theorie geht davon aus, dass die körperlichen Prozesse von den psychologischen unabhängig sind. 1906 wurde Cannon in die American Academy of Arts and Sciences und 1908 in die American Philosophical Society gewählt. Im Jahr 1914 wurde er in die National Academy of Sciences sowie 1932 in die Leopoldina aufgenommen und 1939 zum auswärtigen Mitglied der Royal Society gewählt. 1942 wurde er Ehrenmitglied der damaligen Akademie der Wissenschaften der UdSSR.

Tranexamsäure (AMCHA oder TXA) ist eine Substanz, die in der Medizin zur Hemmung des Fibrinolysesystems verwendet wird. Der Wirkungsmechanismus beruht dabei auf einer Komplexbildung mit Plasminogen, wodurch dessen Bindung an die Fibrinoberfläche gehemmt wird. Damit resultiert letztlich eine Hemmung der Gerinnselauflösung (Fibrinolyse). Es wird daher als Antifibrinolytikum (Fibrinolysehemmer) bezeichnet. Tranexamsäure ist ein synthetischer Stoff, der der Aminosäure Lysin ähnelt. Er zählt wie ε- Aminocapronsäure und p-Aminomethylbenzoesäure zur Gruppe der sogenannten ε-Aminocarbonsäuren. Tranexamsäure blockiert die Bildung von Plasmin durch Hemmung der proteolytischen Aktivität der

• Plasminogenaktivatoren. Dadurch wird Plasmin in

seiner Fähigkeit Fibrin zu lysieren behindert. Bei niedriger Dosis wirkt Tranexamsäure als kompetitiver Hemmer des Plasmins, bei hoher Dosierung als nicht- kompetitiver Hemmer. Alle ε-Aminocarbonsäuren wirken analog. Die Ausscheidung erfolgt zu 95 % über die Nieren und Harnwege (renale Elimination). Auf Grund der fast ausschließlich renalen Eliminierung der Substanz muss die Dosis bei Niereninsuffizienz vor allem bei längerer Anwendung reduziert werden, damit keine Akkumulation von Tranexamsäure im Plasma

• erfolgt. In Abhängigkeit vom Kreatinin im Serum wird

die Anzahl der Einzeldosen pro Tag vermindert.

Damage-Control Surgery Damage-control surgery is a technical strategy to control massive bleeding. This approach prioritizes the control of hemorrhage and contamination on initial surgical intervention and involves leaving the abdominal cavity with a temporary closure and delaying all other definitive surgical maneuvers and reconstructions for subsequent operations. Sometimes referred to as “staged” surgery, damage control promotes survival in patients with the most severe injuries and the greatest blood loss. Some patients have to undergo serial

• perations over a period of many days to avoid the physiological insult of one prolonged operation entailing

extensive blood loss. Between surgical stages, patients are placed in the intensive care unit, where their physiological status is carefully managed, with attention to resuscitation, resolution of acidosis, maintenance

• f normothermia, and elimination of coagulopathy, usually with the use of sedation and mechanical
• ventilation. On subsequent returns to the operating room, definitive surgical reconstruction is performed as

physiologically tolerated, and the abdomen is closed as soon as all reconstruction is complete. The Golden Hour During World War I, the French published the first scientific appreciation of the time-sensitive nature of the treatment of shock after injury, in a report entitled “Du Shock Traumatique dans les Blessures de Guerre: Analyses d’Observations.” Although the death rate has not been shown to rise precipitously at 60 minutes after injury, the recognition that intervention should occur rapidly helped drive the development of emergency medical systems. “The golden hour” moniker summarized this approach for policymakers, though it overlooks the reality that most deaths from truncal hemorrhage occur within 30 minutes after injury. More recently, data from the wars in Iraq and Afghanistan suggest that battlefield survival after injury was closely linked to the interval from injury and evacuation to the first surgical intervention. This prompted a Department of Defense mandate to evacuate all combat casualties by helicopter within 60 minutes after injury, which did pay off in terms of saving lives. The contemporary understanding of the time-sensitive nature of trauma remains paramount, since the interval between injury and surgical intervention fundamentally determines the outcome, both on and off the battlefield. Surgical intervention, however, should not be conflated with triage and resuscitation. Resuscitation is not a substitute for hemorrhage control, and caution should be exercised when resuscitation measures are initiated without a plan for surgical control of hemorrhage. The primary purpose of the golden hour concept is to drive all efforts toward early hemorrhage control, including initial care, triage, rapid evacuation, and resuscitation.

High-Ratio Massive Transfusion Bleeding patients need blood. The use of asanguinous intravenous fluids as a resuscitation medium worsens the outcome. Whole blood, or a surrogate that approximates whole blood, should be used for resuscitation, with simultaneous initiation of hemorrhage-control maneuvers. Component therapy, particularly within the context of an organized massive-transfusion protocol, emphasizing a high ratio of packed red cells to plasma (1:1), was first shown to improve outcomes on the battlefield, with subsequent wider adoption. This approach should be embraced at all facilities that receive trauma patients. Blood products are refrigerated for storage and should be warmed to body temperature through the use of a fluid-warming device during resuscitation. This is an important point, because transfusion of cool blood products in a patient with trauma and hemorrhage will contribute to iatrogenic hypothermia and coagulopathy. The rate of administration should be proportional to the degree of shock and should follow the principles of permissive hypotension. Blood products should be administered at as high a rate as possible (often as fast as 500 ml per minute) in order to obey the principles of hypotensive resuscitation, with a target systolic blood pressure of 80 mm Hg during damage- control surgery.

Ultrasonography Ultrasonographic examination of the abdominal cavity and pericardium during the discovery phase of care (FAST [focused abdominal sonography for trauma]) is as essential as the measurement of vital signs in initial triage and surgical decision making, particularly in a patient with trauma and hypotension.39 FAST examination within minutes after the patient’s arrival at a hospital (or in some cases even in the prehospital environment) is the current standard of care in the United States, European countries, Australia, Japan, and most other developed countries. An extended FAST examination, which includes additional examination of the bilateral pleural spaces, is especially useful, particularly when plain radiography of the chest is delayed. These ultrasonographic examinations allow detection and semiquantification of intraabdominal hemorrhage, which predicts the need for surgical intervention, and detection of traumatic hemopericardium (a surgical emergency), as well as hemothorax and pneumothorax. This can all be accomplished rapidly at the bedside within moments after the patient has arrived at the hospital. Early identification of these conditions allows the provider to immediately intervene, or set in motion a mechanism to intervene, with a hemorrhage-control maneuver such as laparotomy, tube thoracostomy, or thoracotomy without the need for additional radiographic or laboratory studies. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a rapidly emerging technique to control noncompressible, intracavitary hemorrhage below the

• diaphragm. Many surgeons regard this technique as a less invasive alternative to emergency thoracotomy and

aortic cross-clamping for a patient who is hemodynamically compromised but does not have evidence of thoracic hemorrhage and is not in arrest. An aortic occlusion balloon is rapidly placed into the aorta through percutaneous or open access to the common femoral artery, usually during initial triage. The balloon can then be positioned in zone I, just proximal to the aortic hiatus of the diaphragm, to temporarily control infradiaphragmatic exsanguination, once supradiaphragmatic hemorrhage has been ruled out. Alternatively, the balloon can be positioned in zone III to control massive pelvic or junctional hemorrhage, once supradiaphragmatic and intraabdominal hemorrhage have been ruled out. The principle of reasonably ruling out hemorrhage in any cavity proximal to proposed balloon occlusion is of paramount importance. Occlusion distal to a vascular injury may result in acceleration of proximal blood loss and death. Techniques that may be used to rule out proximal hemorrhage include ultrasonography (with its known limitations), plain radiography of the chest and pelvis, diagnostic tube thoracostomy, and diagnostic peritoneal aspiration or lavage.

Focused assessment with sonography in trauma (commonly abbreviated as FAST) is a rapid bedside ultrasound examination performed by surgeons, emergency physicians and certain paramedics as a screening test for blood around the heart (pericardial effusion) or abdominal organs (hemoperitoneum) after trauma. The four classic areas that are examined for free fluid are the perihepatic space (including Morison's pouch or the hepatorenal recess), perisplenic space, pericardium, and the pelvis. With this technique it is possible to identify the presence of intraperitoneal or pericardial free fluid. In the context of traumatic injury, this fluid will usually be due to bleeding. The extended FAST (eFAST) allows for the examination of both lungs by adding bilateral anterior thoracic sonography to the FAST exam. This allows for the detection of a pneumothorax with the absence of normal ‘lung-sliding’ and ‘comet-tail’ artifact (seen on the ultrasound screen). Compared with supine chest radiography, with CT or clinical course as the gold standard, bedside sonography has superior sensitivity (49–99% versus 27–75%), similar specificity (95– 100%), and can be performed in under a minute. A positive FAST - fluid (black stripe, indicated by red arrows) within Morison's pouch.

Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA). REBOA allows temporary control of massive hemorrhage below the level of occlusion while a definitive hemostatic intervention is undertaken. The choice of hemostatic intervention is made on the basis

• f the injury pattern; the intervention is usually an

emergency surgical procedure (laparotomy), pelvic angioembolization, pelvic external fixation, preperitoneal pelvic packing, or a combination of all these interventions. Abdominal visceral ischemia limits the occlusion time to less than 30 minutes, but ideally, the occlusion time should be as short as possible.

Summary Initial care of the severely injured patient has changed substantially in recent decades, in many ways stimulated by the global wartime experience. Continued advancement of trauma care outside of warfare requires a national commitment to research, especially in some areas with great promise but with little data or incomplete acceptance. Trauma care requires an extremely aggressive surgical approach, despite incomplete, imperfect, and rapidly changing information. This approach should be undertaken immediately, beginning at the point of injury. Wider adoption of these advances is necessary to improve survival for severely injured patients, particularly those with massive blood loss.

A 10-year-old girl presented to the pediatric clinic with headache and poor growth. On examination, her height was below the third percentile and her weight was at the tenth percentile. She had dry skin; testing showed no visual-field deficits. Laboratory studies showed a thyrotropin level of more than 150 µU per milliliter (normal range, 0.5 to 4.9), a free thyroxine level of 0.4 ng per deciliter (5.1 pmol per liter) (normal range, 0.8 to 1.4 ng per deciliter [10.3 to 18.0 pmol per liter]), and a prolactin level of 63 ng per milliliter (normal range, 3 to 28). The results of additional testing, which included the evaluation of levels of morning cortisol, gonadotropins, and insulin-like growth factor 1, were normal. Magnetic resonance imaging (MRI) of the head revealed a diffusely enhancing lesion in the sellar region extending to the optic chiasm (Panel A, arrow). A diagnosis of primary hypothyroidism with secondary pituitary hyperplasia was made, and the patient began receiving levothyroxine. Long-standing untreated primary hypothyroidism can cause pituitary hyperplasia owing to hormonal-feedback mechanisms through the hypothalamic–pituitary–thyroid axis. At 10 months of follow-up, the patient’s headaches had resolved, the thyrotropin level had normalized, and the patient had grown 6 cm in height. Repeated MRI of the head showed resolution of the pituitary enlargement (Panel B).

Pituitary Hyperplasia from Primary Hypothyroidism

A 29-Year-Old Woman with Nausea, Vomiting, and Diarrhea

The patient had been in her usual state of good health until the day before presentation, when nausea, vomiting, diarrhea, fever, muscle aches, and a mild nonproductive cough developed suddenly. She had no sinus congestion, sore throat, shortness of breath, or abdominal pain. Over the telephone on the morning before presentation, she reported that her symptoms were severe and had prevented her from attending work. However, when she was evaluated later in the day by a provider at her primary care clinic, she reported that she had had spontaneous improvement in the morning and felt well on arrival at the clinic. During the first event, which had occurred 13 months before presentation, the patient fell asleep while driving and her car crossed into the other lane, over the curb, and into an open space beside the road. She did not collide with any other vehicles or structures and had no trauma. During the second event, which had occurred 7 months before presentation, the patient collided with a turning vehicle. She did not lose consciousness, and the airbags did not deploy. After the crash, she had intermittent painful episodes of muscle spasms in her neck and low back that limited her range of motion. She was too fatigued to seek medical attention until the day after the collision. The patient subsequently underwent evaluation at her primary care clinic. Her score on the Epworth Sleepiness Scale was 20, with scores ranging from 0 (low-normal daytime sleepiness) to 24 (excessive daytime sleepiness). She was referred for a formal sleep study. In addition, she received prescriptions for naproxen and cyclobenzaprine and completed outpatient physical therapy, and her muscle spasms diminished. The patient subsequently underwent evaluation at her primary care clinic. Her score on the Epworth Sleepiness Scale was 20, with scores ranging from 0 (low-normal daytime sleepiness) to 24 (excessive daytime sleepiness). The patient had not undergone any surgical procedures. Medications included omeprazole, varenicline, naproxen, and

• cyclobenzaprine. Hydrocodone–acetaminophen had caused nausea. Just before the conclusion of the office visit,

the patient reported a history of use of nonprescribed oxycodone–acetaminophen tablets and requested initiation

• f therapy with injectable intramuscular naltrexone. Urine toxicology screening was ordered, and oral naltrexone

was prescribed. A follow-up visit was planned for 6 days later, but the patient did not complete the urine toxicology screening or return to the clinic for her scheduled follow-up. However, 2 months later, she requested a referral for psychotherapy because of increased symptoms of stress. At the psychology clinic, the patient reported that she had begun to use illicit drugs — including marijuana, oral opioids, cocaine, and 3,4-methylenedioxymeth- amphetamine — when she was in middle school. She had continued to use multiple substances for 5 years but had abruptly discontinued when she became pregnant, at 19 years of age. She did not use illicit drugs for 8 years after the birth of her daughter but then resumed regular use of oral opioids 3 years before presentation, when she began to work at a bar where drugs were frequently available. Since then, she had used escalating amounts of

• ral oxycodone to satisfy increased cravings and prevent withdrawal symptoms.

The patient reported that she used 120 mg of

• xycodone per day and spent approximately $3000

per month on oxycodone. She had missed work because of withdrawal symptoms, and she worried that she would lose custody of her daughter because of her drug use. She had never been hospitalized for opioid use or had an overdose. On several occasions, she had used nonprescribed buprenorphine, which had alleviated her withdrawal symptoms and cravings, but she had never tried buprenorphine treatment that had been prescribed by a health care provider. In addition, on several

• ccasions, she had tried to initiate treatment with

injectable intramuscular naltrexone but had been unable to abstain from opioid use long enough to receive the treatment. A plan was made for the patient to continue with outpatient cognitive behavioral therapy and mindfulness exercises, and a follow-up visit with her primary care physician was scheduled. One month later, the patient was seen by her primary care physician. Oral-fluid toxicology screening was positive for oxycodone, buprenorphine, benzoylecgonine, and cocaine; testing of the saliva was negative for fentanyl. A diagnosis and management decisions were made.

Treatment for Opioid Use Disorder First-line treatment for this patient would be one of the three medications approved by the Food and Drug Administration (FDA) for the treatment of opioid use disorder: naltrexone, methadone, or buprenorphine. These medications lead to longer retention in treatment and decreased opioid use and opioid cravings. In a meta-analysis, methadone and buprenorphine were strongly associated with decreased rates of overdose and death from any cause. Naltrexone This patient indicated a preference for naltrexone (an opioid antagonist). Oral naltrexone is available in generic form and is administered once daily as a tablet. However, meta-analyses have shown that oral naltrexone is no more effective than placebo in lowering the rate of opioid use or increasing the rate of retention in treatment. Methadone In contrast with naltrexone, methadone (a full opioid agonist) is not associated with a risk of precipitated withdrawal, so abstinence before the initiation of methadone treatment is not necessary. However, because methadone has a relatively long and unpredictable half-life, the treatment must be initiated carefully. An initial low dose and slow approach helps to ensure that the patient is not oversedated during the first several weeks. Buprenorphine Buprenorphine (a partial opioid agonist) can precipitate withdrawal if the patient has not abstained from opioid use for several hours before the first dose and has not begun to have withdrawal symptoms. Like naltrexone, buprenorphine can be prescribed in any clinical setting, although to prescribe buprenorphine in an outpatient setting, a waiver must be obtained from the Drug Enforcement Agency after completion of additional training (8 hours for physicians and 24 hours for nurse practitioners and physician assistants). Risk for Relapse Adherence to treatment is a major challenge for patients who receive any of these three medications. It is worth noting that patients who take methadone may have longer retention in treatment than those who take buprenorphine, and patients who take buprenorphine have longer retention than those who take naltrexone. Opportunities for Improving Care This case shows several ways in which the care of patients with opioid use disorder can be improved. During the patient’s previous encounters with the health care system, there were missed opportunities to discuss and diagnose her opioid use disorder.

Next Steps This patient has at least two promising prognostic characteristics. First, she is seeking treatment and has sought treatment in the past. In this patient, liquid chromatography–mass spectrometry of oral fluid was positive for oxycodone, buprenorphine, benzoylecgonine, and cocaine. Urine is a more commonly tested specimen type than oral fluid, since it can easily be obtained noninvasively, with the additional benefit that drugs of interest or their metabolites are often concentrated in it. However, urine testing for drugs of abuse is potentially complicated by deliberate manipulation

• f the specimen; adulteration, substitution, and dilution can all affect drug detection. Although an abnormal

creatinine level, pH, or osmolality can suggest specimen manipulation, these measures are not entirely sensitive

• r specific.

Final Diagnosis Oxycodone and cocaine use. No comments on the responsibility of physicians on producing this catastrophy were

• given. Nor was the „pain“ racket addressed.

Structural Iatrogenesis — A 43-Year-Old Man with “Opioid Misuse”

• Mr. O., a 43-year-old man with severe, destructive

rheumatoid arthritis, had been receiving acetaminophen–hydrocodone at low doses from his primary care provider (PCP) for 15 years. He worked in an auto-parts factory in southeastern Michigan, and pain control was essential to maintaining his

• employment. His pain had been well managed on a

stable regimen, and he had not shown evidence of

• pioid use disorder.

In 2016, Mr. O.’s PCP retired, and his care was transferred to another PCP in the same office, who followed the patient’s existing pain-management plan. The same year, the insurance company began requiring more frequent prior authorizations and then that prescriptions be sent to the pharmacy every 15

• days. The new PCP was occasionally late providing

these prescriptions and approving prior authorizations because of the required multistep interactions with the insurance company. Three months later, the patient submitted a urine sample that tested positive for unprescribed

• xycodone. When the PCP discussed the result with
• Mr. O., she learned that he had obtained oxycodone

from a friend during one of his gaps in medication. The following month, oxycodone was once again found in his urine. Already overwhelmed by the frequent need for prior authorizations, and noting that Mr. O. had “violated his contract” by submitting two urine samples containing unprescribed opioids, the PCP referred him to a local pain clinic.

Who ever says, „I am only a 3?“

Social Analysis Concept: Structural Iatrogenesis Through a series of events, Mr. O.’s therapeutic relationship with his PCP deteriorated, and he became compelled to obtain medications outside the medical setting, which in turn increased his risk of overdose, as well as his risk

• f arrest for possession of unprescribed opioids. This shift was not precipitated by physiological changes in Mr.

O.’s disease, need for medication, or personal attributes. The term “structure” emphasizes that Mr. O.’s poor outcome was determined by social forces and structures

• utside his control. The term “iatrogenesis” specifically focuses on the harmful role of bureaucratic structures

within medicine itself. In Mr. O.’s case, many of these structures had been instituted to protect patients at risk for

• pioid use disorder: clinicians acted according to prevailing standards of care in chronic pain management; his

prior clinic’s pain contract and urine drug screens were meant to prevent deviation from prescribed opioid use that might place him at risk for overdose or addiction; the pain clinic’s protocol of delayed prescribing was meant to prevent patients from “shopping” for opioid prescriptions; prior authorizations required by the insurance company were intended to reduce overprescription of potentially harmful (and costly) medications. But these systems were not beneficial to Mr. O. in the context of his economically and socially precarious life, which was shaped by a lack

• f transportation and a need to perform painful manual labor for economic survival.

Structural Iatrogenesis Structural iatrogenesis is the causing of clinical harm to patients by bureaucratic systems within medicine, including those intended to benefit them. Clinical Implications: Stopping Structural Iatrogenesis Clinicians who identify structural iatrogenesis may alter structures or create action plans to prevent them from causing harm. Generalizing from Mr. O.’s case, we would offer the following approach: Recognize and alter structures that systematically harm patients. Clinicians may be the first to identify a structure that is systematically harming patients and can then advocate for or directly effect change. For example, in the 1980s, the Food and Drug Administration and physician organizations recommended that women undergo pelvic exams before receiving hormonal contraceptions. These exams were a barrier to contraceptive access and stopped requiring them in their own clinics. By the 1990s, these local changes led to removal of the recommendation from national policy, which increased access to contraception and rates of effective use. Similarly, if Mr. O.’s PCP noticed that her clinic’s opioid-prescribing policy generated frequent gaps in medication coverage for patients in general, she could have advocated for a new approach. It’s important, however, to avoid the pitfall of thinking that structural harm emerges only from “broken” systems. All structures carry a risk of harm, even when they are functioning “properly.”

Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study

Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to

• participate. The primary endpoint, which was assessed in

all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly.

In both studies, fetuses were prospectively included if structural anomalies were detected through routine prenatal ultrasound and if no aneuploidy or large copy number variants were confirmed.

Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks

• f gestation. The partners of these women also had to consent to
• participate. Women were excluded if abnormal aneuploidy

considered to have caused the structural abnormality was detected, if one or both parents were younger than 16 years, or if

• ne or both parents did not or could not provide informed consent.

Parental blood samples were collected for DNA extraction and fetal DNA was obtained from chorionic villi, amniotic fluid, or fetal blood that remained after routine investigations at the two coordinating centres. This DNA was assessed for aneuploidy and CNVs at these centres. Parents and fetuses were excluded from subsequent analyses if tests revealed aneuploidy or CNVs that explained the anomalous structural phenotype of the fetus. DNA

• f parents and fetuses that had not been excluded was then

shipped to the Wellcome Sanger Institute for WES. After WES, we assessed sequence data for candidate pathogenic variants from a modified list of genes that are likely associated with developmental disorders Features of the potential diagnoses in fetuses with structural abnormalities (A) Number of potential diagnoses per fetus that were reviewed by the clinical review panel. (B) Number of potential diagnoses reviewed by the clinical review panel by gene, for all genes with a pathogenic or likely pathogenic variant and for all genes considered in more than one fetus (regardless of diagnostic status, single nucleotide variants and indels only). (C) Proportion

• f diagnostic genetic variants identified in fetuses with each

phenotypic abnormality. NT=nuchal translucency.

In our large prospective cohort study of 610 fetuses with a broad range of fetal structural anomalies that had been detected by prenatal ultrasound scan, we identified a relevant diagnostic genetic variant in a developmental disorder gene in 52 (8·5%) fetuses. In an additional 24 (3·9%) fetuses, a variant of potential clinical usefulness was identified and reported. Overall, we identified a diagnostic or potentially clinically relevant variant in 76 (12·5%) fetuses. Although some previous studies of fetal structural anomalies have reported diagnostic genetic variants in more than 50% of fetuses with a structural abnormality, most previous studies comprise small numbers of selective cases, and the designation of genetic variants as diagnostic was less stringent. The largest previous study used WES in 84 deceased fetuses and found diagnostic genetic variants in 20% of these fetuses. Our lower number of fetuses with diagnostic genetic variants reflects differences in ascertainment methods: we prospectively recruited all suitable cases and undertook WES without genetic review (after excluding aneuploidy and large CNVs) whereas Yates and colleagues11 studied deceased fetuses after termination or spontaneous fetal death.

Pregnancy outcomes associated with different fetal structural anomalies 45 fetuses had abdominal anomalies, 69 fetuses had brain anomalies, 81 fetuses had cardiac anomalies, 23 fetuses had thoracic anomalies, 32 fetuses had facial or cleft lip and palate anomalies, 33 fetuses had hydrops, 93 fetuses had increased nuchal translucency (more than 4·0 mm), 16 fetuses had renal anomalies, 65 fetuses had skeletal anomalies, ten fetuses had spinal anomalies, and 143 fetuses had complex or multisystem

• anomalies. NT=nuchal translucency.

Subscribe to RSS - Socio-demographic Index (SDI) A summary measure that identifies where countries or

• ther geographic areas sit on the spectrum of
• development. Expressed on a scale of 0 to 1, SDI is a

composite average of the rankings of the incomes per capita, average educational attainment, and fertility rates of all areas in the GBD study.

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Als Amyloidose (von altgriechisch ἄµυλον ámylon „Kraftmehl, Stärke“) bezeichnet man die Anreicherung von abnorm veränderten Proteinen meist extrazellulär im Interstitium, also im Zwischenzellraum. Diese unlöslichen Ablagerungen liegen in Form kleiner Fasern, so genannter Fibrillen (β-Fibrillen), vor und werden als Amyloid

• bezeichnet. Der Nachweis von Amyloid erfolgt durch

mikroskopische Untersuchung von Gewebeproben, die zuvor mit Kongorot gefärbt wurden. Die Amyloidablagerungen erscheinen im Hellfeld hellrot, in polarisiertem Licht zeigen sie eine apfelgrüne

• Doppelbrechung. Der Amyloidose liegt eine Störung der

Faltung eines normalerweise löslichen Proteins zu Grunde. Transthyretin (TTR) ist ein Serumprotein, das bei Entzündungszuständen vermindert ist und deshalb als Anti- Akute-Phase-Protein bezeichnet wird. Transthyretin ist bei der Altersamyloidose nachweisbar. Darüber hinaus können genetisch veränderte Varianten des Transthyretin zu vererblichen Amyloidosen mit autosomal-dominantem Erbgang führen. Bislang sind mehr als 80 Mutationen

• bekannt. Die Ablagerungen erfolgen in Augen, Nieren und

Herz und selten im zentralen Nervensystem. Transthyretin (TTR, Thyroxin bindendes Präalbumin, TBPA) ist ein Serum-Transportprotein in Wirbeltieren, das beim Menschen vorwiegend im Plexus choroideus und in der Leber gebildet wird. Es ist am Transport der Schilddrüsenhormone beteiligt. Mutationen im TTR-Gen können Transthyretinmangel und dieser Amyloidose Typ 1

• der 7 sowie Hyperthyroxinämie verursachen (ATTR).

Popeye ist eine Comic- und Zeichentrickfigur des amerikanischen Zeichners Elzie Crisler

• Segar. 70 Jahre nach dem Tod seines

Schöpfers erlangte der Spinat vertilgende Matrose 2009 Gemeinfreiheit in vielen Ländern. Ausgenommen davon sind spätere Medien wie Filme und Computerspiele sowie beispielsweise die Musik.

Ruptur der Bizepssehne

Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med 2018;379:1007-1016. Tafamidis functions as a chaperone that stabilizes the correctly folded tetrameric form of the transthyretin (TTR) protein by binding in one of the two thyroxine-binding sites of the tetramer.