Völlerei, Sexualität, das Sezieren von Leichen oder verschwenderisches Zurschaustellen des eigenen Reichtums: Im Exzess wurde - so die These des Buches - gesellschaftliche Ordnung gestaltet. Wie ...produktiv das Agieren im Übermaß sein konnte, beleuchtet Sarah-Maria Schober an Medizinern, die um 1600 in Basel lebten. Sie folgt den Ärzten an Orte, an denen sie Grenzen austesteten: in Bäder und Haushalte, an ihre Schreibtische und auf die anatomische Bühne. Damit bietet sie zugleich eine quellennahe Analyse einer städtischen Gesellschaft im späten 16. und frühen 17. Jahrhundert. https://creativecommons.org/licenses/by-nc-nd/4.0/
Acquired von Willebrand syndrome (aVWS) has been reported in patients with congenital heart diseases associated with shear stress caused by significant blood flow gradients. Its etiology and impact ...on intraoperative bleeding during pediatric cardiac surgery have not been systematically studied. This single-center, prospective, observational study investigated appropriate diagnostic tools of aVWS compared with multimer analysis as diagnostic criterion standard and aimed to clarify the role of aVWS in intraoperative hemorrhage. A total of 65 newborns and infants aged 0 to 12 months scheduled for cardiac surgery at our tertiary referral center from March 2018 to July 2019 were included in the analysis. The glycoprotein Ib M assay (GPIbM)/von Willebrand factor antigen (VWF:Ag) ratio provided the best predictability of aVWS (area under the receiver operating characteristic curve AUC, 0.81 95% CI, 0.75-0.86), followed by VWF collagen binding assay/VWF:Ag ratio (AUC, 0.70 0.63-0.77) and peak systolic echocardiographic gradients (AUC, 0.69 0.62-0.76). A cutoff value of 0.83 was proposed for the GPIbM/VWF:Ag ratio. Intraoperative high-molecular-weight multimer ratios were inversely correlated with cardiopulmonary bypass (CPB) time (r = -0.57) and aortic cross-clamp time (r = -0.54). Patients with intraoperative aVWS received significantly more fresh frozen plasma (P = .016) and fibrinogen concentrate (P = .011) than those without. The amounts of other administered blood components and chest closure times did not differ significantly. CPB appears to trigger aVWS in pediatric cardiac surgery. The GPIbM/VWF:Ag ratio is a reliable test that can be included in routine intraoperative laboratory workup. Our data provide the basis for further studies in larger patient cohorts to achieve definitive clarification of the effects of aVWS and its potential treatment on intraoperative bleeding.
Immune milieus play an important role in various types of cancer. The present study focuses on the effect of Th1 cytokines on pediatric acute lymphoblastic leukemia (ALL). The reaction of ALL cell ...lines and patient-derived xenografts (PDX) to the most important Th1 cytokines TNF-α (tumor necrosis factor alpha) and IFN-γ (interferon gamma) is analyzed and correlated with the respective cytokine receptors and the intracellular signaling molecules. ALL cell lines and ALL PDX display a great heterogeneity in cell death after incubation with TNF-α and IFN-γ. Several samples show a dose-dependent and additive induction of cell death by both cytokines; others do not react at all or even display an increased viability. Apoptosis is the main type of cell death induced by Th1 cytokines in ALL cells. Over all leukemia cells analyzed, IFN-γ receptor (IFNGR) shows a higher expression than both TNF-receptors, resulting in higher phosphorylation of STAT1 (signal transducer and activator of transcription) compared to phosphorylation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B-cells) in the TNF pathway. The activation of STAT1 correlates with the amount of cell death after stimulation with Th1 cytokines. TNF-α and IFN-γ lead to heterogeneous reactions in ALL cell lines and ALL PDX but are able to induce cell death by apoptosis in the majority of ALL blasts. The correlation of a high expression of IFNGR and following activation of STAT1 with cell death indicates an important role for IFN-γ signaling in this setting.
Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant ...therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking.
We performed a single-arm, multicenter clinical trial using "flip dose" ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network.
From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% 95% confidence interval (CI), 31%-66% and 37% (95% CI, 19%-55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%-95%) and 68% (95% CI, 46%-83%), respectively. Median RFS was 10.3 months (95% CI, 5.7-25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities.
Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing.
Purpose
Veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplantation (HSCT) with a high incidence in pediatric patients. This study aimed to detect signs of ...hypofibrinolysis using thrombelastography.
Methods
In this prospective single-center study, thrombelastographic measurements (EX and TPA tests) were taken during HSCT to detect signs of impaired coagulation, clot formation, or hypofibrinolysis.
Results
Of 51 patients undergoing allogeneic and autologous HSCT, five (9.8%) developed VOD and received defibrotide treatment. Thrombelastography measurements were also obtained from 55 healthy children as a control group. The results show that clot lysis was prolonged in VOD patients compared to other HSCT patients and control group (lysis time, TPA test: day + 14 to + 21: VOD: 330 ± 67 s vs. HSCT: 246 ± 53 s;
p
= 0.0106; control: 234 ± 50 s; control vs. VOD:
p
= 0.0299). The maximum lysis was reduced in HSCT patients compared to controls (EX test: control: 8.3 ± 3.2%; HSCT: day 0 to + 6: 5.3 ± 2.6%,
p
< 0.0001; day + 7 to + 13: 3.9 ± 2.1%,
p
< 0.0001; day + 14 to d + 21: 4.1 ± 2.3%,
p
< 0.0001).
Conclusion
These results suggest that HSCT patients exhibit reduced fibrinolytic capacities and patients diagnosed with VOD show signs of hypofibrinolysis. This prospective study shows that fibrinolysis can be assessed in a rapid and accessible way via thrombelastography. Thrombelastography might be a parameter to support the diagnosis of a VOD and to serve as a follow-up parameter after the diagnosis of a VOD.
1. Background
Chemotherapy-induced nausea and vomiting (CINV) is a feared and burdensome complication after emetogenic chemotherapy (EC), especially in pediatric patients undergoing allogeneic ...hematopoietic stem cell transplantation (HSCT). Antiemetic prophylaxis (AEP) is thus a substantial factor in the transplantation management. Guidelines recommend a comprehensive AEP with NK1R-antagonists (neurokinin-1 receptor), 5-HT3R-antagonists (5-hydroxytryptamine-3 receptor), and corticosteroids. The water-soluble aprepitant derivative fosaprepitant (NK1R-antagonist) was shown to be highly effective in adult patients with moderately to highly EC when combined with granisetron (5-HT3R-antagonist). There is very little experience with fosaprepitant in pediatric patients.
2. Patients and Methods
In this single-center retrospective study, 80 pediatric patients during allogeneic HSCT who received AEP either with intravenous fosaprepitant and granisetron (fosaprepitant group; FG) or a standard prophylaxis regimen with granisetron two times per day(historical control group; CG) were analyzed for safety and efficacy of the prophylaxis regimen. Efficacy of the two AEP regimen was evaluated comparing the vomiting frequency, percentages of patients vomiting and the need for rescue medication (dimenhydrinate) during the acute (<24h) and the delayed (24-120h) CINV phase in both groups. Safety was evaluated comparing drug-related clinical and laboratory-chemical side-effects (exanthema, gastrointestinal symptoms, sweating, liver and kidney parameters, and electrolytes). Exclusion criteria were vomiting or receiving antiemetic medication within 48 hours before the start of antiemetic prophylaxis.
3. Results
A total of 80 pediatric patients with a median age of 9 years (range 2-17 years) who underwent allogeneic HSCT between 2015 and 2018 were consecutively enrolled and analyzed. Patients were transplanted for the treatment of acute leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), ALL-relapse, AML-relapse; total: 36.5% of the patients), myelodysplastic syndromes (4.8% of the patients) solid tumors and lymphoma (neuroblastoma, brain tumor, non-Hodgkin's lymphoma, Hodgkin's lymphoma; 44.9% of the patients), and non-malignant hematopoietic diseases (thalassemia major, sickle cell anemia; 13.8% of the patients). The patients received allogeneic grafts from matched unrelated donors (48.4%), matched family donors (16.2%) and mismatched family donors (35.5%). Distribution of the patient characteristics was not significantly different in both study groups (p>0.05).
The patients of the FG (n=40; HSCT between 2017 and 2018) received a single dose of fosaprepitant (3.5-4 mg per kg bodyweight (mg/kg); maximum 150 mg; intravenous (IV) infusion) directly before starting the myeloablative conditioning and as PRN (pro re nata) medication every five days after HSCT (same dosage; IV infusion), as well as granisetron (2x20 µg/kg per day; starting on the first day of the conditioning; max. 3 mg; IV infusion <30 min.). The patients of the historical CG (n=40; patients transplanted between 2013 and 2014) received granisetron only at the same dosages. Discontinuation of the antiemetic medication was not necessary for any of the patients (CG and FG). Clinical side-effects and laboratory-chemical changes were not significantly different in both study groups (p>0.05). When compared to the patients of the CG, significantly less patients of the FG experienced vomiting in both, the acute (p<0.001) and the delayed CINV phase (p<0.0001); accordingly, significantly less vomiting events (p<0.0001) were observed during both CINV phases in the FG. Furthermore, the FG received significantly fewer doses of dimenhydrinate in comparison to the CG (p<0.001).
4. Conclusions
The prophylaxis regimen with fosaprepitant in combination with granisetron was safe and more effective in comparison to the standard prophylaxis regimen with granisetron only in pediatric patients undergoing allogeneic HSCT with a myeloablative conditioning. However, larger prospective trials are needed to evaluate these findings.
5. Keywords
Chemotherapy-induced nausea and vomiting; antiemetic prophylaxis; fosaprepitant; pediatric patients
6. Acknowledgments
This study was supported by the Stefan-Morsch-Stiftung, Birkenfeld, Germany.
Schlegel:Miltenyi Biotec: Patents & Royalties, Research Funding. Seitz:Miltenyi Biotec: Patents & Royalties, Research Funding. Lang:Miltenyi Biotec: Patents & Royalties, Research Funding. Handgretinger:Miltenyi Biotec: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding.
Chemotherapy-induced nausea and vomiting (CINV) are a major burden for patients undergoing emetogenic chemotherapy. International guidelines recommend an antiemetic prophylaxis with corticosteroids, ...5-HT
R-antagonists and NK
R-antagonists. The NK
R-antagonist fosaprepitant has shown favorable results in pediatric and adult patients. There is little pediatric experience with fosaprepitant.
This non-interventional observation study analyzed 303 chemotherapy courses administered to 83 pediatric patients with a median age of 9 years (2-17 years), who received antiemetic prophylaxis either with fosaprepitant and granisetron with or without dexamethasone (fosaprepitant group/FG; n=41), or granisetron with or without dexamethasone (control group/CG; n=42), during moderately (CINV risk 30-90%) or highly (CINV risk>90%) emetogenic chemotherapy. The two groups' results were compared with respect to the safety and efficacy of the antiemetic prophylaxis during the acute (0-24hrs after chemotherapy), delayed (>24-120hrs after chemotherapy) and both CINV phases. Laboratory and clinical adverse events were compared between the two cohorts.
Adverse events were not significantly different in the two groups (p>0.05). Significantly fewer vomiting events occurred during antiemetic prophylaxis with fosaprepitant in the acute (23 vs 142 events; p<0.0001) and the delayed (71 vs 255 events; p<0.0001) CINV phase. In the control group, the percentage of chemotherapy courses with vomiting was significantly higher during the acute (24%/FG vs 45%/CG; p<0.0001) and delayed CINV phase (28%/FG vs 47%/CG; p=0.0004). Dimenhydrinate (rescue medication) was administered significantly more often in the CG, compared to the FG (114/FG vs 320/CG doses; p<0.0001). Likewise, in the control group, dimenhydrinate was administered in significantly more (p<0.0001) chemotherapy courses during the acute and delayed CINV phases (79 of 150; 52.7%), compared to the fosaprepitant group (45 of 153; 29.4%).
Antiemetic prophylaxis with fosaprepitant and granisetron with or without dexamethasone was well tolerated, safe and effective in pediatric patients. However, larger prospective trials are needed to evaluate these findings.
Due to the high risk of severe infection among pediatric hematology and oncology patients, antimicrobial use is particularly high. With our study, we quantitatively and qualitatively evaluated, based ...on institutional standards and national guidelines, antimicrobial usage by employing a point-prevalence survey with a multi-step, expert panel approach. We analyzed reasons for inappropriate antimicrobial usage.
This cross-sectional study was conducted at 30 pediatric hematology and oncology centers in 2020 and 2021. Centers affiliated to the German Society for Pediatric Oncology and Hematology were invited to join, and an existing institutional standard was a prerequisite to participate. We included hematologic/oncologic inpatients under 19 years old, who had a systemic antimicrobial treatment on the day of the point prevalence survey. In addition to a one-day, point-prevalence survey, external experts individually assessed the appropriateness of each therapy. This step was followed by an expert panel adjudication based upon the participating centers’ institutional standards, as well as upon national guidelines. We analyzed antimicrobial prevalence rate, along with the rate of appropriate, inappropriate, and indeterminate antimicrobial therapies with regard to institutional and national guidelines. We compared the results of academic and non-academic centers, and performed a multinomial logistic regression using center- and patient-related data to identify variables that predict inappropriate therapy.
At the time of the study, a total of 342 patients were hospitalized at 30 hospitals, of whom 320 were included for the calculation of the antimicrobial prevalence rate. The overall antimicrobial prevalence rate was 44.4% (142/320; range 11.1–78.6%) with a median antimicrobial prevalence rate per center of 44.5% (95% confidence interval CI 35.9–49.9). Antimicrobial prevalence rate was significantly higher (p < 0.001) at academic centers (median 50.0%; 95% CI 41.2–55.2) compared to non-academic centers (median 20.0%; 95% CI 11.0–32.4). After expert panel adjudication, 33.8% (48/142) of all therapies were labelled inappropriate based upon institutional standards, with a higher rate (47.9% 68/142) when national guidelines were taken into consideration. The most frequent reasons for inappropriate therapy were incorrect dosage (26.2% 37/141) and (de-)escalation/spectrum-related errors (20.6% 29/141). Multinomial, logistic regression yielded the number of antimicrobial drugs (odds ratio, OR, 3.13, 95% CI 1.76–5.54, p < 0.001), the diagnosis febrile neutropenia (OR 0.18, 95% CI 0.06–0.51, p = 0.0015), and an existing pediatric antimicrobial stewardship program (OR 0.35, 95% CI 0.15–0.84, p = 0.019) as predictors of inappropriate therapy. Our analysis revealed no evidence of a difference between academic and non-academic centers regarding appropriate usage.
Our study revealed there to be high levels of antimicrobial usage at German and Austrian pediatric oncology and hematology centers with a significant higher number at academic centers. Incorrect dosing was shown to be the most frequent reason for inappropriate usage. Diagnosis of febrile neutropenia and antimicrobial stewardship programs were associated with a lower likelihood of inappropriate therapy. These findings suggest the importance of febrile neutropenia guidelines and guidelines compliance, as well as the need for regular antibiotic stewardship counselling at pediatric oncology and hematology centers.
European Society of Clinical Microbiology and Infectious Diseases, Deutsche Gesellschaft für Pädiatrische Infektiologie, Deutsche Gesellschaft für Krankenhaushygiene, Stiftung Kreissparkasse Saarbrücken.
Zusammenfassung
Hintergrund und Ziel der Studie
Die Purpura pigmentosa progressiva (PPP, Morbus Schamberg) ist eine seltene gutartige chronische Dermatose, die häufig als Vaskulitis oder ...Gerinnungsstörung fehldiagnostiziert wird. Obwohl die betroffenen Patienten eine wesentliche Einschränkung ihrer Lebensqualität erfahren, gibt es bislang keine etablierte Therapie. Das Ziel unserer doppelzentrischen Fallserienuntersuchung war die Evaluation der Effektivität und Verträglichkeit der Antioxidantien Rutosid und Ascorbinsäure als Kombinationstherapie bei PPP.
Patienten und Methodik
Es erfolgte die retrospektive Datenauswertung von 35 PPP‐Patienten, die zwischen 2004 und 2011 mit 2 × 50 mg Rutosid und 1 000 mg Ascorbinsäure täglich behandelt wurden. Die mittlere Behandlungsdauer betrug 8,2 Monate.
Ergebnisse
Bei 71,4 % der Patienten kam es zu einer kompletten Abheilung der Hautveränderungen während es bei 20,0 % zu einer mindestens 50%igen Verbesserung der Symptome kam, einhergehend mit einer Steigerung der Lebensqualität. Neun Studienteilnehmer (25,1 %) erlitten nach dem Absetzen der Therapie einen Rückfall. Bei sieben von ihnen wurde daraufhin die Therapie wieder eingeleitet und führte in allen Fällen zu einem erneuten Ansprechen. Bei drei Patienten kam es zu leichten unerwünschten Wirkungen. Patienten mit einer kürzeren Erkrankungsdauer zeigten bessere Behandlungsergebnisse, eine kürzere Latenzzeit bis zum Ansprechen auf die Therapie und ein geringeres Rückfallrisiko.
Schlussfolgerung
Die orale Therapie mit Rutosid und Ascorbinsäure eröffnet eine effektive und gut verträgliche Therapieotion bei PPP. Um ein gutes therapeutisches Ergebnis zu erzielen, wird eine frühe Therapie empfohlen.
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