[Proposal for participation in intensive care and emergency medicine studies for patients unable to give informed consent (Cologne Model)]. / Vorschlag für ein Verfahren zur Teilnahme an intensiv- und notfallmedizinischen Studien bei nichteinwilligungsfähigen Patient*innen (Kölner Modell).

When conducting clinical trials in intensive care and emergency medicine, physicians, ethics committees, and legal experts have differing views regarding the inclusion of patients who are incapable of giving consent. These different views on the participation of patients who are not capable of giving consent also complicate how clinical trials are prepared and conducted. Based on the results of a literature search, a consensus model (Cologne Model) was developed by physicians performing clinical research, ethics committees, and lawyers in order to provide patients, those scientifically responsible for the study, ethics committees, and probate (guardianship) judges with a maximum of patient safety and legal certainty, while simultaneously enabling scientific research.

[Hemophagocytic lymphohistiocytosis in critically ill patients]. / Die hämophagozytische Lymphohistiozytose bei kritisch kranken Patienten.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammation syndrome. In adults, secondary HLH is mostly observed. HLH is often triggered by infections, malignancies or autoimmune disorders. However, HLH cases in association with immunotherapies have been described recently. HLH in critically ill patients is often difficult to differentiate from sepsis. Both conditions can also be present at the same time. Early diagnosis and timely initiation of an adequate immunosuppressive therapy are essential for the further course and the prognosis of HLH. Therefore, HLH should represent a differential diagnosis in critically ill patients with persistent fever and additional symptoms (e.g. enlarged spleen, neurologic symptoms) or laboratory parameters (e.g. hyperferritinemia, cytopenia, increased transaminases) compatible with HLH. The diagnosis of HLH is made using the HLH-2004 criteria. The probability of the presence of HLH can be calculated using the HScore. High-dose corticosteroids represent the cornerstone of HLH treatment. Etoposide, immunoglobulins, anakinra or other drugs are added depending on the trigger. The course of HLH is influenced by the time of treatment initiation, the underlying trigger and the response to treatment. Generally, the prognosis of critically ill HLH patients is poor.

[Cardiovascular therapy for sepsis: when, how and how much?] / Kreislauftherapie bei Sepsis ­ wann, wie und wie viel?

The management of hemodynamic instability in the context of sepsis or septic shock is at the forefront in emergency care as well as in the intensive care unit. Cardiovascular instability has a dramatic impact on the rate of organ complications and mortality from sepsis. According to the guideline for the treatment of sepsis, mean arterial pressure should not fall below 65 mm Hg. Crystalloid balanced fluid and catecholamines are the cornerstones of therapy management for septic cardiovascular instability. In this article, the most important points of what, when and how much regarding circulation therapy are presented and critically discussed.

Sexual quality of life in Hodgkin Lymphoma: a longitudinal analysis by the German Hodgkin Study Group.

BACKGROUND: Health-related quality of life (HRQoL) comprises different domains of physical, mental, and social well-being. In this analysis, we focus on sexual quality of life in Hodgkin Lymphoma (HL) patients. METHODS: Four-thousand one-hundred and sixty patients enroled in the HD10-HD12 trials underwent HRQoL assessment. Instruments included the Quality of Life Questionnaire for survivors (QLQ-S), combining the European Organisation for Research and Treatment of Cancer QLQ-C30, Multidimensional fatigue (FA) inventory (MFI-20) and an additional sexual functioning (SX) scale. We describe SX up to 27 months after therapy and analyse relationship to stage, age, gender, FA, social functioning, and therapy. Statistical methods range from descriptive statistics to a classification of SX courses, and a longitudinal structural equations model with full information maximum likelihood estimation of missing data. In the analysis, a score below 50 was used to describe severe sexual dysfunction. RESULTS: Three-thousand two-hundred and eight patients provided data on SX. Patients in advanced stages reported lower SX than patients in early stages both, before and after the treatment. During follow-up, an improvement of SX compared with baseline was detected, except for those ≥50 years. Patients in early stages reached normal SX, whereas advanced-stage patients remained below the reference value for healthy controls. Sexual functioning during follow-up was significantly and strongly related to previous SX, other HRQoL measures, age, and stage, and to lesser degree with gender and chemotherapy. CONCLUSION: Overall, HL patients have a decreased sexual quality of life at baseline, which improves after therapy and normalises in early-stage patients. Importantly, long-term SX is more closely related to patient characteristics and SX at baseline than to the intensity of treatment.

Fertility and gonadal function in female survivors after treatment of early unfavorable Hodgkin lymphoma (HL) within the German Hodgkin Study Group HD14 trial.

BACKGROUND: In the HD14 trial, 2×BEACOPPescalated+2×ABVD (2+2) has improved the primary outcome. Compared with 4×ABVD, this benefit might be compromised by more infertility in women. Therefore, we analyzed gonadal function and fertility. PATIENTS AND METHODS: Women≤45 years in ongoing remission at least 1 year after therapy were included. Hormone parameters, menopausal symptoms, measures to preserve fertility, menstrual cycle, pregnancies, and offspring were evaluated. RESULTS: Three hundred and thirty one of 579 women addressed participated (57.2%) and 263 per-protocol treated patients qualified (A=ABVD: 137, B=2+2: 126, mean time after therapy 42 and 43 months, respectively). Regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (≤12 months) were not different. Follicle-stimulating hormone and anti-Muellerian hormone were significantly better in arm A. However, pregnancies after therapy favored arm B (A: 15%, B: 26%, P=0.043) and motherhood rates were equivalent to the German normal population. Multivariate analysis revealed prophylactic use of gonadotropin-releasing hormone (GnRH) analogues as highly significant prognostic factor for preservation of fertility (odds ratio=12.87, P=0.001). Severe menopausal symptoms were frequent in women≥30 years (A: 21%, B: 25%). CONCLUSIONS: Hormonal levels after 2+2 indicate a reduced ovarian reserve. However, 2+2 in combination with GnRH analogues does not compromise fertility within the evaluated observation time.

Therapy-related myeloid neoplasms in patients treated for hodgkin lymphoma.

Hodgkin lymphoma (HL) is a malignancy of the lymphatic system with an incidence of 2-3/100.000/year in developed countries. With modern multi-agent chemotherapy protocols optionally combined with radiotherapy (RT), 80% to 90% of HL patients achieve long-term remission and can be considered cured. However, current standard approaches bear a considerable risk for the development of treatment-related late effects. Thus, one major focus of current clinical research in HL is reducing the incidence of these late effects that include heart failure, infertility, chronic fatigue and therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/t-AML). In previous analyses, t-MDS/t-AML after treatment for HL was associated with a poor prognosis. Nearly all patients died rapidly after diagnosis. However, more recent analyses indicated an improved outcome among patients with t-MDS/t-AML who are eligible for modern anti-leukemic treatment and allogeneic stem cell transplantation (aSCT). This article gives an overview of recent reports on the incidence and the treatment of t-MDS/t-AML after HL therapy and describes the efforts currently made to reduce the risk to develop this severe late effect.

TNF-alpha-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species.

Combinations with proteasome inhibitors are currently being investigated to improve the therapy of hematological malignancies. We previously found that proteasome inhibition by bortezomib failed to sensitize anti-CD30 antibody (Ab)-based lymphoma cell killing. In this study, we demonstrate in L540 Hodgkin's lymphoma cells that proteasome inhibition not only communicates apoptosis but also more rapidly causes a loss of CD30 antigen from cell membrane and a simultaneous release of soluble CD30, a targeting competitor. This shedding was catalyzed by the tumor necrosis factor (TNF)-alpha-converting enzyme (TACE, ADAM17) and blocked by the ADAM17-selective inhibitor, Ro32-7315. In parallel with CD30 shedding, bortezomib caused the generation of reactive oxygen species (ROS). As apoptosis and shedding were inhibited by the radical scavenger, N-acetyl-L-cysteine, ROS might have a pivotal function in both effects. In contrast, the pan-caspase inhibitor, zVAD-fmk, blocked bortezomib-induced apoptosis but not CD30 shedding, and Ro32-7315 blocked shedding but allowed apoptosis. This suggests independent terminal signaling pathways that are conflicting in Ab-based immunotherapy. Consequently, shedding inhibition substantially improved the synergistic antitumor efficacy of the human anti-CD30 Ab, MDX-060, and bortezomib. As proteasome inhibition also stimulated loss of TNF receptors, interleukin-6 receptor and syndecan-1 in different leukemia and lymphoma cell lines, we concluded that proteasome inhibition might impede targeted therapy against antigens susceptible to shedding.