[The critically ill CAR T-cell patient : Relevant toxicities, their management and challenges in critical care]. / Der kritisch kranke Patient nach CAR-T-Zell-Therapie : Relevante Nebenwirkungen, deren Management und Herausforderungen an die Intensivmedizin.

BACKGROUND: CAR­T cell therapy has been implemented as clinical routine treatment option during the last decade. Despite beneficial outcomes in many patients severe side effects and toxicities are seen regularly that can compromise the treatment success. METHODS: Literature review: CAR T­cell therapy, toxicities and their management RESULTS: The cytokine release syndrome (CRS) and the immune effector cell-associated neurotoxicity syndrome (ICANS) are seen regularly after CAR T­cell treatment. CRS symptoms can range from mild flu-like symptoms to severe organ dysfunction requiring vasopressor therapy, mechanical ventilation and other intensive care support. ICANS symptoms usually develop later and can range from disorientation and aphasia to potentially life-threatening brain edema. IL­6 is a key factor in the pathophysiology of CRS. The pathophysiology of ICANS is not fully understood. The ASTCT consensus grading is recommended to stratify patients for different management options. An interdisciplinary team including hematologist, intensivist, neurologists and other specialties is needed to optimize the treatment. DISCUSSION: Severe and potentially life-threatening toxicities occur regularly after CAR T­cell therapy. Treatment strategies for CRS and ICANS still need to be evaluated prospectively. Due to the increasing number of patients treated with CAR T­cells the number of patients requiring temporary intensive care management due to CRS and ICANS is expected to increase during the next years.

[Prevalence of cancer patients in German intensive care units]. / Prävalenz von Krebspatienten auf deutschen Intensivstationen.

INTRODUCTION: Cancer is one of the leading causes of death worldwide. Due to increasing comorbidities, age and aggressive chemotherapy, care of cancer patients in intensive care units (ICUs) is more and more necessary. So far, little is known about the care structure of cancer patients in German ICUs. The aim of this work is to collect and evaluate the prevalence and care data of cancer patients on two reference dates. METHODS: German ICUs were invited to participate in a 2-day, prospective, multicenter point prevalence study in ICU cancer patients. Participation in the study was voluntary and the study was not funded. An ethics vote was obtained to conduct the study. The data were anonymously entered into an eCRF (electronic case report form) by the participating centers. Identification of the patients is therefore not possible. RESULTS: About one in four patients on the ICU/IMC ward had hematological-oncological (HO) disease (n = 316/1319, 24%). The proportion depended significantly on the number of beds in each hospital. The most frequent reasons for admission to the ICU/IMC station were postoperative monitoring (n = 83/221, 37.6%), respiratory instability (n = 79/221, 35.7%), circulatory instability (n = 52/221; 23.5%) and the severe infection with sepsis (n = 47/221; 21.3%). In all, 66.5% (n = 147/221) of the patients had a solid tumor and 21.7% (n = 48/221) had hematological cancer, 78.3% (n = 173/221) of the documented cancer patients received "full-code" intensive management, while 42.5% (n = 94/221) of the HO patients were ventilated and 40.7% (n = 90/221) required catecholamines. The median (mean; IQR) SAPS II score was 35 (37.79, IQR = 24-48) and the median (mean, IQR) TISS score was 10 (13.26, IQR = 10-15). Through the analysis and evaluation of the data available in the context of the prevalence study, it was possible for the first time to determine the Germany-wide cross-center prevalence and care situation of hematological cancer patients in intensive care and intermediate care stations. About one in four patients on German ICUs and IMC wards have a major or minor cancer diagnosis (n = 316/1319 = 24%). Care management is complex in this patient population and requires close interdisciplinary collaboration.

[CARs, CRS and neurotoxicity: severe complications after administration of immunotherapy : Essentials for intensivists]. / CAR, CRS und Neurotoxizität: schwere Komplikationen der Immuntherapie : Was der Intensivmediziner wissen muss.

BACKGROUND: The development of chimeric antigen receptor (CAR) T­cells has shown promising results in relapsed/refractory B­cell acute lymphoblastic leukemia/lymphoma (B-ALL) and diffuse large cell B­cell lymphoma. Complications, especially cytokine release syndrome (CRS) and CAR T­cell related encephalopathy syndrome (CRES), can be life threatening. The management of both plays a key role in CAR T­cell therapy. OBJECTIVES: Diagnosis, clinical presentation and development of complications in the treatment with CAR T­cells. MATERIALS AND METHODS: Summary of incidence, mortality and treatment of severe complications after administration of CAR T­cells referring to current studies and therapy recommendations. RESULTS: Complications after administration of CAR T­cells, especially CRS and CRES, can be life threatening. The timely identification of side effects and their appropriate treatment usually leads to complete recovery. CONCLUSIONS: Using a therapy algorithm in the treatment with CAR T­cells allows safe management of toxicities and can be helpful in recognizing them in time.

Management of sepsis in neutropenic cancer patients: 2018 guidelines from the Infectious Diseases Working Party (AGIHO) and Intensive Care Working Party (iCHOP) of the German Society of Hematology and Medical Oncology (DGHO).

Sepsis and septic shock are major causes of mortality during chemotherapy-induced neutropenia for malignancies requiring urgent treatment. Thus, awareness of the presenting characteristics and prompt management is most important. Improved management of sepsis during neutropenia may reduce the mortality of cancer therapies. However, optimal management may differ between neutropenic and non-neutropenic patients. The aim of the current guideline is to give evidence-based recommendations for hematologists, oncologists, and intensive care physicians on how to manage adult patients with neutropenia and sepsis.

[Hematological-oncological intensive care patients : Treatment without borders]. / Der hämatologisch-onkologische Intensivpatient : Therapie ohne Grenzen.

The number of treatment options and success of treating patients with cancer have both significantly increased in recent years. However, many of these patients require intensive care due to comorbidities, treatment-associated complications, or severe infections. At the same time, the boundaries between what is feasible and sensible are difficult to draw. Over the past few years, awareness of the problems these cancer patients may have in the intensive care unit has increased and discussions have begun. This article intends to offer a discussion basis and also possible solution strategies.

[Antifreeze poisoning : The case of a patient with repeated ethylene glycol poisoning]. / Intoxikation nach Frostschutzmittelaufnahme : Der Fall eines Patienten nach wiederholter Ethylenglykolintoxikation.

Ethylene glycol poisoning of incidental or suicidal intention can cause life-threatening metabolic acidosis, diverse secondary damage, and even lead to death. Beside hemodialysis effective therapy consists of the administration of fomepizole and ethanol. We describe a patient after repeated ethylene glycol poisoning with high anion gap metabolic acidosis and acute renal failure. Using hemodialysis, with dialysate containing a specific amount of ethanol, and intravenous ethanol administration we were able to prevent severe secondary organ damage.

Pelvic cellulitis caused by Raoultella planticola in a neutropenic patient.

Raoultella planticola is a gram-negative, encapsulated, aerobic bacterium within the Enterobacteriaceae family. It has been primarily described as pathogen in cases with pneumonia and gastrointestinal infections. Here we describe a case of severe pelvic cellulitis in a patient with neutropenia following induction therapy for myeloid sarcoma. The patient experienced a septic shock and was treated successfully with antibiotic therapy. A literature review is provided to put this case in context with previous reports on R. planticola. This report highlights that awareness for uncommon pathogens is crucial in the clinical management of infections in neutropenic patients.

Consensus statement for cancer patients requiring intensive care support.

This consensus statement is directed to intensivists, hematologists, and oncologists caring for critically ill cancer patients and focuses on the management of these patients.

[Diagnostic management of fever]. / Diagnostisches Management von Fieber.

Fever is a symptom of a wide range of diseases. Its diagnostic management is of crucial importance, whereby the interface between general practitioner and hospital plays an important role. The family practitioner is of particular importance in the detection of life-threatening or complex situations involving fever. The diagnostic algorithm presented here can serve as the basis for rapid and targeted diagnostics. Good communication between the doctor and the hospital doctor is mandatory.

[Cancer patients in operative intensive care medicine]. / Krebspatienten in der operativen Intensivmedizin.

Cancer is one of the leading causes of death worldwide. New targeted and individualized therapies and drugs provide a survival benefit for an increasing number of patients, but can also cause severe side effects. An increasing number of oncology patients are admitted to intensive care units (ICU) because of cancer-related complications or treatment-associated side effects. Postoperative care, respiratory distress and sepsis are the leading causes for admission. Tumor mass syndromes and tumor lysis may require urgent treatment. Traditional anticancer chemotherapy is associated with infections and immunosuppression. Newer agents are generally well-tolerated and side effects are mild or moderate, but overwhelming inflammation and autoimmunity can also occur. Cellular treatment, such as with chimeric antigen receptor modified T­cells, monoclonal and bispecific antibodies targeting immune effectors and tumor cells are associated with cytokine release syndrome (CRS) with hypotension, skin reactions and fever. It is related to excessively high levels of inflammatory cytokines. Immune checkpoint inhibitors can lead to immune-related adverse events (IRAEs), such as colitis and endocrine disorders. Noninfectious respiratory complications, such as pneumonitis can also occur. Recent studies revealed that short-term and medium-term survival of cancer patients is better than previously expected. In this review article we summarize diagnostic and treatment strategies for common life-threatening complications and emergencies requiring ICU admission. Furthermore, strategies for rational admission policies are presented.

[Mortality of hematology-oncology patients with neutropenia in intensivecare]. / Letalität hämatoonkologischer Patienten in Neutropenie auf der Intensivstation.

BACKGROUND: Febrile neutropenia remains one of the most common reasons for hospital admission of patients with underlying oncologic disease. These patients have an up to 10-fold increased risk of developing sepsis, which often leads to these patients being transferred to the intensive care unit (ICU). The survival of neutropenic patients with sepsis in particular has improved in recent years, due to advanced therapy in intensive care (surviving sepsis campaign); however few large international studies of neutropenic cancer patients in the ICU are available. METHODS: In a retrospective study, 59 episodes of neutropenic cancer patients in the internal medicine ICU at the University Hospital of Cologne over a period of 2 years were analyzed. RESULTS: Pneumonia with or without sepsis are the main admission diagnoses of neutropenic cancer patients in the ICU. The mortality rate of these patients is very high (50.8 %). Pneumonia and sepsis, stem cell transplantation, mechanical ventilation, and acute renal failure with or without dialysis are correlated with mortality. CONCLUSION: Cancer patients should be admitted immediately to the ICU if they have signs of sepsis for early monitoring and treatment. Neutropenic patients have an increased risk for infectious complications and a risk for sepsis with higher mortality rates.

Impact of risk factors on outcomes in early-stage Hodgkin's lymphoma: an analysis of international staging definitions.

BACKGROUND: In early-stage Hodgkin's lymphoma (HL), treatment according to the early favorable or unfavorable subgroup is guided by staging definitions, which differ between various study groups worldwide. We analyzed risk factors used in different international staging systems and their impact on the outcome of early-stage HL patients. PATIENTS AND METHODS: In 1173 early-stage HL patients treated homogenously within the German Hodgkin Study Group (GHSG) trials HD10 and HD11, the impact of three staging systems developed and used by the GHSG, the European Organization for Research and Treatment of Cancer (EORTC), and the National Comprehensive Cancer Network (NCCN) in discriminating risk groups for progression-free survival (PFS) and overall survival (OS) was assessed and the relevance of their single risk factors was investigated. RESULTS: All the three staging systems defined an unfavorable risk group out of early-stage patients of comparable size (56%, 55%, and 57%), having a significantly poorer PFS and OS as compared with the corresponding favorable group; 5-year differences between early favorable and early unfavorable in terms of PFS were 9.4% (HR 2.61, 95% CI 1.74-3.91), 6.7% (HR 2.10, 95% CI 1.41-3.13), and 8.6% (HR 2.14, 95% CI 1.45-3.16) with the GHSG, EORTC, and NCCN definition, respectively. Sensitivity was high for all systems (84%, 79%, and 83%); however, there was a low specificity with high rates of false-positive results (1-specificity 54%, 53%, and 55%, respectively). Models of high sensitivity included risk factors associated with large tumor burden and high tumor activity. Most risk factors for tumor-specific end points were also predictive of OS. CONCLUSIONS: Differentiating between a favorable and an unfavorable risk group has significant impact on PFS and OS in early-stage HL patients in the modern treatment era. Risk-adapted treatment strategies using new risk factors with higher specificity are needed.

[Neutropenia and sepsis]. / Neutropenie und Sepsis.

The clinical management of neutropenic infections represents a great diagnostic and therapeutic challenge. Established sepsis criteria only partially reflect the neutropenic setting. Diagnostic procedures are frequently impaired by thrombocytopenia and progressive respiratory insufficiency. Increased tendency to bleed, engraftment, and fulminant progression represent major therapeutic challenges. Thus, crucial for the diagnosis and therapy of neutropenic sepsis are clear and well-communicated algorithms, rapid action, and close collaboration between oncologists and intensivists.

The German evidence-based guidelines for Hodgkin's lymphoma. Aspects for radiation oncologists.

This report reviews aspects of the German evidence-based guidelines for Hodgkin's lymphoma relevant to radiation oncologists. Stage-adapted treatment is discussed with the focus on radiotherapy. Up-to-date literature citations provide an overview of current recommendations.

[Hematologic and oncologic emergencies]. / Hämatologische und onkologische Notfälle.

The rapid development of novel, targeted drugs in cancer medicine has led to an increase in chronically ill cancer patients and hematology patients, who are being treated aggressively despite significant comorbidities and higher age. This development will lead to an increase in the number of hematologic and oncologic emergencies, and these patients will be seen by various specialties. This review article, therefore, aims at providing clinical management algorithms for the most frequent emergencies.

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.