Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial.

Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, ß2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918.

[Initial in-hospital treatment of patients with penetrating trauma due to violence and war]. / Innerklinische Erstversorgung von Patienten mit penetrierendem Trauma nach Gewalt und Krieg.

BACKGROUND: Current political and social developments have brought the topics of violence, in this context attributable to terrorism and sabotage, and since February 2022 awareness of war in particular has again greatly increased. This article aims to present the contextualized dealing with penetrating injuries in terms of initial in-hospital treatment. OBJECTIVE: The question remains to be answered as to what extent penetrating injuries require special attention and to what extent the treatment priorities, options and strategies as well as surgical treatment require adaptation of the usual approach in routine clinical practice in Germany. MATERIAL AND METHOD: The experience of the authors in this field from military operations in Afghanistan, Iraq, the Republic of Mali, Kosovo and Georgia as well as the core content of the Terror and Disaster Surgical Care (TDSC®) course on this topic, have been contextualized and incorporated. In addition, aspects of a comprehensive systematic literature review and current data from a national evaluation on the topic of preparing hospitals in Germany for such scenarios are taken into account. RESULTS AND DISCUSSION: The clinical systems need to be well-prepared for such casualties, especially if they require treatment in large numbers. This is precisely so because the majority of patients are in a relevantly threatening situation (usually in the sense of a hemorrhage), treatment must be very urgently provided and in such scenarios a lack of resources must always be overcome, at least temporarily, especially for example for blood transfusions.

Education and training as a key enabler of successful patient care in mass-casualty terrorist incidents.

BACKGROUND AND PURPOSE: The increase in terrorist attacks with sometimes devastating numbers of victims has become a reality in Europe and has led to a fundamental change in thinking and a reorientation in many fields including health policy. The purpose of this original work was to improve the preparedness of hospitals and to provide recommendations for training. MATERIAL AND METHODS: We conducted a retrospective literature search based on the Global Terrorism Database (GTD) for the period 2000 to 2017. Using defined search strategies, we were able to identify 203 articles. We grouped relevant findings into main categories with 47 statements and recommendations on education and training. In addition, we included data from a prospective questionnaire-based survey on this topic that we conducted at the 3rd Emergency Conference of the German Trauma Society (DGU) in 2019. RESULTS: Our systematic review identified recurrent statements and recommendations. A key recommendation was that regular training should take place on scenarios that should be as realistic as possible and should include all hospital staff. Military expertise and competence in the management of gunshot and blast injuries should be integrated. In addition, medical leaders from German hospitals considered current surgical education and training to be insufficient for preparing junior surgeons to manage patients who have sustained severe injuries by terrorist events. CONCLUSION: A number of recommendations and lessons learned on education and training were repeatedly identified. They should be included in hospital preparations for mass-casualty terrorist incidents. There appear to be deficits in current surgical training which may be offset by establishing courses and exercises.

[Care of the severely injured in mass casualty incidents : What is the difference compared to emergency room management?] / Schwerstverletztenversorgung beim Massenanfall von Verletzten : Worin besteht der Unterschied zum Schockraummanagement?

The management of a severely injured patient according to the standards and principles of individualized trauma care is a well-established procedure in many hospitals. The process is structured and standardized by the content of several course formats. In contrast, a mass casualty incident (MCI, MANV) is a rare and exceptional situation. In this case the treatment priorities and approaches are changed. The main aim in this situation is to ensure the best possible chance of survival for every casualty by organizational measures to mobilize rooms, personnel and material and to temporarily abandon the standards of individualized trauma care. To be prepared for a MCl situation it is necessary to know the realistic scenarios, to update the hospital emergency plan and to adapt all treatment procedures to the transient lack of resources. This article gives an overview of this process and summarizes the current clinical concepts to cope with a MCl situation and the current principles for the care of the severely injured involving many casualties.

Evaluation of the decision-making process within the table-top exercise of the Terror and Disaster Surgical Care (TDSC®) course.

PURPOSE: The threat of terror is omnipresent in Europe and the number of attacks worldwide is increasing. The target of attacks in Europe is usually the civilian population. Incalculable dangerous situations at the scene of the event and severe injury patterns such as complex gunshot and explosion injuries with a high number of highly life-threatening people present rescue forces, emergency physicians and subsequently hospitals with medical, organizational as well as tactical and strategic challenges. The Terror and Disaster Surgical Care (TDSC®) course trains clinical decision-makers to meet these challenges of a TerrorMASCAL in the first 24-48 h. METHODS: A table-top exercise was developed for the TDSC® course as a decision training tool, which was prospectively evaluated in six courses. The evaluation took place in 3 courses of the version 1.0, in 3 courses in the further developed version 2.0 to different target values like, e.g., the accuracy of the in-hospital triage. Furthermore, 16 TDSC® course instructors were evaluated. RESULTS: For the evaluation, n = 360 patient charts for version 1.0 and n = 369 for version 2.0 could be evaluated. Overall, the table-top exercise was found to be suitable for training of internal clinical decision makers. Version 2.0 was also able to depict the action and decision-making paths in a stable and valid manner compared to the previous version 1.0. The evaluation of the instructors also confirmed the further value and improvement of version 2.0. CONCLUSION: With this prospective study, the table-top exercise of the TDSC® course was tested for decision stability and consistency of the participants' decision paths. This could be proven for the selected target variables, it further showed an improvement of the training situation. A further development of the table-top exercise, in particular also using digital modules, will allow a further optimization. http://www.bundeswehrkrankenhaus-ulm.de.

[Safety aspects, emergency preparedness and hazard prevention in hospitals concerning mass casualty incidents (MCI)/terror-related MCI : Prospects on future challenges based on survey results from the 3rd emergency conference of the DGU]. / Sicherheitsaspekte und Vorbereitung zur Notfallvorsorge und Gefahrenabwehr in Kliniken bei MANV/TerrorMANV : Ausblick auf zukünftige Herausforderungen anhand von Umfrageergebnissen zur 3. Notfallkonferenz der DGU.

BACKGROUND: Worldwide terrorist activities since "9/11" and subsequently also in the European region have led to a rethinking in the context of the evaluation of critical infrastructure in Germany, also with respect to security at and in hospitals. OBJECTIVE: This publication deals with the evaluation of existing concepts on topics such as "alerting", "security", "communication" and "preparation" in the aforementioned context. MATERIAL AND METHODS: Based on a literature review as well as a survey among participants of the 3rd emergency conference of the DGU (German Society for Trauma Surgery), this topic and the currently existing situation are further analyzed and presented. RESULTS: The data obtained illustrate that while the majority of hospitals have a hospital alert and response planning, the frequency of updates and intrahospital communication to increase awareness show significant variation. Furthermore, the results illustrate a heterogeneity of the existing intrahospital alerting concepts as well as a lack of security concepts and cooperation with security and guard services. Furthermore, it is evident that the topic of a possible CBRN (chemical, biological, radiological, nuclear) threat is not yet adequately perceived or implemented in the risk analysis. DISCUSSION: The latent threat of terrorist activities appears to have led German hospitals to address the issue of hospital alarm and response planning in their assessment as critical infrastructure and to have implemented this for the most part; however, the subordinated areas and the consequences that can be derived from alarm planning do not yet show the necessary stringency to ultimately ensure adequate responses in these special scenarios with respect to security in and at German hospitals.

Specificities of terrorist attacks: organisation of the in-hospital patient-flow and treatment strategies.

BACKGROUND: Mass-casualty incidents are always a particular challenge not only for healthcare providers and other emergency service responders at the scene but also for receiving hospitals. Terrorism-related mass-casualty incidents can result in a wide variety of different scenarios so that hospitals and their personnel must prepare for far more complex and demanding requirements. PURPOSE: In this article, we describe and discuss in-hospital aspects of mass-casualty terrorist incidents and focus on the special medical and in particular surgical care that is required in this setting. METHODS: The overview presented here is based on the Terror and Disaster Surgical Care (TDSC®) course. The TDSC® course was mainly developed from a comprehensive and structured analysis of the literature, single expert opinions, and expert consensus conferences. The objective of this course is to train clinical decision-makers in how to manage major incidents. RESULTS: The management of a mass-casualty terrorist incident and the care of victims present multiple and unique challenges to hospitals. This applies in particular to the number and distribution of patients arriving at the hospital, injury patterns, infrastructural aspects, and personnel resources. Particular attention must be given to the surgical approach to caring for these patients, e.g., early total care, damage control surgery, or tactical abbreviated surgical care. CONCLUSION: Mass-casualty terrorist incidents are different from other mass-casualty events in many respects that require special attention. The provision of appropriate public services requires in particular that the preparation and training of personnel as well as the organisation of the in-hospital response be tailored to the incident.

Terrorist incidents: strategic treatment objectives, tactical diagnostic procedures and the estimated need of blood and clotting products.

BACKGROUND: Terrorism-related incidents that are associated with mass casualties (mass-casualty terrorist incidents) are a medical and organisational challenge for every hospital because of the special injury patterns involved, the time of the incident, the development of the situation, the initial lack of information, the number of injured, and the number of uninjured survivors who self-refer to a hospital. METHODS: The Terror and Disaster Surgical Care (TDSC®) - Course was developed in order to address mass-casualty terrorist incidents and to provide surgeons with the specialist medical and surgical knowledge and skills required for these special situations. The focus of the TDSC® course is on how to provide surgical care and how to deploy scarce resources in a particular tactical situation in such a way that the number of survivors is maximised. RESULTS: The effective management of such a tactical situation must be based on priorities and first and foremost requires the standardised sorting and categorisation of the injured at the hospital. The aim of triage, or the sorting of the injured, is to immediately identify patients with life-threatening injuries in environments with strained resources. The medical management of mass-casualty terrorist incidents requires tactical abbreviated surgical care (TASC) teams that have the skills needed to perform a primary survey and to provide care for casualties who need immediate surgery (triage category 1-T1). Initial fluid therapy should be restrictive (permissive hypotension) unless contraindicated. Clotting products are replaced in a standardised manner on the basis of patient requirements, which are calculated using rapidly available surrogates (blood gas analysis). Blood products can be administered or kept available depending on risks and triage categories. The highest priority should be given to the identification and management of haemodynamically unstable patients who require immediate surgery for injuries associated with bleeding into body cavities (T1 + +). CONCLUSION: The recommendations and approaches described here should be considered as proposals for hospitals to develop standards or modify well-established standards that enable them to prepare themselves successfully for situations (e.g. mass-casualty terrorist or shooter incidents) in which their resources are temporarily overwhelmed.

Treatment resistance in chronic lymphocytic leukemia: the role of the p53 pathway.

The importance of studying p53 pathway defects in chronic lymphocytic leukemia (CLL) has been promoted by the demonstration of the fundamentally different clinical course of patients with 17p deletion. The observation of resistance to chemotherapy and mutation of the remaining TP53 allele explain the clinical presentation of CLL with 17p deletion. Here we review recent evidence that cases with TP53 mutation in the absence of the deletion of 17p have a similar clinical and biological course as cases carrying the deletion 17p. In addition, other principal components of the DNA damage pathway reportedly are de-regulated by mutation (ATM), deletion (ATM) or potentially more complex down-regulation (miR-34a) in CLL. Nonetheless, challenges remain because we can only explain resistance in a proportion of the cases that are resistant to first line treatment. This is of particular practical interest because our armamentarium of drugs in clinical use that acts independent of the DNA damage pathway is growing, for example antibody-based treatment (alemtuzumab), immuno-modulating drugs (lenalidomide), CDK inhibitors (flavopiridol) and steroids.