A methodological protocol for the development of a national guideline on perioperative management of gastrointestinal tumors in Germany.

BACKGROUND: The success of abdominal cancer surgery depends not only on the surgery itself but is influenced by the overall perioperative management. Given the multitude of perioperative measures and the ever-increasing number of studies on perioperative management, it is difficult to keep track and provide evidence-based perioperative management. The planned guideline on perioperative management will review the existing evidence and derive treatment recommendations. METHODS: The processing of the evidence is carried out by 6 working groups according to an 8-step scheme: after drafting the guideline questions in PICO format (1), a systematic literature search is carried out (2), and the records found are screened by two independent reviewers from the coordination team. Subsequently, the full texts of the potentially relevant articles are made available to the working groups for full text screening (3). All articles to be included are reviewed for methodological quality (4) before summary of findings tables are generated (5). In line with the GRADE approach, confidence in the evidence is assessed (6) before a recommendation is derived from the evidence, using a modified GRADE Evidence to Decision Framework (7). Finally, all recommendations are compiled and agreed within the guideline group (8). DISCUSSION: Guidelines serve as foundation for therapy decisions in everyday clinical practice and should therefore be based on up-to-date research results. However, while primary studies and systematic reviews are critically reviewed for their methodological quality, the process of guideline development is often not comprehensible. A protocol with predefined methodology should therefore create transparency and strengthen confidence in the recommendations. TRIAL REGISTRATION: The guideline is registered in the AWMF (Association of the Scientific Medical Societies) Guideline Register (088-010OL).

Helmet continuous positive airway pressure for patients' transport using a single oxygen cylinder: A bench study.

BACKGROUND: Continuous positive airway pressure (CPAP) is frequently used to treat patients with acute respiratory failure in out-of-hospital settings. Compared to a facemask, the helmet has many advantages for the patient but requires a minimum gas flow of 60 L/min to avoid CO2 rebreathing. The aim of the present bench study was to evaluate the performance of four Venturi devices, connected to a single oxygen cylinder, in delivering helmet-CPAP with clinically relevant gas flow, fraction of inspired oxygen (FiO2), and positive end-expiratory pressure (PEEP) values. METHODS: Three double-inlet Venturi systems (EasyVent, Ventuplus, Compact-HAR) were connected to full 5-L oxygen cylinders using a double flowmeter, and their oxygen requirements to reach different setups (flow 60-80 L/min; FiO2 0.4-0.5-0.6, PEEP 7.5-10-12.5 cmH2O) were tested. The fourth Venturi system (O2-MAX) was directly attached to the tank, and the flow and FiO2 delivered at preset FiO2 0.3 and 0.6 were recorded. The runtime of the cylinder was assessed. RESULTS: EasyVent, Ventuplus, and O2-MAX were able to deliver helmet-CPAP with clinically useful setups when connected to a single oxygen cylinder, while Compact-HAR did not. The runtime of the cylinders ranged between 28 and 60 minutes according to the preset flow and FiO2. The delivered gas flow decreased slowly and linearly with the drop in cylinder pressure until its exhaustion. CONCLUSIONS: Helmet-CPAP might be provided using portable Venturi systems connected to an oxygen cylinder, but not all of them are able to deliver it. The use of a double flowmeter allows delivery of both high flow and high FiO2 when double-inlet Venturi systems are used. Due to the flow drop observed during the cylinder consumption, a flow >60 L/min should be set when helmet-CPAP is started. Considering the flow drop phenomenon, the estimated duration of the tank runtime can be used with a margin of safety when planning patient transport.

Neoantigen-specific CD4+ tumor-infiltrating lymphocytes are potent effectors identified within adoptive cell therapy products for metastatic melanoma patients.

BACKGROUND: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a promising immunotherapeutic approach for patients with advanced solid tumors. While numerous advances have been made, the contribution of neoantigen-specific CD4+T cells within TIL infusion products remains underexplored and therefore offers a significant opportunity for progress. METHODS: We analyzed infused TIL products from metastatic melanoma patients previously treated with ACT for the presence of neoantigen-specific T cells. TILs were enriched on reactivity to neoantigen peptides derived and prioritized from patient sample-directed mutanome analysis. Enriched TILs were further investigated to establish the clonal neoantigen response with respect to function, transcriptomics, and persistence following ACT. RESULTS: We discovered that neoantigen-specific TIL clones were predominantly CD4+ T cells and were present in both therapeutic responders and non-responders. CD4+ TIL demonstrated an effector T cell response with cytotoxicity toward autologous tumor in a major histocompatibility complex class II-dependent manner. These results were validated by paired TCR and single cell RNA sequencing, which elucidated transcriptomic profiles distinct to neoantigen-specific CD4+ TIL. CONCLUSIONS: Despite methods which often focus on CD8+T cells, our study supports the importance of prospective identification of neoantigen-specific CD4+ T cells within TIL products as they are a potent source of tumor-specific effectors. We further advocate for the inclusion of neoantigen-specific CD4+ TIL in future ACT protocols as a strategy to improve antitumor immunity.

VersKiK: Study protocol of an observational registry-based study on the current state of follow-up care and adherence to follow-up guidelines after cancer in childhood or adolescence.

BACKGROUND: This article describes the study design of the quantitative part of the VersKiK study, The primary objectives of this study are to examine the occurrence of late effects in survivors of childhood or adolescent cancer (module 1), investigate health-related vulnerabilities and medical service utilization within this survivor group (modules 1 and 3), and assess the alignment between documented follow-up care for cardiological and audiological late effects with guideline recommendations, along with evaluating the extent of adherence among paediatric cancer survivors (module 3). METHODS: This is a non-interventional retrospective observational cohort study. It is based on stochastically linked insurance claims data from approximately 150,000 statutory insured persons with information concerning around 25,000-30,000 cancer survivors recorded in the German Childhood Cancer Register (GCCR). To explore adherence to selected follow-up guidelines, intention to treat treatment data from clinical study groups for particular diagnostic entities will be additionally included. DISCUSSION: The growing group of survivors after cancer in childhood and adolescence is representing a special population with an increasing demand for life-long healthcare services through relative high probability of late effects. Currently, there is a limited evidence in Germany on utilization of corresponding medical services and adherence to follow-up guidelines. With this study design, we are aiming to address these gaps and, consequently, suggest improvements to existing follow-up guidelines and follow-up care provision in Germany.

MR Imaging and Clinical Characteristics of Diffuse Glioneuronal Tumor with Oligodendroglioma-like Features and Nuclear Clusters.

BACKGROUND AND PURPOSE: Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC) is a new, molecularly defined glioneuronal CNS tumor type. The objective of the present study was to describe MR imaging and clinical characteristics of patients with DGONC. MATERIALS AND METHODS: Preoperative MR images of 9 patients with DGONC (median age at diagnosis, 9.9 years; range, 4.2-21.8 years) were reviewed. RESULTS: All tumors were located superficially in the frontal/temporal lobes and sharply delineated, displaying little mass effect. Near the circle of Willis, the tumors encompassed the arteries. All except one demonstrated characteristics of low-to-intermediate aggressiveness with high-to-intermediate T2WI and ADC signals and bone remodeling. Most tumors (n = 7) showed a homogeneous ground-glass aspect on T2-weighted and FLAIR images. On the basis of the original histopathologic diagnosis, 6 patients received postsurgical chemo-/radiotherapy, 2 were irradiated after surgery, and 1 patient underwent tumor resection only. At a median follow-up of 61 months (range, 10-154 months), 6 patients were alive in a first complete remission and 2 with stable disease 10 and 21 months after diagnosis. The only patient with progressive disease was lost to follow-up. Five-year overall and event-free survival was 100% and 86±13%, respectively. CONCLUSIONS: This case series presents radiomorphologic characteristics highly predictive of DGONC that contrast with the typical aspects of the original histopathologic diagnoses. This presentation underlines the definition of DGONC as a separate entity, from a clinical perspective. Complete resection may be favorable for long-term disease control in patients with DGONC. The efficacy of nonsurgical treatment modalities should be evaluated in larger series.

Long-term care, care needs and wellbeing of individuals after cancer in childhood or adolescence (VersKiK): study protocol of a large scale multi-methods non-interventional study.

BACKGROUND: It has been shown previously that a relevant proportion of childhood cancer survivors suffers from late effects, which are often directly related to the cancer itself or its therapy, resulting in particular follow-up needs, additionally burdening healthcare systems. Being diagnosed with cancer at a vulnerable stage of development, this group of cancer survivors is at comparatively higher risk of relapse or subsequent cancer. Although national and international follow-up guidelines based on treatment modalities have been developed, their implementation seems to leave room for improvement. Additionally, they lack a sufficient consideration of the survivors' psychosocial needs, affecting their adherence to them. The aim of the VersKiK study is to provide representative information on late effects in childhood and adolescence cancer survivors in Germany. The main research objectives are: (1) to describe the state of follow-up care among survivors after a cancer diagnosis in childhood or adolescence; (2) to quantify the occurrence of late effects among this group of survivors; (3) to examine the adherence to selected audiological and cardiological follow-up guidelines and to identify factors affecting it; (4) to explore actual follow-up needs of paediatric cancer survivors; (5) to review selected follow-up guidelines with the aim to improve and expand them. METHODS: VersKiK is designed as a mixed-methods non-interventional study. We will use claims data from statutory health insurance companies in combination with individually linked population-based registry data from the German Childhood Cancer Registry (GCCR). This data base will permit us to quantify diagnoses and procedures in comparison to the general population as well as the adherence to existing follow-up guidelines. Additional information will be obtained through interviews with childhood and adolescence cancer survivors and their informal caregivers, as well as in focus groups with healthcare professionals. DISCUSSION: The present study aims to research the actual needs of individuals after cancer diagnosis and treatment in childhood or adolescence - physical, psychological and organisational - in order to improve existing follow-up guidelines. These improvements might further positively affect not only actual care provided to paediatric cancer survivors, but also benefit healthcare systems in general while decreasing consequent medical visits in this group of patients. TRIAL REGISTRATION: Registered at German Clinical Trial Register (ID: DRKS00025960 and DRKS00026092).

The chance of transition: strategies for multidisciplinary collaboration.

Many long-term childhood cancer survivors suffer from treatment-related late effects, which may occur in any organ and include a wide spectrum of conditions. Long-term follow-up (LTFU) is recommended to facilitate early diagnosis and to ensure better health outcomes. Due to the heterogeneity of these sequelae, different specialists work together in the diagnosis and treatment of these conditions. Experts from both pediatric and internal medicine are involved in age-appropriate care by providing a transition process. Hence, LTFU of childhood cancer survivors is a prototypic example of multidisciplinary care for patients with complex needs treated in a specialized setting. International collaborations of healthcare professionals and scientists involved in LTFU of childhood cancer survivors, such as the International Guideline Harmonization Group, compile surveillance recommendations that can be clinically adopted all over the world. These global networks of clinicians and researchers make a joint effort to address gaps in knowledge, increase visibility and awareness of cancer survivorship and provide an excellent example of how progress in clinical care and scientific research may be achieved by international and multidisciplinary collaboration.

Nonlinear down-conversion in a single quantum dot.

Tailored nanoscale quantum light sources, matching the specific needs of use cases, are crucial building blocks for photonic quantum technologies. Several different approaches to realize solid-state quantum emitters with high performance have been pursued and different concepts for energy tuning have been established. However, the properties of the emitted photons are always defined by the individual quantum emitter and can therefore not be controlled with full flexibility. Here we introduce an all-optical nonlinear method to tailor and control the single photon emission. We demonstrate a laser-controlled down-conversion process from an excited state of a semiconductor quantum three-level system. Based on this concept, we realize energy tuning and polarization control of the single photon emission with a control-laser field. Our results mark an important step towards tailored single photon emission from a photonic quantum system based on quantum optical principles.

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

A patient-specific approach for quantitative and automatic analysis of computed tomography images in lung disease: Application to COVID-19 patients.

PURPOSE: Quantitative metrics in lung computed tomography (CT) images have been widely used, often without a clear connection with physiology. This work proposes a patient-independent model for the estimation of well-aerated volume of lungs in CT images (WAVE). METHODS: A Gaussian fit, with mean (Mu.f) and width (Sigma.f) values, was applied to the lower CT histogram data points of the lung to provide the estimation of the well-aerated lung volume (WAVE.f). Independence from CT reconstruction parameters and respiratory cycle was analysed using healthy lung CT images and 4DCT acquisitions. The Gaussian metrics and first order radiomic features calculated for a third cohort of COVID-19 patients were compared with those relative to healthy lungs. Each lung was further segmented in 24 subregions and a new biomarker derived from Gaussian fit parameter Mu.f was proposed to represent the local density changes. RESULTS: WAVE.f resulted independent from the respiratory motion in 80% of the cases. Differences of 1%, 2% and up to 14% resulted comparing a moderate iterative strength and FBP algorithm, 1 and 3 mm of slice thickness and different reconstruction kernel. Healthy subjects were significantly different from COVID-19 patients for all the metrics calculated. Graphical representation of the local biomarker provides spatial and quantitative information in a single 2D picture. CONCLUSIONS: Unlike other metrics based on fixed histogram thresholds, this model is able to consider the inter- and intra-subject variability. In addition, it defines a local biomarker to quantify the severity of the disease, independently of the observer.

Comprehensive assessments and related interventions to enhance the long-term outcomes of child, adolescent and young adult cancer survivors - presentation of the CARE for CAYA-Program study protocol and associated literature review.

BACKGROUND: Improved, multimodal treatment strategies have been shown to increase cure rates in cancer patients. Those who survive cancer as a child, adolescent or young adult (CAYA), are at a higher risk for therapy-, or disease-related, late or long-term effects. The CARE for CAYA-Program has been developed to comprehensively assess any potential future problems, to offer need-based preventative interventions and thus to improve long-term outcomes in this particularly vulnerable population. METHODS: The trial is designed as an adaptive trial with an annual comprehensive assessment followed by needs stratified, modular interventions, currently including physical activity, nutrition and psycho-oncology, all aimed at improving the lifestyle and/or the psychosocial situation of the patients. Patients, aged 15-39 years old, with a prior cancer diagnosis, who have completed tumour therapy and are in follow-up care, and who are tumour free, will be included. At baseline (and subsequently on an annual basis) the current medical and psychosocial situation and lifestyle of the participants will be assessed using a survey compiled of various validated questionnaires (e.g. EORTC QLQ C30, NCCN distress thermometer, PHQ-4, BSA, nutrition protocol) and objective parameters (e.g. BMI, WHR, co-morbidities like hyperlipidaemia, hypertension, diabetes), followed by basic care (psychological and lifestyle consultation). Depending on their needs, CAYAs will be allocated to preventative interventions in the above-mentioned modules over a 12-month period. After 1 year, the assessment will be repeated, and further interventions may be applied as needed. During the initial trial phase, the efficacy of this approach will be compared to standard care (waiting list with intervention in the following year) in a randomized study. During this phase, 530 CAYAs will be included and 320 eligible CAYAs who are willing to participate in the interventions will be randomly allocated to an intervention. Overall, 1500 CAYAs will be included and assessed. The programme is financed by the innovation fund of the German Federal Joint Committee and will be conducted at 14 German sites. Recruitment began in January 2018. DISCUSSION: CAYAs are at high risk for long-term sequelae. Providing structured interventions to improve lifestyle and psychological situation may counteract against these risk factors. The programme serves to establish uniform regular comprehensive assessments and need-based interventions to improve long-term outcome in CAYA survivors. TRIAL REGISTRATION: Registered at the German Clinical Trial Register (ID: DRKS00012504, registration date: 19th January 2018).

[Pathological-anatomical diagnosis according to the German lung cancer guideline 2018]. / Pathologisch-anatomische Diagnostik gemäß S3-Leitlinie Lungenkarzinom 2018.

The German S3-guideline on prevention, diagnosis, therapy and follow-up of lung cancer, published in February 2018, expands on the 2010 guideline to include a total of 19 recommendations and statements regarding the "processing of lung resection specimens (tumor resection specimens)", "processing of lymph nodes", "histo-pathological typing and immunophenotype", "extent of tumor growth in resection specimens", "resection margins" or "R-classification", "grade of malignancy (grading)", "regression grading" as well as the "examination of molecular targets". The statements regarding the analysis of molecular targets result from the diagnostic requirements of the current targeted therapy of advanced lung cancer. At the same time, a pathological-anatomical diagnosis according to the current S3-guideline fulfills all corresponding requirements in certified lung cancer centers.

[Late effects following childhood cancer treatment : A special challenge for transition medicine]. / Spätfolgen einer Krebsbehandlung im Kindes- und Jugendalter : Eine Herausforderung für die Transitionsmedizin.

BACKGROUND: Childhood cancer survivors are at risk of cancer- and treatment-related chronic health conditions. Since these sequelae may occur years after the end of treatment, many patients are already adults and have completed pediatric oncological care. Thus, successful transition is essential in order to ensure long-term surveillance. OBJECTIVES: The present review outlines the most frequent late effects of childhood cancer treatment. Moreover, difficulties in transition of these patients are discussed and interdisciplinary models of care are presented. RESULTS: Late effects following childhood cancer treatment occur in over two thirds of patients 30 years after the end of the oncological treatment and can affect different organs. The most frequent sequelae are endocrine disturbances, cardiac conditions, and subsequent neoplasms. Many late effects are effectively manageable if detected early. This necessitates an interdisciplinary approach as well as life-long surveillance. CONCLUSIONS: Transition from pediatric to internal medicine care as well as a change in the focus of care, shifting from relapse centered follow-up to late-effects centered surveillance, constitute a special challenge for a successful transition of long-term childhood cancer survivors. Specialized late-effects survivorship clinics offering interdisciplinary care from pediatric oncologists, specialists of internal medicine, and further disciplines enable the early diagnosis and treatment of late-effects.

The influence of genetic variation on late toxicities in childhood cancer survivors: A review.

INTRODUCTION: The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. METHODS: A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. RESULTS: Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (n = 6); BMD (n = 6); gonadal impairment (n = 2); hearing impairment (n = 12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (n < 200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26 = 15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. CONCLUSION: Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration.

Ventilation during extracorporeal support : Why and how.

The main target of extracorporeal support is to achieve viable gas exchange, while minimizing the risk of ventilator-induced lung injury, achieved through a decreased mechanical ventilation load on the natural lung. However, during veno-venous extracorporeal membrane oxygenation (ECMO), mechanical ventilation is still necessary in order to prevent lung collapse and/or if extracorporeal blood flow is not sufficient to guarantee adequate gas exchange. In this review, we will summarize the physiology of extracorporeal support and the rationale for continuing mechanical ventilation in this context. Furthermore, we will review the current clinical practice among ECMO centers and their suggestions regarding mechanical ventilator settings. While optimal ventilatory settings are still a matter of debate, the use of a strategy combining low tidal volume and limited inspiratory pressures is accepted worldwide. On the contrary, the choice of applied positive end-expiratory pressure (PEEP) varies between the total rest strategy and open lung strategy. Finally, the use of assisted or spontaneous ventilation will be discussed.