Responses of patients with cancer to mRNA vaccines depend on the time interval between vaccination and last treatment.

BACKGROUND: Personalized mRNA vaccines are promising new therapeutic options for patients with cancer. Because mRNA vaccines are not yet approved for first-line therapy, the vaccines are presently applied to individuals that received prior therapies that can have immunocompromising effects. There is a need to address how prior treatments impact mRNA vaccine outcomes. METHOD: Therefore, we analyzed the response to BioNTech/Pfizer's anti-SARS-CoV-2 mRNA vaccine in 237 oncology outpatients, which cover a broad spectrum of hematologic malignancies and solid tumors and a variety of treatments. Patients were stratified by the time interval between the last treatment and first vaccination and by the presence or absence of florid tumors and IgG titers and T cell responses were analyzed 14 days after the second vaccination. RESULTS: Regardless of the last treatment time point, our data indicate that vaccination responses in patients with checkpoint inhibition were comparable to healthy controls. In contrast, patients after chemotherapy or cortisone therapy did not develop an immune response until 6 months after the last systemic therapy and patients after Cht-immune checkpoint inhibitor and tyrosine kinase inhibitor therapy only after 12 months. CONCLUSION: Accordingly, our data support that timing of mRNA-based therapy is critical and we suggest that at least a 6-months or 12-months waiting interval should be observed before mRNA vaccination in systemically treated patients.

A new promising oncogenic target (p.C382R) for treatment with pemigatinib in patients with cholangiocarcinoma.

Point mutations of the fibroblast growth factor receptor (FGFR)2 receptor in intrahepatic cholangiocarcinoma (iCC) are mainly of unknown functional significance compared to FGFR2 fusions. Pemigatinib, a tyrosine kinase inhibitor, is approved for the treatment of cholangiocarcinoma with FGFR2 fusion/rearrangement. Although it is hypothesized that FGFR2 mutations may cause uncontrolled activation of the signaling pathway, the data for targeted therapies for FGFR2 mutations remain unclear. In vitro analyses demonstrated the importance of the p.C382R mutation for ligand-independent constitutive activation of FGFR2 with transforming potential. The following report describes the clinical case of a patient diagnosed with an iCC carrying a FGFR2 p.C382R point mutation which was detected in liquid, as well as in tissue-based biopsies. The patient was treated with pemigatinib, resulting in a sustained complete functional remission in fluorodeoxyglucose-positron emission tomography/computed tomography over 10 months to date. The reported case is the first description of a complete functional remission under the treatment with pemigatinib in a patient with p.C383R mutation.

Landscape of Biomarkers and Actionable Gene Alterations in Adenocarcinoma of GEJ and Stomach-A Real World Data Analysis.

After several years of negative phase III trials in gastric and esophageal cancer, a significant breakthrough in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC) is now becoming evident with the emerging of precision oncology and implementation of molecular targets in tumor treatment. In addition, new generation studies such as umbrella and basket trials are focused on these molecular targets, which makes an early molecular diagnosis based on IHC/ISH and NGS necessary. The required companion diagnostics of Her2neu overamplification or PD-L1 expression is based on immunohistochemistry (IHC) or additionally in situ hybridization (ISH) in case of an IHC Her2neu score of 2+. However, there are investigator-dependent differences in the assessment of Her2neu amplification and different PD-L1 scoring systems obtained by IHC/ISH. The use of high-throughput technologies such as next-generation sequencing (NGS) holds the potential to standardize the analysis and thus make them more comparable. In the presented study, real-world multigene sequencing data of 72 Caucasian patients diagnosed with metastatic adenocarcinomas of GEJ and stomach were analyzed. In the clinical companion diagnostics, we found ESCAT level I molecular targets in one-third of our patients, which directly determined the therapy. In addition, we found potential targets in 14/72 patients (19.4%) who potentially qualify for precision therapies in corresponding molecular studies. The study highlights the importance of comprehensive molecular profiling for precision treatment of GEJ/GC and indicates that a biomarker evaluation should be performed for all patients with metastatic adenocarcinomas before the initiation of first-line treatment and during second-line or subsequent treatment.

A case of thrombocytopenia and multiple thromboses after vaccination with ChAdOx1 nCoV-19 against SARS-CoV-2.

Recently, reports of severe thromboses, thrombocytopenia, and hemorrhage in persons vaccinated with the chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19, AZD1222, Vaxzevria; Oxford/AstraZeneca) against severe acute respiratory syndrome coronavirus 2 have emerged. We describe an otherwise healthy 30-year-old woman who developed thrombocytopenia, ecchymosis, portal vein thrombosis, and cerebral venous sinus thrombosis the second week after she received the ChAdOx1 nCoV-19 vaccine. Extensive diagnostic workup for thrombosis predispositions showed heterozygosity for the prothrombin mutation, but no evidence of myeloproliferative neoplasia or infectious or autoimmune diseases. Her only temporary risk factor was long-term use of oral contraceptive pills (OCPs). Although both the prothrombin mutation and use of OCPs predispose to portal and cerebral vein thrombosis, the occurrence of multiple thromboses within a short time and the associated pattern of thrombocytopenia and consumption coagulopathy are highly unusual. A maximum 4T heparin-induced thrombocytopenia (HIT) score and a positive immunoassay for anti-platelet factor 4/heparin antibodies identified autoimmune HIT as a potential pathogenic mechanism. Although causality has not been established, our case emphasizes the importance of clinical awareness. Further studies of this potentially new clinical entity have suggested that it should be regarded as a vaccine-induced immune thrombotic thrombocytopenia.

Rare SARS-CoV-2 antibody development in cancer patients.

SARS-CoV-2 antibody development and immunity will be crucial for the further course of the pandemic. Until now, it has been assumed that patients who are infected with SARS-CoV-2 will develop antibodies as has been the case with other coronaviruses, like MERS-CoV and SARS-CoV. In the present study, we analyzed the development of antibodies in 77 patients with an oncologic diagnosis 26 days after positive RT-qPCR testing for SARS-CoV2. RT-qPCR and anti-SARS-CoV2-antibody methods from BGI (MGIEasy Magnetic Beads Virus DNA/RNA Extraction Kit) and Roche (Elecsys Anti-SARS-CoV-2 immunoassay) were used, respectively, according to the manufacturers' specifications. Surprisingly, antibody development was detected in only 6 of 77 individuals with a confirmed history of COVID-19. Despite multiple testing, the remaining patients did not show measurable antibody concentrations in subsequent tests. These results undermine the previous hypothesis that SARS-CoV2 infections are regularly associated with antibody development and cast doubt on the provided immunity to COVID-19. Understanding the adaptive and humoral response to SARS-CoV2 will play a key role in vaccine development and gaining further knowledge on the pathogenesis.

SARS-CoV-2 infections in cancer outpatients-Most infected patients are asymptomatic carriers without impact on chemotherapy.

Oncologic patients are regarded as the population most at risk of developing a severe course of COVID-19 due to the fact that malignant diseases and chemotherapy often weaken the immune system. In the face of the ongoing SARS-CoV-2 pandemic, how particular patients deal with this infection remains an important question. In the period between the 15 and 26 April 2020, a total of 1227 patients were tested in one of seven oncologic outpatient clinics for SARS-CoV-2, regardless of symptoms, employing RT-qPCR. Of 1227 patients, 78 (6.4%) were tested positive of SARS-CoV-2. Only one of the patients who tested positive developed a severe form of COVID-19 with pneumonia (CURB-65 score of 2), and two patients showed mild symptoms. Fourteen of 75 asymptomatic but positively tested patients received chemotherapy or chemo-immunotherapy according to their regular therapy algorithm (±4 weeks of SARS-CoV-2 test), and 48 of 78 (61.5%) positive-tested patients received glucocorticoids as co-medication. None of the asymptomatic infected patients showed unexpected complications due to the SARS-CoV-2 infection during the cancer treatment. These data clearly contrast the view that patients with an oncologic disease are particularly vulnerable to SARS-CoV-2 and suggest that compromising therapies could be continued or started despite the ongoing pandemic. Moreover the relatively low appearance of symptoms due to COVID-19 among patients on chemotherapy and other immunosuppressive co-medication like glucocorticoids indicate that suppressing the response capacity of the immune system reduces disease severity.

Mobile IT solutions for home health care.

PURPOSE: Harnessing the advantage of mobile information technology (IT) solutions at the point of care and contributing to patients' safety by involving them. DESIGN/METHODOLOGY/APPROACH: International collaboration between specialists in health communication processes and information management and systems. METHODS USED: Case studies, design science. FINDINGS: User-friendly portable IT applications going beyond documentation of patient records and administration require an understanding of complex communication processes between patients and the different caregivers. Home care increasingly faces structural deficits to be mitigated by integration of IT solutions. Platforms chosen in combination with services should be well established. How to implement this must be scrutinized by comprehensive research as initiated here. Preliminary results indicate potentials for novel mobile applications. PRACTICAL IMPLICATIONS: Contribution to increasing patients' safety by developing mobile solutions to support health care. Those may also contribute to cost savings in health care. SOCIAL IMPLICATIONS: Health care experiences an increasing significance for Western industrialized countries because of demographic developments. Care generally shifts from inpatient to outpatient settings; the global shortage of qualified nurses becomes even more prevailing. More support, among others by IT and enhanced interprofessional communication, is demanded for an improved quality and efficiency of care processes. ORIGINALITY/VALUE: Mutual approach benefits from the partner's understanding of complex interactions among clinicians, health services, and patients: the ability to design, monitor, and evaluate research strategies integrating care (information) needs is invaluable when applying creative technology solutions within health care domain.

Impaired regulation of cardiac function in sepsis, SIRS, and MODS.

In sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction syndrome (MODS), a severe prognostically relevant cardiac autonomic dysfunction exists, as manifested by a strong attenuation of sympathetically and vagally mediated heart rate variability (HRV). The mechanisms underlying this attenuation are not limited to the nervous system. They also include alterations of the cardiac pacemaker cells on a cellular level. As shown in human atrial cardiomyocytes, endotoxin interacts with cardiac hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels, which mediate the pacemaker current If and play an important role in transmitting sympathetic and vagal signals on heart rate and HRV. Moreover, endotoxin sensitizes cardiac HCN channels to sympathetic signals. These findings identify endotoxin as a pertinent modulator of the autonomic nervous regulation of heart function. In MODS, the vagal pathway of the autonomic nervous system is particularly compromised, leading to an attenuation of the cholinergic antiinflammatory reflex. An amelioration of the blunted vagal activity appears to be a promising novel therapeutic target to achieve a suppression of the inflammatory state and thereby an improvement of prognosis in MODS patients. Preliminary data revealed therapeutic benefits (increased survival rates and improvements of the depressed vagal activity) of the administration of statins, beta-blockers, and angiotensin-converting enzyme inhibitors in patients with MODS.

Is external defibrillation an electric threat for bystanders?

BACKGROUND: Safety precautions during defibrillation and cardioversion are generally taken very seriously. The actual hazard for bystanders and rescuers, however, has rarely been investigated. Recently, continuing chest compressions during defibrillation has been suggested to improve outcome from cardiac arrest. This article is to review reports on electric shocks to persons other than patients and to discuss the pertinent biomedical principles. METHODS: Systematic search in medical literature databases and consecutive hand-search of reference lists. RESULTS: A total of 29 adverse events are reported in the medical literature; seven due to accidental or intentional defibrillator misuse, three due to device malfunction, four during training/maintenance procedures, and 15 during regular resuscitation efforts. Tingling sensations and minor burns are frequently reported consequences of inadvertent shocks. There are no accounts on immediate life-threatening conditions or long-term disability in rescuers/bystanders inflicted by defibrillation/cardioversion of a patient. Discharging a defibrillator directly to a healthy person's chest can be lethal. CONCLUSIONS: External electric therapy is likely to be safer than traditionally assumed, especially with self-adhesive thoracic electrodes. Sound clinical experiments are urgently needed before safety measures are revised.

A reference automated external defibrillator provider course for Europe.

BACKGROUND: Scientific evidence is scarce in relation to the effectiveness of different methods of teaching automated external defibrillator (AED) use to laypeople. A reference course is needed in order to test new courses or methods against a comparative standard. OBJECTIVE: To propose a reference AED provider course that can be used as a comparator when testing new courses or teaching methods. METHODS: All national resuscitation councils that are represented in the European Resuscitation Council were sent a questionnaire about the AED provider courses run by them or under their auspices. RESULTS: Sixteen national resuscitation councils responded to the enquiry. Apart from the individual course timetables, there was remarkable consistency amongst the European countries as regards organisation, structure, content and methods. CONCLUSIONS: A reference AED provider course for laypeople, based on a synthesis of existing European courses, is suggested as a tool for research. Prior completion of a basic life support provider course is mandatory. Course duration is 2 h 45 min (excluding breaks), with 1 h 40 min practice time for the participants, 25 min for theory, 20 min for practical demonstrations by the instructor and 20 min for introduction, discussion and closure. A manual is distributed at the start of the course. The ratio of instructors to participants is one to six. Lectures are interactive between the instructor and the class. AED use is practised in groups of six participants. Participants prove their competency by means of a formal test that simulates a cardiac arrest scenario. Using this course as a comparator during research into the methodology of AED teaching would provide a reference against which other courses could be tested.

A reference basic life support provider course for Europe.

BACKGROUND: Good scientific evidence is scarce in relation to the effectiveness of different methods of teaching basic life support (BLS) to the general public. In order to test new courses or methods a reference course is needed as a comparative standard. OBJECTIVE: To propose a reference BLS provider course that can be used as a comparator when testing new courses or teaching methods. METHODS: All national resuscitation councils that are represented in the European Resuscitation Council (ERC) were sent a questionnaire about the BLS provider courses run by them or under their auspices. RESULTS: Sixteen national resuscitation councils responded to the enquiry. Their responses regarding organisation, structure, content and methods of the courses were found to be remarkably consistent between European countries. Few issues had a high variance. CONCLUSIONS: Based on the responses received, a reference BLS provider course for lay persons is suggested as a tool for research. The course duration is 3 h 15 min (excluding breaks), with 2 h 15 min practice time for the participants, 30 min for theory and 20 min for practical demonstrations by the instructor. A manual is distributed at the start of the course. The ratio of instructors to participants is one to six. The lectures are interactive between the instructor and the participants. Cardiopulmonary resuscitation (CPR) is practised on manikins in groups of six. A formal BLS scenario test may be held at the end of the course as part of a research study or if the candidates so request. It is suggested that by using this reference course during research into lay person BLS teaching, it will be easier to make comparisons between different studies.

Skeletal chest injuries secondary to cardiopulmonary resuscitation.

OBJECTIVE: To review the evidence on the incidence of rib and sternal fractures after conventional closed-chest compression in the treatment of cardiac arrest in adults and children, and after active compression-decompression cardiopulmonary resuscitation (ACD-CPR). METHODS: Medline search and additional review of the cited literature in the articles found. RESULTS: Reports on conventional CPR in adults suggest an incidence of rib fractures ranging from 13 to 97%, and of sternal fractures from 1 to 43%. Reports on CPR in children suggest an incidence of rib fractures of 0-2%, and no sternal fractures. ACD-CPR has been reported as causing rib fractures in 4-87%, and sternal fractures in 0-93% of cases. CONCLUSIONS: Sound methodological studies on thoracic fractures due to chest compression do not exist and the available studies cannot be compared one with another. In infants and toddlers, manual CPR rarely causes skeletal chest injuries. In adults, sternal fractures occur in at least one-fifth and rib fractures as well as rib and/or sternal fractures in at least one-third of the patients during conventional CPR. There is no compelling evidence to show that an increased complication rate is associated with ACD-CPR. Rib or sternal fractures are unlikely to increase mortality, as they rarely cause severe internal organ damage. Further prospective studies are desirable to assess complications by post-mortem examinations that explicitly address them. In particular, clinical evaluation of mechanical CPR devices should be accompanied by a thorough assessment of the associated complications because data specific to this modality are not available.