Liquid profiling of circulating tumor DNA in colorectal cancer: steps needed to achieve its full clinical value as standard care

The analysis of circulating tumor DNA (ctDNA) is at the threshold of implementation into standard care for colorectal cancer (CRC) patients. However, data about the clinical utility of liquid profiling (LP), its acceptance by clinicians, and its integration into clinical workflows in real‐world settings remain limited. Here, LP tests requested as part of routine care since 2016 were retrospectively evaluated. Results show restrained request behavior that improved moderately over time, as well as reliable diagnostic performance comparable to translational studies, with an overall agreement of 91.7%. Extremely low ctDNA levels at < 0.1% in over 20% of cases, a high frequency of concomitant driver mutations (in up to 14% of cases), and ctDNA levels reflecting the clinical course of disease were revealed. However, certain limitations hampering successful translation of ctDNA into clinical practice were uncovered, including the lack of clinically relevant ctDNA thresholds, appropriate time points of LP requests, and integrative evaluation of ctDNA, imaging, and clinical findings. In conclusion, these results highlight the potential clinical value of LP for CRC patient management and demonstrate issues that need to be addressed for successful long‐term implementation in clinical workflows.     

Impact of target point deviations on control and complication probabilities in stereotactic radiosurgery of AVMs and metastases.

OBJECTIVE: Determination of the impact of inaccuracies in the determination and setup of the target point in stereotactic radiosurgery (SRS) on the expectable complication and control probabilities. METHODS: Two randomized samples of patients with arteriovenous malformation (AVM) (n=20) and with brain metastases (n=20) treated with SRS were formed, and the probability for complete obliteration (COP) or complete remission (CRP), the size of the 10 Gy-volume in the brain tissue (VOI10), and the probability for radiation necrosis (NTCP) were calculated. The dose-effect relations for COP and CRP were fitted to clinical data. Target point deviations were simulated through random vectors and the resulting probabilities and volumes were calculated and compared with the values of the treatment plan. RESULTS: The decrease of the relative value of the control probabilities at 1mm target point deviation was up to 4% for AVMs and up to 10% for metastases. At 2 mm the median decrease was 5% for AVMs and 9% for metastases. The value for the target point deviation, at which COP and CRP decreased about 0.05 in 90% of the cases, was 1.3 mm. The increase of NTCP was maximally 0.0025 per mm target point deviation for AVMs and 0.0035/mm for metastases. The maximal increase of VOI10 was 0.7 cm(3)/mm target point deviation in both patient groups. CONCLUSIONS: The upper limit for tolerable target point deviations is at 1.3mm. If this value cannot be achieved during the system test, a supplementary safety margin should be applied for the definition of the target volume. A better accuracy level is desirable, in order to ensure optimal chances for the success of the treatment. The target point precision is less important for the minimization of the probability of radiation necroses.     

Weight gain in pregnancy according to maternal height and weight

Abstract Weight gain during pregnancy is of great importance for the health of mother and child. There is considerable individual variability with regard to the weight gain, with maternal height and pre-pregnancy body weight being important determinants. We aim to assess the usefulness of the maternal body mass index (BMI) and other ways of combining maternal weight and height in predicting weight gain during pregnancy. We analyzed data of more than 2.2 million pregnancies taken from the German perinatal statistics of 1995-2000. We found that BMI is not useful as a predictor of weight gain during pregnancy. We developed an alternative system of using maternal weight and height to predict weight gain by classifying pregnant women according to their weight and height. This allows an assessment of weight gain by comparing a given pregnant woman to other women with similar weights and heights.     

Transplanted human cones incorporate into the retina and function in a murine cone degeneration model

Once human photoreceptors die, they do not regenerate, thus, photoreceptor transplantation has emerged as a potential treatment approach for blinding diseases. Improvements in transplant organization, donor cell maturation, and synaptic connectivity to the host will be critical in advancing this technology for use in clinical practice. Unlike the unstructured grafts of prior cell-suspension transplantations into end-stage degeneration models, we describe the extensive incorporation of induced pluripotent stem cell (iPSC) retinal organoid–derived human photoreceptors into mice with cone dysfunction. This incorporative phenotype was validated in both cone-only as well as pan-photoreceptor transplantations. Rather than forming a glial barrier, Müller cells extended throughout the graft, even forming a series of adherens junctions between mouse and human cells, reminiscent of an outer limiting membrane. Donor-host interaction appeared to promote polarization as well as the development of morphological features critical for light detection, namely the formation of inner and well-stacked outer segments oriented toward the retinal pigment epithelium. Putative synapse formation and graft function were evident at both structural and electrophysiological levels. Overall, these results show that human photoreceptors interacted readily with a partially degenerated retina. Moreover, incorporation into the host retina appeared to be beneficial to graft maturation, polarization, and function.     

Evolution of thrombolytic therapy in patients with HeartWare ventricular assist device thrombosis: a single-institutional experience

Open in a separate window OBJECTIVESPump thrombosis remains a major challenge in heart failure patients with left ventricular HeartWare assist device. Current International Society for Heart and Lung Transplantation recommendations favour surgical pump exchange over lysis because safety and efficacy of lysis has been controversially reported. This study summarizes our experience on our HeartWare thrombosis prevention strategy as well as thrombolysis through implementation of our institutional standardized HeartWare assist device protocol.METHODSOutcomes of all HeartWare thrombosis patients admitted between 2010 and 2020 were analysed. Thrombolysis therapy using tissue plasminogen activator was used as the first-line therapy in this study and thrombolysis therapy efficacy was defined as freedom from stroke, bleeding, recurrent HeartWare assist device thrombosis or surgical device exchange within 30 days after lysis application.RESULTSA total of 507 patients have been included in this study and 66 patients (13%) collectively developed a first HeartWare-thrombosis after a median of 12 months (8–22 months) after HeartWare implantation. Forty patients were treated with unstandardized lysis, of whom 7 patients had thrombolysis associated complications, such as incomplete thrombus resolution requiring surgical pump exchange in 4 patients, but also intracranial haemorrhage occurring in 3 patients. Three patients died in the non-protocol group. Eight device thrombosis patients were treated according to our protocol, showing no lysis-associated complication.CONCLUSIONSDespite current recommendations, preferring surgical HeartWare pump exchange in thrombosis, thrombolysis therapy for first HeartWare thrombosis can be safe and effective in a standardized protocol setting, including anticoagulation adjustment and intensified blood pressure control management.     

Endoscopic management of anastomotic hemorrhage from pancreatogastrostomy

Background  Hemorrhage from pancreatic-enteric anastomosis after pancreaticoduodenectomy (PD) is a critical condition due to its difficult accessibility and delicate condition, and therefore remains a major challenge for the surgeon in charge. Objective  This study analyzed presentation and management of pancreatogastrostomy hemorrhage (PGH) after PD to determine the respective roles of endoscopy and surgery. Patients and methods  Patients who underwent PD with pancreatogastrostomy between 1989 and January 2008 were identified from a pancreatic resection database and analyzed with regards to PGH, treatment strategy and outcome, and incidence of postoperative complications. Results  Out of 265 consecutive patients with PD, 10 patients (3.7%) experienced an episode of PGH, detected on average on postoperative day 5. No patient with PGH died during hospital stay as opposed to a mortality rate of 2.7% in patients without PGH. Morbidity rates were 50% versus 48% and length of hospital stay was 23 versus 21 days for patients with and without PGH, respectively, with no statistical differences between the groups. Endoscopic approach to control PGH was successful in nine patients. Pancreatogastrostomies were not compromised regarding procedure or air insufflations and no concomitant development of pancreatic fistula was observed. Open surgery was inevitable in one patient with recurrent PGH in order to achieve hemostasis, but resulted in pancreatic fistula and protracted hospital stay. Conclusions  The present study demonstrates a feasible endoscopic approach for the management of PGH with high success rate and no concomitant procedure-related morbidity. Medical illustrations: Lothar Knorn, Bonn.     

The Munich Shoulder Questionnaire (MSQ): development and validation of an effective patientreported tool for outcome measurement and patient safety in shoulder surgery

ABSTRACT: BACKGROUND: Outcome measurement in shoulder surgery is essential to evaluate the patient safety and treatment efficiency. Currently this is jeopardized by the fact that most patient-reported selfassessment instruments are not comparable. Hence, the aim was to develop a reliable selfassessment questionnaire which allows an easy follow-up of patients. The questionnaire also allows the calculation of 3 well established scoring systems, i.e. the Shoulder Pain and Disability Index (SPADI), the Constant-Murley Score (CMS), and the Disabilities of the Arm, Shoulder and Hand (DASH) Score. The subjective and objective items of these three systems were condensed into a single 30-questions form and validated against the original questionnaires. METHODS: A representative collective of patients of our shoulder clinic was asked to fill in the newly designed self-assessment Munich Shoulder Questionnaire (MSQ). At the same time, the established questionnaires for self-assessment of CONSTANT, SPADI and DASH scores were handed out. The obtained results were compared by linear regression analysis. RESULTS: Fifty one patients completed all questionnaires. The correlation coefficients of the results were r = 0.91 for the SPADI, r = -0.93 for the DASH and r = 0.94 for the CMS scoring system, respectively. CONCLUSIONS: We developed an instrument which allows a quantitative self-assessment of shoulder function. It provides compatible data sets for the three most popular shoulder function scoring systems by one single, short 30-item. This instrument can be used by shoulder surgeons to effectively monitor the outcome, safety and quality of their treatment and also compare the results to published data in the literature.     

Exact Solution of a Constraint Optimization Problem for the Thermoelectric Figure of Merit

In the classical theory of thermoelectricity, the performance integrals for a fully self-compatible material depend on the dimensionless figure of merit zT. Usually these integrals are evaluated for constraints z =  const. and zT =  const., respectively. In this paper we discuss the question from a mathematical point of view whether there is an optimal temperature characteristics of the figure of merit. We solve this isoperimetric variational problem for the best envelope of a family of curves z(T)T.     

Animal models for neonatal diseases in humans

The development of vaccines for infants and young children requires the use of animal models at various stages of preclinical development. Animal models are being used to assess the quantity and quality of the immune response, onset and duration of the response, induction of systemic versus local immunity, protection against challenge infection for the assessment of vaccine efficacy, as well as safety and toxicity of the vaccine formulation itself. A variety of animal models are available, each with its own specific advantages and disadvantages. Here, we review the most common animal models for preclinical vaccine development for human infants.