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Abstract Background Preoperative evaluation of axillary lymph node status is crucial for the selection of both systemic and surgical treatment in early breast cancer. This study assessed the particular role of additional shear wave elastography (SWE) in axillary staging in patients undergoing initial breast cancer diagnostics. Methods One hundred patients undergoing axillary lymph node biopsy due to a sonographically suspicious axillary lymph node were prospectively evaluated with SWE using virtual touch tissue imaging quantification (VTIQ). Mean values of tissue stiffness for axillary tissue and lymph node tissue were measured prior to core-cut biopsy of the lymph node. All lymph nodes were clip-marked during the biopsy. Cut-off values to differentiate between malignant and benign lymph nodes were defined using Youden’s index. Results Lymph nodes with evidence of malignant tumor cells in the final pathological examination showed a significantly higher velocity as measured by SWE, with a mean velocity of 3.48 ± 1.58 m/s compared to 2.33 ± 0.62 m/s of benign lymph nodes (p

BackgroundDifferences in medical treatment between women and men are common and involve out-of-hospital emergency care, the intensity of pain treatment, and the use of antifibrinolytic treatment in emergency trauma patients. If woman and man receive different antifibrinolytic treatment in highly-standardized major transplant surgery is unknown.MethodsWe conducted a retrospective cohort study on patients who underwent liver transplantation at Heidelberg University Hospital, Heidelberg, Germany between 2004 and 2017. Logistic regression analyses were performed to determine if sex is associated with the administration of TXA during liver transplantation. Secondary endpoints included venous thrombotic complications, graft failure, mortality, myocardial infarction, hepatic artery thrombosis, and stroke within the first 30 days after liver transplant as well as length of hospital stay and length of intensive care unit stay.ResultsOut of 779 patients who underwent liver transplantation, 262 patients received TXA. Female sex was not associated with intraoperative administration of TXA [adjusted OR: 0.929 (95% CI 0.654; 1.320), p = 0.681]. The secondary endpoints graft failure (13.2% vs. 8.4%, women vs. men, p = 0.039), pulmonary embolism (3.4% vs. 0.9%, women vs. men, p = 0.012), stroke (1.7% vs. 0.4%, women vs. men, p = 0.049), and deep vein thrombosis (0.8% vs. 0%, women vs. men, p = 0.031) within 30 days after liver transplantation were more frequent in women. Mortality, myocardial infarction, and other secondary endpoints did not differ between groups. However, in women, the use of TXA was associated with a lower rate in thromboembolic complications.ConclusionOur data indicate that different from other scenarios with massive bleeding complications the administration of TXA during liver transplantation is not associated with sex. However, sex is associated with the risk for complications, and in woman TXA might have a preventive effect on the rate of thromboembolic complications. Reasons underlying the observed sex bias rate remain uncertain.

Abstract Gene therapy based on the CRISPR/Cas9 system has emerged as a promising strategy for treating the monogenic fragile skin disorder recessive dystrophic epidermolysis bullosa (RDEB). With this approach problematic wounds could be grafted with gene edited, patient‐specific skin equivalents. Precise gene editing using homology‐directed repair (HDR) is the ultimate goal, however low efficiencies have hindered progress. Reframing strategies based on highly efficient non‐homologous end joining (NHEJ) repair aimed at excising dispensable, mutation‐harboring exons offer a promising alternative approach for restoring the COL7A1 open reading frame. To this end, we employed an exon skipping strategy using dual single guide RNA (sgRNA)/Cas9 ribonucleoproteins (RNPs) targeted at three novel COL7A1 exons (31, 68, and 109) containing pathogenic heterozygous mutations, and achieved exon deletion rates of up to 95%. Deletion of exon 31 in both primary human RDEB keratinocytes and fibroblasts resulted in the restoration of type VII collagen (C7), leading to increased cellular adhesion in vitro and accurate C7 deposition at the dermal‐epidermal junction in a 3D skin model. Taken together, we extend the list of COL7A1 exons amenable to therapeutic deletion. As an incidental finding, we find that long‐read Nanopore sequencing detected large on‐target structural variants comprised of deletions up to >5 kb at a frequency of ~10%. Although this frequency may be acceptable given the high rates of intended editing outcomes, our data demonstrate that standard short‐read sequencing may underestimate the full range of unexpected Cas9‐mediated editing events.

BackgroundEndovascular thrombectomy (EVT) reduces disability in patients with acute ischemic stroke (AIS); however, its efficacy in patients aged >80 years remains unclear.ObjectivesThis study aimed to assess the impact of premorbid modified Rankin Scale (pmRS) scores and age on patients with AIS undergoing EVT and the effect of EVT on functional outcome and mortality.MethodsWe conducted a retrospective cohort study and screened the Heidelberg Recanalization Registry (HeiReKa) database for patients with AIS between 1999 and 2021. Outcomes were stratified by age (

Background: Neck reflex points (NRPs) are 2 × 6 potentially tender areas of the neck, denominated NRP-C0 to NRP-C7. They are different from muscular trigger points and become tender in response to chronic trigeminal irritation. NRP examination has a high inter-rater reproducibility. We investigated the prevalence of NRPs in two populations to investigate their usefulness as a clinical test for trigeminal irritation. Methods: In total, 165 patients with chronic pain and 431 students were examined for NRP tenderness using a three-level pain scale: absent pain (PI = 0), mild tenderness (PI = 1), or marked tenderness (PI = 2). Results: In patients, we found more tender NRPs than in the student group (p < 0.001), and on the left side, more tender NRPs were found in NRP-C0–C4. Left and right NRPs appeared independently (kappa 0.1–0.4), except for NRP-C7 (kappa 0.55). Females had more tender NRPs (p < 0.001). Tenderness was independent of age, BMI, and pre-existing diseases. Conclusions: NRP tenderness occurs more frequently in patients than in students, independent from potential covariates. Our results, together with previous findings, support the use of NRP examination as a clinical test for chronic silent inflammation of the trigeminal region. These data provide a base for further studies investigating correlations of NRPs with clinical findings.

Background Postoperative pancreatic fistula (POPF) remains the most common and serious complication after distal pancreatectomy. Many attempts at lowering fistula rates have led to unrewarding insignificant results as still up to 30% of the patients suffer from clinically relevant POPF. Therefore, the development of new innovative methods and procedures is still a cornerstone of current surgical research.The cavitron ultrasonic surgical aspirator (CUSA) device is a well-known ultrasound-based parenchyma transection method, often used in liver and neurosurgery which has not yet been thoroughly investigated in pancreatic surgery, but the first results seem very promising.Methods The CUSA-1 trial is a randomised controlled pilot trial with two parallel study groups. This single-centre trial is assessor and patient blinded. A total of 60 patients with an indication for open distal pancreatectomy will be intraoperatively randomised after informed consent. The patients will be randomly assigned to either the control group with conventional pancreas transection (scalpel or stapler) or the experimental group, with transection using the CUSA device. The primary safety endpoint of this trial will be postoperative complications ≥grade 3 according to the Clavien-Dindo classification. The primary endpoint to investigate the effect will be the rate of POPF within 30 days postoperatively according to the ISGPS definition. Further perioperative outcomes, including postpancreatectomy haemorrhage, length of hospital stay and mortality will be analysed as secondary endpoints.Discussion Based on the available literature, CUSA may have a beneficial effect on POPF occurrence after distal pancreatectomy. The rationale of the CUSA-1 pilot trial is to investigate the safety and feasibility of the CUSA device in elective open distal pancreatectomy compared with conventional dissection methods and gather the first data on the effect on POPF occurrence. This data will lay the groundwork for a future confirmatory multicentre randomised controlled trial.Ethics and dissemination The CUSA-1 trial protocol was approved by the ethics committee of the University of Heidelberg (No. S-098/2022). Results will be published in an international peer-reviewed journal and summaries will be provided in lay language to study participants and their relatives.Trial registration number DRKS00027474.

Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmonary disease (COPD) are far from being understood. Here, we determine disease-related changes in cellular and molecular compositions within the alveolar space and peripheral blood of a cohort of COPD patients and controls. Myeloid cells were the largest cellular compartment in the alveolar space with invading monocytes and proliferating macrophages elevated in COPD. Modeling cell-to-cell communication, signaling pathway usage, and transcription factor binding predicts TGF-β1 to be a major upstream regulator of transcriptional changes in alveolar macrophages of COPD patients. Functionally, macrophages in COPD showed reduced antigen presentation capacity, accumulation of cholesteryl ester, reduced cellular chemotaxis, and mitochondrial dysfunction, reminiscent of impaired immune activation.

Abstract Background Pancreatic ductal carcinoma (PDAC) is the fourth most frequent cause of cancer-related death in the Western world, and its incidence is rising. In patients that undergo curative resection, local recurrence (LR) is frequent. A recently described surgical technique of extended pancreatoduodenectomy (PD) termed the TRIANGLE operation has been proposed as a promising approach to reduce LR and improve disease-free survival in PDAC patients. Methods The TRIANGLE trial is a multicentre confirmatory randomised controlled superiority trial with two parallel study groups. A total of 270 patients with suspected or histologically confirmed pancreatic head cancer scheduled for PD will be included in the trial and randomly assigned to the intervention group (extended PD defined as Inoue level 3 dissection along the superior mesenteric and celiac artery as well as removal of all soft tissue in the so-called triangle between the celiac artery, the SMA and the mesenterico-portal axis) or the control group (conventional PD with lymphadenectomy and removal of soft tissue according to current guidelines). The primary endpoint of the trial will be the disease-free survival of patients. Other perioperative outcomes as well as oncological parameters and patient-reported outcomes will be analysed as secondary outcomes. Discussion Despite multimodal treatment, LR remains high and disease-free survival is limited following PD for PDAC. The TRIANGLE operation could address these shortcomings of conventional PD as indicated in several retrospective studies. However, this technique could be associated with more adverse events for patients including intractable diarrhoea. The TRIANGLE trial will close the evidence gap as well as offer a risk-benefit assessment of this more radical approach to PD. Trial registration German Clinical Trials Register DRKS00030576 (UTN U1111-1243-4412) 19th December 2022.

Abstract Background Oesophageal cancer (EC) is the sixth leading cause of cancer death worldwide. Oesophageal resection is the only curative treatment option for EC which is frequently performed via an abdominal and right thoracic approach (Ivor-Lewis operation). This 2-cavity operation is associated with a high risk of major complications. To reduce postoperative morbidity, several minimally invasive techniques have been developed that can be broadly classified into either hybrid oesophagectomy (HYBRID-E) via laparoscopic/robotic abdominal and open thoracic surgery or total minimally invasive oesophagectomy (MIN-E). Both, HYBIRD-E and MIN-E, compare favourable to open oesophagectomy. However, there is still an evidence gap comparing HYBRID-E with MIN-E with regard to postoperative morbidity. Methods The MICkey trial is a multicentre randomized controlled superiority trial with two parallel study groups. A total of 152 patients with oesophageal cancer scheduled for elective oesophagectomy will be randomly assigned 1:1 to the control group (HYBRID-E) or to the intervention group (MIN-E). The primary endpoint will be overall postoperative morbidity assessed via the comprehensive complication index (CCI) within 30 days after surgery. Specific perioperative parameters, as well as patient-reported and oncological outcomes, will be analysed as secondary outcomes. Discussion The MICkey trial will address the yet unanswered question whether the total minimally invasive oesophagectomy (MIN-E) is superior to the HYBRID-E procedure regarding overall postoperative morbidity. Trial registration DRKS00027927 U1111-1277-0214. Registered on 4th July 2022

Background Rheumatic immune-related adverse events (R-irAEs) occur in 5–15% of patients receiving immune checkpoint inhibitors (ICI) and, unlike other irAEs, tend to be chronic. Herein, we investigate the factors influencing cancer and R-irAEs outcomes with particular focus on adverse effects of anti-inflammatory treatment.Methods In this prospective, multicenter, long-term, observational study, R-irAEs were comprehensively analyzed in patients with malignant melanoma (MM, n=50) and non-small cell lung cancer (NSCLC, n=41) receiving ICI therapy who were enrolled in the study between August 1, 2018, and December 11, 2022.Results After a median follow-up of 33 months, progressive disease or death occurred in 66.0% and 30.0% of MM and 63.4% and 39.0% of patients with NSCLC. Male sex (progression-free survival (PFS): p=0.013, and overall survival (OS): p=0.009), flare of a pre-existing condition (vs de novo R-irAE, PFS: p=0.010) and in trend maximum glucocorticoid (GC) doses >10 mg and particularly ≥1 mg/kg prednisolone equivalent (sex-adjusted PFS: p=0.056, OS: p=0.051) were associated with worse cancer outcomes. Patients receiving disease-modifying antirheumatic drugs (DMARDs) showed significantly longer PFS (n=14, p=0.011) and OS (n=20, p=0.018). Effects of these variables on PFS and/or OS persisted in adjusted Cox regression models. Additionally, GC treatment negatively correlated with the time from diagnosis of malignancy and the latency from ICI start until R-irAE onset (all p

Abstract Background Recently, the combination of the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab with first-line chemotherapy has demonstrated to improve outcome for patients with advanced small cell lung cancer (SCLC), leading to approval of this regimen. At the same time, accumulating (pre-)clinical data suggest synergisms of radiotherapy and immunotherapy via the radiation-mediated induction of anti-tumor immunogenicity. Combining the recent findings, the TREASURE trial aims at further enhancing response to upfront chemo-immunotherapy by the addition of thoracic radiotherapy (TRT). Methods/design The TREASURE trial is a randomized, multicenter, phase II clinical trial ( ClinicalTrials.gov identifier, NCT04462276). One hundred four patients suffering from extensive disease (ED) SCLC, with any response to the standard of care induction chemo-immunotherapy will be randomized to receive atezolizumab maintenance therapy with or without TRT. The primary endpoint of this study is overall survival (OS). Secondary endpoints include further measures of efficacy, safety, and the collection of biomarker samples. A safety interim analysis will take place after n = 23 patients receiving TRT have been observed for three months after the end of TRT. Discussion This trial will investigate whether treatment efficacy can be improved by adding TRT to atezolizumab maintenance therapy in ED SCLC patients with any response after chemo-immunotherapy. Safety and feasibility of such a regimen will be evaluated, and biomaterials for a translational research project will be collected. Together, the results of this trial will deepen our comprehension of how checkpoint inhibition and radiotherapy interact and contribute to the evolving landscape of SCLC therapy. Trial registration Clinicaltrials.gov identifier: NCT04462276 (Date of initial registration: 8th July 2020), https://clinicaltrials.gov/ct2/show/NCT04462276 Eudra-CT Number: 2019-003916-29 (Date of initial registration: 30th March 2020), https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003916-29/DE

Summary: Systemic inflammation is established as part of late-stage severe lung disease, but molecular, functional, and phenotypic changes in peripheral immune cells in early disease stages remain ill defined. Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small-airway inflammation, emphysema, and severe breathing difficulties. Using single-cell analyses we demonstrate that blood neutrophils are already increased in early-stage COPD, and changes in molecular and functional neutrophil states correlate with lung function decline. Assessing neutrophils and their bone marrow precursors in a murine cigarette smoke exposure model identified similar molecular changes in blood neutrophils and precursor populations that also occur in the blood and lung. Our study shows that systemic molecular alterations in neutrophils and their precursors are part of early-stage COPD, a finding to be further explored for potential therapeutic targets and biomarkers for early diagnosis and patient stratification.

Background: Neck reflex points (NRPs) are 2 × 6 potentially tender areas of the neck, denominated NRP-C0 to NRP-C7. They are different from muscular trigger points and become tender in response to chronic trigeminal irritation. NRP examination has a high inter-rater reproducibility. We investigated the prevalence of NRPs in two populations to investigate their usefulness as a clinical test for trigeminal irritation. Methods: In total, 165 patients with chronic pain and 431 students were examined for NRP tenderness using a three-level pain scale: absent pain (PI = 0), mild tenderness (PI = 1), or marked tenderness (PI = 2). Results: In patients, we found more tender NRPs than in the student group (p < 0.001), and on the left side, more tender NRPs were found in NRP-C0–C4. Left and right NRPs appeared independently (kappa 0.1–0.4), except for NRP-C7 (kappa 0.55). Females had more tender NRPs (p < 0.001). Tenderness was independent of age, BMI, and pre-existing diseases. Conclusions: NRP tenderness occurs more frequently in patients than in students, independent from potential covariates. Our results, together with previous findings, support the use of NRP examination as a clinical test for chronic silent inflammation of the trigeminal region. These data provide a base for further studies investigating correlations of NRPs with clinical findings. [ABSTRACT FROM AUTHOR]