Development and characterization of NILK-2301, a novel CEACAM5xCD3 κλ bispecific antibody for immunotherapy of CEACAM5-expressing cancers.

BACKGROUND: T-cell retargeting to eliminate CEACAM5-expressing cancer cells via CEACAM5xCD3 bispecific antibodies (BsAbs) showed limited clinical activity so far, mostly due to insufficient T-cell activation, dose-limiting toxicities, and formation of anti-drug antibodies (ADA). METHODS: We present here the generation and preclinical development of NILK-2301, a BsAb composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format). RESULTS: NILK-2301 binds CD3ɛ on T-cells with its lambda light chain arm with an affinity of ≈100 nM, and the CEACAM5 A2 domain on tumor cells by its kappa light chain arm with an affinity of ≈5 nM. FcγR-binding is abrogated by the "LALAPA" mutation (Leu234Ala, Leu235Ala, Pro329Ala). NILK-2301 induced T-cell activation, proliferation, cytokine release, and T-cell dependent cellular cytotoxicity of CEACAM5-positive tumor cell lines (5/5 colorectal, 2/2 gastric, 2/2 lung), e.g., SK-CO-1 (Emax = 89%), MKN-45 (Emax = 84%), and H2122 (Emax = 97%), with EC50 ranging from 0.02 to 0.14 nM. NILK-2301 binds neither to CEACAM5-negative or primary colon epithelial cells nor to other CEACAM family members. NILK-2301 alone or in combination with checkpoint inhibition showed activity in organotypic tumor tissue slices and colorectal cancer organoid models. In vivo, NILK-2301 at 10 mg/kg significantly delayed tumor progression in colon- and a pancreatic adenocarcinoma model. Single-dose pharmacokinetics (PK) and tolerability in cynomolgus monkeys at 0.5 or 10 mg/kg intravenously or 20 mg subcutaneously showed dose-proportional PK, bioavailability ≈100%, and a projected half-life in humans of 13.1 days. NILK-2301 was well-tolerated. Data were confirmed in human FcRn TG32 mice. CONCLUSIONS: In summary, NILK-2301 combines promising preclinical activity and safety with lower probability of ADA-generation due to its format compared to other molecules and is scheduled to enter clinical testing at the end of 2023.

[Pathophysiology, Diagnostics and Therapy of Pulmonary Contusion - Recommendations of the Interdisciplinary Group on Thoracic Trauma of the Section NIS of the German Society for Trauma Surgery (DGU) and the German Society for Thoracic Surgery (DGT)]. / Pathophysiologie, Diagnostik und Therapie der Lungenkontusion ­ Empfehlungen der interdisziplinären Arbeitsgruppe der Sektion NIS der DGU und DGT zur Thoraxtraumaversorgung.

Pulmonary contusion usually occurs in combination with other injuries and is indicative of a high level of force. Especially in multiply injured patients, pulmonary contusions are frequently detected. The injury is characterised by dynamic development, which might result in difficulties in recognising the actual extent of the injury at an early stage. Subsequently, correct classification of the extent of injury and appropriate initiation of therapeutic steps are essential to achieve the best possible outcome. The main goal of all therapeutic measures is to preserve lung function as best as possible and to avoid associated complications such as the development of pneumonia or Acute Respiratory Distress Syndrome (ARDS).The present report from the interdisciplinary working group "Chest Trauma" of the German Society for Trauma Surgery (DGU) and the German Society for Thoracic Surgery (DGT) includes an extensive literature review on the background, diagnosis and treatment of pulmonary contusion. Without exception, papers with a low level of evidence were included due to the lack of studies with large cohorts of patients or randomised controlled studies. Thus, the recommendations given in the present article correspond to a consensus of the aforementioned interdisciplinary working group.Computed tomography (CT) of the chest is recommended for initial diagnosis; the extent of pulmonary contusion correlates with the incidence and severity of complications. A conventional chest X-ray may initially underestimate the injury, but is useful during short-term follow-up.Therapy for pulmonary contusion is multimodal and symptom-based. In particular, intensive care therapy with lung-protective ventilation and patient positioning are key factors of treatment. In addition to invasive ventilation, non-invasive ventilation should be considered if the patient's comorbidities and compliance allows this. Furthermore, depending on the extent of the lung injury and the general patient's condition, ECMO therapy may be considered as an ultima ratio. In particular, this should only be performed at specialised hospitals, which is why patient assignment or anticipation of early transfer of the patient should be anticipated at an early time during the course.

[Thoracic Surgery Without Chest Tube: The Current Situation in Germany]. / Thoraxchirurgie ohne Thoraxdrainage ­ aktuelle Situation in Deutschland.

BACKGROUND: Over the last decades, several techniques have been implemented to reduce the invasiveness of thoracic surgery. Omitting chest tubes can lead to less postoperative pain and a shorter length of hospital stay. This study examines the extent to which German surgeons use the tubeless technique and what experience they have had with it. MATERIALS AND METHODS: We conducted a nationwide survey, supported by the German Society of Thoracic Surgery (DGT). A digital questionnaire was sent to all leading thoracic surgeons with DGT membership between July and September 2020. RESULTS: 63 of 161 surgeons (39%) returned the questionnaires. The tubeless technique was used in 1.9% of thoracic surgery procedures performed last year. 59% of hospitals have implemented the technique; 24% of them also performed lung resections that way. The majority of respondents (79%) believe that the tubeless technique causes less postoperative pain; 16% see no advantage. Pleural effusion was ranked as the most important contraindication (76%). All participating surgeons agree that the absence of an air fistula is a prerequisite for performing lung resections using the tubeless technique - commonly checked by an underwater leak test (73%), and/or with a digital drainage system (53%), partially under pressure controlled ventilated lungs. Almost half of the respondents (46%) have not observed any complications using the tubeless technique. CONCLUSION: Most German thoracic surgeons consider the tubeless technique safe and advantageous over the conventional technique. However, the case load is low and only 59% of the surgeons surveyed have experience with this technique. Randomised clinical trials concerning selection criteria and the procedural pathway may help increase the use.

[Occult and Retained Haemothorax - Recommendations of the Interdisciplinary Thoracic Trauma Task Group of the German Trauma Society (DGU - Section NIS) and the German Society for Thoracic Surgery (DGT)]. / Okkulter und residueller Hämatothorax nach Thoraxtrauma ­ Empfehlungen der interdisziplinären Arbeitsgruppe Thoraxtrauma der Sektion NIS der Deutschen Gesellschaft für Unfallchirurgie (DGU) und der Deutschen Gesellschaft für Thoraxchirurgie (DGT).

The management of occult and retained haemothorax is challenging for all involved in the care of polytrauma patients in terms of diagnosis and treatment. The focus of decision making is preventing sequelae such as pleural empyema and avoiding a trapped lung. An interdisciplinary task force of the German Society for Thoracic Surgery (DGT) and the German Trauma Society (DGU) on thoracic trauma offers recommendations for post-trauma care of patients with occult and/or retained haemothorax, as based on a comprehensive literature review.

CT texture analysis and node-RADS CT score of mediastinal lymph nodes - diagnostic performance in lung cancer patients.

BACKGROUND: Texture analysis derived from computed tomography (CT) can provide clinically relevant imaging biomarkers. Node-RADS is a recently proposed classification to categorize lymph nodes in radiological images. The present study sought to investigate the diagnostic abilities of CT texture analysis and Node-RADS to discriminate benign from malignant mediastinal lymph nodes in patients with lung cancer. METHODS: Ninety-one patients (n = 32 females, 35%) with a mean age of 64.8 ± 10.8 years were included in this retrospective study. Texture analysis was performed using the free available Mazda software. All lymph nodes were scored accordingly to the Node-RADS classification. All primary tumors and all investigated mediastinal lymph nodes were histopathologically confirmed during clinical workup. RESULTS: In discrimination analysis, Node-RADS score showed statistically significant differences between N0 and N1-3 (p < 0.001). Multiple texture features were different between benign and malignant lymph nodes: S(1,0)AngScMom, S(1,0)SumEntrp, S(1,0)Entropy, S(0,1)SumAverg. Correlation analysis revealed positive associations between the texture features with Node-RADS score: S(4,0)Entropy (r = 0.72, p < 0.001), S(3,0) Entropy (r = 0.72, p < 0.001), S(2,2)Entropy (r = 0.72, p < 0.001). CONCLUSIONS: Several texture features and Node-RADS derived from CT were associated with the malignancy of mediastinal lymph nodes and might therefore be helpful for discrimination purposes. Both of the two quantitative assessments could be translated and used in clinical routine.

Iatrogenic Tracheal Rupture Related to Prehospital Emergency Intubation in Adults: A 15-Year Single Center Experience.

OBJECTIVE: Iatrogenic tracheal rupture is an unusual and severe complication that can be caused by tracheal intubation. The frequency, management, and outcome of iatrogenic tracheal rupture due to prehospital emergency intubation in adults by emergency response physicians has not yet been sufficiently explored. METHODS: Adult patients with iatrogenic tracheal ruptures due to prehospital emergency intubation admitted to an academic referral center over a 15-year period (2004-2018) with consideration of individual risk factors were analyzed. RESULTS: Thirteen patients (eight female) with a mean age of 67 years met the inclusion criteria and were analyzed. Of these, eight tracheal ruptures (62%) were caused during the airway management of cardiopulmonary resuscitation (CPR). Stylet use and difficult laryngoscopy requiring multiple attempts were documented in eight cases (62%) and four cases (30%), respectively. Seven patients (54%) underwent surgery, while six patients (46%) were treated conservatively. The overall 30-day mortality was 46%; five patients died due to their underlying emergencies and one patient died of tracheal rupture. Three survivors (23%) recovered with severe neurological sequelae and four (30%) were discharged in good neurological condition. Survivors had significantly smaller mean rupture sizes (2.7cm versus 6.3cm; P <.001) and less cutaneous emphysema (n = 2 versus n = 6; P = .021) than nonsurvivors. CONCLUSIONS: Iatrogenic tracheal rupture due to prehospital emergency intubation is a rare complication. Published risk factors are not consistently present and may not be applicable to identify patients at high risk, especially not in rescue situations. Treatment options depend on individual patient condition, whereas outcome largely depends on the underlying disease and rupture extension.

[Molecule pathology in the treatment of lung cancer-Interdisciplinary view of the importance in thoracic surgery]. / Molekularpathologie in der Behandlung des Lungenkarzinoms ­ interdisziplinärer Blick auf die thoraxchirurgische Bedeutung.

Treatment modalities of lung cancer have rapidly evolved in recent years by the establishment of tumor-specific targeted drugs and immunomodulatory concepts and the complexity has rapidly increased. This development is accompanied by improved survival data and knowledge of other spectra of side effects and recurrence characteristics. This development requires that clinicians maintain a constant vigilance in the stratification of treatment options. This article gives an overview of the current clinically relevant approaches of targeted treatment of lung cancer and points out possible links to thoracic surgery. The presentation of the options of targeted therapy demonstrates which role they play in the adjuvant treatment in cases of proven mutations of epidermal growth factor receptor (EGFR), when a salvage operation can be used and how a curative treatment concept can be elaborated in individual cases through targeted treatment. Every lung cancer ultimately requires a molecular analysis of treatment-relevant mutation patterns at the earliest possible time in the diagnostics. Interdisciplinary concepts can individually guarantee the long-term survival of the patient.

Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-ß.

Post-surgery liver failure is a serious complication for patients after extended partial hepatectomies (ePHx). Previously, we demonstrated in the pig model that transplantation of mesenchymal stromal cells (MSC) improved circulatory maintenance and supported multi-organ functions after 70% liver resection. Mechanisms behind the beneficial MSC effects remained unknown. Here we performed 70% liver resection in pigs with and without MSC treatment, and animals were monitored for 24 h post surgery. Gene expression profiles were determined in the lung and liver. Bioinformatics analysis predicted organ-independent MSC targets, importantly a role for thrombospondin-1 linked to transforming growth factor-ß (TGF-ß) and downstream signaling towards providing epithelial plasticity and epithelial-mesenchymal transition (EMT). This prediction was supported histologically and mechanistically, the latter with primary hepatocyte cell cultures. MSC attenuated the surgery-induced increase of tissue damage, of thrombospondin-1 and TGF-ß, as well as of epithelial plasticity in both the liver and lung. This suggests that MSC ameliorated surgery-induced hepatocellular stress and EMT, thus supporting epithelial integrity and facilitating regeneration. MSC-derived soluble factor(s) did not directly interfere with intracellular TGF-ß signaling, but inhibited thrombospondin-1 secretion from thrombocytes and non-parenchymal liver cells, therewith obviously reducing the availability of active TGF-ß.

Human tissue cultures of lung cancer predict patient susceptibility to immune-checkpoint inhibition.

Despite novel immunotherapies being approved and established for the treatment of non-small cell lung cancer (NSCLC), ex vivo models predicting individual patients' responses to immunotherapies are missing. Especially immune modulating therapies with moderate response rates urge for biomarkers and/or assays to determine individual prediction of treatment response and investigate resistance mechanisms. Here, we describe a standardized ex vivo tissue culture model to investigate individual tumor responses. NSCLC tissue cultures preserve morphological characteristics of the baseline tumor specimen for up to 12 days ex vivo and also maintain T-cell function for up to 10 days ex vivo. A semi-automated analysis of proliferating and apoptotic tumor cells was used to evaluate tissue responses to the PD-1 inhibitor nivolumab (n = 12), from which two cases could be successfully correlated to the clinical outcome. T-cell responses upon nivolumab treatment were investigated by flow cytometry and multispectral imaging. Alterations in the frequency of the Treg population and reorganization of tumor tissues could be correlated to nivolumab responsiveness ex vivo. Thus, our findings not only demonstrate the functionality of T cells in NSCLC slice cultures up to 10 days ex vivo, but also suggests this model for stratifying patients for treatment selection and to investigate in depth the tumor-associated T-cell regulation.

[How severe is the effect of the coronavirus pandemic on the department of surgery of a university hospital? : An analysis of the first 7 weeks]. / Wie stark trifft die Corona-Pandemie die chirurgische Klinik eines universitären Maximalversorgers? : Eine Analyse der ersten 7 Wochen.

BACKGROUND: The corona pandemic poses enormous financial challenges for hospitals. Using the example of a clinic for visceral, transplantation, thorax and vascular surgery (VTTG), the performance development of inpatient care in the first 7 weeks in comparison to the previous year as well as an evaluation of the compensation measures laid down by law were evaluated. METHODOLOGY: Based on the performance figures, a comparison was made between the period from 16 March to 3 May 2019 and the same period in 2020. Changes in the number of cases, case mix, case mix index and day mix index as well as the bed occupancy days were recorded. The monetary measures from the COVID-19 Hospital Relief Act were applied to these changes and the adequacy was evaluated. RESULTS: Compared to the previous year there was a decrease in inpatient admissions of 120 patients during the observation period. As a result there was a decrease of 370 points in case mix and 1433 days of occupancy. For the whole VTTG this resulted in a decrease in revenue of approximately 0.8 million €, which was completely compensated by the flat rate payment for empty beds. The individual areas of the VTTG showed a heterogeneous picture in relation to the compensation for the loss of revenue. Elective units in particular showed a shortfall up to 128,163 € with respect to inpatient treatment for 7 weeks. CONCLUSION: The measures taken by the Government are an important support for the economic security of German hospitals. The lack of differentiation of measures by specialty leads to a heterogeneous picture in compensation for VTTG revenues and has to be understood as an alarm signal especially for elective surgical healthcare.

Thoracotomy for emergency repair of iatrogenic tracheal rupture: single center analysis of perioperative management and outcomes.

BACKGROUND: Iatrogenic tracheal ruptures are rare but life-threatening airway complications that often require surgical repair. Data on perioperative vital functions and anesthetic regimes are scarce. The goal of this study was to explore comorbidity, perioperative management, complications and outcomes of patients undergoing thoracotomy for surgical repair. METHODS: We retrospectively evaluated adult patients who required right thoracotomy for emergency surgical repair of iatrogenic posterior tracheal ruptures and were admitted to a university hospital over a 15-year period (2004-2018). The analyses included demographic, diagnostic, management and outcome data on preinjury morbidity and perioperative complications. RESULTS: Thirty-five patients who met the inclusion criteria were analyzed. All but two patients (96%) presented with critical underlying diseases and/or emergency tracheal intubations. The median time (interquartile range) from diagnosis to surgery was 0.3 (0.2-1.0) days. The durations of anesthesia, surgery and one-lung ventilation (OLV) were 172 (128-261) min, 100 (68-162) min, and 52 (40-99) min, respectively. The primary airway management approach to OLV was successful in only 12 patients (34%). Major complications during surgery were observed in 10 patients (29%). Four patients (11%) required cardiopulmonary resuscitation, one of whom received extracorporeal membrane oxygenation, and another one of these patients died during surgery. Major complications were associated with significantly higher all-cause 30-day mortality (p = 0.002) and adjusted mortality (p = 0.001) compared to patients with minor or no complications. CONCLUSIONS: Surgical repair of iatrogenic tracheal ruptures requires advanced perioperative care in a specialized center due to high morbidity and potential complications. Airway management should include early anticipation of alternative OLV approaches to provide acceptable conditions for surgery.

Clinical consequences of chest tube malposition in trauma resuscitation: single-center experience.

PURPOSE: Evaluation of trauma patients with chest tube malposition using initial emergency computed tomography (CT) and assessment of outcomes and the need for chest tube replacement. METHODS: Patients with an injury severity score > 15, admitted directly from the scene, and requiring chest tube insertion prior to initial emergency CT were retrospectively reviewed. Injury severity, outcomes, and the positions of chest tubes were analyzed with respect to the need for replacement after CT. RESULTS: One hundred seven chest tubes of 78 patients met the inclusion criteria. Chest tubes were in the pleural space in 58% of cases. Malposition included intrafissural positions (27%), intraparenchymal positions (11%) and extrapleural positions (4%). Injury severity and outcomes were comparable in patients with and without malposition. Replacement due to malfunction was required at similar rates when comparing intrapleural positions with both intrafissural or intraparenchymal positions (11 vs. 23%, p = 0.072). Chest tubes not reaching the target position (e.g., pneumothorax) required replacement more often than targeted tubes (75 vs. 45%, p = 0.027). Out-of-hospital insertions required higher replacement rates than resuscitation room insertions (29 vs. 10%, p = 0.016). Body mass index, chest wall thickness, injury severity, insertion side and intercostal space did not predict the need for replacement. CONCLUSIONS: Patients with malposition of emergency chest tubes according to CT were not associated with worse outcomes compared to patients with correctly positioned tubes. Early emergency chest CT in the initial evaluation of severely injured patients allows precise detection of possible malposition of chest tubes that may require immediate intervention.

Trabeculectomy Improves Vessel Response Measured by Dynamic Vessel Analysis (DVA) in Glaucoma Patients.

PURPOSE: To determine the effects of surgical IOP reduction (trabeculectomy) on retinal blood flow parameters in glaucoma patients using Dynamic Vessel Analysis (DVA). METHODS: 26 eyes of 26 patients with progressive primary open-angle glaucoma (POAG) despite maximal topical therapy were examined before and after trabeculectomy. The responses of the retinal vessels to flickering light provocation were measured with DVA the day before surgery and 4 to 6 weeks after trabeculectomy. Between 3 and 4 weeks before surgery all local therapies were stopped and a systemic therapy with acetazolamide and conservative free topic steroidal eye drops was started. RESULTS: In 19 patients (73%), an inadequate response to the flicker stimulation was measured preoperatively. In these patients, the maximum dilation of arteries and veins was reduced significantly as compared to healthy eyes. In this group, the maximum dilation of the arteries following the flicker provocation improved from 1.4% before to 3.8% following trabeculectomy (p<0.01). In retinal veins, this parameter increased from 3.1% to 4.6% (p<0.05). In the 7 patients whose arterial and venous reactions to flickering light provocation preoperatively did not differ from healthy eyes, there was no significant change after surgery. The initial baseline values of arteries and veins (MU) did not deviate significantly in both groups. CONCLUSION: POAG patients with progressive disease and impaired vascular regulation profit from IOP lowering trabeculectomy concerning vascular reactivity and dilative reserve, indicating a possible improvement of retinal perfusion following effective IOP control. Future studies with long-term follow-up must determine the clinical importance of these findings for the treatment of glaucoma patients.

[Hemorrhage after accidental overdosage of enoxaparin: monitoring and therapy]. / Kasuistik - Hämorrhagie nach akzidenteller Überdosierung mit Enoxaparin: Monitoring und Therapie.

At the morning of the sixth postoperative day after a complex cardiac surgery procedure, a patient accidentally received a subcutaneous injection of 450 mg Enoxaparin sodium (Clexane®, Sanofi GmbH, Frankfurt, Germany). A few hours later an excessive coagulopathy developed and necessitated the transfusion of allogenic blood products. The present case report describes and discusses our diagnostic and therapeutic approaches.