A soluble LAG-3 protein (eftilagimod alpha) and an anti-PD-L1 antibody (avelumab) tested in a phase I trial: a new combination in immuno-oncology.

BACKGROUND: Eftilagimod alpha (efti) is a major histocompatibility complex class II agonist activating antigen-presenting cells which leads to greater systemic type 1 T helper response and more cytotoxic CD8+ T-cell activation. This phase I trial evaluated the administration of efti, a soluble lymphocyte activation gene-3 (LAG-3) protein, combined with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab in advanced solid tumors. PATIENTS AND METHODS: Patients with heavily pretreated metastatic solid tumors received intravenous avelumab (800 mg) combined with subcutaneously administered efti (6 or 30 mg) for up to 12 cycles, followed by avelumab monotherapy. The primary endpoint was the assessment of the recommended phase II dose (RP2D) of efti in combination with avelumab. RESULTS: Twelve patients with different tumor entities were enrolled (six patients in each cohort). During treatment, no dose-limiting toxicities occurred, and the severity of most adverse events was grade 1 or 2. In total, nine serious adverse events were documented, resulting in a fatal outcome in two cases, but none of them were assessed to be treatment related. Five patients (42%) achieved partial response. The median progression-free survival was 1.96 months and the median overall survival was not reached, with a 12-month survival rate of 75%. CONCLUSION: Subcutaneously administered efti plus avelumab was well tolerated, and efti of 30 mg was determined to be RP2D. The activity is promising and warrants further investigation in future phase II trials.

Elastic TPU Mesh as Abdominal Wall Inlay Significantly Reduces Defect Size in a Minipig Model.

Background: The open abdomen with mesh implantation, followed by early reoperation with fascial closure, is a modern surgical approach in difficult clinical situations such as severe abdominal sepsis. As early fascial closure is not possible in many cases, mesh-mediated fascial traction is helpful for conditioning of a minimized ventral hernia after open abdomen. The aim of this study was to evaluate the clinical utilization of an innovative elastic thermoplastic polyurethane mesh (TPU) as an abdominal wall inlay in a minipig model. Methods: Ten minipigs were divided in two groups, either receiving an elastic TPU mesh or a nonelastic polyvinylidene fluoride (PVDF) mesh in inlay position of the abdominal wall. After 8 weeks, mesh expansion and abdominal wall defect size were measured. Finally, pigs were euthanized and abdominal walls were explanted for histological and immunohistochemical assessment. Results: Eight weeks after abdominal wall replacement, transversal diameter of the fascial defect in the TPU group was significantly smaller than in the PVDF group (4.5 cm vs. 7.4 cm; p = 0.047). Immunhistochemical analysis showed increased Ki67 positive cells (p = 0.003) and a higher number of apoptotic cells (p = 0.047) after abdominal wall replacement with a TPU mesh. Collagen type I/III ratio was increased in the PVDF group (p = 0.011). Conclusion: Implantation of an elastic TPU mesh as abdominal wall inlay is a promising approach to reduce the size of the ventral hernia after open abdomen by mesh-mediated traction. However, this effect was associated with a slightly increased foreign body reaction in comparison to the nonelastic PVDF.

MRI Evaluation of an Elastic TPU Mesh under Pneumoperitoneum in IPOM Position in a Porcine Model.

BACKGROUND: The frequency of laparoscopic approaches increased in hernia surgery over the past years. After mesh placement in IPOM position, the real extent of the meshes configurational changes after termination of pneumoperitoneum is still largely unknown. To prevent a later mesh folding it might be useful to place the mesh while it is kept under tension. Conventionally used meshes may lose their Effective Porosity under these conditions due to poor elastic properties. The aim of this study was to evaluate a newly developed elastic thermoplastic polyurethane (TPU) containing mesh that retains its Effective Porosity under mechanical strain in IPOM position in a porcine model. It was visualized under pneumoperitoneum using MRI in comparison to polyvinylidenefluoride (PVDF) meshes with similar structure. METHODS: In each of ten minipigs, a mesh (TPU containing or native PVDF, 10 × 20 cm) was randomly placed in IPOM position at the center of the abdominal wall. After 8 weeks, six pigs underwent MRI evaluation with and without pneumoperitoneum to assess the visibility and elasticity of the mesh. Finally, pigs were euthanized and abdominal walls were explanted for histological and immunohistochemical assessment. The degree of adhesion formation was documented. RESULTS: Laparoscopic implantation of elastic TPU meshes in IPOM position was feasible and safe in a minipig model. Mesh position could be precisely visualized and assessed with and without pneumoperitoneum using MRI after 8 weeks. Elastic TPU meshes showed a significantly higher surface increase under pneumoperitoneum in comparison to PVDF. Immunohistochemically, the amount of CD45-positive cells was significantly lower and the Collagen I/III ratio was significantly higher in TPU meshes after 8 weeks. There were no differences regarding adhesion formation between study groups. CONCLUSIONS: The TPU mesh preserves its elastic properties in IPOM position in a porcine model after 8 weeks. Immunohistochemistry indicates superior biocompatibility regarding CD45-positive cells and Collagen I/III ratio in comparison to PVDF meshes with a similar structure.

Long-term outcome and quality of life after initial and repeat resection of colorectal liver metastasis: A retrospective analysis.

BACKGROUND: Repeat hepatectomy is a widely accepted treatment for patients with recurrent colorectal liver metastasis (CRLM). The aim of this study was to compare initial and repeat hepatic resection concerning overall survival, prognostic factors and postoperative quality of life. METHODS: Data on patients who underwent initial or repeat hepatic resection for CRLM between 2010 and 2016 were prospectively collected and retrospectively evaluated. Follow-up data, EORTC QLQ-C30 and QLQ-LMC21 questionnaire results for quality of life (QoL) evaluation were analyzed. RESULTS: 160 patients at a median age of 62.8 ± 11.8 years were analyzed. 122 were initially resected and 38 underwent a repeat hepatic resection. Disease-free survival (DSF) was superior in the initial resection group (p < 0.001), while there was no difference in overall survival (OS) (p = 0.288). BMI >30 (p = 0.012), extrahepatic tumor manifestation (p = 0.037), >1 CRLM manifestation (p = 0.009), and perioperative chemotherapy (p = 0.006) in the initial resection group and primary left colon tumor (p = 0.001) in the repeat resection group were identified as prognostic factors in multivariate Cox regression analysis. EORTC QLQ-LMC-21 module symptom score displayed an increased occurrence of a dry mouth in the initial hepatectomy group (p = 0.003). EORTC QLQ-C30 general functioning and symptom scores showed no difference. CONCLUSION: Repeat hepatic resection for CRLM is as effective as primary surgical treatment in terms of OS and QoL. Patients should be selected carefully concerning prognostic factors as DFS is decreased after repeat hepatic resection.

[Video-assisted retroperitoneal debridement : Minimally invasive treatment and long-term results for necrotizing pancreatitis]. / Videoassistiertes retroperitoneales Débridement : Minimalinvasive Therapie und Langzeitverlauf bei nekrotisierender Pankreatitis.

BACKGROUND: Among patients with necrotizing pancreatitis 15-20% develop infected necrosis, which entails mortality rates of up to 20%. Particularly driven by the results of the Dutch Pancreatitis Study Group there has been a paradigm change from open necrosectomy to step-up treatment with initial percutaneous and/or endoscopic drainage followed, if necessary, by minimally invasive retroperitoneal debridement. AIM OF THE STUDY: Description of case series in which patients underwent video-assisted retroperitoneal debridement (VARD) including follow-up focused on quality of life. METHODS: Systematic cohort study including all patients who underwent a VARD procedure at the Department of General, Visceral and Transplantation Surgery at Aachen University Hospital from 2011 to 2015. Quality of life was recorded using the EORTC QLQ-C 30 questionnaire and compared to a representative sample of the German general population. RESULTS: The VARD procedure was performed in 9 cases, although in 1 case conversion to an open approach due to an acute bleeding was necessary. There was no 30-day and 60-day mortality following VARD. During the postoperative stay no patient required specific treatment for surgical complications. In particular, no enterocutaneous fistula or organ perforation was observed. Regarding the quality of life score there was no significant difference concerning the global health status, compared to the sample from the general population. DISCUSSION: Our data reinforce that a step-up approach in patients with necrotizing pancreatitis is a feasible and safe treatment procedure. For the first time, we could demonstrate satisfactory results in a long-term follow-up including QOL.

Port-site incisional hernia - A case series of 54 patients.

BACKGROUND: The increased use of laparoscopy has resulted in certain complications specifically associated with the laparoscopic approach, such as port-site incisional hernia (PIH). Until today, it is not finally clarified if port-site closure should be performed by fascia suture or not. Furthermore, the optimal treatment strategy in PIH (suture vs. mesh) is still widely unclear. The aim of this study was to present our experience with PIH in two independent departments and to derive possible treatment strategies from these results. METHODS: Between 2003 and 2013, 54 patients were operated due to port-site incisional hernia in two surgical centres. Their data were collected and retrospectively analyzed depending on surgical technique of port-site hernia repair (Mesh repair group, n = 13 vs. Suture only group, n = 41). RESULTS: Port site incisional hernia occurred in 96% (52 patients) after the use of trocars with 10 mm or larger diameter. Patients treated with mesh repair had significantly higher body mass index (BMI) (32 ± 9 vs. 27 ± 4; p = 0.023) and significantly higher rates of cardiac diseases (77% vs. 39%; p = 0.026) than patients in the suture only group. Mean fascial defect size was significantly larger in the Mesh repair group than in the Suture only group (31 ± 24 mm vs. 24 ± 32 mm; p = 0.007) and mean time of operation was significantly longer in patients operated with mesh repair (83 ± 47 min vs. 40 ± 28 min; p < 0.001). There were no significant differences in mean hospital stay (3 ± 4 days; p = 0.057) and hernia recurrence rates (9%; p = 0.653) between study groups. Mean time of follow up was 32 ± 35 months. CONCLUSIONS: In Port sites of 10 mm and larger diameter fascia should be closed by suture, whereas the risk of hernia development in 5 mm trocar placements seems to be a rare complication. Port-site incisional hernia should be treated by suture or mesh repair depending on fascial defect size and the patients' risk factors regarding preexisting deseases and body mass index.

Fascial closure after open abdomen: initial indication and early revisions are decisive factors--a retrospective cohort study.

BACKGROUND: The surgical treatment method in which the peritoneal cavity is opened anteriorly and deliberately left open, hence often called "open abdomen" has become the standard of care in damage-control procedures as well as in the management of intra-abdominal hypertension and in severe intra-abdominal sepsis. Whereas open abdomen has been closed in two stages traditionally, a modern trend is to close the fascial layers within the initial hospitalization to avoid complications like enterocutaneous fistula and hernia formation. The aim of this study was to determine crucial factors influencing the possibility of fascial closure after open abdomen. METHODS: Between 2003 and 2013, 355 adult patients were treated with open abdomen in our institution. Their data were collected and retrospectively analyzed. They were divided into two groups depending on fascial closure or not (fascial closure, n = 137 (39%) vs. non-fascial closure, n = 218 (61%)). RESULTS: The patients who reached fascial closure had a significantly higher rate of initially performed open abdomen (97 patients (71%) vs. 118 (54%), p = 0.002) and the periods of time until a second and a third look operation were significantly shorter (2.7 ± 2.5 vs. 4.2 ± 6.6 days, p = 0.021 and 5.6 ± 3.7 vs. 8.5 ± 8.6 days, p = 0.006). Furthermore, the presence of peritonitis (64 patients (47%) vs. 83 patients (38%), p = 0.023) and large bowel resection (74 patients (54%) vs. 90 patients (41%), p = 0.022) were significantly higher in this group. Rates of in-hospital mortality (97 patients (44%) vs. 38 patients (28%), p = 0.002) and the presence of pancreatitis (19 patients (9%) vs. 3 patients (2%), p = 0.013) were significantly higher in the non-fascial closure group. CONCLUSIONS: The probability to reach fascial closure after open abdomen seems to increase when open abdomen is performed initially and when early second and third look operations are performed. The presence of pancreatitis seems to be the only negative prognostic marker concerning fascial closure.

[ECG changes in patients with chronic non-cancer pain: a prospective observational study]. / EKG-Veränderungen bei Patienten mit chronischen Nichttumorschmerzen : Eine prospektive Beobachtungsstudie.

BACKGROUND: Patients with chronic non-cancer pain not only show reduced quality of life, but also chronic morbidity and increased mortality. However, little is known about prevalence and type of abnormal electrocardiogram (ECG) recordings in these individuals. MATERIAL AND METHODS: A total of 100 consecutive patients (≥ 18 years) with chronic (≥ 3 months) non-cancer pain were examined prospectively using ECG recordings and a questionnaire [German Pain Society (DGSS); further questions]. Data were collected at the first and next two follow-up outpatients' clinic appointments. RESULTS: Participation rate was 98%. Of all patients, 26% had an abnormal ECG, while 5% of these patients had an abnormal ECG first at the follow-up when consuming a different analgesic regimen. Findings were QTc prolongation (16%), ventricular block (7%), artrioventricular block (6%), and atrial fibrillation (4%). CONCLUSION: The prevalence of abnormal ECG recordings should be considered in the pain management of these patients. General ECG screening in this population should be discussed. Future studies should examine a larger population to identify potential risk factors (e.g., medication).

Immunohistochemical detection of macrophage migration inhibitory factor in fetal and adult bovine epididymis: release by the apocrine secretion mode?

Originally defined as a lymphokine inhibiting the random migration of macrophages, the macrophage migration inhibitory factor (MIF) is an important mediator of the host response to infection. Beyond its function as a classical cytokine, MIF is currently portrayed as a multifunctional protein with growth-regulating properties present in organ systems beyond immune cells. In previous studies, we detected substantial amounts of MIF in the rat epididymis and epididymal spermatozoa, where it appears to play a role during post-testicular sperm maturation and the acquisition of fertilization ability. To explore its presence in other species not yet examined in this respect, we extended the range of studies to the bull. Using a polyclonal antibody raised against MIF purified from bovine eye lenses, we detected MIF in the epithelium of the adult bovine epididymis with the basal cells representing a prominently stained cell type. A distinct accumulation of MIF at the apical cell pole of the epithelial cells and in membranous vesicles localized in the lumen of the epididymal duct was obvious. In the fetal bovine epididymis, we also detected MIF in the epithelium, whereas MIF accumulation was evident at the apical cell surface and in apical protrusions. By immunoelectron microscopy of the adult bovine epididymis, we localized MIF in apical protrusions of the epithelial cells and in luminal membrane-bound vesicles that were found in close proximity to sperm cells. Although the precise origin of the MIF-containing vesicles remains to be delineated, our morphological observations support the hypothesis that they become detached from the apical surface of the epididymal epithelial cells. Additionally, an association of MIF with the outer dense fibers of luminal spermatozoa was demonstrated. Data obtained in this study suggest MIF release by an apocrine secretion mode in the bovine epididymis. Furthermore, MIF localized in the basal cells of the epithelium and in the connective tissue could be responsible for regulating the migration of macrophages in order to avoid contact of immune cells with spermatozoa that carry a wide range of potent antigens.

Purification and characterization of macrophage migration inhibitory factor as a secretory protein from rat epididymis: evidences for alternative release and transfer to spermatozoa.

BACKGROUND: The cytokine macrophage migration inhibitory factor (MIF), originally described as a T cell product, has recently been identified to mediate cellular interactions in several endocrine organs. Western blots analysis of rat epididymal homogenates using an anti-MIF antibody indicated the presence of substantial amounts of an immunoreactive protein with the apparent Mr of 12 kDa. Our study aimed to characterize the molecular nature of this immunoreactive factor. MATERIALS AND METHODS: The purified 12 kDa protein and a cloned cDNA fragment were characterized by sequence analysis. Furthermore, expression pattern and localization of the 12 kDa protein were investigated using in situ hybridization, immunohistochemistry, immunoelectron microscopy, and western blots experiments on epididymal sections, isolated epididymal vesicles, and outer dense fibers from spermatozoa. RESULTS: The N-terminal amino acid sequence analysis over 10 amino acids revealed a 100% homology of the 12 kDa protein to the N-terminus of the cytokine MIF. These data were confirmed by sequence analysis of a reverse transcription polymerase chain reaction (RT-PCR) amplified cDNA fragment from rat epididymis, which also showed complete homology to the MIF cDNA sequence. MIF protein and mRNA were localized in the epithelial cells of the epididymis in a regional distribution manner, with the expression maximal in the caput. Immune cells were not labeled. MIF is the first classical cytokine identified to be expressed by the epididymal epithelial cells. Immunoelectron microscopy detected MIF immunoreactivity in the cytoplasm, with no reaction visible in the Golgi complex and the cisternae of the endoplasmic reticulum. At the apical cell surface, MIF accumulated in stereocilia and vesicles that were pinched off from the plasma membrane. MIF detection in vesicles isolated from epididymal secretion together with the lack of a N-terminal signal sequence for translocation in the endoplasmic reticulum strongly suggested a nonclassical secretion mode. Furthermore, MIF was identified as a new component of the outer dense fibers (ODF), a cytoskeletal element of the mid- and principal piece of the sperm tail. CONCLUSION: The cytokine MIF was identified in substantial amounts in the epithelial cells of rat epididymis and in the outer dense fibers of rat epididymal spermatozoa. Our results indicate a nonclassical secretion mode for MIF and suggest a cell-to-cell transfer of MIF via vesicles to the sperm cells.

Macrophage migration inhibitory factor (MIF) as a paracrine mediator in the interaction of testicular somatic cells.

Originally the macrophage migration inhibitory factor (MIF) was described as a classical T-cell cytokine. Recently, a much broader tissue distribution for MIF has been revealed. We demonstrated that MIF protein and mRNA are present in the Leydig cells of the normal adult rat testis. Addition of recombinant MIF to cultures of rat seminiferous tubules resulted in decreased secretion of inhibin, whereas follistatin and activin levels remained unchanged, suggesting a paracrine role for MIF in Sertoli cell regulation. Furthermore, MIF showed unique compensatory production in the rat testis. Depletion of the original MIF source, the Leydig cells, by the specific toxin EDS prompted MIF expression by the previously negative Sertoli cells. Leydig cell re-population of the interstitial tissue by precursor cells resulted in a switch back to production by Leydig cells. Therefore, testicular MIF appears to be under very tight paracrine control. MIF has thus been identified as a new mediator in the cross-talk between Leydig cells and the somatic cells of the seminiferous tubules of the rat testis.

Population-based survey of human sodium and potassium excretion.

1. During the 1989 National Heart Foundation Risk Factor Prevalence Survey a subsample in Hobart collected 24 h urine samples to measure electrolyte excretion. 2. The ranges were 30-344 mmol/24 h for Na+ excretion (mean 160 mmol/24 h for men, 124 mmol/24 h for women), and 25-119 mmol/24 h for K+ excretion (mean 77 mmol/24 h for men, 68 mmol/24 h for women). 3. As in other surveys, women excreted about 20-25% less Na+ and K+ than men, although there was no significant sex difference in the ratio of Na+/K+ excretion. 4. The recommended dietary intake (RDI) for Na+ and K+ was followed simultaneously by 19% of subjects, and 13% had a 24 h urinary Na+/K+ ratio less than or equal to 1.0. 5. Observance of the RDI limited the value of iodized salt for goitre prophylaxis. 6. Sodium excretion rates were outside the therapeutic range of thiazide diuretics in 22% of subjects. 7. Diet groups for long-term prospective cohort studies to test the prophylactic value of avoiding salt could apparently be recruited from existing subsamples of the population.

[Subsepsis allergica in a patient with type I polyglandular autoimmune syndrome]. / Subsepsis allergica bei einer Patientin mit polyglandulärem Autoimmunsyndrom Typ I.

A 10.6 year old Turkish girl developed + the signs of a polyglandular autoimmune syndrome (PGA) type I since her first year of age. Apart from the endocrine and non-endocrine symptoms of PGA, she suffered from an acute state of illness with therapy-resistant fever and multiform exanthemas in the early course of disease. All included the criteria of Wissler-Fanconi syndrome became clear which has not yet been reported in association with PGA. Although this syndrome generally is considered an equivalent of Still's syndrome, rheumatoid symptoms could not be ascertained during the following 9-year-course of PGA.