Histopathological growth patterns of resected non-colorectal,non-neuroendocrine liver metastases: a retrospective multicenter study

Background

Distinct Histopathological Growth Patterns can be identified in liver metastases from melanoma, breast and colorectal cancers. For each of these distinct liver metastasis types the HGP has proven a biomarker for survival after partial hepatectomy, with the desmoplastic type marking favourable prognosis. Whether HGPs can be considered a pan-cancer phenomenon remains unknown. This study therefore evaluates the presence of HGPs and their prognostic value across non-colorectal non-neuroendocrine liver metastases.

Methods

A retrospective multicentre cohort study was performed in patients who underwent curative intent resection of non-colorectal non-neuroendocrine liver metastasis. HGPs were assessed on Haematoxylin and Eosin slides according to consensus guidelines and classified as desmoplastic or non-desmoplastic. Overall- and recurrence-free survival were evaluated using Kaplan–Meier and multivariable Cox regression analysis.

Results

In total, 132 patients with liver metastasis from 25 different tumour types were eligible for analysis, of which 26 (20%) had a desmoplastic HGP. Five-year OS and RFS (95%CI) were 53% (36–78%) versus 40% (30–53%), and 33% (19–61%) versus 15% (9–27%) for patients with desmoplastic compared to non-desmoplastic metastases, respectively (p?=?0.031 & p?=?0.004). On multivariable analysis (adjusted HR [95%CI]) a desmoplastic HGP was prognostic for both OS (0.46 [0.25–0.86]) and RFS (0.38 [0.21–0.69]).

Conclusions

This study demonstrates that HGPs apply to liver metastases across a wide variety of primary tumour origins. They hold a prognostic value in these cases, suggesting that HGPs could represent a pan-cancer biomarker for survival after surgical resection of liver metastases.

     

Dependency of R2 and R2* relaxation on Gd-DTPA concentration in arterial blood: Influence of hematocrit and magnetic field strength

Dynamic susceptibility contrast (DSC) MRI is clinically used to measure brain perfusion by monitoring the dynamic passage of a bolus of contrast agent through the brain. For quantitative analysis of the DSC images, the arterial input function is required. It is known that the original assumption of a linear relation between the R₂^(*) relaxation and the arterial contrast agent concentration is invalid, although the exact relation is as of yet unknown. Studying this relation in vitro is time-consuming, because of the widespread variations in field strengths, MRI sequences, contrast agents, and physiological conditions. This study aims to simulate the R₂^(*) versus contrast concentration relation under varying physiological and technical conditions using an adapted version of an open-source simulation tool. The approach was validated with previously acquired data in human whole blood at 1.5 T by means of a gradient-echo sequence (proof-of-concept). Subsequently, the impact of hematocrit, field strength, and oxygen saturation on this relation was studied for both gradient-echo and spin-echo sequences. The results show that for both gradient-echo and spin-echo sequences, the relaxivity increases with hematocrit and field strength, while the hematocrit dependency was nonlinear for both types of MRI sequences. By contrast, oxygen saturation has only a minor effect. In conclusion, the simulation setup has proven to be an efficient method to rapidly calibrate and estimate the relation between R₂^(*) and gadolinium concentration in whole blood. This knowledge will be useful in future clinical work to more accurately retrieve quantitative information on brain perfusion.     

Cure of prediabetic mice by viral infections involves lymphocyte recruitment along an IP-10 gradient

Viruses can cause but can also prevent autoimmune disease. This dualism has certainly hampered attempts to establish a causal relationship between viral infections and type 1 diabetes (T1D). To develop a better mechanistic understanding of how viruses can influence the development of autoimmune disease, we exposed prediabetic mice to various viral infections. We used the well-established NOD and transgenic RIP-LCMV models of autoimmune diabetes. In both cases, infection with the lymphocytic choriomeningitis virus (LCMV) completely abrogated the diabetic process. Interestingly, such therapeutic viral infections resulted in a rapid recruitment of T lymphocytes from the islet infiltrate to the pancreatic draining lymph node, where increased apoptosis was occurring. In both models this was associated with a selective and extensive expression of the chemokine IP-10 (CXCL10), which predominantly attracts activated T lymphocytes, in the pancreatic draining lymph node, and in RIP-LCMV mice it depended on the viral antigenic load. In RIP-LCMV mice, blockade of TNF-alpha or IFN-gamma in vivo abolished the prevention of T1D. Thus, virally induced proinflammatory cytokines and chemokines can influence the ongoing autoaggressive process beneficially at the preclinical stage, if produced at the correct location, time, and levels.     

Prehospital emergency endotracheal intubation using the Bonfils intubation fiberscope.

Among all prehospital emergency intubations, difficulties occur in 7-10%. Furthermore, intubation conditions often worsen when the cervical spine is immobilized in trauma patients. We report on six patients in whom the Bonfils intubation fiberscope, a reusable, rigid fiberoptic device, was used for emergency endotracheal intubation in the field. Three of these patients had an anticipated or unanticipated difficult airway: two trauma patients with immobilized cervical spine and one patient in cardiac arrest in whom direct laryngoscopy failed twice. Endotracheal intubation with the Bonfils intubation fiberscope was successful in all cases in the first attempt. The Bonfils intubation fiberscope therefore demonstrated its value as an additional airway management device in both emergency and prehospital settings.     

Cross-competition of CD8+ T cells shapes the immunodominance hierarchy during boost vaccination

CD8+ T cell responses directed against multiple pathogen-derived epitopes are characterized by defined immunodominance hierarchy patterns. A possible explanation for this phenomenon is that CD8+ T cells of different specificities compete for access to epitopes on antigen-presenting cells, and that the outcome of this so-called cross-competition reflects the number of induced T cells. In our study using a vaccinia virus infection model, we found that T cell cross-competition is highly relevant during boost vaccination, thereby shaping the immunodominance hierarchy in the recall. We demonstrate that competition was of no importance during priming and was unaffected by the applied route of immunization. It strongly depended on the timing of viral antigen expression in infected APCs, and it was characterized by poor proliferation of T cells recognizing epitopes derived from late viral proteins. To our knowledge, this is the first demonstration of the functional importance of T cell cross-competition during a viral infection. Our findings provide a basis for novel strategies for how boost vaccination to defined antigens can be selectively improved. They give important new insights into the design of more efficient poxviral vectors for immunotherapy.     

Quality of occlusal outcome following space closure in cases of lower second premolar aplasia using lingual orthodontic molar mesialization without maxillary counterbalancing extraction

Background

Controlled space closure in cases of isolated lower second premolar aplasia (ILSPA) without maxillary counterbalancing extraction is challenging. Anterior anchorage loss may occur during space closure resulting in compromised occlusal results in terms of an absence of proper canine guidance during laterotrusive mandible movements.In order to evaluate the effectiveness of Herbst telescope anchorage in combination with double-cable, pull mechanics and a completely customized lingual appliance for orthodontic space management in cases of ILSPA, we tested the null hypothesis that there is a significant deterioration in the sagittal canine relationship towards an Angle-Class-II occlusion expressed as a loss of anterior anchorage following space closure with molar mesialization.

Methods

Twenty-five consecutively de-bonded subjects (female / male 17 / 8; aged at T0 (start of MB Tx) 12.3 to 20.6 years; mean age 15.0 / SD 1.7 years) were included in this retrospective analysis using the inclusion criteria of least of one lower second premolar aplasia; completed treatment with a totally customized lingual appliance (CCLA) in combination with Herbst telescopes. Exclusion criteria were the absence of counterbalancing maxillary extractions, as well as additional tooth aplasia other than lower second premolars. A total of 33 single, lower premolar aplasia space closures (right / left sided 17 / 16) were assessed using plaster casts and intra-oral photographs scaled to the plaster casts, at bonding (T0), Herbst insertion (T1), following gap closure (T2) and de-bonding (T3). Parallelism of roots was controlled by panoramic x-rays at T3.

Results

The mean aplasia space at T0 was 7.5 mm (SD 2.6). Complete space closure was achieved in all 33 situations. The null hypothesis was rejected. There was a significant improvement in the initial canine relationships (mean 3.5 mm distal occlusion at T0) to a mean 0.1 mm at T3. When evaluated against the individual treatment plan, the following amounts of planned improvements were achieved: space closure 100%, canine relationship 97.5%, overjet 93.9%, overbite 96.4%, parallel roots in space closure site 93.9%.

Conclusion

Herbst telescope anchorage in combination with double-cable pull mechanics and a CCLA for orthodontic space closure can deliver predictable, high-quality treatment results.

     

Native infective endocarditis: Which determinants of outcome remain after surgical treatment?

Summary Surgical therapy of native infective endocarditis is still considered as a particular challenge, due to remaining morbidity and mortality up to 20%. Further risk analysis and characterization of clinical features is of great importance for further improvement of surgical results. The aim of this retrospective study was a risk analysis concerning clinical features of the pre–, intra– and postoperative period. Between 02/1997 and 12/2003, 165 patients (130 male, 35 female, age 55.5 ± 13.8 years) were referred for surgical therapy of infective endocarditis at our institution. Preoperative, intraoperative and postoperative features were evaluated for their influence on the early postoperative course and the mid–term follow–up. In the majority of patients (pts) the aortic valve was infected (n = 83, 50.3% of pts), followed by mitral valve (n = 33; 20.0%), tricuspid valve (n = 10, 6.0%) and pulmonary valve (n = 2; 1.2%). Double valve affection was recorded in 37 pts (22.4%). Streptococci (n = 66, 40.0%) and staphylococci (n = 66, 40.0%) were the most common pathogens. The overall hospital mortality rate was 10.9% (n = 18), during follow–up (mean follow–up 3.3 ± 2.5 years) a further 20 pts (12.1%) died. Main predictors for hospital mortality in multivariate analysis were older age (p = 0.01), prolonged ICU stay, prolonged intubation (p = 0.03; p = 0.02) and the continuous postoperative need of alpha–catecholamine medication (p < 0.01). Significant predictors of overall mortality were older age (> 70 years) and diabetes (p = 0.03; p = 0.03). Reinfection occurred in 6.1% of patients (n = 10). Actuarial freedom from recurrent infection was 97% at 1 year and 93.9% at 5 years. Surgical therapy of infective endocarditis is associated with good clinical results in the early and mid–term follow–up. Predictors of outcome particular include preoperative risk constellation or comorbidity (age, diabetes) and variables of the immediate postoperative course.     

Benign and Malignant Epididymal Masses Evaluated With Scrotal Sonography

Objective. The purpose of this study was to determine whether the clinical history and sonographic appearance of solid epididymal masses could aid in distinguishing benign and malignant disease. Methods. We retrospectively reviewed the medical records of all patients who had solid epididymal masses evaluated by scrotal sonography at our institution between 1996 and 2004. We evaluated multiple clinical and sonographic variables, including lesion size, location, echogenicity, color Doppler characteristics, and calcifications. Results. Of the 85 patients included in the study, 25 (29%) underwent surgical intervention, and 5 (6%) had malignant disease. A mass size of greater than 1.5 cm and the presence of color Doppler flow were statistically significant markers for malignancy (P < .05). Combining these 2 variables as a test for malignancy yielded sensitivity of 100%, specificity of 80%, a positive predictive value of 24%, and a negative predictive value of 100%. Conclusions. Most solid epididymal masses (94%) are benign. A size of greater than 1.5 cm and the presence of color Doppler flow may help identify possible malignant masses.     

Thermo-sensitive transition of monomethoxy poly(ethylene glycol)-block-poly(trimethylene carbonate) films to micellar-like nanoparticles.

Monomethoxy poly(ethylene glycol)-block-poly(trimethylene carbonate) (mPEG(3)-PTMC(11), M(n) of mPEG=3.1 x 10(3) and M(n) of PTMC=10.8 x 10(3)g/mol) was synthesized by ring-opening polymerization of TMC using mPEG(3) as an initiator and stannous octoate as a catalyst. The block copolymer has a broad melting range with a peak at 49.5 degrees C and a heat of fusion of 47.6J/g. The heat of fusion normalized to the mPEG content is higher than that of the mPEG(3) polymer, suggesting that PTMC segments are also semi-crystalline. The mPEG(3)-PTMC(11) films were stable in water at room temperature, whereas at 37 degrees C the film specimens disintegrated and the amphiphilic block copolymer self-assembled into micellar-like nanoparticles with average sizes up to 210nm. The critical association concentration (CAC) of the formed micellar-like particles is 1.35 x 10(-3)mg/ml. The average size and polydispersity index of the formed mPEG(3)-PTMC(11) nanoparticles depend on temperature and storage time: the values decrease with increases in temperature and in storage time. By co-dissolving dexamethasone with mPEG(3)-PTMC(11) during the film preparation, micellar-like nanoparticles loaded with dexamethasone can be obtained after the film to micellar-like nanoparticles transition. A high loading efficiency of 93.3 wt.% was achieved. The sustained release of the drug was complete in 20d.     

The multi-omics promise in context: from sequence to microbial isolate

The numbers and diversity of microbes in ecosystems within and around us is unmatched, yet most of these microorganisms remain recalcitrant to in vitro cultivation. Various high-throughput molecular techniques, collectively termed multi-omics, provide insights into the genomic structure and metabolic potential as well as activity of complex microbial communities. Nonetheless, pure or defined cultures are needed to (1) decipher microbial physiology and thus test multi-omics-based ecological hypotheses, (2) curate and improve database annotations and (3) realize novel applications in biotechnology. Cultivation thus provides context. In turn, we here argue that multi-omics information awaits integration into the development of novel cultivation strategies. This can build the foundation for a new era of omics information-guided microbial cultivation technology and reduce the inherent trial-and-error search space. This review discusses how information that can be extracted from multi-omics data can be applied for the cultivation of hitherto uncultured microorganisms. Furthermore, we summarize groundbreaking studies that successfully translated information derived from multi-omics into specific media formulations, screening techniques and selective enrichments in order to obtain novel targeted microbial isolates. By integrating these examples, we conclude with a proposed workflow to facilitate future omics-aided cultivation strategies that are inspired by the microbial complexity of the environment.