Development and validation of a clinical prediction-score model for distant metastases in major salivary gland carcinoma.

BACKGROUND: The most common pattern of failure in major salivary gland carcinoma (SGC) is development of distant metastases (DMs). The objective of this study was to develop and validate a prediction score for DM in SGC. PATIENTS AND METHODS: Patients with SGC treated curatively at four tertiary cancer centers were divided into discovery (n = 619) and validation cohorts (n = 416). Multivariable analysis using competing risk regression was used to identify predictors of DM in the discovery cohort and create a prediction score of DM; the optimal score cut-off was determined using a minimal P value approach. The prediction score was subsequently evaluated in the validation cohort. The cumulative incidence and Kaplan-Meier methods were used to analyze DM and overall survival (OS), respectively. RESULTS: In the discovery cohort, DM predictors (risk coefficient) were: positive margin (0.6), pT3-4 (0.7), pN+ (0.7), lymphovascular invasion (0.8), and high-risk histology (1.2). High DM-risk SGC was defined by sum of coefficients greater than two. In the discovery cohort, the 5-year incidence of DM for high- versus low-risk SGC was 50% versus 8% (P < 0.01); this was similar in the validation cohort (44% versus 4%; P < 0.01). In the pooled cohorts, this model performed similarly in predicting distant-only failure (40% versus 6%, P < 0.01) and late (>2 years post surgery) DM (22% versus 4%; P < 0.01). Patients with high-risk SGC had an increased incidence of DM in the subgroup receiving postoperative radiation therapy (46% versus 8%; P < 0.01). The 5-year OS for high- versus low-risk SGC was 48% versus 92% (P < 0.01). CONCLUSION: This validated prediction-score model may be used to identify SGC patients at increased risk for DM and select those who may benefit from prospective evaluation of treatment intensification and/or surveillance strategies.

Surveilling the Potential for Precision Medicine-driven PD-1/PD-L1-targeted Therapy in HNSCC.

Immunotherapy is becoming an accepted treatment modality for many patients with cancer and is now approved for use in platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Despite these successes, a minority of patients with HNSCC receiving immunotherapy respond to treatment, and few undergo a complete response. Thus, there is a critical need to identify mechanisms regulating immune checkpoints in HNSCC such that one can predict who will benefit, and so novel combination strategies can be developed for non-responders. Here, we review the immunotherapy and molecular genetics literature to describe what is known about immune checkpoints in common genetic subsets of HNSCC. We highlight several highly recurrent genetic lesions that may serve as biomarkers or targets for combination immunotherapy in HNSCC.

Core-shell alginate@silica microparticles encapsulating probiotics.

Lactobacillus rhamnosus GG (LGG) was encapsulated in core-shell alginate-silica microcapsules by coating the electrosprayed ionogel with a silica shell via hydrolysis/condensation of alkoxysilane precursors. The viability of encapsulated LGG highly depends on the mineralisation conditions (in aqueous or organic phases), identified as a critical step. More importantly, due to the unswelling of silica and to its mesoporosity that allows nutriment-metabolite diffusion, it was possible to avoid cell leakage and additionally insure bacterial growth inside the microcapsules. The results of this work gave a proof-of-concept for controlled bacterial proliferation in microcompartments, which have straightforward applications in oral delivery of probiotics.

Dielectric and mechanical relaxation in isooctylcyanobiphenyl (8*OCB).

The dynamics of isooctylcyanobiphenyl (8*OCB) was characterized using dielectric and mechanical spectroscopies. This isomer of the liquid crystalline octylcyanobiphenyl (8OCB) vitrifies during cooling or on application of pressure, exhibiting the typical features of glass-forming liquids: non-Debye relaxation function, non-Arrhenius temperature dependence of the relaxation times, τ(α), a dynamic crossover at T ∼ 1.6T(g). This crossover is evidenced by changes in the behavior of both the peak shape and the temperature dependence of τ(α). The primary relaxation time at the crossover, 2 ns at ambient pressure, is the smallest value reported to date for any molecular liquid or polymer. Interestingly, at all temperatures below this crossover, τ(α) and the dc conductivity remain coupled (i.e., conform to the Debye-Stokes-Einstein relation). Two secondary relaxations are observed in the glassy state, one of which is identified as the Johari-Goldstein process. Unlike the case for 8OCB, no liquid crystalline phase could be attained for 8*OCB, demonstrating that relatively small differences in chemical structure can effect substantial changes in the intermolecular potential.

Correlation between primary and secondary Johari-Goldstein relaxations in supercooled liquids: invariance to changes in thermodynamic conditions.

The primary alpha and the secondary Johari-Goldstein (JG) beta relaxations of supercooled glass-forming neat epoxy resin and 2-picoline in mixture with tristyrene are monitored by broadband dielectric relaxation spectroscopy at ambient pressure and elevated pressures. For different combinations of pressure and temperature that maintain the alpha-relaxation time constant, the frequency dispersion of the alpha relaxation is unchanged, as previously found in other glass-formers, but remarkably the JG beta-relaxation time remains constant. This is more clear evidence of a strong connection between the alpha- and JG beta-relaxation times, a fact that should be taken into account in the construction of a viable theory of glass transition.

Changes of relaxation dynamics of a hydrogen-bonded glass former after removal of the hydrogen bonds.

Dielectric relaxation spectra of two closely related glass formers, dipropylene glycol [H-(C3H6O)2-OH] and dipropylene glycol dimethyl ether [CH3-O-(C3H6O)2-CH3], were measured at ambient and elevated pressures in the supercooled and the glassy states are presented. Hydrogen bonds formed in dipropylene glycol are removed when its ends are replaced by two methyl groups to become dipropylene glycol dimethyl ether. In the process, the primary relaxation, the excess wing, and the resolved secondary relaxation of dipropylene glycol are all modified when the structure is transformed to become dipropylene glycol dimethyl ether. The modifications include the pressure and temperature dependences of these relaxation processes and their interrelations. Thus, by comparing the dielectric spectra of these two closely related glass formers at ambient and elevated pressures, the differences in the relaxation dynamics and properties in the presence and absence of hydrogen bonding are identified.

Temperature and pressure dependence of the dynamics in a poly(methyl acrylate) side-chain liquid-crystalline polymer.

The molecular dynamics of a side-chain polymer liquid crystal with a poly(methyl acrylate) backbone and a (p-alkoxy-phenyl)-benzoate mesogenic group have been studied in the unaligned state as a function of temperature and pressure using dielectric spectroscopy. Polarizing optical microscopy, differential scanning calorimetry, and pressure-volume-temperature (PVT) measurements revealed three transition temperatures separating four phases (glass, smectic, nematic, and isotropic). Different dynamic processes have been identified reflecting librational modes (gamma process), local relaxation of the mesogenic group (beta process), the segmental mode (alpha process) associated with the dynamic glass transition, and a slower process (delta process) reflecting the side-chain dynamics within the liquid crystal order. Pressure exerts a stronger influence on the alpha as compared to the delta process. Starting from the nematic phase, pressure was found to induce the nematic-to-smectic transformation. The associated dynamic changes were in excellent agreement with the PVT results implying that the dynamics are directly coupled to the thermodynamic state. Pressure was found to enhance the stability of the smectic order within the P-T phase diagram.

Dynamics of side-chain liquid-crystalline polymers: a dielectric spectroscopy investigation.

We have studied the dynamics in two side-chain liquid-crystalline derivatives of poly(norbornene diethylester) with dielectric spectroscopy within the temperature range 190-433 K and the pressure range 1-3000 bars. Optical microscopy, x-ray scattering, and differential scanning calorimetry (DSC) revealed the formation of a nematic- and a smectic-A phase, respectively, in the polymers with the shorter and longer spacers. Multiple relaxation processes exist originating from the backbone and mesogenic dipoles. In the smectic-A phase two relaxation processes exist above the DSC glass temperature (alpha and alpha(')) which merge with decreasing temperature or with increasing pressure, thus suggesting a common molecular mechanism. The faster process is the segmental (alpha) relaxation associated with the dynamic glass transition, whereas the slower process reflects mainly the side-chain dynamics within the smectic layers. Pressure was found to increase the glass temperature in the nematic and smectic phases and the dT(g)/dP was 18.7 and 16.9 K/kbar, respectively. However, the effect of pressure in inducing the isotropic-to-smectic transition is more drastic as dT(SI)/dP=26.4 K/kbar.

Mitral valve repair versus mitral valve replacement.

Over the past 40 years mitral valve surgery has changed dramatically. After initial enthusiasm with the introduction of valve prostheses in the 1960s, a renewed interest in repair techniques began in the 1970s with the introduction of annuloplasty rings. These repair techniques revealed that the integrity of the subvalvular apparatus plays an important role in left ventricular function. When considering the major series comparing early and late results of mitral valve repair versus prosthetic mitral valve replacement, operative mortality rate is lower for patients with mitral valve repair. Long-term results also show a superior survival rate after mitral valve reconstruction. In addition, several problems can occur with the prosthetic valve, such as thromboembolism and endocarditis. All of these factors favor valve repair over replacement. The success of mitral valve repair depends on many factors: etiology of the mitral valve disease and the resultant pathomorphology of the valve, patient's circumstances such as age or contraindication for anticoagulation, and the experience of the surgeon. The decision whether to repair or replace the mitral valve depends on these factors. Data in the literature and in large collective databases reflect the advantages of mitral valve repair, with over 75% of current mitral valve surgeries being repairs. In the past 5 years the exposure of the mitral valve through a right lateral minithoracotomy using video assistance has developed into a widespread technique. This approach allows complex mitral valve repair as well as mitral valve replacement even with biological stentless prostheses, with decreased morbidity. The addition of radiofrequency ablation for restoration of sinus rhythm enhances the outcome after mitral valve surgery, and can also be easily performed through a minithoracotomy technique.

[Mitral valve repair versus mitral valve replacement]. / Mitralklappenrekonstruktion vs. Mitralklappenersatz.

Over the past 40 years mitral valve surgery has changed dramatically. After initial enthusiasm with the introduction of valve prostheses in the 1960s, a renewed interest in repair techniques began in the 1970s with the introduction of annuloplasty rings. These repair techniques revealed that the integrity of the subvalvular apparatus plays an important role in left ventricular function. When considering the major series comparing early and late results of mitral valve repair versus prosthetic mitral valve replacement, operative mortality rate is lower for patients with mitral valve repair. Long-term results also show a superior survival rate after mitral valve reconstruction. In addition, several problems can occur with the prosthetic valve, such as thromboembolism and endocarditis. All of these factors favor valve repair over replacement. The success of mitral valve repair depends on many factors: etiology of the mitral valve disease and the resultant pathomorphology of the valve, patient's circumstances such as age or contraindication for anticoagulation, and the experience of the surgeon. The decision whether to repair or replace the mitral valve depends on these factors. Data in the literature and in large collective databases reflect the advantages of mitral valve repair, with over 75 % of current mitral valve surgeries being repairs.In the past 5 years the exposure of the mitral valve through a right lateral minithoracotomy using video assistance has developed into a widespread technique. This approach allows complex mitral valve repair as well as mitral valve replacement even with biological stentless prostheses, with decreased morbidity. The addition of radiofrequency ablation for restoration of sinus rhythm enhances the outcome after mitral valve surgery, and can also be easily performed through a minithoracotomy technique.

Resection of atherosclerotic aneurysm at origin of aberrant right subclavian artery.

In two patients (75- and 88-years-old), with the aid of cardiopulmonary bypass and using a transaortic approach, a rare calcified aneurysm at the origin of an aberrant right subclavian artery was closed with a prosthetic patch. The aneurysm was partially resected and the remainder closed over the patch. This technique obviates the need for hazardous clamping of the aorta around the base of the calcified aneurysm and allows secure closure of the origin of the aneurysm.

MutS recognition of exocyclic DNA adducts that are endogenous products of lipid oxidation.

The ability of the methyl-directed mismatch repair system to recognize and repair the exocyclic adducts propanodeoxyguanosine (PdG) and pyrimido[1,2-alpha]purin-10(3H)-one (M(1)G), the major adduct derived from the endogenous mutagen malondialdehyde, has been assessed both in vivo and in vitro. Both adducts were site-specifically incorporated into M13MB102 DNA, and the adducted genomes were electroporated into wild-type or mutS-deficient Escherichia coli strains. A decrease in mutations caused by both adducts was observed in mutS-deficient strains, suggesting that MutS was binding to the adducts and blocking repair by nucleotide excision repair. This hypothesis was supported by the differences in mutation frequency observed when hemimethylated genomes containing PdG on the (-)-strand were electroporated into a uvrA(-) strain. The ability of purified MutS to bind to PdG- or M(1)G-containing 31-mer duplexes in vitro was assessed using both surface plasmon resonance and gel shift assays. MutS bound to M(1)G:T-containing duplexes with similar affinity to a G:T mismatch but less strongly to M(1)G:C- and PdG-containing duplexes. Dissociation from each of the adduct-containing duplexes occurred at a faster rate than from a G:T mismatch. The present results indicate that MutS can bind to exocyclic adducts resulting from endogenous DNA damage and trigger their removal by mismatch repair or protect them from removal by nucleotide excision repair.

Aortic root reconstruction with preservation of native aortic valve and sinuses in aortic root dilatation with aortic regurgitation.

BACKGROUND: We assessed the results of a modified technique for aortic root reconstruction including preservation of the native aortic valve and sinuses. METHODS: A modified technique for reconstruction of the aortic root was devised in which the native aortic sinuses are preserved and remodeled, the diameter of the sinotubular junction is reduced, the ventriculoaortic junction is reinforced with a Dacron prosthesis, and the coronary ostia are reimplanted. Since January 1995, this modified operative technique was performed in 13 patients with a mean age of 54 +/- 21 years. The median grade of aortic regurgitation was 3; in 10 patients it was caused by dilatation of the sinotubular junction, and 3 had additional annuloaortic ectasia. RESULTS: The aortic crossclamping time was 61 +/- 18 minutes. In-hospital mortality was 2 of 13 (15. 3%) patients, both deaths being related to complications of aortic dissection. In 1 patient aortic regurgitation increased to grade 3, necessitating aortic valve replacement. At a mean follow-up of 2.1 years, the remaining 10 patients had stable aortic valve function with a median grade of regurgitation of 1. The mean New York Heart Association functional class was 1.2. CONCLUSIONS: Aortic root reconstruction with preservation of the native aortic valve and sinuses allows symmetric reconstruction of the aortic sinuses and adaptation of the diameters of the sinotubular and ventriculoaortic junctions, thus optimizing aortic valve function. Moreover, it prevents contact of the aortic valve leaflets with the Dacron graft, which may enhance the durability of the repair.

Rare fatal simultaneous mould infection of the lung caused by Aspergillus flavus and the basidiomycete Coprinus sp. in a leukemic patient.

The basidiomycete Coprinus sp. was isolated repeatedly from bronchial secretions and bronchoalveolar lavage of a 40-year-old woman suffering from a relapse of acute lymphoblastic leukemia 5 years after she underwent autologous bone marrow transplantation. Post-mortem microbiological investigation of lung tissue revealed simultaneously growing Coprinus sp. and Aspergillus flavus. Histopathological examination of the lung demonstrated septate hyphae characteristic of both Aspergillus and Coprinus. The basidiomycete Coprinus sp. should be considered as a potential opportunistic pathogen because of its excellent growth at 37 degrees C.

Disseminated mycosis due to Scedosporium prolificans in an AIDS patient with Burkitt lymphoma.

A case of fatal disseminated infection caused by the dematiaceous hyphomycete Scedosporium prolificans diagnosed post mortem is reported in a 60-year-old male patient with acquired immunodeficiency syndrome who additionally suffered from Burkitt's lymphoma. The patient was significantly granulocytopenic following aggressive chemotherapy and irradiation. He developed dyspnoea at rest and chest pain despite a normal chest radiograph. Fluconazole treatment was carried out empirically because no sign of a fungal infection was detected ante mortem, either by mycological cultivation or by serological investigation. First post-mortem examination revealed a disseminated fungal infection involving the central nervous system. Scedosporium prolificans was cultured from the kidney, spleen and myocardium. In vitro, the fungal isolate was found to be highly resistant to all available systemic antimycotics.

[Invasive mold infections in the university clinics of Leipzig in the period from 1992-1994]. / Invasive Schimmelpilzinfektionen am Universitätsklinikum Leipzig im Zeitraum 1992-1994.

Invasive mould infection, e. g. aspergillosis in the first place, is a common infection in immunocompromised patients. The diagnosis of invasive mould infection is difficult in the absence of confirmation by tissue biopsy and histological studies. Therefore, prevalence of invasive mould infections at the School of Medicine of the Leipzig University between 1992 and 1994 was investigated. The diagnosis of invasive mould infection was suspected on clinical, mycological, and radiological findings. The definitive diagnosis was obtained by identification of characteristic mould hyphae on stained smears, and/or positive culture, and/or the detection of Aspergillus antigen (Pastorex) in serum, bronchial secretion, or bronchoalveolar fluid, and confirmed by histopathology. In altogether 21 patients the definitive diagnosis invasive mould infection was recorded, among them 20 invasive aspergilloses. Underlying diseases were leukaemia (n = 11), aplastic anaemia (n = 2), non-Hodgkin-lymphoma (n = 1), systemic lupus erythematosus (n = 1), kidney transplantation (n = 1), peritonitis after Billroth II anastomosis (n = 1), Polymyalgia rheumatica (n = 1), AIDS plus Burkitt lymphoma (n = 1), glioblastoma (n = 1), and subarachnoid haemorrhage (n = 1). As causative fungi were isolated: Aspergillus fumigatus (n = 13), Aspergillus terreus (n = 1), Aspergillus flavus as rare simultaneous injection with the basidiomycete Coprinus spec. in a leukaemic patient (n = 1), and the dematiaceous fungus Scedosporium prolificans in an AIDS patient with Burkitt lymphoma (n = 1). In four patients the invasive mould infection was confirmed histopathologically without isolation and differentiation of the causative agent. Nineteen of the 21 patients with invasive mould infections died corresponding to a mortality rate of 90%.

Peracute disseminated fatal Aspergillus fumigatus sepsis as a complication of corticoid-treated systemic lupus erythematosus.

Immunocompromised and granulocytopenic patients and those receiving long-term or high-dose corticoid treatment are predisposed to disseminating Aspergillus infections. However, Aspergillus infection has been described only rarely in patients with autoimmune diseases. We report on a woman suffering from systemic lupus erythematosus treated by antibiotics and high-dose corticosteroids, a primary risk factor, who developed a peracute disseminated fatal Aspergillus fumigatus infection involving the central nervous system. The present case is compared with 10 previous reports of invasive aspergillosis in systemic lupus erythematosus found by a literature search.