Expression of DNA mismatch repair proteins in melanoma patients treated with immune checkpoint inhibitors.

PURPOSE: To investigate the protein expression of DNA mismatch repair (MMR) proteins in patients with cutaneous melanoma (CM) under immune checkpoint inhibitor (ICI) therapy. METHODS: Immunohistochemistry was performed on tumor tissue for MMR proteins MLH1, MSH2, MSH6, and PMS2 in 50 metastatic CM patients treated with ICI (ipilimumab, nivolumab, pembrolizumab). RESULTS: Best overall response (BOR) rate was 48% (24/50). Reduced MMR protein expression (nuclear expression in < 80% of tumor cells) was observed in 8 patients (16%). Compared to other clinical parameters, baseline neutrophil/lymphocyte ratio and reduced intratumoral MMR protein expression (P = 0.0033) were determined as the only parameters significantly associated with favorable BOR. However, in this small study population, reduced MMR protein expression did not reach statistical significance in multivariate analysis. CONCLUSION: Reduced MMR protein expression is observed in CM and might predict favorable BOR in patients treated with ICI, as was observed for other entities. However, these findings need to be substantiated in larger patient cohorts.

The effect of olfactory training on olfactory bulb volumes in patients with idiopathic olfactory loss.

Olfactory loss impacts around 20% of the population and is associated with the reduction of pleasure from eating and drinking, sex and depression (1). Encouragingly, research findings have consistently demonstrated that olfactory training (OT) can improve olfactory function in people with olfactory loss due to various aetiologies (2). The most commonly used method for OT involves smelling four different odours (lemon, eucalyptus, rose and cloves), twice daily, for 12 weeks.

Variable versus conventional lung protective mechanical ventilation during open abdominal surgery (PROVAR): a randomised controlled trial.

BACKGROUND: Experimental studies showed that controlled variable ventilation (CVV) yielded better pulmonary function compared to non-variable ventilation (CNV) in injured lungs. We hypothesized that CVV improves intraoperative and postoperative respiratory function in patients undergoing open abdominal surgery. METHODS: Fifty patients planned for open abdominal surgery lasting >3 h were randomly assigned to receive either CVV or CNV. Mean tidal volumes and PEEP were set at 8 ml kg-1 (predicted body weight) and 5 cm H2O, respectively. In CVV, tidal volumes varied randomly, following a normal distribution, on a breath-by-breath basis. The primary endpoint was the forced vital capacity (FVC) on postoperative Day 1. Secondary endpoints were oxygenation, non-aerated lung volume, distribution of ventilation, and pulmonary and extrapulmonary complications until postoperative Day 5. RESULTS: FVC did not differ significantly between CVV and CNV on postoperative Day 1, 61.5 (standard deviation 22.1) % vs 61.9 (23.6) %, respectively; mean [95% confidence interval (CI)] difference, -0.4 (-13.2-14.0), P=0.95. Intraoperatively, CVV did not result in improved respiratory function, haemodynamics, or redistribution of ventilation compared to CNV. Postoperatively, FVC, forced expiratory volume at the first second (FEV1), and FEV1/FVC deteriorated, while atelectasis volume and plasma levels of interleukin-6 and interleukin-8 increased, but values did not differ between groups. The incidence of postoperative pulmonary and extrapulmonary complications was comparable in CVV and CNV. CONCLUSIONS: In patients undergoing open abdominal surgery, CVV did not improve intraoperative and postoperative respiratory function compared with CNV. CLINICAL TRIAL REGISTRATION: NCT 01683578.

[Imaging of visceral vessels]. / Bildgebende Darstellung viszeraler Gefäße.

Visceral vessel processes are primarily or secondarily included in a multitude of clinical abdominal symptoms, with which the specialist in internal medicine is confronted. The spectrum ranges from more sharply outlined manifestations, such as chronic ischemic bowel disease up to dysfunctional disturbances of blood pressure regulation, such as high-grade renal artery stenosis. Sometimes diseases with prognostic implications, such as arterial aneurysms, are revealed as incidental findings. As a rule the B­mode and duplex ultrasound can often be complemented by computed tomography (CT) and magnetic resonance imaging (MRI), as in aneurysms or portal vein thrombosis or the indications for subsequent digital subtraction angiography (DSA) and catheter-based therapy can be directly obtained from duplex and Doppler ultrasound. The present review article focuses on the use of these methods in the most important diseases, with the exception of acute abdomen because this requires further detailed etiological and diagnostic systematization.

[Imaging representation of peripheral veins]. / Bildgebende Darstellung peripherer Venen.

Several techniques are available for imaging of the venous system of the legs and pelvic region. In cases of suspected deep leg vein thrombosis B­mode compression ultrasound is applied. Its accuracy is sufficient to either confirm or exclude the diagnosis with certainty. For examination of the iliac veins, however, flow information has to be added by pulsed wave (PW) Doppler or color Doppler sonography. In cases of suspected arm vein thrombosis, ultrasound is also the method of choice. The more proximal or the central parts of the venous system, i. e. brachiocephalic veins or the superior and inferior vena cava can be visualized by cross-sectional imaging procedures. Computed tomography (CT) angiography accurately shows the vessel lumen and magnetic resonance imaging (MRI) provides more details of the surrounding soft tissue. The use of classical contrast medium phlebography is nowadays restricted to interventions on proximal or central parts of the venous system. In addition, venous imaging is required in the field of chronic venous insufficiency. For both differential diagnostics and choice of treatment options, e. g. for varicose veins, the mainstay is venous ultrasound.

[Imaging of vessels supplying the brain]. / Bildgebende Darstellung hirnversorgender Gefäße.

Nowadays, several technically validated modalities are available for imaging both the extracranial and intracranial segments of arteries supplying blood to the brain. In the acute stroke setting, computed tomography (CT) angiography is of utmost importance because it provides the key diagnostic criteria indicative for the use of catheter-based recanalization techniques. Ultrasound imaging of extracranial arteries is most suitable for detecting an underlying stenosis of the internal carotid artery (ICA) in patients with stroke, transient ischemic attacks (TIA), retinal vessel occlusion and amaurosis fugax. Ultrasound imaging enables measurement of the methodologically most reliable criteria for grading stenosis of the ICA, which defines the indications for revascularization procedures in this territory. Magnetic resonance imaging (MRI) in the cross-sectional mode is of greatest value in confirming or excluding an arterial dissection even in short arterial segments, whereas MR angiography generates a more global view of the cerebral circulation. In most cases classical digital subtraction angiography (DSA) is no longer needed for diagnostic purposes only. Conversely, it is an indispensable component of any interventional approach and thus of growing importance. Ultrasound imaging is not indicated for the clarification of vertigo or syncope. In addition, there is no evidence that ultrasound screening of the ICA adds any value to the care of asymptomatic persons.

Noninvasive assessment and quantification of tumour vascularisation using MRI and CT in a tumour model with modifiable angiogenesis - An animal experimental prospective cohort study.

BACKGROUND: To investigate vascular-related pathophysiological characteristics of two human lung cancers with modifiable vascularisation using MRI and CT. METHODS: Tumour xenografts with modifiable vascularisation were established in 71 rats (approval by the Animal Care Committee was obtained) by subcutaneous transplantation of two human non-small-cell lung cancer (NSCLC) cells (A549, H1299) either alone or co-transplanted with vascular growth promoters. The vascularity of the tumours was assessed noninvasively by MRI diffusion-weighted-imaging (DWI), T2-weighted, and time-of-flight (TOF) sequences) as well as contrast-enhanced CT (CE-CT), using clinical scanners. As a reference standard, histological examinations (CD-31, fluorescent beads) were done after explantation. RESULTS: Microvessel density (MVD) was higher in co-transplanted tumours (171 ± 19 number/mm2) than in non-co-transplanted tumours (111 ± 11 number/mm2; p = 0.002). Co-transplanted tumours showed higher growth rates and larger tumour vessels at TOF-MRI as well as larger necrotic areas at CE-CT. In co-transplanted tumours, DWI revealed higher cellularity (lower minimal ADCdiff 166 ± 15 versus 346 ± 27 mm2/s × 10-6; p < 0.001), highly necrotic areas (higher maximal ADCdiff 1695 ± 65 versus 1320 ± 59 mm2/s × 10-6; p < 0.001), and better-perfused tumour stroma (higher ADCperf 723 ± 36 versus 636 ± 51 mm2/s × 10-6; p = 0.005). Significant correlations were found using qualitative and quantitative parameters: maximal ADCperf and MVD (r = 0.326); maximal ADCdiff and relative necrotic volume on CE-CT (r = 0.551); minimal ADCdiff and MVD (r = -0.395). CONCLUSIONS: Pathophysiological differences related to vascular supply in two human lung cancer cell lines with modifiable vascularity are quantifiable with clinical imaging techniques. Imaging parameters of vascularisation correlated with the results of histology. DWI was able to characterise both the extent of necrosis and the level of perfusion.

[Olfactory dysfunction : Update on diagnosis and treatment]. / Riechstörungen : Update zur Diagnostik und Therapie.

Olfactory dysfunction is a common disorder, particularly in elderly people. From the etiologic point of view, we distinguish between sinunasal and non-sinunasal causes of dysosmia. As an important early symptom of neurodegenerative disease, dysosmia is particularly relevant in the diagnosis of Parkinson's or Alzheimer's disease. In addition to complete ENT examination and olfactory testing, e.g., with "Sniffin' Sticks", modern imaging procedures, e. g. MRI, are becoming more and more important for diagnostics, prognosis, and treatment decisions. Olfactory testing in children needs to be adapted to their shorter concentration span and limited range of known olfactory stimuli. Depending on the etiology, olfactory training, antiphlogistic measures, and surgical procedures are most promising. In cases of intracranial causes of dysosmia, neurosurgeons should know and respect anatomic structures of the olfactory signal pathway, not least for long-term prognosis.

[Dyspnea. Profile of the most important diagnostic tests]. / Dyspnoe. Profile der wichtigsten diagnostischen Tests.

The diagnostic pathway for the evaluation of patients with dyspnea requires a thorough history taking and physical examination. Based on the results of these basic steps a broad variety of additional diagnostic tests are available. Each test can contribute valuable information when correctly indicated and performed. Among these are electrocardiography (ECG), laboratory parameters, X-ray examination, echocardiography, spirometry and whole body plethysmography and finally spiroergometry. This article presents a focused review of what each of these diagnostic modalities can contribute to the diagnostic process for dyspnea.

Radiochemotherapy-induced changes of tumour vascularity and blood supply estimated by dynamic contrast-enhanced CT and fractal analysis in malignant head and neck tumours.

OBJECTIVE: To investigate radiochemotherapy (RChT)-induced changes of transfer coefficient (K(trans)) and relative tumour blood volume (rTBV) estimated by dynamic contrast-enhanced CT (DCE-CT) and fractal analysis in head and neck tumours (HNTs). METHODS: DCE-CT was performed in 15 patients with inoperable HNTs before RChT, and after 2 and 5 weeks. The dynamics of K(trans) and rTBV as well as lacunarity, slope of log(lacunarity) vs log(box size), and fractal dimension were compared with tumour behaviour during RChT and in the 24-month follow-up. RESULTS: In 11 patients, an increase of K(trans) and/or rTBV after 20 Gy followed by a decrease of both parameters after 50 Gy was noted. Except for one local recurrence, no tumour residue was found during the follow-up. In three patients with partial tumour reduction during RChT, a decrease of K(trans) accompanied by an increase in rTBV between 20 and 50 Gy was detected. In one patient with continuous elevation of both parameters, tumour progressed after RChT. Pre-treatment difference in intratumoral heterogeneity with its decline under RChT for the responders vs non-responders was observed. CONCLUSION: Initial growth of K(trans) and/or rTBV followed by further reduction of both parameters along with the decline of the slope of log(lacunarity) vs log(box size) was associated with positive radiochemotherapeutic response. Increase of K(trans) and/or rTBV under RChT indicated a poor outcome. ADVANCES IN KNOWLEDGE: The modification of K(trans) and rTBV as measured by DCE-CT may be applied for the assessment of tumour sensitivity to chose RChT regimen and, consequently, to reveal clinical impact allowing individualization of RChT strategy in patients with HNT.

[Diagnosis of olfactory disorders]. / Diagnostik bei Riechstörungen.

Alongside a structured case history, the measurement of olfactory function and diagnosis of olfactory dysfunction is of great clinical importance. Validated and established methods have been developed to this aim. The "Sniffin' Sticks" test battery is an easy-to-use tool for assessing olfactory function. Recording of olfactory event-related potentials is a more objective approach, which is particularly important in medicolegal cases. Imaging techniques such as MRI and CT provide additional information in the diagnosis of olfactory disorders. The latter techniques enable the anatomical structures of the skull and brain with the areas relevant to olfactory function to be evaluated.

[Dysosmia : current aspects of diagnostics and therapy]. / Riechstörungen : Aktuelles zur Diagnostik und Therapie.

Olfactory dysfunction is a common disorder, especially in elderly people. From the etiological point of view a differentiation is made between sinunasal, traumatic and non-sinunasal causes of dysosmia. Olfactory disorders are often observed in neurodegenerative diseases, especially in patients with Parkinson's disease or Alzheimer's disease. Apart from an extensive medical history important diagnostic tools are a complete ear nose and throat (ENT) examination including nasal endoscopy and olfactory testing, for example, with "sniffin' sticks". For diagnostic purposes modern imaging procedures, such as magnetic resonance imaging (MRI) are becoming more and more important. For testing children, olfactory testing needs to be adapted and depending on the etiology, olfactory training, antiphlogistic and surgical procedures are the most promising therapeutic approaches. In cases of intracranial causes of dysosmia neurosurgeons should know and respect the anatomical structures of the olfactory signal pathway, not least for the long-term prognosis.

Modification of staging and treatment of head and neck cancer by FDG-PET/CT prior to radiotherapy.

BACKGROUND AND PURPOSE: Reliable tumor staging is a fundamental pre-requisite for efficient tumor therapy and further prognosis. The aim of this study was to compare head and neck cancer (HNC) staging before and after FDG-PET/CT, evaluating the stage modifications for radiotherapy (RT) planning. PATIENTS AND METHODS: A total of 102 patients with untreated primary HNC, who underwent conventional staging and staging including FDG-PET/CT before RT, were enrolled in this retrospective study. Blinded pre-FDG-PET/CT and post-FDG-PET/CT staging data were compared. The impact on patient management was tested by comparing the intention before and after FDG-PET/CT. RESULTS: Significant modifications of T, N, and M stage as well as clinical stage were detected after inclusion of FDG-PET/CT data (p = 0.002, 0.0006, 0.001, 0.03, respectively). Overall, the implementation of FDG-PET/CT led to modification of RT intention decision in 14 patients. CONCLUSIONS: FDG-PET/CT demonstrates essential influence on tumor staging in HNC patients scheduled for irradiation. Implementation of FDG-PET/CT in imaging protocol improves selection of candidates for curative and palliative RT and allows further optimization of treatment management and therapy intention.

Is there a correlation between hippocampus and amygdala volume and olfactory function in healthy subjects?

Both amygdala (AG) and hippocampus (HC) are integral parts of the olfactory system. The present study, including a large number of healthy subjects, was performed to compare HC and AG volumes, measured by manual tracing, in relation to specific olfactory functions, including odor threshold, discrimination, identification, and odor memory tasks. It also aimed to provide age-related normative data about the volume of the HC and AG. A total of 117 healthy volunteers participated (age range 19-77 years, mean age 37 years; 62 women, 55 men). Using the "Sniffin' Sticks", subjects received lateralized tests for odor threshold, and odor discrimination. In addition, an odor memory and an odor identification task were performed bilaterally. A Mini-Mental-State test excluded dementia. MR scans were performed using a 1.5 T scanner for later manual volumetric measurements. Volumetric measurements exhibited a good reproducibility. The average volume for the right HC was 3.29 cm(3) (SD 0.47), for the left HC it was 3.15 cm(3) (SD 0.47). The average right AG had a volume of 1.60 cm(3) (SD 0.31), left 1.59 cm(3) (SD 0.3). Increasing age was accompanied by a decrease of HC and AG volumes, which were much more pronounced for the right compared to the left side. Only the volume of the right HC showed a small but significant correlation with odor threshold (r(117)=0.21; p=0.02). Importantly, this correlation was not mediated by age as indicated by the significant partial correlation when controlling for age (r(114)=0.18; p=0.049). In conclusion, the present data obtained in a relatively large group of subjects demonstrates a small correlation between the volume of the HC, as an integral part of the olfactory system, and smell function. In addition, these data can be used as the basis for normative values of HC and AG volumes, separately for men, women and different age groups. This is of potential interest in diseases with acute or chronic impairment of olfactory function, in metabolic or neurodegenerative diseases or in disorders with damage of areas involved in adult neurogenesis.

Two or four hour [¹8F]FMISO-PET in HNSCC. When is the contrast best?

UNLABELLED: [¹8F]Fluoromisonidazole positron emission tomography (FMISO-PET) is a non invasive imaging technique that can assist detecting intra tumour regions of hypoxia. FMISO-PET evinces comparatively low signal-to-noise-ratio (SNR) and may be acquired dynamically or after different uptake times post injection (p.i.). The aim of this study was to identify, if static images acquired two hours (MISO2) or four hours (MISO4) p.i. reveal higher contrast. PATIENTS, METHODS: As part of a prospective trial, 23 patients with cancers of the head and neck underwent [¹8F]fluorodeoxyglucose (FDG) PET before and during curative radiochemotherapy. Additionally, FMISO-PET studies 2 h and 4 h p.i. were done before treatment and after a mean dose of 11Gy, 23 Gy and 57 Gy during RCT. After coregistration, a dedicated software was used to define the gross tumour volume (GTV) by FDG PET for the primary tumour. This volume was overlaid to the FMISO images and hypoxia within the GTV was determined. The contrast between hypoxia determined by MISO2 and by MISO4 was investigated and analysed with the Wilcoxon-matched-pairs test. RESULTS: Mean SUVmax in tumours of all examinations was 2.2 (stdev: 0.4, min: 1.3, max: 3.4) after 2 h and 2.4 (stdev: 0.7, min: 1.1, max: 4.4) after 4 h. In the neck musculature the mean SUVmax was 1.5 at both time points and the mean SUVmean decreased from 1.2 after 2 h to 1.1 after 4 h, respectively. These effects resulted in significantly rising contrast ratios from MISO2 to MISO4. The differently defined contrasts revealed significantly higher values for examinations 4 h p.i. (p < 0.002). CONCLUSION: Data acquisition of [¹8F]FMISO should be done 4 h p.i. to gather the optimal contrast, preferably allowing further analysis, e. g. hypoxic sub volume definition for therapy planning.

Tumour bed irradiation of human tumour xenografts in a nude rat model using a common X-ray tube.

Studies that investigate the radiation of human tumour xenografts require an appropriate radiation source and highly standardized conditions during radiation. This work reports on the design of a standardized irradiation device using a commercially available X-ray tube with a custom constructed lead collimator with two circular apertures and an animal bed plate, permitting synchronous irradiation of two animals. Dosimetry and the corresponding methodology for radiotherapy of human non-small cell lung cancer xenograft tumours transplanted to and growing subcutaneously on the right lower limb in a nude rat model were investigated. Procedures and results described herein prove the feasibility of use of the device, which is applicable for any investigation involving irradiation of non-tumorous and tumorous lesions in small animals.

Diffusion-weighted MRI for tumour volume delineation: comparison with morphological MRI.

Diffusion-weighted magnetic resonance imaging (dwMRI) is sensitive to tissue microstructure on the cellular level and may therefore help to define biological tumour subvolumes and add complementary information to morphology-based cancer treatment protocols and therapy monitoring. The purpose of this study was therefore to evaluate the potential of dwMRI as compared with morphological MRI (mMRI) for tumour volume delineation using a nude rat human tumour xenograft model. Sixteen tumour-bearing rats (10 H1299, six FaDu) were examined with mMRI (T2-weighted true fast imaging with steady precession (TrueFISP), T1-weighted fast low angle shot (FLASH), T2-weighted dual echo steady state (DESS)) and echo-planar dwMRI in a clinical scanner at 1.5 T. For each method, we compared tumour volume and intra- and inter-observer variability of tumour outer edge delineation (disregarding intra-tumoural structure) as well as tumour signal-to-noise ratio (SNR) and tumour-to-muscle contrast-to-noise ratio (CNR). Tumours were visualised with significantly higher SNR and CNR in dwMRI. Median tumour volumes as measured by dwMRI (3.5 cm(3)) and mMRI (TrueFISP: 3.3 cm(3); FLASH: 3.3 cm(3); DESS: 3.2 cm(3)) were not significantly different and significantly correlated. Related to partial volume effects, the intra- and inter-observer variability of dwMRI (intra/inter: 12%/12%) was larger than for mMRI (TrueFISP: 4%/4%; FLASH: 5%/5%; DESS: 5%/5%). In conclusion, dwMRI allows tumour delineation with overall volume estimation comparable with mMRI approaches but slightly higher observer variability. Thus, besides tumour outline, it may potentially supplement morphology-based therapy planning and monitoring with additional biological information.

Increasing olfactory bulb volume due to treatment of chronic rhinosinusitis--a longitudinal study.

Differentiation of progenitor cells into neurons in the olfactory bulb depends on olfactory stimulation that can lead to an increase in olfactory bulb volume. In this study, we investigated whether the human olfactory bulb volume increases with increasing olfactory function due to treatment of chronic rhinosinusitis. Nineteen patients with chronic rhinosinusitis were investigated before and after treatment. For comparison, additional measurements were performed in 18 healthy volunteers. Volumetric measurements of the olfactory bulb were based on planimetric manual contouring of magnetic resonance scans. Olfactory function was evaluated separately for each nostril using tests for odour threshold, odour discrimination and odour identification. Measurements were performed on two occasions, 3 months apart. In healthy controls, the olfactory bulb volume did not change significantly between the two measurements. In contrast, the olfactory bulb volume in patients increased significantly from the initial 64.5 +/- 3.2 to 70.0 +/- 3.5 mm(3) on the left side (P = 0.02) and from 60.9 +/- 3.5 to 72.4 +/- 2.8 mm(3) on the right side (P < 0.001). The increase in olfactory bulb volume correlated significantly with an increase in odour thresholds (r = 0.60, P = 0.006, left side; r = 0.49, P = 0.03, right side), but not with changes in odour discrimination or odour identification. Results of this study support the idea that stimulation of olfactory receptor neurons impacts on the cell death in the olfactory bulb, not only in rodents but also in humans. To our knowledge, this is the first longitudinal study that describes an enlargement of the human olfactory bulb due to improvement of peripheral olfactory function.

Olfactory bulb ventricles as a frequent finding in magnetic resonance imaging studies of the olfactory system.

UNLABELLED: Background. In some species an embryologic cavity inside the olfactory bulb (OB) persists and is called olfactory bulb ventricle (OBV). It is generally assumed that OBVs in humans are solitary findings representing remnants of embryologic structures that were not fully regressed, although the incidence of OBVs was never examined. Using magnetic resonance imaging (MRI), the present study aimed to study the incidence of OBVs in healthy human subjects. Material and methods. A total of 122 individuals participated. Volumes of the right and left OB were determined using MRI scans and a standardized protocol for OB analysis. For comparison, OBs of 42 cadavers were collected and sectioned. Results. The main finding of this study was the high incidence of OBV-like structures in our study group. Seventy-two out of 122 (59%) participants yielded signs for an OBV whereas three out of 42 postmortem OBs contained histologically detectable OBV. DISCUSSION: This stands in disagreement with the previous assumption of complete obliteration at the time of birth. This discrepancy may be explained by the fact that our present findings are based on modern MRI techniques with much higher resolution than 10 or 20 years ago. Another possible explanation for the discrepancy between studies based on MRI and histopathology might relate to postmortem resorption of cerebrospinal fluid from OBVs. Especially with a long postmortem interval OBVs may collapse and may no longer appear as an open cavity.