CD73 expression in lymph node metastases in patients with head and neck cancer

Introduction: CD73 is an enzyme crucial in the metabolism of immunosuppressive adenosine. In cancer, it has various functions including tumor growth and metastases. Squamous cell carcinoma of the head and neck has an overall poor prognosis, also due to early spread of metastatic cells.

Materials and methods: Tumor and lymph node specimens of 65 patients with HNSCC were subjected to immunohistochemical and H-score analysis of CD73 expression. Demographics, diagnoses, histopathology and subsequent outcome were analyzed.

Results: The primary cancer was squamous cell carcinoma in all patients (male/female 55:10) with the following locations: oral cavity n:16, oropharynx n:28, hypopharynx n:11 and larynx n:10. H-score for CD73 expression in the primary lesion and metastatic lymph nodes was significantly higher in advanced compared to early stages with no significant differences among tumor locations. High CD73 expression was associated with reduced overall survival rates at a mean follow-up of 83.4 months (6–204 months).

Conclusions: CD73 expression in HNSCC correlated positively with tumor stage and was associated with poor prognosis. Therefore, CD73 expression in primary lesions and regional metastases appears to predict HNSCC patients at high risk of all tumor sites. Therapeutic approaches targeting CD73 might seem promising for this patient population.     

Beta Cyclodextrins Enhance Adenoviral-Mediated Gene Delivery to the Intestine

Purpose. In general, the intestinal epithelium is quite refractory to viral and non-viral methods of gene transfer. In this report, various cyclodextrin formulations were tested for their ability to enhance adenoviral transduction efficiency in two models of the intestinal epithelium: differentiated Caco-2 cells and rat jejunum. Methods. Transduction efficiency of replication-deficient adenovirus type 5 vectors encoded with either the E. coli beta-galactosidase or the jellyfish green fluorescent protein gene was assessed by X-gal staining or visualization of fluorescence 48 hours after infection. In vivo experiments were performed using an intestinal loop ligation technique. Results. Several formulations of neutral and positively charged beta cyclodextrins significantly enhanced adenoviral-mediated gene transfer in the selected models. The cyclodextrin formulations studied increased adenoviral transduction in the intestine by enhancing both viral binding and internalization. Viral binding was significantly increased on cell membranes treated with positively charged cyclodextrins, as seen with confocal microscopy and rhodamine-labeled virus. Permeability studies and TEER readings revealed that the most successful formulations gently disrupt cell membranes. This enhances internalization of viral particles and results in increased levels of gene expression. Conclusions. These formulations can be of value in gene transfer to cells and tissues in which adenoviral infection is limited due to a lack of fiber and _v integrin receptors. They are simple to prepare and do not affect the ability of the virus to transduce target cells.     

Multiple spinal “miliary” hemangioblastomas in von Hippel-Lindau (vHL) disease without cerebellar involvement

We report on a 57-year-old male presenting with radicular pain in the nerve roots of L5 and S1 on the right side and dysuria. Magnetic resonance imaging (MRI) of the lumbar spine showed multiple (up to 20) small, intradural enhancing nodules attached to the cauda equina down to the sacrum, the largest 1 cm in diameter at the level Th12/ L1 compressing the conus. Additionally, small nodules in the cervico-thoracal region adjacent to the cord, but no cerebellar or cerebral abnormalities, were detected in a consecutive MRI of the remaining neuroaxis. The histology of a resected lesion at Th12/L1 revealed hemangioblastoma of the reticular type. Together with a history of left eye enucleation performed 17 years ago for angiomatosis of the retina and the immunohistochemical detection of von Hippel-Lindau (vHL) protein within the removed spinal hemangioblastoma, a diagnosis of vHL disease was established. Family history and screening for visceral manifestations of vHL disease were negative. In contrast to cerebellar or solitary spinal hemangioblastomas, multiple spinal hemangioblastomas without cerebellar involvement in vHL represent unusual manifestations. Unlike the case for solitary lesions in non-syndromic patients, a surgical cure does not seem feasible in this case. The role of treatment modalities is discussed. Received: 3 July 1998 / Accepted: 19 August 1998     

The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly.

Holoprosencephaly (HPE) is a common developmental anomaly of the human forebrain and midface where the cerebral hemispheres fail to separate into distinct left and right halves. We have previously reported haploinsufficiency for Sonic Hedgehog ( SHH ) as a cause for HPE. We have now performed mutational analysis of the complete coding region and intron-exon junctions of the SHH gene in 344 unrelated affected individuals. Herein, we describe 13 additional unrelated affected individuals with SHH mutations, including nonsense and missense mutations, deletions and an insertion. These mutations occur throughout the extent of the gene. No specific genotype-phenotype association is evident based on the correlation of the type or position of the mutations. In conjunction with our previous studies, we have identified a total of 23 mutations in 344 unrelated cases of HPE. They account for 14 cases of familial HPE and nine cases of sporadic HPE. Mutations in SHH were detected in 10 of 27 (37%) families showing autosomal dominant transmission of the HPE spectrum, based on structural anomalies. Interestingly, three of the patients with an SHH mutation also had abnormalities in another gene that is expressed during forebrain development. We suggest that the interactions of multiple gene products and/or environmental elements may determine the final phenotypic outcome for a given individual and that variations among these factors may cause the wide variability in the clinical features seen in HPE.     

Performance and skill retention of intubation by paramedics using seven different airway devices--a manikin study

IntroductionEndotracheal intubation (ETI) is the most widespread method for emergency airway management. Several studies reported that ETI requires considerable skill and experience and if performed incorrectly, may result in serious adverse events. Unrecognized tube misplacement or oesophageal intubation is associated with high prehospital morbidity. This study investigates the usability of supraglottic airway devices compared to ETI and the skill retention of 41 previously inexperienced paramedics following training using a manikin model.Methods41 paramedics participated in this study. None had prior experience in airway management, apart from bag-valve ventilation. After a standardised audio-visual lecture lasting 45 min, the paramedics participated in a practical demonstration using the advanced patient simulator SimMan^® (Laerdal Medical, Stavanger, Norway). Afterwards, paramedics were instructed to perform airway-management using seven different techniques to secure the airway (ETI, Laryngeal mask unique [LMA], Proseal, Laryngeal tube disposable [LT-D^®], I-Gel^®, Combitube^®, and EasyTube^®) following a randomized sequence. Participants underwent reassessment after 3 months without any further training or practice in airway-management.ResultsDuring the initial training session, ETI was successfully performed in 78% of cases, while 3 months later the success rate was 58%. For the supraglottic airway devices, five out of six were successfully used by all paramedics at both time points, the exception being Proseal^®. Our data show successful skill retention (success rate: 100%) after 3 months for five out of six supraglottic airway devices. Time to ventilation (T3) was significantly less for LMA, LT-D^® and I-Gel^® at all time points compared to ETI.ConclusionETI performed by inexperienced paramedics is associated with a low success rate. In contrast, supraglottic airway devices like LMA, LT-D^®, I-Gel^®, Combitube^® and EasyTube^® are fast, safe and easy-to-use. Within the limitations of a manikin-study, this study suggests that inexperienced medical staff might benefit from using supraglottic airway devices for emergency airway management.     

Lack of significant estrogen and progesterone receptor expression in nasal telangiectasias in hereditary hemorrhagic telangiectasia: an immunohistochemical analysis

Obstructive sleep apnea syndrome (OSAS) is characterized by snoring and apnea during sleep leading to decreased oxygen saturation and disturbed sleep, excessive daytime sleepiness and neuropsychological disturbances. This study investigates cognitive neuropsychological abilities in a group of 53 OSAS patients before and after treatment with uvulopalatopharyngoplasty. General intellectual ability, verbal learning and memory as well as executive functioning were measured at baseline and 6 months postoperatively. After surgery there were significant improvements in verbal learning and memory (mean change - 39, SD 57.3, p <0.001), recall (mean change - 24.3, SD 39.3, p <0.001) and executive functioning (as assessed by percentage of errors on the Wisconsin Card Sorting Test; mean change-9.1, SD 15.7, p <0.001). These improvements were in accordance with improvements in the degree of sleep apnea, the oxygen desaturation index (mean change -9.7, SD 15.9, p <0.001) and arterial minimum oxygen saturation (mean change 4.5%, SD 10.2%, p <0.01). Surgical treatment seems to improve verbal learning, memory and recall and executive functions in parallel with better oxygenation in OSAS.     

False-positive radio-iodinated metaiodobenzylguanidine (123I-MIBG) accumulation in a mast cell-infiltrated infantile haemangioma

Radio-iodinated metaiodobenzylguanidine (¹²³I-MIBG) is used for the detection and staging of neuroblastoma, pheochromcytoma and other neuroendocrine tumours in diagnostic nuclear medicine. A specific uptake and storage mechanism provides the basis for imaging with ¹²³I-MIBG. Nevertheless, cases of false-positive ¹²³I-MIBG scintigraphy with accumulation in non-chromaffin tumours have been described. Here, we present a case of a false-positive ¹²³I-MIBG scan in a case of a mast-cell infiltrated infantile haemangioma and discuss the possible uptake mechanism.Radio-iodinated metaiodobenzylguanidine (¹²³I-MIBG) has been used for several years for the detection and staging of neuroblastoma, pheochromcytoma and other neuroendocrine tumours. ¹²³I-MIBG is transported across the plasma membrane by the human norepinephrine transporter (NET); a smaller amount enters the cell by passive diffusion. Intracellularly, the vesicular monoamine transporters (VMATs) accumulate ¹²³I-MIBG in catecholamine storing granules [1, 2]. This specific uptake and storage mechanism provides the basis for the imaging of neuroendocrine tumours such as pheochromocytomas and neuroblastomas. Nevertheless, cases of false-positive ¹²³I-MIBG scintigraphy with accumulation in non-chromaffin tumours such as angiomyolipoma [3], adrenocortical carcinoma [4], adrenocortical adenoma [5], juvenile capillary angioma [6] or cavernous haemangioma [7] have been described. Here, we present another case of a false-positive ¹²³I-MIBG scan of a tumour within the adrenal gland area and discuss the possible mechanism. A 3-month-old girl presented with constipation. Abdominal ultrasound showed a round, strictly delineated, inhomogeneously hypoechogenic structure with a diameter of 18 × 30 mm at the upper renal pole. On the basis of these findings, adrenal haemorrhage was suspected. A follow-up ultrasound examination 6 weeks later confirmed the structure. The inhomogeneous appearance of the structure was increasing; the diameter was unchanged. An MRI examination of the abdomen was performed on a 1.5 T system (Avanto; Siemens, Erlangen, Germany). The following imaging sequences were applied: coronal T₂ weighted (_w) STIR-BLADE [8], repetition time/echo time (TR/TE) 4500/47 ms; transversal T_2w BLADE (TR/TE, 5640/118 ms); coronal T_1w BLADE (TR/TE, 1280/55 ms); transversal T_1w BLADE (TR/TE, 1400/55 ms) and transversal T_1w TSE (TR/TE, 510/9.5 ms). On T_2w images, the tumour mass proved to be only of moderate hyperintensity. The size was 34 × 22 × 28 mm, located in the area of the right adrenal gland. After application of 1 ml gadoteridol (Prohance; Bracco Diagnostics, Princeton, USA), the tumour showed an intensive contrast media enhancement (Figure 1). A ¹²³I-MIBG scan was obtained, which showed focal tracer uptake in the area of the right adrenal gland (Figure 2), corresponding to the tumour mass in the MRI examination (Figure 3) and suggestive of neuroblastoma. On the basis of the imaging data, neuroblastoma with negative urine vanillylmandelic acid and positive ¹²³I-MIBG scintigraphy was assumed and an open biopsy was performed. During surgery, a highly vascularised tissue was found in the adrenal gland. The histological examination revealed a compact vascular lesion with morphological and immunohistochemical criteria (Figure 4a,b) consistent with infantile haemangioma. Within the tumour, mast cell infiltration, which was positive upon VMAT2 staining, was seen (Figure 4c,d)Open in a separate windowFigure 1Transversal T₁ weighted BLADE MRI image (repetition time/echo time 1400/55 ms, after injection of 1 ml gadoteridol), showing a tumour mass (red arrow) in the area of the right adrenal gland. See the intensive contrast enhancement of the tumour.Open in a separate windowFigure 2¹²³I-MIBG scintigraphy (SPECT) in transversal, sagittal and coronal projections. See the intensive accumulation of the radiotracer in the area of the right adrenal gland (blue crosshairs).Open in a separate windowFigure 3Coronal and transversal fusion images obtained after automatic coregistration using the mutual information method of the ¹²³I-MIBG SPECT and the T₁ weighted BLADE MRI data (Esoft; Siemens, Erlangen, Germany). The fused images confirm the almost identical localisation of the radiotracer uptake in the SPECT and the tumour in the MRI examination (red arrows).Open in a separate windowFigure 4Staining. (a) Hemotoxylin (HE) for tumour histology. (b) GLUT1 (brown) for glucose transporters, confirming the diagnosis of infantile haemangioma. (c) VMAT2 (brown) for amine transporters. (d) Giemsa (blue) for mast cells. Magnification throughout ×20.