Ultrasound-Guided Interstitial Brachytherapy in the Treatment of Advanced Vaginal Recurrences from Cervical and Endometrial Carcinoma

BACKGROUND: In advanced vaginal recurrences of cervical and endometrial carcinomas therapeutic options are rare because of preceding therapy. PATIENTS AND METHODS: 23 patients developing advanced vaginal recurrences of cervical and endometrial carcinomas were included. 15 patients started with external-beam therapy to the pelvis and eight patients after preceding radiotherapy underwent brachytherapy alone. All patients had ultrasound-guided implantation of transvaginal or transperineal interstitial needles for brachytherapy. Median prescribed total dose was 64 Gy. RESULTS: 18 patients (78%) achieved complete remission. Six patients are alive without tumor and one with tumor after a median follow-up of 64 months. 14 patients died of tumor and two of intercurrent disease. 5-year disease-specific survival and local control rate were 43% and 47%, respectively, in patients with complete remission. Univariate analysis found time to relapse > 2 years, initial diameter < or = 4 cm, initial volume < 15 cm(3), no extension to the pelvic side wall, volume before brachytherapy < 7.5 cm(3), brachytherapy coverage index > 0.8, and prescribed total dose > 64 Gy being positive predictors for local control and survival. CONCLUSION: The use of ultrasound guidance for placement of interstitial needles in template-based brachytherapy of advanced recurrent gynecologic malignancies is a feasible, safe, and cheap method with encouraging results. Today, ultrasound imaging can be also used to some extent for treatment planning which requires further development. Patient- and treatment-related prognostic factors can be defined.     

Neural connections between the hypothalamus and the liver

After receiving information from afferent nerves, the hypothalamus sends signals to peripheral organs, including the liver, to keep homeostasis. There are two ways for the hypothalamus to signal to the peripheral organs: by stimulating the autonomic nerves and by releasing hormones from the pituitary gland. In order to reveal the involvement of the autonomic nervous system in liver function, we focus in this study on autonomic nerves and neuroendocrine connections between the hypothalamus and the liver. The hypothalamus consists of three major areas: lateral, medial, and periventricular. Each area has some nuclei. There are two important nuclei and one area in the hypothalamus that send out the neural autonomic information to the peripheral organs: the ventromedial hypothalamic nucleus (VMH) in the medial area, the lateral hypothalamic area (LHA), and the periventricular hypothalamic nucleus (PVN) in the periventricular area. VMH sends sympathetic signals to the liver via the celiac ganglia, the LHA sends parasympathetic signals to the liver via the vagal nerve, and the PVN integrates information from other areas of the hypothalamus and sends both autonomic signals to the liver. As for the afferent nerves, there are two pathways: a vagal afferent and a dorsal afferent nerve pathway. Vagal afferent nerves are thought to play a role as sensors in the peripheral organs and to send signals to the brain, including the hypothalamus, via nodosa ganglia of the vagal nerve. On the other hand, dorsal afferent nerves are primary sensory nerves that send signals to the brain via lower thoracic dorsal root ganglia. In the liver, many nerves contain classical neurotransmitters (noradrenaline and acetylcholine) and neuropeptides (substance P, calcitonin gene-related peptide, neuropeptide Y, vasoactive intestinal polypeptide, somatostatin, glucagon, glucagon-like peptide, neurotensin, serotonin, and galanin). Their distribution in the liver is species-dependent. Some of these nerves are thought to be involved in the regulation of hepatic function as well as of hemodynamics. In addition to direct neural connections, the hypothalamus can affect metabolic functions by neuroendocrine connections: the hypothalamus-pancreas axis, the hypothalamus-adrenal axis, and the hypothalamus-pituitary axis. In the hypothalamus-pancreas axis, autonomic nerves release glucagon and insulin, which directly enter the liver and affect liver metabolism. In the hypothalamus-adrenal axis, autonomic nerves release catecholamines such as adrenaline and noradrenaline from the adrenal medulla, which also affects liver metabolism. In the hypothalamus-pituitary axis, release of glucocorticoids and thyroid hormones is stimulated by pituitary hormones. Both groups of hormones modulate hepatic metabolism. Taken together, the hypothalamus controls liver functions by neural and neuroendocrine connections.     

Prognostic value of the combined assessment of proliferating cell nuclear antigen immunostaining and nuclear DNA content in invasive human mammary carcinomas

The expression of theS-phase associated, nuclear protein proliferating cell nuclear antigen (PCNA) was investigated in routinely paraffin-embedded surgical specimens from 209 breast cancer patients. Cytometric DNA assessments were performed on fine-needle aspirates, upon which the primary diagnosis of breast cancer had been based. The mean clinical follow-up was 16 years (range 13–20 years). The percentage of PCNA immunoreactive tumour cells ranged between less than 5 to 60% (mean value 13.34%). There was a direct association between PCNA expression, high histological tumour grade (p<0.01), and DNA aneuploidy (p=0.009). In a subgroup of 22 patients with near-diploid DNA distribution patterns the PCNA expression yielded additional prognostic information. Patients with tumours of near-diploid DNA histograms and more than 20% of PCNA immunoreactive neoplastic cells had a significantly worse clinical course, than patients with neardiploid tumours containing less than 20% PCNA immunoreactive cells (p=0.0001). In contrast, the PCNA immunoreactivity did not yield additional prognostic information for patients with distinctly diploid or highly aneuploid tumour variants. In a multivariate analysis comprising all 209 patients, nodal status (p<0.01), tumour size (p<0.01), and DNA ploidy (p<0.01) were found to have significant prognostic effect. The findings indicate that carcinomas characterised by high proliferative activity and near-diploid DNA distribution patterns can show rapid tumour progression. The combined assessment of the PCNA immunoreactivity and of the nuclear DNA content in routinely processed surgical specimens of breast cancer patients appears to be of prognostic value.     

Antithrombotic properties of trillium coated connectors

Trillium coating (Medtronic Inc., Minneapolis, MN) offers, in addition to the presence of heparin, endothelium-like properties of its negatively charged surface. Its thromboresistant properties on coated connectors are tested here and compared with uncoated standard connectors, as well as with the Carmeda BioActive surface (CBAS) heparin surface coating. A partial cardiopulmonary bypass bovine model (body weight 68 +/- 5 kg) was selected, and the surfaces were exposed to the blood stream (pump flow 3.5 L/min) for up to 350 minutes without systemic heparinization. Thereafter, another set of samples was exposed to stagnant blood for 20 minutes. Besides hemodynamic, hematologic, and biochemical analyses, the macroscopic appearance of 45 blood exposed surface samples were graded semiquantitatively on a scale of 0 to 10: no macroscopic deposits = grade 0, one spot (1 mm diameter) = grade 1, two spots = grade 2, five or more spots = grade 5, 10% of the surface covered with clots = grade 6, 100% covered = grade 10. When exposed to blood flow, Trillium and CBAS coatings showed a statistically significant (p = 0.03) better thromboresistance (score: 0 +/- 0 for both) than uncoated connectors (score: 0.8 +/- 1.5) in this nonheparinized model. The same holds true when the connectors were exposed to stagnant blood (score: 0 +/- 0 for both coatings vs 4.3 +/- 2.8 for controls; p = 0.03). Therefore, Trillium coating exhibits significant antithrombotic properties that outperform standards for connectors used in clinical perfusion.     

Using Metamodeling to Identify the Optimal Strategy for Colorectal Cancer Screening

ObjectivesMetamodeling can address computational challenges within decision-analytic modeling studies evaluating many strategies. This article illustrates the value of metamodeling for evaluating colorectal cancer screening strategies while accounting for colonoscopy capacity constraints.MethodsIn a traditional approach, the best screening strategy was identified from a limited subset of strategies evaluated with the validated Adenoma and Serrated pathway to Colorectal CAncer model. In a metamodeling approach, metamodels were fitted to this limited subset to evaluate all potentially plausible strategies and determine the best overall screening strategy. Approaches were compared based on the best screening strategy in life-years gained compared with no screening. Metamodel runtime and accuracy was assessed.ResultsThe metamodeling approach evaluated >40 000 strategies in <1 minute with high accuracy after 1 adaptive sampling step (mean absolute error: 0.0002 life-years) using 300 samples in total (generation time: 8 days). Findings indicated that health outcomes could be improved without requiring additional colonoscopy capacity. Obtaining similar insights using the traditional approach could require at least 1000 samples (generation time: 28 days). Suggested benefits from screening at ages <40 years require adequate validation of the underlying Adenoma and Serrated pathway to Colorectal CAncer model before making policy recommendations.ConclusionsMetamodeling allows rapid assessment of a vast set of strategies, which may lead to identification of more favorable strategies compared to a traditional approach. Nevertheless, metamodel validation and identifying extrapolation beyond the support of the original decision-analytic model are critical to the interpretation of results. The screening strategies identified with metamodeling support ongoing discussions on decreasing the starting age of colorectal cancer screening.     

Active Case Finding of Current Bornavirus Infections in Human Encephalitis Cases of Unknown Etiology,Germany, 2018–2020

Human bornavirus encephalitis is a severe and often fatal infection caused by variegated squirrel bornavirus 1 (VSBV-1) and Borna disease virus 1 (BoDV-1). We conducted a prospective study of bornavirus etiology of encephalitis cases in Germany during 2018–2020 by using a serologic testing scheme applied along proposed graded case definitions for VSBV-1, BoDV-1, and unspecified bornavirus encephalitis. Of 103 encephalitis cases of unknown etiology, 4 bornavirus infections were detected serologically. One chronic case was caused by VSBV-1 after occupational-related contact of a person with exotic squirrels, and 3 acute cases were caused by BoDV-1 in virus-endemic areas. All 4 case-patients died. Bornavirus etiology could be confirmed by molecular methods. Serologic testing for these cases was virus specific, discriminatory, and a practical diagnostic option for living patients if no brain tissue samples are available. This testing should be guided by clinical and epidemiologic suspicions, such as residence in virus-endemic areas and animal exposure.