CIN2 + detection in high-risk HPV patients with no or minor cervical cytologic abnormalities: a clinical approach validated by machine learning.

PURPOSE: To evaluate the feasibility and diagnostic value of the combination of colposcopy, cytology and hrHPV (high-risk human papilloma virus) PCR (polymerase chain reaction) testing in patients with no or minor cytologic abnormalities and HPV high risk infection and to find the best predictors for the presence of CIN2 + in this patient collective. METHODS: Three hundred and thirty-four hrHPV patients with normal cytology or minor cytologic abnormalities who had a colposcopic examination at the center of colposcopy at the university hospital Aachen in 2021 were enrolled in this retrospective cohort analysis. Multivariate logistic regression and a machine-learning technique (random forests, leave-one-out analysis) were used. RESULTS: The overall risk for CIN2 + in hrHPV-positive patients with normal cytology was 7.7% (N = 18) (5% for CIN3 +), 18% (N = 16) (10.1% for CIN3 +) in patients with PAP IIp (ASC-US) and 62.5% (N = 5) (25% for CIN3 +) in patients with PAP IIg (AGC). Variables that show a statistically significant influence for the CIN-status are 'major change' as the result of colposcopy, transformation zone type T1, PAP IIg upon referral (AGC) and hrHPV category 1a (HPV 16/18) detection. Using machine learning (random forests) techniques, the main influencing variables were confirmed. A monotonously decreasing risk for CIN2 + from hrHPV category 1a to 3 (in accordance to the IACR guidelines) was found. CONCLUSION: In the collective of hrHPV patients with no or minor cytologic abnormalities, the result of colposcopy and HPV PCR status are key predictors for the detection of CIN2 + with a monotonously decreasing risk for CIN2 + from hrHPV category 1a to 3.

Evaluation of urinary continence status and its influence on quality of life after gyneco-oncological treatment of female pelvic malignancies at an oncological center.

Urinary incontinence (UI) could negatively affect a person's quality of life (QoL). This study investigates the association among gynecological cancers, their treatments, UI, and its effect on the QoL of survivors of gynecological cancer. This cross-sectional questionnaire-based study included 121 cases from 405 patients who had undergone gyneco-oncological therapy. The participants were asked whether they experienced any form of UI and whether it impacted their QoL. The following therapies were used to treat the 12 gynecologic tumor types found in the participants: surgery (n = 116, 95.87%), chemotherapy (CTx) (n = 51, 42.2%), radiotherapy (RTx) (n = 31, 25.6%), and antibody therapy (ABT) (n = 11, 9.1%). No significant association was determined between tumor type and UI. However, body mass index (BMI), radical hysterectomy, vulvar or vaginal surgery, and presence of UI before treatment had significant impacts on the presence of UI. The surgical access routes, CTx, ABT, and hysterectomy had significant impacts on the severity of UI after treatment. Among all patients, 55.4% reported very good QoL. These reports of good QoL by patients could be due to their very good adjustment to the situation, with regard to being diagnosed with and receiving treatment for cancer, or due to the patients considering UI to not be much of an issue. Additionally, 34% of patients reported they had not been informed about the risk of UI before treatment. Informing patients about UI as one of the risks of therapy before initiating the treatment is crucial as patients who had been informed beforehand coped with UI far better than those who were not informed. Hence, the treatment of UI is often successful, so patients should be encouraged to receive urogynecological consultation.

Microcirculatory perfusion shift in the gut wall layers induced by extracorporeal circulation.

OBJECTIVE: Extracorporeal circulation (ECC) is regularly applied to maintain organ perfusion during major aortic and cardiovascular surgery. During thoracoabdominal aortic repair, ECC-driven selective visceral arterial perfusion (SVP) results in changed microcirculatory perfusion (shift from the muscularis toward the mucosal small intestinal layer) in conjunction with macrohemodynamic hypoperfusion. The underlying mechanism, however, is unclear. Therefore, the aim of this study was to assess in a porcine model whether ECC itself or the hypoperfusion induced by SVP is responsible for the mucosal/muscular shift in the small intestinal wall. METHODS: A thoracoabdominal aortic approach was performed in 15 healthy pigs divided equally into three groups: group I, control; group II, thoracic aortic cross-clamping with distal aortic perfusion; and group III, thoracic aortic cross-clamping with distal aortic perfusion and SVP. Macrocirculatory and microcirculatory blood flow was assessed by transit time ultrasound volume flow measurement and fluorescent microspheres. In addition, markers for metabolism and intestinal ischemia-reperfusion injury were determined. RESULTS: ECC with a roller pump induced a significant switch from the muscularis and mucosal layer of the small intestine, even with adequate macrocirculation (mucosal/muscular perfusion ratio: group I vs II, P = .005; group I vs III, P = .0018). Furthermore, the oxygen extraction ratio increased significantly in groups II (>30%) and III (>40%) in the beginning of the ECC compared with the control (group I vs II, P = .0037; group I vs III, P = .0062). Lactate concentrations and pH values did not differ between groups I and II; but group III demonstrated a significant shifting toward a lactate-associated acidosis (lactate: group I vs III, P = .0031; pH: group I vs III, P = .0001). CONCLUSIONS: We demonstrated a significant shifting between the small intestinal gut wall layers induced by roller pump-driven ECC. The shift occurs independently of macrohemodynamics, with a significant effect on aerobic metabolism in the gut wall. Consequently, an optimal intestinal perfusion cannot be guaranteed by a roller pump; therefore, perfusion techniques need to be optimized.

Inference for blocked randomization under a selection bias model.

We provide an asymptotic test to analyze randomized clinical trials that may be subject to selection bias. For normally distributed responses, and under permuted block randomization, we derive a likelihood ratio test of the treatment effect under a selection bias model. A likelihood ratio test of the presence of selection bias arises from the same formulation. We prove that the test is asymptotically chi-square on one degree of freedom. These results correlate well with the likelihood ratio test of Ivanova et al. (2005, Statistics in Medicine 24, 1537-1546) for binary responses, for which they established by simulation that the asymptotic distribution is chi-square. Simulations also show that the test is robust to departures from normality and under another randomization procedure. We illustrate the test by reanalyzing a clinical trial on retinal detachment.

[Hematological changes in adolescent anorexia nervosa]. / Hämatologische Veränderungen bei Anorexia nervosa im Kindes- und Jugendalter.

OBJECTIVE: Hematological changes often occur in patients with acute anorexia nervosa (AN). However, the relationship between these disturbances and other clinical parameters remains unclear. METHOD: Leucocyte, erythrocyte, and thrombocyte counts as well as hematocrit, hemoglobin, and differential blood counts were collected at admission and after weight restoration in 88 female adolescent patients with the diagnosis of AN according to DSM-IV. These were then compared to clinical parameters. RESULTS: At admission, there were mild changes in the blood count, most of which, however, were reversible after weight gain. Patients with a greater weight loss, a lower age-adjusted BMI, and a history of taking psychotropic drugs were more likely to develop hematological abnormalities. CONCLUSIONS: Although most of the hematological changes in adolescent patients with AN were mild, patients with high weight loss and/or low age-adjusted BMI as well as those on psychotropic medication should be monitored carefully in order to avoid severe medical complications. An altered immune function in adult patients with chronic AN might contribute to a higher rate of infections and thus to an increased mortality.

Body mass index in adolescent anorexia nervosa patients in relation to age, time point and site of admission.

Body mass index (BMI) at admission is an important predictor of outcome in adolescent eating disorders. However, few studies have investigated BMI at admission, its changes in recent years, or modifying factors, such as duration of illness and age at onset in different geographical regions. Thus, this study aimed to investigate changes in BMI at admission over the past decade in one clinic, the differences in BMI between various treatment sites and the influence of duration of illness before admission and age at admission. Our sample consisted of 158 adolescent female patients with anorexia nervosa (AN) admitted between 2001 and 2009 to a major university hospital and 169 adolescent female patients recruited in a multicenter study between 2007 and 2010. We assessed the differences between departments in different regions of Germany in the multi-site sample. Changes over time in age-adjusted BMI and age at admission as well as modifying factors for age-adjusted BMI at admission, such as age at admission and duration of illness, were assessed in a representative local sample. There were no significant differences between departments in different regions of Germany. Over the course of the local study, there was a small but significant increase in the age-adjusted BMI score and absolute BMI at admission. In addition, there was a positive association between year of admission and age at admission. Older adolescents with AN had a lower age-adjusted BMI score and a longer duration of illness at the time of admission. The BMI at admission, which is one of the most important predictors of outcome in AN, has increased slightly during the past 10 years. Education strategies for parents and professionals should continue to be improved to further shorten the duration of illness before admission, especially for older adolescents.

The impact of selective visceral perfusion on intestinal macrohemodynamics and microhemodynamics in a porcine model of thoracic aortic cross-clamping.

INTRODUCTION: Despite its presumed effectiveness and clinical use, the physiology of selective visceral perfusion combined with distal aortic perfusion during open thoracoabdominal aortic surgery has not been characterized. Thus, the aim of this study was to establish a translatable model of thoracic aortic-clamping to assess the effect of selective visceral perfusion with added distal aortic perfusion on local intestinal macrohemodynamics and microhemodynamics, intestinal histopathology, and markers of inflammation and intestinal damage. METHODS: A thoracolaparotomy was performed in 15 pigs, and the aorta was exposed, including the origins of celiac trunk and superior mesenteric artery. The animals were divided into three cohorts: control (I), thoracic aortic cross-clamping (II), and thoracic aortic cross-clamping with selective visceral perfusion plus distal aortic perfusion using extracorporeal circulation (III). Macrocirculatory and microcirculatory blood flow was assessed by transit time ultrasound volume flow measurements and fluorescent microspheres. Intestinal ischemia-reperfusion injury was determined by the analysis of perioperative intestinal fatty acid-binding protein (IFABP) and interleukin-8 (IL-8) levels and correlated with histopathologic changes. RESULTS: Severe intestinal tissue injury and an inflammatory response were observed in cohort II compared with cohort III for IL-8 (38.2 vs 3.56 pg/mL; P = .04). The procedure in cohort III resulted in a flow and pressure-associated intestinal hypoperfusion compared with cohort I in the superior mesenteric artery (mean blood pressure, 24.1 ± 10.4 vs 67.2 ± 7.4 mm Hg; P < .0001; mean flow rates: 353.3 ± 133.8 vs 961.7 ± 310.8 mL/min; P < .0001). This was paralleled in cohort III vs cohort I by a significant mucosal injury (IFABP, 713 ± 307.1 vs 170 ± 115.4 pg/mL; P = .014) despite a profound recruitment of intestinal microcirculation (338% ± 206.7% vs 135% ± 123.7%; P = .05). CONCLUSIONS: This study reports a novel large-animal model of thoracic aortic cross-clamping that allows the study of visceral perfusion strategies. However, we demonstrated with IL-8 and IFABP measurements that thoracoabdominal aortic aneurysm surgery with selective visceral perfusion and distal aortic perfusion is superior to the clamp-and-sew technique, even though small intestinal tissue damage cannot be completely avoided by selective visceral perfusion and distal aortic perfusion. In any case, this model seems to be a platform to evaluate and optimize measures for gut wall protection.

HPV High-risk Multiple Infection Is a Key Predictor of Cervical Dysplasia in Diagnostic LEEPs: a Retrospective Cohort Analysis.

Objective This study aimed to identify predictors for the presence of cervical dysplasia in diagnostic LEEPs (Loop Electrical Excision Procedure) of the cervix. Materials/Methods The study was designed as a retrospective single-institution cohort analysis of all patients who underwent LEEP without prior proof of high-grade intraepithelial lesion (diagnostic LEEP) between 2015 and 2020 in the Department of Obstetrics and Gynecology of University Hospital Aachen. In order to identify the most meaningful predictive variables for CIN status (CIN2+ or non-CIN2+), multivariate logistic regression was performed and a machine-learning method was used. Results A total of 849 patients with an indication for loop excision of the cervix were assessed for eligibility. Finally, 125 patients without prior proof of CIN2+ were included into the study. Based on the final multivariate logistic regression model, multiple high-risk HPV infections (p = 0.001), the presence of a T2 transformation zone (p = 0.003) and major lesion changes (p = 0.015) as a result of the colposcopy examination were found to be statistically significant for CIN status based on the diagnostic LEEP. Subsequent ROC analysis showed a high predictive value for the model of 88.35% (AUC). The machine-learning technique (recursive partitioning) identified similar variables as important for CIN status with an accuracy of 75%. Conclusion For clinical decision-making, the result of the colposcopy examination (T2, major change) as well as the results of HPV testing (multiple high-risk HPV infections) are stronger indicators for clinicians to perform diagnostic excisional procedures of the cervix than the presence of high-grade cytological abnormalities.

Development of a bedside tool-kit for assessing sensitization in patients with chronic osteoarthritis knee pain or chronic knee pain after total knee replacement.

ABSTRACT: Different pathophysiological mechanisms contribute to the pain development in osteoarthritis (OA). Sensitization mechanisms play an important role in the amplification and chronification of pain and may predict the therapeutic outcome. Stratification of patients according to their pain mechanisms could help to target pain therapy. This study aimed at developing an easy-to-use, bedside tool-kit to assess sensitization in patients with chronic painful knee OA or chronic pain after total knee replacement (TKR). In total, 100 patients were examined at the most affected knee and extrasegmentally by the use of 4 standardized quantitative sensory testing parameters reflecting sensitization (mechanical pain threshold, mechanical pain sensitivity, dynamic mechanical allodynia, and pressure pain threshold), a bedside testing battery of equivalent parameters including also temporal summation and conditioned pain modulation, and pain questionnaires. Machine learning techniques were applied to identify an appropriate set of bedside screening tools. Approximately half of the patients showed signs of sensitization (46%). Based on machine learning techniques, a composition of tests consisting of 3 modalities was developed. The most adequate bedside tools to detect sensitization were pressure pain sensitivity (pain intensity at 4 mL pressure using a 10-mL blunted syringe), mechanical pinprick pain sensitivity (pain intensity of a 0.7 mm nylon filament) over the most affected knee, and extrasegmental pressure pain sensitivity (pain threshold). This pilot study presents a first attempt to develop an easy-to-use bedside test to probe sensitization in patients with chronic OA knee pain or chronic pain after TKR. This tool may be used to optimize individualized, mechanism-based pain therapy.

Bleeding propensity of cavernous malformations: impact of tight junction alterations on the occurrence of overt hematoma.

OBJECT: Endothelial tight junction (TJ) expression is mostly absent in cerebral cavernous malformations (CMs), which causes increased perilesional erythrocyte and fluid oozing. However, in a subset of CM lesions, foci of preserved TJ staining are observed along endothelial cell contacts. The clinical relevance of this finding is unclear. This study investigates the relevance of the focal TJ protein expression and its association with CM bleeding propensity. METHODS: Immunohistochemical staining for the TJ proteins claudin-5, occludin, and ZO-1 was performed on 32 CM specimens that were resected during 2008-2010. The patients were allocated to 2 groups according to TJ protein expression, and the clinical and radiological parameters of aggressiveness were analyzed and compared. RESULTS Complete absence of TJ expression was identified in 20 specimens, and focal TJ protein expression in 12. CMs without TJ immunoreactivity were significantly larger (p = 0.022) and had a significantly greater propensity for development of frank hematomas (p = 0.028) and perilesional edema (p = 0.013). Symptom severity, multiplicity, developmental venous anomaly (DVA) presence, and CM location did not show a significant difference depending on TJ expression. CONCLUSIONS: In a univariate analysis the authors observed significantly less propensity for frank hematomas and perilesional edema as well as smaller size in CM lesions with focal TJ expression compared with CMs without TJ expression. The observed difference in TJ protein expression might be the reason for differences in bleeding propensity of the CM lesions. Although this finding cannot be used in predictive manner at this time, it is a basis for further multivariate analyses of possible CM biological predictors.

Relationship between positive thyroglobulin doubling time and 18F-FDG PET/CT-positive, 131I-negative lesions.

AIM: In patients with differentiated thyroid carcinoma (DTC), metastases can either show iodine-131 (I) uptake on whole-body scintigraphy or F-2-fluoro-2-deoxy-D-glucose (F-FDG) uptake on combined PET and X-ray computed tomography (PET/CT), or a mix of both. The present study investigates the relationship between uptake patterns and prognosis in DTC patients, using thyroglobulin doubling time (TgDT) as a surrogate marker of prognosis. MATERIALS AND METHODS: We retrospectively examined F-FDG PET/CT and I WBS in 65 DTC patients who were referred to our department of nuclear medicine for F-FDG PET/CT between May 2007 and June 2011. RESULTS: Eight patients were excluded from analysis because of other diseases that caused intense F-FDG uptake or because of failure to show I WBS uptake. F-FDG uptake was seen in 30 out of 57 (53%) patients, of whom 14 showed some degree of I uptake. In these 30 positive scans, we identified a total of 181 F-FDG-positive lesions. Of these, 60 lesions (33%) showed concurrent I uptake on whole-body scintigraphy. Of the nine patients with a positive TgDT in the patient group eight had F-FDG-positive, I-negative lesions, indicating poorer prognosis for this group. CONCLUSION: In this initial exploratory retrospective study there appears to be an association between a positive TgDT and F-FDG-positive, I-negative metastases, which should encourage further studies in order to establish whether F-FDG PET-CT is the preferred primary imaging modality in patients with a positive TgDT. Roughly two-thirds of patients with a negative TgDT will show at least some degree of I positivity, potentially enabling further I therapy.

Risk factors for mortality and failure of conservative treatment after aortic type B dissection.

BACKGROUND: Despite medical treatment, one third of patients with uncomplicated type B aortic dissections experience severe late complications. The aim of this study was to identify patients at high risk of mortality during follow-up. METHODS: A total of 183 patients with acute Stanford type B dissection were treated in one of the university hospitals (Aachen [Germany], Maastricht [The Netherlands], and Innsbruck [Austria]) between 1997 and 2010. Records indicated that 120 patients were treated conservatively. Of these patients, 16 were lost to follow-up. The maximum diameter, extent of the dissection, and patency of the side branches were determined from computed tomography angiography data. Survival and treatment failure were analyzed by univariate and multivariate Cox regression analysis. The univariate analysis investigated the influence of aortic diameter (≥41 vs <41 mm) on survival, and the multivariate analysis investigated the influence of aortic diameter, age, sex, and surgery on survival. RESULTS: During the follow-up period, the initial treatment was converted to surgical treatment in 21 patients (20.2%). Sixteen of the 104 patients (15.4%) died after a mean of 845.5±805.9 days. The mean maximum aortic transversal diameter at admission was 41.2±8.7 mm. The multivariate analysis identified aortic diameter (P=.004; hazard ratio, 1.07) and age (P=.038; hazard ratio, 1.05) as risk factors that significantly reduce survival. CONCLUSIONS: Our study revealed both early aortic dilatation and older age as risk factors for increased mortality after conservative treatment of type B dissection.

Efficacy of antegrade pyeloperfusion to protect the renal pelvis in kidney microwave ablation using an in vivo swine model.

PURPOSE: The purpose of this study was to evaluate the efficacy of antegrade pyeloperfusion with cooled 5% of glucose solution to protect the renal collecting system during microwave ablation (MWA). MATERIALS AND METHODS: Computed tomographically guided nephrostomy was performed in 1 kidney in each of 14 female pigs by placing a 6F nephrostomy catheter. Pyeloperfusion was performed through infusion of cooled 5% of glucose solution via the nephrostomy catheter (4°C; 10 mL/min). Microwave ablation (915 MHz) was performed at 45 W for 10 minutes in the irrigated and the non-irrigated kidneys creating a central lesion and a peripheral lesion in each kidney. Maximum ablation diameters were measured and ablation volumes were calculated after the animals were killed. The extent of thermal injury of the renal pyelon was assessed histopathologically in the slice of maximal thermal injury on a 10-point scale ranging from 0 (none) to 10 (complete). RESULTS: Pyeloperfusion did not impact the ablation volume or the degree of thermal injury to the collecting system for the central or peripheral MWA procedures: The mean (SD) volume of the MWA zones was equivalent for the irrigated versus non-irrigated kidneys for the peripheral (3.07 [2.39] mL vs 3.87 [3.08] mL) and central MWA procedures (2.26 [1.55] mL vs 2.40 [1.60] mL). The mean (SD) histologic scores of the thermal damage of the pyelon were similar for the irrigated versus non-irrigated kidneys in the peripheral MWA (1.0 [2.7] vs 0.2 [0.6]) and in the central MWA (1.6 [2.7] vs 3.4 [3.4]). CONCLUSIONS: In MWA, cooled antegrade pyeloperfusion is not useful to modulate the ablation volume in peripheral or central locations. Accordingly, pyeloperfusion may not be useful as a protective measure to avoid thermal damage in MWA of the kidney. Therefore, MWA of central renal tumors does not seem advisable.

Outcome after mitral valve operations with depressed left ventricular function.

We retrospectively investigated 42 patients (27 men, 15 women; mean age, 67 years) with severe mitral valve incompetence and endstage cardiomyopathy (ejection fraction<30%) who were operated on between January 2002 and March 2009. Of these, 14 were in New York Heart Association class IV, and 27 were in class III. The etiology was ischemic in 18 patients and idiopathic dilated in 24. Mitral valve repair was performed in 25 patients, and 17 had mitral valve replacement. The mean logistic EuroSCORE was 33.41. The mean follow-up was 44.52 months. There were no perioperative deaths. Three patients died within 30 days postoperatively. Thirty-day mortality was lower than predicted by EuroSCORE (7.14% vs. 33.41%). The median functional class improved from 3 to 2 during follow-up. Ejection fraction improved from 24% to 42% at 6 weeks, then decreased to 33%. The midterm survival rate was 86%, and 81% after 1 and 2 years. Freedom from reoperation at 2 years was 85%; 6 patients needed reoperation for recurrent mitral regurgitation. Despite high operative risk, mitral valve surgery can be performed successfully with acceptably low mortality in patients with endstage cardiomyopathy. Patients experience substantial clinical improvement and a moderate recovery of left ventricular function.