Ultra-High-b-Value Kurtosis Imaging for Noninvasive Tissue Characterization of Ovarian Lesions.

Background MRI with contrast material enhancement is the imaging modality of choice to evaluate sonographically indeterminate adnexal masses. The role of diffusion-weighted MRI, however, remains controversial. Purpose To evaluate the diagnostic performance of ultra-high-b-value diffusion kurtosis MRI in discriminating benign and malignant ovarian lesions. Materials and Methods This prospective cohort study evaluated consecutive women with sonographically indeterminate adnexal masses between November 2016 and December 2018. MRI at 3.0 T was performed, including diffusion-weighted MRI (b values of 0-2000 sec/mm2). Lesions were segmented on b of 1500 sec/mm2 by two readers in consensus and an additional independent reader by using full-lesion segmentations on a single transversal slice. Apparent diffusion coefficient (ADC) calculation and kurtosis fitting were performed. Differences in ADC, kurtosis-derived ADC (Dapp), and apparent kurtosis coefficient (Kapp) between malignant and benign lesions were assessed by using a logistic mixed model. Area under the receiver operating characteristic curve (AUC) for ADC, Dapp, and Kapp to discriminate malignant from benign lesions was calculated, as was specificity at a sensitivity level of 100%. Results from two independent reads were compared. Histopathologic analysis served as the reference standard. Results A total of 79 ovarian lesions in 58 women (mean age ± standard deviation, 48 years ± 14) were evaluated. Sixty-two (78%) lesions showed benign and 17 (22%) lesions showed malignant histologic findings. ADC and Dapp were lower and Kapp was higher in malignant lesions: median ADC, Dapp, and Kapp were 0.74 µm2/msec (range, 0.52-1.44 µm2/msec), 0.98 µm2/msec (range, 0.63-2.12 µm2/msec), and 1.01 (range, 0.69-1.30) for malignant lesions, and 1.13 µm2/msec (range, 0.35-2.63 µm2/msec), 1.45 µm2/msec (range, 0.44-3.34 µm2/msec), and 0.65 (range, 0.44-1.43) for benign lesions (P values of .01, .02, < .001, respectively). AUC for Kapp of 0.85 (95% confidence interval: 0.77, 0.94) was higher than was AUC from ADC of 0.78 (95% confidence interval: 0.67, 0.89; P = .047). Conclusion Diffusion-weighted MRI by using quantitative kurtosis variables is superior to apparent diffusion coefficient values in discriminating benign and malignant ovarian lesions and might be of future help in clinical practice, especially in patients with contraindication to contrast media application. © RSNA, 2020 Online supplemental material is available for this article.

Adherence to gynecological screening impacted by experienced orthodontic treatment in childhood.

BACKGROUND: Dental and cervical controls are two established screening programs in Germany. Compliance to orthodontic treatment in childhood is essential for dental health and one of the first health interventions that requires adherent behavior; therefore, it may be associated with participation in further screening programs in adulthood. However, it is not yet known whether early orthodontic treatment influences long-term screening adherence. METHODS: Using a questionnaire administered during a visit to a special dysplasia outpatient service, this case-control study evaluated women's personal history of orthodontic care, long-term satisfaction, and dental and gynecological screening adherence. Oral health status and dental anxiety were assessed with validated instruments. Cases were categorized as cervical dysplasia only (S2) or cervical dysplasia with conization (S1) and compared to healthy controls with a normal PAP smear. RESULTS: A study population of 233 participants included 132 cases and 101 controls. The control group had had orthodontic treatment during childhood more often than our study population with abnormal PAP smears (68.3% controls versus 56.1% subjects; p < 0.005). Orthodontic treatment was not associated with attending dental appointment or gynecological check-ups. However, women with an orthodontic treatment in childhood were significantly more often vaccinated against human papillomavirus than women without orthodontic treatment (p < 0.03). CONCLUSION: Data suggest that women with orthodontic treatment in childhood are more conscious about prevention strategies in adulthood; therefore, compliant behavior might be established in childhood.

Impact of a cervical dysplasia and its treatment on quality of life and sexual function.

PURPOSE: In this case-control study, the impact on quality of life and sexual function in women with cervical dysplasia and conization will be evaluated, in order to address coping with such a premalignant lesion and to improve strategies for salutogenesis. METHODS: This multicenter case-control study evaluates women at special dysplasia outpatient clinic (T1) as well as 3 (T2) and 6 (T3) months after the diagnosis of a dysplasia. The women were subgrouped upon dysplasia only (S2) or dysplasia with conization (S1). Sexual function as well as cervix-related and general quality of life was assessed using validated instruments (FSFI-d, EORTC-QLQ-CX24, SF-36). RESULTS: Women with dysplasia had a lower sexual functioning than controls (FSFI: S1: 23.8 ± 9.7 (p < 0.003); S2: 25.3 ± 7.5 (p < 0.03); K: 29.1 ± 4.5) as well as a lower physical component score (SF-36: S1: 51.3 ± 8.6 (p < 0.02); S2: 51.7 ± 7.8 (p < 0.05); K: 54.2 ± 6.6) and had a significantly reduced body image (EORTC-QLQ-CX24: S1: 75.7 (p < 0.001); S2: 76.5 (p < 0.001), K:89.2). Sexual functioning was not affected by conization in the observational period over 6 months; however, sexual worry was impacted. Over temporal progression women who underwent conization worried more. Regression analysis revealed a cervical dysplasia to impact sexual function. CONCLUSION: Data suggest that women with the diagnosis of a cervical dysplasia are impaired in their sexual function as well as general and cervix-related quality of life, mostly independent of conization or further observation. To improve salutogenesis in the long run, the communication on dysplasia and its treatment strategy at the beginning, as well as part of aftercare, or psychosomatic intervention, might be treatment options for women at risk.

Changes in the microarchitecture of the pancreatic cancer stroma are linked to neutrophil-dependent reprogramming of stellate cells and reflected by diffusion-weighted magnetic resonance imaging.

In pancreatic cancer (PDAC) intratumor infiltration of polymorphonuclear neutrophils (PMN) is associated with histologically apparent alterations of the tumor growth pattern. The aim of this study was to examine possible associations between PMN infiltration, tumor microarchitecture, and water diffusivity in diffusion-weighted magnetic resonance imaging (DW-MRI), and to further asses the underlying mechanisms. Methods: DW-MRI was performed in 33 PDAC patients prior to surgery. In parallel, tissue specimen were examined histologically for growth pattern, azurocidin-positive PMN infiltrates, and the presence of alpha-smooth muscle actin (α-SMA) and metalloproteinase 9 (MMP9)-positive myofibroblastic cells. For confirmation of the histological findings, a tissue microarray of a second cohort of patients (n=109) was prepared and examined similarly. For in vitro studies, the pancreatic stellate cell line RLT was co-cultivated either with isolated PMN, PMN-lysates, or recombinant azurocidin and characterized by Western blot, flow cytometry, and proteome profiler arrays. Results: Tumors with high PMN density showed restricted water diffusion in DW-MRI and histologic apparent alterations of the tumor microarchitecture (microglandular, micropapillary, or overall poorly differentiated growth pattern) as opposed to tumors with scattered PMN. Areas with altered growth pattern lacked α-SMA-positive myofibroblastic cells. Tissue microarrays confirmed a close association of high PMN density with alterations of the tumor microarchitecture and revealed a significant association of high PMN density with poor histologic grade of differentiation (G3). In vitro experiments provided evidence for direct effects of PMN on stellate cells, where a change to a spindle shaped cell morphology in response to PMN and to PMN-derived azurocidin was seen. Azurocidin incorporated into stellate cells, where it associated with F-actin. Down-regulation of α-SMA was seen within hours, as was activation of the p38-cofilin axis, up-regulation of MMP9, and acquisition of intracellular lipid droplets, which together indicate a phenotype switch of the stellate cells. Conclusion: In PDAC, PMN infiltrates are associated with alterations of the tumor microarchitecture. As a causal relationship, we propose a reprogramming of stellate cells by PMN-derived azurocidin towards a phenotype, which affects the microarchitecture of the tumor.

Oncotype DX® in breast cancer patients: clinical experience, outcome and follow-up-a case-control study.

PURPOSE: Breast cancer is the leading cause of death from cancer in women and the most common cancer in the world [1]. To date, many patients with estrogen-receptor-positive (ER+) breast cancer are overtreated with chemotherapy when the rationale for adjuvant chemotherapy is based on clinicopathologic parameters. Different studies were able to demonstrate that a 21-gene expression assay (Oncotype DX® Genomic Health, Redwood City, CA) can predict the benefit from adjuvant chemotherapy in ER+ breast cancers [2, 3] and provide additional prognostic information independent of clinicopathological features [4]. RESULTS: Data from all patients with ER+ Her2neu- breast cancer undergoing Oncotype DX® testing between 2011 and 2014 at a tertiary referral center in Germany were analyzed. Oncotype DX® was performed in 69 cases, in 2 cases data were missing and in 3 cases Oncotype DX® could not be performed by the company. The results showed a low risk in 39 cases, an intermediate risk in 22 cases and a high risk in 3 cases. Based on Oncotype results, treatment recommendations were changed in 39 of 64 patients (61%). Before Oncotype DX® testing, chemotherapy was recommended in 67 patients, afterwards only in 25 patients. Data from 44 of 67 patients were matched to controls for stage, tumor grade, menopausal and hormone receptor status. Within a mean observation time of 19.7 months, cancer recurrence was observed in two patients. CONCLUSIONS: Oncotype DX® testing can be recommended for risk-tailored chemotherapy. Results should be validated in larger prospective studies.

Implementation of a novel efficacy score to compare sealing and cutting devices in a porcine model.

BACKGROUND: In general surgery, minimally invasive laparoscopic procedures have been steadily increasing over the last decade. The application of advanced bipolar and ultrasonic energy devices for sealing and cutting of blood vessels plays a vital role in routine clinical procedures. The advantages of energy-based instruments are enhanced sealing capability combined with both fast sealing time and minimal thermal injury. The purpose of this study was to compare the safety and efficacy profiles of nine laparoscopic sealing and cutting devices in a porcine model, with a new scoring system. METHODS: Comparative studies in a porcine model were performed to assess vessel sealing, burst pressure, thermal spread, maximum heat, sealing/cooling time, and compression strength over the full jaw. Nine different devices from five manufacturers were tested in this study. The sealing and cutting devices (SCD) score has been developed to enable standardized comparisons of various devices. For this purpose, the most important parameters were identified through a consensus approach. RESULTS: All sealed vessels with different devices could withstand a median pressure of more than 300 mmHg (range 112-2046 mmHg). The time for the sealing procedure was 7.705 s (range 5.305-18.38 s) for the ultrasonic and 7.860 s (range 5.08-10.17 s) for the bipolar devices. The ultrasonic instruments reached a median temperature of 218.1 °C (range 81.3-349.75 °C) and the bipolar devices a temperature of 125.5 °C (range 94.1-133.35 °C). The tissue reached a median temperature of 61.9 (range 47.1-80.6 °C) after ultrasonic sealing and 76.7 °C (range 63.1-94.2 °C) after bipolar sealing. The median SCD score was 10.47 (range 7.16-13.72). CONCLUSION: All the instruments used seemed safe for use on the patient. The SCD score allows an indirect comparability of the instruments.

Influence of Paclitaxel and Heparin on Vitality, Proliferation and Cytokine Production of Endometrial Cancer Cells.

BACKGROUND: Cancer patients have a higher risk for thromboembolic events compared to healthy individuals and are often treated with heparins. A beneficial effect of heparins on tumor patients above and beyond the classic anticoagulation effect has been reported, leading to an increased focus on the use of heparins in anticancer treatment. In recent years, it has become apparent that microenvironments greatly affect tumor development and can be a major source of tumor-promoting factors. Cytokines play an important role in tumor microenvironments, inducing carcinogenesis and influencing tumor progression by promoting angiogenesis, metastatic potential and immunosuppression. The possible interaction of heparins and cytokines could also have an effect on cancer cells. METHODS: This study investigated the effect of paclitaxel (PTX) combined with heparins on the vitality of endometrial cancer cells using viability and cytotoxicity assays. The study also examined whether treatment with paclitaxel and heparin influences cytokine secretion or expression. RESULTS: Heparin treatment did not influence cell viability, and no influence of heparins in combination with paclitaxel was seen for the evaluated cancer cell lines HEC-1-A, KLE, RL 95-2 and AN3-CA compared to untreated cells. Secretion of the cytokines CCL5, CCL2 and IL-6 increased after paclitaxel treatment in several endometrial cancer cell lines, but no general effect on cytokine secretion was detected after heparin treatment. A significant decrease in CCL5 expression was only detected in KLE cells following treatment with heparin and paclitaxel, and an increase in the expression of CCL5 in RL 95-2 cells. CONCLUSION: Further in-depth studies are needed to investigate the functions of cytokines CCL2, CCL5 and IL-6 in endometrial cancer cells treated with paclitaxel. Although no general effect on cytokine secretion was detected following heparin treatment, a selective modulatory impact could exist.

PARP inhibition sensitizes endometrial cancer cells to paclitaxel-induced apoptosis.

PARP inhibitors are used in the treatment of gynecological malignancies and it has been demonstrated in preclinical studies that PARP inhibition sensitizes cancer cells to cytotoxic agents. In the present study, PARP expression was detected in different endometrial cancer cell lines by western blot analysis, and PARP activity was measured using an enzymatic assay. In addition, the endometrial cancer cell lines were treated with paclitaxel or carboplatin in combination with the PARP inhibitor PJ34 prior to a cell viability assay and apoptotic nuclei measurement. PARP protein was detected in all four cell lines examined, although its activity varied between the cell lines. Treatment with PJ34 in combination with paclitaxel decreased endometrial cancer cell viability compared with treatment with paclitaxel alone. These results indicate that the inhibition of PARP with PJ34 sensitizes endometrial cancer cells to cytotoxic treatment with paclitaxel.

Detection of Human Papillomavirus Infection in Patients with Vaginal Intraepithelial Neoplasia.

INTRODUCTION: Vaginal intraepithelial neoplasia (VAIN) is a pre-malignant lesion, potentially leading to vaginal cancer. It is a rare disease, representing less than 1% of all intraepithelial neoplasia of the female genital tract. Similar to cervical intraepithelial neoplasia (CIN), there are three different grades of VAIN. VAIN 1 is also known as a low-grade squamous intraepithelial lesion (LSIL), whereas VAIN 2 and VAIN 3 both represent high-grade squamous intraepithelial lesions (HSIL). Risk factors for the development of VAIN are similar to those for cervical neoplasia, i.e. promiscuity, starting sexual activity at an early age, tobacco consumption and infection with human papillomavirus (HPV). However, compared to other intraepithelial neoplasia such as CIN or VIN (vulvar intraepithelial neoplasia), there still is little understanding about the natural course of VAIN and its capacity for pro- or regression. Furthermore, there is controversial data about the HPV detection rate in VAIN lesions. PATIENTS AND METHODS: 67 patients with histologically confirmed VAIN, who were diagnosed between 2003 and 2011 at the University Women´s Hospital of Heidelberg Germany, were included in this study. The biopsies of all participating patients were subjected to HPV genotyping. GP-E6/E7 Nested Multiplex PCR (NMPCR) was used to identify and genotype HPV. Eighteen pairs of type-specific nested PCR primers were assessed to detect the following "high-risk" HPV genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68, as well as the "low-risk" genotypes 6/11, 42, 43 and 44. The data was analyzed with the software SAS (Statistical Analysis System). RESULTS: All 67 cases were eligible for DNA analysis. The median age was 53 years. The largest group with 53% (n = 36) was formed by women, who were first diagnosed with VAIN between the age of 41 to 60 years. 50% (n = 37) of the patients presented a VAIN in the upper 1/3 of the vagina. 58 (87%) were diagnosed with HSIL (VAIN). The median age in patients with LSIL (VAIN) was 53 years and in patients with HSIL (VAIN) 53.5 years. 12 women (18%) had an immunosuppression. HPV positivity was confirmed in 37 patients (55%). Except for a single patient, who had a triple infection with HPV types 6/11, 16 and 68, only infections with one single HPV genotype were detected. An infection with the HPV genotypes 31, 39, 45, 51, 58, 59, 66, 42, 43 and 44 couldn't be found in any of the patients. In 28 patients with diagnosed VAIN, an infection with HPV 16 could be shown, 24 (86%) of them were diagnosed with a HSIL (VAIN). 16 (24%) women presented condylomata and 13 of them (81%) had a positive HPV status. However, only 47% of the women without condylomata presented a positive HPV status, resulting in a significant correlation (p = 0.0164) between condylomata and HPV infection. In 28 of all 67 patients (42%), recurrence of the neoplasia occurred. CONCLUSION: HPV 16 is the main virus-type to be associated with the development of a VAIN. Also, HPV 16 infection, VIN or condylomata acuminata in the past medical history seemed to be significant factors for early relapse.