Alina Abramian

Prognostic significance of tumor-associated macrophages in endometrial adenocarcinoma

OBJECTIVE Endometrial adenocarcinoma is one of the most common gynecologic malignancies worldwide and in stages confined to the uterus considered to have an excellent prognosis. However, in advanced or recurrent cases when surgery fails to achieve disease control other treatment options are less effective. Thus, new therapeutic avenues are needed. METHODS To provide the rationale for the use of novel agents that target immune checkpoints 163 type I endometrial cancer samples were immunohistochemically screened for the presence of CD163(+) tumor-associated macrophages and Foxp3(+) regulatory T cells. Further, a D2-40-based evaluation of lymph vessel density and lymphovascular space invasion was carried out. Correlation analysis with clinicopathological parameters was performed; Kaplan-Meier curves were generated; multivariate analysis was undertaken as appropriate. RESULTS A substantial amount of tumor-associated macrophages and regulatory T cells was detected in all specimens characterizing endometrial cancer as an immunogenic tumor. However, only the increased infiltration of tumor-associated macrophages was proportionally associated with advanced FIGO stages, high tumor grade, increased lymph vessel density, lymphovascular space invasion and lymph node metastasis. Thus, the presence of tumor-associated macrophages indicates aggressive tumor behavior and appeared to be an independent prognostic factor for recurrence-free survival. CONCLUSIONS Our results make future therapeutic approaches that target tumor-associated macrophages reasonable to improve the outcome of women with advanced or recurrent endometrial adenocarcinoma.

CPAP combined with inhaled nitric oxide for treatment of lung hypoplasia and persistent foetal circulation due to prolonged PPROM

BACKGROUND Second trimester preterm premature rupture of the membranes (PPROM) before 24 weeks of gestation is associated with a high morbidity and mortality rate. AIM To demonstrate the efficacy of early continuous positive airway pressure (CPAP) combined with inhaled nitric oxide (iNO) for treatment of preterm infants with lung hypoplasia and persistent foetal circulation (PFC) due to very early PPROM and prolonged severe oligohydramnios. METHODS Seven infants with prolonged PPROM, lung hypoplasia, respiratory distress and persistent foetal circulation were intubated in the delivery room for subsequent surfactant and iNO application. As our new treatment strategy was to keep the period of mechanical ventilation as short as possible, all infants were switched on nasal CPAP combined with iNO within the first 24 hours. RESULTS Mean gestational age at PPROM was 19+6 weeks (range 14+2 to 23+6 weeks) and the average latency period between rupture of membranes and delivery was 10+3 weeks (7+3 to 16+4 weeks). Infants were born at 30+3 weeks of gestation (28+3 to 33+1 weeks) with an average birth weight of 1468g (884 to 2200g). In all neonates CPAP combined with iNO reversed PFC and 6 patients stabilised without the need for reintubation and mechanical ventilation. One infant had to be reintubated following 12 hours of CPAP combined with iNO due to respiratory insufficiency. All seven infants survived to discharge. CONCLUSION CPAP combined with iNO might be a promising approach for therapy of preterm infants with lung hypoplasia and persistent foetal circulation due to very early PPROM.

Staging of Primary Breast Cancer Is not Indicated in Asymptomatic Patients with Early Tumor Stages

Background: The routinely practiced staging for distant metastasis in patients with primary breast cancer has been increasingly questioned. Patients and Methods: Data from 742 patients with breast cancer who had completed staging (chest x-ray, liver ultrasound, and bone scan) were retrospectively analyzed. Present findings were transferred to a dataset of a voluntarily monitored benchmarking project by the West German Breast Center that included patient data of 179 breast cancer centers. Results: Routine staging examinations revealed in 1.2% (n = 9) distant metastasis and in 38.8% (n = 288) suspicious results. In total, 15 patients (2%) had distant metastases confirmed by additional diagnostics. The existence of distant metastases correlated with tumor size, nodal state, and lymphatic vessel spread. Tumor size and nodal state were independent predictors for disseminated disease. The risk of exhibiting distant metastases was 0.77% for patients with tumor stage pT1 pN1. Based on these findings, in 159,310 patients 41,728 chest x-rays, 43,950 liver ultrasounds, and 39,037 bone scans could have been avoided. Conclusion: Asymptomatic patients with tumor stages ≤ pT1 pN1 do not benefit from staging of primary breast cancer. Suspending staging examinations for these patients could reduce cost without restricting oncologic safety.

Ebstein's anomaly of the tricuspid valve in association with tetralogy of fallot and absent pulmonary valve syndrome.

Ebstein’s anomaly and absent pulmonary valve syndrome belong to the rarest congenital heart defects. Their association has never been reported so far. We present the unusual case of a fetus at 23 weeks of gestation with Ebstein’s anomaly, tetralogy of Fallot, absent pulmonary valve and agenesis of the arterial duct. The main diagnostic features were apical displacement of the septal leaflet of the tricuspid valve with an offset from the mitral valve of 8 mm, a pronounced atrialization of the right ventricle, a large malalignment ventricular septal defect with overriding aorta in combination with absence of the pulmonary valve leaflets, to and fro flow pattern over the stenotic pulmonary valve annulus, turbulent flow in the pulmonary trunk, massive dilatation of the pulmonary trunk plus the pulmonary arteries and a right aortic arch with retroesophageal course of an aberrant left subclavian artery. The arterial duct and the thymus were absent. The remaining fetal anatomy was unremarkable. Amniocentesis revealed a normal male karyotype; 22q11 microdeletion was ruled out. After being counseled on the unfavorable prognosis, the parents opted for termination of pregnancy. The prenatal cardiac findings were confirmed at autopsy; however, a severely hypoplastic thymus was found instead of the suspected aplasia.

Individual management of cervical cancer in pregnancy.

PurposeThe management of cervical cancer in pregnancy persists to be challenging. Therefore, identification of factors that influence the choice of therapeutic management is pivotal for an adequate patient counseling.MethodsWe present a literature review of 26 studies reporting 121 pregnancies affected by cervical cancer. Additionally, we add a retrospective case series of five patients with pregnancy-associated cervical cancer diagnosed and treated in our clinic between 2006 and 2013.ResultsThe literature review revealed that the therapeutic management during pregnancy varies according to the gestational age at diagnosis, while in the postpartum period no influence on the treatment choice could be detected. Also in our case series the choice of oncologic therapy was influenced by the gestational age, the wish to continue the pregnancy and the risks of delaying definitive treatment.ConclusionsThere are no standardized procedures concerning the treatment of cervical cancer in pregnancy. Therefore, in consultation with the patient and a multidisciplinary team, an adequate individualized treatment plan should be determined.

Preoperative MRI in Patients with Locoregional Recurrent Breast Cancer: Influence on Treatment Modalities

RATIONALE AND OBJECTIVES The purpose of this analysis was to evaluate the impact of preoperative magnetic resonance imaging (MRI) on management in patients with locoregional recurrent breast cancer. MATERIALS AND METHODS Forty-three patients who underwent treatment for locoregional relapse of breast cancer from 2008 through 2012 were analyzed. All patients underwent both conventional surveillance by mammography, ultrasound, and clinical examination and subsequent bilateral breast MRI. RESULTS Preoperative MRI detected additional tumor foci in 15 of 43 patients (34.9%). In two cases (4.7%), the diagnosis of occult sites had no influence on the subsequent treatment. Two patients (4.7%) had an unfavorable change of surgical management with unnecessary additional resection of benign foci. Eleven patients benefited from the MRI scan detecting malignant occult lesions (25.6%) resulting in either additional surgical resection or radiotherapy. Patient and tumor characteristics in primary disease did not differ significantly between patients with a favorable impact on surgical management and patients who experienced either no benefit or even disadvantage from MRI scan. CONCLUSIONS Preoperative breast MRI has a strong impact on the management of locoregional recurrent breast cancer. This study demonstrates that breast MRI is a powerful supplement to conventional diagnostic work-up, both during follow-up or preoperative treatment planning in recurrent disease.

Total or Subtotal Colectomy in Patients Undergoing Surgery for Primary or Recurrent Epithelial Ovarian Cancer

Background: There is controversy as to whether performing a total or subtotal colectomy is justified in patients with advanced ovarian cancer, given its potential for morbidity and a negative effect on long-term quality of life. The aim of this study was to assess the perioperative complications, mortality and outcomes of patients who underwent total or subtotal colectomy as part of the surgical procedure for primary or recurrent epithelial ovarian cancer. Patients and Methods: All patients who had undergone surgery including a total or subtotal colectomy for advanced or recurrent ovarian cancer between 2005 and 2013 at our institution were retrospectively identified. Results: In this time period, 339 patients underwent surgery for epithelial ovarian cancer, which in 11 (3%) patients included a total or subtotal colectomy. Severe grade 3-4 postoperative complications occurred in 3 (27%) patients, and 1 (9%) patient died within 60 days of surgery. Conclusion: A total or subtotal colectomy is associated with increased but acceptable morbidity in selected patients undergoing primary cytoreductive surgery. However, in the recurrent/palliative setting, total or subtotal colectomy should be avoided as the prognosis is poor and the morbidity outweighs the clinical benefit.

Introducing Hyperthermic Intraperitoneal Chemotherapy into Gynecological Oncology Practice - Feasibility and Safety Considerations: Single-Center Experience

Background: Within the surgical oncology community interest is increasingly focusing on combining surgical cytoreduction and regional chemotherapeutic drug delivery to manage solid abdominal tumors. In particular, the role of hyperthermic intraperitoneal chemotherapy (HIPEC) is evolving for treating epithelial ovarian carcinomas (EOCs), as EOCs remain confined to the peritoneal cavity for most of their natural history. Currently there is no evidence from prospective trials to confirm an overall survival benefit associated with HIPEC. In addition, there are no generally accepted regimens, which results in heterogeneous clinical procedures. Methods: We have initiated a HIPEC program at our institution and completed a phase I study of HIPEC with cisplatin in patients with platinum-sensitive recurrent EOC. The data have been published and prove the feasibility of this approach. In the process of introducing HIPEC, several safety measures had to be taken into consideration. Results: We present the implications and requirements of introducing HIPEC in clinical practice and discuss our proposed procedure referring to the recent literature. Conclusion: HIPEC is feasible and can be performed safely in daily gynecological oncology routine provided that certain considerations and precautions are taken into account during its introduction to guarantee a proper and safe operating sequence.

Identifizierung und Charakterisierung tumorinduzierter Immunmechanismen in einem C57Bl/6 syngenen Maus-Ovarialkarzinommodell

Das Ovarialkarzinom ist das prognostisch ungunstigste gynakologische Malignom. Es besitzt jedoch ein hohes immunogenes Potenzial, welches immuntherapeutische Behandlungsansatze vielversprechend erscheinen lasst. In der praklinischen Evaluation von Immuntherapien sind Mausmodelle von groser Bedeutung. In dieser Arbeit wurden in einem C57Bl/6 syngenen Maus-Ovarialkarzinommodell immunsupprimierende Mechanismen myeloider und lymphoider Zellen identifiziert und charakterisiert. Durch Peritoneallavage gewonnene Makrophagen gesunder Mause wurden uber 6 Tage in Uberstand von Maus-Ovarialkarzinomzellen kultiviert. Die Expression immunsuppressiver Marker wurde anschliesend durchflusszytometrisch analysiert. Zur Evaluation der Auswirkung des Tumorwachstums auf immunsuppressive Mechanismen in vivo wurden Diphterietoxinrezeptor- und Luciferase-exprimierende syngene Ovarialkarzinomzellen intraperitoneal (i.p.) in C57Bl/6-Mause injiziert und nach zweiwochigem Tumorwachstum mittels Diphtherietoxin i.p. entfernt. Vier, sechs und acht Wochen nach Tumorinduktion wurden das Tumorwachstum mittels dem In Vivo Imaging System (IVIS) und das peritumorale Immunmilieu im Aszites und in peritonealen Tumorherden von Mausen mit und ohne Depletion durchflusszytometrisch verglichen. In vitro zeigte sich fur die in Tumorzelluberstand kultivierten Makrophagen eine Aufregulation antiinflammatorischer Marker. In vivo zeigte sich bei Tumorprasenz eine hohe Konzentration immunsupprimierender Zellen (tumorassoziierte Makrophagen (TAMs), regulatorische T-Zellen), und eine Verminderung proinflammatorischer Zellen (zytotoxische T-Zellen) im Vergleich zu depletierten und tumorfreien Mausen. Anhand unseres Maus-Ovarialkarzinommodells konnten wir zeigen, dass die Prasenz von Ovarialkarzinomzellen zur Ausbildung eines immunsuppressiven Milieus fuhrt. Insbesondere TAMs spielen hierbei als antiinflammatorische Immunzellen eine wichtige Rolle. Diese Ergebnisse bilden die Basis fur zukunftige Immuntherapien beim Ovarialkarzinom.