Morphokinetic analysis of early human embryonic development and its relationship to endometriosis resection: a retrospective time-lapse study using the KIDScore™ D3 and D5 implantation data algorithm.

RESEARCH QUESTION: Does complete resection of endometriosis improve embryo quality as assessed by morphokinetic parameters using time-lapse microscopy? DESIGN: For this retrospective study we analysed 237 fertilised, cultured and transferred embryos from 128 fresh IVF and/ or ICSI transfer cycles. Endometriosis was confirmed or excluded by laparoscopy. Patients were stimulated with recombinant FSH using GnRH agonist and antagonist protocols. After fertilisation, a time-lapse incubation system was used for observation. Embryo quality was assessed using the KIDScore™ D3 and D5 implantation data algorithm. RESULTS: The analysis showed a median KIDScore™ D5 of 2.6 (on a scale of 1 to 9.9) for embryos from patients with endometriosis without complete resection. The control group without endometriosis achieved a score of 6.8 (p = 0.003). The median score for embryos from endometriosis patients with complete resection was 7.2, which was a significant increase compared to embryos from patients without complete resection (p = 0.002). We observed an effect size of r = 0.4 for complete resection versus no resection of endometriosis using the KIDScore™ D5. There were no differences in KIDScore™ D3 between the three patient groups. Pregnancy and miscarriage rates showed the same clinical trends. In three of our four case series of patients who underwent IVF/ ICSI cycles before and after complete resection, we found a marked improvement in embryo quality after complete resection. CONCLUSIONS: Complete resection of endometriosis could significantly improve the otherwise poor embryo quality of patients undergoing IVF-procedures. The data, therefore, strongly support recommending surgery to patients with endometriosis prior to assisted reproduction.

Role of HIPEC after Complete Cytoreductive Surgery (CRS) in Peritoneal Recurrence of Platinum-Sensitive Recurrent Ovarian Cancer (OC): The Aim for Standardization at Two Reference Centers for CRS.

BACKGROUND: This bicentric study evaluated cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for platinum-sensitive recurrent ovarian cancer patients. METHODS: The data of 88 patients with the first peritoneal recurrence of platinum-sensitive epithelial ovarian cancer who underwent CRS and HIPEC from a prospective HIPEC registry were retrospectively investigated. Endpoints were feasibility, chemotherapeutic compound, time of exposure, complications, and overall survival. RESULTS: The median follow-up was 4.7 years (95%-CI 4.6-5.5). The median age was 55.8 years (IQR: 50.3-66.2). Eighty-four patients (95.5%) had high-grade serous histology. The median peritoneal cancer index was 12.0 (IQR: 7.0-20.5). Sixty-five patients (73.9%) had complete cytoreduction (CCR 0). Thirty-eight patients (43.2%) received HIPEC for 60 min, and fifty patients (56.8%) for 90 min. Eighteen patients (20.5%) had grade III to IV complications. One patient (1.1%) died perioperatively. The overall median survival was 43.1 months (95%-CI 34.1-52.2), and the 5-year survival rate was 39.7%. Only 90 min HIPEC and cisplatin were associated with survival. CONCLUSION: In well-selected patients with platinum-sensitive recurrent ovarian cancer, survival may correlate with complete CRS and 90 min cisplatin-based HIPEC. We confirmed the results of primary OC studies; therefore, this combination should be used for further analysis in the recurrent situation.

Prolonged Exposition with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) May Provide Survival Benefit after Cytoreductive Surgery (CRS) in Advanced Primary Epithelial Ovarian, Fallopian Tube, and Primary Peritoneal Cancer.

Background: The usage of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced gynecological cancers is increasing. Methods: Prospectively collected data of 85 advanced primary ovarian/fallopian tube cancer and peritoneal carcinoma patients of a single center were investigated. Results: A total 48, 37, 62, and 25 patients were enrolled into the HIPEC with/without neoadjuvant chemotherapy (upfront vs. interval) and into the 60 min and 90 min long HIPEC groups, respectively. Better overall survival (OS) was observed in the 90 min HIPEC group (p = 0.0330), compared to the 60 min HIPEC group. Neither OS (p = 0. 2410), disease-specific (p = 0. 3670), nor recurrence-free survival (p = 0.8240) differed between upfront and interval HIPEC. Higher peritoneal carcinomatosis index (PCI) values were associated with worse disease-specific survival (p = 0.0724). Age (p = 0.0416), body mass index (p = 0.0044), PCI (p < 0.0001), the type (p = 0.0016) and duration (p = 0.0012) of HIPEC, and increased perioperative morbidity (p < 0.0041) had the greatest impact on OS. Conclusions: Increasing data support the value of HIPEC in the treatment of advanced ovarian cancer. Ongoing prospective studies will definitively clarify the role and timing of this additional therapeutic approach.

Extraperitoneal Approach During Peritonectomy in the Right Upper Quadrant for Peritoneal Metastases from Ovarian Malignancies.

AIM: To present the extraperitoneal approach for the removal of peritoneal metastases in the right upper abdomen in patients with ovarian cancer and to evaluate safety and potential advantages with comparison with the traditional approach. PATIENTS AND METHODS: Detailed description of the right upper quadrant peritonectomy as extraperitoneal approach. Procedure-specific short-term complications were retrospectively analyzed in a cohort of patients. RESULTS: Sixty-four patients were included. Full-thickness diaphragmatic resection was performed in 17% of primary cases, and in 44% of the patients with recurrent ovarian carcinoma. The rate of complete cytoreduction (CC-0) was 70%. The most common postoperative complication was pleural effusion (32%). CONCLUSION: The extraperitoneal approach for peritonectomy of the right upper quadrant in patients with ovarian cancer is feasible, with improved access to the right subdiaphragmatic area. This enables a high rate of complete cytoreduction, and simplified and safe surgical dissection in an uncontaminated area under secured vascular structures. The early postoperative outcomes are comparable to those of the traditional transperitoneal approach.

Malignant Struma Ovarii Τreated With Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

BACKGROUND/AIM: Malignant struma ovarii is an extremely rare tumor entity among ovarian tumors. In the presence of ascites and peritoneal metastases, the preoperative appearance may resemble the most common epithelial ovarian carcinoma (EOC) and accordingly, the surgical therapy may be identical if a preoperative histology diagnosis is not possible. The objective of this case report is to present a patient with histopathologically confirmed malignant struma ovarii who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS and HIPEC) with the aim of complete tumor resection. CASE REPORT: This study reports on a patient with preoperatively proven peritoneal metastasis of an 18 cm ovarian tumor with large struma ovarii and papillary thyroid carcinoma within the struma, who was treated with CRS and HIPEC after neoadjuvant chemotherapy. CONCLUSION: This disease has a significantly better prognosis than EOC, however, HIPEC could provide an additional effect in examining the presence of peritoneal metastasis.

SARS-CoV-2 in pregnancy and possible transfer of immunity: assessment of peripartal maternal and neonatal antibody levels and a longitudinal follow-up.

OBJECTIVES: In the current Severe Acute Respiratory Distress Coronavirus 2 (SARS-CoV-2) pandemic there is still great uncertainty about the effects of an infection in pregnancy especially regarding a possible fetal transmission of antibodies to SARS-CoV-2 and the longevity of this immunity. METHODS: Sixteen women who were infected with SARS-CoV-2 during pregnancy and their offspring were included. The antibody response to SARS-CoV-2 was measured in mother and umbilical cord blood peripartum and in a follow-up examination 6-11 weeks after birth. Medical history, symptoms regarding SARS-CoV-2, obstetric and neonatal information were queried following recommendations by the WHO. RESULTS: A total of 73% of the women and one third of the infants developed antibodies to SARS-CoV-2 spike (S) protein receptor binding domain (RBD), with a long interval between infection and birth proving favorable for a transplacentar transfer of antibodies to the neonates. All infants showed declining or vanishing antibody-titers in the follow-up examination, while the titers of their mothers were stable or even increased. CONCLUSIONS: Our results demonstrate that transplacental transfer of SARS-CoV-2-specific antibodies is possible, but also indicate that the immunity that may be gained as a result might decrease in newborns postpartum. This provides important evidence that could be useful for further studies covering vaccination during pregnancy.

Peripartal anti-SARS-CoV-2-IgA/IgG in asymptomatic pregnant women during regional SARS-CoV-2-outbreak.

OBJECTIVES: The Severe Acute Respiratory Distress Corona Virus 2 (SARS-CoV-2) pandemic poses special challenges for the society and especially the medical staff. Even if a rather mild course is assumed among pregnant women the measures to prevent transmission of the infection are of outstanding importance. METHODS: To screen asymptomatic pregnant women during admission to our university maternal hospital we focused on anti-SARS-CoV-2-specific IgG and IgA antibody responses. Hundred and fifty one women admitted to the hospital for childbirth or caesarean delivery were included. In case of suspicious anti-SARS-CoV-2-antibody levels an RT-PCR was performed to confirm an ongoing infection with SARS-CoV-2. RESULTS: A total of 89% showed negative results for anti-SARS-CoV-2-IgA antibodies, whereas 3% were borderline and 7% positive (both labeled as suspicious). In only one patient with suspicious serology we detected SARS-CoV-2-RNA in the following RT-PCR. 2% presented anti-SARS-CoV-2-IgG antibodies, all being positive for anti-SARS-CoV-2-IgA. The observed positive rate of our study collective of 10.6% seemed much higher than the expected one (1.3%) based on the reports of the Robert Koch Institute and the specifications given by the test's manufacturer. The expected positive predictive value (PPV) was 4.3-6.7 times higher than the observed one. CONCLUSIONS: To our knowledge this is the first report of anti-SARS-CoV-2-antibody levels in the peripartum period of asymptomatic women. As the positive anti-SARS-CoV-2 serology poorly correlated with the confirmatory RT-PCR and the fact that mainly the detection of the virus by PCR correlates with the patient's infectiousness we suggest to rather perform a SARS-CoV-2-PCR-based admission screening in perinatal centers to prevent the spread of the disease.

Immune response to SARS-CoV-2 in health care workers following a COVID-19 outbreak: A prospective longitudinal study.

OBJECTIVE: Currently, little is known about the progression of an immune response against SARSCoV- 2 upon infection or sub-infection-exposure over time. We examined the serologic response in healthcare workers up to 12 weeks after a well-documented and contained outbreak and compared results with findings from earlier serologic testing in the same population. METHODS: This study followed 166 health care workers of the University Perinatal Care Center, Regensburg, Germany, for up to 12 weeks. 27 of the subjects had previously tested positive for the presence of SARS-CoV-2 by PCR testing and developed COVID-19. Serologic responses were tested with two independent commercially available test kits. RESULTS: 77.8 % of COVID-19 study subjects developed a specific IgG-response over the course of the 12-week study, while none of the COVID-19 contact groups had a detectable IgG response. Amongst most COVID-19 patients the values of detectable IgG-responses significantly increased over time as confirmed with both tests, while that of positive IgA responses decreased. Between the number of reported symptoms and antibody responses in COVID-19 patients no correlation was found and no new cases of seroconversion were identified in asymptomatic coworkers with negative PCR during the outbreak. CONCLUSIONS: Immune response after COVID-19 increases significantly over time but still approximately 22 % of COVID-19 patients did not mount a measurable serologic immune response within 60 days. Exposed co-workers did not develop any relevant antibody levels at all. We conclude that immunity after infection increases over time, but the antibody response does not develop reliably in all infected people.

Successful containment of Covid-19 outbreak in a large maternity and perinatal center while continuing clinical service.

With increasing number of SARS-CoV-2 infections and COVID-19 patients to be taken care of by the health system, more and more health workers become affected by the disease. It has been reported that right from the beginning of the outbreak in Lombardy up to 20% of the doctors and nurses became infected. Under these circumstances, the regular operation of health institutions already suffering from a shortage of staff becomes difficult. This has led to complete or partial shutdowns of hospitals, either due to a lack of uninfected personnel or because of uncontrollable chains of infection endangering patients. In one of the largest university perinatal center in Bavaria with more than 3000 births per year, an outbreak of COVID-19 occurred in March 2020, affecting 36 staff members, including doctors, nurses, and midwives. Here, we describe the outbreak and present the measures contributing to the successful containment of the outbreak within three weeks. At the same time, clinical services could be maintained, however, not without deployment of personnel exposed to employees infected with SARS-CoV-2. Apart from massive testing of personnel in pre-defined phases and increased hygiene measures, including a general obligation to wear surgical face masks, we identified the need to monitor cases of illness across all groups of employees, to ensure social distancing within personnel and to evaluate contacts of clinical personnel outside of the hospital environment, in order to be able to interpret chains of infections and to disrupt them. Overall, only a bundle of measures is needed to contain such an outbreak.

[Management of intra-abdominal dysgerminoma During pregnancy - A Case Report and Literature Review]. / Management Unterbauchraumforderungen in der Schwangerschaft ­ Fallbeschreibung eines extraovariell-intraabdominalen Dysgerminoms mit Überblick über die Literatur.

INTRODUCTION: Dysgerminomas are rare malignant germ cell tumors. They usually arise from the ovary, but case reports describing extraovarian dysgerminomas do exist. When treated adequately the disease has a good prognosis. Dysgerminomas diagnosed during pregnancy are very rare. METHODOLOGY: Report of extraovarian intra-abdominal dysgerminoma during pregnancy. Systematic literature review. CASE REPORT: A 35-year-old second gravida was diagnosed with a suspected intra-abdominal mass at 20 gestational weeks. During an exploratory laparotomy, a tumor infiltrating the transverse colon and histologically identified as a dysgerminoma was resected. Ovaries were clinically unremarkable. The induction of chemotherapy was postponed until after delivery. At 34 gestational weeks the patient underwent cesarean section and tumor debulking. Four cycles of bleomycin, etoposide and cisplatin were administered. After 12 months, cystic ovaries were found. Hysterectomy with bilateral adnexectomy was performed but no malignancy found. After 16 months, the patient was still in complete remission. CONCLUSION: We describe the first-ever published dysgerminoma in gravida primarily evolving intraabdominally and not affecting the ovaries. The decision for cytoreductive surgery, prolongation of pregnancy and postponing chemotherapy until after delivery combined the best benefit for the baby with a good maternal prognosis. Due to limited data regarding dysgerminomas in pregnancy, individual interdisciplinary concepts are mandatory.

The Role of Deconstructive Teaching in the Training of Laparoscopy.

BACKGROUND AND OBJECTIVES: Skills-lab training is crucial for the development of advanced laparoscopic skills. In this study, we examined whether a systematic deconstructive and comprehensive tutoring approach improves training results in laparoscopic suturing and intracorporeal knot tying. METHODS: Sixteen residents in obstetrics and gynecology participating in structured skills-lab laparoscopy training were randomized in 2 equal-sized groups receiving 1-on-1 tutoring either in the traditional method or according to the Peyton's 4-step approach, involving an additional training step, with the trainees instructing the tutor to perform the exercises. A validated assessment tool (revised Objective Structured Assessment of Technical Skills) and the number of completed square knots per training session and the mean time per knot were used to assess the efficacy of training in both groups. RESULTS: Trainees in Peyton's group achieved significantly higher revised Objective Structured Assessment of Technical Skills scores (28.6 vs 23.9 points; P = .05) and were able to improve their scores during autonomous training repetitions, in contrast to the trainees not in Peyton's group (difference +4.75 vs -4.29 points, P = .02). Additionally, they seemed to be able to perform a greater number of successful knots during the exercise and to complete each knot quicker with the later observations failing to reach the threshold of statistical significance. CONCLUSION: Peyton's 4-step approach seemed to be superior for teaching laparoscopic skills to obstetrics and gynecology residents in the skills-lab setting and can be therefore proposed for training curricula.

Cognate Nonlytic Interactions between CD8+ T Cells and Breast Cancer Cells Induce Cancer Stem Cell-like Properties.

Targeting of tumor immune escape mechanisms holds enormous therapeutic potential. Still, most patients progress under immune checkpoint blockade and some even become hyperprogressors. To investigate how cancer cells respond to activated but ineffective T cells, we challenged peptide-loaded MCF-7 breast cancer cells with antigen-specific CD8+ T cells in which lytic granules had been destroyed by pretreatment with Concanamycin A. Gene expression analysis after coculture revealed simultaneous induction of PD-L1, IDO1, CEACAM1, and further immunoregulatory checkpoints in breast cancer cells. Strikingly, we further observed gene signatures characteristic for dedifferentiation and acquisition of pluripotency markers including Yamanaka factors. Cognate interaction with nonlytic CD8+ T cells also increased the proportion of stem cell-like cancer cells in a cell-to-cell contact- or (at least) proximity-dependent manner in various cell lines and in primary breast cancer cell cultures; this induction of stem cell-like properties was confirmed by enhanced tumor-forming capacity in immunodeficient mice. Resulting tumors were characterized by enhanced cell density, higher proliferation rates, and increased propensity for lymphoid metastasis. These findings describe a widely underappreciated pathway for immune escape, namely immune-mediated dedifferentiation of breast cancer cells, which is associated with profound changes in gene expression and cellular behavior. As the enhanced malignant potential of cancer cells after nonlytic cognate interactions with CD8+ T cells enables increased tumor growth and metastasis in BALB/cnu/nu mice, the described mechanism may provide a possible explanation for the clinical phenomenon of hyperprogression in response to unsuccessful immunotherapy. SIGNIFICANCE: This study shows that ineffective immune responses not only fail to clear a malignancy, but can also activate pathways in cancer cells that promote stemness and tumor-seeding capacity.

Evaluation of Sentinel Lymph Node Biopsy and Axillary Lymph Node Dissection for Breast Cancer Treatment Concepts - a Retrospective Study of 1,214 Breast Cancer Patients.

BACKGROUND: Most breast cancer patients require lumpectomy with axillary sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND). The ACOSOG Z0011-trial failed to detect significant effects of ALND on disease-free and overall survival among patients with limited sentinel lymph node (SLN) metastases. Intense dose-dense chemotherapy and supraclavicular fossa radiation (SFR) are indicated for patients with extensive axillary metastases. In this multicentered study, we investigated the relevance of ALND after positive SLNB to determine adequate adjuvant therapy. METHODS: We retrospectively analyzed data from 1,214 patients with clinically nodal negative T1-T2 invasive breast cancer undergoing surgery at Hanau City Hospital Breast cancer center. RESULTS: 681 patients underwent ALND after SLNB. 20 patients (8.5%) from the group with 1 or 2 SLN metastases (n = 236) showed more than 3 lymph node metastases after ALND. 13 patients (31.7%) from the group with more than 2 SLN metastases (n = 41) were diagnosed with a minimum of 4 axillary lymph node metastases after ALND. CONCLUSIONS: In 8.5% of the patients with 1 or 2 SLN metastases, ALND detected more than 3 macrometastases, setting the indication for intense dose-dense chemotherapy and SFR. More than 2 SLN metastases, T stage and grading predict lymph node metastases.

Micro-ribonucleic acids and extracellular vesicles repertoire in the spent culture media is altered in women undergoing In Vitro Fertilization.

MicroRNAs (miRNAs) are class of small RNA molecules with major impact on gene regulation. We analyzed the potential of miRNAs secreted from pre-implantation embryos into the embryonic culture media as biomarkers to predict successful pregnancy. Using microarray analysis, we profiled the miRNome of the 56 spent culture media (SCM) after embryos transfer and found a total of 621 miRNAs in the SCM. On average, we detected 163 miRNAs in SCM of samples with failed pregnancies, but only 149 SCM miRNAs of embryos leading to pregnancies. MiR-634 predicted an embryo transfer leading to a positive pregnancy with an accuracy of 71% and a sensitivity of 85%. Among the 621 miRNAs, 102 (16.4%) showed a differential expression between positive and negative outcome of pregnancy with miR-29c-3p as the most significantly differentially expressed miRNA. The number of extracellular vehicles was lower in SCM with positive outcomes (3.8 × 109/mL EVs), as compared to a negative outcome (7.35 × 109/mL EVs) possibly explaining the reduced number of miRNAs in the SCM associated with failed pregnancies. The analysis of the miRNome in the SCM of couples undergoing fertility treatment lays the ground towards development of biomarkers to predict successful pregnancy and towards understanding the role of embryonic miRNAs found in the SCM.

Are There Breast Cancer Patients with Node-Negative Small Tumours, Who Do Not Benefit from Adjuvant Systemic Therapy?

OBJECTIVE: To identify subgroups of patients with pT1 pN0 breast cancer (BC) who might not profit from adjuvant systemic therapy (AST). METHODS: Data of 3,774 pT1 pN0 BC patients from 17 certified BC centres within the BRENDA study group were collected between 1992 and 2008 and retrospectively analysed. Uni- and multivariate analyses were performed using Kaplan-Meier methods and Cox regression models. RESULTS: 279 (7.4%) of the pT1 pN0 BC patients were T1a, 944 (25.0%) were T1b and 2,551 (67.6%) were T1c. There was no significant difference (p > 0.1) in recurrence-free survival (RFS)/overall survival (OAS) between patients with pT1a, pT1b, and T1c. Patients receiving any type of AST had a better outcome compared to women without AST after adjusting for age, tumour size, and intrinsic subtypes (RFS: p < 0.001; OAS: p < 0.001). AST was the most important prognostic parameter for RFS followed by intrinsic subtypes and age. CONCLUSION: Patients with pT1 pN0 BC profit from AST independently of molecular subtypes, tumour size, age or comorbidity, with 5-year RFS of more than 95%. The correct definition of subgroups of patients who do not need AST is still an open question.

Factors influencing the development of visceral metastasis of breast cancer: A retrospective multi-center study.

PURPOSE: Visceral metastasis of breast cancer (BC) is an alarming development and correlates with poor median overall survival. The purpose of this retrospective study is to examine the risk factors for developing visceral metastasis by considering tumor biology and patient characteristics. METHODS: Using the BRENDA database, the risk factors such as histological and intrinsic subtypes of BC, age at primary diagnosis, grading, nodal status, tumor size and year of primary diagnosis were examined in univariate and multivariate analysis. Categorical variables were compared by using χ2 tests. Furthermore, multivariate Cox proportional hazards regression models, Kaplan-Meier product-limit method and log-rank test were applied. The results of two tree-building algorithms, "exhausted CHAID" (Chi-squared Automatic Interaction Detector) and CART (Classification and Regression Trees) were verified with further multivariate analysis, radial basis function networks (RBF-net), feedforward multilayer perceptron networks (MLP) and logistic regression. RESULTS: In a patient collective of 886 metastasized patients, 56.9% had developed visceral metastases and 27.1% visceral-only metastases. The different histological and intrinsic subtypes of BC and the grading correlate significantly with the visceral-only metastasis behavior, whereas the age at primary diagnosis, the nodal status, the tumor size and the year of the primary diagnosis had no influence. Patients with ductal/other BC, LuminalB/HER2, TNBC, HER2 overexpressing subtype and grade 3 had an increased risk for the development of visceral-only metastasis. CONCLUSIONS: Intrinsic and histological subtypes as well as the grading of BC affected significantly the visceral metastasis behavior.

Pattern of metastatic spread and subcategories of breast cancer.

PURPOSE: The development of metastases is the most aggressive attribute of breast cancer. In this retrospective multicenter study, we evaluated if and how the different pathological breast cancer subtypes influence the spreading of tumor cells, the development of metastasis and the survival of breast cancer patients. METHODS: This retrospective German multicenter study is based on the BRENDA collective including 9625 breast cancer patients treated in the adjuvant setting. We used the χ 2 tests for the analysis of the categorical variables between groups of patients with different sites of metastasis. Survival distributions and median survival times were estimated using the Kaplan-Meier product-limit method. The log-rank test was applied to compare survival rates. The Cox proportional hazards model was used to estimate the hazard ratio and confidence intervals. RESULTS: 886 women developed metastases during a time interval of 53 months after primary diagnosis. Luminal A tumor patients were more likely to get bone metastases than lung, liver or CNS metastases. Patients with a triple-negative subtype were, however, the least affected by metastasis in the skeleton. They were most likely to develop visceral metastases. Location, numbers of metastases herein and the subtype influenced the overall survival (OAS). Altogether, the best OAS was found in patients with the luminal A subtype, the worst in patients with the triple-negative subtype. CONCLUSIONS: Knowledge of the typical metastatic pattern of the subtypes of breast cancer will help to personalize therapeutic options and follow-up examinations of cancer patients.

Do Patients with Luminal A Breast Cancer Profit from Adjuvant Systemic Therapy? A Retrospective Multicenter Study.

BACKGROUND: Luminal A breast cancers respond well to anti-hormonal therapy (HT), are associated with a generally favorable prognosis and constitute the majority of breast cancer subtypes. HT is the mainstay of treatment of these patients, accompanied by an acceptable profile of side effects, whereas the added benefit of chemotherapy (CHT), including anthracycline and taxane-based programs, is less clear-cut and has undergone a process of critical revision. METHODS: In the framework of the BRENDA collective, we analyzed the benefits of CHT compared to HT in 4570 luminal A patients (pts) with primary diagnosis between 2001 and 2008. The results were adjusted by nodal status, age, tumor size and grading. RESULTS: There has been a progressive reduction in the use of CHT in luminal A patients during the last decade. Neither univariate nor multivariate analyses showed any statistically significant differences in relapse free survival (RFS) with the addition of CHT to adjuvant HT, independent of the nodal status, age, tumor size or grading. Even for patients with more than 3 affected lymph nodes, there was no significant difference (univariate: p = 0.865; HR 0.94; 95% CI: 0.46-1.93; multivariate: p = 0.812; HR 0.92; 95% CI: 0.45-1.88). CONCLUSIONS: The addition of CHT to HT provides minimal or no clinical benefit at all to patients with luminal A breast cancer, independent of the RFS-risk. Consequently, risk estimation cannot be the initial step in the decisional process. These findings-that are in line with several publications-should encourage the critical evaluation of applying adjuvant CHT to patients with luminal A breast cancer.

Adenosine-generating ovarian cancer cells attract myeloid cells which differentiate into adenosine-generating tumor associated macrophages - a self-amplifying, CD39- and CD73-dependent mechanism for tumor immune escape.

BACKGROUND: Ovarian cancer (OvCA) tissues show abundant expression of the ectonucleotidases CD39 and CD73 which generate immunomodulatory adenosine, thereby inhibiting cytotoxic lymphocytes. Little, however, is known about the effect of adenosine on myeloid cells. Considering that tumor associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) constitute up to 20 % of OvCA tissue, we investigated the effect of adenosine on myeloid cells and explored a possible contribution of myeloid cells to adenosine generation in vitro and ex vivo. METHODS: Monocytes were used as human blood-derived myeloid cells. After co-incubation with SK-OV-3 or OAW-42 OvCA cells, monocyte migration was determined in transwell assays. For conversion into M2-polarized "TAM-like" macrophages, monocytes were co-incubated with OAW-42 cells. Ex vivo TAMs were obtained from OvCA ascites. Macrophage phenotypes were investigated by intracellular staining for IL-10 and IL-12. CD39 and CD73 expression were assessed by FACS analysis both on in vitro-induced TAM-like macrophages and on ascites-derived ex situ-TAMs. Myeloid cells in solid tumor tissue were analyzed by immunohistochemistry. Generation of biologically active adenosine by TAM-like macrophages was measured in luciferase-based reporter assays. Functional effects of adenosine were investigated in proliferation-experiments with CD4(+) T cells and specific inhibitors. RESULTS: When CD39 or CD73 activity on OvCA cells were blocked, the migration of monocytes towards OvCA cells was significantly decreased. In vivo, myeloid cells in solid ovarian cancer tissue were found to express CD39 whereas CD73 was mainly detected on stromal fibroblasts. Ex situ-TAMs and in vitro differentiated TAM-like cells, however, upregulated the expression of CD39 and CD73 compared to monocytes or M1 macrophages. Expression of ectonucleotidases also translated into increased levels of biologically active adenosine. Accordingly, co-incubation with these TAMs suppressed CD4(+) T cell proliferation which could be rescued via blockade of CD39 or CD73. CONCLUSION: Adenosine generated by OvCA cells likely contributes to the recruitment of TAMs which further amplify adenosine-dependent immunosuppression via additional ectonucleotidase activity. In solid ovarian cancer tissue, TAMs express CD39 while CD73 is found on stromal fibroblasts. Accordingly, small molecule inhibitors of CD39 or CD73 could improve immune responses in ovarian cancer.