Internet Access and Use by Patients with Gynecologic Malignancies: A Cross-Sectional Study.

The influence of digitalization on information-seeking, decision-making properties of patients, therapy monitoring, and patient-physician interactions has and will change the global health sector tremendously. With this study, we add knowledge on the degree of digitalization, digital device availability, the use and availability of home and mobile internet access, and the willingness to use novel forms of patient-physician interactions in a group of gynecologic cancer patients. From July 2017 to March 2022, 150 women with a diagnosis of gynecologic malignancy at the University Hospital of Cologne participated in this questionnaire-based cohort study. Any one of three potential internet access devices (stationary computer, smartphone, or tablet) is owned by 94% of patients and the only patient intrinsic factor that is significantly associated with the property of any one of these internet access devices is age. The Internet is used daily or several times per week to assess information on their disease by 92.8%, 90.1% use the Internet for communicational purposes and 71.9% and 93.6% are willing to communicate with their treating physicians via E-Mail or even novel forms of communication, respectively. In conclusion, the predominant majority of gynecologic cancer patients can be reached by modern internet-based E-Health technologies.

Expression of Potential Antibody-Drug Conjugate Targets in Cervical Cancer.

(1) Background: There is a huge unmet clinical need for novel treatment strategies in advanced and recurrent cervical cancer. Several cell membrane-bound molecules are up-regulated in cancer cells as compared to normal tissue and have revived interest with the introduction of antibody-drug conjugates (ADCs). (2) Methods: In this study, we characterize the expression of 10 potential ADC targets, TROP2, mesotheline, CEACAM5, DLL3, folate receptor alpha, guanylatcyclase, glycoprotein NMB, CD56, CD70 and CD138, on the gene expression level. Of these, the three ADC targets TROP2, CEACAM5 and CD138 were further analyzed on the protein level. (3) Results: TROP2 shows expression in 98.5% (66/67) of cervical cancer samples. CEACAM5 shows a stable gene expression profile and overall, 68.7% (46/67) of cervical cancer samples are CEACAM-positive with 34.3% (23/67) of cervical cancer samples showing at least moderate or high expression. Overall, 73.1% (49/67) of cervical cancer samples are CD138-positive with 38.8% (26/67) of cervical cancer samples showing at least moderate or high expression. (4) Conclusions: TROP2, CEACAM5 or CD138 do seem suitable for further clinical research and the data presented here might be used to guide further clinical trials with ADCs in advanced and recurrent cervical cancer patients.

Clinical Applicability of Tissue Polypeptide Antigen and CA-125 in Gynecological Malignancies.

BACKGROUND: Nowadays there still is no sufficient screening tool for ovarian and uterine cancer. OBJECTIVE: The current study aimed to investigate whether cancer antigen 125 (CA-125), tissue polypeptide antigen (TPA) or the combination of both markers are able to act as screening tools for ovarian or uterine cancer. METHODS: A total of 275 blood samples from different cohorts (ovarian cancer, uterine cancer, benign control group) were prospectively drawn and analyzed. RESULTS: Established biomarkers TPA and CA-125 showed elevated serum concentrations in patients with malignant tumors as compared to healthy women and women with benign diseases. In ROC curve analyses, both biomarkers were well able to discriminate between malignant and healthy, benign or overall non-malignant cases in the whole sample, with AUCs of 0.842 and above. While TPA was the best diagnostic marker in patients with uterine cancer, CA 125 was the best in patients with ovarian cancer. CONCLUSIONS: TPA and CA-125 both showed promising results for the detection of gynecologic malignancies. The combination of CA-125 and TPA did not improve sensitivity in comparison to single markers.

Immunogenic Biomarkers HMGB1 and sRAGE Are Potential Diagnostic Tools for Ovarian Malignancies.

BACKGROUND: High mobility group box 1 (HMGB1), soluble receptor of advanced glycation end products (sRAGE) and programmed cell death markers PD-1 and PD-L1 are immunogenic serum biomarkers that may serve as novel diagnostic tools for cancer diagnosis. METHODS: We investigated the four markers in sera of 231 women, among them 76 with ovarian cancer, 87 with benign diseases and 68 healthy controls, using enzyme immunoassays. Discrimination between groups was calculated using receiver operating characteristic (ROC) curves and sensitivities at fixed 90% and 95% specificities. RESULTS: HMGB1 levels were significantly elevated and sRAGE levels were decreased in cancer patients as compared to benign and healthy controls. In consequence, the ratio of HMGB1 and sRAGE discriminated best between diagnostic groups. The areas under the curve (AUCs) of the ROC curves for differentiation of cancer vs. healthy were 0.77 for HMGB1, 0.65 for sRAGE and 0.78 for the HMGB1/sRAGE ratio, and slightly lower for the differentiation of cancer vs. benigns with 0.72 for HMGB1, 0.61 for sRAGE and 0.74 for the ratio of both. The highest sensitivities for cancer detection at 90% specificity versus benign diseases were achieved using HMGB1 with 41.3% and the HMGB1/sRAGE ratio with 39.2%, followed by sRAGE with 18.9%. PD-1 showed only minor and PD-L1 no power for discrimination between ovarian cancer and benign diseases. CONCLUSION: HMGB1 and sRAGE have differential diagnostic potential for ovarian cancer detection and warrant inclusion in further validation studies.

Method Comparison and Clinical Performance of Breast Cancer Tumor Markers on Novel Multiplex Immunoassay and Automatized LOCI Technology Platforms.

Tumor marker determinations are valuable tools for the guidance of breast cancer patients during the course of disease. They are assessed on diverse analytical platforms that may be associated with differences according to the methods applied and the clinical performance. To investigate the method dependency and clinical significance of breast cancer protein tumor markers, CEA, CA 15-3, CA 125, CA 19-9 and AFP were measured in a total of 154 biobanked samples from 77 patients with breast cancer, 10 with DCIS, 31 with benign breast diseases and 36 healthy controls using a Millipore multiplex biomarker panel (MP) and an automized version of the routinely used Vista LOCI technology. The markers were compared between methods and investigated for diagnostic performance. CEA, CA 15-3 and AFP showed good correlations between both platforms with correlation coefficients of R = 0.85, 0.85 and 0.92, respectively, in all samples, but similarly also in the various subgroups. CA 125 and CA 19-9 showed only moderate correlations (R = 0.71 and 0.56, respectively). Absolute values were significantly higher for CEA, CA 15-3, CA 125 and AFP in the Vista LOCI as compared with the MP method and vice versa for CA 19-9. The diagnostic performance for discrimination of breast cancer from healthy controls was similar for both methods with AUCs in ROC curves for CEA (MP 0.81, 95% CI 0.72-0.91; LOCI 0.81; 95% CI 0.72-0.91) and CA-15-3 (MP 0.75, 95% CI 0.65-0.86; LOCI 0.67, 95% CI 0.54-0.79). Similar results were obtained for the comparison of breast cancer with benign breast diseases regarding CEA (AUC MP 0.62, 95% CI 0.51-0.73; LOCI 0.64, 95% CI 0.53-0.74) and CA-15-3 (MP 0.70, 95% CI 0.6-0.81; LOCI 0.66, 95% CI 0.54-0.77). Both platforms show moderate to good method comparability for tumor markers with similar clinical performance. However, absolute levels in individual patients should be interpreted with care.

Digital droplet PCR-based quantification of ccfHPV-DNA as liquid biopsy in HPV-driven cervical and vulvar cancer.

PURPOSE: More than 99% of cervical cancers and up to 40% of vulvar cancers are human papillomavirus (HPV) related. HPV 16 and 18 are the most relevant subtypes. Novel technologies allow the detection of minimal amounts of circulating cell-free HPV DNA (ccfHPV-DNA). The aim of this study was to evaluate ccfHPV-DNA assessed by droplet digital PCR (ddPCR) as a biomarker for molecular therapy monitoring in early, advanced, relapsed and metastatic HPV-driven cervical and vulvar cancer. METHODS: Inclusion criteria of the study were histologically proven HPV 16/18-driven cervical and vulvar cancer with first diagnosed disease, newly diagnosed recurrence, or progression of disease. Blood samples were taken pre- and post-therapeutically. Circulating cell-free HPV DNA was quantified using ddPCR and the results were correlated with clinical data. RESULTS: The mean copy number of ccfHPV-DNA was 838.6 (± 3089.1) in pretreatment and 2.3 (± 6.4) in post-treatment samples (p < 0.05). The copy number of ccfHPV-DNA increased with higher FIGO stages (p < 0.05), which are commonly used for clinical staging/assessment. Furthermore, we compared the distribution of copy numbers between T-stage 1 versus T-stage 2/3. We could show higher copy number level of ccfHPV-DNA in T-stage 2/3 (p < 0.05). CONCLUSIONS: Therapy monitoring with determination of ccfHPV-DNA by ddPCR with a small amount of plasma reflects response to therapy and appears feasible for patients in advanced cancer stages of cervical and vulvar cancer. This promising tool should be examined as marker of therapy monitoring in particular in novel HPV-directed therapies.

Prognostic factors in undifferentiated uterine sarcoma: a subanalysis of the SARCUT study.

PURPOSE: The aim of this study was to analyze the prognostic factors related to the recurrence rate and overall survival of patients with undifferentiated uterine sarcoma. METHODS: An international multicenter study involving 43 international centers, the SARCUT study, collected 966 uterine sarcoma cases; among them 39 cases corresponded to undifferentiated uterine sarcoma and where included in the present subanalysis. The risk factors related to the oncological outcomes where analyzed. RESULTS: The median age of the patients was 63 (range 14-85) years. Seventeen (43.5%) patients presented FIGO stage I. The 5-year overall survival (OS) was 15.3% and 12-months disease-free survival (DFS) 41%. FIGO stage I was significantly associated with a better prognosis. In addition, patients who received adjuvant radiotherapy showed significant longer disease-free survival compared to those without adjuvant radiotherapy (20.5 vs. 4.0 months, respectively; p = 0.04) and longer overall survival (34.7 vs. 18.2 months, respectively; p = 0.05). Chemotherapy administration was associated with shorter DFS (HR 4.41, 95% CI 1.35-14.43, p = 0.014). Persistent disease after primary treatment (HR = 6.86, 95% CI 1.51-31.09, p = 0.012) and FIGO stage IV (HR 4.12, 95%CI 1.37-12.44, p = 0.011) showed significant worse prognosis for OS. CONCLUSION: FIGO stage seems to be the most important prognostic factor in patients with undifferentiated uterine sarcoma. Adjuvant radiotherapy seems to be significantly associated also to a better disease-free and overall survival. On the contrary, the role of chemotherapy administration remains unclear since was associated to a shorted DFS.

Combined targeting of soluble latent TGF-ß and a solid tumor-associated antigen with adapter CAR T cells.

Solid tumors consist of malignant and nonmalignant cells that together create the local tumor microenvironment (TME). Additionally, the TME is characterized by the expression of numerous soluble factors such as TGF-ß. TGF-ß plays an important role in the TME by suppressing T cell effector function and promoting tumor invasiveness. Up to now CAR T cells exclusively target tumor-associated antigens (TAA) located on the cell membrane. Thus, strategies to exploit soluble antigens as CAR targets within the TME are needed. This study demonstrates a novel approach using Adapter CAR (AdCAR) T cells for the detection of soluble latent TGF-ß within the TME of a pancreatic tumor model. We show that AdCARs in combination with the respective adapter can be used to sense soluble tumor-derived latent TGF-ß, both in vitro and in vivo. Sensing of the soluble antigen induced cellular activation and effector cytokine production in AdCAR T cells. Moreover, we evaluated AdCAR T cells for the combined targeting of soluble latent TGF-ß and tumor cell killing by targeting CD66c as TAA in vivo. In sum, our study broadens the spectrum of targetable moieties for AdCAR T cells by soluble latent TGF-ß.

Cervical Intraepithelial Neoplasia 3 (Cervical Intraepithelial Neoplasia 3/High-Grade Squamous Intraepithelial Lesion) in Human Papillomavirus-Vaccinated Women-Results From a Tertiary Referral Center.

OBJECTIVE: High-grade cervical intraepithelial neoplasia (CIN 3) still develops in some vaccinated women despite established effectiveness of prophylactic human papillomavirus (HPV) vaccination. The purpose of this study was to define characteristics of women with CIN 3 after HPV vaccination referred to a gynecological dysplasia unit. MATERIALS AND METHODS: Retrospective analysis of HPV-vaccinated women with CIN 3 in a single German center. Between July 2018 and September 2020, 791 women were referred to our university hospital-based dysplasia unit for colposcopic evaluation of abnormal cytological findings. Human papillomavirus vaccination status was retrieved. Human papillomavirus typing was performed in lesional biopsies and cervical swabs. RESULTS: Nine women were identified who had previously been vaccinated with the quadrivalent HPV vaccine (Q-HPV) and were diagnosed with histologically confirmed CIN 3/high-grade squamous intraepithelial lesion. The Q-HPV had been administered between 12 and 28 years of age and 1-13 years before CIN 3 diagnosis. Nine different high-risk (HR)-HPV types were found in the CIN 3 biopsies, 6 monoinfections (twice HPV 16, once HPV 18, HPV 31, HPV 52, HPV 58, respectively) and 3 dual infections (HPV 33 + 52, HPV 51 + 52, HPV 53 + 66). Seven of these 9 HR-HPV types are not covered by Q-HPV, but only 2 CIN 3 lesions carried HR-HPV types not included in the nonavalent HPV vaccine. CONCLUSIONS: It is important to implement vaccination recommendations and administer HPV vaccination as early as possible in HPV-naive individuals. Because not all HR-HPV types are covered by the available HPV vaccines, other types may still cause CIN 3/high-grade squamous intraepithelial lesion. This requires further screening after vaccination, especially in women who were previously vaccinated with the bivalent or the quadrivalent HPV vaccine.

Placental Invasion into the Small Bowel Intestine Through a Myomectomy Scar: A Case Report With Literature Review.

Although extremely rare, uterine damage after hysteroscopic myomectomy sets the precondition for various life-threatening placental attachment disorders like placenta percreta (PP) or scar pregnancy. Due to vast clinical similarities, these terms are often used interchangeably. We report a case of a 47-yr-old patient at 27 wk + 4 d of gestation who presented with rectal bleeding. Clinical history revealed a previous uterine posterior wall myomectomy. The patient received intensive diagnostic work-up including sonography and magnetic resonance imaging. Under the suspicion of a bleeding Meckel diverticulum, an emergency laparotomy was performed. Intraoperatively it was observed that the placental tissue infiltrated the small bowel intestine at the location of the previous myomectomy. The adjacent intestine and the infiltrating placenta were surgically removed. The placenta could be easily detached from the uterus, which is why no hysterectomy was performed. Retrospectively, no radiologic or clinical hints of PP or scar pregnancy were evident before the surgery. Moreover, the pathologic work-up carried out afterwards proved no histopathologic evidence for PP. Our case underlines several clinical and pathologic difficulties. First, invasive placenta disorders including infiltration of intestinal organs have to be considered even after minor surgical interventions such as myomectomy. Second, clinical presentation is extremely variable and sometimes misleading, depending on the localization and the type of invasion. Our case underlines the importance of histopathologic work-up for distinguishing between various placenta attachment disorders such as PP and scar pregnancy. Given the large overlap in clinical presentation, pathophysiology and definition, we propose that the current definitions for PP and scar pregnancy have to be carefully reevaluated and broadened.

Digital Technical and Informal Resources of Breast Cancer Patients From 2012 to 2020: Questionnaire-Based Longitudinal Trend Study.

BACKGROUND: Digitalization offers enormous potential in medicine. In the era of digitalization, the development of the use of digital, technical, and informal resources of breast cancer patients and factors influencing the degree of digitization of patients has been insufficiently researched. OBJECTIVE: The aim of this study was to assess the development of the use of digital technical and informal resources in a well-defined patient cohort. METHODS: A longitudinal study on 513 breast cancer patients from 2012 to 2020 was conducted using a questionnaire that included the main aspects of the degree of digitalization, including digital device availability and use, stationary and mobile internet access and use, and communication and information seeking regarding breast cancer diagnosis and treatment. RESULTS: The majority of patients (421/513, 82.1%) owned the technical resources to benefit from eHealth, used the internet to obtain information (292/509, 57.4%), and were willing to use new eHealth solutions (379/426, 89%). Two-thirds of the patients discussed information about their cancer on the internet with their doctor, one-third found additional treatment options on the internet, and 15.3% (44/287) of the patients stated that this had changed their cancer therapy. The degree of digitization is increasing yet still significantly depends on 3 factors: (1) age (whereas 100% [39/39] of the <59-year-old group used the internet in 2020, 92% of the 60 to 69-year-old group [11/12] and only 47% [6/13] of the >70-year-old group used the internet), (2) education (internet use significantly depended on education, as only 51.8% [59/114] of patients with primary school education used the internet, but 82.4% [126/153] with middle school education and 90.3% [213/236] with high school education used the internet; P<.001), and (3) household size (67.7% [111/164] of patients living alone used the internet, whereas 84.7% [287/339] of patients living in a house with ≥2 people used the internet; P<.001). CONCLUSIONS: To implement digital solutions in health care, knowledge of the composition and degree of the use of digital technical and informal resources of the patient group for which the respective solution is developed is crucial for success. TRIAL REGISTRATION: German Register of Clinical Studies DRKS00012364; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00012364.

Isolated bladder exstrophy in prenatal diagnosis.

PURPOSE: Isolated classic bladder exstrophy (CBE) is the most common variant of the bladder-exstrophy-epispadias complex (BEEC). The BEEC represents a spectrum ranging from isolated epispadias over CBE to the most severe form, cloacal exstrophy. We report on a series of 12 cases with CBE diagnosed prenatally and illustrate the spectrum of prenatal ultrasound findings with comparison to prior published reports on this entity. METHODS: This was a retrospective study involving 12 fetuses with CBE at two large tertiary referral centers in Germany over a 14-year period (2004-2018). RESULTS: Median diagnosis was made with ultrasound in 24 + 5 (IQR25,75: 21 + 2, 29 + 0) weeks of gestation. All fetuses presented with the pathognomonic findings non-visualization of the fetal bladder and protruding abdominal mass below the umbilical cord insertion. All fetuses showed normal kidney anatomy and normal amniotic fluid throughout pregnancy. Epispadia was visible prenatally on ultrasound in 6/8 male fetuses. 1/12 Parents opted for termination of pregnancy, 11/12 fetuses were live born and received reconstructive surgery. CONCLUSIONS: Isolated CBE is an extremely rare prenatal sonographic finding. Prenatal diagnostics should exclude additional malformations within the spectrum of cloacal malformations.

Prenatal Diagnosis of Hydro(metro)colpos: A Series of 20 Cases.

BACKGROUND: Hydrocolpos and hydrometrocolpos are rare malformations caused by accumulation of secretion due to congenital obstruction of the vagina. Hydro(metro)colpos may be isolated or can be combined with other malformations as part of a syndromic disorder. We report on a series of 20 cases with hydro(metro)colpos diagnosed prenatally, delineate the differential diagnoses, and illustrate the spectrum of associated malformations. SUBJECTS AND METHODS: This was a retrospective study involving 20 fetuses with hydro(metro)colpos at two large tertiary referral centers in Germany over an 18-year period (2000-2017). RESULTS: The median diagnosis was made at 30+4 weeks of gestation, the earliest at 20+6 weeks, the latest at 37+2 weeks. All 20 fetuses presented with the typical cystic structure behind the fetal bladder. Additional malformations included urogenital malformations, hexadactyly, and heart defects. Postnatal follow-up revealed that hydro(metro)colpos was associated with anorectal malformation in 11/20 fetuses, McKusick-Kaufman syndrome or Bardet-Biedl syndrome in 4/20 fe tuses, Mayer-Rokitansky-Küster-Hauser syndrome in 3/20 fetuses, and Herlyn-Werner-Wunderlich syndrome in 1/20. In 1 fetus pressure from an intraabdominal teratoma resulted in prenatal hydro(metro)colpos. CONCLUSION: Hydro(me tro)colpos is a rare prenatal sonographic feature. Multidisciplinary prenatal counseling should include all potential syndromes that can present with hydro(metro)colpos in the prenatal setting.

Ribavirin in Acute Hepatitis E Infection in Patients with Gynecological Cancer: A Case Series.

Hepatitis E virus infection is usually a self-limited disease. However, during the last years there has been growing evidence for prolonged and chronic infection occurring in patients with immunosuppression. Also patients with malignant and rheumatic diseases have been identified to be at risk for chronic hepatitis E. However, their course and prognosis are not well characterized and there have been no reports of hepatitis E virus infection in patients with gynecological cancer. Here, we report three Caucasian females with breast and ovarian cancers presenting with elevation of aminotransferase levels during anticancer treatment. Although only few or no clinical hints suggested hepatitis E virus infection, the diagnosis of hepatitis E virus infection was confirmed by seroconversion, which might occur with some delay, and/or by polymerase chain reaction. While two patients had a self-limited course, the third patient with a high-risk oncological constellation required ribavirin in order to resume chemotherapy. These cases highlight the need for hepatitis E virus testing in patients with gynecological cancer and elevated aminotransferase levels. Further, these cases show that in selected high-risk patients, ribavirin treatment may be necessary based on the decision of a multidisciplinary team.

Outcome of Bronchopulmonary Sequestration with Massive Pleural Effusion after Intrafetal Vascular Laser Ablation.

OBJECTIVE: To assess the outcome of 12 fetuses with bronchopulmonary sequestration (BPS) and massive pleural effusion after intrafetal vascular laser ablation (VLA). METHODS: All fetuses with BPS and massive pleural effusion that were treated with intrafetal VLA during a 5-year period (2012-2016) were reviewed for safety, intrauterine course, and postnatal outcome. RESULTS: In the study period, 12 fetuses with BPS were treated with VLA. In 7 (58.3%) fetuses, complete cessation of blood flow was achieved after the first VLA, while in 5 (41.7%) fetuses, residual perfusion of the feeding vessel was demonstrated at follow-up. A second intervention was successful in 4 of 5 (80%) fetuses. Overall, in 11 of 12 (91.7%) fetuses, complete coagulation of the feeding vessel could be achieved, followed by a reduction in size or complete resolution of the BPS. All 11 fetuses with successful prenatal intervention were live-born at a median gestational age of 39+1 (range, 37+5-41+2) weeks. Postnatally, 2 (18.2%) of the 11 newborns underwent sequestrectomy, as well as the preterm newborn on which a second fetal intervention was not feasible. CONCLUSION: VLA is an effective and safe treatment of BPS that appears to be of benefit in improving prognosis and decreasing the need for postnatal sequestrectomy.

Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative.

Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment.Experimental Design: We investigated the expression of several druggable targets (phospho-S6S240 ribosomal protein, PTEN, PDGFR-α, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models.Results: In uterine sarcomas and STUMPs, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6S240 correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240 in response prediction to PI3K/mTOR inhibition.Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6S240 expression is a potential predictive biomarker for response to treatment. Clin Cancer Res; 23(5); 1274-85. ©2017 AACR.

Impact of Extended Primary Surgery on Suboptimally Operable Patients With Advanced Ovarian Cancer.

OBJECTIVES: Extensive surgical efforts to achieve an optimal debulking (no residual tumor) in primary surgery of ovarian cancer are today's criterion standard in gyneco-oncologic surgery. However, it is controversial whether extensive surgery, including resections of metastases in the upper abdomen and bowel resections, is justifiable in patients with not completely operable lesions. METHODS: All patients who had undergone surgery for ovarian cancer in the years 2002 to 2013 at our institution were viewed (n = 472). We retrospectively identified 278 operations for primary ovarian cancer. Ninety-six (35%) of the 278 patients showed postoperative tumor residuals and were included in this study. RESULTS: Fifty-five (57%) of 96 patients underwent bowel resection, showing significantly higher complication rates (64% vs 39% minor complications, P = 0.017; 31% vs 9.8% severe complications, P = 0.013) compared with patients without bowel resections as well as no improvement in progression-free or overall survival (median overall survival, 19.5 vs 32.9; P = 0.382). Multiple anastomoses (≥2) were associated with higher rates for anastomotic leakage (16.7% vs 2.6%, P = 0.02) and a higher mortality (16.7% vs 0%, P = 0.04) compared with patients with only 1 anastomosis. Extensive surgery of the upper abdomen was not associated with a significant increase in complication rates. CONCLUSIONS: Because of the increased morbidity of bowel resections without any evidence for improvement of survival, we suggest to restrain from further resection of intestines if an optimal debulking seems not feasible after removal of the major tumor bulk.

HIPEC ROC I: a phase I study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum-based chemotherapy in patients with platinum-sensitive recurrent epithelial ovarian cancer.

This phase I study tested the safety, feasibility, pharmacokinetics and pharmacodynamics of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion (HIPEC) in patients with platinum-sensitive recurrent epithelial ovarian cancer (EOC) undergoing secondary cytoreductive surgery followed by postoperative platinum-based intravenous chemotherapy. Twelve patients with operable, recurrent platinum-sensitive EOC (recurrence ≥6 months after first-line therapy) were included according to the classical 3+3 dose-escalation design at three dose levels-60, 80 and 100 mg/m(2). After surgical cytoreduction, a single dose of cisplatin was administered via HIPEC for 90 min at 41-43°C. Postoperatively, all patients were treated with standard intravenous platinum-based combination chemotherapy. One of six patients experienced a dose-limiting toxicity (grade 3 renal toxicity) at a dose of 100 mg/m(2). The remaining five patients treated with 100 mg/m(2) tolerated their treatment well. The recommended phase II dose was established at 100 mg/m(2). The mean peritoneal-to-plasma AUC ratio was 19·5 at the highest dose level. Cisplatin-induced DNA adducts were confirmed in tumor samples. Common postoperative grade 1-3 toxicities included fatigue, postoperative pain, nausea, and surgical site infection. The ability to administer standard intravenous platinum-based chemotherapy after HIPEC was uncompromised. Cisplatin administered as HIPEC at a dose of 100 mg/m(2) has an acceptable safety profile in selected patients undergoing secondary cytoreductive surgery for platinum-sensitive recurrent EOC. Favorable pharmacokinetic and pharmacodynamic properties of HIPEC with cisplatin were confirmed at all dose levels, especially at 100 mg/m(2). The results are encouraging to determine the efficacy of HIPEC as a complementary treatment in patients with EOC.

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.

Interval debulking surgery in patients with Federation of Gynecology and Obstetrics (FIGO) stage IIIC and IV ovarian cancer.

BACKGROUND: The feasibility of neoadjuvant chemotherapy (NAC) and the outcome in patients with Federation of Gynecology and Obstetrics (FIGO) IIIC and IV ovarian cancer were assessed. PATIENTS AND METHODS: 67 patients undergoing interval debulking surgery (IDS) and ≥ 4 courses of platinum-based NAC were analyzed for survival, perioperative morbidity and mortality. RESULTS: The median follow-up was 30 months. The median progression-free survival (PFS) was 17 months, the overall survival (OS) 34 months. The PFS of patients without residual disease (n = 23; 34.3%) was 31 months (p = 0.003), the OS 65 months (p = 0.001). PFS and OS were significantly longer in patients with no residual disease than in patients with 1-10 mm (n = 34; 47.9%) (p = 0.005 and p = 0.0001, respectively) residual disease. No survival benefit was seen for patients with 1-10 mm compared to > 1 cm (n = 12; 16.9%) residual disease (PFS p = 0.518; OS p = 0.077). 1 patient (1.4%) died; 12 patients needed interventional treatment or operation (16.9%) within the first 30 days postoperatively. Out of these, 5 patients (7.0%) had residual or lasting disability. CONCLUSIONS: NAC and IDS are safe and feasible in this series of patients with unfavorable prognosis. IDS does not change the goal of complete cytoreduction and therefore does not compensate for a less radical surgical approach.