Optimal Treatment Duration of Bevacizumab as Front-Line Therapy for Advanced Ovarian Cancer: AGO-OVAR 17 BOOST/GINECO OV118/ENGOT Ov-15 Open-Label Randomized Phase III Trial.

PURPOSE: To compare standard versus extended duration of bevacizumab treatment in combination with front-line chemotherapy in women with newly diagnosed stage IIB-IV ovarian cancer. METHODS: In this multicenter, open-label, randomized phase III trial (ClinicalTrials.gov identifier: NCT01462890), patients with newly diagnosed International Federation of Gynecology and Obstetrics stage IIB-IV epithelial ovarian, fallopian tube, or peritoneal cancer underwent primary cytoreductive surgery followed by six cycles of chemotherapy (paclitaxel 175 mg/m2 plus carboplatin area under the curve 5 once every 3 weeks) and bevacizumab (15 mg/kg once every 3 weeks). Patients were randomly assigned 1:1 to receive bevacizumab for either 15 or 30 months, stratified by International Federation of Gynecology and Obstetrics stage/residual tumor. The primary end point was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary end points included overall survival (OS), safety, and tolerability. RESULTS: Between November 11, 2011, and August 6, 2013, 927 women were randomly assigned. There was no difference in PFS between treatment arms (hazard ratio, 0.99; 95% CI, 0.85 to 1.15; unstratified log-rank P = .90). Median PFS was 24.2 versus 26.0 months with standard versus extended duration of bevacizumab, respectively; restricted mean PFS was 39.5 versus 39.3 months, respectively. There was no OS difference between treatment arms (hazard ratio, 1.04; 95% CI, 0.87 to 1.23; P = .68). Serious/nonserious adverse events of special interest occurred in 29% versus 34% of patients in the standard versus experimental arms, respectively, and were consistent with the known safety profile of standard bevacizumab. CONCLUSION: Longer treatment duration with bevacizumab for up to 30 months did not improve PFS or OS in patients with primary epithelial ovarian, fallopian tube, or peritoneal cancer. A bevacizumab treatment duration of 15 months remains the standard of care.

p53 and p16 expression profiles in vulvar cancer: a translational analysis by the Arbeitsgemeinschaft Gynäkologische Onkologie Chemo and Radiotherapy in Epithelial Vulvar Cancer study group.

BACKGROUND: There are 2 known pathways for tumorigenesis of vulvar squamous cell carcinoma-a human papillomavirus-dependent pathway characterized by p16 overexpression and a human papillomavirus-independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of human papillomavirus dependency with a favorable prognosis has been proposed. OBJECTIVE: The objective of the study was to further understand the role of human papillomavirus and p53 status in vulvar squamous cell carcinoma and characterize its clinical relevance. STUDY DESIGN: The Arbeitsgemeinschaft Gynaecological Oncology Chemo and Radiotherapy in Epithelial Vulvar Cancer-1 study is a retrospective cohort study of 1618 patients with primary vulvar squamous cell carcinoma Fédération Internationale de Gynécologie et d'Obstétrique stage ≥1B treated at 29 gynecologic cancer centers in Germany between 1998 and 2008. For this translational substudy, formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. Human papillomavirus status and subtype were analyzed by polymerase chain reaction. RESULTS: p16 immunohistochemistry was positive in 166 of 550 tumors (30.2%); p53 staining in 187 of 597 tumors (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); 3 groups were defined: p53+ (n=163), p16+/p53- (n=132), and p16-/p53- (n=116). Human papillomavirus DNA was detected in 85.6% of p16+/p53- tumors; human papillomavirus-16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs 72 years for p53+, respectively, 69 years for p16-/p53- tumors; P<.0001) and showed lower rates of lymph-node involvement (28.0% vs 42.3% for p53+, respectively, 30.2% for p16-/p53- tumors; P=.050). Notably, 2-year-disease-free and overall survival rates were significantly different among the groups: disease-free survival, 47.1% (p53+), 60.2% (p16-/p53-), and 63.9% (p16+/p53-) (P<.001); overall survival, 70.4% (p53+), 75.4% (p16-/p53-), and 82.5% (p16+/p53-) (P=.002). In multivariate analysis, the p16+/p53- phenotype showed a consistently improved prognosis compared with the other groups (hazard ratio, 0.66; 95% confidence interval, 0.44-0.99; P=.042). CONCLUSION: p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of vulvar squamous cell carcinoma with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized.

Suspensory Ligaments of the Female Genital Organs: MRI Evaluation with Intraoperative Correlation.

The uterus, which plays an important role in the reproductive process, provides a home for the developing fetus and so must be in a stable, though flexible, location. Various structures with suspensory ligaments help provide this berth. MRI with high spatial resolution allows us to detect and evaluate these relatively fine structures. Under physiologic conditions, MRI can be used to depict uterine and ovarian ligaments (ie, the uterosacral, cardinal, and round ligaments, as well as the suspensory ligament of the ovary). In the presence of pathologic conditions (inflammation, endometriosis, tumors), the suspensory ligaments may appear thickened or invaded, which makes their delineation easier. Understanding the normal anatomy of the suspensory ligaments of the female genital organs and using a standardized nomenclature are essential for identifying and reporting related pathologic conditions. The female pelvic anatomy and the suspensory ligaments of the female genital organs are described as depicted with MRI. Also, the compartmental anatomy of the female pelvis is explained, including the extraperitoneal pelvic spaces. Finally, a checklist is provided for structured reporting of the MRI findings in the female pelvis. Online supplemental material is available for this article. ©RSNA, 2018.

Robotically assisted peritoneal mesometrial resection (PMMR) in endometrial cancer supported by ICG labeling of the compartmental lymphatic system.

•Peritoneal mesometrial resection is a compartment based radical hysterectomy in endometrial cancer•ICG staining of the lymph-vessel system facilitates identification of compartment borders•Fluorescence based HD-video documentation supports education in surgery of endometrial cancer.

B3-lesions of the breast and cancer risk - an analysis of mammography screening patients.

The use of mammography screening, followed by needle core biopsy (NCB), is associated with an increasing amount of invasive procedures. A considerable amount of specimens must be classified as lesions with uncertain malignant potential (B3-lesion). In these cases, an open biopsy is indicated for further diagnosis. We evaluated patients with B3-lesions to determine the risk of malignancy corresponding to the histopathological NCB results and the type of radiological lesion identified. A total of 95 patients participating in the German mammography screening program with a B3-lesion following NCB (104 B3-lesions in total) were included in our analysis. We analyzed the correlation between the initial histopathological findings from the NCB specimen and cancer risk. We further analyzed the correlations of malignant results with the type of mammographic lesion. In 23 cases (22%), histopathological examination following excision revealed a malignant lesion, including invasive and in situ carcinoma. The positive predictive value of the subgroups of B3-lesions ranged between 0.11 and 0.31; the B3-lesion associated with the highest cancer risk was the atypical ductal hyperplasia; however, no significant difference was observed between the B3-lesion subgroups (P=0.309) regarding the risk of malignancy. Comparing the different types of mammographic findings, such as radiological mass or microcalcifications, there was no significant difference in the risk for malignancy (P=0.379). The different types of B3-lesions did not exhibit differences in the risk for malignancy, and the morphological type of mammographic lesion does not appear to be correlated with cancer risk; therefore, our results underline the need for open biopsy in patients with B3-lesions following NCB.

Intraoperative navigation in robotically assisted compartmental surgery of uterine cancer by visualisation of embryologically derived lymphatic networks with indocyanine-green (ICG).

BACKGROUND AND OBJECTIVES: To evaluate feasibility of intraoperative visualization of embryologically defined organ compartments and their drainage by ICG in uterine cancer. METHODS: Total of 2.5 mg of ICG have been injected into cervix or corpus in uterine cancer patients immediately prior to surgery. Green fluorescence was intermittently detected during robotically assisted laparoscopic surgery (Firefly System®, Intuitve Surgical Inc.). Total of 36 patients with uterine cancer without macroscopically suspicious nodes were evaluated with respect to their compartmental lymphatic network, collecting lymphatic vessels, and the connection to the postponed lymph basins. RESULTS: Müllerian (sub) compartment and transport of lymph fluid along the lymphatic collectors and connecting vessels to the postponed lymph basins could be visualized invariably in all patients. Cervix drained along the ligamentous and caudal part of vascular mesometria, whereas midcorporal and fundal drainage occurred along the upper part of vascular mesometria and along the mesonephric pathway along the ovarian vessels. CONCLUSIONS: Visualization of lymphatic network and downstream flow of lymphatic fluid to the postponed lymph basins by ICG is feasible; it can be used to navigate along compartment boarders for education, intraoperative orientation, and quality control. It seems to confirm the compartmental order of pelvic organ systems and postponed lymph basins. J. Surg. Oncol. 2016;113:554-559. © 2016 Wiley Periodicals, Inc.

Temsirolimus in women with platinum-refractory/resistant ovarian cancer or advanced/recurrent endometrial carcinoma. A phase II study of the AGO-study group (AGO-GYN8).

OBJECTIVES: To evaluate activity and toxicity of mTOR inhibitor temsirolimus in patients with platinum-refractory/resistant ovarian cancer (OC) or advanced/recurrent endometrial carcinoma (EC). METHODS: Women with epithelial ovarian, fallopian tube or primary peritoneal cancer were eligible, when they had progression during treatment with a platinum based regimen or within 6 months after receiving a platinum based regimen and a previous taxane treatment. Women with advanced/recurrent EC, no longer amenable to curative surgery and/or radiotherapy were eligible when they had no previous or only adjuvant chemotherapy. Preceding endocrine therapy for metastatic/recurrent disease was allowed. Patients received weekly IV infusions of 25mg temsirolimus. Primary endpoint was progression free survival rate after 4 months (OC) or 6 months (EC). A two stage design was applied. RESULTS: Forty-four patients (OC: n=22; EC: n=22) were enrolled and received temsirolimus treatment. Median age was 56 years (OC) or 63 years (EC). After eight weeks of treatment, 10 of 21 evaluable patients in the OC cohort and 8 of 20 evaluable patients in the EC cohort had progressive disease. Thus efficacy did not meet the predefined levels during the first stage of recruitment and the trial was stopped. Some patients in both cohorts had long lasting PFS (>7 months). Toxicity of temsirolimus was mild. CONCLUSIONS: Temsirolimus treatment was well tolerated in our patients, but did not meet the predefined efficacy criteria. In our study as in other trials on rapalogs in OC or EC, a few patients had long lasting disease stabilisations.

Evaluation of a novel ELISA for the tumor-associated antigen CA 72-4 in patients with ovarian cancer.

AIM: Cancer antigen 72-4 (CA 72-4) is an established tumor marker in ovarian cancer. We evaluated a new solid-phase ELISA (DRG TM-CA 72-4 ELISA). MATERIALS & METHODS: Repeated measures of test samples and controls were performed to evaluate reliability and reproducibility. Afterward, we performed analyses on the sera of 150 patients with primarily diagnosed ovarian cancer. Results were compared with those of the Cobas CA 72-4 kit. Results were correlated with clinical patient data. RESULTS: Results of the DRG TM-CA 72-4 ELISA were reproducible with acceptable deviations within measures, and the measured CA 72-4 serum concentrations were well in accordance with the references. High concentrations were significantly associated with grading, tumor stage and tumor residuals after surgery.

Embryologically based radical hysterectomy as peritoneal mesometrial resection (PMMR) with pelvic and para-aortic lymphadenectomy for loco-regional tumor control in endometrial cancer: first evidence for efficacy.

OBJECTIVE: To evaluate the feasibility and efficacy of embryologically based compartmental surgery for locoregional tumor control in intermediate and high risk endometrial cancer: peritoneal mesometrial resection with therapeutic pelvic and para-aortic lymphadenectomy by robotically assisted laparoscopy. METHODS: 75 consecutive surgically treated patients with uterine malignancies have been analyzed. 68 patients with histologically proven endometrial cancer and complete robotically assisted surgery have been included in this study on morbidity and oncological outcome. 56 % of the patients were at intermediate/high risk with either stage IAG3 or IB (n = 22) or stage II-IV (n = 16). Adjuvant EBRT was offered to three patients only (4 %), whereas five received isolated vaginal brachytherapy (7 %). Indocyanine-green (ICG) fluorescence lymphography is demonstrated being useful for additional intraoperative visualization of the compartment borders and lymphatic drainage to the postponed lymph compartments. RESULTS: After a mean follow-up of 32 months, there were only two loco-regional recurrences (2.9 %). Both recurrences were apparently cured by salvage therapy. 9 patients died; 6 (8.8 %) from metastatic disease (5) or unknown cause (1), 3 (4.4 %) from intercurrent disease without evidence of disease. One patient (1.4 %) experienced a peritoneal carcinosis and is alive. There were 8/68 perioperative complications (12 %). No perioperative mortality was observed. CONCLUSIONS: Embryologically defined compartmental surgery by robotically assisted laparoscopy seems to be feasible and safe in endometrial cancer. The low loco-regional recurrence rate of 2.9 % in spite of a very low percentage of adjuvant radiotherapy and 56 % of intermediate/high risk tumors should stimulate to initiate a multicentre trial to evaluate the value of compartmental surgery for prevention of locoregional recurrence in endometrial cancer.

Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. METHODS: In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118. FINDINGS: Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). INTERPRETATION: Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability. FUNDING: Boehringer Ingelheim.

Implementation of FAST-PET/MRI for whole-body staging of female patients with recurrent pelvic malignancies: A comparison to PET/CT.

OBJECTIVES: To compare the diagnostic competence of FAST-PET/MRI and PET/CT for whole-body staging of female patients suspect for a recurrence of a pelvic malignancy. METHODS: 24 female patients with a suspected tumor recurrence underwent a PET/CT and subsequent PET/MRI examination. For PET/MRI readings a whole-body FAST-protocol was implemented. Two readers separately evaluated the PET/CT and FAST PET/MRI datasets regarding identification of all tumor lesions and qualitative assessment of visual lesion-to-background contrast (4-point ordinal scale). RESULTS: Tumor relapse was present in 21 of the 24 patients. Both, PET/CT and PET/MRI allowed for correct identification of tumor recurrence in 20 of 21 cases. Lesion-based sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy for the detection of malignant lesions were 82%, 91%, 97%, 58% and 84% for PET/CT and 85%, 87%, 96%, 63% and 86% for PET/MRI, lacking significant differences. Furthermore, no significant difference for lesion-to-background contrast of malignant and benign lesions was found. CONCLUSION: FAST-PET/MRI provides a comparably high diagnostic performance for restaging gynecological cancer patients compared to PET/CT with slightly prolonged scan duration, yet enabling a markedly reduced radiation exposure.

Integrated PET/MRI for whole-body staging of patients with primary cervical cancer: preliminary results.

PURPOSE: To assess the diagnostic value of integrated PET/MRI for whole-body staging of cervical cancer patients, as well as to investigate a potential association between PET/MRI derived functional parameters and prognostic factors of cervical cancer. METHODS: The present study was approved by the local institutional review board. Twenty-seven patients with histopathologically confirmed cervical cancer were prospectively enrolled in our study. All patients underwent a whole-body PET/MRI examination after written informed consent was obtained. Two radiologists separately evaluated the PET/MRI data sets regarding the determination of local tumor extent of primary cervical cancer lesions, as well as detection of nodal and distant metastases. Furthermore, SUV and ADC values of primary tumor lesions were analyzed and correlated with dedicated prognostic factors of cervical cancer. Results based on histopathology and cross-sectional imaging follow-up served as the reference standard. RESULTS: PET/MRI enabled the detection of all 27 primary tumor lesions of the uterine cervix and allowed for the correct determination of the T-stage in 23 (85 %) out of the 27 patients. Furthermore, the calculated sensitivity, specificity and diagnostic accuracy for the detection of nodal positive patients (n = 11) were 91 %, 94 % and 93 %, respectively. PET/MRI correctly identified regional metastatic disease (N1-stage) in 8/10 (80 %) patients and non-regional lymph node metastases in 5/5 (100 %) patients. In addition, quantitative analysis of PET and MRI derived functional parameters (SUV; ADC values) revealed a significant correlation with pathological grade and tumor size (p < 0.05). CONCLUSIONS: The present study demonstrates the high potential of integrated PET/MRI for the assessment of primary tumor and the detection of lymph node metastases in patients with cervical cancer. Providing additional prognostic information, PET/MRI may serve as a valuable diagnostic tool for cervical cancer patients in a pretreatment setting.

Single nucleotide polymorphisms of the EpCAM-coding gene TACSTD1 in patients with ovarian cancer and their potential translational aspects.

PURPOSE: EpCAM is overexpressed in many neoplasms including ovarian cancer. We screened the EpCAM-coding gene TACSTD1 for single nucleotide polymorphisms (SNPs), which could alter ovarian cancer risk, impact upon disease progression, or alter binding of the therapeutic EpCAM-binding antibody, catumaxomab. METHODS: DNA fragments of 10 healthy volunteers were analyzed to identify SNPs. Subsequently, DNA of ovarian cancer patients (n = 117) and age-matched healthy controls (n = 115) was genotyped by restriction fragment length polymorphism and pyrosequencing. TACSTD1 genotypes 4461T>C were cloned into a gene expression vector; Hek293 cells were subsequently used for stable transfection. FACS analysis of the transfected Hek293 cells was conducted with HO-3-the EpCAM binding site of catumaxomab-to determine antibody binding. RESULTS: One SNP was detected in exon 3 (4461T>C; rs1126497), resulting in an amino acid exchange at position 115 (Met115Thr). Another polymorphism was found in the 3'UTR (17225A>G; rs1421). Genotyping of patients and controls for these SNPs did not reveal significant differences in genotype distribution. Regarding 17225A>G, the homozygous AA-genotype was associated with diminished progression-free survival (PFS; p = 0.032). Overall survival, FIGO-stage, grading, and age did not differ significantly between genotypes. FACS analysis of transfected Hek293 cells overexpressing EpCAM 115Met/Thr showed binding of HO-3 to both proteins. CONCLUSIONS: The AA-genotype of 17225A>G seems to be associated with diminished PFS in ovarian cancer patients. The amino acid exchange resulting from 4461T>C does not appear to alter binding of HO-3, suggesting that treatment with catumaxomab can be offered to patients regardless of their TACSTD1-genotype.

Diagnostic value of diffusion-weighted imaging in simultaneous 18F-FDG PET/MR imaging for whole-body staging of women with pelvic malignancies.

UNLABELLED: The aim of this study was to assess the diagnostic benefit of diffusion-weighted imaging (DWI) in an (18)F-FDG PET/MR imaging protocol for whole-body staging of women with primary or recurrent malignancies of the pelvis. METHODS: Forty-eight patients with a primary pelvic malignancy or suspected recurrence of a pelvic malignancy were included in our study. All patients underwent a whole-body (18)F-FDG PET/MR imaging examination that included DWI. Two radiologists separately evaluated the PET/MR imaging datasets without DWI followed by a second interpretation with DWI. First, both readers identified all primary tumors, as well as lymph node and distant metastases. In a second session, PET and DWI data were assessed qualitatively. Image interpretation comprised lesion conspicuity defined as visual lesion-to-background contrast (4-point ordinal scale) and diagnostic confidence (3-point ordinal scale) for all tumors. The results from histopathologic examination and cross-sectional imaging follow-up (≥6 mo) were used as the reference standard. Statistical analysis was performed to assess the significance of differences between obtained values. RESULTS: Among the 122 suspected lesions seen, 98 (80.3%) were considered malignant. PET/MR imaging without DWI had a sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of 92.9%, 87.5%, 96.8%, 75.0%, and 91.8%, respectively, for the detection of malignant lesions. PET/MR imaging with DWI had slightly higher values (94.9%, 83.3%, 95.9%, 80.0%, and 92.6%, respectively), but the difference was not significant (P > 0.05). In the qualitative assessment of lesion-to-background contrast, PET had significantly (P < 0.05) higher values (3.79 ± 0.58) than DWI (3.63 ± 0.77). Furthermore, significantly (P < 0.05) higher scores were found for diagnostic confidence using PET (2.68 ± 0.64) for the determination of malignant lesions, when compared with DWI (2.53 ± 0.69). CONCLUSION: DWI in PET/MR imaging has no diagnostic benefit for whole-body staging of women with pelvic malignancies. The omission of DWI for staging or restaging gynecologic cancer may significantly reduce examination times, thus increasing patient comfort without a relevant decrease in diagnostic competence.

Simultaneous positron emission tomography/magnetic resonance imaging for whole-body staging in patients with recurrent gynecological malignancies of the pelvis: a comparison to whole-body magnetic resonance imaging alone.

OBJECTIVES: The objective of this study was to assess the diagnostic value of integrated positron emission tomography/magnetic resonance imaging (PET/MRI) for whole-body staging of patients with recurrent gynecological pelvic malignancies, in comparison to whole-body MRI alone. MATERIALS AND METHODS: The study was approved by the local institutional ethics committee. Written informed consent was obtained before each examination. Thirty-four consecutive patients with a suspected recurrence of cervical (n = 18) or ovarian (n = 16) cancer were prospectively enrolled for an integrated PET/MRI examination, which comprised a diagnostic, contrast-enhanced whole-body MRI protocol including dedicated sagittal dynamic imaging of the pelvis. Two radiologists separately evaluated the data sets regarding lesion count, lesion detection, lesion characterization, and diagnostic confidence. Mean and median values were calculated for each rating. Statistical analyses were performed both per-patient and per-lesion bases using a Wilcoxon signed-rank test to indicate potential significant differences among PET/MRI and MRI (alone) data sets. RESULTS: Malignant lesions were present in 25 of the 34 patients. Positron emission tomography/magnetic resonance imaging offered correct and superior identification of all 25 patients with cancer recurrence, compared with MRI alone (23/25). A total of 118 lesions (malignant, 89; benign, 29) were detected. Positron emission tomography/magnetic resonance imaging correctly identified 88 (98.9%) of 89 malignant lesions, whereas MRI alone allowed for correct identification of 79 (88.8%) of the 89 malignant lesions. In addition, PET/MRI provided significantly higher lesion contrast and diagnostic confidence in the detection of malignant lesions (P < 0.001) compared with MRI alone. CONCLUSIONS: These first results demonstrate the high diagnostic potential of integrated PET/MRI for the assessment of recurrence of female pelvic malignancies compared with MRI alone.

The haplotype of three polymorphisms in the SATB1 promoter region impacts survival in breast cancer patients.

Special AT-rich sequence binding protein 1 (SATB1) has regulatory effects on gene expression and appears to play an important role in tumor progression. The present study screened the promoter region of the SATB1 gene for polymorphisms, evaluated the corresponding haplotypes regarding alterations in promoter activity in vitro and analyzed the impact of these haplotypes on the clinical course of breast cancer patients. A cohort of 241 female Caucasian breast cancer patients who had been treated was enrolled in this retrospective analysis. The median follow-up time was 93 months (range, 4-155 months). PCR products from DNA of 10 healthy, unrelated volunteers were analyzed to identify new polymorphisms within the promoter region. Genotyping was conducted using restriction fragment length polymorphism and pyrosequencing. PCR constructs with the respective alleles from the four most frequent haplotypes were cloned into the vector pGEM®-T Easy and then transferred into the luc2-containing reporter vector pGl 4.10® for transfection of HEK293 cells. The pGl 4.73® vector, containing hRluc, was used for normalizing the transfection rates. Sequencing the region -3807 to -2828 bp upstream of ATG from ten healthy blood donors, three single nucleotide polymorphisms consisting of base exchanges were identified: -3600T>C, -3363A>G and -2984C>T. The SATB1 -3600T/-3363A/-2984C haplotype had lower promoter activity than all other constructs in vitro and exhibited a significant association with nodal status (P<0.05). Kaplan-Meier survival analysis revealed significantly improved overall survival for homozygous SATB1 -3600T/-3363A/-2984C haplotype carriers compared with heterozygous carriers or the other haplotypes (P=0.033). The SATB1 -3600T/-3363A/-2984C haplotype is associated with lower promoter activity and appears to impact upon survival in breast cancer patients.

Definition of compartment-based radical surgery in uterine cancer: modified radical hysterectomy in intermediate/high-risk endometrial cancer using peritoneal mesometrial resection (PMMR) by M Höckel translated to robotic surgery.

BACKGROUND: The technique of compartment-based radical hysterectomy was originally described by M Höckel as total mesometrial resection (TMMR) for standard treatment of stage I and II cervical cancer. However, with regard to the ontogenetically-defined compartments of tumor development (Müllerian) and lymph drainage (Müllerian and mesonephric), compartments at risk may also be defined consistently in endometrial cancer. This is the first report in the literature on the compartment-based surgical approach to endometrial cancer. Peritoneal mesometrial resection (PMMR) with therapeutic lymphadenectomy (tLNE) as an ontogenetic, compartment-based oncologic surgery could be beneficial for patients in terms of surgical radicalness as well as complication rates; it can be standardized for compartment-confined tumors. Supported by M Höckel, PMMR was translated to robotic surgery (rPMMR) and described step-by-step in comparison to robotic TMMR (rTMMR). METHODS: Patients (n = 42) were treated by rPMMR (n = 39) or extrafascial simple hysterectomy (n = 3) with/without bilateral pelvic and/or periaortic robotic therapeutic lymphadenectomy (rtLNE) for stage I to III endometrial cancer, according to International Federation of Gynecology and Obstetrics (FIGO) classification. Tumors were classified as intermediate/high-risk in 22 out of 40 patients (55%) and low-risk in 18 out of 40 patients (45%), and two patients showed other uterine malignancies. In 11 patients, no adjuvant external radiotherapy was performed, but chemotherapy was applied. RESULTS: No transition to open surgery was necessary. There were no intraoperative complications. The postoperative complication rate was 12% with venous thromboses, (n = 2), infected pelvic lymph cyst (n = 1), transient aphasia (n = 1) and transient dysfunction of micturition (n = 1). The mean difference in perioperative hemoglobin concentrations was 2.4 g/dL (± 1.2 g/dL) and one patient (2.4%) required transfusion. During follow-up (median 17 months), one patient experienced distant recurrence and one patient distant/regional recurrence of endometrial cancer (4.8%), but none developed isolated locoregional recurrence. There were two deaths from endometrial cancer during the observation period (4.8%). CONCLUSIONS: We conclude that rPMMR and rtLNE are feasible and safe with regard to perioperative morbidity, thus, it seems promising for the treatment of intermediate/high-risk endometrial cancer in terms of surgical radicalness and complication rates. This could be particularly beneficial for morbidly obese and seriously ill patients.

Definition of compartment-based radical surgery in uterine cancer: radical hysterectomy in cervical cancer as 'total mesometrial resection (TMMR)' by M Höckel translated to robotic surgery (rTMMR).

BACKGROUND: Radical hysterectomy has been developed as a standard treatment in Stage I and II cervical cancers with and without adjuvant therapy. However, there have been several attempts to standardize the technique of radical hysterectomy required for different tumor extension with variable success. Total mesometrial resection as ontogenetic compartment-based oncologic surgery - developed by open surgery - can be standardized identically for all patients with locally defined tumors. It appears to be promising for patients in terms of radicalness as well as complication rates. Robotic surgery may additionally reduce morbidity compared to open surgery. We describe robotically assisted total mesometrial resection (rTMMR) step by step in cervical cancer and present feasibility data from 26 patients. METHODS: Patients (n = 26) with the diagnosis of cervical cancer were included. Patients were treated by robotic total mesometrial resection (rTMMR) and pelvic or pelvic/periaortic robotic therapeutic lymphadenectomy (rtLNE) for FIGO stage IA-IIB cervical cancer. RESULTS: No transition to open surgery was necessary. No intraoperative complications were noted. The postoperative complication rate was 23%. Within follow-up time (mean: 18 months) we noted one distant but no locoregional recurrence of cervical cancer. There were no deaths from cervical cancer during the observation period. CONCLUSIONS: We conclude that rTMMR and rtLNE is a feasible and safe technique for the treatment of compartment-defined cervical cancer.

Definition of compartment based radical surgery in uterine cancer-part I: therapeutic pelvic and periaortic lymphadenectomy by Michael höckel translated to robotic surgery.

Objective. To define compartment based therapeutic pelvic and periaortic lymphadenectomy in cervical and endometrial cancer. Compartment based oncologic surgery appears to be favorable for patients in terms of radicality as well as complication rates, and the same appears to be true for robotic surgery. We describe a method of robotically assisted compartment based lymphadenectomy step by step in uterine cancer and demonstrate feasibility data from 35 patients. Methods. Patients with the diagnosis of endometrial (n = 16) or cervical (n = 19) cancer were included. Patients were treated by rTMMR (robotic total mesometrial resection) or rPMMR (robotic peritoneal mesometrial resection) and pelvic or pelvic/periaortic rtLNE (robotic therapeutic lymphadenectomy) with cervical cancer FIGO IB-IIA or endometrial cancer FIGO I-III. Results. No transition to open surgery was necessary. Complication rates were 13% for endometrial cancer and 21% for cervical cancer. Within follow-up time median (22/20) month we noted 1 recurrence of cervical cancer and 2 endometrial cancer recurrences. Conclusions. We conclude that compartment based rtLNE is a feasible and safe technique for the treatment of uterine cancers and is favorable in aspects of radicality and complication rates. It should be analyzed in multicenter studies with extended followup on the basis of the described technique.

Utility of mesothelin, L1CAM and Afamin as biomarkers in primary ovarian cancer.

BACKGROUND: We evaluated the prognostic value of the new serum biomarkers mesothelin (cell surface glycoprotein and tumor differentiation antigen), L1 cell adhesion molecule (L1CAM) and afamin (vitamin D-binding protein) alone and in combination with cancer antigen 125 (CA125) in serum samples of 154 patients with first-diagnosis of primary ovarian cancer, before surgery and after platinum-based chemotherapy. We correlated these findings with clinical parameters and evaluated their prognostic value with regard to overall survival (OS). MATERIALS AND METHODS: Blood (9 ml) was obtained before surgery (n=154) and after chemotherapy (n=82) for the measurement of serum markers using commercial Enzyme Linked Immunosorbent Assay (ELISA) kits for mesothelin, L1CAM, afamin and CA125. Mesothelin positivity was defined as >2.0 nM, L1CAM as >10 ng/ml, afamin as <45 mg/l and CA125 as >35 U/ml, respectively. RESULTS: Before surgery, mesothelin positivity significantly correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.002), residual postoperative tumor (p<0.0001), serous histological subtype (p<0.0001) and higher age (p=0.013). Elevated CA125 levels significantly correlated with advanced FIGO stage (p<0.0001) and grading (p=0.012). After chemotherapy, mesothelin as well as CA125 levels, were significantly associated with FIGO stage (p=0.041 and p=0.017) and residual tumor (p=0.022 and p=0.002) while L1CAM correlated with platinum sensitivity (p=0.041). In contrast, afamin at all determined time points showed no correlation with any of these parameters. The combination of markers did not add any significant power to their use. CONCLUSION: Mesothelin and L1CAM appear to correlate with clinical prognostic parameters and might be useful biomarkers for therapy monitoring and, thus, could serve as attractive targets for therapy of ovarian cancer.