Publications by authors named "Nicole Concin"

85 Publications

ESGO/ISUOG/IOTA/ESGE Consensus Statement on pre-operative diagnosis of ovarian tumors.

Int J Gynecol Cancer 2021 Jun 10. Epub 2021 Jun 10.

Gynaecologic Oncology, Hammersmith Hospital, Imperial College, London, UK.

The European Society of Gynaecological Oncology (ESGO), the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), the International Ovarian Tumour Analysis (IOTA) group, and the European Society for Gynaecological Endoscopy (ESGE) jointly developed clinically relevant and evidence-based statements on the pre-operative diagnosis of ovarian tumors, including imaging techniques, biomarkers, and prediction models. ESGO/ISUOG/IOTA/ESGE nominated a multidisciplinary international group, including expert practising clinicians and researchers who have demonstrated leadership and expertise in the pre-operative diagnosis of ovarian tumors and management of patients with ovarian cancer (19 experts across Europe). A patient representative was also included in the group. To ensure that the statements were evidence-based, the current literature was reviewed and critically appraised. Preliminary statements were drafted based on the review of the relevant literature. During a conference call, the whole group discussed each preliminary statement and a first round of voting was carried out. Statements were removed when a consensus among group members was not obtained. The voters had the opportunity to provide comments/suggestions with their votes. The statements were then revised accordingly. Another round of voting was carried out according to the same rules to allow the whole group to evaluate the revised version of the statements. The group achieved consensus on 18 statements. This Consensus Statement presents these ESGO/ISUOG/IOTA/ESGE statements on the pre-operative diagnosis of ovarian tumors and the assessment of carcinomatosis, together with a summary of the evidence supporting each statement.
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http://dx.doi.org/10.1136/ijgc-2021-002565DOI Listing
June 2021

The Long-Term Prognostic Significance of Circulating Tumor Cells in Ovarian Cancer-A Study of the OVCAD Consortium.

Cancers (Basel) 2021 May 26;13(11). Epub 2021 May 26.

Department of Obstetrics and Gynecology, Medical University of Vienna, 1090 Vienna, Austria.

Introduction: We previously reported the prognostic impact of circulating tumor cells (CTCs) in a multicenter study on minimal residual disease in primary ovarian cancer. With additional follow-up data, we evaluated the combined CTC approach (CTCs), in particular for the patients who had survived more than five years.

Material And Methods: Blood samples taken at baseline and six months after adjuvant treatment (follow-up) were assessed by quantitative PCR (qPCR) measuring PPIC transcripts and immunofluorescent staining (IF). A positive result with either IF or qPCR was classified as CTC-positive. Further, PPIC was assessed in the primary tumor tissue.

Results: The concordance of IF and qPCR was 65% at baseline and 83% after treatment. Results showed that 50.5% of the baseline and 29.5% of the follow-up samples were CTC-positive. CTCs after treatment were associated with increased mortality after adjusting for FIGO stage (HR 2.574, 95% CI: 1.227-5.398, = 0.012), a higher risk of recurrence after adjusting for peritoneal carcinosis (HR 4.068, 95% CI: 1.948-8.498, < 0.001), and increased mortality after five survived years.

Discussion: The two-sided analytical approach revealed CTC subpopulations associated with ovarian cancer progression and may illuminate a potential treatment-related shift in molecular phenotypes. That approach can identify patients who have elevated risk of recurrence and death due to ovarian cancer and who may require risk-adapted treatment strategies.
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http://dx.doi.org/10.3390/cancers13112613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198007PMC
May 2021

Uterine serous carcinoma.

Gynecol Oncol 2021 Apr 29. Epub 2021 Apr 29.

Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy.

Serous endometrial cancer represents a relative rare entity accounting for about 10% of all diagnosed endometrial cancer, but it is responsible for 40% of endometrial cancer-related deaths. Patients with serous endometrial cancer are often diagnosed at earlier disease stage, but remain at higher risk of recurrence and poorer prognosis when compared stage-for-stage with endometrioid subtype endometrial cancer. Serous endometrial cancers are characterized by marked nuclear atypia and abnormal p53 staining in immunohistochemistry. The mainstay of treatment for newly diagnosed serous endometrial cancer includes a multi-modal therapy with surgery, chemotherapy and/or radiotherapy. Unfortunately, despite these efforts, survival outcomes still remain poor. Recently, The Cancer Genome Atlas (TCGA) Research Network classified all endometrial cancer types into four categories, of which, serous endometrial cancer mostly is found within the "copy number high" group. This group is characterized by the increased cell cycle deregulation (e.g., CCNE1, MYC, PPP2R1A, PIKCA, ERBB2 and CDKN2A) and TP53 mutations (90%). To date, the combination of pembrolizumab and lenvatinib is an effective treatment modality in second-line therapy, with a response rate of 50% in advanced/recurrent serous endometrial cancer. Owing to the unfavorable outcomes of serous endometrial cancer, clinical trials are a priority. At present, ongoing studies are testing novel combinations of various targeted and immunotherapeutic agents in newly diagnosed and advanced/recurrent endometrial cancer - an important strategy for serous endometrial cancer, whereby tumors are usually p53+ and pMMR, making response to PD-1 inhibitor monotherapy unlikely. Here, the rare tumor working group (including members from the European Society of Gynecologic Oncology (ESGO), Gynecologic Cancer Intergroup (GCIG), and Japanese Gynecologic Oncology Group (JGOG)), performed a narrative review reporting on the current landscape of serous endometrial cancer and focusing on standard and emerging therapeutic options for patients affected by this difficult disease.
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http://dx.doi.org/10.1016/j.ygyno.2021.04.029DOI Listing
April 2021

Response to: Are we confident treating pT1a G1 lymphovascular space invasion-negative patients (with myometrial invasion) with chemoradiotherapy on the basis of p53abn?

Int J Gynecol Cancer 2021 Jun 28;31(6):947. Epub 2021 Apr 28.

Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands.

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http://dx.doi.org/10.1136/ijgc-2021-002668DOI Listing
June 2021

Combination of weekly paclitaxel-carboplatin plus standard bevacizumab as neoadjuvant treatment in stage IB-IIB cervical cancer.

Int J Gynecol Cancer 2021 Jun 15;31(6):824-828. Epub 2021 Apr 15.

University Hospital Leuven, Department of Gynaecology and Obstetrics, Division of Gynaecological Oncology, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium

Objective: In this study we investigated response rates of bevacizumab in addition to weekly paclitaxel and carboplatin in neoadjuvant setting in cervical cancer stage IB-IIB.

Methods: In this retrospective study we included patients with FIGO 2018 stage IB-IIB cervical cancer. Treatment consisted of 9 weeks' neoadjuvant paclitaxel and carboplatin (paclitaxel 60 mg/m, carboplatin AUC 2.7; both weekly) and bevacizumab (15 mg/kg every 3 weeks). The radiologic response rate was analyzed using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. The definition of optimal pathological response was complete disappearance of tumor (complete response, pCR) or residual disease with less than 3 mm stromal invasion (pPR1). Suboptimal pathologic response (pPR2) was defined as persistent residual disease with more than 3 mm stromal invasion.

Results: A total of 30 patients were included. Six patients had FIGO 2018 stage IB1-IB2 (20%), one had stage IB3 (3%), five had stage IIA (17%), and 18 had stage IIB (60%). After completing the neoadjuvant chemotherapy, all patients showed a RECIST response (seven (23%) complete response; 23 (77%) partial response). Six patients (20%) were judged to be still inoperable. After radical hysterectomy, optimal pathological response was observed in 11 patients (38%) (pCR in nine patients (29%) and pPR1 in two patients (8%)). Six patients (20%) received postoperative adjuvant chemoradiotherapy. Hematological toxicity was similar to neoadjuvant weekly paclitaxel and carboplatin, as we reported earlier. Grade IV proteinuria or hypertension was not observed and no administration of bevacizumab was delayed or dose-reduced.

Conclusion: Bevacizumab in addition to weekly paclitaxel and carboplatin showed a 100% radiological RECIST response and an optimal pathological response of 38%. Although bevacizumab has an established role in the treatment of recurrent cervical cancer in combination with paclitaxel and carboplatin, we did not observe a tendency toward superior effect on the pathological response rate of bevacizumab in the neoadjuvant chemotherapy setting.
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http://dx.doi.org/10.1136/ijgc-2021-002432DOI Listing
June 2021

ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma.

Radiother Oncol 2021 01;154:327-353

Department of Radiation Oncology, Leiden University Medical Center, Leiden Netherlands.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.
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http://dx.doi.org/10.1016/j.radonc.2020.11.018DOI Listing
January 2021

ESGO/ESTRO/ESP Guidelines for the management of patients with endometrial carcinoma.

Virchows Arch 2021 Feb;478(2):153-190

Department of Pathology, Hospital Universitari Arnau de Vilanova, University of Lleida, CIBERONC, Irblleida, Spain.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.
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http://dx.doi.org/10.1007/s00428-020-03007-zDOI Listing
February 2021

Impact of clinical factors and surgical outcome on long-term survival in high-grade serous ovarian cancer: a multicenter analysis.

Int J Gynecol Cancer 2021 May 9;31(5):713-720. Epub 2021 Feb 9.

Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

Introduction: Long-term survivors of ovarian cancer are a unique group of patients in whom prognostic factors for long-term survival have been poorly described. Such factors may provide information for a more personalized therapeutic approach. The objective of this study is to determine further characteristics of long-term survivors with high-grade serous ovarian cancer.

Methods: Long-term survivors were defined as patients living longer than 8 years after first diagnosis and were recruited within seven high volume centers across Europe from November 1988 to November 2008. The control group included patients with high-grade serous ovarian cancer with less than 5 years' survival identified from the systematic 'Tumorbank ovarian cancer' database. A subanalysis of Charité patients only was performed separately for in-depth analysis of tumor dissemination. Propensity score matching with nearest-neighbor caliper width was used to match long-term survivors and the control group regarding age, FIGO stage, and residual tumor.

Results: A total of 276 patients with high-grade serous ovarian cancer were included, divided into 131 long-term survivors and 145 control group patients. After propensity score matching and multivariable adjustment, platinum sensitivity (p=0.002) was an independent favorable prognostic factor whereas recurrence (p<0.001) and ascites (p=0.021) were independent detrimental predictors for long-term survival. Significantly more long-term survivors tested positive for mutation in the BRCA1 gene than the BRCA2 gene (p=0.016). Intraoperatively, these patients had less tumor involvement of the upper abdomen at initial surgery (p=0.024). Complexity of surgery and surgical techniques were similar in both cohorts.

Conclusion: Platinum sensitivity constitutes a favorable factor for long-term survival whereas tumor involvement of the upper abdomen, ascites, and recurrence have a negative impact. Based on clinical estimation, long-term survival is associated with combinations of clinical, surgical, and molecular factors.
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http://dx.doi.org/10.1136/ijgc-2020-002023DOI Listing
May 2021

ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma.

Int J Gynecol Cancer 2021 Jan 18;31(1):12-39. Epub 2020 Dec 18.

Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multi-disciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.
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http://dx.doi.org/10.1136/ijgc-2020-002230DOI Listing
January 2021

Definition and Independent Validation of a Proteomic-Classifier in Ovarian Cancer.

Cancers (Basel) 2020 Sep 4;12(9). Epub 2020 Sep 4.

Department of Obstetrics and Gynecology, Medical University of Vienna, Molecular Oncology Group, Gynecologic Cancer Unit, Comprehensive Cancer Center, 1090 Vienna, Austria.

Mass-spectrometry-based analyses have identified a variety of candidate protein biomarkers that might be crucial for epithelial ovarian cancer (EOC) development and therapy response. Comprehensive validation studies of the biological and clinical implications of proteomics are needed to advance them toward clinical use. Using the Deep MALDI method of mass spectrometry, we developed and independently validated (development cohort: = 199, validation cohort: = 135) a blood-based proteomic classifier, stratifying EOC patients into good and poor survival groups. We also determined an age dependency of the prognostic performance of this classifier, and our protein set enrichment analysis showed that the good and poor proteomic phenotypes were associated with, respectively, lower and higher levels of complement activation, inflammatory response, and acute phase reactants. This work highlights that, just like molecular markers of the tumor itself, the systemic condition of a patient (partly reflected in proteomic patterns) also influences survival and therapy response in a subset of ovarian cancer patients and could therefore be integrated into future processes of therapy planning.
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http://dx.doi.org/10.3390/cancers12092519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564837PMC
September 2020

ESGO-SIOPE guidelines for the management of adolescents and young adults with non-epithelial ovarian cancers.

Lancet Oncol 2020 07;21(7):e360-e368

Paediatric Oncology, University Hospital Bonn, Bonn, Germany.

The European Society of Gynaecological Oncology and the European Society for Paediatric Oncology jointly developed clinically relevant and evidence-based guidelines for the management of adolescents and young adults aged 15 to 25 years with non-epithelial ovarian cancers, including malignant ovarian germ cell tumours, sex cord-stromal tumours, and small cell carcinoma of the ovary of hypercalcaemic type. The developmental process of these guidelines is based on a systematic literature review and critical appraisal process involving an international multidisciplinary developmental group consisting of experts from relevant disciplines (paediatric oncology, paediatric surgery, medical oncology, pathology, psycho-oncology, gynaecological oncology, and reproductive endocrinology). Given the specific and often complex issues involved in treating this group of patients, fertility sparing surgery and decrease of acute and long-term toxicities from treatment were important criteria for guidelines definition. Prior to publication, the guidelines were reviewed by 54 independent international practitioners in cancer care delivery.
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http://dx.doi.org/10.1016/S1470-2045(20)30091-7DOI Listing
July 2020

ESGO contribution to the WHO initiative on elimination of cervical cancer.

Int J Gynecol Cancer 2020 04 2;30(4):434-435. Epub 2020 Mar 2.

Department of Surgery, Institut Bergonie, Bordeaux, France.

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http://dx.doi.org/10.1136/ijgc-2020-001286DOI Listing
April 2020

Para-aortic lymph node surgical staging in locally-advanced cervical cancer: comparison between robotic versus conventional laparoscopy.

Int J Gynecol Cancer 2020 04 19;30(4):466-472. Epub 2020 Feb 19.

Gynecological Oncology, KU Leuven University Hospitals Leuven, Leuven, Flanders, Belgium

Objective: With the expansion of the use of minimally invasive surgical techniques within the field of gynecological oncology, a robot assisted procedure seems to be an attractive technique for para-aortic lymph node sampling. The aim of this study was to compare robotic versus conventional laparoscopic para-aortic lymphadenectomy in patients with locally advanced cervical cancer.

Methods: In this monocentric retrospective study, we included patients with locally-advanced cervical cancer (International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2-IVA or IB1 with suspicious pelvic lymph nodes), who underwent a para-aortic lymphadenectomy up to the inferior mesenteric artery between December 1994 and December 2016 (robotic technique starting from December 2012).

Results: A total of 217 patients were included in the study (robotic, n=55 vs laparoscopic, n=162). When comparing conventional laparoscopic versus robotic para-aortic lymphadenectomy, the median age was 48 versus 49 years and the median body mass index was 24.4 vs 24.7 kg/m, respectively. In the robotic or laparoscopic group, 85% and 83% were squamous carcinomas, respectively. Patients who underwent a robotic procedure had a higher American Society of Anesthesiologists (ASA) score (ASA2: 62% vs 56%, ASA3: 20% vs 2%, p<0.001), more prior major abdominal surgery (18% vs 6%, p=0.016), less estimated blood loss (median, 25 mL vs 62.5 mL, p<0.001), more para-aortic lymph nodes removed (11 vs 6, p<0.001), shorter postoperative stay (1.8 vs 2.3 days, p=0.002), and a higher, but non-significant, rate of metastatic para-aortic lymph nodes (13% vs 5%, p=0.065) compared with the laparoscopic procedure, respectively. There was no difference in complication rates between the two approaches. The most frequent complications were grade I and grade II according to the Clavien Dindo classification. No difference was observed in progression-free survival between robotic and laparoscopic para-aortic lymphadenectomy after 2 years (both groups 66%) (p=0.472). Also, 2 year overall survival was similar between the groups (77% vs 81% for robotic vs conventional laparoscopy group, respectively) (p=0.749).

Conclusion: Robotic para-aortic lymphadenectomy in patients with locally-advanced cervical cancer resulted in better perioperative outcomes and similar survival outcomes when compared with a conventional laparoscopic approach.
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http://dx.doi.org/10.1136/ijgc-2019-000961DOI Listing
April 2020

Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer.

Clin Cancer Res 2020 03 3;26(6):1220-1228. Epub 2019 Dec 3.

Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Tissue factor (TF) is a potential target in cervical cancer, as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody-drug conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase I/II study (NCT02001623).

Patients And Methods: Patients with recurrent or metastatic cervical cancer received tisotumab vedotin 2.0 mg/kg every 3 weeks until progressive disease, unacceptable toxicity, or consent withdrawal. The primary objective was safety and tolerability. Secondary objectives included antitumor activity.

Results: Of the 55 patients, 51% had received ≥2 prior lines of treatment in the recurrent or metastatic setting; 67% had prior bevacizumab + doublet chemotherapy. Fifty-one percent of patients had squamous cell carcinoma. The most common grade 3/4 treatment-emergent adverse events (AEs) were anemia (11%), fatigue (9%), and vomiting (7%). No grade 5 treatment-related AEs occurred. Investigator-assessed confirmed objective response rate (ORR) was 24% [95% confidence interval (CI): 13%-37%]. Median duration of response (DOR) was 4.2 months (range: 1.0-9.7); four patients responded for >8 months. The 6-month progression-free survival (PFS) rate was 29% (95% CI: 17%-43%). Independent review outcomes were comparable, with confirmed ORR of 22% (95% CI: 12%-35%), median DOR of 6.0 months (range: 1.0-9.7), and 6-month PFS rate of 40% (95% CI: 24%-55%). Tissue factor expression was confirmed in most patients; no significant association with response was observed.

Conclusions: Tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in patients with previously treated recurrent or metastatic cervical cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2962DOI Listing
March 2020

Part I of GANNET53: A European Multicenter Phase I/II Trial of the Hsp90 Inhibitor Ganetespib Combined With Weekly Paclitaxel in Women With High-Grade, Platinum-Resistant Epithelial Ovarian Cancer-A Study of the GANNET53 Consortium.

Front Oncol 2019 10;9:832. Epub 2019 Sep 10.

Department of Obstetrics and Gynecology, Medical University of Innsbruck, Austrian AGO, Innsbruck, Austria.

Stabilized mutant p53 protein (mutp53) is a novel target in epithelial ovarian cancer. Due to aberrant conformation, mutp53 proteins depend on folding support by the Hsp90 chaperone. Hsp90 blockade induces degradation of mutp53, resulting in tumor cell cytotoxicity and increased sensitivity to chemotherapeutics. Preclinical synergy of the Hsp90 inhibitor ganetespib combined with paclitaxel provided the rationale for testing the combination in platinum-resistant ovarian cancer (PROC) patients in the GANNET53 trial (NCT02012192). Eligible patients had high-grade PROC with ≤ 4 prior lines of chemotherapy. Weekly paclitaxel (80 mg/m) and increasing doses of ganetespib (100, 150 mg/m) were given i.v. on days 1, 8, 15 in a 28 days cycle until disease progression or unacceptable toxicity. Endpoints were safety and determination of phase II dose. Dose limiting toxicity (DLT) was defined as grade 4 toxicity (with exceptions) occurring in cycles 1&2. Ten patients (median age 59 years; range 43-70) were enrolled. No DLT occurred in cohort 1 (4 patients treated with paclitaxel + ganetespib 100 mg/m), nor in cohorts 2 and 3 (6 patients treated with paclitaxel + ganetespib 150 mg/m). The most common adverse event (AE) related to ganetespib was transient grade 1/2 diarrhea ( = 6). Related grade 1/2 AEs in >2 patients included QTc prolongation ( = 4), nausea ( = 3), anemia ( = 3), headache ( = 3), fatigue ( = 3), and dyspnoea ( = 3). Most frequently related grade 3/4 AEs were diarrhea ( = 3) and neutropenia ( = 2). There was 1 death on study due to hemorrhage from a duodenal ulcer. Three patients discontinued study treatment due to serious AEs (digestive hemorrhage = 1, cardiac failure = 1, abdominal pain and vomiting = 1), 6 due to progressive disease, one due to investigator and patient decision. Two patients achieved a partial response (ORR 20%) and 4 patients a stable disease (disease control rate of 60%). Median PFS was 2.9 months (1.6 months in cohort 1 at 100 mg/m ganetespib, 5.1 months in cohorts 2+3 at 150 mg/m ganetespib). The combination of ganetespib 150 mg/m with paclitaxel 80 mg/m once weekly for 3 out of 4 weeks was generally well-tolerated with no DLTs, and therefore chosen for the randomized phase II trial.
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http://dx.doi.org/10.3389/fonc.2019.00832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746955PMC
September 2019

Fetal weight estimation at term - ultrasound versus clinical examination with Leopold's manoeuvres: a prospective blinded observational study.

BMC Pregnancy Childbirth 2019 Apr 11;19(1):122. Epub 2019 Apr 11.

Department of Obstetrics and Gynaecology, Division of Obstetrics and Fetomaternal Medicine, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria.

Background: Fetal weight estimation is of key importance in the decision-making process for obstetric planning and management. The literature is inconsistent on the accuracy of measurements with either ultrasound or clinical examination, known as Leopold's manoeuvres, shortly before term. Maternal BMI is a confounding factor because it is associated with both the fetal weight and the accuracy of fetal weight estimation. The aim of our study was to compare the accuracy of fetal weight estimation performed with ultrasound and with clinical examination with respect to BMI.

Methods: In this prospective blinded observational study we investigated the accuracy of clinical examination as compared to ultrasound measurement in fetal weight estimation, taking the actual birth weight as the gold standard. In a cohort of all consecutive patients who presented in our department from January 2016 to May 2017 to register for delivery at ≥37 weeks, examination was done by ultrasound and Leopold's manoeuvres to estimate fetal weight. All examiners (midwives and physicians) had about the same level of professional experience. The primary aim was to compare overall absolute error, overall absolute percent error, absolute percent error > 10% and absolute percent error > 20% for weight estimation by ultrasound and by means of Leopold's manoeuvres versus the actual birth weight as the given gold standard, namely separately for normal weight and for overweight pregnant women.

Results: Five hundred forty-three patients were included in the data analysis. The accuracy of fetal weight estimation was significantly better with ultrasound than with Leopold's manoeuvres in all absolute error calculations made in overweight pregnant women. For all error calculations performed in normal weight pregnant women, no statistically significant difference was seen in the accuracy of fetal weight estimation between ultrasound and Leopold's manoeuvres.

Conclusions: Data from our prospective blinded observational study show a significantly better accuracy of ultrasound for fetal weight estimation in overweight pregnant women only as compared to Leopold's manoeuvres with a significant difference in absolute error. We did not observe significantly better accuracy of ultrasound as compared to Leopold's manoeuvres in normal weight women. Further research is needed to analyse the situation in normal weight women.
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http://dx.doi.org/10.1186/s12884-019-2251-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458793PMC
April 2019

Vascular endothelial growth factor receptor 2 (VEGFR2) correlates with long-term survival in patients with advanced high-grade serous ovarian cancer (HGSOC): a study from the Tumor Bank Ovarian Cancer (TOC) Consortium.

J Cancer Res Clin Oncol 2019 Apr 27;145(4):1063-1073. Epub 2019 Feb 27.

Department of Gynecology, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.

Objective: The impact of angiogenesis on long-term survival of high-grade serous ovarian cancer (HGSOC) patients remains unclear. This study investigated whether angiogenic markers correlated with 5-year progression-free survival (PFS) in a large cohort of matched advanced HGSOC tissue samples.

Methods: Tumor samples from 124 primary HGSOC patients were retrospectively collected within the Tumor Bank Ovarian Cancer ( http://www.toc-network.de ). All patients were in advanced stages (FIGO stage III-IV). No patient had received anti-angiogenesis therapy. The cohort contains 62 long-term survivors and 62 controls matched by age and post-surgical tumor residuals. Long-term survivors were defined as patients with no relapse within 5 years after the end of first-line chemotherapy. Controls were patients who suffered from first relapse within 6-36 months after primary treatment. Samples were assessed for immunohistochemical expression of vascular endothelial growth factor (VEGF) A and VEGF receptor 2 (VEGFR2). Expression profiles of VEGFA and VEGFR2 were compared between the two groups.

Results: Significant correlation between VEGFA and VEGFR2 expression was observed (p < 0.0001, Spearman coefficient 0.347). A high expression of VEGFR2 (VEGFR2) was found more frequently in long-term survivors (77.4%, 48/62) than in controls (51.6%, 30/62, p = 0.001), independent of FIGO stage and VEGFA expression in multivariate analysis (p = 0.005). Also, VEGFR2 was found the most frequently in women with PFS ≥ 10 years (p = 0.001) among all 124 patients. However, no significant association was detected between VEGFA expression and 5-year PFS (p = 0.075).

Conclusions: VEGFR2 overexpression significantly correlated with long-term PFS in HGSOC patients, independent of age, FIGO stage, tumor residual and VEGFA expression.
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http://dx.doi.org/10.1007/s00432-019-02877-4DOI Listing
April 2019

Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial.

Lancet Oncol 2019 03 8;20(3):383-393. Epub 2019 Feb 8.

Department of Oncology, Phase 1 Unit, Rigshospitalet, Copenhagen, Denmark.

Background: Tisotumab vedotin is a first-in-human antibody-drug conjugate directed against tissue factor, which is expressed across multiple solid tumour types and is associated with poor clinical outcomes. We aimed to establish the safety, tolerability, pharmacokinetic profile, and antitumour activity of tisotumab vedotin in a mixed population of patients with locally advanced or metastatic (or both) solid tumours known to express tissue factor.

Methods: InnovaTV 201 is a phase 1-2, open-label, dose-escalation and dose-expansion study done at 21 centres in the USA and Europe. Patients (aged ≥18 years) had relapsed, advanced, or metastatic cancer of the ovary, cervix, endometrium, bladder, prostate, oesophagus, squamous cell carcinoma of the head and neck or non-small-cell lung cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and had relapsed after or were not eligible to receive the available standard of care. No specific tissue factor expression level was required for inclusion. In the dose-escalation phase, patients were treated with tisotumab vedotin between 0·3 and 2·2 mg/kg intravenously once every 3 weeks in a traditional 3 + 3 design. In the dose-expansion phase, patients were treated at the recommended phase 2 dose. The primary endpoint was the incidence of adverse events, including serious adverse events, infusion-related, treatment-related and those of grade 3 or worse, and study drug-related adverse events, analysed in all patients who received at least one dose of tisotumab vedotin (full analysis population). This trial is registered with ClinicalTrials.gov, number NCT02001623, and is closed to new participants with follow-up ongoing.

Findings: Between Dec 9, 2013, and May 18, 2015, 27 eligible patients were enrolled to the dose-escalation phase. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2·2 mg/kg dose; therefore, 2·0 mg/kg of tisotumab vedotin intravenously once every 3 weeks was established as the recommended phase 2 dose. Between Oct 8, 2015, and April 26, 2018, 147 eligible patients were enrolled to the dose-expansion phase. The most common (in ≥20% of patients) treatment-emergent adverse events of any grade were epistaxis (102 [69%] of 147 patients), fatigue (82 [56%]), nausea (77 [52%]), alopecia (64 [44%]), conjunctivitis (63 [43%]), decreased appetite (53 [36%]), constipation (52 [35%]), diarrhoea (44 [30%]), vomiting (42 [29%]), peripheral neuropathy (33 [22%]), dry eye (32 [22%]), and abdominal pain (30 [20%]). The most common adverse events of grade 3 or worse were fatigue (14 [10%] of 147 patients), anaemia (eight [5%]), abdominal pain (six [4%]), hypokalaemia (six [4%]), conjunctivitis (five [3%]), hyponatraemia (five [3%]), and vomiting (five [3%]). 67 (46%) of 147 patients had a treatment-emergent serious adverse event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. Infusion-related reactions occurred in 17 (12%) of 147 patients. Across tumour types, the confirmed proportion of patients who achieved an objective response was 15·6% (95% CI 10·2-22·5; 23 of 147 patients). There were nine deaths across all study phases (three in the dose-escalation phase and six in the dose-expansion phase); only one case of pneumonia in the dose-expansion phase was considered possibly related to study treatment.

Interpretations: Tisotumab vedotin has a manageable safety profile with encouraging preliminary antitumour activity across multiple tumour types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumours.

Funding: Genmab A/S.
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http://dx.doi.org/10.1016/S1470-2045(18)30859-3DOI Listing
March 2019

Polymer-Ligand-Based ELISA for Robust, High-Throughput, Quantitative Detection of p53 Aggregates.

Anal Chem 2018 11 29;90(22):13273-13279. Epub 2018 Oct 29.

Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center - Gynecologic Cancer Unit , Medical University of Vienna , Waehringer Guertel 18-20 , 1090 Vienna , Austria.

A growing number of diseases are being linked to protein misfolding and amyloid formation. Recently, p53 was also shown to associate into amyloid aggregates, raising the question of whether cancer development is associated with protein aggregation as well. However, a lack of suitable tools has hampered the evaluation of their clinical relevance. Herein, we report an enzyme-linked-immunosorbent-assay (ELISA) system based on a polyionic, high-molecular-weight ligand that specifically captures aggregated oligomers and amyloid proteins. We proved that naturally occurring tetramers of p53 are not bound, but high-molecular-weight aggregates are bound and subsequently detected. For the first time, this assay allows the quantitative detection of p53 aggregates from cell lysates, which was demonstrated using 22 ovarian-cancer cell lines as well as 7 patient-derived tumor tissues. The levels of p53 aggregates within the missense-mutated tissue samples varied more than 12-fold. This simple, robust method allows studying the abundance and clinical relevance of protein aggregates. This could help our understanding of the role of protein misfolding in cancer or even in predicting therapy responses to aggregation-targeting drugs.
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http://dx.doi.org/10.1021/acs.analchem.8b02373DOI Listing
November 2018

Correction: Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells.

Cell Death Differ 2019 Mar;26(4):780

Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen, D-37077, Germany.

Since publication of this article, the authors reported that the online version is missing the links to most of the Supplementary data, specifically, Supplementary Figures S1-S9; Supplementary Table S1; all legends to Supplementary Material.
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http://dx.doi.org/10.1038/s41418-018-0190-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460385PMC
March 2019

The genetic landscape of 87 ovarian germ cell tumors.

Gynecol Oncol 2018 10 28;151(1):61-68. Epub 2018 Aug 28.

Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; Division of Gynaecological Oncology, Leuven Cancer Institute, Kuleuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address:

Background: Ovarian germ cell tumors (OGCT) are rare gynecological neoplasms, mostly affecting children and young women. The underlying molecular genetic background of these tumors is poorly characterized.

Methods: We analyzed somatic copy number aberration (CNA) profiles in 87 OGCT tumors and performed whole exome sequencing (WES) on 24 OGCT tumor and matched germline samples to further elucidate their molecular genetic landscape.

Results: The overall mutation rate was very low in OGCT compared to other human cancers, with an average of 0.05 mutations per Mb, consistent with their embryological origin. We identified recurrent mutations in KIT and KRAS, while CNA profiling revealed frequent focal amplifications affecting PIK3CA and AKT1 in yolk sac tumors, recurrent focal deletions affecting chromosomal regions 1p36.32, 2q11.1, 4q28.1, 5p15.33, 5q11.1 and 6q27, as well as gains in chromosome 12p that were present in all tumors, except for pure immature teratomas.

Conclusion: We here present the first whole exome sequencing data and to our knowledge the largest CNA study in OGCT. We confirmed that earlier reported KIT mutations were frequent in dysgerminomas and mixed forms with a dysgerminoma component, whereas chromosome 12p gains were present in all histological subtypes except pure immature teratomas. We detected recurrent KRAS mutations, recurrent focal deletions and an enrichment in the PI3K/AKT/PTEN pathway in yolk sac tumors. Several of these aberrations involve targetable pathways, offering novel treatment modalities for OGCT.
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http://dx.doi.org/10.1016/j.ygyno.2018.08.013DOI Listing
October 2018

Tumor Treating Fields in combination with paclitaxel in recurrent ovarian carcinoma: Results of the INNOVATE pilot study.

Gynecol Oncol 2018 09 27;150(3):471-477. Epub 2018 Jul 27.

Oncology Institute of Southern, Switzerland, Bellinzona.

Background: Tumor Treating Fields (TTFields) are an anti-mitotic therapy comprising continuous delivery of low-intensity alternating electric fields at intermediate frequencies to the tumor region by a home-use medical device.

Methods: The INNOVATE (EF-22) Study was a phase 2, single arm clinical trial, which tested the safety and efficacy of TTFields (200 kHz) in combination with weekly paclitaxel (weekly for 8 weeks and then on days 1, 8, 15 of each subsequent 28 day-cycle; starting dose 80 mg/m) in 31 patients with recurrent, platinum-resistant ovarian carcinoma. The primary endpoint was safety and secondary endpoints included OS, PFS and RR.

Results: Median age was 60 (range: 45-77), 24 patients (77%) had serous histology, 16 patients (52%) ECOG score 0 and 15 (48%) ECOG 1, the median number of prior chemotherapy lines was 4 (range: 1-11). All patients received prior platinum-based chemotherapy and 30 (97%) received prior taxanes. No serious adverse events related to TTFields were reported. There was no increase in grade 3-4 adverse events compared to the frequency of such events reported in the literature with single agent weekly paclitaxel. Twenty-six patients (84%) had the expected TTFields-related dermatitis but only one patient permanently discontinued TTFields due to dermatitis. The median PFS was 8.9 months, 7 patients (25%) had partial response and the clinical benefit rate was 71%. The median overall survival was not reached: the one-year survival rate was 61%.

Conclusion: TTFields combined with weekly paclitaxel were safe in platinum-resistant recurrent ovarian cancer and warrants evaluation in a randomized phase 3 trial.
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http://dx.doi.org/10.1016/j.ygyno.2018.07.018DOI Listing
September 2018

Morphology and tumour-infiltrating lymphocytes in high-stage, high-grade serous ovarian carcinoma correlated with long-term survival.

Histopathology 2018 Dec 7;73(6):1002-1012. Epub 2018 Oct 7.

Tumorbank Ovarian Cancer Network, Berlin, Germany.

Aims: Advanced-stage ovarian high-grade serous carcinoma (HGSC) is a poor-prognosis cancer; however, a small and poorly characterised subset of patients shows long-term survival. We aimed to establish a cohort of HGSC long-term survivors for histopathological and molecular analysis.

Methods And Results: Paraffin blocks from 151 patients with primary FIGO III/IV HGSC and progression-free survival (PFS) >5 years were collected within the Tumorbank Ovarian Cancer (TOC) Network; 77 HGSC with a PFS <3 years were used as a control group. A standardised analysis of histological type and morphological features was performed. Ki67 index, tumour-infiltrating lymphocytes (TILs) and major histocompatibility complex expression (MHC1/2) were determined by immunohistochemistry. A total of 117 of 151 tumours (77.5%) in the long-term survivor group fulfilled the World Health Organisation (WHO) criteria of HGSC after review, and of these, 83 patients (70.9%) fulfilled all clinical criteria for inclusion into our cohort. Tumours of long-term survivors had significantly higher CD3 and CD8 TILs and were more frequently positive for MHC2 than controls (P = 0.004, P = 0.025, P = 0.048). However, there were also long-term survivors (up to 20%) with low TILs or low MHC expression. TILs and MHC had no impact on survival in long-term survivors. Morphological and Ki67 analysis revealed no differences between long-term survivors and controls.

Conclusions: HGSC from long-term survivors have higher-level T cell infiltration and antigen-presentation capacity; however, this is not a prerequisite for an excellent prognosis. Histopathological criteria are not capable to identify these patients. Further extensive clinical and molecular characterisation of this enigmatic subgroup is ongoing to understand the reasons of long-term survival in HGSC.
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http://dx.doi.org/10.1111/his.13711DOI Listing
December 2018

AB0 blood groups and rhesus factor expression as prognostic parameters in patients with epithelial ovarian cancer - a retrospective multi-centre study.

BMC Cancer 2018 04 19;18(1):447. Epub 2018 Apr 19.

Department of Gynaecology and Obstetrics, Medical University of Innsbruck, Innrain 52, Christoph-Probst-Platz, 6010, Innsbruck, Austria.

Background: AB0 blood groups and Rhesus factor expression have been associated with carcinogenesis, response to treatment and tumor progression in several malignancies. The aim of the present study was to test the hypothesis that AB0 blood groups and Rhesus factor expression are associated with clinical outcome in patients with epithelial ovarian cancer (EOC).

Methods: AB0 blood groups and Rhesus factor expression were evaluated in a retrospective multicenter study including 518 patients with EOC. Their association with patients' survival was assessed using univariate and multivariable analyses.

Results: Neither AB0 blood groups nor Rhesus factor expression were associated with clinico-pathological parameters, recurrence-free, cancer-specific, or overall survival. In a subgroup of patients with high-grade serous adenocarcinoma, however, blood groups B and AB were associated with a better 5-year cancer-specific survival rate compared to blood groups A and 0 (60.3 ± 8.6% vs. 43.8 ± 3.6%, p = 0.04). Yet, this was not significant in multivariable analysis.

Conclusions: AB0 blood groups and Rhesus factor expression are both neither associated with features of biologically aggressive disease nor clinical outcome in patients with EOC. Further investigation of the role of the blood group B antigen on cancer-specific survival in the subgroup of high-grade serous should be considered.
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http://dx.doi.org/10.1186/s12885-018-4289-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909228PMC
April 2018

Immunobiochemical pathways of neopterin formation and tryptophan breakdown via indoleamine 2,3-dioxygenase correlate with circulating tumor cells in ovarian cancer patients- A study of the OVCAD consortium.

Gynecol Oncol 2018 05 9;149(2):371-380. Epub 2018 Mar 9.

Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center - Gynecologic Cancer Unit, Medical University of Vienna, Vienna, Austria. Electronic address:

Objective: Circulating tumor cells (CTCs) may represent a chronic stimulus for the immune system. In the present study we investigated the potential association of CTCs, the immune activation marker neopterin, and the ratio of kynurenine to tryptophan (Kyn/Trp) as a measure for tryptophan breakdown.

Methods: Neopterin, tryptophan and kynurenine levels were measured in plasma samples from patients with benign gynecological diseases (n=65) and with primary advanced epithelial ovarian cancer (EOC) at diagnosis (n=216) and six months after adjuvant platinum-based chemotherapy (n=45) by an enzyme-linked immunosorbent assay and high performance liquid chromatography. The presence of CTCs had been assessed in a previous study by qPCR-based analysis of CTC-related transcripts in the blood. The respective plasma levels in EOC and benign samples were compared using a two-tailed Chi or Fisher's exact test. The associations of the analytes and Kyn/Trp with clinicopathological parameters, platinum-sensitivity, and the presence of CTC-related transcripts were assessed using a two-sided t-test. Associations with patient outcome were evaluated using Cox regression analysis.

Results: In EOC, elevated Kyn/Trp and neopterin levels were associated with advanced disease, peritoneal carcinomatosis, ascites, sub-optimal debulking, poor response to therapy and worse outcome. Likewise, neopterin and Kyn/Trp were elevated in CTC-positive patients, both at diagnosis and at follow-up in platinum-sensitive disease.

Conclusions: We observed concomitant alterations of CTCs and immune system related biomarkers suggesting that immune responses along with increase of neopterin and Kyn/Trp concentrations are not necessarily only located at the site of the tumor, but may also go on in the circulation.
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http://dx.doi.org/10.1016/j.ygyno.2018.02.020DOI Listing
May 2018

The relative risk of second primary cancers in Austria's western states: a retrospective cohort study.

BMC Cancer 2017 Oct 24;17(1):699. Epub 2017 Oct 24.

Department of Clinical Epidemiology of the Tyrolean State Hospitals Ltd, Cancer Registry of Tyrol, Tirolkliniken GmbH, Innsbruck, Austria.

Background: Cancer survivors are at risk of developing a second primary cancer (SPC) later in life because of persisting effects of genetic and behavioural risk factors, the long-term sequelae of chemotherapy, radiotherapy and the passage of time. This is the first study with Austrian data on an array of entities, estimating the risk of SPCs in a population-based study by calculating standardized incidence ratios (SIRs).

Methods: This retrospective cohort study included all invasive incident cancer cases diagnosed within the years 1988 to 2005 being registered in the Tyrol and Vorarlberg Cancer Registries. Person years at risk (PYAR) were calculated from time of first diagnosis plus 2 months until the exit date, defined as the date of diagnosis of the SPC, date of death, or end of 2010, whichever came first. SIR for specific SPCs was calculated based on the risk of these patients for this specific cancer.

Results: A total of 59,638 patients were diagnosed with cancer between 1988 and 2005 and 4949 SPCs were observed in 399,535 person-years of follow-up (median 5.7 years). Overall, neither males (SIR 0.90; 95% CI 0.86-0.93) nor females (SIR 1.00; 95% CI 0.96-1.05) had a significantly increased SIR of developing a SPC. The SIR for SPC decreased with age showing a SIR of 1.24 (95% CI 1.12-1.35) in the age group of 15-49 and a SIR of 0.85 (95% CI 0.82-0.89) in the age group of ≥ 65. If the site of the first primary cancer was head/neck/larynx cancer in males and females (SIR 1.88, 95% CI 1.67-2.11 and 1.74, 95% CI 1.30-2.28), cervix cancer in females (SIR 1.40, 95% CI 1.14-1.70), bladder cancer in males (SIR 1.20, 95% CI 1.07-1.34), kidney cancer in males and females (SIR 1.22, 95% 1.04-1.42 and 1.29, 95% CI 1.03-1.59), thyroid gland cancer in females (SIR 1.40, 95% CI 1.11-1.75), patients showed elevated SIR, developing a SPC.

Conclusions: Survivors of head & neck, bladder/kidney, thyroid cancer and younger patients show elevated SIRs, developing a SPC. This has possible implications for surveillance strategies.
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http://dx.doi.org/10.1186/s12885-017-3683-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655958PMC
October 2017