Importance of pathological review of gestational trophoblastic diseases: results of the Belgian Gestational Trophoblastic Diseases Registry.

OBJECTIVE: To evaluate the added value of a centralized pathology review of the diagnoses of gestational trophoblastic diseases by expert pathologists and its potential impact on clinical management in a prospective multicenter study based on the Belgian Gestational Trophoblastic Diseases Registry. METHODS: From July 2012 to December 2020, the two referral centers of the registry were solicited to advise on 1119 cases. Referral pathologists systematically reviewed all of the initial histological diagnoses. Cases initially assessed by expert pathologists were excluded. A total of 867 files were eligible for the study. Concordance between diagnoses of gestational trophoblastic diseases made by general 'non-expert' and expert pathologists was analyzed together with the potential impact of the alterations on clinical management. Expert pathologists were working in an academic setting with high exposure to placental pathology and national recognition. RESULTS: The rate of discordance between expert and non-expert pathologists for the initial diagnoses was 35%. Almost 95% of complete moles were confirmed by the expert pathologists, but only 61% for partial moles. Compared with previous studies, ancillary techniques (p57 immunohistochemistry, karyotype) were used twice as often by both groups of pathologists in this survey. The diagnosis of gestational trophoblastic neoplasia was altered in 42% of cases. When the initial diagnosis was altered, the clinical relevance of this correction was estimated as down staging, up staging, or not relevant in 65%, 33% and 2% of cases respectively. CONCLUSION: Systematic centralized pathological review of gestational trophoblastic diseases modified the diagnosis in a third of cases. The results also show that a change in diagnosis would impact clinical management in 98% of patients.

Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways.

Uterine leiomyosarcomas (uLMS) are rare, aggressive malignancies for which limited treatment options are available. To gain novel molecular insights into uLMS and identify potential novel therapeutic targets, we characterized 84 uLMS samples for genome-wide somatic copy number alterations, mutations, gene fusions and gene expression and performed a data integration analysis. We found that alterations affecting TP53, RB1, PTEN, MED12, YWHAE and VIPR2 were present in the majority of uLMS. Pathway analyses additionally revealed that the PI3K/AKT/mTOR, estrogen-mediated S-phase entry and DNA damage response signaling pathways, for which inhibitors have already been developed and approved, frequently harbored genetic changes. Furthermore, a significant proportion of uLMS was characterized by amplifications and overexpression of known oncogenes (CCNE1, TDO2), as well as deletions and reduced expression of tumor suppressor genes (PTEN, PRDM16). Overall, it emerged that the most frequently affected gene in our uLMS samples was VIPR2 (96%). Interestingly, VIPR2 deletion also correlated with unfavorable survival in uLMS patients (multivariate analysis; HR = 4.5, CI = 1.4-14.3, p = 1.2E-02), while VIPR2 protein expression was reduced in uLMS vs. normal myometrium. Moreover, stimulation of VIPR2 with its natural agonist VIP decreased SK-UT-1 uLMS cell proliferation in a dose-dependent manner. These data suggest that VIPR2, which is a negative regulator of smooth muscle cell proliferation, might be a novel tumor suppressor gene in uLMS. Our work further highlights the importance of integrative molecular analyses, through which we were able to uncover the genes and pathways most frequently affected by somatic alterations in uLMS.

The genetic landscape of 87 ovarian germ cell tumors.

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.

Diffusely Metastasized Adenocarcinoma Arising in a Mucinous Carcinoid of the Ovary: A Case Report.

Mucinous (goblet cell) carcinoids are a rare type of ovarian carcinoid tumors. Only a limited number of primary mucinous carcinoids of the ovary have been reported in the literature. We describe the case of a 55-year-old woman with a diffusely metastasized adenocarcinoma arising in a primary ovarian mucinous carcinoid. The differential diagnosis with a metastatic goblet cell carcinoid from the appendix or elsewhere can be very challenging. In our case, especially the immunohistochemical profile of the tumor with diffuse positivity for cytokeratin 7 and PAX8, and no expression of cytokeratin 20 and CDX2, directed us toward a primary ovarian origin. Expression of PAX8 in ovarian mucinous carcinoid has never been reported before.

Human Chorionic Gonadotropin Regression Curves after Partial or Complete Molar Pregnancy in Flanders: Are They Different from Regression Curves from the Eighties?

BACKGROUND/AIMS: We updated human chorionic gonadotropin (hCG) regression curves created in the eighties after evacuation of complete and partial molar (CM and PM, respectively) pregnancies using modern hCG assays. We created similar curves for patients in need of chemotherapy (gestational trophoblastic neoplasia [GTN]). METHODS: A total of 126 patients who were diagnosed with gestational trophoblastic disease from 1990 to 2014 were included. We compared curves from 2 groups, CM and PM, with historical ones. The third group was a comparison of GTN patients receiving first-line chemotherapy and patients in need of a switch of chemotherapy. RESULTS: The regression curves were comparable to historical ones. According to the latter, mean time to normalization was 14-15 weeks after evacuation. We observed a normalization within 12 (CM) and 12.7 (PM) weeks. In addition, a remarkable but not statistically significant vertical shift (20 IU/L higher) was observed prior to day 60 compared with historical curves. The comparison in GTN patients showed a statistical significant difference, even at day 7. CONCLUSION: The presented hCG regression curves in the Flemish region were comparable with the ones of the eighties but with a vertical shift, hypothetically due to more sensitive assays. In addition, regression curves in GTN patients receiving chemotherapy can be used to evaluate response.

Staging with Unilateral Salpingo-Oophorectomy and Expert Pathological Review Result in No Recurrences in a Series of 81 Intestinal-Type Mucinous Borderline Ovarian Tumors.

OBJECTIVE: Recent studies suggest that mucinous borderline ovarian tumors (MBOTs) belong to a high-risk group that is more likely to develop an invasive recurrence. The objective is to determine these risk factors. METHODS: A monocentric retrospective review of all consecutive patients with intestinal-type MBOT diagnosed between 1993 and 2013. All tumors were evaluated by one pathologist without knowledge of clinical outcome. Extensive surgical staging and pathological tumor sampling (1 block/cm diameter in tumors <10 cm and 2 blocks/cm diameter in tumors >10 cm) were performed in all cases. RESULTS: A total of 81 patients were included. Patients with micro-invasion were also included. None of the patients recurred. No bilateral tumors, nor tumors with International Federation of Gynecology and Obstetrics stage II or higher, were diagnosed. Median follow-up was 87 months. CONCLUSIONS: In our series of pure intestinal-type MBOT, including micro-invasion, no recurrences were observed. Given the heterogeneity of these tumors staging with at least unilateral salpingo-oophorectomy, extensive pathological sampling, and expert pathological review are of paramount importance to be able to diagnose a pure intestinal-type MBOT and excluding gastrointestinal mucinous tumors and more important, excluding an invasive focus, defining a mucinous ovarian carcinoma. When these conditions are fulfilled, the prognosis of pure intestinal-type MBOT is excellent.

Establishment and characterization of uterine sarcoma and carcinosarcoma patient-derived xenograft models.

OBJECTIVE: Uterine sarcomas (US) and carcinosarcomas (CS) are rare, aggressive cancers. The lack of reliable preclinical models hampers the search for new treatment strategies and predictive biomarkers. To this end, we established and characterized US and CS patient-derived xenograft (PDX) models. METHODS: Tumor fragments of US and CS were subcutaneously implanted into immunocompromised mice. Engrafted xenograft and original tumors were compared by means of histology, immunohistochemistry, whole-genome low-coverage sequencing for copy number variations, and RNA sequencing. RESULTS: Of 13 implanted leiomyosarcomas (LMS), 10 engrafted (engraftment rate of 77%). Also 2 out of 7 CS (29%) and one high-grade US (not otherwise specified) models were successfully established. LMS xenografts showed high histological similarity to their corresponding human tumors. Expression of desmin and/or H-caldesmon was detected in 8/10 LMS PDX models. We noticed that in CS models, characterized by the concomitant presence of a mesenchymal and an epithelial component, the relative distribution of the components is varying over the generations, as confirmed by changes in vimentin and cytokeratin expression. The similarity in copy number profiles between original and xenograft tumors ranged from 57.7% to 98.2% for LMS models and from 47.4 to 65.8% for CS models. Expression pattern stability was assessed by clustering RNA expression levels of original and xenograft tumors. Six xenografts clustered together with their original tumor, while 3 (all LMS) clustered apart. CONCLUSIONS: We present here a panel of clinically annotated uterine sarcoma and carcinosarcoma PDX models, which will be a useful tool for preclinical testing of new therapies.

Neoadjuvant Weekly Paclitaxel-Carboplatin Is Effective in Stage I-II Cervical Cancer.

OBJECTIVE: Neoadjuvant chemotherapy (NACT) followed by surgery in cervical cancer is widely studied with paclitaxel-ifosfamide-cisplatinum 3 weekly (TIP). Although the response rates with TIP are high, the toxicity is substantial. Therefore, this study evaluates dose-dense paclitaxel-carboplatin (TC) as an alternative. METHODS: In this prospective phase 2 study trial, we included 36 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB1 to IIB cervical cancer, who received 9 weeks' NACT dose-dense TC (median weekly dose paclitaxel 60 mg/m, carboplatinum area under the curve 2.7). Radiological response was evaluated by RECIST (Response Evaluation Criteria in Solid Tumors). Optimal pathologic response (OPT) was defined as complete disappearance of tumor (complete response [CR]) or residual disease with less than 3-mm stromal invasion (PR1). Suboptimal pathologic response consisted of persistent residual disease with more than 3-mm stromal invasion (PR2). RESULTS: Nine patients had a FIGO stage IB1 (25%), 7 had stage IB2(19%), 3 had stage IIA (8%), and 17 had stage IIB disease (47%). Evaluation by magnetic resonance imaging after NACT showed 32 RECIST responses (89%) (CR in 11, PR in 21). Patients who were inoperable had insufficient reduction of the tumor to be operable (4 patients), progressive disease (1 patient), or stable disease (1 patient). Thirty patients were suitable for surgery after NACT. Pathology showed OPT in 50% (CR in 10, PR1 in 5). Thirteen patients had pathologic lymph nodes on radiological evaluation before start of chemotherapy. After chemotherapy, the lymph nodes were negative in 6 (47%) of these patients (pathologic complete remission). Postoperative chemoradiotherapy was administered in 11 patients (2 because of close resection margins, 5 because of metastatic lymph node after surgery, 2 because of close resection margins and metastatic lymph nodes after surgery, and 1 tumor >4 cm after NACT). Hematologic toxicity was acceptable with no febrile neutropenia and a low nonhematologic toxicity. The estimated 5-year overall survival was 70.8%. CONCLUSIONS: Neoadjuvant TC dose-dense in cervical carcinoma has a high response rate, comparable with TIP, and an acceptable toxicity.

Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes.

BACKGROUND: Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene. METHODS: Exome sequencing was performed in 145 patients with Joubert syndrome (JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes. RESULTS: We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy (JATD). The CEP120-associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype. CONCLUSION: Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies.

Fertility Preservation Is Safe for Serous Borderline Ovarian Tumors.

OBJECTIVES: This study aimed to determine the overall survival (OS) and progression-free interval and the influence of fertility-preserving surgery (FPS) versus radical surgery (RS) in patients with serous borderline ovarian tumor (BOT). METHODS: Clinical parameters of patients with serous BOT treated between 1993 and 2013 in one institution were retrospectively investigated. All tumors were examined by one pathologist with experience in gynecological pathology. RESULTS: One hundred thirty-two patients with serous BOT (inclusive 16 microinvasive) were analyzed (45% were ≤40 years), with a median follow-up of 6 years. Thirty-two percent (42/132) of the patients received FPS; 14% (18/132) relapsed (invasive or borderline). The 5-year progression-free survival was 89%. The risk of recurrence was higher in patients 40 years or younger (P = 0.019), after FPS (P = 0.002), in patients with a higher International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.016), for bilateral BOT (P = 0.0132), and for the micropapillary variant (P = 0.067). The OS at 5 years was 97%. There was no statistically significant difference in OS between FPS and RS [all (6 of 90) patients, except for 1, with RS died]. One patient died of relapsed BOT. Among the recurrences, low-grade invasive carcinoma was diagnosed in 4 patients. Three of these 4 patients were originally operated radically, 2 had a micropapillary variant FIGO stage III, and 1 had a papillary pattern FIGO stage II with microinvasion; all 3 had noninvasive implants and are alive. One patient with a micropapillary variant, FIGO stage IIIC with microinvasion and invasive implants, received FPS and died of disease. CONCLUSIONS: The risk of recurrence is higher after FPS compared with RS; however, no influence on OS was observed. This was because most of the patients relapsed as BOT. Fertility preservation is justified in young patients with serous borderline tumors.

Choriocarcinoma in Situ in a Partial Hydatidiform Mole A: Case Report.

BACKGROUND: Choriocarcinoma most frequently arises in a complete hydatidiform mole. Less common are cases following a normal pregnancy or a nonmolar abortion. Its occurrence after a partial hydatidiform mole is extremely rare. CASE REPORT: Here we report a choriocarcinoma in situ diagnosed after dilation and curettage for a first tri- mester partial hydatidiform mole. The diagnosis was con- firmed by immunohistochemistry, fluorescent in situ hybridization, and microsatellite instability genotyping of the products of conception and blood of the mother and father. We demonstrated a diandric triploidy. At the time of diagnosis CT scan showed lung metastasis. The pa- tient was classified as high-risk gestational trophoblas- tic neoplasia and treated with high-dose methotrexate- etoposide. CONCLUSION: This is the first reported case of a cho- riocarcinoma arising in a first trimester partial mol.

Neoadjuvant chemotherapy followed by large cone resection as fertility-sparing therapy in stage IB cervical cancer.

BACKGROUND: Standard treatment of cervical cancer FIGO stage IB1 is a radical hysterectomy with pelvic lymphadenectomy. As the number of patients with a preserved fertility wish has increased, the need for fertility sparing surgery emerges. In this study we discuss 11 patients with cervical carcinoma stage IB treated with neoadjuvant chemotherapy followed by large cone resection. METHODS: In this retrospective study we included 10 patients with FIGO stage IB1 and 1 patient with IB2 cervical cancer, who first received a pelvic lymphadenectomy followed by neoadjuvant chemotherapy and conization. Paclitaxel-ifosfamide-carboplatin or a combination of paclitaxel-carboplatin was used as neoadjuvant chemotherapy. RESULTS: Complete response after chemotherapy was observed in 64%, partial response in 27% and 9% had progressive disease. All patients with response underwent a conization, with no residual disease on pathology in 80%. Patients with residual disease were treated by radical hysterectomy. In 9 patients fertility sparing surgery could be performed and 6 (67%) got pregnant. Five patients had 7 children and two patients had four missed abortions. Two premature deliveries at 32 and 33weeks were described, both in the same patient. Recurrence was observed in one patient that was treated with simple hysterectomy followed by radiochemotherapy. Median follow up time is 58months with all patients alive and no evidence of disease until now. CONCLUSIONS: Neoadjuvant chemotherapy followed by conization seems to be a promising new fertility sparing treatment modality in patients with cervical carcinoma stage IB1, but further studies with larger populations should confirm these data.

Para-aortic lymph node metastases in locally advanced cervical cancer: Comparison between surgical staging and imaging.

OBJECTIVE: Compare surgical staging with imaging (PET-CT, PET or CT) of the para-aortic lymph nodes (PAOLN) in locally advanced cervical cancer (LACC). METHODS: Monocentric retrospective study of 336 patients with cervical cancer FIGO stage IB2-IVA. All patients underwent staging of the PAOLN using imaging by PET-CT, PET or CT. Two hundred and four patients with normal or not overtly malignant PAOLN on imaging underwent surgical PAOLN staging up to the inferior mesenteric artery (189 endoscopy and 15 laparotomy). RESULTS: The patients were divided into 4 groups: 16 with positive surgical staging and negative PAOLN imaging (sPAOLN+), 172 negative surgical staging (sPAOLN-), 20 positive imaging without surgical staging (iPAOLN+) and 128 negative imaging without surgical staging (iPAOLN-). Median operative time of staging was 70 (40-160) min and median number of removed PAOLN was 5 (0-24). Operative complications were 10 peroperative bleedings, 2 ureteral traumas, 1 carbon dioxide retention and 1 retroperitoneal abscess. The median follow-up was 31 (1-218) months. Overall survival at 2 years was for sPAOLN+, sPAOLN-, iPAOLN+, and iPAOLN- 40%, 83%, 58%, and 69%, respectively (p<0.001 for sPAOLN+ and iPAOLN+ versus sPAOLN- and iPAOLN-). The most frequent site of recurrence was distant LN metastases (outside the pelvic and PAO area) (36%) for sPAOLN+. For sPAOLN-, iPAOLN+, and iPAOLN- the most frequent site of recurrence was the cervix (27%, 66% and 26%, respectively). CONCLUSION: Despite negative imaging, PAOLN metastases were present in 8% at surgical staging. Overall survival is significantly influenced by the presence of PAOLN metastases.

Characterization of patient-derived tumor xenograft models of endometrial cancer for preclinical evaluation of targeted therapies.

OBJECTIVE: Endometrial carcinoma (EC) is the sixth most common cancer in women and therapies are limited for advanced and recurrent disease. Patient-derived tumor xenograft (PDTX) models are becoming popular tools in translational research because of their histological and genetic similarity to the original tumors and the ability to predict therapeutic response to treatments. Here, we established and characterized a panel of 24 EC PDTX models which includes the major histological and genetic subtypes observed in patients. METHODS: Fresh tumor tissues collected from primary, metastatic and recurrent type I and type II EC patients were engrafted in immunocompromised mice. Histology, vimentin, and cytokeratin expression were evaluated, together with Microsatellite instability (MSI), mutation profiling by Whole Exome Sequencing and copy number profiling by Whole Genome Low Coverage Sequencing. The efficacy of both PI3K and MEK inhibitors was evaluated in a model of endometrioid carcinoma harboring PTEN, PIK3CA and KRAS mutations. RESULTS: We observed good similarity between primary tumors and the corresponding xenografts, at histological and genetic level. Among the engrafted endometrioid models, we found a significant enrichment of MSI and POLE mutated tumors, compared to non-engrafted samples. Combination treatment with NVP-BEZ235 and AZD6244 showed the possibility to stabilize the tumor growth in one model originated from a patient who already received several lines of chemotherapy. CONCLUSION: The established EC PDTX models, resembling the original human tumors, promise to be useful for preclinical evaluation of novel combination and targeted therapies in specific EC subgroups.

Termination of pregnancy for renal malformations.

BACKGROUND: We studied the correlation between prenatal diagnosis and postmortem investigations in pregnancies terminated for renal malformations. METHODS: Over a 5-year period, 77 cases of termination of pregnancy (TOP) for renal malformations were reviewed. Chromosomal anomalies (n = 9) and cases without conventional or virtual autopsy were excluded (n = 15). In 53 cases, prenatal ultrasound diagnosis and conventional autopsy findings were compared. In addition, we compared the accuracy of conventional and virtual autopsy findings in 17 cases. RESULTS: Full agreement was observed in 60.4% (32/53) of cases. In 26.4% (14/53) of the cases, the presence of additional malformations did not alter the final diagnosis. However, in 11.3% (6/53) the final diagnosis was adjusted because of major additional findings. One case showed a total disagreement. Conventional and virtual autopsy were in full agreement in 52.9% (9/17). Postmortem magnetic resonance imaging (MRI) description and detection of malformations was less complete and failed to correctly diagnose 5/17 cases (29.4%). In 17.6% (3/17) of the cases, postmortem MRI revealed malformations not confirmed by conventional autopsy. CONCLUSIONS: A high correlation between prenatal ultrasound and postmortem investigations was observed. Conventional autopsy remains the gold standard to reveal additional major and minor malformations, leading to a correct final diagnosis. The added value of virtual necropsy for renal pathology was limited.

Identification of a novel, recurrent MBTD1-CXorf67 fusion in low-grade endometrial stromal sarcoma.

Endometrial stromal sarcomas (ESSs) are a genetically heterogeneous group of rare uterine neoplasms that are commonly driven by recurrent gene rearrangements. In conventional low-grade ESS, JAZF1-SUZ12, PHF1-JAZF1, EPC1-PHF1 and MEAF6-PHF1, and recently described ZC3H7-BCOR chimeric fusions have been reported in > 50% of cases. Conversely, oncogenic t(10;17)(q22;p13) translocation yields YWHAE-FAM22A/B chimeric proteins that are associated with histologically high-grade and clinically more aggressive ESS. Integrating whole-transcriptome paired-end RNA sequencing with fluorescence in situ hybridization (FISH) and banding cytogenetics, we identified MBTD1 (malignant brain tumor domain-containing 1) and CXorf67 (chromosome X open reading frame 67) as the genes involved in the novel reciprocal t(X;17)(p11.2;q21.33) translocation in two independent low-grade ESS of classical histology. The presence of the MBTD1-CXorf67 fusion transcript was validated in both cases using reverse-transcription polymerase chain reaction followed by Sanger sequencing. A specific FISH assay was developed to detect the novel t(X;17) translocation in formalin-fixed paraffin-embedded material, and resulted in identification of an additional low-grade ESS case positive for the MBTD1-CXorf67 fusion among 25 uterine stromal tumors [14 ESS and 11 undifferentiated endometrial sarcomas (UESs)] that were negative for JAZF1 and YWHAE rearrangements. Gene expression profiles of seven ESS (including three with YWHAE and two with JAZF1 rearrangements) and four UES without specific chromosomal aberrations indicated clustering of tumors with MBTD1-CXorf67 fusion together with low-grade JAZF1-associated ESS. The chimeric MBTD1-CXorf67 fusion identifies yet another cytogenetically distinct subgroup of low-grade ESS and offers the opportunity to shed light on the functions of two poorly characterized genes.

Somatic copy number alterations predict response to platinum therapy in epithelial ovarian cancer.

OBJECTIVE: Platinum resistance remains an obstacle in the treatment of epithelial ovarian cancer (EOC). The goal of this study was to profile EOCs for somatic copy number alterations (SCNAs) as predictive markers of platinum response. METHODS: SCNAs were assessed in a discovery (n=86) and validation cohort (n=115) of high risk stage I or stage II-IV EOCs using high-resolution SNP arrays. ASCAT and GISTIC identified all significantly overrepresented amplified or deleted chromosomal regions. Cox regression and univariate analysis assessed which SCNAs correlated with overall survival (OS), progression-free survival (PFS), platinum-free interval (PFI) and platinum response. Relevant SCNAs were also assessed in a pooled analysis involving both cohorts and published SCNA data from The Cancer Genome Atlas (TCGA; n=227). RESULTS: We identified 53 regions to be significantly overrepresented in EOC. Of these, 6 were associated with OS, PFS or PFI in the discovery cohort at P<0.05. In the validation cohort, amplifications of chromosomal region 14q32.33, which contains AKT1 as a potential driver gene, also correlated with OS (OR=1.670; P=0.018). In a pooled analysis of 428 tumors, involving the discovery, validation and TCGA cohorts, 14q32.33 amplifications significantly reduced OS, PFS and PFI (HR=2.69, P=1.7×10(-4); HR=1.82, P=1.9×10(-2) and HR=1.80, P=2.2×10(-2) respectively). Moreover, AKT1 mRNA expression correlated with the number of chromosomal copies of the 14q32.33 region (P=2.8×10(-11);R(2)=0.26). CONCLUSIONS: We established that amplifications in 14q32.33 were associated with reduced OS, PFS, PFI and platinum resistance in three independent cohorts, suggesting that AKT1 amplifications act as a potentially predictive marker for EOC treated with platinum-based chemotherapy.

Whole-body MRI with diffusion-weighted sequence for staging of patients with suspected ovarian cancer: a clinical feasibility study in comparison to CT and FDG-PET/CT.

OBJECTIVES: To evaluate whole-body MRI with diffusion-weighted sequence (WB-DWI/MRI) for staging and assessing operability compared with CT and FDG-PET/CT in patients with suspected ovarian cancer. METHODS: Thirty-two patients underwent 3-T WB-DWI/MRI, (18) F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and CT before diagnostic open laparoscopy (DOL). Imaging findings for tumour characterisation, peritoneal and retroperitoneal staging were correlated with histopathology after DOL and/or open surgery. For distant metastases, FDG-PET/CT or image-guided biopsies were the reference standards. For tumour characterisation and peritoneal staging, WB-DWI/MRI was compared with CT and FDG-PET/CT. Interobserver agreement for WB-DWI/MRI was determined. RESULTS: WB-DWI/MRI showed 94 % accuracy for primary tumour characterisation compared with 88 % for CT and 94 % for FDG-PET/CT. WB-DWI/MRI showed higher accuracy of 91 % for peritoneal staging compared with CT (75 %) and FDG-PET/CT (71 %). WB-DWI/MRI and FDG-PET/CT showed higher accuracy of 87 % for detecting retroperitoneal lymphadenopathies compared with CT (71 %). WB-DWI/MRI showed excellent correlation with FDG-PET/CT (κ = 1.00) for detecting distant metastases compared with CT (κ = 0.34). Interobserver agreement was moderate to almost perfect (κ = 0.58-0.91). CONCLUSIONS: WB-DWI/MRI shows high accuracy for characterising primary tumours, peritoneal and distant staging compared with CT and FDG-PET/CT and may be valuable for assessing operability in ovarian cancer patients. KEY POINTS: • Whole-body MRI with diffusion weighting (WB-DWI/MRI) helps to assess the operability of suspected ovarian cancer. • Interobserver agreement is good for primary tumour characterisation, peritoneal and distant staging. • WB-DWI/MRI improves mesenteric/serosal metastatic spread assessment compared with CT and FDG-PET/CT. • Retroperitoneal/cervical-thoracic nodal staging using qualitative DWI criteria was reasonably accurate. • WB-DWI/MRI and FDG-PET/CT showed the highest diagnostic impact for detecting thoracic metastases.

Epithelial ovarian cancer: rationale for changing the one-fits-all standard treatment regimen to subtype-specific treatment.

OBJECTIVE: Epithelial ovarian cancers (EOCs) are, although still treated as a single disease entity, often classified into type I tumors (low-grade serous, mucinous, endometrioid, clear cell) and type II tumors (high-grade serous, undifferentiated cancers, carcinosarcomas). The aim of our study was to determine the incidence, clinical relevance, and prognostic and predictive impact of somatic mutations in both types I and II EOCs. METHODS: Two hundred sixty-two evaluable, primary, high-risk stage I (grade 3, or aneuploid grade 1 or 2, or clear cell) and stage II-IV EOCs, collected at the University Hospitals Leuven and within the European Organisation for Research and Treatment of Cancer 55971 trial, were genotyped for hotspot mutations in KRAS (COSMIC [Catalogue of Somatic Mutations in Cancer] coverage >97%), BRAF (>94%), NRAS (>97%), PIK3CA (>79%), PTEN, FBXW7 (>57%), AKT2, AKT3, and FOXL2, using Sequenom MassARRAY. RESULTS: Of the 13% histopathologically classified type I tumors, 49% were KRAS or PIK3CA mutant versus only 2.9% in the type II tumors (87%). Mucinous subtypes harbored significantly more KRAS mutations than all nonmucinous tumors (50% vs 4%, P < 0.001). PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and endometrioid carcinoma (20%) and were frequently associated with endometriosis. Moreover, low-grade serous tumors were more frequently KRAS or BRAF mutated (44%) than high-grade serous tumors (0.6%). KRAS or PIK3CA mutation did not correlate with progression-free survival or overall survival. Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%). CONCLUSIONS: Somatic mutations are rare in type II EOCs, whereas type I EOCs contain distinct diseases with different driver mutations. In general, these tumors respond worse to standard paclitaxel carboplatin therapy. Clinical trials with molecular targeted therapy in the different subtypes of type I tumors are urgently needed using this theragnostic information.

Fetal heart pathology on postmortem 3-T magnetic resonance imaging.

INTRODUCTION: Postmortem magnetic resonance imaging (pmMRI) is increasingly used in perinatology, typically as an alternative or complement to conventional necropsy for central nervous system anomalies. Overall, it provides reliable information on structural malformations but was shown to be of limited use in examining the fetal heart. OBJECTIVE: We aimed to assess the fetal heart on 3-T pmMRI in a consecutive series of fetuses with structural congenital heart defects (CHD) and to determine diagnostic evaluation limits in case of CHD. METHODS: A single-center database was retrospectively reviewed. Only fetuses having CHD of functional significance were included. Fetal cardiac anatomy was assessed on T2-weighted 3D multiplanar reconstructed images acquired using isovolumetric voxel size (0.3-0.8 mm(3) ), which allows to visualize cardiac structures in situ in multiple fetal body planes. Cardiac pathology was classified into complex and isolated CHD. On the basis of clinically relevant findings, pmMRI was considered either diagnostic or not diagnostic. RESULTS: A total of 24 fetuses were included in this study. The median gestational age was 22 weeks and 2 days (range 12w5d-34w6d). The median delay between delivery of the fetus and MR was 6 h and 30 min (range 1 h and 30 min-19 h). PmMRI was diagnostic for 12 out of 13 (92.3%) complex CHD and for 6 out of 11 (54.5%) isolated CHD. In case of valvular malformation, a tentative diagnosis was reached in 7/11 cases (64%) on the basis of indirect features. CONCLUSIONS: Postmortem MRI is a valid diagnostic tool for CHD in fetuses beyond 16 weeks up to term.