A phase II, multicenter, open-label study of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancer: ALEPRO trial.

BACKGROUND: Low-grade serous and endometrioid ovarian cancers and adult-type granulosa cell tumors are rare ovarian malignancies that show high estrogen receptor positivity. Recurrences of these subtypes of ovarian cancer are often treated with conventional chemotherapy, although response rates are disappointing. PRIMARY OBJECTIVE: To determine the overall response rate of the combination therapy of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancers. STUDY HYPOTHESIS: The combination therapy of abemaciclib and letrozole will provide a clinically meaningful therapeutic benefit, with an overall response rate of >25%. TRIAL DESIGN: This is a phase II, international, multicenter, open-label, single-arm study to evaluate the efficacy and safety of abemaciclib and letrozole in patients with advanced, recurrent, and/or metastatic estrogen receptor-positive, rare ovarian cancer. The study will follow a tandem two-stage design. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients must have histologically confirmed low-grade serous/endometrioid ovarian cancer or adult-type granulosa cell tumor with estrogen receptor positivity on immunohistochemistry. Patients need to have recurrent and measurable disease according to Radiologic Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A maximum of two prior lines of endocrine therapy are allowed, and patients cannot have previously received a cyclin-dependent kinase inhibitor. Patients with platinum-refractory disease are not allowed in any stage of the study. PRIMARY ENDPOINT: Investigator-assessed confirmed overall response rate, defined as the proportion of patients with a complete or partial response according to RECIST v1.1. SAMPLE SIZE: 40 to 100 patients will be included, depending on the results of the interim analysis. Patients will be included in Belgium, France and the Netherlands. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Patient recruitment will be completed by the end of 2025 and reporting of the final study results will be done by the end of 2027. TRIAL REGISTRATION NUMBER: NCT05872204.

Outcome analysis of HDR compared to PDR IGABT in locally advanced cervical cancer: a single-center cohort analysis.

PURPOSE: This monocentric study aimed to assess the impact of technical advancement in brachytherapy (BT) on local control (LC) and cancer-specific survival (CSS) in locally advanced cervical cancer (LACC). METHODS: Since 2010, 211 patients with LACC have been treated with 45/50.4 Gy or 60 Gy radiochemotherapy (RTCT) followed by image-guided adaptive brachytherapy (IGABT) at the authors' institution. In 2013, combined intracavitary and interstitial brachytherapy (BT IC/IS) was implemented and in 2018, pulsed-dose-rate BT (PDR-BT) was replaced by high-dose-rate BT (HDR-BT). LC, CSS, and morbidity according to the RTOG/EORTC scoring system were analyzed. Dose-volume parameters for the high-risk clinical target volume (HRCTV) and organs at risk (OAR) were reported. RESULTS: While 27 (12.8%) patients died of LACC, complete local remission was achieved in 199 (94.3%). Local relapse decreases with a high D95 in the HRCTV (hazard ratio, HR = 0.85, p = 0.0024). D95 in the HRCTV is lower after 60 Gy even if interstitial BT is used. Mean D95 in the HRCTV is 78.2 Gy, 83.3 Gy, and 83.4 Gy with PDR-BT IC, PDR-BT IC/IS, and HDR-BT IC/IS, respectively, after 45/50.4 Gy. D2 cc of OARs is significantly reduced by using interstitial BT. The mean rectum and sigmoid D2 cc are about 61.5 Gy with PDR-BT IC/IS and significantly decreased with HDR-BT IC/IS. This translates into a low fistula incidence. A very low rate of severe gastrointestinal (3.4%) and genitourinary (2.3%) toxicity was observed with HDR-BT IC/IS. CONCLUSION: This large monocentric study provides further evidence that implementation of BT IC/IS has an impact on D95 in the HRCTV, LC, and CSS. There are no differences between HDR and PDR in terms of efficacy, D95 in the HRCTV, and toxicity grade ≥ 3.

Multicentric development and evaluation of 18F-FDG PET/CT and MRI radiomics models to predict para-aortic lymph node involvement in locally advanced cervical cancer.

PURPOSE: To develop machine learning models to predict para-aortic lymph node (PALN) involvement in patients with locally advanced cervical cancer (LACC) before chemoradiotherapy (CRT) using 18F-FDG PET/CT and MRI radiomics combined with clinical parameters. METHODS: We retrospectively collected 178 patients (60% for training and 40% for testing) in 2 centers and 61 patients corresponding to 2 further external testing cohorts with LACC between 2010 to 2022 and who had undergone pretreatment analog or digital 18F-FDG PET/CT, pelvic MRI and surgical PALN staging. Only primary tumor volumes were delineated. Radiomics features were extracted using the Radiomics toolbox®. The ComBat harmonization method was applied to reduce the batch effect between centers. Different prediction models were trained using a neural network approach with either clinical, radiomics or combined models. They were then evaluated on the testing and external validation sets and compared. RESULTS: In the training set (n = 102), the clinical model achieved a good prediction of the risk of PALN involvement with a C-statistic of 0.80 (95% CI 0.71, 0.87). However, it performed in the testing (n = 76) and external testing sets (n = 30 and n = 31) with C-statistics of only 0.57 to 0.67 (95% CI 0.36, 0.83). The ComBat-radiomic (GLDZM_HISDE_PET_FBN64 and Shape_maxDiameter2D3_PET_FBW0.25) and ComBat-combined (FIGO 2018 and same radiomics features) models achieved very high predictive ability in the training set and both models kept the same performance in the testing sets, with C-statistics from 0.88 to 0.96 (95% CI 0.76, 1.00) and 0.85 to 0.92 (95% CI 0.75, 0.99), respectively. CONCLUSIONS: Radiomic features extracted from pre-CRT analog and digital 18F-FDG PET/CT outperform clinical parameters in the decision to perform a para-aortic node staging or an extended field irradiation to PALN. Prospective validation of our models should now be carried out.

European multidisciplinary tumor boards support cross-border networking and increase treatment options for patients with rare gynecological tumors.

OBJECTIVE: To evaluate outcomes of European cross-border multidisciplinary tumor boards in terms of participation, adherence to treatment recommendations, and access to novel treatment strategies. METHODS: The European reference network for rare gynecological tumors (EURACAN G2 domain) aims to improve the diagnosis, management, and treatment of patients with these cancers. Cross-border multidisciplinary tumor boards were initiated to facilitate intercollegiate clinical discussions across Europe and increase patients' access to specialist treatment recommendations and clinical trials. All G2 healthcare providers were invited to participate in monthly multidisciplinary meetings. Patient data were collected using a standardized form and case summaries were distributed before each meeting. After each tumor board, a meeting summary with treatment recommendations was sent to all participants and the project manager at the coordinating center. The multidisciplinary tumor board format and outcomes were regularly discussed at G2 domain meetings. Anonymized clinical data and treatment recommendations were registered in a prospective database. For this report, clinical data were collected between November 2017 and December 2020 and follow-up data retrieved until May 2021. RESULTS: During the 3-year period, 31 multidisciplinary tumor boards were held with participants from 10 countries and 20 centers. 91 individual patients were discussed between one and six times for a total of 109 case discussions. Follow-up data were retrieved from 64 patients and 80 case discussions. Adherence to treatment recommendations was 99%. Multidisciplinary tumor board recommendations resulted in 11 patients getting access to off-label treatment and one patient being enrolled in a clinical trial in another European country. 14/91 patients were recommended for surveillance only when additional treatment had been considered locally. CONCLUSION: Cross-border multidisciplinary tumor boards enable networking and clinical collaboration between healthcare professionals in different countries. Surveillance strategies, off-label drug use, and increased participation in clinical trials are possible benefits to patients with rare gynecological tumors.

PARa-aOrtic LymphAdenectomy in locally advanced cervical cancer (PAROLA trial): a GINECO, ENGOT, and GCIG study.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) fails to detect approximately 25% of aortic lymph node metastasis in patients with PET/CT stage IIIC1 cervical cancer. Surgical staging could lead to treatment modification and to improved para-aortic and distant control. PRIMARY OBJECTIVES: To demonstrate if chemoradiation with tailored external beam radiation field based on surgical staging and pathologic examination of the para-aortic lymph node is associated with improved 3-year disease-free survival compared with patients staged with PET/CT staging only. STUDY HYPOTHESIS: Surgical staging followed by tailored chemoradiation will improve disease-free survival while avoiding unnecessary prophylactic extended-field chemoradiation in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1 cervical cancer. TRIAL DESIGN: This is an international multicenter, randomized, phase III study. Eligible patients will be randomized 1:1 between PET/CT staging followed by chemoradiation (control arm), or surgical staging followed by tailored chemo-radiation (experimental arm). Randomization will be stratified by tumor stage according to TNM classification, center, and adjuvant treatment. MAJOR INCLUSION/EXCLUSION CRITERIA: Main inclusion criteria are histologically proven PET/CT FIGO stage IIIC1 cervical cancer. Main exclusion criteria include unequivocal positive common iliac or para-aortic lymph node at pre-therapeutic imaging PET/CT. PRIMARY ENDPOINTS: The primary endpoint is disease-free survival defined as the time from randomization until first relapse (local, regional, or distant), or death from any cause. SAMPLE SIZE: 510 eligible patients ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The estimated date for completing accrual will be Q2 2027. The estimated date for presenting results will be Q4 2030. TRIAL REGISTRATION NUMBER: NCT05581121.

Periostin in lymph node pre-metastatic niches governs lymphatic endothelial cell functions and metastatic colonization.

Although lymph node (LN) metastasis is an important prognostic parameter in cervical cancer, the tissue remodeling at a pre-metastatic state is poorly documented in LNs. We here identified periostin (POSTN) as a component of non-metastatic LNs by applying proteomic analyses and computerized image quantifications on LNs of patients with cervical cancer. We provide evidence for remarkable modifications of POSTN and lymphatic vessel distributions and densities in non-metastatic sentinel and metastatic human LNs, when compared to distant non-metastatic LNs. POSTN deposition at a pre-metastatic stage was demonstrated in a pre-clinical murine model (the ear sponge assay). Its expression by fibroblastic LN cells was assessed by in situ hybridization and in vitro cultures. In vitro, POSTN promoted lymphatic endothelial cell functions and tumor cell proliferation. Accordingly, the in vivo injection of recombinant POSTN together with VEGF-C boosted the lymphangiogenic response, while the metastatic potential of tumor cells was drastically reduced using a POSTN blocking antibody. This translational study also supports the existence of an unprecedented dialog "in cascade", between the primary tumor and the first pelvic nodal relay in early cervical cancer, and subsequently from pelvic LN to para-aortic LNs in locally advanced cervical cancers. Collectively, this work highlights the association of POSTN deposition with lymphangiogenesis in LNs, and provides evidence for a key contribution of POSTN in promoting VEGF-C driven lymphangiogenesis and the seeding of metastatic cells.

Diagnostic Performance of Immunohistochemistry Compared to Molecular Techniques for Microsatellite Instability and p53 Mutation Detection in Endometrial Cancer.

Molecular algorithms may estimate the risk of recurrence and death for patients with endometrial cancer (EC) and may impact treatment decisions. To detect microsatellite instabilities (MSI) and p53 mutations, immunohistochemistry (IHC) and molecular techniques are used. To select the most appropriate method, and to have an accurate interpretation of their results, knowledge of the performance characteristics of these respective methods is essential. The objective of this study was to assess the diagnostic performance of IHC versus molecular techniques (gold standard). One hundred and thirty-two unselected EC patients were enrolled in this study. Agreement between the two diagnostic methods was assessed using Cohen's kappa coefficient. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of the IHC were calculated. For MSI status, the sensitivity, specificity, PPV and NPV were 89.3%, 87.3%, 78.1% and 94.1%, respectively. Cohen's kappa coefficient was 0.74. For p53 status, the sensitivity, specificity, PPV, and NPV were 92.3%, 77.1%, 60.0% and 96.4%, respectively. Cohen's kappa coefficient was 0.59. For MSI status, IHC presented a substantial agreement with the polymerase chain reaction (PCR) approach. For the p53 status, the moderate agreement observed between IHC and next generation sequencing (NGS) methods implies that they cannot be used interchangeably.

[Dysmenorrhea and pelvic pain secondary to an accessory and cavitated uterine mass]. / Dysménorrhée et douleurs pelviennes secondaires à une masse utérine cavitaire accessoire.

An accessory and cavitated uterine mass (ACUM) is a rare anomaly with an embryological origin of dysfunctionning female gubernaculum. It is an accessory mass internally lined with normal endometrium, separated from the uterine cavity and located near the insertion of the round ligament. ACUM's clinical manifestations are severe dysmenorrhea and/or chronic pelvic pain. It is a relatively unknown condition, which makes its diagnosis complicated and suggests a large differential diagnosis. We report the case of a 31-year-old female presenting with pelvic chronic pain and crippling dysmenorrhea. The initial work-up consists of a magnetic resonance imaging showing an interstitial lesion possibly corresponding to an ACUM. This supposition was then confirmed by histopathology.

La masse utérine cavitaire accessoire (MUCA) est une anomalie rare dont l'origine est embryologique et serait liée à un dysfonctionnement du gubernaculum féminin. Il s'agit d'une masse accessoire non communicante située à proximité de l'insertion du ligament rond, tapissée par un endomètre normal. La MUCA se manifeste par une dysménorrhée sévère et/ou des douleurs pelviennes chroniques. Il s'agit d'une pathologie relativement méconnue, ce qui rend son diagnostic difficile, et qui suggère un large diagnostic différentiel. Nous rapportons ici le cas d'une femme de 31 ans présentant des douleurs pelviennes chroniques et une dysménorrhée invalidante. La mise au point initiale par résonance magnétique pelvienne a montré la présence d'une lésion interstitielle pouvant correspondre à une MUCA, qui a ensuite été confirmée à l'examen histopathologique.

[Meningioma under progestin treatment : what attitude to adopt ?] / Méningiome sous traitement progestatif : quelle attitude adopter ?

The risks of meningioma associated with the use of cyproterone acetate at high doses (25 to 100 mg/day) have been known since 2007. Recently, two additional molecules have been incriminated: nomegestrol acetate and chlormadinone acetate. The higher the cumulative dose and the longer the treatment duration, the bigger the risk of meningioma (12-fold after 5 years of treatment for nomegestrol acetate, and 7-fold after 3.5 years of treatment for chlormadinone acetate). Nevertheless, these medications have many indications that demonstrate their importance in the daily practice of the general practitioner, of the gynecologist and of the reproductive endocrinologist. Therefore, caution is required when introducing a powerful progestin that is incriminated in the long term at high doses. If the benefit/risk balance favours the initiation of progestin therapy, it is recommended to use the minimal effective dose and to limit the duration of use. Clinical and brain imaging monitoring should also be performed. Finally, if a meningioma develops on progestin, it is recommended that any medication containing a progesterone agonist be suspended.

Les risques de méningiome liés à la consommation de l'acétate de cyprotérone à de fortes doses (25 à 100 mg/jour) sont connus depuis 2007. Récemment, deux molécules supplémentaires ont été incriminées : l'acétate de nomégestrol et l'acétate de chlormadinone. Le risque de développer un méningiome est d'autant plus important que la dose cumulée est grande et que la prescription se prolonge dans le temps (risque multiplié par 12 à partir de 5 ans de traitement pour l'acétate de nomégestrol, et multiplié par 7 à partir de 3,5 ans de traitement par acétate de chlormadinone). Néanmoins, ces médications possèdent de nombreuses indications témoignant de leur importance dans la pratique quotidienne du médecin généraliste, du gynécologue et de l'endocrinologue de la reproduction. Dès lors, la vigilance est de mise lors de l'introduction d'un progestatif puissant incriminé à long terme et à haute dose. Si la balance bénéfices/risques plaide en faveur de l'instauration d'un traitement par progestatif, il est recommandé d'utiliser la dose minimale efficace et d'en limiter la durée d'utilisation. Une surveillance clinique et par imagerie cérébrale systématique est vivement recommandée. Enfin, en cas de détection d'un méningiome, il est recommandé de suspendre toute médication contenant un agoniste de la progestérone.

Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup.

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.

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.

The pre-metastatic niche in lymph nodes: formation and characteristics.

Lymph node metastasis is a crucial prognostic parameter in many different types of cancers and a gateway for further dissemination to distant organs. Prior to metastatic dissemination, the primary tumor prepares for the remodeling of the draining (sentinel) lymph node by secreting soluble factors or releasing extracellular vesicles that are transported by lymphatic vessels. These important changes occur before the appearance of the first metastatic cell and create what is known as a pre-metastatic niche giving rise to the subsequent survival and growth of metastatic cells. In this review, the lymph node structure, matrix composition and the emerging heterogeneity of cells forming it are described. Current knowledge of the major cellular and molecular processes associated with nodal pre-metastatic niche formation, including lymphangiogenesis, extracellular matrix remodeling, and immunosuppressive cell enlisting in lymph nodes are additionally summarized. Finally, future directions that research could possibly take and the clinical impact are discussed.

[18F]FDG PET radiomics to predict disease-free survival in cervical cancer: a multi-scanner/center study with external validation.

PURPOSE: To test the performances of native and tumour to liver ratio (TLR) radiomic features extracted from pre-treatment 2-[18F] fluoro-2-deoxy-D-glucose ([18F]FDG) PET/CT and combined with machine learning (ML) for predicting cancer recurrence in patients with locally advanced cervical cancer (LACC). METHODS: One hundred fifty-eight patients with LACC from multiple centers were retrospectively included in the study. Tumours were segmented using the Fuzzy Local Adaptive Bayesian (FLAB) algorithm. Radiomic features were extracted from the tumours and from regions drawn over the normal liver. Cox proportional hazard model was used to test statistical significance of clinical and radiomic features. Fivefold cross validation was used to tune the number of features. Seven different feature selection methods and four classifiers were tested. The models with the selected features were trained using bootstrapping and tested in data from each scanner independently. Reproducibility of radiomics features, clinical data added value and effect of ComBat-based harmonisation were evaluated across scanners. RESULTS: After a median follow-up of 23 months, 29% of the patients recurred. No individual radiomic or clinical features were significantly associated with cancer recurrence. The best model was obtained using 10 TLR features combined with clinical information. The area under the curve (AUC), F1-score, precision and recall were respectively 0.78 (0.67-0.88), 0.49 (0.25-0.67), 0.42 (0.25-0.60) and 0.63 (0.20-0.80). ComBat did not improve the predictive performance of the best models. Both the TLR and the native models performance varied across scanners used in the test set. CONCLUSION: [18F]FDG PET radiomic features combined with ML add relevant information to the standard clinical parameters in terms of LACC patient's outcome but remain subject to variability across PET/CT devices.

Convolutional neural networks for PET functional volume fully automatic segmentation: development and validation in a multi-center setting.

PURPOSE: In this work, we addressed fully automatic determination of tumor functional uptake from positron emission tomography (PET) images without relying on other image modalities or additional prior constraints, in the context of multicenter images with heterogeneous characteristics. METHODS: In cervical cancer, an additional challenge is the location of the tumor uptake near or even stuck to the bladder. PET datasets of 232 patients from five institutions were exploited. To avoid unreliable manual delineations, the ground truth was generated with a semi-automated approach: a volume containing the tumor and excluding the bladder was first manually determined, then a well-validated, semi-automated approach relying on the Fuzzy locally Adaptive Bayesian (FLAB) algorithm was applied to generate the ground truth. Our model built on the U-Net architecture incorporates residual blocks with concurrent spatial squeeze and excitation modules, as well as learnable non-linear downsampling and upsampling blocks. Experiments relied on cross-validation (four institutions for training and validation, and the fifth for testing). RESULTS: The model achieved good Dice similarity coefficient (DSC) with little variability across institutions (0.80 ± 0.03), with higher recall (0.90 ± 0.05) than precision (0.75 ± 0.05) and improved results over the standard U-Net (DSC 0.77 ± 0.05, recall 0.87 ± 0.02, precision 0.74 ± 0.08). Both vastly outperformed a fixed threshold at 40% of SUVmax (DSC 0.33 ± 0.15, recall 0.52 ± 0.17, precision 0.30 ± 0.16). In all cases, the model could determine the tumor uptake without including the bladder. Neither shape priors nor anatomical information was required to achieve efficient training. CONCLUSION: The proposed method could facilitate the deployment of a fully automated radiomics pipeline in such a challenging multicenter context.

Tumor total lesion glycolysis and number of positive pelvic lymph nodes on pretreatment positron emission tomography/computed tomography (PET/CT) predict survival in patients with locally advanced cervical cancer.

OBJECTIVE: The aim of this study was to investigate the prognostic value of metabolic parameters obtained at pretreatment [18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) in patients with locally advanced cervical cancer. We hypothesize that these metabolic parameters could optimize the treatment decision and thus favor the outcome of patients suffering locally advanced cervical cancer. METHODS: Patients with locally advanced cervical cancer underwent pretreatment PET/CT. Standard uptake values (maximum, mean, peak), metabolic tumor volume, and total lesion glycolysis were measured in the tumor and in the hypermetabolic pelvic lymph nodes. The relationship between clinical, pathological, and PET/CT metabolic parameters with recurrence-free survival and overall survival was assessed by Cox regression analysis. RESULTS: 115 patients with a median age of 52 years (range 23-77) presented with locally advanced cervical cancer. After a mean follow-up of 33.0 months after initiation of therapy, 26 patients (22.6%) recurred of which 17 patients had distant metastasis; 18 (15.7%) patients died. Recurrence-free survival at 2 and 5 years was 79.2% and 72.2%, respectively. The total lesion glycolysis of the tumor and the delay between diagnosis and treatment were significantly associated with recurrence-free survival in the multivariate analysis (HR 1.00, p=0.004, and HR 2.04, p=0.02, respectively). Only the total lesion glycolysis of the tumor ≥373.54 (HR 2.49, 95% CI 1.15 to 5.38; p=0.02) remained significant after log rank testing. Overall survival at 2 and 5 years was 91.7% and 68.8%, respectively. The number of PET-positive pelvic lymph nodes was the only independent prognostic factor for overall survival in the multivariate analysis (HR 1.43, 95% CI 1.13 to 1.81; p=0.003). CONCLUSION: Tumor total lesion glycolysis and the number of positive pelvic lymph nodes on pretreatment PET/CT appear to be independent prognostic factors for recurrence and survival in patients with locally advanced cervical cancer. This may help to select patients who may benefit from therapeutic optimization and closer surveillance.

A Simple Laparoscopic Procedure to Restore a Normal Vaginal Length After Colpohysterectomy With Large Upper Colpectomy for Cervical and/or Vaginal Neoplasia.

Colpohysterectomy is sometimes associated with a large upper colpectomy resulting in a shortened vagina, potentially impacting sexual function. We report on a preliminary experience of a laparoscopic colpoplasty to restore a normal vaginal length. Patients with shortened vaginas after a laparoscopic colpohysterectomy were considered for a laparoscopic modified Davydov's procedure to create a new vaginal vault using the peritoneum of the rectum and bladder. From 2010 to 2014, 8 patients were offered this procedure, after informed preoperative consent. Indications were 2 extensive recurrent vaginal intraepithelial neoplasias grade 3 and 6 radical hysterectomies for cervical cancer. Mean vaginal length before surgery was 3.8 cm (standard deviation, 1.6). Median operative time was 50 minutes (range, 45-90). Blood loss was minimal (50-100 mL). No perioperative complications occurred. Median vaginal length at discharge was 11.3 cm (range, 9-13). Sexual intercourse could be resumed around 10 weeks after surgery. At a median follow-up of 33.8 months (range, 2.4-51.3), 6 patients remained sexually active but 2 had stopped. Although this experience is small, this laparoscopic modified Davydov's procedure seems to be an effective procedure, adaptable to each patient's anatomy. If the initial postoperative regular self-dilatation is carefully observed, vaginal patency is durably restored and enables normal sexual function.

Unique recurrence patterns of cervical intraepithelial neoplasia after excision of the squamocolumnar junction.

Recent studies have identified a putative cell of origin for cervical intraepithelial neoplasia (CIN) and cervical cancer at the squamocolumnar junction (SCJ) and suggest that these cells may not regenerate after excision (loop electrosurgical excision procedure). Our study addressed the impact of SCJ excision on the temporal dynamics, histologic and viral (human papillomavirus, HPV) characteristics of recurrent CIN. One hundred and thirty-one consecutive patients treated by excision and attending follow-up visits were enrolled. We compared recurrent and initial CIN with attention to excision margins, timing of recurrence, CIN grade, HPV types, p16 immunophenotype and SCJ immunophenotype. During the follow-up period (up to 4 years), 16 (12.2%) recurrences were identified. Four (25%) were identified at the first follow-up visit, closely resembled the initial CIN 2/3 in grade and HPV type and were typically SCJ marker positive [SCJ(+)], suggesting nonexcised (residual) disease. Twelve (75%) manifested after the first postoperative visit and all were in the ectocervix or in mature metaplastic epithelium. All of the 12 delayed recurrences were classified as CIN 1 and were SCJ (-). In total, 9 out of 11 SCJ (-) recurrences (82%) followed regressed spontaneously. Taken together, these results show that new lesions developing from any HPV infection are delayed and occur within the ectocervix or metaplastic epithelium. This markedly lower risk of CIN 2/3 after successful SCJ excision suggests that the removal of the SCJ could be a critical variable in reducing the risk of subsequent CIN 2/3 and cervical cancer.

Phase II study of weekly paclitaxel/carboplatin in combination with prophylactic G-CSF in the treatment of gynecologic cancers: A study in 108 patients by the Belgian Gynaecological Oncology Group.

OBJECTIVE: To investigate the addition of prophylactic G-CSF to each weekly paclitaxel/carboplatin course in patients with recurrent platinum-resistant ovarian (OC), or recurrent or advanced endometrial (EC) or cervical carcinoma (CC). METHODS: 108 patients were enrolled i.e. 36 in each cohort. Eighteen courses of paclitaxel (60 mg/m(2)) and carboplatin (AUC 2.7) were administered weekly. G-CSF (filgrastim) was given to all patients on day 5 (and if needed on day 6). RESULTS: For patients with OC, 91% had platinum-resistant and 9% platinum-refractory disease. Median number of prior chemotherapy lines was 3 for OC, 1 for EC, and 1 for CC. Grade 3-4 neutropenia was observed in 34% of patients (95% CI: 26%-44%, P<0,0001) (OC 29%, EC 36%, CC 38%). This is lower compared to historical data in all cohorts (84%). Confirmed sepsis was observed in 5%, grade 3-4 thrombocytopenia in 41%, grade 2-3 peripheral neuropathy in 17% of patients. In 71% of patients dose was delayed. Dose reduction was necessary for carboplatin in 47% and paclitaxel in 18% of patients. ORR was 51% (OC 48%, EC 45%, CC 58%). Median (95% CI) PFS and OS was 7.1 (5.1-8.1) and 12.7 (10.2-16.3) months, respectively (OC 7 and 13, EC 6 and 19, CC 6 and 14). CONCLUSION: Weekly paclitaxel/carboplatin with G-CSF is an effective treatment with acceptable toxicity in patients with platinum-resistant or platinum-refractory OC, advanced or recurrent EC and CC. The incidence of grade 3-4 neutropenia is lower with the addition of weekly G-CSF compared with earlier studies without routine use of prophylactic G-CSF.

Clinical efficacy and toxicity of radio-chemotherapy and magnetic resonance imaging-guided brachytherapy for locally advanced cervical cancer patients: A mono-institutional experience.

BACKGROUND: To evaluate efficacy and toxicity of radio-chemotherapy (RCT) and MR-guided pulsed-dose-rate (PDR) adaptive brachytherapy (IGABT) for locally advanced cervical cancer (LACC). MATERIAL AND METHODS: Between 2007 and 2014 85 patients with FIGO stage 1B1 N+ or ≥ 1B2 cervical cancer were treated with RCT+ IGABT. The treatment consisted of a pelvic± paraaortic external beam radiotherapy (EBRT) (45-50.4 Gy ± 10 Gy boost to primary tumor and/or to pathologic lymph nodes) with concurrent cisplatin followed by 25-35 Gy of PDR IGABT in 30-50 pulses. The ratio of 3D-CFRT/IMRT was 61/24 patients. Dose-volume parameters of high-risk clinical target volume (HR-CTV), intermediate-risk clinical target volume (IR-CTV) and D2cm(3) organs at risk (OARs) were reported. Local control (LC), cancer-specific survival (CCS) and overall survival (OS) were analyzed actuarially and morbidity crude rates were scored using CTCAEv4.0. RESULTS: Mean follow-up was 36 months (range 6-94). The mean D90 and D98 for HR-CTV was 84.4 ± 9 Gy and 77 ± 8.1 Gy, while for IR-CTV was 69.1 ± 4.3 Gy and 64.8 ± 4.3 Gy, respectively. The mean D2cm(3) for OARs was the following: bladder: 77.3 ± 10.5 Gy, rectum: 65 ± 6.8 Gy, sigmoid: 63 ± 7.9 Gy and intestine: 64.0 ± 9.1 Gy. Three year LC, CSS and OS were: 94%, 85% and 81%. The three-year regional- and distant control rates were 95% and 74%. Node negative patients had significantly higher three-year CSS (100 vs. 72%, p = 0.016) and OS (92 vs. 72%, p = 0.001) compared to node positive ones. Three-year actuarial late Grade ≥ 3 morbidity was the following: GI: 8%, GU: 5%, Vaginal: 8%. The frequency of Grade ≥ 3 hematological toxicities including anemia/leukopenia/neutropenia/thrombocytopenia were 8.6%/34.7%/24.3%/24.3%, respectively. CONCLUSION: This large mono-institutional experience builds up further evidences that IGABT in conjunction with RCT should be the standard of care for patients suffering LACC.