Pregnancy and obstetric outcomes after fertility-sparing management of endometrial cancer and atypical hyperplasia: a multicentre cohort study.

STUDY QUESTION: What are the pregnancy and obstetric outcomes in women with atypical hyperplasia (AH) or early-stage endometrial cancer (EC) managed conservatively for fertility preservation? SUMMARY ANSWER: The study found a live birth rate of 62% in patients with AH or EC after conservative treatment, with higher level of labour induction, caesarean section, and post-partum haemorrhage. WHAT IS KNOWN ALREADY: Fertility-sparing treatment is a viable option for women with AH or EC during childbearing years, but the outcomes of such treatments, especially regarding pregnancy and obstetrics, need further exploration. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study analysed data from January 2010 to October 2022, involving 269 patients from the French national register of patients with fertility-sparing management of AH/EC. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women above 18 years of age, previously diagnosed with AH/EC, and approved for fertility preservation were included. Patients were excluded if they were registered before 2010, if their treatment began <6 months before the study, or if no medical record on the pregnancy was available. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 95 pregnancies in 67 women were observed. Pregnancy was achieved using ART in 63 cases (66%) and the live birth rate was 62%, with early and late pregnancy loss at 26% and 5%, respectively. In the 59 cases resulting in a live birth, a full-term delivery occurred in 90% of cases; 36% of cases required labour induction and 39% of cases required a caesarean section. The most common maternal complications included gestational diabetes (17%) and post-partum haemorrhaging (20%). The average (±SD) birthweight was 3110 ± 736 g; there were no significant foetal malformations in the sample. No significant difference was found in pregnancy or obstetric outcomes between ART-obtained and spontaneous pregnancies. However, the incidence of induction of labour, caesarean section, and post-partum haemorrhage appears higher than in the general population. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study may introduce bias, and the sample size might be insufficient for assessing rare obstetric complications. WIDER IMPLICATIONS OF THE FINDINGS: This study offers valuable insights for healthcare providers to guide patients who received fertility-sparing treatments for AH/EC. These pregnancies can be successful and with an acceptable live birth rate, but they seem to be managed with caution, leading to possible tendency for more caesarean sections and labour inductions. No increase in adverse obstetric outcomes was observed, with the exception of suspicion of a higher risk of post-partum haemorrhaging, to be confirmed. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Quality of information and decision regrets during fertility-sparing management for atypical hyperplasia and endometrial cancer in a prospective cohort study.

OBJECTIVE: To evaluate satisfaction with information, treatment, and decision regret during management to preserve fertility for atypical hyperplasia (AH) or endometrial cancer (EC). METHODS: A cohort study with standardized management using chlormadinone acetate was established through a national referral centre between January 2013 and November 2019. During this period, a questionnaire was given to 136 patients aged 19 to 43 years who were followed for fertility preservation for AH or EC. The questionnaire included the validated EORTC-QLQ-INFO25, as well as questions from the validated EVAPIL questionnaire, the Treatment Satisfaction with Medicines Questionnaire, and the Decision Regret Scales concerning treatment tolerability and general satisfaction. The main outcomes measured were the quality and satisfaction with the information and treatment received and the decision regret. RESULTS: 75 patients (55.1 %) responded to the questionnaire. Overall, patients were satisfied with the information received (median 75.0, range: 25-100) and thought it was helpful (median 100.0, range: 25-100). However, 54.7 % wished for more information. Most women (52.0 %) indicated that psychological support should be available. Patients who were less satisfied with the information received or wished to receive more information thought about stopping treatment more frequently. Decision regret was not related to treatment outcome (remission, hysterectomy, live birth), and 47 of the 56 patients who did not obtain a live birth did not regret fertility preservation. None of the nine patients who regretted fertility preservation obtained a live birth. Almost all the patients reported side effects. CONCLUSIONS: Dedicated information tools that detail conservative treatment for AH and EC as well as its secondary effects should be provided to improve adherence to treatment and follow-up. Furthermore, psychological support should be systematically proposed.

Transcriptomic Profiling of Upper Tract Urothelial Carcinoma: Bladder Cancer Consensus Classification Relevance, Molecular Heterogeneity, and Differential Immune Signatures.

Analyses of large transcriptomics data sets of muscle-invasive bladder cancer (MIBC) have led to a consensus classification. Molecular subtypes of upper tract urothelial carcinomas (UTUCs) are less known. Our objective was to determine the relevance of the consensus classification in UTUCs by characterizing a novel cohort of surgically treated ≥pT1 tumors. Using immunohistochemistry (IHC), subtype markers GATA3-CK5/6-TUBB2B in multiplex, CK20, p16, Ki67, mismatch repair system proteins, and PD-L1 were evaluated. Heterogeneity was assessed morphologically and/or with subtype IHC. FGFR3 mutations were identified by pyrosequencing. We performed 3'RNA sequencing of each tumor, with multisampling in heterogeneous cases. Consensus classes, unsupervised groups, and microenvironment cell abundance were determined using gene expression. Most of the 66 patients were men (77.3%), with pT1 (n = 23, 34.8%) or pT2-4 stage UTUC (n = 43, 65.2%). FGFR3 mutations and mismatch repair-deficient status were identified in 40% and 4.7% of cases, respectively. Consensus subtypes robustly classified UTUCs and reflected intrinsic subgroups. All pT1 tumors were classified as luminal papillary (LumP). Combining our consensus classification results with those of previously published UTUC cohorts, LumP tumors represented 57.2% of ≥pT2 UTUCs, which was significantly higher than MIBCs. Ten patients (15.2%) harbored areas of distinct subtypes. Consensus classes were associated with FGFR3 mutations, stage, morphology, and IHC. The majority of LumP tumors were characterized by low immune infiltration and PD-L1 expression, in particular, if FGFR3 mutated. Our study shows that MIBC consensus classification robustly classified UTUCs and highlighted intratumoral molecular heterogeneity. The proportion of LumP was significantly higher in UTUCs than in MIBCs. Most LumP tumors showed low immune infiltration and PD-L1 expression and high proportion of FGFR3 mutations. These findings suggest differential response to novel therapies between patients with UTUC and those with MIBC.

Improving Human Papillomavirus-Related Cervical Cancer Screening in Patients With Systemic Lupus Erythematosus.

Women with systemic lupus erythematosus (SLE), especially when exposed to immunosuppressive drugs, are at higher risk of human papillomavirus (HPV)-related cervical cancer.1 A recent study has shown that cervical cancer screening (CCS) coverage is worryingly low in this population.2.

[Conservative treatments for endometrial cancer]. / Traitements conservateurs en cas de cancer de l'endomètre.

CONSERVATIVE TREATMENTS FOR ENDOMETRIAL CANCER Treatment for early endometrial cancer remains based on hysterectomy. However, in patients of reproductive age with a pregnancy desire, conservative alternative may be considered in case of atypical hyperplasia or endometrial endometrial adenocarcinoma without myometrial invasion. The conservative treatment consists in proposing a protocol preserving the uterus, based on an antigonadotropic treatment (oral or intrauterine progestin, GnRH agonist) allowing a regression of the endometrial lesion. The pre-therapeutic assessment includes at least a review of initial histological slides, a fertility evaluation and a pelvic MRI. To check the remission and the absence of recurrence, hysteroscopy guided biopsies are performed every 3-4 months. Pregnancy is allowed after at least 3 months of treatment if the remission of lesions is proven histologically. In this circumstance, there is no contraindication to ovulation stimulation. Hysterectomy is finally indicated in case of progression of tumor lesions, non-remission of lesions at 12 months and if pregnancy project is abandoned.

TRAITEMENTS CONSERVATEURS EN CAS DE CANCER DE L'ENDOMÈTRE Le traitement du cancer de l'endomètre au stade précoce demeure fondé sur l'hystérectomie. Toutefois, chez les patientes en âge de procréer ayant un désir de grossesse, l'alternative conservatrice peut être envisagée en cas d'hyperplasie atypique ou d'un adénocarcinome endométrial de type endométrioïde sans envahissement myométrial. Le traitement conservateur consiste à proposer un protocole conservant l'utérus, fondé sur un traitement antigonadotrope (progestatif oral ou intra-utérin, agoniste de la GnRH) permettant une régression de la lésion endométriale. Le bilan préthérapeutique inclut au minimum une relecture des lames histologiques ayant fait le diagnostic de lésion endométriale, un bilan de fertilité et une IRM pelvienne. Pour vérifier la rémission et l'absence de récidive, des biopsies guidées par hystéroscopie tous les trois à quatre mois sont effectuées. La grossesse est autorisée après au moins trois mois de traitement si la rémission des lésions est prouvée histologiquement. Dans cette circonstance, il n'existe pas de contre-indication à une stimulation de l'ovulation. L'hystérectomie est finalement indiquée en cas de progression des lésions tumorales, de non-rémission des lésions à douze mois et en cas de succès ou abandon du projet de grossesse.

Breast metastasis of a lung carcinoma.

Breast metastasis is a rare phenomenon (0.2-1.3%)1 compared to primary breast lesions. Several neoplasms have been reported to metastasize to the breast such as melanoma, lymphoma and lung cancer. In this article, we report a case of breast metastasis of lung cancer confirmed by biopsy and immunohistochemistry with CT and ultrasound imaging.

Novel mutations in antiviral multiresistant HSV-2 genital lesion: A case report.

HSV-2 antiviral resistance mainly occurs in immunocompromised patients and especially in HIV-positive individuals receiving long-term antiviral treatment. Those situations can be challenging as few alternatives are available for HSV infection management. To describe clinical and virological significance of two novel potential HSV-2 resistance mutations after treating an obese patient with a pseudotumoral genital HSV-related lesion. Consecutive different antiviral treatments were used: valacyclovir (VACV) then foscarnet (FOS) then topical cidofovir (CDV) and finally imiquimod. Under VACV, genotypic resistance testing revealed a novel mutation within viral thymidine kinase (TK, gene UL23) not previously reported but probably accounting for antiviral resistance: W89G, similar to W88R mutation reported in HSV-1 TK, known to be associated with ACV resistance for HSV-1. Under FOS, while initial mutations were still present, a second genotypic resistance testing performed on persisting lesions showed a novel mutation within viral DNA polymerase (DNA pol, gene UL30): C625R. All three antivirals used in this case are small molecules and pharmacokinetics of VACV, FOS, and CDV have not been evaluated in animals and there are very few studies in human. As small molecules are poorly bound to proteins and distribution volume is increased in obese patients, there is risk of underdosage. This mechanism is suspected to be involved in emergence of resistance mutation and further data is needed to adapt, closely to patient profile, antiviral dosage. This report describes a chronic HSV-2 genital lesion, with resistance to current antivirals and novel mutations within viral TK and DNA pol which may confer antiviral resistance.

Impact of vulvar reconstruction on the accuracy of a nomogram for predicting local recurrence after surgery for vulvar cancer.

BACKGROUND DATA: Vulvar carcinoma is a rare disease accounting for 3%-5% of all gynaecological cancers. Although surgery is the standard treatment at an early stage, the outcomes are highly correlated with clear resection margins. Therefore, surgical defects can be important and require reconstruction. The aim of this study was to evaluate vulvar reconstructions using a previously validated nomogram predicting the risk of local recurrence at 2 years. METHODS: Patients who underwent surgery for vulvar cancer between 1998 and 2017 were extracted from eight FRANCOGYN centres. We estimated the probability of local recurrence at 2 years using a previously validated nomogram and compared it with actual relapse in patients with or without vulvar reconstruction. Patients were clustered into tiertiles according to their nomogram score: low-, intermediate-, and high-risk for local relapse probability. RESULTS: We reviewed 254 patients, of whom 49 underwent immediate vulvar reconstruction. The predicted and actual probability of two-year local relapse were 20.1% and 15.7%, respectively, with a concordance index of 0.75. In the low- and intermediate-risk groups, the difference between predicted and observed recurrence was less than 10% in patients with or without vulvar reconstruction. For the high-risk group, the difference reached 25% and observed recurrence probability was lower in patients who underwent vulvar plasty compared with those who did not (20.0% vs. 36.2%, respectively). Local recurrence-free survival rates following vulvar reconstruction were comparable at two years (82.1% vs. 84.8%, respectively, p = 0.26). CONCLUSION: Vulvar reconstruction after surgical resection for vulvar cancer is safe. Vulvar reconstruction should be considered in aggressive cases to decrease local recurrence.

Prospective study of fertility-sparing treatment with chlormadinone acetate for endometrial carcinoma and atypical hyperplasia in young women.

OBJECTIVE: To confirm that the efficiency of the use of chlormadinone acetate for 6 months to obtain remission of atypical hyperplasia or endometrial carcinoma is comparable to that of the use of other fertility-sparing treatments. METHOD: The present study is based on the PREFERE prospective registry. All the patients received 3 or 6 months of chlormadinone acetate and were evaluated by hysteroscopic resection and pipelle sampling every 3 months. RESULTS: Ninety-four patients were included. Seventy-nine patients achieved complete remission at 6 months (84%). No patients stopped treatment because of a lack of tolerance. Twenty-four per cent of the patients achieved a live birth. CONCLUSION: Chlormadinone acetate is an effective and well-tolerated fertility-sparing treatment. Its benefits over other progestins are its tolerability, and its absence of contraindications, which make it a good choice for patients with thromboembolism and high vascular risk.

PD-1/PD-L1 expression in anal squamous intraepithelial lesions.

INTRODUCTION: Studies have shown that the PD-1/PD-L1 immunomodulatory pathway slows down anti-tumor immunity in a number of cancers. The description of the expression of these molecules has never been performed in anal low-grade/high grade squamous intra-epithelial lesions (LSIL/HSIL respectively). MATERIALS AND METHODS: Patients followed in the AIN3 cohort were routinely sampled. For each selected sample, an immunohistochemical study was performed with anti-CD8, PD-1, PD-L1 antibodies. The presence and distribution of CD8+ lymphocytes, and the presence of PD-1+ lymphocytes and PD-L1+ epithelial cells were assessed. The comparison of these characteristics was performed between the HSIL and LSIL groups. RESULTS: 33 patients were included and 78 samples selected (60 HSIL and 18 LSIL). CD8+ lymphocytes were observed more frequently in HSIL versus LSIL in the lamina propria or intra epithelial (respectively 90% vs. 60%, p = 0.01; and 62% vs. 33%, p = 0.04). PD-1+ lymphocytes were observed more frequently in HSIL versus LSIL (41% vs 11%, p = 0.03). There was no difference between HSIL and LSIL for PD-L1+ epithelial cells. CONCLUSIONS: Anal dysplastic lesions are accompanied by an inflammatory lymphocytic infiltrate expressing CD8 and PD-1, more frequent in high-grade lesions. These results highlight the involvement of the PD-1/PD-L1 pathway in the natural history of anal dysplasia.

Presence of Human Papillomavirus (HPV) Apolipoprotein B Messenger RNA Editing, Catalytic Polypeptide-Like 3 (APOBEC)-Related Minority Variants in HPV-16 Genomes From Anal and Cervical Samples but Not in HPV-52 and HPV-58.

Background: The aim of this study was to investigate the presence of minority variants (MVs) in high-risk human papillomavirus (HPV) types (HPV-16, -52, and -58) from cervical and anal smears. Methods: Whole HPV genome ultra-deep sequencing (UDS) was performed on cervical and anal smears collected during patient follow-up. Bioinformatics analyses were performed using Bowtie2 (Geneious). Results: We assessed 55 HPV-16-positive, 20 HPV-52-positive, and 17 HPV-58-positive samples, with significant differences in patient characteristics for the 2 anatomic sites. HPV-16 MVs were detected in 20 samples (36%), with no difference between cervical and anal samples. We did not find an association between the presence of MVs and cytovirological parameters. Seven HPV-16 genomes (13%) were apolipoprotein B messenger RNA editing, catalytic polypeptide-like 3 (APOBEC) edited. Among the cervical HPV-16-positive samples, most MVs (55%) resulted from APOBEC-related mutations. MVs were detected in 10 HPV-52-positive (50%) and 12 HPV-58-positive (71%) samples, with no difference between cervical and anal samples. No APOBEC-related mutations were found on HPV-58 or HPV-52 genomes. Conclusions: Overall, high-risk HPV MVs were found in about half of all cases in both anal and cervical samples. Interestingly, we reported for the first time a differential impact of APOBEC3 mutagenic activity depending on high-risk HPV type.

18F-FDG Uptake in Well-Differentiated Neuroendocrine Tumors Correlates with Both Ki-67 and VHL Pathway Inactivation.

BACKGROUND: 18F-FDG-PET scan positivity correlates with poor prognosis in neuroendocrine neoplasms (NEN). Glucose transporter 1 (GLUT1) and carbonic anhydrase 9 (CA9) are markers of aggressiveness in tumors. Together with von Hippel-Lindau protein (pVHL), they are involved in tumor cell metabolism via the hypoxia-inducible factor signaling pathway. The aim of this study was to compare, in a series of well-differentiated neuroendocrine tumors (NET), the 18F-FDG uptake and expression of the proliferation markers Ki-67, GLUT1, CA9, and pVHL. PATIENTS AND METHODS: This retrospective study included 27 patients with well-differentiated NET. 18F-FDG-PET images were evaluated by the maximum standardized uptake value (SUVmax). GLUT1, CA9, and pVHL were analyzed by immunohistochemistry. RESULTS: The NET were of pancreatic (n = 19), midgut (n = 4), duodenal (n = 1), esophageal (n = 1), rectal (n = 1), and pulmonary (n = 1) origin. Eight, 11, and 8 tumors were grade 1, 2, and 3, respectively. The mean/median Ki-67 index was 15/10% (1-60). The mean/median SUVmax was 6.2/5.2 (1.4-18.7). SUVmax correlated with greater tumor size (p = 0.03), higher expression of Ki-67 (p = 0.04), and lower expression of pVHL (p = 0.008). In the group of 16 NET with a low proliferative index (Ki-67 index <10%), 5/6 (83%) of the tumors with a high SUVmax had decreased pVHL expression (p = 0.0013). CONCLUSION: This study confirms that 18F-FDG-PET uptake correlates with both tumor size and proliferation in well-differentiated NET, and it highlights a subset of low-grade but 18F-FDG-PET-positive NET related to sporadic inactivation of the VHL pathway.

Magnetic Resonance Imaging Compared with Rectal Endoscopic Sonography for the Prediction of Infiltration Depth in Colorectal Endometriosis.

STUDY OBJECTIVE: To compare the accuracies of magnetic resonance imaging (MRI) and rectal endoscopic sonography (RES) in the prediction of the infiltration depth of colorectal endometriosis. DESIGN: A retrospective cohort study (Canadian Task Force classification II-2). SETTING: A university teaching hospital. PATIENTS: Forty patients with symptomatic deep infiltrating endometriosis (DIE) of the rectum who underwent colorectal resection were included. INTERVENTIONS: All patients underwent abdominopelvic MRI and RES preoperatively to assess the infiltration depth of colorectal endometriosis, and segmental resection of the rectosigmoid by laparoscopy was performed if RES showed bowel invasion. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive and negative likelihood ratios (LRs), and intermethod agreement were calculated for DIE muscularis and submucosal/mucosal infiltration confirmed by histopathological analysis. MEASUREMENTS AND MAIN RESULTS: For MRI detection of DIE muscularis infiltration, the sensitivity, specificity, PPV, NPV, and negative LR were 68%, 100%, 100%, 20%, and 0.32, respectively. For the MRI detection of DIE submucosal/mucosal involvement, the sensitivity, specificity, PPV, NPV, and positive and negative LRs were 47%, 81%, 69%, 63%, 2.49, and 0.65, respectively. The PPV of RES detection of DIE muscularis infiltration was 93%. For the RES detection of DIE submucosal/mucosal layers, the sensitivity, specificity, PPV, NPV, and positive and negative LRs were 79%, 48%, 58%, 71%, 1.51, and 0.44, respectively. CONCLUSION: In the current study, MRI is valuable for detecting endometriosis of the rectum but is less accurate in detecting submucosal/mucosal involvement than RES. Magnetic resonance imaging was not successful for preoperative determination of segmental resection versus a more conservative approach. When bowel involvement is detected by MRI, RES is not essential. When symptoms suggest DIE in patients without intestinal lesions detected by MRI, RES is necessary to exclude bowel invasion.

Liver resection in patients with hepatic hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Rendu-Weber disease, is a rare genetic disorder characterized by widespread telangiectasia and vascular malformations involving the liver in most of the cases. The consequences of this pathologically underlying parenchyma on liver resection have been poorly described. METHODS: More than 2,000 liver resections were performed at our institution over a 14-year period, whereby 2 major hepatectomies for malignancy were performed on patients with HHT with liver involvement. In addition, a systematic search was performed in the PubMed database to identify all original articles on hepatectomy in patients with HHT. RESULTS: The first patient underwent a left hepatectomy for cholangiocarcinoma with an uneventful postoperative course. The second patient underwent right hepatectomy and segment 3 resection for colorectal liver metastases. The postoperative course was marked by ascites without liver failure. For both patients, 90-day mortality was nil. CONCLUSION: In selected HHT patients with liver involvement, liver resections, including major hepatectomies, can be safely performed. Specific attention should be paid to postoperative liver function and ascites.