Chemotherapy is not needed when complete evacuation of gestational choriocarcinoma leads to hCG normalization.

BACKGROUND: The standard treatment for gestational choriocarcinoma is chemotherapy. OBJECTIVE: To describe the risk of recurrence with expectant management of gestational choriocarcinoma that has reached a normal human chorionic gonadotropin level after tumor removal without adjuvant chemotherapy. METHODS: A retrospective multicenter international cohort study was conducted from 1981 to 2017 involving 11 gestational trophoblastic disease reference centers with patient's follow-up extended until 2023. Clinical and biological data of included patients were extracted from each center's database. The inclusion criteria were i) histological diagnosis of gestational choriocarcinoma in any kind of placental tissue retrieved, ii) spontaneous normalization of human chorionic gonadotropin level following choriocarcinoma retrieval, iii) patient did not receive any oncological treatment for the choriocarcinoma, iv) and at least 6 months of follow-up after the first human chorionic gonadotropin level normalization. RESULTS: Among 80 patients with retrieved gestational choriocarcinoma and whose human chorionic gonadotropin level normalized without any other oncological therapy, none had a recurrence of choriocarcinoma after a median follow-up of 50 months. The median interval between choriocarcinoma excision and human chorionic gonadotropin level normalization was 48 days. The International Federation of Gynecology and Obstetrics/World Health Organization risk score was ≤6 in 93.7% of the cases. CONCLUSIONS: This multicenter international study reports that selected patients with gestational choriocarcinoma managed in gestational trophoblastic disease reference centers did not experience any relapse when the initial tumor evacuation is followed by human chorionic gonadotropin level normalization without any additional treatment. Expectant management may be a safe approach for highly selected patients.

Impact of molecular genotyping on the diagnosis and treatment of human chorionic gonadotropin-producing tumors.

OBJECTIVES: To assess the use of molecular genotyping to accurately diagnose and treat human chorionic gonadotropin (hCG)-producing tumors and to evaluate the discriminating capacity of molecular testing on prognosis and overall survival. METHODS: We conducted a retrospective descriptive study of patients registered with the French Reference Center for Trophoblastic Disease between 1999 and 2021. We included all patients with hCG-producing tumors for whom results of molecular genotyping were available. RESULTS: Fifty-five patients with molecular genotyping were included: 81.2 % (n = 45) had tumors of gestational origin, 12.7 % (n = 7) of non-gestational origin and 5.5 % (n = 3) of undetermined origin. The results of molecular genotyping influenced the treatment decisions for 17 % of patients in this cohort. Overall survival was 93.3 % for patients with gestational tumors (after a median follow-up of 74 months) compared to 71.4 % for patients with non-gestational tumors (after a median follow-up of 23 months). CONCLUSION: In atypical presentations of hCG-producing tumors, molecular genotyping is a valuable tool to guide diagnosis and tailor treatment recommendations.

[Contribution of meb to endometriosis patients' diagnosis and treatment]. / Apport de la réunion de concertation pluridisciplinaire à la pertinence du diagnostic et du traitement de l'endométriose.

OBJECTIVES: Diagnosis and treatment of endometriosis may be complex and therefore justify the discussion of therapeutic decisions in a multidisciplinary endometriosis board (MEB). The development of endometriosis regional expert centers requires an assessment of the quality and relevance of MEB. METHODS: Qualitiative retrospective study on patients whose management was discussed in Centre Hospitalier Lyon-Sud between June 2013 and December 2017. RESULTS: Among 376 patients presented in MEB, 309 (80.2%) were painful and 184 (59.5%) had complex endometriosis. A complete clinical evaluation was performed in 120 (38.8%) patients. MRI was performed for 370 (98.4%) patients including 303 (81.9%) with a second reading by an expert radiologist. These second readings allowed a diagnosis correction in 88 (60.7 %) patients with complex endometriosis. MR enterography (27.8 %) and rectal endoscopic sonography (14.4%) were the most frequently used third-line exams to complete the initial imaging of digestive lesion in patients with rectal endometriosis. Surgery was proposed for 199 (52,9%) patients including 108 (58,7%) with complex endometriosis. CONCLUSION: One of the major interests of MEB in endometriosis is the second reading of MRI, which, by identifying complex endometriosis initially undiagnosed or underestimated, enabled to better discuss the benefits/risks of therapeutic choices, and to organize complex surgeries when those were retained. The development of MEB in regional expert centers will contribute to optimizing the relevance of care for patients with endometriosis.

[Elaboration of a national biobank for the study of gestational trophoblastic diseases]. / Création d'une biobanque nationale pour l'étude des maladies trophoblastiques gestationnelles.

AIM: To generate a national biobank made up of samples of the highest quality for the purpose of inciting basic research on gestational trophoblastic diseases (GTD). MATERIAL AND METHODS: Three priority axes of research were defined to optimize the nature, method of collection, and storage of the samples. These are: to enhance our understanding of GTD, develop new diagnostic tests, and identify new therapeutic targets. The protocol for patient inclusion and sample processing was determined after extensive literature review and collaboration with international experts in the field of GTD. RESULTS: For each patient with a GTD and for control patients (legally induced abortions), chorionic villi, decidua and tumor samples (fresh, immersed in RNA-protective solution and fixed in formaldehyde), blood (serum, plasma, RNA, and peripheral blood mononuclear cells), urine (supernatant), and cell cultures of villous cytotrophoblasts are prospectively collected. Associations are then made between the collected samples and numerous clinical and biological data, such as human chorionic gonadotropic plasma levels following curettage in the case of a hydatidiform mole. CONCLUSION: Such a collection of high quality samples and their associated data open up new perspectives for both national and international collaborative research projects.

Risk of gestational trophoblastic neoplasia after hCG normalisation according to hydatidiform mole type.

OBJECTIVE: The risk of gestational trophoblastic neoplasia (GTN) after a hydatidiform mole (HM) is well known. However, the risk of GTN after normalisation of hCG in HM is poorly reported. The aim of this study was to evaluate the risk of GTN after normalisation of hCG according to HM types. METHODS: This prospective cohort study carried out between 2000 and 2010 used the database of the French Trophoblastic Disease Centre (FTDC). A total of 2008 registered patients with ascertained types of HM were analysed. Cases of GTN occurring after normalisation of hCG were analysed. RESULTS: A GTN developed in 239 out of 1980 HMs (12.1%) and 6 out of these 239 post-molar GTN (2.5%) were diagnosed after normalisation of hCG. The risk of GTN after normalisation of hCG was 0.34% (6/1747) following a HM, 0% (0/593) after a partial HM (PHM), 0.36% (4/1122) after a complete HM (CHM), and 9.5% (2/21) after a multiple pregnancy with HM. CONCLUSIONS: The risk of post-molar GTN justifies hCG monitoring in all women with HM. However, after normalisation of hCG, monitoring of PHM can be stopped safely while it should be maintained for CHM and more importantly for multiple pregnancies with HM.

[Living birth after partial hysterectomy for chemorefractory gestational choriocarcinoma]. / Naissance vivante après hystérectomie partielle pour choriocarcinome gestationnel chimiorésistant.

Chemotherapy is the reference treatment for gestational trophoblastic neoplasia. In case of chemoresistance, hysterectomy has to be considered even in women wishing to conceive. A 31-year-old nulliparous patient presented a recurrent invasive mole, despite two regimens of chemotherapy. She underwent a partial uterine resection of an intramyometrial choriocarcinoma followed by a third-line regimen. Two years later she gave birth by cesarean section at 32 weeks of amenorrhea to a healthy child after a spontaneous pregnancy. In order to preserve patient's fertility, conservative uterine surgery is an alternative to hysterectomy for selected chemoresistant gestational trophoblastic neoplasia.

[Review: Repetitive hydatidiform moles]. / Review : les môles hydatiformes à répétition.

Repetitive moles are rare. They are either sporadic or familial, with or without consanguinity. Some of them can be explained by a NLRP7 mutation, which causes genomic parental imprinting alteration, with a preferential paternal phenotypic expression. Currently, no effective therapeutic solution has been developed. Among the 1687 patients declared to the French Trophoblastic Disease Reference Center, 13 presented at least two hydatidiform moles, thus less than 1% of the patients. A mutation of the NLRP7 gene was shown in six of 12 tested patients (50%) among whom three presented a homozygous mutation and three a heterozygous mutation. For an affected patient, type of mole can indifferently be a complete hydatidiform mole or a partial hydatidiform mole. We describe these cases and compare them to those already published.

Predictive values of hCG clearance for risk of methotrexate resistance in low-risk gestational trophoblastic neoplasias.

BACKGROUND: Early identification of patients at high risk for chemoresistance among those treated with methotrexate (MTX) for low-risk gestational trophoblastic neoplasia (GTN) is needed. We modeled human chorionic gonadotropin (hCG) decline during MTX therapy using a kinetic population approach to calculate individual hCG clearance (CL(hCG)) and assessed the predictive value of CL(hCG) for MTX resistance. PATIENTS AND METHODS: A total of 154 patients with low-risk GTN treated with 8-day MTX regimen were retrospectively studied. NONMEM was used to model hCG decrease equations between day 0 and day 40 of chemotherapy. Receiver operating characteristic curve analysis defined the best CL(hCG) threshold. Univariate/multivariate survival analyses determined the predictive value of CL(hCG) and compared it with published predictive factors. RESULTS: A monoexponential equation best modeled hCG decrease: hCG(t) = 3900 x e(-0.149 x t). Median CL(hCG) was 0.57 l/day (quartiles: 0.37-0.74). Only choriocarcinoma pathology [yes versus no: hazard ratio (HR) = 6.01; 95% confidence interval (CI) 2.2-16.6; P < 0.001] and unfavorable CL(hCG) quartile (< or =0.37 versus >0.37 l/day: HR = 6.75; 95% CI 2.7-16.8; P < 0.001) were significant independent predictive factors of MTX resistance risk. CONCLUSION: In the second largest cohort of low-risk GTN patients reported to date, choriocarcinoma pathology and CL(hCG) < or =0.37 l/day were major independent predictive factors for MTX resistance risk.

[Evaluation of treatment relating to gestational trophoblastic tumor registered to the French Trophoblastic Disease Reference Center (TDRC) in Lyon from 1999 to 2005]. / Evaluation de la prise en charge des tumeurs trophoblastiques gestationnelles enregistrées au Centre de référence des maladies trophoblastiques de Lyon de 1999 à 2005.

OBJECTIVES: The aim of this study was both to analyse if gestational trophoblastic neoplasia (GTN) registered to the French Trophoblastic Disease Reference Center (TDRC) in Lyon (France) were managed according to the FIGO criteria for diagnosis of GTN and if chemotherapy was adapted to the 2000 FIGO prognostic scoring system. PATIENTS AND METHODS: Retrospective, descriptive analysis of 167 GTN registered to GTC of Lyon between 1999 and 2005. RESULTS: On the one hand, 66% of women (104/158) had a diagnosis of GTN according to FIGO criteria. One third (n=54) of the patients therefore had a premature or erroneous diagnosis of a tumor, when the treatment started. No supporting element of this premature diagnosis has been found out for 26 patients. The identification of lung and vaginal metastasis and histological diagnosis of invasive mole appeared as the most mentioned inappropriate criteria for diagnosis. On the other hand, chemotherapy was adapted to 2000 FIGO scoring in 91, 5% of cases. Twelve low risk GTN were treated with polychemotherapy and two high risk GTN were treated with monochemotherapy. Moreover 29% of the patients received a non adequate treatment due to deviations from the recommended protocol. DISCUSSION AND CONCLUSION: Non respect of FIGO criteria for the diagnosis of GTN can lead to erroneous diagnosis of tumors. Identification of lung or vaginal metastasis or diagnosis of invasive mole should not automatically justify the diagnosis of gestational trophoblastic neoplasia if the decrease in HCG occurs properly. Respect of FIGO criteria for the diagnosis of GTN and adaptation of chemotherapy to 2000 FIGO scoring are necessary to avoid inadequate treatment of gestational trophoblastic neoplasia.

Estimates of the number of cancer patients hospitalized in a geographic area using claims data without a unique personal identifier.

OBJECTIVE: In French national claims databases, claims are currently anonymous i.e. not linked to individual patients. In order to improve our estimate of the medical activity related to cancer in one French region, a statistical method was developed to use claims data to assess the number of cancer patients hospitalized in acute care. METHODS: This method used the medical and administrative information available in the claims (i.e. age, primary site, length of stay) to predict an average number of stays per patient, followed by a number of patients. It was based on a two-phase study design using an internal dataset which contained personal identifiers to estimate the model parameters. RESULTS: The predicted number of acute care patients hospitalized in one or several health care centers in one French region was 38,109 with a 95% predictive interval (37,990; 38,228) for the first six months of 2002. A prediction error of 24 per thousand was found. CONCLUSION: We provide a good estimate of the morbidity in acute care hospitals using claims data that is not linked to individual patients. This estimate reflects the medical activity and can be used to anticipate acute care needs.

Quantitative ultrasound parameters as well as bone mineral density are better predictors of trochanteric than cervical hip fractures in elderly women. Results from the EPIDOS study.

RATIONALE: Hip fractures can be separated into cervical and trochanteric fractures. Trochanteric fractures have been associated with up to twice the short-term mortality of cervical fractures in the elderly. There is also evidence suggesting that the mechanisms are different. Evidence from the literature remains limited on the predictive power of bone mineral density (BMD) and quantitative ultrasounds (QUS) for both types of hip fractures. METHODS: 5703 elderly women aged 75 years or more, who were recruited from the voting lists in the EPIDOS study, and had baseline calcaneal ultrasounds (QUS) and DXA measurements at the hip and the whole body, were analyzed in this paper. Among those, 192 hip fractures occurred during an average follow-up of 4 years, 108 cervical and 84 trochanteric fractures. RESULTS: Femoral neck, trochanteric and whole body BMD were able to predict trochanteric hip fracture (RR's and 95% CI were, respectively, 3.2 (2.4-4.2); 4.8 (3.5-6.6); and 2.8 (2.2-3.6)) more accurately than cervical fractures (respectively, 2.1 (1.7-2.7); 2.3 (1.8-3.0); 1.2 (1.0-1.6)). All ultrasound parameters, SOS, BUA, and stiffness index (SI) were significant predictors of trochanteric (RR's respectively 3.0 (2.2-4.1), 2.5(2.0-3.1), and 3.5(2.6-4.7)) but not cervical fractures. After adjustment for femoral neck or trochanteric BMD ultrasound parameters were still significant predictors of trochanteric fracture, and stiffness tended to be a better predictor of trochanteric fractures than either BUA or SOS with a relative risk of 2.25 (1.6-3.1). CONCLUSIONS: A significant decrease of all bone measurements, BMD and QUS, was highly predictive of trochanteric fractures, whereas a decrease of femoral neck and trochanteric BMD were only associated with a slight increase in cervical fracture risk and a low total body BMD or QUS parameters were not significant predictors of cervical fractures. In women who sustained a hip fracture, the decrease of BMD and QUS values increases the risk of trochanteric fracture as compared to cervical fracture. Trochanteric fractures were mostly a consequence of a generalized low BMD and QUS, whereas other parameters might be involved in cervical fractures.

Role of CD36 in membrane transport and utilization of long-chain fatty acids by different tissues.

The transmembrane glycoprotein CD36 has been identified in isolated cell studies as a putative transporter of long-chain fatty acids. To examine the physiological role of CD36, we studied FA uptake and metabolism by tissues of CD36 null mice after injection with two fatty acid analogs. Compared to controls, uptake was substantially reduced (50-80%) in heart, skeletal muscle, and adipose tissues of null mice. The reduction in uptake was associated with a large decrease in fatty acid incorporation into triglycerides, which could be accounted for by an accumulation of diacylglycerides. Thus CD36 facilitates a major fraction of fatty acid uptake by myocardial, skeletal muscle, and adipose tissues, where it is highly expressed. Its role in other tissues where its expression is low and cell-specific could not be determined in these studies.

Defective fatty acid uptake in the spontaneously hypertensive rat is a primary determinant of altered glucose metabolism, hyperinsulinemia, and myocardial hypertrophy.

Genetic linkage studies implicated deficiency of CD36, a membrane fatty acid (FA) transporter, in the hypertriglyceridemia and hyperinsulinemia of the spontaneously hypertensive rat (SHR). In this study we determined whether loss of CD36 function in FA uptake is a primary determinant of the SHR phenotype. In vivo, tissue distribution of iodinated, poorly oxidized beta-methyliodophenyl pentadecanoic acid (BMIPP) was examined 2 h after its intravenous injection. Fatty acid transport was also measured in vitro over 20 to 120 s in isolated adipocytes and cardiomyocytes obtained from SHR and from a congenic line (SHRchr4) that incorporates a piece of chromosome 4 containing wild-type CD36. SHR heart and adipose tissue exhibited defects in FA uptake and in conversion of diglycerides to triglycerides that are similar to those observed in the CD36 null mouse. However, a key difference in SHR tissues is that fatty acid oxidation is much more severely impaired than fatty acid esterification, which may underlie the 4-5-fold accumulation of free BMIPP measured in SHR muscle. Studies with isolated adipocytes and cardiomyocytes directly confirmed both the defect in FA transport and the fact that it is underestimated by BMIPP. Heart, oxidative muscle, and adipose tissue in the SHR exhibited a large increase in glucose uptake measured in vivo using [(18)F]fluorodeoxyglucose. Supplementation of the diet with short-chain fatty acids, which do not require CD36-facilitated transport, eliminated the increase in glucose uptake, the hyperinsulinemia, and the heart hypertrophy in the SHR. This indicated that lack of metabolic energy consequent to deficient FA uptake is the primary defect responsible for these abnormalities. Hypertension was not alleviated by the supplemented diet suggesting it is unrelated to fuel supply and any contribution of CD36 deficiency to this trait may be more complex to determine. It may be worth exploring whether short-chain FA supplementation can reverse some of the deleterious effects of CD36 deficiency in humans, which may include hypertrophic cardiomyopathy.

Catabolism of HDL1 cholesteryl ester in the rat. Effect of ethinyl estradiol treatment.

The present study was performed in control and ethinyl estradiol-treated rats in order to determine the mechanisms involved in the catabolism of HDL1 cholesteryl ester. Ligand blottings on liver membranes showed that purified HDL1, containing about 70% apolipoprotein E and 10% apolipoprotein AI, bind to the LDL receptor (130 kDa) and not to HB2 (100 kDa) or SR-BI (82 kDa), candidate HDL receptors. Immunoblots showed that the treatment increased the hepatic level of the LDL receptor five- to ten-fold, strongly decreased that of SRBI and did not change that of HB2. An in vivo kinetic study showed that the turnover of HDL1 cholesteryl ester is more rapid in treated than control rats. The liver participation (60%) in this clearance was not modified by the treatment. Therefore, it can be concluded that the catabolism of HDL1 cholesteryl ester, in control as in treated rats, is essentially ensured by the uptake of entire particles in the hepatocytes via LDL receptors.

Muscle-specific overexpression of FAT/CD36 enhances fatty acid oxidation by contracting muscle, reduces plasma triglycerides and fatty acids, and increases plasma glucose and insulin.

Increasing evidence has implicated the membrane protein CD36 (FAT) in binding and transport of long chain fatty acids (FA). To determine the physiological role of CD36, we examined effects of its overexpression in muscle, a tissue that depends on FA for its energy needs and is responsible for clearing a major fraction of circulating FA. Mice with CD36 overexpression in muscle were generated using the promoter of the muscle creatine kinase gene (MCK). Transgenic (MCK-CD36) mice had a slightly lower body weight than control litter mates. This reflected a leaner body mass with less overall adipose tissue, as evidenced by magnetic resonance spectroscopy. Soleus muscles from transgenic animals exhibited a greatly enhanced ability to oxidize fatty acids in response to stimulation/contraction. This increased oxidative ability was not associated with significant alterations in histological appearance of muscle fibers. Transgenic mice had lower blood levels of triglycerides and fatty acids and a reduced triglyceride content of very low density lipoproteins. Blood cholesterol levels were slightly lower, but no significant decrease in the cholesterol content of major lipoprotein fractions was measured. Blood glucose was significantly increased, while insulin levels were similar in the fed state and higher in the fasted state. However, glucose tolerance curves, determined at 20 weeks of age, were similar in control and transgenic mice. In summary, the study documented, in vivo, the role of CD36 to facilitate cellular FA uptake. It also illustrated importance of the uptake process in muscle to overall FA metabolism and glucose utilization.

A unique amyloidogenic apolipoprotein serum amyloid A (apoSAA) isoform expressed by the amyloid resistant CE/J mouse strain exhibits higher affinity for macrophages than apoSAA1 and apoSAA2 expressed by amyloid susceptible CBA/J mice.

CBA/J and other inbred strains of mice that express the amyloidogenic apolipoprotein serum amyloid A (apoSAA) apoSAA2, together with apoSAA1, are susceptible to amyloid A (AA) amyloidosis, whereas CE/J mice that express a single unique isoform, apoSAACEJ, are resistant. Studies indicate that CBA/JxCE/J hybrid mice that express apoSAA2 in the presence of apoSAACEJ are protected from amyloidogenesis. To define a mechanism by which expression of apoSAACEJ may protect from AA formation in the presence of apoSAA2, binding of recombinant apoSAA (r-apoSAA) isoforms, validated by N-terminal sequencing, to a murine macrophage cell line was investigated. Maximal specific binding occurred after incubation of radiolabeled apoSAA with IC-21 macrophages (1x105 cells/ml) for 30 min at 4 degreesC. The binding of 125I-r-apoSAA1, 125I-r-apoSAA2 and 125I-r-apoSAACEJ was specific and saturable, with an affinity (Kd) of about 2.8, 3.2 and 1.3 nM, respectively, and approximately 2-4x106 sites per cell. Competitive binding experiments indicate apoSAACEJ binds with higher affinity to macrophages than does either apoSAA1 or apoSAA2. We suggest that greater cellular affinity of apoSAACEJ compared to apoSAA2 may contribute to protection from AA amyloid in certain CBA/JxCE/J hybrid mice by interfering with interaction of apoSAA2 by macrophages and hence either membrane associated or intracellular degradation.

The acute phase response in apolipoprotein A-1 knockout mice: apolipoprotein serum amyloid A and lipid distribution in plasma high density lipoproteins.

In plasma, the bulk of apoSAA, a positive acute phase reactant protein, is transported in high density lipoproteins (HDL), especially HDLH (apoA1-rich HDL). In this study we tested whether apoA1 deficiency would adversely affect apoSAA concentration and lipid distribution in mouse plasma lipoproteins. Acute phase response (APR) was induced in C57BL/6J (apoA1+/+) and apoA1-knockout mice (apoA1-/-) by a subcutaneous injection of silver nitrate. The APR increased cholesterol concentrations in LDL of apoA1-/- mice and apoA1+/+ mice in a like manner. In contrast to apoA1+/+ mice, concentrations of cholesterol, phospholipids and proteins in both HDLL (1.063

Myristic acid-rich fat raises plasma LDL by stimulating LDL production without affecting fractional clearance in gerbils fed a cholesterol-free diet.

The imbalance that develops between low-density lipoprotein (LDL) production and clearance during saturated fat consumption is responsible for expanding the circulating LDL pool. To assess the imbalance attributable to fatty acids alone, i.e., without the interaction of dietary cholesterol, the most fat-sensitive species available (the gerbil) was challenged with either a 12:0+14:0 rich-fat (high coconut, low safflower) or high 18:2 (high safflower, low coconut) fat for 4-5 wks. The plasma lipoprotein cholesterol profile, including lipoprotein composition, particle size and 125I-LDL turnover were measured. Although total plasma cholesterol (TC) was threefold higher with saturated fatty acid (SFA) feeding (230 vs. 70 mg/100 mL; 5.9 +/- 0.1 vs. 1.8 +/- 0.05 mmol/L, P < 0. 0001) and LDL cholesterol (LDL-C) was fivefold greater (10 vs. 54 mg/100 mL; 0.26 +/- 0.02 vs. 1.4 +/- 0.02 mmol/L, P < 0.001), the high-density lipoprotein (HDL2) fraction increased the most (27 vs. 79 mg/100 mL; 0.7 +/- 0.02 vs. 2.0 +/- 0.1 mmol/L, P < 0.05) with minimal HDL3 (NS) difference (16 vs. 26 mg/100 mL; 0.43 +/- 0.08 vs. 0. 7 +/- 0.05 mmol/L). Particle composition and size did not differ between groups. LDL kinetic analyses revealed that the fractional catabolic rate did not differ between gerbils with these extreme fat intakes, implicating overproduction and not reduced clearance as the primary consideration in LDL expansion. Thus SFA-induced cholesterolemia can be severe in the absence of dietary cholesterol with a greater impact on high-density lipoprotein than LDL and without an appreciable role attributed to LDL clearance (receptors).