[Effectiveness of "threshold" in the management of ovarian cancer: A review of the literature]. / Efficacité des « seuils ¼ dans la prise en charge des cancers de l'ovaire : revue de la littérature.

OBJECTIVE: The "Institut national du cancer" has established since 2007 a minimum threshold of 20 patients per year per center to treat patients with gynecologic cancer. This review aims to assess whether the literature data validate this approach, and specifically for ovarian cancer. METHODS: A search of the MEDLINE database was conducted, to reference all relevant articles evaluating one hand the links between the survival of patients with ovarian cancer and the average volume of patients per center and by operator; and secondly the relationship between quality of oncological surgery and these volumes. RESULTS: Nineteen studies met our inclusion criteria; seventeen were retrospective and two were prospective; population samples ranged from 476 to 96,802 patients. The most important data, quantitatively and qualitatively, concern the evaluation of survival based on the average volume per center, with 8 out of 13 studies finding a statistically significant correlation between average volume per center and survival. Data on the quality of surgery are less abundant and more heterogeneous, depending on the definition of the "optimal" surgery by the authors. CONCLUSION: The establishment of threshold centers appears to be an effective way to improve survival in ovarian cancer. However, these thresholds would have to be specific to ovarian cancer and not extended to "gynecological cancers."

[Epidemiology and risk factors for cancer of the uterus]. / Epidémiologie et facteurs de risque des cancers de l'utérus.

Cancers of the uterus correspond to cervical cancers and uterine corpus cancers. Cervical cancer is common among young women, especially in immunocompromised populations. Its carcinogenesis is induced by the human papilloma virus (HPV). All factors promoting the HPV contamination and/or limiting the clearance of HPV or promoting its progression are risk factors for cervical cancer: sex at an early age, multiple sexual partners, multiparty, smoking, hormonal contraceptives, immunosuppression or certain infections. Cancers of the uterine corpus, substantially represented by endometrial cancers, represent the fourth leading cause of cancer in women in France. Risk factors are related to hyperestrogenism with early age of menarche and late menopause, obesity, diabetes, inadequate hormone-replacement therapy for menopause. Endometrial cancers fall in the scope of familial cancers making evoke a Lynch syndrome/HNPCC.

Pregnancy stimulates tumor angiogenesis in breast carcinoma.

The mechanisms responsible for the poor prognosis of pregnancy-associated breast cancer (PABC) remain not well-understood. We studied angiogenesis and lymphangiogenesis as they are known prognostic factors in breast cancer. We conducted a case control study of breast cancer comparing women with and without PABC matched for age and histological parameters. Surgical specimen sections were immunostained with anti-CD31 for angiogenesis and anti-D2-40 for lymphangiogenesis, then analyzed using vessel density, ratio of the vascular area and the Chalkley count. Seventeen patients with PABC and 22 controls were included. Angiogenesis was significantly increased in tumor tissues, and tended to be higher in healthy breast tissues from the PABC group compared to controls. In contrast, no difference between the two groups was found concerning lymphangiogenesis both in tumor and healthy breast tissues. Pregnancy enhances angiogenesis in breast cancer. This phenomenon appears to explain the poor prognosis of PABC.

Evaluation of a method of predicting lymph node metastasis in endometrial cancer based on five pre-operative characteristics.

OBJECTIVE: We recently developed an algorithm based on five clinical and pathological characteristics to predict lymph node (LN) metastasis in endometrial cancer. The aim of this study was to evaluate the accuracy of using this algorithm with preoperative characteristics. STUDY DESIGN: In this retrospective multicenter study, we evaluated the accuracy of using an algorithm to predict LN metastasis using preoperative tumor characteristics provided by endometrial sampling pathological characteristics (histological subtype and grade) and by magnetic resonance imaging (MRI) for primary site tumor extension. RESULTS: In total, 181 patients were included in this study, and 14 patients had pelvic LN metastasis (7.7%). Using preoperative tumor characteristics, the algorithm showed good discrimination with an area under the receiver operating characteristic curve (AUC) of 0.83 (95% confidence interval (IC95)=0.79-0.87) and was well calibrated (average error=1.9% and maximal error=8.5%). LN metastasis prediction by the algorithm using preoperative data was as accurate as that obtained using the final tumor characteristics (AUC=0.77 (CI95=0.70-0.83), average error=2.8% and maximal error=23.2%). CONCLUSION: Our algorithm was accurate in predicting pelvic LN metastasis even with the use of preoperative tumor characteristics provided by endometrial sampling and MRI. These findings, however, should be verified in a larger database before our algorithm is implemented for widespread use.

tRNA methyltransferase homolog gene TRMT10A mutation in young onset diabetes and primary microcephaly in humans.

We describe a new syndrome of young onset diabetes, short stature and microcephaly with intellectual disability in a large consanguineous family with three affected children. Linkage analysis and whole exome sequencing were used to identify the causal nonsense mutation, which changed an arginine codon into a stop at position 127 of the tRNA methyltransferase homolog gene TRMT10A (also called RG9MTD2). TRMT10A mRNA and protein were absent in lymphoblasts from the affected siblings. TRMT10A is ubiquitously expressed but enriched in brain and pancreatic islets, consistent with the tissues affected in this syndrome. In situ hybridization studies showed that TRMT10A is expressed in human embryonic and fetal brain. TRMT10A is the mammalian ortholog of S. cerevisiae TRM10, previously shown to catalyze the methylation of guanine 9 (m(1)G9) in several tRNAs. Consistent with this putative function, in silico topology prediction indicated that TRMT10A has predominant nuclear localization, which we experimentally confirmed by immunofluorescence and confocal microscopy. TRMT10A localizes to the nucleolus of ß- and non-ß-cells, where tRNA modifications occur. TRMT10A silencing induces rat and human ß-cell apoptosis. Taken together, we propose that TRMT10A deficiency negatively affects ß-cell mass and the pool of neurons in the developing brain. This is the first study describing the impact of TRMT10A deficiency in mammals, highlighting a role in the pathogenesis of microcephaly and early onset diabetes. In light of the recent report that the type 2 diabetes candidate gene CDKAL1 is a tRNA methylthiotransferase, the findings in this family suggest broader relevance of tRNA methyltransferases in the pathogenesis of type 2 diabetes.

A nomogram for predicting lymph node metastasis of presumed stage I and II endometrial cancer.

OBJECTIVE: Our objective was to develop a nomogram based on pathological hysterectomy characteristics to provide a more individualized and accurate estimation of lymph node metastasis in endometrial cancer. STUDY DESIGN: Data from the Surveillance, Epidemiology, and End Results database for 18,294 patients who underwent hysterectomy and lymphadenectomy were analyzed. A multivariate logistic regression analysis of selected prognostic features was performed, and a nomogram to predict lymph node metastasis was constructed. A cohort of 434 patients was used for the external validation. RESULTS: The nomogram showed good discrimination with an area under the receiver operating characteristic curve of 0.80 (95% confidence interval, 0.79-0.81) in the training set and 0.79 (95% confidence interval, 0.78-0.80) in the validation set. The nomogram was well calibrated. CONCLUSION: We developed a nomogram based on 5 clinical and pathological characteristics to predict lymph node metastasis with a high concordance probability.

Kinetochore KMN network gene CASC5 mutated in primary microcephaly.

Several genes expressed at the centrosome or spindle pole have been reported to underlie autosomal recessive primary microcephaly (MCPH), a neurodevelopmental disorder consisting of an important brain size reduction present since birth, associated with mild-to-moderate mental handicap and no other neurological feature nor associated malformation. Here, we report a mutation of CASC5 (aka Blinkin, or KNL1, or hSPC105) in MCPH patients from three consanguineous families, in one of which we initially reported the MCPH4 locus. The combined logarithm of odds score of the three families was >6. All patients shared a very rare homozygous mutation of CASC5. The mutation induced skipping of exon 18 with subsequent frameshift and truncation of the predicted protein. CASC5 is part of the KMN network of the kinetochore and is required for proper microtubule attachment to the chromosome centromere and for spindle-assembly checkpoint (SAC) activation during mitosis. Like MCPH gene ASPM, CASC5 is upregulated in the ventricular zone (VZ) of the human fetal brain. CASC5 binds BUB1, BUBR1, ZWINT-1 and interestingly it binds to MIS12 through a protein domain which is truncated by the mutation. CASC5 localized at the equatorial plate like ZWINT-1 and BUBR1, while ASPM, CEP152 and PCTN localized at the spindle poles in our patients and in controls. Comparison of primate and rodent lineages indicates accelerated evolution of CASC5 in the human lineage. Our data provide strong evidence for CASC5 as a novel MCPH gene, and underscore the role of kinetochore integrity in proper volumetric development of the human brain.

Pregnancy-associated breast cancers: do they differ from other breast cancers in young women?

The impact of pregnancy in the physiopathology of pregnancy-associated breast cancer (PABC) is still unclear. We compared the characteristics of PABCs and breast cancers not associated with pregnancy (non-PABCs) in terms of their loco-regional invasion and histological phenotype. We conducted a retrospective chart review on women less than 43 years of age treated for breast cancer from January 1, 2004 to December 31, 2010. We compared age at diagnosis, loco-regional invasion and histological data. We recorded 282 breast cancers in 276 patients. Forty-one tumors (14.5%) were PABCs. PABC patients were significantly younger than non-PABC patients. Compared with the non-PABCs, PABCs were twice more frequent advanced tumors (T3-4) and have twice more frequent HER2 over-expression and hormone negative status. The more aggressive histological profile observed in the PABCs, especially in post-partum tumors and women older than 35 years of age, seems to be a direct consequence of the association with pregnancy.

The survival impact of systematic lymphadenectomy in endometrial cancer with the use of propensity score matching analysis.

OBJECTIVE: We sought to evaluate whether patients with endometrial cancer in the Surveillance, Epidemiology, and End Results database who underwent lymphadenectomy demonstrate improved survival. STUDY DESIGN: The study population comprised 50,969 patients. The 3-year cause-specific survival was tested by using propensity score matching (PSM) analysis. RESULTS: The PSM analysis generated a balanced, matched cohort in which baseline characteristics were not significantly different. The benefit of systematic lymphadenectomy appears to be significant for presumed stage I International Federation of Gynecology and Obstetrics grade 3 cancers and presumed stages II-III cancer. The omission of lymphadenectomy in stage I did not appear to show a deleterious survival consequence if the differentiation grade was moderate (grade 2) or well (grade 1). CONCLUSION: Using PSM analysis, our results show no evidence of benefit in terms of survival for systematic lymphadenectomy in women with stage I endometrial cancer, except for grade 3 cancers.