To cite this version:H M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT AbstractObjective: Pelvic exenteration requires complete resection of the tumor with negative margins to be considered a curative surgery. The purpose of this review is to assess the optimal preoperative evaluation and surgical approach in patients with recurrent cervical cancer to increase the chances of achieving a curative surgery with decreased morbidity and mortality in the era of concurrent chemoradiotherapy. Methods:Review of English publications pertaining to cervical cancer within the last 25 years were included using PubMed and Cochrane Library searches.Results: Modern imaging (MRI and PET-CT) does not accurately identify local extension of microscopic disease and is inadequate for preoperative planning of extent of resection. Today, only half of pelvic exenteration procedures obtain uninvolved surgical margins. Conclusion:Clear margins are required for curative pelvic exenterations, but are poorly predictable by pre-operative assessment. More extensive surgery, i.e. the infra-elevator exenteration with vulvectomy, is a logical surgical choice to increase the rate of clear margins and to improve patient survival following surgery for recurrent cervical carcinoma.

Mutations in mitochondrial DNA (mtDNA) are associated with a broad spectrum of clinical disorders. The segregation pattern of pathogenic mtDNAs is an important determinant of both the onset and the severity of the disease phenotype, but the mechanisms controlling mtDNA segregation remain poorly understood. To investigate this, we previously generated heteroplasmic mice containing two different mtDNA haplotypes and showed that BALB/c mtDNA was invariably selected over NZB mtDNA in blood and spleen. Here, we have characterized this process in hematopoietic tissues and tested whether it involves the presentation of mtDNA-encoded peptides by MHC class Ib molecules. Selection against NZB mtDNA was widespread across different hematopoietic cell lineages and proportional to heteroplasmy levels. Backcrossing heteroplasmic mice with CAST/Ei, a strain in which the MHC class Ib molecule H2-M3 is silent, completely abolished selection against NZB mtDNA in the spleen. To test whether this effect depended on an intact immune system, we generated heteroplasmic mice missing functional copies of Tap1, beta2m or Rag1 to impair presentation or recognition of mtDNA-encoded peptides. The kinetics of selection against NZB mtDNA were unaltered in these mice compared with their wild-type littermates. We conclude that mtDNA selection in hematopoietic tissues is not based on an immune mechanism, but likely involves metabolic signaling.

Melanoma is among the most aggressive cancers due to its tendency to metastasize early. Phenotype switching between a proliferative and an invasive state has been suggested as a critical process for metastasis, though the mechanisms that regulate state transitions are complex and remain poorly understood. Brother of Regulator of Imprinted Sites (BORIS), also known as CCCTC binding factor-Like (CTCFL), is a transcriptional modulator that becomes aberrantly expressed in melanoma. Yet, the role of BORIS in melanoma remains elusive. Here, we show that BORIS is involved in melanoma phenotype switching. Genetic modification of BORIS expression in melanoma cells combined with whole-transcriptome analysis indicated that BORIS expression contributes to an invasion-associated transcriptome. In line with these findings, inducible BORIS overexpression in melanoma cells reduced proliferation and increased migration and invasion, demonstrating that the transcriptional switch is accompanied by a phenotypic switch. Mechanistically, we reveal that BORIS binds near the promoter of transforming growth factor-beta 1 (TFGB1), a well-recognized factor involved in the transition towards an invasive state, which coincided with increased expression of TGFB1. Overall, our study indicates a pro-invasive role for BORIS in melanoma via transcriptional reprogramming.