The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirus-type-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNVs), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNVs as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring ERBB2 (5.8%) domain mutations were significantly more sensitive to single agents afatinib or neratinib when compared to wild-type tumors in preclinical in vitro and in vivo models (P = 0.001). In contrast, pan-HER and PIK3CA inhibitors demonstrated limited in vitro activity and were only transiently effective in controlling in vivo growth of PIK3CA-mutated cervical cancer xenografts. Importantly, combinations of copanlisib and neratinib were highly synergistic, inducing long-lasting regression of tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway. These findings define the genetic landscape of cervical cancer, suggesting that a large subset of cervical tumors might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.

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Authors evaluated the outcome of intracapsular cesarean myomectomy by a prospective case-control study on 68 patients who underwent intracapsular cesarean myomectomy, compared with a control group of 72 patients with myomatosic pregnant uterus who underwent cesarean section (CS) without myomectomy. Mostly of removed myomas were subserous or intramural, fundal in 37 women (54.4%), corporal in 22 (32.3%) and peri-low uterine segment in 9 women (18.7%). The average myoma' size was 8 cm (1.5-20), in 40 women, with 8 myomas measuring 4-6 cm, 14 myomas between 10 and 12 cm and >13 cm in 6 patients. Difference in blood tests and surgical outcome in intracapsular cesarean myomectomy was non significant (p > 0.05). The average duration of hospitalization of intracapsular cesarean myomectomies was 5 days. There was no correlation between complications or duration of hospital stay and patient age, gravidity, parity or indication for CS. The intracapsular cesarean myomectomy could be a reliable, feasible and safe obstetric procedure. Meticulous attention to gentle hemostasis, sharp pseudocapsule dissection, adequate approximation of the myometrium edges and all dead spaces to prevent hematoma formation, can further increase the safety of the procedure, without significant complications by experienced obstetricians.

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