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AimsA unique fibrosarcoma‐like tumour of the uterine cervix harbouring a rearrangement of a neurotrophic tyrosine kinase receptor (NTRK) gene (NTRK1 or NTRK3) has recently been described in 11 young women, some with recurrence and/or metastasis. The aims of this study were to expand the morphological spectrum of this tumour by reporting three additional cases that showed adenosarcoma‐like features not previously described, one of which is the first reported to respond to targeted therapy, and to evaluate 19 conventional uterine adenosarcomas for evidence of NTRK rearrangement.Methods and resultsThree patients presented with a polyp or mass confined to the cervix. The constellation of polypoid growth, spindle cell morphology, entrapped endocervical glands and intraglandular stromal projections raised diagnostic consideration for adenosarcoma with stromal overgrowth. Deep cervical wall invasion was present in two cases at hysterectomy, and the third was removed by polypectomy. All three stained for S100 and pan‐Trk, but were negative for a spectrum of other diagnostic markers. All three harboured NTRK rearrangements (TPM3–NTRK1, TPR–NTRK1, and SPECC1L–NTRK3). One patient developed pleural metastases at 16 months, received the NTRK inhibitor larotrectinib, and is free of disease 15 months later. Two others are alive without disease. None of the uterine adenosarcomas showed any S100 or pan‐Trk staining, or rearrangement of NTRK1, NTRK2 or NTRK3 on next‐generation sequencing.ConclusionsUnusual adenosarcoma‐like spindle cell neoplasms of the cervix may represent an NTRK fusion sarcoma, which can be detected by S100 and pan‐Trk staining and confirmed by NTRK molecular testing. Conventional uterine adenosarcomas do not harbour NTRK rearrangements.

The extent of tight junction (TJ) formation is one of many factors that regulate motility, invasion, and metastasis. Claudins are required for the formation and maintenance of TJs. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are highly expressed in the majority of ovarian cancers. We report here that CLDN3 and CLDN4 each serve to constrain the growth of human 2008 cancer xenografts and limit metastatic potential. Knockdown of CLDN3 increased in vivo growth rate by 2.3-fold and knockdown of CLDN4 by 3.7-fold in the absence of significant change in in vitro growth rate. Both types of tumors exhibited increase in birth rate as measured by Ki67 staining and decrease in death rate as reflected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Knockdown of either claudin did not alter expression of other TJ protein but did reduce TJ formation as measured by transepithelial resistance and paracellular flux of dextran, enhance migration and invasion in in vitro assays, and increase lung colonization following intravenous injection. Knockdown of CLDN3 and CLDN4 increased total lung metastatic burden by 1.7-fold and 2.4-fold, respectively. Loss of either CLDN3 or CLDN4 resulted in down-regulation of E-cadherin mRNA and protein, increased inhibitory phosphorylation of glycogen synthase kinase-3β (GSK-3β), and activation of β-catenin pathway signaling as evidenced by increases in nuclear β-catenin, the dephosphorylated form of the protein, and transcriptional activity of β-catenin/T-cell factor (TCF). We conclude that both CLDN3 and CLDN4 mediate interactions with other cells in vivo that restrain growth and metastatic potential by sustaining expression of E-cadherin and limiting β-catenin signaling.

Most women with endometrial cancer survive the disease. The 5-year survival among patients diagnosed and treated at early stages is estimated to be 96%. A large number of studies have demonstrated a high prevalence of cardiovascular death among endometrial cancer survivors. It is possible that obesity and metabolic syndrome, risk factors for cardiovascular disease, may contribute to the high prevalence of cardiovascular death among endometrial cancer survivors. No prior studies have examined causes of death among women with endometrial cancer.The aim of this retrospective cohort study was to determine the leading causes of death among patients with invasive epithelial endometrial cancer. Data were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. Causes of death were stratified by grade and stage.Of the 44,145 patients with endometrial cancer enrolled in SEER from 1973 to 1988, 33,232 (75.3%) with incident cases had died by 2008 at the time of last follow-up.Overall, patients with endometrial cancer were most likely to die of cardiovascular disease (35.9%; 95% confidence interval, 35.3%Y36.3%) followed by other causes of death, other malignancies, and endometrial cancer. Death due to cardiovascular disease was most likely among patients with low-grade localized cancer and least likely among those with high-grade advanced cancer. Moreover, death due to endometrial cancer was most likely to occur in women with highgrade advanced disease. Among the entire population of women, the risk of death is greatest from endometrial cancer in the first 5 years after diagnosis; risk of death from cardiovascular disease becomes greater in the next 5 years and thereafter.These findings suggest that higher risk of cardiac death among endometrial cancer patients is a reflection of the likelihood of cure following treatment of low-grade disease and of the high prevalence of cardiac disease and risk factors among survivors. Lifestyle modifications and other interventions that reduce the risk of cardiovascular death are likely to improve overall survival in the women who do not die of endometrial cancer.

Peritoneal carcinomatosis is a major source of morbidity and mortality in patients with advanced abdominal neoplasms. Intraperitoneal chemotherapy (IPC) is an area of intense interest given its efficacy in ovarian cancer. However, IPC suffers from poor drug penetration into peritoneal tumors. As such, extensive cytoreductive surgery is required prior to IPC. Here, we explore the utility of iRGD, a tumor-penetrating peptide, for improved tumor-specific penetration of intraperitoneal compounds and enhanced IPC in mice. Intraperitoneally administered iRGD significantly enhanced penetration of an attached fluorescein into disseminated peritoneal tumor nodules. The penetration was tumor-specific, circulation-independent, and mediated by the neuropilin-binding RXXK tissue-penetration peptide motif of iRGD. Q-iRGD, which fluoresces upon cleavage, including the one that leads to RXXK activation, specifically labeled peritoneal metastases displaying different growth patterns in mice. Importantly, iRGD enhanced intratumoral entry of intraperitoneally co-injected dextran to approximately 300% and doxorubicin to 250%. Intraperitoneal iRGD/doxorubicin combination therapy inhibited the growth of bulky peritoneal tumors and reduced systemic drug toxicity. iRGD delivered attached fluorescein and co-applied nanoparticles deep into fresh human peritoneal metastasis explants. These results indicate that intraperitoneal iRGD co-administration serves as a simple and effective strategy to facilitate tumor detection and improve the therapeutic index of IPC for peritoneal carcinomatosis.