Rigid bronchoscopy: a consultant survey.

INTRODUCTION: Inhalation of foreign bodies represents a potentially fatal emergency in both adults and children. Chest x-ray, in isolation, is neither sensitive nor specific. Rigid bronchoscopy represents the gold standard to diagnose and retrieve paediatric foreign bodies. Cases are encountered infrequently, creating anxieties about their management. Little is known about the confidence in, and maintenance of, rigid bronchoscopy skills by ear, nose and throat teams. METHODS: A 15-question survey was completed by 50 practising otolaryngology consultants in England. RESULTS: Results show that almost 40% of otolaryngology consultants covering rigid bronchoscopy have not performed bronchoscopy in more than 5 years. Consultants raised concerns about the anaesthetic support and the speed of equipment assembly. Questions on clinical practice showed disparities in practice in the same scenario. CONCLUSIONS: The authors advocate addressing many of the issues raised by the study with a greater availability of simulation courses and regular scheduled intradepartmental teaching days for all professionals involved. National guidelines on criteria for transfer to tertiary centres would improve the consistency of practice.

Psychological impact of lung cancer screening using a novel antibody blood test followed by imaging: the ECLS randomized controlled trial.

BACKGROUND: The Early CDT®-Lung antibody blood test plus serial computed tomography scans for test-positives (TPGs) reduces late-stage lung cancer presentation. This study assessed the psychological outcomes of this approach. METHODS: Randomized controlled trial (n = 12 208) comparing psychological outcomes 1-12 months post-recruitment in a subsample (n = 1032) of TPG, test-negative (TNG) and control groups (CG). RESULTS: Compared to TNG, TPG had lower positive affect (difference between means (DBM), 3 months (3m: -1.49 (-2.65, - 0.33)), greater impact of worries (DBM 1m: 0.26 (0.05, 0.47); 3m: 0.28 (0.07, 0.50)), screening distress (DBM 1m: 3.59 (2.28, 4.90); 3m: 2.29 (0.97, 3.61); 6m: 1.94 (0.61, 3.27)), worry about tests (odds ratio (OR) 1m: 5.79 (2.66, 12.63) and more frequent lung cancer worry (OR 1m: 2.52 (1.31, 4.83); 3m: 2.43 (1.26, 4.68); 6m: 2.87 (1.48, 5.60)). Compared to CG, TPG had greater worry about tests (OR 1m: 3.40 (1.69, 6.84)). TNG had lower negative affect (log-transformed DBM 3m: -0.08 (-0.13, -0.02)), higher positive affect (DBM 1m: 1.52 (0.43, 2.61); 3m: 1.43 (0.33, 2.53); 6m: 1.27 (0.17, 2.37)), less impact of worries (DBM 3m: -0.27 (-0.48, -0.07)) and less-frequent lung cancer worry (OR 3m: 0.49 (0.26, 0.92)). CONCLUSIONS: Negative psychological effects in TPG and positive effects in TNG were short-lived and most differences were small.

RX-5902, a novel ß-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. RX-5902 is a novel anti-cancer agent that inhibits phosphorylated-p68 and thus attenuates nuclear ß-catenin signaling. The purpose of this study was to evaluate the ability of ß-catenin signaling blockade to enhance the efficacy of anti-CTLA-4 and anti-PD-1 immune checkpoint blockade in immunocompetent, preclinical models of TNBC. METHODS: Treatment with RX-5902, anti-PD-1, anti-CTLA-4 or the combination was investigated in BALB/c mice injected with the 4 T1 TNBC cell line. Humanized BALB/c-Rag2nullIl2rγnullSIRPαNOD (hu-CB-BRGS) mice transplanted with a human immune system were implanted with MDA-MB-231 cells. Mice were randomized into treatment groups according to human hematopoietic chimerism and treated with RX-5902, anti-PD-1 or the combination. At sacrifice, bone marrow, lymph nodes, spleen and tumors were harvested for flow cytometry analysis of human immune cells. RESULTS: The addition of RX-5902 to CTLA-4 or PD-1 inhibitors resulted in decreased tumor growth in the 4 T1 and human immune system and MDA-MB-231 xenograft models. Immunologic analyses demonstrated a significant increase in the number of activated T cells in tumor infiltrating lymphocytes (TILs) with RX-5902 treatment compared to vehicle (p < 0.05). In the RX-5902/nivolumab combination group, there was a significant increase in the percentage of CD4+ T cells in TILs and increased systemic granzyme B production (p < 0.01). CONCLUSIONS: Conclusions: RX-5902 enhanced the efficacy of nivolumab in a humanized, preclinical model of TNBC. Several changes in immunologic profiles were noted in mice treated with RX-5902 and the combination, including an increase in activated TILs and a decrease in human myeloid populations, that are often associated with immunosuppression in a tumor microenvironment. RX-5902 also was shown to potentiate the effects of checkpoint inhibitors of CTLA4 and the PD-1 inhibitor in the 4 T-1 murine TNBC model. These findings indicate that RX-5902 may have important immunomodulatory, as well as anti-tumor activity, in TNBC when combined with a checkpoint inhibitor.

RX-3117 (Fluorocyclopentenyl-Cytosine)-Mediated Down-Regulation of DNA Methyltransferase 1 Leads to Protein Expression of Tumor-Suppressor Genes and Increased Functionality of the Proton-Coupled Folate Carrier.

(1) Background: RX-3117 (fluorocyclopentenyl-cytosine) is a cytidine analog that inhibits DNA methyltransferase 1 (DNMT1). We investigated the mechanism and potential of RX-3117 as a demethylating agent in several in vitro models. (2) Methods: we used western blotting to measure expression of several proteins known to be down-regulated by DNA methylation: O6-methylguanine-DNA methyltransferase (MGMT) and the tumor-suppressor genes, p16 and E-cadherin. Transport of methotrexate (MTX) mediated by the proton-coupled folate transporter (PCFT) was used as a functional assay. (3) Results: RX-3117 treatment decreased total DNA-cytosine-methylation in A549 non-small cell lung cancer (NSCLC) cells, and induced protein expression of MGMT, p16 and E-cadherin in A549 and SW1573 NSCLC cells. Leukemic CCRF-CEM cells and the MTX-resistant variant (CEM/MTX, with a deficient reduced folate carrier) have a very low expression of PCFT due to promoter hypermethylation. In CEM/MTX cells, pre-treatment with RX-3117 increased PCFT-mediated MTX uptake 8-fold, and in CEM cells 4-fold. With the reference hypomethylating agent 5-aza-2'-deoxycytidine similar values were obtained. RX-3117 also increased PCFT gene expression and PCFT protein. (4) Conclusion: RX-3117 down-regulates DNMT1, leading to hypomethylation of DNA. From the increased protein expression of tumor-suppressor genes and functional activation of PCFT, we concluded that RX-3117 might have induced hypomethylation of the promotor.

Core outcome set for uncomplicated acute appendicitis in children and young people.

BACKGROUND: Research studies to inform clinical practice and policy in children and young people with appendicitis are hampered by inconsistent selection and reporting of outcomes. The aim of this study was to develop a core outcome set for reporting all studies of uncomplicated acute appendicitis in children and young people. METHODS: Systematic literature reviews, qualitative interviews with parents and patients treated for uncomplicated acute appendicitis, and a Study-Specific Advisory Group informed a long list of outcomes. Outcomes were then prioritized by stakeholders based in the UK (patients, parents, and paediatric and general surgeons) in an online three-round Delphi consensus process, followed by face-to-face consensus meetings. RESULTS: A long list of 40 items was scored by 147 key stakeholders in the first Delphi round, of whom 90 completed the two subsequent Delphi rounds. The final core outcome set comprises 14 outcomes: intra-abdominal abscess, reoperation (including interventional radiology procedure), readmission to hospital, bowel obstruction, wound infection, antibiotic failure, wound complication, negative appendicectomy, recurrent appendicitis, death, patient stress/psychological distress, length of hospital stay, time away from full activity and child's quality of life. CONCLUSION: A core outcome set comprising 14 outcomes across five key domains has been developed for reporting studies in children and young people with uncomplicated acute appendicitis. Further work is required to determine how and when to measure these outcomes.

ANTECEDENTES: Los estudios de investigación que sirvan de base para la práctica clínica y la política en niños y adultos jóvenes con apendicitis se ven obstaculizados por inconsistencias en la selección y descripción de los resultados. El objetivo de este estudio fue desarrollar un conjunto central de resultados para todos los estudios de apendicitis aguda no complicada en niños y adultos jóvenes. MÉTODOS: Para establecer una lista de resultados se efectuaron revisiones sistemáticas de la literatura, entrevistas cualitativas con padres y pacientes tratados por apendicitis aguda no complicada, y consulta con un Grupo de Asesoramiento Específico para el Estudio. Seguidamente, los resultados se priorizaron de acuerdo con los intereses de las partes interesadas (pacientes, padres, y cirujanos pediátricos y generales) en el Reino Unido a través de un proceso de consenso Delphi de tres rondas en Internet, seguido de reuniones personales de consenso. RESULTADOS: Un total de 147 participantes puntuaron una larga lista de 40 ítems en la primera ronda Delphi, de los cuales 90 completaron las dos rondas Delphi subsiguientes. El conjunto final incluye 14 resultados: absceso intra-abdominal, reoperación (incluyendo procedimientos radiológicos intervencionistas), reingreso, obstrucción intestinal, infección de herida, otras complicaciones de la herida, fracaso del tratamiento con antibióticos, apendicectomía blanca, apendicitis recidivante, muerte, estrés del paciente/sufrimiento psicológico, duración de la estancia hospitalaria, tiempo alejado de todas sus actividades y calidad de vida. CONCLUSIÓN: Se ha desarrollado un conjunto central de resultados que incluye 14 resultados en cinco dominios clave para la descripción de estudios en niños y adultos jóvenes con apendicitis aguda no complicada. Se requieren más trabajos para determinar cómo y cuándo conviene medir estos resultados.

First-in-Class Phosphorylated-p68 Inhibitor RX-5902 Inhibits ß-Catenin Signaling and Demonstrates Antitumor Activity in Triple-Negative Breast Cancer.

RX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear shuttling of ß-catenin. The purpose of this study was to evaluate the efficacy of RX-5902 in preclinical models of triple-negative breast cancer (TNBC) and to explore effects on ß-catenin expression. A panel of 18 TNBC cell lines was exposed to RX-5902, and changes in proliferation, apoptosis, cellular ploidy, and effector protein expression were assessed. Gene expression profiling was used in sensitive and resistant cell lines with pathway analysis to explore pathways associated with sensitivity to RX-5902. The activity of RX-5902 was confirmed in vivo in cell line and patient-derived tumor xenograft (PDX) models. RX-5902 demonstrated potent antiproliferative activity in vitro against TNBC cell lines with an average IC50 of 56 nmol/L in sensitive cell lines. RX-5902 treatment resulted in the induction of apoptosis, G2-M cell-cycle arrest, and aneuploidy in a subset of cell lines. RX-5902 was active in vivo against TNBC PDX models, and treatment resulted in a decrease in nuclear ß-catenin. RX-5902 exhibited dose-proportional pharmacokinetics and plasma and tumor tissue in nude mice. Pathway analysis demonstrated an increase in the epithelial-to-mesenchymal transformation (EMT), TGFß, and Wnt/ß-catenin pathways associated with sensitivity to RX-5902. RX-5902 is active against in vitro and in vivo preclinical models of TNBC. Target engagement was confirmed with decreases in nuclear ß-catenin and MCL-1 observed, confirming the proposed mechanism of action. This study supports the continued investigation of RX-5902 in TNBC and combinations with immunotherapy.

Characterization and validation of multimodal annihilation-gamma/near-infrared/visible laparoscopic system.

Minimally invasive robotic surgery using fluorescence-guided images with a video laparoscope has been widely used because of its advantages of small incision, fast recovery time, and efficiency. However, the penetration depth limitation of fluorescence is a disadvantage caused by the absorption and scattering in tissues and blood cells. If this limitation can be overcome by additional imaging modalities, the surgical procedure can be quite efficient and precise. High-energy annihilation-gamma photons have a stronger penetration capability than visible and fluorescence photons. To characterize and validate a multimodal annihilation-gamma/near-infrared (NIR)/visible laparoscopic imaging system, an internal detector composed of an annihilation-gamma detector and an optical system was assembled inside a surgical stainless pipe with an outer diameter of 15.8 mm and an external detector with a dimension of 100 × 100 mm2 placed at the opposite side of the internal detector. Integrated images of 511-keV gamma rays, NIR fluorescence, and visible light were obtained simultaneously. The 511-keV gamma image could be clearly seen with the acquisition of 5 s, while NIR and visible images could be presented in real time. This multimodal system has the potential for improving the surgery time and the quality of patient care.

The cost of diabetic foot ulcers and amputations to the National Health Service in England.

AIM: To estimate the healthcare costs of diabetic foot disease in England. METHODS: Patient-level data sets at a national and local level, and evidence from clinical studies, were used to estimate the annual cost of health care for foot ulceration and amputation in people with diabetes in England in 2014-2015. RESULTS: The cost of health care for ulceration and amputation in diabetes in 2014-2015 is estimated at between £837 million and £962 million; 0.8% to 0.9% of the National Health Service (NHS) budget for England. More than 90% of expenditure was related to ulceration, and 60% was for care in community, outpatient and primary settings. For inpatients, multiple regression analysis suggested that ulceration was associated with a length of stay 8.04 days longer (95% confidence interval 7.65 to 8.42) than that for diabetes admissions without ulceration. CONCLUSIONS: Diabetic foot care accounts for a substantial proportion of healthcare expenditure in England, more than the combined cost of breast, prostate and lung cancers. Much of this expenditure arises through prolonged and severe ulceration. If the NHS were to reduce the prevalence of diabetic foot ulcers in England by one-third, the gross annual saving would be more than £250 million. Diabetic foot ulceration is a large and growing problem globally, and it is likely that there is potential to improve outcomes and reduce expenditure in many countries.

RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment.

INTRODUCTION: RX-3117 is an oral, small molecule cytidine analog anticancer agent with an improved pharmacological profile relative to gemcitabine and other nucleoside analogs. The agent has excellent activity against various cancer cell lines and xenografts including gemcitabine-resistant variants and it has excellent oral bioavailability; it is not a substrate for the degradation enzyme cytidine deaminase. RX-3117 is being evaluated at a daily oral schedule of 700 mg (5 days/week for 3 weeks) which results in plasma levels in the micromolar range that have been shown to be cytotoxic to cancer cells. It has shown clinical activity in refractory bladder cancer and pancreatic cancer. Areas covered: The review provides an overview of the relevant market and describes the mechanism of action, main pharmacokinetic/pharmacodynamic features and clinical development of this investigational small molecule. Expert opinion: RX-3117 is selectively activated by uridine-cytidine kinase 2 (UCK2), which is expressed only in tumors and has a dual mechanism of action: DNA damage and inhibition of DNA methyltransferase 1 (DNMT1). Because of its tumor selective activation, novel mechanism of action, excellent oral bioavailability and candidate biomarkers for patient selection, RX-3117 has the potential to replace gemcitabine in the treatment of a spectrum of cancer types.

Comparison of the efficacy of diegnogest and levonorgestrel-releasing intrauterine system after laparoscopic surgery for endometriosis.

AIM: To compare the efficacy between dienogest and levonorgestrel-releasing intrauterine system (LNG-IUS) after laparoscopic surgery for endometriosis. METHODS: A total of 285 women were diagnosed as endometriosis by laparoscopy between 2011 and 2015. Patients were grouped into no treatment (n = 83), treatment with dienogest (n =130) and treatment with LNG-IUS (n =72) after laparoscopic surgery. The changes of the pain scores were checked at 6, 12 and 24 months after the surgery, and the rates of disease recurrence and treatment discontinuation rate were determined. RESULTS: The participants' mean age was 38.9 years (range 21-54 years). The mean age of LNG-IUS group (43.7 years) was significantly higher than the no treatment and dienogest groups (39.3 vs 33.9 years, respectively). At 6 and 12 months, the median pain scores in treatment (dienogest and LNG-IUS) groups were significantly lower than control group. Both treatment groups had significantly lower recurrence rate than control group (3.8% and 9.7%, respectively, vs 32.5%, P =0.001). No significant difference was found in the recurrence rate between the two treatment groups (P =0.461). Patients in the LNG-IUS group showed lower rate of discontinuation due to complication (27.8%) than those in dienogest group (35.6%, P =0.010). CONCLUSION: LNG-IUS treatment in the patients with endometriosis is effective for postoperative pain control and preventing recurrence, however, the LNG-IUS group is older, it is difficult to compare the efficacy between dienogest and LNG-IUS in present study.

Folate receptor-targeted lipid-albumin nanoparticles (F-LAN) for therapeutic delivery of an Akt1 antisense oligonucleotide.

BACKGROUND: RX-0201 is an antisense oligonucleotide (ASO) against Akt1 currently in clinical trial for metastatic renal cancer. PURPOSE: To improve the delivery of RX-0201 using folate receptor-targeted lipid-albumin nanoparticles (F-LAN). METHODS: F-LAN were synthesized with the composition of DOTAP/soyPC/TPGS/folate-PEG-DSPE (25:70:4:1 m/m), a cationic human serum albumin-pentaethylenehexamine (HSA-PEHA) conjugate and RX-0201. The nanoparticles were evaluated in KB human carcinoma cells in vitro and in a KB murine xenograft tumour model in vivo for pharmacokinetics and antitumor activities. RESULTS: The F-LAN-RX-0201 had a mean particle size of 108.6 ± 5.8 nm, zeta potential of 10.5 ± 3.2 mV and ASO loading efficiency of 71.5 ± 4.5%. In KB cells, uptake and Akt1 inhibition by F-LAN-RX-0201 were greater than those of non-targeted LAN-RX-0201 and could be partially blocked by excess free folate. F-LAN-RX-0201 inhibited cell growth with an IC50 of 11.9 µM. In contrast, LAN-RX-0201 showed lower cytotoxicity with an IC50 of 32.0 µM. No significant cytotoxicity was observed with up to 250 µM of free RX-0201. Pharmacokinetic studies showed that F-LAN-RX-0201 had a longer terminal half-life than free RX-0201 (442 vs. 219 min). In a KB xenograft tumour model, F-LAN-RX-0201 exhibited greater tumour inhibition than LAN-RX-0201 at 16 mg/kg. Moreover, F-LAN-RX-0201 at 16 mg/kg showed comparable tumour inhibition compared to free RX-0201 at a much higher dose of 90 mg/kg. CONCLUSIONS: F-LAN-RX-0201 showed promise as a therapeutic agent for tumours with elevated folate-receptor expression.

Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer.

Background: Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. Patients and methods: To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287-395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. Results: We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3' partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations. Conclusions: Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6-7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.

Factors influencing the decision to attend screening for cancer in the UK: a meta-ethnography of qualitative research.

Background: This review aimed to better understand experiences of being invited to cancer screening and associated decision-making. Methods: Qualitative evidence explaining UK cancer screening attendance decisions was systematically identified. Data were extracted and meta-ethnography used to identify shared themes, synthesize findings and generate higher level interpretations. Results: Thirty-four studies met inclusion criteria. They related to uptake of breast, cervical, colorectal, prostate, ovarian and lung cancer screening. Three primary themes emerged from the synthesis. 'Relationships with the health service' shaped decisions, influenced by trust, compliance with power, resistance to control or surveillance and perceived failures to meet cultural, religious and language needs. 'Fear of cancer screening' was both a motivator and barrier in different ways and to varying degrees. Strategies to negotiate moderate fear levels were evident. 'Experiences of risk' included the creation of alternative personal risk discourses and the use of screening as a coping strategy, influenced by disease beliefs and feelings of health and wellness. Conclusions: The findings highlight the importance of the provider-patient relationship in screening uptake and enrich our understanding of how fear and risk are experienced and negotiated. This knowledge can help promote uptake and improve the effectiveness of cancer screening.

Understanding the information needs of people with haematological cancers. A meta-ethnography of quantitative and qualitative research.

Clinical practice in haematological oncology often involves difficult diagnostic and treatment decisions. In this context, understanding patients' information needs and the functions that information serves for them is particularly important. We systematically reviewed qualitative and quantitative evidence on haematological oncology patients' information needs to inform how these needs can best be addressed in clinical practice. PsycINFO, Medline and CINAHL Plus electronic databases were searched for relevant empirical papers published from January 2003 to July 2016. Synthesis of the findings drew on meta-ethnography and meta-study. Most quantitative studies used a survey design and indicated that patients are largely content with the information they receive from physicians, however much or little they actually receive, although a minority of patients are not content with information. Qualitative studies suggest that a sense of being in a caring relationship with a physician allows patients to feel content with the information they have been given, whereas patients who lack such a relationship want more information. The qualitative evidence can help explain the lack of association between the amount of information received and contentment with it in the quantitative research. Trusting relationships are integral to helping patients feel that their information needs have been met.

The radiosensitizing effect of fluorocyclopentenyl-cytosine (RX-3117) in ovarian and lung cancer cell lines.

RX-3117 (fluorocyclopentenyl-cytosine) is a novel cytidine analog currently being evaluated in a Phase Ib clinical trial in cancer patients with solid tumors. The radiosensitizing effect of RX-3117 was studied in A2780 ovarian cancer cells and non-small cell lung cancer cell lines and related to cell survival and the effect on cell cycle and cell cycle proteins. RX-3117 has a schedule-dependent radiosensitizing effect, but only at pre-incubation (dose modifying factors: 1.4-1.8), observed at pulse and fractionated irradiation. Radiosensitizion was also seen in a three-dimensional spheroid model. At the low radiosensitizing concentration, RX-3117 in combination with radiation led to an accumulation of cells in S-phase, which was accompanied with an increase of cell cycle proteins such as p-Chk2 and p-cdc25C. In addition, RX-3117 caused DNA damage and increased apoptosis. In conclusion, our in vitro experiments showed a radiosensitizing effect of RX-3117.

The Cytidine Analog Fluorocyclopentenylcytosine (RX-3117) Is Activated by Uridine-Cytidine Kinase 2.

Fluorocyclopentenylcytosine (RX-3117) is an orally available cytidine analog, currently in Phase I clinical trial. RX-3117 has promising antitumor activity in various human tumor xenografts including gemcitabine resistant tumors. RX-3117 is activated by uridine-cytidine kinase (UCK). Since UCK exists in two forms, UCK1 and UCK2, we investigated which form is responsible for RX-3117 phosphorylation. For that purpose we transfected A549 and SW1573 cell lines with UCK-siRNAs. Transfection of UCK1-siRNA efficiently downregulated UCK1-mRNA, but not UCK2-mRNA expression, and did not affect sensitivity to RX-3117. However, transfection of UCK2-siRNA completely downregulated UCK2-mRNA and protein and protected both A549 and SW1573 against RX-3117. UCK enzyme activity in two panels of tumor cell lines and xenograft cells correlated only with UCK2-mRNA expression (r = 0.803 and 0.915, respectively), but not with UCK1-mRNA. Moreover, accumulation of RX-3117 nucleotides correlated with UCK2 expression. In conclusion, RX-3117 is activated by UCK2 which may be used to select patients potentially sensitive to RX-3117.

Mitotically Active Leiomyoma in a Woman with Mayer-Rokitansky-Küster-Hauser Syndrome: A Case Report.

BACKGROUND: Cases of women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome developing leiomyomata are rare. A case with mitotically active leiomyomata has not previously been described to our knowledge. CASE: A 43-year-old woman with MRKH syndrome found to have an incidental pelvic mass on imaging studies underwent a diagnostic laparoscopy, followed by resection of leiomyomata and uterine remnant via mini laparotomy. Histopathology revealed focal infarction associated with a mitotically active area in one of the leiomyomata but with no evidence of marked cytologic atypia or hypercellularity. Focal adenomyosis was also noted. CONCLUSION: Studies have shown that mitotically active smooth cell tumors of the uterus having 5-9 mitoses/10 hpf and no cellular atypia have a metastatic rate too low to be regarded as sarcomas. Although the pathology findings in this case are benign with no need for continued surveillance by gynecologic oncology, regular follow-up with a gynecologist annually may be indicated for early diagnosis of recurrence secondary to the uncommon characteristics of this benign tumor, especially in this rare category of patients with Müllerian agenesis. Mitotically active leiomyomata can occur in patients with Müllerian agenesis, but the likelihood that a pelvic mass in a patient with MRKH syndrome is a sarcoma is extremely low.