Endometrial cancer PDX-derived organoids (PDXOs) and PDXs with FGFR2c isoform expression are sensitive to FGFR inhibition.

Endometrial cancer (EC) patients with metastatic/recurrent disease have limited treatment options and poor survival outcomes. Recently, we discovered the FGFR2c splice isoform is associated with poor prognosis in EC patients. Here we report the establishment of 16 EC patient-derived xenografts (PDX)-derived organoids (PDXOs) with or without FGFR2c expression. In vitro treatment of 5 EC PDXOs with BGJ398 showed significant cell death in 3 models with FGFR2c expression. PDXs with high/moderate FGFR2c expression showed significant tumour growth inhibition (TGI) following 21-day treatment with FGFR inhibitors (BGJ398 or pemigatinib) and significantly prolonged survival in 4/5 models. Pemigatinib + cisplatin combination therapy (n = 5) resulted in significant TGI and prolonged survival in one of two p53abn PDXs. All five models treated with cisplatin alone showed de novo resistance and no survival benefit. Seven-day treatment with BGJ398 revealed a significant reduction in angiogenesis and CD206 + M2 macrophages. These data collectively support the evaluation of FGFR inhibitors in a clinical trial.

A review of the occurrence of naturally occurring radioactive materials and radiological risk assessment in South African soils.

According to reports, exposure to high concentrations of naturally occurring radioactive substances like Uranium-238, Thorium-232, and Potassium-40 poses serious health concerns. This review study aims to report the concentrations of radionuclides in various South African soil and their equivalent risk assessments, which have been sparingly reported. For South Africa, most radionuclide concentrations above the permissible limits of 33, 45, and 420 Bq.kg-1 for 238U, 232Th, and 40K, respectively, have been found in some soil samples taken near industrialization activities, including mining and oil exploration and production. Thus, the amount of radionuclides is a good indicator of the kind of soil, the local geology, and the mineral make-up of the parent rocks. The increases in radiation exposure to people and the environment have been reported to cause various radiological health hazards. Thus, this review study can be used as a data source to track probable radioactive contamination from soils found in South Africa.

Safety and feasibility of hyperthermic intraperitoneal chemotherapy during interval cytoreductive surgery in patients with advanced high-grade serous ovarian, fallopian tube, peritoneal cancer in an Australian context.

AIMS: To assess the safety and feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) during cytoreduction surgery (CRS) in advanced high-grade serous ovarian, fallopian tube and peritoneal cancer within an Australian context. METHODS: Data were collected from 25 consecutive patients undergoing CRS and HIPEC from December 2018 to July 2022 at the Peritoneal Malignancy Service at the Mater Hospital Brisbane, Australia. Data collected included demographics, clinical variables, surgical procedures and complications and intra-operative and post-operative indexes of morbidity. RESULTS: Twenty-five women who underwent CRS and HIPEC from December 2018 to July 2022 were included in analysis. Findings indicate that CRS with HIPEC is associated with low morbidity. CONCLUSION: While judicious patient selection is imperative, HIPEC during CRS was well tolerated by all patients and morbidity was comparable to results from the previously reported OVHIPEC-1 trial. HIPEC appears to be a safe and feasible addition to CRS for the treatment of advanced ovarian cancer in Australian practice.

Patient-derived xenograft models capture genomic heterogeneity in endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprises four molecular subtypes with differing etiology, prognoses, and responses to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. As pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models. METHODS: Here, we report whole exome or whole genome sequencing of 11 PDX models and their matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC. RESULTS: PDX models were successfully generated from grade 2/3 tumors, including three uterine carcinosarcomas. The models showed similar histomorphology to the primary tumors and represented all four molecular subtypes of EC, including five mismatch-repair deficient models. The different PDX lineages showed a wide range of inter-tumor and intra-tumor heterogeneity. However, for most PDX models, one arm recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease; however, all lacked the HR deficiency genomic signature. CONCLUSIONS: EC PDX models represent the four molecular subtypes of disease and can capture intra-tumor heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi; however, deeper and more durable responses will likely require combination of PARPi with other agents.

Activity concentrations and radiological hazard assessments of 226Ra, 232Th, and 40K in soil samples of oil-producing areas of South Africa.

The specific activity of natural radionuclide in soil samples of the oil-producing areas of South Africa was measured using a High Purity Germanium detector. The activity of226Ra, 232Th, and 40K in the soil range from 16.5 ± 1.3 to 64.9 ± 3.1, 16.8 ± 1.5 to 88.6 ± 1.2, 135.2 ± 17.5 to 604.8 ± 13.4 Bqkg-1 for Mossel Bay; 14.3 ± 1.2 to 48.9 ± 8.2, 22.3 ± 1.4 to 45.1 ± 3.2, 237.7 ± 10.9 to 486.5 ± 40.1 Bqkg-1 for Cape Town; 10.5 ± 1.1 to 25.8 ± 3.2, 13.1 ± 1.9 to 44.3 ± 5.2, 140.2 ± 10.9 to 229.8 ± 12.8 Bqkg-1 for Nelson Mandela Bay and 5.6 ± 2.2 to 13.1 ± 2.9, 4.5 ± 2.5 to 14.1 ± 2.7, 62.7 ± 22.6 to 126.5 ± 21.2 Bqkg-1 for Msunduzi. Most soil samples' radiological hazards were within the world average.

Preclinical Evaluation of a Fluorescent Probe Targeting Receptor CDCP1 for Identification of Ovarian Cancer.

Optimal cytoreduction for ovarian cancer is often challenging because of aggressive tumor biology and advanced stage. It is a critical issue since the extent of residual disease after surgery is the key predictor of ovarian cancer patient survival. For a limited number of cancers, fluorescence-guided surgery has emerged as an effective aid for tumor delineation and effective cytoreduction. The intravenously administered fluorescent agent, most commonly indocyanine green (ICG), accumulates preferentially in tumors, which are visualized under a fluorescent light source to aid surgery. Insufficient tumor specificity has limited the broad application of these agents in surgical oncology including for ovarian cancer. In this study, we developed a novel tumor-selective fluorescent agent by chemically linking ICG to mouse monoclonal antibody 10D7 that specifically recognizes an ovarian cancer-enriched cell surface receptor, CUB-domain-containing protein 1 (CDCP1). 10D7ICG has high affinity for purified recombinant CDCP1 and CDCP1 that is located on the surface of ovarian cancer cells in vitro and in vivo. Our results show that intravenously administered 10D7ICG accumulates preferentially in ovarian cancer, permitting visualization of xenograft tumors in mice. The data suggest CDCP1 as a rational target for tumor-specific fluorescence-guided surgery for ovarian cancer.

Radioprotective potential of Costus afer against the radiation-induced hematological and histopathological damage in mice.

PURPOSE: This study investigated the possible radioprotective effect of Costus afer extract (CAE) on hematological and histopathological parameters of mice. MATERIALS AND METHODS: Fifty-four male mice with mass between 37-43 g, 11-13 weeks old were used for this study. We divided the mice into six different groups containing nine animals, which were then further sub-divided into irradiated groups and un-irradiated groups. Animals received 250 mg/kg body weight extract of CAE by oral gavage for 6 days in addition to feeding and water ad libitum. Animals in the irradiated group were exposed to radiation at the Department of Radiotherapy and Oncology, Grey's Hospital using a linear accelerator. Blood samples were collected at 48-hour post-irradiation for the hematology test followed by histopathology examination of kidney and liver. RESULTS: Our findings revealed that 3 Gy and 6 Gy dose of X-ray radiation caused a significant reduction in the white blood cell, packed cell volume, hemoglobin, neutrophils, lymphocytes, eosinophils, and platelet counts compared with the control group. However, the administration of CAE before irradiation significantly increased the mentioned parameters. There was no increase in red blood cell and monocyte among treated groups compared with the control. Histopathological changes in the kidney and liver sections revealed that no visible lesion in the pretreated mice. Hepatocytes seem to be within normal histological limits. CONCLUSIONS: This study concludes that CAE offered some protection against radiation-induced hematological alterations, but there was no significant improvement in the histopathological parameters. Thus, further studies are needed to validate its radioprotective effect on histopathological variables.

Development of a surgical competency assessment tool for sentinel lymph node dissection by minimally invasive surgery for endometrial cancer.

INTRODUCTION: Sentinel lymph node dissection is widely used in the staging of endometrial cancer. Variation in surgical techniques potentially impacts diagnostic accuracy and oncologic outcomes, and poses barriers to the comparison of outcomes across institutions or clinical trial sites. Standardization of surgical technique and surgical quality assessment tools are critical to the conduct of clinical trials. By identifying mandatory and prohibited steps of sentinel lymph node (SLN) dissection in endometrial cancer, the purpose of this study was to develop and validate a competency assessment tool for use in surgical quality assurance. METHODS: A Delphi methodology was applied, included 35 expert gynecological oncology surgeons from 16 countries. Interviews identified key steps and tasks which were rated mandatory, optional, or prohibited using questionnaires. Using the surgical steps for which consensus was achieved, a competency assessment tool was developed and subjected to assessments of validity and reliability. RESULTS: Seventy percent consensus agreement standardized the specific mandatory, optional, and prohibited steps of SLN dissection for endometrial cancer and informed the development of a competency assessment tool. Consensus agreement identified 21 mandatory and three prohibited steps to complete a SLN dissection. The competency assessment tool was used to rate surgical quality in three preselected videos, demonstrating clear separation in the rating of the skill level displayed with mean skills summary scores differing significantly between the three videos (F score=89.4; P<0.001). Internal consistency of the items was high (Cronbach α=0.88). CONCLUSION: Specific mandatory and prohibited steps of SLN dissection in endometrial cancer have been identified and validated based on consensus among a large number of international experts. A competency assessment tool is now available and can be used for surgeon selection in clinical trials and for ongoing, prospective quality assurance in routine clinical care.

Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial.

PURPOSE: Intrauterine levonorgestrel (LNG-IUD) is used to treat patients with endometrial adenocarcinoma (EAC) and endometrial hyperplasia with atypia (EHA) but limited evidence is available on its effectiveness. The study determined the extent to which LNG-IUD with or without metformin (M) or weight loss (WL) achieves a pathological complete response (pCR) in patients with EAC or EHA. PATIENTS AND METHODS: This phase II randomized controlled clinical trial enrolled patients with histologically confirmed, clinically stage 1 FIGO grade 1 EAC or EHA; a body mass index > 30 kg/m2; a depth of myometrial invasion of less than 50% on MRI; a serum CA125 ≤ 30 U/mL. All patients received LNG-IUD and were randomized to observation (OBS), M (500 mg orally twice daily), or WL (pooled analysis). The primary outcome measure was the proportion of patients developing a pCR (defined as absence of any evidence of EAC or EHA) after 6 months. RESULTS: From December 2012 to October 2019, 165 patients were enrolled and 154 completed the 6-months follow up. Women had a mean age of 53 years, and a mean BMI of 48 kg/m2. Ninety-six patients were diagnosed with EAC (58%) and 69 patients with EHA (42%). Thirty-five participants were randomized to OBS, 36 to WL and 47 to M (10 patients were withdrawn). After 6 months the rate of pCR was 61% (95% CI 42% to 77%) for OBS, 67% (95% CI 48% to 82%) for WL and 57% (95% CI 41% to 72%) for M. Across the three treatment groups, the pCR was 82% and 43% for EHA and EAC, respectively. CONCLUSION: Complete response rates at 6 months were encouraging for patients with EAC and EHA across the three groups. TRIAL REGISTRATION: U.S. National Library of Medicine, NCT01686126.

A review of experimental and computational attempts to remedy stability issues of perovskite solar cells.

Photovoltaic technology using perovskite solar cells has emerged as a potential solution in the photovoltaic makings for cost-effective manufacturing solutions deposition/coating solar cells. The hybrid perovskite-based materials possess a unique blend from low bulk snare concentrations, ambipolar, broad optical absorption properties, extended charge carrier diffusion, and charge transport/collection properties, making them favourable for solar cell applications. However, perovskite solar cells devices suffer from the effects of natural instability, leading to their rapid degradation while bared to water, oxygen, as well as ultraviolet rays, are irradiated and in case of high temperatures. It is essential to shield the perovskite film from damage, extend lifetime, and make it suitable for device fabrications. This paper focuses on various device strategies and computational attempts to address perovskite-based solar cells' environmental stability issues.

Comparison between laparoscopic and robotic surgery for sentinel lymph node mapping in endometrial cancer using indocyanine green and near infra-red fluorescence imaging.

Indocyanine green (ICG) and near infra-red fluorescence imaging in minimally invasive surgery is an option to map sentinel lymph nodes (SLN). The aim of this study was to compare the outcomes of SLN mapping between laparoscopic and robotic surgery. One-hundred-and-forty women with histologically confirmed endometrial cancer, were treated with a minimally invasive hysterectomy, bilateral salpingo-oophorectomy and SLN mapping. After anaesthetic induction, ICG was superficially injected into cervical submucosa and deeply injected into the cervical stroma at the 3 and 9 o'clock positions (1.25 mg/site). Eleven cases were abandoned after ICG injection (laparoscopic surgery seven cases and robotic surgery four cases) because of obesity, technical difficulty and peritoneal disease. One-hundred-and-eleven patients were analysed. Seventy-six patients had a laparoscopic procedure and 33 patients had robotic surgery. The overall and bilateral detection rates were 97% and 83% for laparoscopic surgery and 88% and 73% for robotic surgery. Laparoscopic surgery was superior to robotic surgery in terms of overall detection (p-value .046). There was no significant difference in the intra-operative SLN identification time or SLN dissection time between laparoscopy and robotic surgery (p-value .247 and .145, respectively). Further research is required to compare laparoscopy and robotic surgery in terms of SLN detection.Impact StatementWhat is already known on this subject? Sentinel lymph node (SLN) mapping aims to avoid complications and provide useful staging information for endometrial cancer. ICG has been shown to improve the detection rate and NPV compared with other tracers (blue dye and technetium 99). No data exists comparing SLN mapping rates using ICG in laparoscopy and robotic surgery.What do the results of this study add? The overall and bilateral detection rates were 97% and 83% for laparoscopic surgery and 88% and 73% for robotic surgery. Laparoscopic surgery was superior to robotic surgery in terms of overall detection. There was no significant difference in the intra-operative SLN identification time or SLN dissection time between laparoscopy and robotic surgery.What are the implications of these findings for clinical practice and/or further research?: This study confirms that laparoscopy and robotic surgery are not different in terms of bilateral detection rate and SLN operating time; the study population is small.

Soil-to-crop transfer of natural radionuclides in farm soil of South Africa.

The activity concentration of natural radionuclides in farm soil and most common indigenous food crops (maize, potato, cowpea) in oil-producing (Philippi, Uitenhage, and Hertenbos farms) and non-oil-producing (Ukulinga farm) areas of South Africa was measured using a Hyper Pure Germanium detector. Consequently, the transfer of these radionuclides from soil-to-crops was estimated. The mean activity concentration of 226Ra, 232Th, and 40K for farm soil samples are 30.71 ± 11.77, 31.97 ± 8.90, 345.97 ± 98.62 Bq.kg-1 for Philippi; 18.67 ± 6.70, 31.55 ± 11.48, 191.93 ± 33.39 Bq.kg-1 for Uitenhage; 38.03 ± 17.44, 41.18 ± 31.54, 381.89 ± 163.40 Bq.kg-1 for Hartenbos; and 8.47 ± 2.87, 8.65 ± 3.52, 94.22 ± 25.97 ± 25.97 Bq.kg-1 for Ukulinga. The mean activity concentration of 226Ra, 232Th, and 40K for crop samples are 4.54 ± 1.47, 4.87 ± 1.69, 140.18 ± 35.38 Bq.kg-1 for Philippi; 9.17 ± 4.79, 3.85 ± 1.87, 136.75 ± 22.04 Bq.kg-1 for Uitenhage; 7.97 ± 2.91, 4.62 ± 2.40, 105.97 ± 48.65 Bq.kg-1 for Hartenbos; and 4.23 ± 1.63, 2.72 ± 1.19, 48.36 ± 15.55 Bq.kg-1 for Ukulinga. The activity concentration and soil-to-crop transfer factors for 40K were found to be much higher, possibly because this element is critical in crop growth. The results showed that the crop samples' transfer factor is in the order cowpea>potato>maize. This study showed that activity concentrations of 226Ra, 232Th, and 40K in crops and the corresponding transfer factors depend on activity concentrations of the same radionuclides in soil.

Survival outcomes after delayed cytoreduction surgery following neoadjuvant chemotherapy in advanced epithelial ovarian cancer.

OBJECTIVE: Interval cytoreduction following neoadjuvant chemotherapy is a well-recognized treatment alternative to primary debulking surgery in the treatment of advanced epithelial ovarian cancer where patient and/or disease factors prevent complete macroscopic disease resection to be achieved. More recently, the strain of the global COVID-19 pandemic on hospital resources has forced many units to alter the timing of interval surgery and extend the number of neoadjuvant chemotherapy cycles. In order to support this paradigm shift and provide more accurate counseling during these unprecedented times, we investigated the survival outcomes in advanced epithelial ovarian cancer patients with the intent of maximal cytoreduction following neoadjuvant chemotherapy with respect to timing of surgery and degree of cytoreduction. METHODS: A retrospective review of all patients aged 18 years and above with FIGO (2014) stage III/IV epithelial ovarian cancer treated with neoadjuvant chemotherapy and the intention of interval cytoreduction surgery between January 2008 and December 2017 was conducted. Overall and progression-free survival outcomes were analyzed and compared with patients who only received chemotherapy. Outcome measures were correlated with the number of neoadjuvant chemotherapy cycles and amount of residual disease following surgery. RESULTS: Six hundred and seventy-one patients (median age 67 (range 20-91) years) were included in the study with 572 patients treated with neoadjuvant chemotherapy and surgery and 99 patients with chemotherapy only. There was no difference in the proportion of patients in whom complete cytoreduction was achieved based on number of cycles of neoadjuvant chemotherapy (2-4 cycles: 67.7%, n=337/498); ≥5 cycles: 62.2%, n=46/74). Patients undergoing cytoreduction surgery after neoadjuvant chemotherapy had a median 5-year progression-free and overall survival of 24 and 38 months, respectively. No significant difference in overall survival between surgical groups was observed (interval cytoreduction: 41 months vs delayed cytoreduction: 43 months, p=0.52). Those who achieved complete cytoreduction to R0 (no macroscopic disease) had a significant median overall survival advantage compared with those with any macroscopic residual disease (R0: 49-51 months vs R<1: 22-39 months, p<0.001 vs R≥1: 23-26 months, p<0.001). CONCLUSIONS: Survival outcomes do not appear to be worse for patients treated with neoadjuvant chemotherapy if cytoreduction surgery is delayed beyond three cycles. In advanced epithelial ovarian cancer patients the imperative to achieve complete surgical cytoreduction remains gold standard, irrespective of surgical timing, for best survival benefit.

Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma.

High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we report the effect on preclinical models of OCC of disrupting glycogen utilization using the glucose analogue 2-deoxy-D-glucose (2DG). At concentrations significantly lower than previously reported for other cancers, 2DG markedly improves the efficacy in vitro of carboplatin chemotherapy against chemo-sensitive TOV21G and chemo-resistant OVTOKO OCC cell lines, and this is accompanied by the depletion of glycogen. Of note, 2DG doses-of more than 10-fold lower than previously reported for other cancers-significantly improve the efficacy of carboplatin against cell line and patient-derived xenograft models in mice that mimic the chemo-responsiveness of OCC. These findings are encouraging, in that 2DG doses, which are substantially lower than previously reported to cause adverse events in cancer patients, can safely and significantly improve the efficacy of carboplatin against OCC. Our results thus justify clinical trials to evaluate whether low dose 2DG improves the efficacy of carboplatin in OCC patients.

Low-cost fabrication of optical tissue phantoms for use in biomedical imaging.

The rapid development of new optical imaging techniques is dependent on the availability of low-cost and easily reproducible standards for technique validation. This work describes a low-cost fabrication process of an agar gel-based phantom that may accurately simulate the optical properties of different human tissues at 532 and 630nm wavelengths. It was designed to match the optical properties of the brain, bladder wall, and lung tissues. These low-cost phantoms use agar powders dissolved in water as the bulk matrix. The latter is loaded with varying amounts of India ink, and aluminium oxide Al2O3 particles for optical absorption and scattering targets. The optical properties (absorption and scattering coefficients), the primary design factor and critical parameters of these phantoms were deduced from measurements of the total attenuation coefficients ( µ t ) . It is anticipated that the constructed tissue phantoms have the potential to be used as a reference standard since it's possible to preserve the optical properties in a period exceeding two years, under ideal storage conditions.

Incidence of adverse events in minimally invasive vs open radical hysterectomy in early cervical cancer: results of a randomized controlled trial.

BACKGROUND: Standard treatment of early cervical cancer involves a radical hysterectomy and retroperitoneal lymph node dissection. The existing evidence on the incidence of adverse events after minimally invasive vs open radical hysterectomy for early cervical cancer is either nonrandomized or retrospective. OBJECTIVE: The purpose of this study was to compare the incidence of adverse events after minimally invasive vs open radical hysterectomy for early cervical cancer. STUDY DESIGN: The Laparoscopic Approach to Carcinoma of the Cervix trial was a multinational, randomized noninferiority trial that was conducted between 2008 and 2017, in which surgeons from 33 tertiary gynecologic cancer centers in 24 countries randomly assigned 631 women with International Federation of Gynecology and Obstetrics 2009 stage IA1 with lymph-vascular invasion to IB1 cervical cancer to undergo minimally invasive (n = 319) or open radical hysterectomy (n = 312). The Laparoscopic Approach to Carcinoma of the Cervix trial was suspended for enrolment in September 2017 because of an increased risk of recurrence and death in the minimally invasive surgery group. Here we report on a secondary outcome measure: the incidence of intra- and postoperative adverse events within 6 months after surgery. RESULTS: Of 631 randomly assigned patients, 536 (85%; mean age, 46.0 years) met inclusion criteria for this analysis; 279 (52%) underwent minimally invasive radical hysterectomy, and 257 (48%) underwent open radical hysterectomy. Of those, 300 (56%), 91 (16.9%), and 69 (12.8%) experienced at least 1 grade ≥2 or ≥3 or a serious adverse event, respectively. The incidence of intraoperative grade ≥2 adverse events was 12% (34/279 patients) in the minimally invasive group vs 10% (26/257) in the open group (difference, 2.1%; 95% confidence interval, -3.3 to 7.4%; P=.45). The overall incidence of postoperative grade ≥2 adverse events was 54% (152/279 patients) in the minimally invasive group vs 48% (124/257) in the open group (difference, 6.2%; 95% confidence interval, -2.2 to 14.7%; P=.14). CONCLUSION: For early cervical cancer, the use of minimally invasive compared with open radical hysterectomy resulted in a similar overall incidence of intraoperative or postoperative adverse events.

Microenvironment engineering of osteoblastic bone metastases reveals osteomimicry of patient-derived prostate cancer xenografts.

Representative in vitro models that mimic the native bone tumor microenvironment are warranted to support the development of more successful treatments for bone metastases. Here, we have developed a primary cell 3D model consisting of a human osteoblast-derived tissue-engineered construct (hOTEC) indirectly co-cultured with patient-derived prostate cancer xenografts (PDXs), in order to study molecular interactions in a patient-derived microenvironment context. The engineered biomimetic microenvironment had high mineralization and embedded osteocytes, and supported a high degree of cancer cell osteomimicry at the gene, protein and mineralization levels when co-cultured with prostate cancer PDXs from a lymph node metastasis (LuCaP35) and bone metastasis (BM18) from patients with primary prostate cancer. This fully patient-derived model is a promising tool for the assessment of new molecular mechanisms and as a personalized pre-clinical platform for therapy testing for patients with prostate cancer bone metastases.

Minimally Invasive versus Abdominal Radical Hysterectomy for Cervical Cancer.

BACKGROUND: There are limited data from retrospective studies regarding whether survival outcomes after laparoscopic or robot-assisted radical hysterectomy (minimally invasive surgery) are equivalent to those after open abdominal radical hysterectomy (open surgery) among women with early-stage cervical cancer. METHODS: In this trial involving patients with stage IA1 (lymphovascular invasion), IA2, or IB1 cervical cancer and a histologic subtype of squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma, we randomly assigned patients to undergo minimally invasive surgery or open surgery. The primary outcome was the rate of disease-free survival at 4.5 years, with noninferiority claimed if the lower boundary of the two-sided 95% confidence interval of the between-group difference (minimally invasive surgery minus open surgery) was greater than -7.2 percentage points (i.e., closer to zero). RESULTS: A total of 319 patients were assigned to minimally invasive surgery and 312 to open surgery. Of the patients who were assigned to and underwent minimally invasive surgery, 84.4% underwent laparoscopy and 15.6% robot-assisted surgery. Overall, the mean age of the patients was 46.0 years. Most patients (91.9%) had stage IB1 disease. The two groups were similar with respect to histologic subtypes, the rate of lymphovascular invasion, rates of parametrial and lymph-node involvement, tumor size, tumor grade, and the rate of use of adjuvant therapy. The rate of disease-free survival at 4.5 years was 86.0% with minimally invasive surgery and 96.5% with open surgery, a difference of -10.6 percentage points (95% confidence interval [CI], -16.4 to -4.7). Minimally invasive surgery was associated with a lower rate of disease-free survival than open surgery (3-year rate, 91.2% vs. 97.1%; hazard ratio for disease recurrence or death from cervical cancer, 3.74; 95% CI, 1.63 to 8.58), a difference that remained after adjustment for age, body-mass index, stage of disease, lymphovascular invasion, and lymph-node involvement; minimally invasive surgery was also associated with a lower rate of overall survival (3-year rate, 93.8% vs. 99.0%; hazard ratio for death from any cause, 6.00; 95% CI, 1.77 to 20.30). CONCLUSIONS: In this trial, minimally invasive radical hysterectomy was associated with lower rates of disease-free survival and overall survival than open abdominal radical hysterectomy among women with early-stage cervical cancer. (Funded by the University of Texas M.D. Anderson Cancer Center and Medtronic; LACC ClinicalTrials.gov number, NCT00614211 .).

L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution.

LINE-1 (L1) retrotransposons are a source of insertional mutagenesis in tumor cells. However, the clinical significance of L1 mobilization during tumorigenesis remains unclear. Here, we applied retrotransposon capture sequencing (RC-seq) to multiple single-cell clones isolated from five ovarian cancer cell lines and HeLa cells and detected endogenous L1 retrotransposition in vitro. We then applied RC-seq to ovarian tumor and matched blood samples from 19 patients and identified 88 tumor-specific L1 insertions. In one tumor, an intronic de novo L1 insertion supplied a novel cis-enhancer to the putative chemoresistance gene STC1. Notably, the tumor subclone carrying the STC1 L1 mutation increased in prevalence after chemotherapy, further increasing STC1 expression. We also identified hypomethylated donor L1s responsible for new L1 insertions in tumors and cultivated cancer cells. These congruent in vitro and in vivo results highlight L1 insertional mutagenesis as a common component of ovarian tumorigenesis and cancer genome heterogeneity.