Erratum: [Corrigendum] Chloroquine potentiates the anticancer effect of sunitinib on renal cell carcinoma by inhibiting autophagy and inducing apoptosis.

[This corrects the article DOI: 10.3892/ol.2017.7635.].

Combined Stereotactic Body Radiation Therapy and Immune Checkpoint Inhibition for Liver Metastases: Safety and Outcomes in a Pooled Analysis of 3 Phase 1 Trials.

PURPOSE: Stereotactic body radiation therapy (SBRT) safely and effectively controls liver metastases (LMs), but its safety and efficacy when combined with immune checkpoint inhibitors (ICIs) are not well characterized. This analysis of 3 phase 1 trials of combination SBRT and ICI evaluates whether LM-SBRT increases the risk for hepatotoxicity when combined with ICI and explores efficacy endpoints. METHODS AND MATERIALS: Data were analyzed from 3 phase 1 trials of combination SBRT and ICI for patients with metastatic solid tumors conducted between 2016 and 2020. ICI was administered per trial protocol with LM-SBRT delivered to 45 Gy in 3 fractions with mean liver dose <16 Gy and ≥700 cc of normal liver spared 17.1 Gy. Hepatic adverse events (HAEs) were defined as hepatic failure, autoimmune hepatitis, or elevation of aspartate transaminase, alanine transaminase, bilirubin, or alkaline phosphatase using Common Terminology Criteria for Adverse Events version 4.0. Cumulative incidence of HAEs and local failure were modeled with death as a competing risk. Competing risk regression was performed using Fine-Gray modeling. Survival was estimated via the Kaplan-Meier method. RESULTS: Two hundred patients were analyzed, including 81 patients with LM, 57 of whom received LM-SBRT. The 12-month rate of any grade ≥2 HAE was 11% and 10% in LM-SBRT and non-LM-SBRT patients, respectively non-significant (NS). Radiographic evidence for liver disease and dual-agent ICI was significantly associated with HAEs on univariable and multivariable analysis, but liver dose metrics were not. Patients with LM had significantly worse progression-free and overall survival compared with those without, and local failure of treated LM was significantly higher than for treated extrahepatic metastases (28% vs 4% at 12 months, P < .001). CONCLUSIONS: Combination LM-SBRT and ICI did not significantly increase the risk for HAEs compared with ICI without LM-SBRT, suggesting hepatotoxicity is largely driven by factors other than liver radiation therapy, such as choice of ICI. LM is associated with worse overall survival and local control outcomes.

Monitoring Intrafraction Motion of the Prostate During Radiation Therapy: Suggested Practice Points From a Focused Review.

PURPOSE: External beam radiation therapy to the prostate is typically delivered after verification of prostatic position with image guidance. Prostate motion can occur during the delivery of each radiation treatment between the time of localization imaging and completion of treatment. The objective of this work is to review the literature on intrafraction motion (IFM) of the prostate during radiation therapy and offer clinical recommendations on management. METHODS AND MATERIALS: A comprehensive literature review was conducted on prostate motion during prostate cancer radiation therapy. Information was organized around 3 key clinical questions, followed by an evidence-based recommendation. RESULTS: IFM of the prostate during radiation therapy is typically ≤3 mm and is unlikely to compromise prostate dosimetry to a clinically meaningful degree for men treated in a relatively short treatment duration with planning target volume (PTV) margins of ≥3 to 5 mm. IFM of 5 mm or more has been observed in up to ∼10% of treatment fractions, with limited dosimetric effect related to the infrequency of occurrence and longer fractionation of therapy. IFM can be monitored in continuous or discontinuous fashion with a variety of imaging platforms. Correction of IFM may have the greatest value when tighter PTV margins are desired (such as with stereotactic body radiation therapy or intraprostatic nodule boosting), ultrahypofractionated courses, or when treatment time exceeds several minutes. CONCLUSIONS: This focused review summarizes literature and provides practical recommendations regarding IFM in the treatment of prostate cancer with external beam radiation therapy.

An AI-based universal phantom analysis method based on XML-SVG wireframes with novel functional object identifiers.

Objective.Quality assurance (QA) testing must be performed at regular intervals to ensure that medical devices are operating within designed specifications. Numerous QA phantoms and software packages have been developed to facilitate measurements of machine performance. However, due to the hard-coded nature of geometric phantom definition in analysis software, users are typically limited to the use of a small subset of compatible QA phantoms. In this work, we present a novel AI-based universal Phantom (UniPhan) algorithm that is not phantom specific and can be easily adapted to any pre-existing image-based QA phantom.Approach.Extensible Markup Language Scalable Vector Graphics (XML-SVG) was modified to include several new tags describing the function of embedded phantom objects for use in QA analysis. Functional tags include contrast and density plugs, spatial linearity markers, resolution bars and edges, uniformity regions, and light-radiation field coincidence areas. Machine learning was used to develop an image classification model for automatic phantom type detection. After AI phantom identification, UniPhan imported the corresponding XML-SVG wireframe, registered it to the image taken during the QA process, performed analysis on the functional tags, and exported results for comparison to expected device specifications. Analysis results were compared to those generated by manual image analysis.Main results.XML-SVG wireframes were generated for several commercial phantoms including ones specific to CT, CBCT, kV planar imaging, and MV imaging. Several functional objects were developed and assigned to the graphical elements of the phantoms. The AI classification model was tested for training and validation accuracy and loss, along with phantom type prediction accuracy and speed. The results reported training and validation accuracies of 99%, phantom type prediction confidence scores of around 100%, and prediction speeds of around 0.1 s. Compared to manual image analysis, Uniphan results were consistent across all metrics including contrast-to-noise ratio, modulation-transfer function, HU accuracy, and uniformity.Significance.The UniPhan method can identify phantom type and use its corresponding wireframe to perform QA analysis. As these wireframes can be generated in a variety of ways this represents an accessible automated method of analyzing image-based QA phantoms that is flexible in scope and implementation.

A Contemporary Report of Low-Dose-Rate Brachytherapy for Prostate Cancer Using MRI for Risk Stratification: Disease Outcomes and Patient-Reported Quality of Life.

PURPOSE: We examined a prospective consecutive cohort of low dose rate (LDR) brachytherapy for prostate cancer to evaluate the efficacy of monotherapy for unfavorable-intermediate risk (UIR) disease, and explore factors associated with toxicity and quality of life (QOL). METHODS: 149 men with prostate cancer, including 114 staged with MRI, received Iodine-125 brachytherapy alone (144-145 Gy) or following external beam radiation therapy (110 Gy; EBRT). Patient-reported QOL was assessed by the Expanded Prostate Index Composite (EPIC) survey, and genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively recorded (CTC v4.0). Global QOL scores were assessed for decline greater than the minimum clinically important difference (MCID). Univariate analysis (UVA) was performed, with 30-day post-implant dosimetry covariates stratified into quartiles. Median follow-up was 63 mo. RESULTS: Men with NCCN low (n = 42) or favorable-intermediate risk (n = 37) disease were treated with brachytherapy alone, while most with high-risk disease had combined EBRT (n = 17 of 18). Men with UIR disease (n = 52) were selected for monotherapy (n = 42) based on clinical factors and MRI findings. Freedom from biochemical failure-7 yr was 98%. Of 37 men with MRI treated with monotherapy for UIR disease, all 36 men without extraprostatic extension were controlled. Late Grade 2+/3+ toxicity occurred in 55/3% for GU and 8/2% for GI, respectively. Fifty men were sexually active at baseline and had 2 yr sexual data; 37 (74%) remained active at 2 yr. Global scores for urinary incontinence (UC), urinary irritation/obstruction (UIO), bowel function, and sexual function (SF) showed decreases greater than the MCID (p < 0.05) in UC at 2 mo, UIO at 2 and 6 mo, and SF at 2-24 mo, and >5 yr. Analysis did not reveal any significant associations with any examined rectal or urethral dosimetry for late toxicity or QOL. CONCLUSION: Disease outcomes and patient-reported QOL support LDR brachytherapy, including monotherapy for UIR disease.

Hematuria following Post-Prostatectomy Radiotherapy: Incidence Increases with Long-Term Followup.

PURPOSE: Hematuria following post-prostatectomy radiotherapy (PPRT) is inadequately characterized. We performed a consecutive cohort study of patients treated with PPRT at our institution to characterize this complication including impact on patient-reported quality of life. MATERIALS AND METHODS: Patients with potential followup ≥4 years following PPRT were identified. Freedom from ≥grade 2 hematuria (FFG2H; macroscopic blood) was estimated using the Kaplan-Meier method. Predictors of ≥grade 2 hematuria (G2H) were assessed via log-rank tests and the Cox model. Urinary patient-reported quality of life by EPIC-26 (26-question Expanded Prostate Cancer Index Composite) was compared for patients with/without hematuria using mixed-effects regression. RESULTS: A total of 216 men received PPRT (median 68.4 Gy, IQR 68.0-68.4) from 2007 to 2016 at a median of 20 months (IQR 9-45) after prostatectomy. Median followup was 72 months (IQR 54-99). A total of 85 men developed hematuria, of whom 49 (58%) underwent cystoscopy, 13 (15%) required intervention and 26 (31%) experienced recurrent hematuria. Eight-year FFG2H was 55%. G2H was highest in men treated with anticoagulation/antiplatelet therapy (HR 3.24, p <0.001), men with bladder V65 Gy ≥43% (HR 1.97, p=0.004) and men with medication allergies (HR 1.73, p=0.049). Age <65 years (HR 0.81, p=0.374) and diabetes mellitus (HR 0.49, p=0.098) were not associated with G2H. Change in urinary continence (mean -3.5, 95% CI: 10.1, 3.1) and irritation/obstruction (mean -3.0, 95% CI: 5.8, -0.3) domain scores did not exceed the minimally clinically important difference for men with/without hematuria. CONCLUSIONS: Hematuria following PPRT is common, especially among men with medication allergies and those on anticoagulation/antiplatelet therapy; however, PPRT-related hematuria is typically self-limited. Limiting bladder V65 Gy may reduce PPRT-related hematuria.

A knowledge-based intensity-modulated radiation therapy treatment planning technique for locally advanced nasopharyngeal carcinoma radiotherapy.

BACKGROUND: To investigate the feasibility of a knowledge-based automated intensity-modulated radiation therapy (IMRT) planning technique for locally advanced nasopharyngeal carcinoma (NPC) radiotherapy. METHODS: One hundred forty NPC patients treated with definitive radiation therapy with the step-and-shoot IMRT techniques were retrospectively selected and separated into a knowledge library (n = 115) and a test library (n = 25). For each patient in the knowledge library, the overlap volume histogram (OVH), target volume histogram (TVH) and dose objectives were extracted from the manually generated plan. 5-fold cross validation was performed to divide the patients in the knowledge library into 5 groups before validating one group by using the other 4 groups to train each neural network (NN) machine learning models. For patients in the test library, their OVH and TVH were then used by the trained models to predict a corresponding set of mean dose objectives, which were subsequently used to generate automated plans (APs) in Pinnacle planning system via an in-house developed automated scripting system. All APs were obtained after a single step of optimization. Manual plans (MPs) for the test patients were generated by an experienced medical physicist strictly following the established clinical protocols. The qualities of the APs and MPs were evaluated by an attending radiation oncologist. The dosimetric parameters for planning target volume (PTV) coverage and the organs-at-risk (OAR) sparing were also quantitatively measured and compared using Mann-Whitney U test and Bonferroni correction. RESULTS: APs and MPs had the same rating for more than 80% of the patients (19 out of 25) in the test group. Both AP and MP achieved PTV coverage criteria for no less than 80% of the patients. For each OAR, the number of APs achieving its criterion was similar to that in the MPs. The AP approach improved planning efficiency by greatly reducing the planning duration to about 17% of the MP (9.85 ± 1.13 min vs. 57.10 ± 6.35 min). CONCLUSION: A robust and effective knowledge-based IMRT treatment planning technique for locally advanced NPC is developed. Patient specific dose objectives can be predicted by trained NN models based on the individual's OVH and clinical TVH goals. The automated planning scripts can use these dose objectives to efficiently generate APs with largely shortened planning time. These APs had comparable dosimetric qualities when compared to our clinic's manual plans.

Hypoxia-Induced Placenta-Specific microRNA (miR-512-3p) Promotes Hepatocellular Carcinoma Progression by Targeting Large Tumor Suppressor Kinase 2.

BACKGROUND: Sustained proliferation and active metastasis are hallmarks of cancer, and they pose major challenges to the development of treatments and a cure for hepatocellular carcinoma (HCC). Thus, the mechanisms of proliferation, migration, and invasion of cancer cells need to be investigated. Many studies indicate that dysregulation of microRNA plays important roles in the progression of HCC, but the role of placenta-specific microRNA (miR-512-3p) in HCC has not been systematically investigated. PURPOSE: In the current study, the expression, biological function, and mechanisms of miR-512-3p involvement in HCC were investigated. METHODS: Real-time quantitative polymerase chain reaction assays were conducted to determine miR-512-3p levels in HCC tissues and cell lines. The StarBase V3.0 online platform was used to compare miR-512-3p levels in HCC tissues with TCGA data and to identify potential miR-512-3p target genes. Associations between miR-512-3p and clinicopathological characteristics were analyzed statistically. MTT, ethynyl deoxyuridine, and transwell assays were performed to assess cell viability, proliferation, migration, and invasion. The luciferase reporter gene assay was used to verify target genes. Recuse assays were performed to confirm whether large tumor suppressor kinase 2 (LATS2) participated in the regulatory effects of miR-512-3p on HCC cell proliferation and motility, and whether miR-512-3p mediated the tumor-promoting effects of hypoxia. RESULTS: miR-512-3p was upregulated in HCC and it was associated with worse survival and unfavorable clinicopathological characteristics. Functional assays indicated that miR-512-3p contributed to HCC cell proliferation, migration, and invasion. Mechanistically, LATS2-a downstream target of miR-512-3p-mediated the tumor-promoting effects of miR-512-3p in HCC. Hypoxia could elevate miR-512-3p levels in HCC cells, and miR-512-3p partially mediated the tumor-promoting effects of hypoxia. CONCLUSION: Hypoxia-induced miR-512-3p contributes to HCC cell proliferation, migration, and invasion by targeting LATS2 and inhibiting the Hippo/yes-associated protein 1 pathways.

A prospective trial of stereotactic body radiation therapy for unresectable pancreatic cancer testing ablative doses.

BACKGROUND: We explored the safety and efficacy of ablative doses of stereotactic body radiation therapy (SBRT) for unresectable pancreatic cancer. METHODS: This phase I/II trial included patients with unresectable pancreatic cancer previously treated with any number of cycles of induction chemotherapy. Patients were enrolled according to a 3+3 dose escalation design at 10, 12.5, and 15 Gy ×3, with subsequent patients at the maximally tolerated dose (MTD). Treatment was delivered to gross tumor delineated with MRI fusion using image-guidance to fiducial markers. Dose-limiting toxicity (DLT) was defined as grade 3+ toxicity within 30 days. Secondary endpoints included late gastrointestinal (GI) toxicity, freedom from local failure (FFLF), and survival. RESULTS: Fifteen patients received a median 10 cycles of chemotherapy. There were no DLTs, and the MTD was 15 Gy ×3. Thirty-day toxicity included grade 2 nausea (46%) and grade 2 diarrhea (7%). Median survival after SBRT was 12.8 months (23 months after diagnosis) and median relapse-free survival was 7 months. At 1-year, FFLF was 80%. Four patients had grade 3+ GI bleeding after 30 days (median 6 months). Grade 3+ GI bleeding was associated with tumor volume (P=0.01), heterogeneity of dose within the planning target volume (PTV) (V120, P=0.03), and duodenal dose (V26-30 Gy, P<0.2). CONCLUSIONS: This aggressive SBRT regimen demonstrated limited 30-day morbidity, a moderate degree of local control, and a moderate risk for late GI bleeding. Further work is necessary to define the most appropriate hypofractionated radiation therapy (RT) regimen in the ablative dose range.

Clinical and Dosimetric Implications of Intrafractional Cylinder Movement During Vaginal Cuff Brachytherapy.

Introduction To quantify the dosimetric and clinical effects of intrafractional cylinder movement in patients receiving high-dose-rate vaginal cuff brachytherapy (VBT) without a formal immobilization device and the implication of motion on institutional clinical outcomes. Methods From 2013-2018, 119 patients were treated with VBT with no formal immobilization device at a single institution. As a quality assessment study, pre-and post-cylinder brachytherapy kilovoltage (kV) images were acquired for 37 fractions in nine consecutive patients who underwent VBT and clinical care representative of institutional practice standards. The D90 and D90 EqD2 were calculated according to each patient's average intrafractional movement throughout the treatment course. The D2cc for organs-at-risk (OARs) were also re-evaluated following the simulated movements. The survival outcomes and toxicity were recorded from the 119 patients. Toxicity was graded as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results The measured mean ± standard deviation movement was 5.0 mm ± 3.5, with 62% moving caudad. The D90 from each patient's maximum and average movements were lower than the pre-planned doses: 71%, and 89%, respectively. The doses to the OARs were lower than the pre-planned doses. After a median follow-up of 20 months, there were three local recurrences with a median time of 14.5 months (range: 10-31). There were two acute grade 3+ toxicities and one late grade 3+ toxicity. There was a moderate correlation (r = 0.40) between body mass index (BMI) and intrafraction movement with caudad being more common in smaller BMIs (p = 0.0216). Conclusions Intrafractional vaginal cylinder movement without a table fixation device is about 5.0 mm, with the majority of movements moving caudad. While institutional outcomes suggest that local control may not be compromised, consideration of more formal immobilization devices is warranted, especially for those patients with lower BMIs.

Increased glutamine anabolism sensitizes non-small cell lung cancer to gefitinib treatment.

To better understand the resistance mechanism of non-small cell lung cancers (NSCLCs) to gefitinib, the metabolic profiles of gefitinib-resistant A549 cells and gefitinib-sensitive PC-9 cells were analyzed with a metabolomics analytical platform. A549 and PC-9 cells exhibited significant differences in the levels of glutamine-related metabolites. After gefitinib treatment, the glutamine level decreased in A549 cells but showed no change in PC-9 cells. The glutamine consumed by A549 cells was used to generate ATP and glutathione (GSH). As glutamine utilization was suppressed in gefitinib-treated PC-9 cells, the resulting ATP shortage and ROS accumulation led to cell death. The difference in glutamine metabolism was caused by differential changes in the levels of glutamine synthetase (GS, encoded by glutamate-ammonia ligase (GLUL)). GLUL expression was upregulated in gefitinib-sensitive cells, but it was either absent from gefitinib-resistant cells or no significant change was observed in the gefitinib-treated cells. GLUL overexpression in A549 cells significant sensitized them to gefitinib and decreased their invasive capacity. Conversely, knockout GS in PC-9 cells reduced gefitinib sensitivity and enhanced metastasis. Furthermore, the continuous exposure of gefitinib-sensitive HCC827 cells to gefitinib created gefitinib-resistant (GR) HCC827 cells, which exhibited a GLUL deletion and resistance to gefitinib. Thus, GLUL plays a vital role in determining the sensitivity of NSCLCs to gefitinib. Elevated GS levels mediate increased glutamine anabolism, and this novel mechanism sensitizes NSCLCs to gefitinib. The inhibition of glutamine utilization may serve as a potential therapeutic strategy to overcome gefitinib resistance in the clinic.

Chloroquine potentiates the anticancer effect of sunitinib on renal cell carcinoma by inhibiting autophagy and inducing apoptosis.

Sunitinib based adjuvant chemotherapy combined with chloroquine (CQ) for the treatment of renal cell carcinoma (RCC) is in clinical trials; however, its anti-RCC effect and the mechanism remain unclear. In the present study, the anti-RCC effect of sunitinib with CQ and the underlying mechanism was investigated. An MTT assay demonstrated that CQ enhanced the proliferation inhibitory effect of sunitinib against the OS-RC-2 RCC cell line. CQ inhibited sunitinib-induced autophagy in OS-RC-2, which was evidenced by the inhibition of autophagic vacuoles, acidic vesicular organelle formation, light chain 3 (LC3)-II recruitment to the autophagosomes and the conversion of LC3-I to LC3-II, as induced by sunitinib. The inhibition of autophagy by CQ enhanced sunitinib-induced apoptosis, which was characterized by the activation of caspase-3, caspase-9, Bcl-2 and p53. Additionally, the exposure of OS-RC-2 cells to CQ and sunitinib resulted in the inhibition of AKT, tuberous sclerosis complex 2, mechanistic target of rapamycin and p70 ribosomal S6 kinase, which are associated with cell proliferation. In in vivo study, a combination of sunitinib with CQ in mice significantly reduced OS-RC-2 cell xenograft growth compared with the sunitinib alone group. In conclusion, the present study demonstrated that CQ may enhance the anti-RCC effect of sunitinib by inhibiting the autophagy induced by sunitinib, and enhance the rate of apoptosis. Inhibiting cell proliferation may also serve a role in the synergistic antitumor effect of sunitinib and CQ. These data suggest that combination therapy of sunitinib with CQ may be a promising strategy for adjuvant chemotherapy in RCC.

Treatment of retrogastric pancreatic pseudocysts by laparoscopic transgastric cystogastrostomy.

This paper discusses variations of laparoscopic transgastric cystogastrostomy in management of retrogastric pancreatic pseudocysts for 8 patients with symptom or pseudocysts (larger than 6 cm) companied with clinical manifestations. Using a Harmonic scalpel, two 3-5-cm incisions were made in the anterior and posterior gastric wall respectively. In the last step, the anterior gastrotomy was closed with an Endo-GIA stapler. All cases were successfully treated without large blood loss and without conversion to open surgery. The mean operative time was 114.29±19.24 min, blood loss was 157.14±78.70 mL, and mean hospital stay was 8.29±2.98 days. Gastric fistula occurred in one case on the postoperative day 7, and closed 1 month later. No bleeding was seen in all patients during the perioperative follow-up period. CT scans, given one month after the surgeries, displayed that the pancreatic pseudocysts disappeared or decreased in size, and ultrasounds showed no fluid or food residue in stomas at the third and fifth month following surgery. No patient experienced a recurrence during the follow-up period. Transgastric laparoscopic cystogastrostomy is a minimally invasive surgical procedure with a high rate of success and a low rate of recurrence, accompanied by rapid recovery. It is easy to master, safe to perform and may be the preferred option to treat retrogastric pancreatic pseudocysts.

MYC Controls Human Pluripotent Stem Cell Fate Decisions through Regulation of Metabolic Flux.

As human pluripotent stem cells (hPSCs) exit pluripotency, they are thought to switch from a glycolytic mode of energy generation to one more dependent on oxidative phosphorylation. Here we show that, although metabolic switching occurs during early mesoderm and endoderm differentiation, high glycolytic flux is maintained and, in fact, essential during early ectoderm specification. The elevated glycolysis observed in hPSCs requires elevated MYC/MYCN activity. Metabolic switching during endodermal and mesodermal differentiation coincides with a reduction in MYC/MYCN and can be reversed by ectopically restoring MYC activity. During early ectodermal differentiation, sustained MYCN activity maintains the transcription of "switch" genes that are rate-limiting for metabolic activity and lineage commitment. Our work, therefore, shows that metabolic switching is lineage-specific and not a required step for exit of pluripotency in hPSCs and identifies MYC and MYCN as developmental regulators that couple metabolism to pluripotency and cell fate determination.

The synthesis, structure-toxicity relationship of cisplatin derivatives for the mechanism research of cisplatin-induced nephrotoxicity.

Cisplatin is a widely used antineoplastic drug, while its nephrotoxicity limits the clinical application. Although several mechanisms contributing to nephrotoxicity have been reported, the direct protein targets are unclear. Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay in human renal proximal tubule cells (HK-2) and pig kidney epithelial cells (LLC-PK1). To the best of our knowledge, this study represented the first report regarding the structure-toxicity relationship (STR) of cisplatin derivatives. The potency of biotin-pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity.

External Validation and Optimization of International Consensus Clinical Target Volumes for Adjuvant Radiation Therapy in Bladder Cancer.

PURPOSE: International consensus (IC) clinical target volumes (CTVs) have been proposed to standardize radiation field design in the treatment of patients at high risk of locoregional failure (LRF) after radical cystectomy. The purpose of this study was to externally validate the IC CTVs in a cohort of postsurgical patients followed up for LRF and identify revisions that might improve the IC CTVs' performance. METHODS AND MATERIALS: Among 334 patients with pT3 to pT4 bladder cancer treated with radical cystectomy, LRF developed in 58 (17%), of whom 52 had computed tomography scans available for review. Images with LRF were exported into a treatment planning system, and IC CTVs were contoured and evaluated for adequacy of coverage of each LRF with respect to both the patient and each of 6 pelvic subsites: common iliac (CI) region, obturator region (OR), external and internal iliac region, presacral region, cystectomy bed, or other pelvic site. Revisions to the IC contours were proposed based on the findings. RESULTS: Of the 52 patients with documented LRF, 13 (25%) had LRFs that were outside of the IC CTV involving 17 pelvic subsites: 5 near the CI CTV, 5 near the OR CTV, 1 near the external and internal iliac region, and 6 near the cystectomy bed. The 5 CI failures were located superior to the CTV, and the 5 OR failures were located medial to the CTV. Increasing the superior boundary of the CI to a vessel-based definition of the aortic bifurcation, as well as increasing the medial extension of the OR by an additional 9 mm, decreased the number of patients with LRF outside of the IC CTV to 7 (13%). CONCLUSIONS: Modified IC CTVs inclusive of a slight adjustment superiorly for the CI region and medially for the OR may reduce the risk of pelvic failure in patients treated with adjuvant radiation therapy.

Prognostic value of quantitative PET/CT in patients with a nonsmall cell lung cancer and another primary cancer.

OBJECTIVE: The staging and management of patients with newly diagnosed nonsmall cell lung cancer (NSCLC) in the setting of recently diagnosed other (metachronous or synchronous) primary cancer are challenging. This retrospective cohort study was carried out to test our hypothesis that baseline 2-deoxy-2-[F]fluoro-D-glucose (F-FDG) PET/CT parameters, including whole-body metabolic tumor volume (MTVWB), total lesion glycolysis (TLGWB), and maximum standardized uptake value (SUVmaxWB), are associated with the overall survival (OS) of such patients. PATIENTS AND METHODS: A total of 110 NSCLC patients (52 men and 58 women, aged 68.6±7.8 years) with other primary malignant cancers who had baseline F-FDG PET/CT scans were retrospectively reviewed. MTVWB, TLGWB, and SUVmaxWB were measured. Kaplan-Meier analysis with the log-rank test and Cox regression models were used to assess the association of OS with F-FDG PET/CT parameters and clinical risk factors. RESULTS: Kaplan-Meier analysis and univariate Cox regression models showed significant associations of OS with ln(MTVWB), ln(TLGWB), ln(SUVmaxWB), TNM stage, and treatment type (surgery vs. no treatment). Multivariable Cox regression models showed a significant relationship of OS with ln(MTVWB) [hazard ratio (HR)=1.368, P=0.001], ln(TLGWB) (HR=1.313, P<0.001), and ln(SUVmaxWB) (HR=1.739, P=0.006), adjusted for age, treatment type, tumor histology, and TNM stage. The TNM stage was not associated significantly with OS when MTVWB, TLGWB, or SUVmaxWB were included in the multivariable models. CONCLUSION: MTVWB, TLGWB, and SUVmaxWB from baseline F-FDG PET/CT are associated individually with OS of patients with both NSCLC and other primary malignant tumors independent of age, treatment type, tumor histology, and TNM stage.

Triple-tandem high-dose-rate brachytherapy for early-stage medically inoperable endometrial cancer: Initial report on acute toxicity and dosimetric comparison to stereotactic body radiation therapy.

PURPOSE: Stereotactic body radiotherapy (SBRT) may be appealing in medically inoperable endometrial cancer to avoid procedural risks. We performed a dosimetric comparison to triple-tandem, high-dose-rate (HDR) brachytherapy. METHODS AND MATERIALS: Six consecutive clinical stage I, grade 1-2, medically inoperable endometrial cancer patients were treated with triple-tandem HDR brachytherapy. We report patient factors and acute toxicity. Also, we performed dosimetric comparison to SBRT using both 3D conformal arc (3DArc) and volumetric-modulated arc therapy. D2cc values for normal tissues were calculated and compared to the HDR plans. RESULTS: Median age was 57 years. Patient comorbidities included morbid obesity, congestive heart failure, diabetes, and pulmonary emboli. In three patients who received prior external beam radiation (EBRT), median EBRT and HDR doses were 46 Gy and 20 Gy, respectively. The median dose with HDR brachytherapy monotherapy was 35 Gy. Acute toxicities during EBRT included gastrointestinal (3/3 with grade 1-2) and genitourinary (3/3 with grade 1-2). Acute toxicities during HDR brachytherapy were gastrointestinal (2/6 total with grade 1-2) and genitourinary (2/6 total with grade 1). The mean D2cc/Gy of prescription dose for rectum, sigmoid, and bladder were 0.58, 0.40, and 0.47 respectively. Overall, doses to normal tissues were higher for SBRT plans as compared to HDR. Also, the R50 (ratio of the 50% prescription isodose volume to the PTV) was lowest with HDR brachytherapy. CONCLUSIONS: In medically inoperable, clinical stage I endometrial cancer patients with multiple comorbidities, definitive triple-tandem, HDR brachytherapy results in mild acute toxicity. In addition, HDR brachytherapy achieves relatively lower doses to surrounding normal tissues as compared to SBRT.

Concise Review: Control of Cell Fate Through Cell Cycle and Pluripotency Networks.

Pluripotent stem cells (PSCs) proliferate rapidly with a characteristic cell cycle structure consisting of short G1- and G2-gap phases. This applies broadly to PSCs of peri-implantation stage embryos, cultures of embryonic stem cells, induced pluripotent stem cells, and embryonal carcinoma cells. During the early stages of PSC differentiation however, cell division times increase as a consequence of cell cycle remodeling. Most notably, this is indicated by elongation of the G1-phase. Observations linking changes in the cell cycle with exit from pluripotency have raised questions about the role of cell cycle control in maintenance of the pluripotent state. Until recently however, this has been a difficult question to address because of limitations associated with experimental tools. Recent studies now show that pluripotency and cell cycle regulatory networks are intertwined and that cell cycle control mechanisms are an integral, mechanistic part of the PSC state. Studies in embryonal carcinoma, some 30 years ago, first suggested that pluripotent cells initiate differentiation when in the G1-phase. More recently, a molecular "priming" mechanism has been proposed to explain these observations in human embryonic stem cells. Complexity in this area has been increased by the realization that pluripotent cells exist in multiple developmental states and that in addition to each having their own characteristic gene expression and epigenetic signatures, they potentially have alternate modes of cell cycle regulation. This review will summarize current knowledge in these areas and will highlight important aspects of interconnections between the cell cycle, self-renewal, pluripotency, and cell fate decisions. Stem Cells 2016;34:1427-1436.

Cell-Cycle Control of Bivalent Epigenetic Domains Regulates the Exit from Pluripotency.

Here we show that bivalent domains and chromosome architecture for bivalent genes are dynamically regulated during the cell cycle in human pluripotent cells. Central to this is the transient increase in H3K4-trimethylation at developmental genes during G1, thereby creating a "window of opportunity" for cell-fate specification. This mechanism is controlled by CDK2-dependent phosphorylation of the MLL2 (KMT2B) histone methyl-transferase, which facilitates its recruitment to developmental genes in G1. MLL2 binding is required for changes in chromosome architecture around developmental genes and establishes promoter-enhancer looping interactions in a cell-cycle-dependent manner. These cell-cycle-regulated loops are shown to be essential for activation of bivalent genes and pluripotency exit. These findings demonstrate that bivalent domains are established to control the cell-cycle-dependent activation of developmental genes so that differentiation initiates from the G1 phase.