PR55α-controlled protein phosphatase 2A inhibits p16 expression and blocks cellular senescence induction by γ-irradiation.

Cellular senescence is a permanent cell cycle arrest that can be triggered by both internal and external genotoxic stressors, such as telomere dysfunction and DNA damage. The execution of senescence is mainly by two pathways, p16/RB and p53/p21, which lead to CDK4/6 inhibition and RB activation to block cell cycle progression. While the regulation of p53/p21 signaling in response to DNA damage and other insults is well-defined, the regulation of the p16/RB pathway in response to various stressors remains poorly understood. Here, we report a novel function of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase, as a potent inhibitor of p16 expression and senescence induction by ionizing radiation (IR), such as γ-rays. The results show that ectopic PR55α expression in normal pancreatic cells inhibits p16 transcription, increases RB phosphorylation, and blocks IR-induced senescence. Conversely, PR55α-knockdown by shRNA in pancreatic cancer cells elevates p16 transcription, reduces RB phosphorylation, and triggers senescence induction after IR. Furthermore, this PR55α function in the regulation of p16 and senescence is p53-independent because it was unaffected by the mutational status of p53. Moreover, PR55α only affects p16 expression but not p14 (ARF) expression, which is also transcribed from the same CDKN2A locus but from an alternative promoter. In normal human tissues, levels of p16 and PR55α proteins were inversely correlated and mutually exclusive. Collectively, these results describe a novel function of PR55α/PP2A in blocking p16/RB signaling and IR-induced cellular senescence.

Comparison of sequential versus concurrent chemoradiation regimens in non-metastatic muscle-invasive bladder cancer.

PURPOSE: The treatment approach for non-metastatic bladder cancer is guided by an invasion of the muscular layer of the bladder wall. Radical cystectomy is the recommended treatment for muscle-invasive disease. However, it has considerable morbidity and mortality and is not suited for many patients. Trimodality therapy consisting of chemoradiation after transurethral resection of bladder tumor offers a definitive approach with bladder-sparing potential. However, there is a lack of research defining the optimal combination of chemotherapy and radiation in this setting. MATERIALS AND METHODS: We extracted patient data from the National Cancer Database to compare survival outcomes and demographic factors in 2,227 non-metastatic bladder cancer patients who were treated with chemotherapy sequential to or concurrently with radiation. Sequential treatment was defined as chemotherapy beginning >14 days before radiation, and concurrent was defined as beginning within 14 days of the first radiation. RESULTS: The sequential treatment group patients were younger (mean age, 74 vs. 78 years; p < 0.001) with more advanced disease. We found no difference in overall survival between patients who received chemotherapy sequential to radiation and those who received concurrent chemoradiation only (p = 0.533). CONCLUSION: Our data are concordant with a previous prospective study, and support that chemotherapy prior to radiation does not decrease survival outcomes relative to patients receiving only concurrent chemoradiation. Given that the sequential group had an overall higher stage but no difference in survival, downstaging chemotherapy prior to radiation may be helpful in these patients. Further studies including a larger, multi-institutional clinical trial are indicated to support clinical decision-making.

p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase.

We have previously reported an important role of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase, in the support of critical oncogenic pathways required for oncogenesis and the malignant phenotype of pancreatic cancer. The studies in this report reveal a novel mechanism by which the p53 tumor suppressor inhibits the protein-stability of PR55α via FBXL20, a p53-target gene that serves as a substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins. Our studies show that inactivation of p53 by siRNA-knockdown, gene-deletion, HPV-E6-mediated degradation, or expression of the loss-of-function mutant p53R175H results in increased PR55α protein stability, which is accompanied by reduced protein expression of FBXL20 and decreased ubiquitination of PR55α. Subsequent studies demonstrate that knockdown of FBXL20 by siRNA mimics p53 deficiency, reducing PR55α ubiquitination and increasing PR55α protein stability. Functional tests indicate that ectopic p53R175H or PR55α expression results in an increase of c-Myc protein stability with concomitant dephosphorylation of c-Myc-T58, which is a PR55α substrate, whose phosphorylation otherwise promotes c-Myc degradation. A significant increase in anchorage-independent proliferation is also observed in normal human pancreatic cells expressing p53R175H or, to a greater extent, overexpressing PR55α. Consistent with the common loss of p53 function in pancreatic cancer, FBXL20 mRNA expression is significantly lower in pancreatic cancer tissues compared to pancreatic normal tissues and low FBXL20 levels correlate with poor patient survival. Collectively, these studies delineate a novel mechanism by which the p53/FBXL20 axis negatively regulates PR55α protein stability.

Protective Effects of Metformin Against Biochemical Failure Following Radical Prostatectomy or Radiation Therapy in Localized Prostate Cancer.

OBJECTIVE: To assess the impact of metformin on biochemical failure (BF) in localized prostate cancers (PC) treated with radical prostatectomy or radiation therapy. MATERIALS AND METHODS: About 1449 patients undergoing radical prostatectomy (n = 1338, 92.3%) or radiation therapy (n = 108, 7.5%) for localized PC between July 2007 and January 2020 were evaluated for metformin use, demographic/oncologic characteristics, and biochemical outcomes. Androgen deprivation therapy was utilized per NCCN guidelines. BF rates were assessed overall and at 1, 3, and 5 years. Time to BF was estimated via Kaplan-Meier; logistic regression and Cox proportionate hazards models were generated to adjust for significant differences. RESULTS: Of 1449 patients, 148 (10.2%) utilized metformin at time of diagnosis, while 1,301 (89.8%) did not. Patients on metformin were significantly older, had higher body mass indexes, and more aggressive disease (Gleason score >7). At a mean ± SD follow-up of 3.6 ± 2.6 years, patients on metformin were less likely to experience BF at later timepoints; however, univariate analysis showed no differences at 1, 3, and 5 years. In multivariate analysis, patients on metformin were significantly less likely to experience BF at 5 years and overall in both treatment groups. In Cox regression, metformin was independently associated with a 40% relative risk reduction in BF. CONCLUSION: In multivariate analysis, metformin use was associated with a significant risk reduction in BF overall and at 5 years following primary treatment; this trend was not witnessed in univariate analysis. This suggests the need for future investigations of metformin's role in disease-free survival in men with localized PC.

Correction: Inhibition of RAC1 GTPase sensitizes pancreatic cancer cells to γ-irradiation.

[This corrects the article DOI: 10.18632/oncotarget.2500.].

PR55α regulatory subunit of PP2A inhibits the MOB1/LATS cascade and activates YAP in pancreatic cancer cells.

PP2A holoenzyme complexes are responsible for the majority of Ser/Thr phosphatase activities in human cells. Each PP2A consists of a catalytic subunit (C), a scaffold subunit (A), and a regulatory subunit (B). While the A and C subunits each exists only in two highly conserved isoforms, a large number of B subunits share no homology, which determines PP2A substrate specificity and cellular localization. It is anticipated that different PP2A holoenzymes play distinct roles in cellular signaling networks, whereas PP2A has only generally been defined as a putative tumor suppressor, which is mostly based on the loss-of-function studies using pharmacological or biological inhibitors for the highly conserved A or C subunit of PP2A. Recent studies of specific pathways indicate that some PP2A complexes also possess tumor-promoting functions. We have previously reported an essential role of PR55α, a PP2A regulatory subunit, in the support of oncogenic phenotypes, including in vivo tumorigenicity/metastasis of pancreatic cancer cells. In this report, we have elucidated a novel role of PR55α-regulated PP2A in the activation of YAP oncoprotein, whose function is required for anchorage-independent growth during oncogenesis of solid tumors. Our data show two lines of YAP regulation by PR55α: (1) PR55α inhibits the MOB1-triggered autoactivation of LATS1/2 kinases, the core member of the Hippo pathway that inhibits YAP by inducing its proteasomal degradation and cytoplasmic retention and (2) PR55α directly interacts with and regulates YAP itself. Accordingly, PR55α is essential for YAP-promoted gene transcriptions, as well as for anchorage-independent growth, in which YAP plays a key role. In summary, current findings demonstrate a novel YAP activation mechanism based on the PR55α-regulated PP2A phosphatase.

Can the Student Outperform the Master? A Plan Comparison Between Pinnacle Auto-Planning and Eclipse knowledge-Based RapidPlan Following a Prostate-Bed Plan Competition.

PURPOSE: Pinnacle Auto-Planning and Eclipse RapidPlan are 2 major commercial automated planning engines that are fundamentally different: Auto-Planning mimics real planners in the iterative optimization, while RapidPlan generates static dose objectives from estimations predicted based on a prior knowledge base. This study objectively compared their performances on intensity-modulated radiotherapy planning for prostate fossa and lymphatics adopting the plan quality metric used in the 2011 American Association of Medical Dosimetrists Plan Challenge. METHODS: All plans used an identical intensity-modulated radiotherapy beam setup and a simultaneous integrated boost prescription (68 Gy/56 Gy to prostate fossa/lymphatics). Auto-Planning was used to retrospectively plan on 20 patients, which were subsequently employed as the library to build an RapidPlan model. To compare the 2 engines' performances, a test set including 10 patients and the Plan Challenge patient was planned by both Auto-Planning (master) and RapidPlan (student) without manual intervention except for a common dose normalization and evaluated using the plan quality metric that included 14 quantitative submetrics ranging over target coverage, spillage, and organ at risk doses. Plan quality metric scores were compared between the Auto-Planning and RapidPlan plans using the Mann-Whitney U test. RESULTS: There was no significant difference between the overall performance of the 2 engines on the 11 test cases ( P = .509). Among the 14 submetrics, Auto-Planning and RapidPlan showed no significant difference on most submetrics except for 2. On the Plan Challenge case, Auto-Planning scored 129.9 and RapidPlan scored 130.3 out of 150, as compared with the average score of 116.9 ± 16.4 (range: 58.2-142.5) among the 125 Plan Challenge participants. CONCLUSION: Using an innovative study design, an objective comparison has been conducted between 2 major commercial automated inverse planning engines. The 2 engines performed comparably with each other and both yielded plans at par with average human planners. Using a constant-performing planner (Auto-Planning) to train and to compare, RapidPlan was found to yield plans no better than but as good as its library plans.

Technical Assessment of an Automated Treatment Planning on Dose Escalation of Pancreas Stereotactic Body Radiotherapy.

BACKGROUND: Stereotactic body radiotherapy has been suggested to provide high rates of local control for locally advanced pancreatic cancer. However, the close proximity of highly radiosensitive normal tissues usually causes the labor-intensive planning process and may impede further escalation of the prescription dose. PURPOSE: The present study aims to evaluate the consistency and efficiency of Pinnacle Auto-Planning for pancreas stereotactic body radiotherapy with original prescription and escalated prescription. METHODS: Twenty-four patients with pancreatic cancer treated with stereotactic body radiotherapy were studied retrospectively. The prescription is 40 Gy over 5 consecutive fractions. Most of patients (n = 21) also had 3 other different dose-level targets (6 Gy/fraction, 5 Gy/fraction, and 4 Gy/fraction). Two types of plans were generated by Pinnacle Auto-Planning with the original prescription (8 Gy/fraction, 6 Gy/fraction, 5 Gy/fraction, and 4 Gy/fraction) and escalated prescription (9 Gy/fraction, 7 Gy/fraction, 6 Gy/fraction, and 5 Gy/fraction), respectively. The same Auto-Planning template, including beam geometry, intensity-modulated radiotherapy objectives and intensity-modulated radiotherapy optimization parameters, were utilized for all the auto-plans in each prescription group. The intensity-modulated radiotherapy objectives do not include any manually created structures. Dosimetric parameters including percentage volume of PTV receiving 100% of the prescription dose, percentage volume of PTV receiving 93% of the prescription dose, and consistency of the dose-volume histograms of the target volumes were assessed. Dmax and D1 cc of highly radiosensitive organs were also evaluated. RESULTS: For all the pancreas stereotactic body radiotherapy plans with the original or escalated prescriptions, auto-plans met institutional dose constraints for critical organs, such as the duodenum, small intestine, and stomach. Furthermore, auto-plans resulted in acceptable planning target volume coverage for all targets with different prescription levels. All the plans were generated in a one-attempt manner, and very little human intervention is necessary to achieve such plan quality. CONCLUSIONS: Pinnacle3 Auto-Planning consistently and efficiently generate acceptable treatment plans for multitarget pancreas stereotactic body radiotherapy with or without dose escalation and may play a more important role in treatment planning in the future.

Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.

Times Not to Forget Radiotherapy When Treating Patients With Lymphoma.

Radiation therapy remains an important component of lymphoma treatment. It has evolved with improvements in technology and a better understanding of how to successfully integrate it into lymphoma treatment. There are specific clinical presentations where omission of radiation therapy could adversely affect patient outcome and should not be overlooked. Radiation therapy may serve an important role as primary treatment, as a component of combined modality therapy, as adjuvant therapy to maximize local control, and as an important component of salvage therapy for relapsed or primary refractory lymphoma and in the successful palliation of lymphoma. This review identifies those clinical presentations where the use of radiation therapy should not be overlooked or should at least be considered.

Automatic planning on hippocampal avoidance whole-brain radiotherapy.

Mounting evidence suggests that radiation-induced damage to the hippocampus plays a role in neurocognitive decline for patients receiving whole-brain radiotherapy (WBRT). Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) has been proposed to reduce the putative neurocognitive deficits by limiting the dose to the hippocampus. However, urgency of palliation for patients as well as the complexities of the treatment planning may be barriers to protocol enrollment to accumulate further clinical evidence. This warrants expedited quality planning of HA-WBRT. Pinnacle3 Automatic treatment planning was designed to increase planning efficiency while maintaining or improving plan quality and consistency. The aim of the present study is to evaluate the performance of the Pinnacle3 Auto-Planning on HA-WBRT treatment planning. Ten patients previously treated for brain metastases were selected. Hippocampal volumes were contoured on T1 magnetic resonance (MR) images, and planning target volumes (PTVs) were generated based on RTOG0933. The following 2 types of plans were generated by Pinnacle3 Auto-Planning: the one with 2 coplanar volumetric modulated arc therapy (VMAT) arcs and the other with 9-field noncoplanar intensity-modulated radiation therapy (IMRT). D2% and D98% of PTV were used to calculate homogeneity index (HI). HI and Paddick Conformity index (CI) of PTV as well as D100% and Dmax of the hippocampus were used to evaluate the plan quality. All the auto-plans met the dose coverage and constraint objectives based on RTOG0933. The auto-plans eliminated the necessity of generating pseudostructures by the planners, and it required little manual intervention which expedited the planning process. IMRT quality assurance (QA) results also suggest that all the auto-plans are practically acceptable on delivery. Pinnacle3 Auto-Planning generates acceptable plans by RTOG0933 criteria without time-consuming planning process. The expedited quality planning achieved by Auto-Planning (AP) may facilitate protocol enrollment of patients to further investigate the hippocampal-sparing effect and be used to ensure timely start of palliative treatment in future clinical practice.

Prostate bed target interfractional motion using RTOG consensus definitions and daily CT on rails : Does target motion differ between superior and inferior portions of the clinical target volume?

PURPOSE: Using high-quality CT-on-rails imaging, the daily motion of the prostate bed clinical target volume (PB-CTV) based on consensus Radiation Therapy Oncology Group (RTOG) definitions (instead of surgical clips/fiducials) was studied. It was assessed whether PB motion in the superior portion of PB-CTV (SUP-CTV) differed from the inferior PB-CTV (INF-CTV). PATIENTS AND METHODS: Eight pT2-3bN0-1M0 patients underwent postprostatectomy intensity-modulated radiotherapy, totaling 300 fractions. INF-CTV and SUP-CTV were defined as PB-CTV located inferior and superior to the superior border of the pubic symphysis, respectively. Daily pretreatment CT-on-rails images were compared to the planning CT in the left-right (LR), superoinferior (SI), and anteroposterior (AP) directions. Two parameters were defined: "total PB-CTV motion" represented total shifts from skin tattoos to RTOG-defined anatomic areas; "PB-CTV target motion" (performed for both SUP-CTV and INF-CTV) represented shifts from bone to RTOG-defined anatomic areas (i. e., subtracting shifts from skin tattoos to bone). RESULTS: Mean (± standard deviation, SD) total PB-CTV motion was -1.5 (±â€¯6.0), 1.3 (±â€¯4.5), and 3.7 (±â€¯5.7) mm in LR, SI, and AP directions, respectively. Mean (±â€¯SD) PB-CTV target motion was 0.2 (±1.4), 0.3 (±2.4), and 0 (±3.1) mm in the LR, SI, and AP directions, respectively. Mean (±â€¯SD) INF-CTV target motion was 0.1 (±â€¯2.8), 0.5 (±â€¯2.2), and 0.2 (±â€¯2.5) mm, and SUP-CTV target motion was 0.3 (±â€¯1.8), 0.5 (±â€¯2.3), and 0 (±â€¯5.0) mm in LR, SI, and AP directions, respectively. No statistically significant differences between INF-CTV and SUP-CTV motion were present in any direction. CONCLUSION: There are no statistically apparent motion differences between SUP-CTV and INF-CTV. Current uniform planning target volume (PTV) margins are adequate to cover both portions of the CTV.

Prostate Cancer, Version 1.2016.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after an initial diagnosis of prostate cancer and management options for localized, regional, and metastatic disease. Recommendations for disease monitoring, treatment of recurrent disease, and systemic therapy for metastatic castration-recurrent prostate cancer also are included. This article summarizes the NCCN Prostate Cancer Panel's most significant discussions for the 2016 update of the guidelines, which include refinement of risk stratification methods and new options for the treatment of men with high-risk and very-high-risk disease and progressive castration-naïve disease.

Technical Note: Fabricating Cerrobend grids with 3D printing for spatially modulated radiation therapy: A feasibility study.

PURPOSE: Grid therapy has promising applications in the radiation treatment of large tumors. However, research and applications of grid therapy are limited by the accessibility of the specialized blocks that produce the grid of pencil-like radiation beams. In this study, a Cerrobend grid block was fabricated using the 3D printing technique. METHODS: A grid block mold was designed with flared tubes which follow the divergence of the beam. The mold was 3D printed using a resin with the working temperature below 230 °C. The melted Cerrobend liquid at 120 °C was cast into the resin mold to yield a block with a thickness of 7.4 cm. At the isocenter plane, the grid had a hexagonal pattern, with each pencil beam diameter of 1.4 cm; the distance between the beam centers was 2.1 cm. RESULTS: The dosimetric properties of the grid block were studied using small field dosimeters: a pinpoint ionization chamber and a stereotactic diode. For a 6 MV photon beam, its valley-to-peak ratio was 20% at dmax and 30% at 10 cm depth; the output factor was 84.9% at dmax and 65.1% at 10 cm depth. CONCLUSIONS: This study demonstrates that it is feasible to implement 3D printing technique in applying grid therapy in clinic.

Preclinical evaluation of investigational radiopharmaceutical RISAD-P intended for use as a diagnostic and molecular radiotherapy agent for prostate cancer.

BACKGROUND: The androgen receptor (AR) plays a dominant role in the pathogenesis of prostate cancer. 5-Radioiodo-3'-O-(17ß-succinyl-5α-androstan-3-one)-2'-deoxyuridin-5'-yl phosphate (RISAD-P) is an AR-targeting reagent developed for noninvasive assessment of AR and proliferative status of the AR-expressing tumors, and for molecular radiotherapy with Auger electron-emitting radionuclides. In this study, the preclinical toxicity and targeting potential of RISAD-P was evaluated. METHODS: Effects of nonradioactive ISAD-P and RISAD-P labeled with (123) I, (124) I, and (125) I were evaluated in male mice. Expanded-acute single dose toxicity studies, hematologic toxicity, liver and kidney function, pharmacokinetics, biodistribution, and imaging studies were conducted. Imaging and pilot therapy studies were conducted in transgenic mice. RESULTS: RISAD-P is not toxic at doses projected for clinical use. Its tissue distribution compares favorably with the distribution reported for (18) F-dihydrotestosterone derivatives. RISAD-P has excellent prostate cancer targeting properties. One hour after (125) IRISAD-P administration, nearly 10% of the injected dose is associated with prostate tumor. The tumor clearance is biphasic and plateaus between 24 and 48 hr post-injection. The estimated radiation doses calculated for 1 g tumor using the MIRD convention are well within the therapeutic range with values of 170, 250, 1,240 Gy × MBq(-1) × g(-1) for (125) I-, (123) I-, and (124) I-labeled RISAD-P, respectively. The transient uptake of radioactivity is observed in the genitourinary tract and stomach. Without the potassium iodide blockade, thyroid uptake is also observed. CONCLUSIONS: Biodistribution, toxicity, and radiation dosimetry studies suggest that RISAD-P holds characteristics of a promising candidate for imaging of AR expression and tumor proliferation, as well as molecular radiotherapy for metastatic or locally, regionally advanced prostate cancer.

Inhibition of RAC1 GTPase sensitizes pancreatic cancer cells to γ-irradiation.

Radiation therapy is a staple treatment for pancreatic cancer. However, owing to the intrinsic radioresistance of pancreatic cancer cells, radiation therapy often fails to increase survival of pancreatic cancer patients. Radiation impedes cancer cells by inducing DNA damage, which can activate cell cycle checkpoints. Normal cells possess both a G1 and G2 checkpoint. However, cancer cells are often defective in G1 checkpoint due to mutations/alterations in key regulators of this checkpoint. Accordingly, our results show that normal pancreatic ductal cells respond to ionizing radiation (IR) with activation of both checkpoints whereas pancreatic cancer cells respond to IR with G2/M arrest only. Overexpression/hyperactivation of Rac1 GTPase is detected in the majority of pancreatic cancers. Rac1 plays important roles in survival and Ras-mediated transformation. Here, we show that Rac1 also plays a critical role in the response of pancreatic cancer cells to IR. Inhibition of Rac1 using specific inhibitor and dominant negative Rac1 mutant not only abrogates IR-induced G2 checkpoint activation, but also increases radiosensitivity of pancreatic cancer cells through induction of apoptosis. These results implicate Rac1 signaling in the survival of pancreatic cancer cells following IR, raising the possibility that this pathway contributes to the intrinsic radioresistance of pancreatic cancer.

Prostate cancer, version 2.2014.

Prostate cancer has surpassed lung cancer as the most common cancer in men in the United States. The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer based on clinical evidence and expert consensus. NCCN Panel guidance on treatment decisions for patients with localized disease is represented in this version. Significant updates for early disease include distinction between active surveillance and observation, a new section on principles of imaging, and revisions to radiation recommendations. The full version of these guidelines, including treatment of patients with advanced disease, can be found online at the NCCN website.

A nonhuman primate model of human radiation-induced venocclusive liver disease and hepatocyte injury.

BACKGROUND: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. METHODS AND MATERIALS: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. RESULTS: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. CONCLUSIONS: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

Prostate cancer, version 1.2014.

The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer. This report highlights notable recent updates. Radium-223 dichloride is a first-in-class radiopharmaceutical that recently received approval for the treatment of patients with symptomatic bone metastases and no known visceral disease. It received a category 1 recommendation as both a first-line and second-line option. The NCCN Prostate Cancer Panel also revised recommendations on the choice of intermittent or continuous androgen deprivation therapy based on recent phase III clinical data comparing the 2 strategies in the nonmetastatic and metastatic settings.