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Background: The utilization of stereotactic body radiation therapy (SBRT) is increasing for primary and secondary lung neoplasms. Despite encouraging results, SBRT is associated with an increased risk of osteoradionecrosis-induced rib fracture. We aimed to (1) evaluate potential clinical, demographic, and procedure-related risk factors for rib fractures and (2) describe the radiographic features of post-SBRT rib fractures. Methods: We retrospectively identified 106 patients who received SBRT between 2015 and 2018 for a primary or metastatic lung tumor with at least 12 months of follow up. Exclusion criteria were incomplete records, previous ipsilateral thoracic radiation, or relevant prior trauma. Computed tomography (CT) images were reviewed to identify and characterize rib fractures. Multivariate logistic regression modeling was employed to determine clinical, demographic, and procedural risk factors (e.g., age, sex, race, medical comorbidities, dosage, and tumor location). Results: A total of 106 patients with 111 treated tumors met the inclusion criteria, 35 (32%) of whom developed at least one fractured rib (60 total fractured ribs). The highest number of fractured ribs per patient was five. Multivariate regression identified posterolateral tumor location as the only independent risk factor for rib fracture. On CT, fractures showed discontinuity between healing edges in 77% of affected patients. Conclusions: Nearly one third of patients receiving SBRT for lung tumors experienced rib fractures, 34% of whom experienced pain. Many patients developed multiple fractures. Post-SBRT fractures demonstrated a unique discontinuity between the healing edges of the rib, a distinct feature of post-SBRT rib fractures. The only independent predictor of rib fracture was tumor location along the posterolateral chest wall. Given its increasing frequency of use, describing the risk profile of SBRT is vital to ensure patient safety and adequately inform patient expectations. [ABSTRACT FROM AUTHOR]

Background: US Food and Drug Administration Investigation Device Exemption studies and academic journals emphasize the importance of two-year follow-up data in reporting outcomes of total shoulder arthroplasty, but there is limited data evaluating appropriate follow-up length. We aim to evaluate change in postoperative outcomes and complications between one and two years following anatomic and reverse total shoulder arthroplasties. Methods: We retrospectively identified 250 patients who underwent anatomic and reverse total shoulder arthroplasties between 2013 and 2016 from a single surgeon arthroplasty registry. Patients without both one- and two-year follow-up data were excluded. We compared American Shoulder and Elbow Surgeons (ASES) score, Visual Analog Scale for pain, and goniometer-measured range of motion. Results: Patient-reported outcome measurements (p > 0.05) did not change between one and two years postoperatively following both reverse (n = 146) and anatomic (n = 104) total shoulder arthroplasties. Range of motion increased slightly (p < 0.05), but this change was not clinically relevant. There were no additional complications. Discussion: Minimum two-year clinical follow-up may not be necessary for future shoulder arthroplasty Investigation Device Exemption and other peer-reviewed investigations. Patient-reported outcomes (ASES and pain score) and range of motion plateau at one year postoperatively without additional complications. One-year follow-up is an acceptable minimum follow-up length. Level of evidence: Level III—retrospective analysis. [ABSTRACT FROM AUTHOR]

Background: Lower-extremity arthroplasty constitutes the largest burden on health-care spending of any Medicare diagnosis group. Demand for upper extremity arthroplasty also continues to rise. It is necessary to better understand costs as health care shifts toward a bundled-payment accounting approach. We aimed (1) to identify whether variation exists in total cost for different types of joint arthroplasty, and, if so, (2) to determine which cost parameters drive this variation.Methods: The cost of the episode of inpatient care for 22,215 total joint arthroplasties was calculated by implementing time-driven activity-based costing (TDABC) at a single orthopaedic specialty hospital from 2015 to 2018. Implant price, supply costs, personnel costs, and length of stay for total knee, total hip, anatomic total shoulder, reverse total shoulder, total elbow, and total ankle arthroplasty were analyzed. Individual cost parameters were compared with total cost and volume.Results: Higher implant cost appeared to correlate with higher total costs and represented 53.8% of the total cost for an inpatient care cycle. Total knee arthroplasty was the least-expensive and highest-volume procedure, whereas total elbow arthroplasty had the lowest volume and highest cost (1.65 times more than that of total knee arthroplasty). Length of stay was correlated with increased personnel cost but did not have a significant effect on total cost.Conclusions: Total inpatient cost at our orthopaedic specialty hospital varied by up to a factor of 1.65 between different fields of arthroplasty. The highest-volume procedures-total knee and hip arthroplasty-were the least expensive, driven predominantly by lower implant purchase prices.Clinical Relevance: We are not aware of any previous studies that have accurately compared cost structures across upper and lower-extremity arthroplasty with a uniform methodology. The present study, because of its uniform accounting process, provides reliable data that will allow clinicians to better understand cost relationships between different procedures. [ABSTRACT FROM AUTHOR]

Several recent studies have investigated psilocybin as a novel therapeutic compound for the treatment of existential distress in patients with cancer, demonstrating persistent, positive effects on mood. This editorial discusses two articles in the current issue of Cancer that report findings of a group‐based psilocybin‐assisted intervention for treatment of depression in patients diagnosed with cancer. [ABSTRACT FROM AUTHOR]

Purpose: AGS-1C4D4 is a human monoclonal antibody against prostate stem cell antigen (PSCA), a cell-surface protein expressed by most prostate cancers. AGS-1C4D4 is produced in Chinese hamster ovary (CHO) cells and has an identical sequence to AGS-PSCA, an anti-PSCA antibody produced in mouse hybridoma cells that has completed Phase I testing. Preclinical studies demonstrated comparability of AGS-1C4D4 to AGS-PSCA with respect to pharmacokinetics (PK) and tumor inhibition. However, because of differences in antibody-dependent cellular cytotoxicity between AGS-PSCA and AGS-1C4D4, a limited Phase I trial using AGS-1C4D4 was performed evaluating safety and PK. Patients and methods: Thirteen patients with metastatic castration-resistant prostate cancer were enrolled. AGS-1C4D4 was administered intravenously every 3 weeks for four planned doses at 6, 12, 24, or 48 mg/kg. Primary endpoints were safety and PK. Secondary endpoints were immunogenicity and clinical activity. Disease assessments were conducted every 12 weeks and included radiographic and PSA evaluations. Patients with stable disease could receive extended treatment beyond four infusions. Results: Adverse events were primarily grade 1-2, without any grade 3-4 drug-related toxicities or infusion reactions. Anti-AGS-1C4D4 antibodies were not detected. Similar to AGS-PSCA, serum AGS-1C4D4 concentrations declined biphasically and elimination was characterized by slow clearance (CL) and a long terminal half-life ( t). Median CL for the four dose levels ranged from 0.10 to 0.14 ml/h kg, and t ranged from 2.2 to 2.9 weeks. No PSA reductions ≥50% were observed. Six patients (46%) had radiographically stable disease, lasting a median of 24 weeks. Conclusion: AGS-1C4D4 was well-tolerated and demonstrated linear PK. Despite preclinical differences in antibody-dependent cellular cytotoxicity, AGS-1C4D4 and AGS-PSCA have similar safety and PK profiles. The recommended Phase II dose is 48 mg/kg. [ABSTRACT FROM AUTHOR]

Context: Patients on investigational clinical trials and their caregivers experience poor quality of life (QOL), which declines as the disease progresses. Objective: To examine the effect of a standardized cognitive-behavioral problem-solving educational intervention on the QOL of patients enrolled on investigational clinical trials and their caregivers. Design: Prospective, multi-institution, randomized trial. QOL was measured repeatedly over 6 months. Participants: Patients were simultaneously enrolled onto phase 1, 2, or 3 Institutional Review Board (IRB)-approved cancer clinical trials. Intervention: Intervention arm dyads participated in three conjoint educational sessions during the first month, learning the COPE problem solving model. Nonintervention arm dyads received usual care. Outcome Measures: Global QOL was measured by the City of Hope Quality of Life Instruments for Patients or Caregivers; problem solving skills were measured by the Social Problem Solving Inventory-Revised. Results: The results are reported using the CONSORT statement. The analytic data set included 476 dyads including 1596 patient data points and 1576 care giver data points. Patient QOL showed no significant difference in the rate of change between the intervention and usual care arms ( p = 0.70). Caregiver QOL scores in the intervention arm declined, but at less than half the rate in the control arm ( p = 0.02). Conclusions: The COPE intervention enabled the average caregiver to come much closer to stable QOL over the 6-month follow-up. Future studies should enroll subjects much earlier in the cancer illness trajectory, a common patient/caregiver theme. The maximum effect was seen in caregivers who completed the 6-month follow-up, suggesting that the impact may increase over time. [ABSTRACT FROM AUTHOR]

The article presents a randomised, double-blind study which compares denosumab with zoledronic acid for prevention and treatment of skeletal-related events in male patients with bone metastases from castration-resistant prostate cancer. An interactive voice response system was employed to assign patients to receive certain dosage of one of the two drugs. The study concludes that denosumab is better than zoledronic acid in preventing skeletal-related events.

Abstract: Virtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease. Although docetaxel is the standard of care for these patients and is associated with a modest prolongation of survival, there is an urgent need for novel treatment strategies for metastatic prostate cancer. In the last several years, great strides have been made in our understanding of the biological and molecular mechanisms driving prostate cancer growth and progression, and this has resulted in widespread clinical testing of numerous new targeted therapies. This review discusses some of the key therapeutic agents that have emerged for the treatment of metastatic castration-resistant prostate cancer in the last 5years, with an emphasis on both molecular targets and clinical trial design. These agents include mammalian target of rapamycin (mTOR) pathway inhibitors, anti-angiogenic drugs, epidermal growth factor receptor (EGFR) inhibitors, insulin-like growth factor (IGF) pathway inhibitors, apoptosis-inducing drugs, endothelin receptor antagonists, receptor activator of nuclear factor κB (RANK) ligand inhibitors, vitamin D analogues, cytochrome P17 enzyme inhibitors, androgen receptor modulators, epigenetic therapies, vaccine therapies, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 blocking agents. [Copyright &y& Elsevier]

Functionally protected forms of three conformationally constrained diaminodicarboxylic acids were synthesized and characterized. 2,2′-Diaminospiro[3.3]heptane-2,2′-dicarboxylic acid, an analogue of diaminopimelic acid, was prepared in racemic form and the structure established by X-ray crystallographic analysis of the methyl ester hydrochloride. trans-1,4-Diaminocyclohexane-1,4-dicarboxylic acid was prepared and its structure established by X-ray crystallographic analysis of the corresponding Cbz-protected ethyl ester. cis- and trans-2,6-diamino-1,2,3,5,6,7-hexahydro-s-indacene-2,6-dicarboxylic acids were synthesized and the structures assigned by X-ray crystallographic analysis of the corresponding Boc-protected ethyl ester and Cbz-protected ethyl ester, respectively. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to evaluate the efficacy and safety of atrasentan (Xinlay), a selective endothelin-A receptor antagonist, in patients with metastatic hormone-refractory prostate cancer (HRPC).Methods: This multinational, double-blind, placebo-controlled trial enrolled 809 men with metastatic HRPC. Patients were randomized 1:1 to receive either atrasentan 10 mg per day or placebo. The primary endpoint was time to disease progression (TTP), which was determined according to radiographic and clinical measures. Analyses of overall survival and changes in biomarkers also were performed.Results: Atrasentan did not reduce the risk of disease progression relative to placebo (hazards ratio, 0.89; 95% confidence interval, 0.76-1.04; P = .136). Most patients progressed radiographically at the first 12-week bone scan without concomitant clinical progression. In exploratory analyses, increases from baseline to final bone alkaline phosphatase (BAP) and prostate-specific antigen (PSA) levels were significantly lower with atrasentan treatment (P < .05 for each). The median time to BAP progression (>/=50% increase from nadir) was twice as long with atrasentan treatment (505 days vs 254 days; P < .01). The delay in time to PSA progression did not reach statistical significance. Atrasentan generally was tolerated well, and the most common adverse events associated with treatment were headache, rhinitis, and peripheral edema, reflecting the vasodilatory and fluid-retention properties of endothelin-A receptor antagonism.Conclusions: Atrasentan did not delay disease progression in men with metastatic HRPC despite evidence of biologic effects on PSA and BAP as markers of disease burden. [ABSTRACT FROM AUTHOR]

Background: Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease. Methods: In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group. Results: Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02). Conclusions: As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468.) N Engl J Med 2007;356:2271-81. [ABSTRACT FROM AUTHOR]

Prostate cancer is the leading cause of cancer in men in the United States, with 234,460 men expected to be diagnosed as having the disease-In 2006 (33% of cancers in men), and the third leading cause of cancer deaths in men, with 27,350 men expected to die of the disease (9% of cancer deaths). Through early detection and improved local therapies, including surgery or radiation therapy, a large number of men will be cured, but unfortunately, a significant number of men will still experience relapse of disease and require continued surveillance and ongoing therapy. This article discusses approaches to treatment of men who have recurrent disease, including active surveillance, androgen ablation therapy, secondary hormone therapy, chemotherapy, bisphosphonates, radiation therapy, and future directions. [ABSTRACT FROM AUTHOR]

The article discusses the increase of interest in the role of epigenetics for the development and treatment of cancer. Epigenetics refers to modifications which influence phenotype without altering genotype. Epigenetic changes are reversible but stably maintained during the cell cycle. Several mechanisms of epigenetic control have been identified, including specific histone modification patterns which predict the risk of prostate cancer recurrence.

CG7870 is a replication-selective oncolytic adenovirus genetically engineered to replicate preferentially in prostate tissue. In a previous phase I/II clinical trial of intraprostatic delivery of CG7870 for locally recurrent prostate cancer this virus was well tolerated. In this phase I study CG7870 was administered as a single intravenous infusion in a group-sequential dose escalation design (1 × 1010 to 6 × 1012 viral particles (vp)) to 23 patients with hormone-refractory metastatic prostate cancer. Flulike symptoms (fever, fatigue, rigors, nausea, and/or vomiting) were the most common adverse events. Three therapy-related grade 3 adverse events were reported, one of which (fatigue) was serious. At doses greater than 1012 vp all five patients experienced asymptomatic grade 1 to 2 transaminitis and/or isolated D-dimer elevations starting on day 2 through 8; dose escalation was therefore halted at 6 × 1012 vp. All tested patients had CG7870 genomes present in the peripheral blood for at least 90 minutes after infusion; patients in the highest dose group had persistence of genomes through 29 days. A “secondary” or “delayed” peak in plasma CG7870 genome copies (defined as a >10-fold increase in CG7870 genomes from nadir concentration) suggestive of active viral replication and shedding into the bloodstream was detected in 16/23 (70%) patients. CG7870 was detected in the saliva of 3 patients, whereas all urine samples tested negative. All patients developed antibodies to CG7870. Dose-related increases in interleukins 6 and 10 (IL-6, IL-10) blood levels were detected. The peak IL-6 concentration after CG7870 treatment was associated with a transient, asymptomatic decrease in blood pressure. No partial or complete prostate-specific antigen (PSA) responses were observed; however, 5 patients had a decrease in serum PSA of 25% to 49% following a single treatment, including 3 of 8 patients at the highest dose levels.Molecular Therapy (2006) 14, 107–117; doi: 10.1016/j.ymthe.2006.02.011 [ABSTRACT FROM AUTHOR]

Abstract: Prostate cancer traditionally was managed by monotherapy, and treatment was almost exclusively provided by the urologic surgeon. As ongoing clinical trials in advanced disease identify novel agents or combination therapies with good tolerability and potential survival benefits, multidisciplinary management may offer optimal care for men with high-risk prostate cancer, as it does for women with breast cancer. Patients with high-risk recurrent or metastatic disease should be informed of clinical trials for which they may be eligible. [Copyright &y& Elsevier]

The purpose of the study was to evaluate response and survival in patients with metastatic urothelial cancer treated with combination gemcitabine and paclitaxel administered on a biweekly schedule at doses of 3000 mg/m2 and 150 mg/m2, respectively. Patients with adequate organ function and performance status were accrued through 7 institutions, stratified by prior therapy status, and treated as noted. Response was evaluated by 1979 bi-dimensional World Health Organization (WHO) criteria. Of 55 eligible patients, 17 had a partial and 5 had a complete response rate for an overall response rate of 40% (27–54%). One complete response and one partial response were observed in the 6 previously treated patients. Overall median survival was 11.8 months (11.9 months in the chemonaive cohort). Grade 3 or 4 myelosuppression occurred in 56%, but only 4 serious infections were observed. We conclude that because of a lower than expected complete response rate, even when corrected for prognostic groupings, this regimen is not recommended for routine use in patients with metastatic urothelial cancer. Insufficient patients with poor renal function or prior therapy were accrued to reach conclusions regarding its utility in these subgroups. [Copyright &y& Elsevier]

Despite improvements in early detection of prostate cancer when it is clinically localized—and therefore most amenable to curative local therapies—∼33% of men with early prostate cancer will develop biochemical failure with a rising prostate-specific antigen (PSA) during follow-up. The early use of androgen suppression in this group of men has changed the clinical picture of androgen-independent disease. Now, there are men on androgen suppression who will develop biochemical failure and remain free of clinical or radiographic evidence of metastatic disease for a period of time. There is no standard approach to this group of men, who have a rising PSA on androgen deprivation, because there are little or no data about strategies that may improve survival, delay time to progression, or improve quality of life. Therefore, current management of this population remains controversial. In an effort to determine which of these 2 approaches—second-line hormone therapy or chemotherapy—is optimal in delaying the time to progression, the Eastern Cooperative Oncology Group (ECOG) developed protocol E1899. Although both approaches offer the potential for response (reduction in PSA and prolonging the time to clinical progression), they have very different toxicity profiles, making impact on quality of life another important end point. This randomized trial evaluating second-line hormonal therapy using ketoconazole and hydrocortisone versus docetaxel and estramustine combination chemotherapy on progression-free survival in asymptomatic men with a rising PSA on androgen ablation for prostate cancer is the subject of this article. [Copyright &y& Elsevier]

The preparation and characterization of the following bis-imidazole and bis-pyridine complexes of octamethyltetraphenylporphyrinatoiron(III), Fe(III) OMTPP, octamethyltetraphenylporphyrinatoiron (III), Fe-(III)OETPP, and tetra-β,β-tetramethylenetetraphenylporphyrinatoiron(III), Fe(III)TC[SUB6]TPP, are reported: paral-[FeOMTPP(1-Melm)[SUB2]]Cl, perp-[FeOMTPP(1-Melm)[SUB2]]Cl, [FeOETPP(1-Melm)[SUB2]Cl, [FeTC[SUB6]TPP(l-Melm)[SUB2]]Cl,[FeOMTPP(4Me[SUB2]Npy[SUB2]]Cl, and [FeOMTPP(2-MeHim)[SUB2]]Cl. Crystal structure analysis shows that paral-[FeOMTPP(1-Melm)[SUB2]]Cl has its axial ligands in close to parallel orientation (the actual dihedral angle between the planes of the imidazole ligands is 19.5°), while perp-[FeOMTPP(l-Melm)[SUB2]]Cl has the axial imidazole ligand planes oriented at 90° to each other and 29° away from the closest N[SUBP]-Fe-N[SUBP] axis. [FeOETPP-(1-Melm)[SUB2]]Cl has its axial ligands close to perpendicular orientation (the actual dihedral angle between the planes of the imidazole ligands is 73.1°). In all three cases the porphyrin core adopts relatively purely saddled geometry. The [FeTC[SUB6]TPP1-Melm)[SUB2]]Cl complex is the most planar and has the highest contribution of a ruffled component in the overall saddled structure compared to all other complexes in this study. The estimated numerical contribution of saddled and ruffled components is 0.68:0.32, respectively. Axial ligand planes are perpendicular to each other and 15.3° away from the closest N[SUBP]-Fe-N[SUBP] axis. The Fe-N[SUBP] bond is the longest in the series of octaalkyltetraphenylporphyrinatoiron complexes due to [FeTC[SUB6]TPP-(1-Melm)[SUB2]]Cl having the least distorted porphyrin core. In addition to these three complexes, two crystalline forms each of [FeOMTPP(4-Me[SUB2]NPy)[SUB2]Cl and [FeOMTPP(2-MeHlm)[SUB2]]Cl were obtained. [ABSTRACT FROM AUTHOR]

Differentiation therapy is an area of oncology that is in its infancy. Theoretically, the concept of differentiation therapy involves turning a cancer cell ‘off’ biologically and reverting to a more ‘benign’ phenotype. Many agents have been studied over the past few years, with many already either in use clinically or showing future promise. [Copyright &y& Elsevier]

Bone metastases are the most frequent complication of advanced prostate cancer and are responsible for the vast majority of disease-related morbidity and mortality. With the extensive number of predictive models for patients with prostate cancer, we can now determine to some degree which patients are at highest risk for progression to metastatic bone disease and therefore might benefit from earlier or more aggressive therapy. Combining this with our better understanding of the molecular biology underlying the progression to bone metastasis, we are able to identify more specific targets or pathways to approach therapeutically to prevent or delay the development of metastatic bone disease. General strategies for the prevention of bone metastases include bone-targeting approaches, antimetastatic therapies, and purely antineoplastic agents. Bisphosphonates comprise the most studied and effective of the bone-targeted agents and now have relatively sound clinical data supporting their role not only in the treatment of bone metastases, but also in the secondary prevention and, in some cases, primary prevention, of new skeletal complications. Their ease of administration and relatively low short- and long-term toxicities make them ideal for potential treatment earlier in the disease process as well. Radioisotopes have been studied and used for decades for the treatment of painful bone metastases but only recently have data accumulated demonstrating their efficacy in the prevention of new metastases. The endothelin receptor antagonist, atrasentan, has recently been shown to delay the progression of systemic disease and potentially improve survival in patients with prostate cancer. It appears to do so, at least in part, by bone-targeting mechanisms. Antimetastatic strategies are also promising for the prevention of bone metastases and include matrix metalloproteinase inhibitors, gene therapy, and other novel approaches, such as inhibiting tyrosine kinases or NFkB and... [ABSTRACT FROM AUTHOR]

Reaction of VO(acac)[sub 2] with 1,2-dithiols in the presence of triethylamine gives pentacoordinate oxovanadium complexes [HNEt[sub 3]][sub 2][VO(bdt)[sub 2]] (1), [HNEt[sub 3]][sub 2][VO(tdt)[sub 2]] (2), and [HNEt[sub 3]][sub 2][VO(bdtCI[sub 2])[sub 2]] (3) (where H[sub 2]bdt = 1,2-benzenedithiol, H[sub 2]tdt = 3,4-toluenedithiol, and H[sub 2]bdtCI[sub 2] = 3,6-dichloro-1,2-benzenedithiol). Compounds 1-3 have been characterized by IR, UV/visible, EPR, and mass spectroscopies. The X-ray crystal stuctures of 1 and 2 show hydrogen-bonding interactions between the terminal oxo atom and triethylammonium counterions and between ligand sulfur atoms and the counterions. These interactions are comparable with those found at the active sites of mononuclear molybdenum enzymes. [ABSTRACT FROM AUTHOR]

Examines the electronic structure of molybdenyl complexes. Application of magnetic circular dichroism and absorption spectroscopy; Use of density functional calculations to provide a framework for spectral interpretation; Energy transition of [MoOS[sub 4][sup -] chromophores.

Discusses the synthesis and characterizations of oxomolybdenum(V) complexes with three thiolate sulfur donor atoms as it occurs in the molybdenum center of sulfite oxidase. Determination of the crystal structure; Differences in spectroscopic properties; Electrochemistry.

Discusses differentiation therapy for prostate cancer. Metabolites of vitamin A; Short-chain fatty acids; Peroxisome proliferator-activated receptor agonists; Vitamin D and its analogs; Hybrid polar compounds.

Examines the role of endothelin axis in prostate cancer. Characteristics of endothelin axis; Pattern of endothelin expression in the normal prostate and in prostate carcinoma; Proliferative effects of endothelin on other peptide growth factors; Impact of endothelin production on bone formation; Possible therapeutic benefit of endothelin [subA] on prostate cancer.

Describes a study on the application of magnetic circular dichroism (MCD) spectroscopy to assign the optical spectra in high and low symmetry molybdenyl complexes. Effective Cs coordination symmetry of the LMoOX2 complexes; Comparison of MCD data with dimethyl sulphoxide (DMSO) reductase with models.

The title compound, also known as imexon, C4H5N3O, is an iminopyrrolidone that, due to its selective growth inhibitory effect against multiple myeloma, has been under investigation as an anticancer agent since the 1970s. Crystals of the title compound were grown from absolute ethanol saturated with imexon at 296 K, by slow evaporation. Under these conditions, imexon crystallizes as plates with well developed (100) faces. The crystals readily twin by a twofold rotation about the a axis. When crystallized via rapid evaporation of solvent, the resulting powder has a slightly larger unit cell. Simulation of the powder pattern using the atomic parameters and the larger powder cell agree well with measured powder patterns but indicate some preferred orientation towards the (100) plane. The anticancer molecule crystallizes as a zwitterion, with the imino N atom doubly protonated. Each molecule makes four hydrogen bonds which form continuous tapes of molecules along [010]. [ABSTRACT FROM AUTHOR]

The structure of an iridolactone isolated from Valeriana laxiflora was established as (4R,4aR,6S,7S,7aS)-6-hydroxy-7-hydroxymethyl-4-methylperhydrocyclopenta[c]pyran-1-one chloroform solvate, C10H16O4·CHCl3. The two rings are cis-fused. The δ-lactone ring adopts a slightly twisted half-chair conformation with approximate planarity of the lactone group and the cyclopentane ring adopts an envelope conformation. The hydroxy group, the hydroxymethyl group and the methyl group all have bb orientations. The absolute configuration was determined using anomalous dispersion data enhanced by the adventitious inclusion of a chloroform solvent molecule. Hydrogen bonding, crystal packing and ring conformations are discussed in detail. [ABSTRACT FROM AUTHOR]

Physical impairments following cancer treatment have been linked with the toxic effects of these treatments on muscle mass and strength, through their deleterious effects on skeletal muscle mitochondrial oxidative capacity. Accordingly, we designed the present study to explore relationships of skeletal muscle mitochondrial oxidative capacity with physical performance and perceived cancer-related psychosocial experiences of cancer survivors. We assessed skeletal muscle mitochondrial oxidative capacity using in vivo phosphorus-31 magnetic resonance spectroscopy (31P MRS), measuring the postexercise phosphocreatine resynthesis time constant, τPCr, in 11 post-chemotherapy participants aged 34–70 years. During the MRS procedure, participants performed rapid ballistic knee extension exercise to deplete phosphocreatine (PCr); hence, measuring the primary study outcome, which was the recovery rate of PCr (τPCr). Patient-reported outcomes of psychosocial symptoms and well-being were assessed using the Patient-Reported Outcomes Measurement Information System and the 36-Item Short Form health survey (SF-36). Rapid bioenergetic recovery, reflected through a smaller value of τPCr was associated with worse depression (rho ρ = − 0.69, p = 0.018, and Cohen's d = − 1.104), anxiety (ρ = − 0.61, p =.046, d = − 0.677), and overall mental health (ρ = 0.74, p = 0.010, d = 2.198) scores, but better resilience (ρ = 0.65, p = 0.029), and coping-self efficacy (ρ = 0.63, p = 0.04) scores. This is the first study to link skeletal muscle mitochondrial oxidative capacity with subjective reports of cancer-related behavioral toxicities. Further investigations are warranted to confirm these findings probing into the role of disease status and personal attributes in these preliminary results. [ABSTRACT FROM AUTHOR]

Patients with sarcomatoid renal cancer in good, intermediate and poor prognostic groups were randomized 1:1 sunitinib and gemcitabine (SG) versus sunitinib and assessed for response rate in this cooperative group phase II trial. Sunitinib but not the SG met the preset threshold of success. Grade = 3 events were seen. EA1808 was the first randomized cytotoxic trial for sarcomatoid RCC. Introduction: Sarcomatoid renal cancer (sRCC) patients have poor outcomes. EA1808 evaluated sunitinib and gemcitabine (SG) and sunitinib alone (S) in sRCC in a randomized cooperative group phase II trial (NCT01164228). Patients and Methods: Pts were aggregated 1:1 to SG (45 pts) or S (40 pts) using a 2-stage design. sRCC pts with = 1 prior nonvascular endothelial growth factor tyrosine kinase inhibitor were stratified into prognostic groups: good (clear cell, < 20% sarcomatoid, PS 0), intermediate (20%-50% sarcomatoid, PS 0), and poor (nonclear cell or > 50% sarcomatoid or PS 1). The primary endpoint was response rate (RR). For SG, the null RR was 15% and a 30% RR was of interest. For S, a 20% RR was of interest vs. a 5% null rate. Secondary endpoints were progression-free survival, overall survival, and safety. Results: Both arms met protocol cr iter ia for stage 2 of accrual. A total of 47 pts were randomized to SG and 40 to S. The SG arm had 9 of 45 evaluable patient responses (RR of 20%; CI = [13%-31%]) not meeting the predetermined threshold for success. The sunitinib arm met its endpoint with 6/37 (RR of 16%; CI = [9%-27%]) evaluable responses. Grade = 3 events were experienced by 36 in the SG arm and 17 in the sunitinib arm Conclusions: EA1808 was the largest and first randomized cytotoxic trial for sarcomatoid RCC. Sunitinib alone but not the SG met the preset threshold of success. Cytotoxic chemotherapy is only useful in limited clinical scenarios for sRCC. [ABSTRACT FROM AUTHOR]

The title compound, C25H32N2O3, was synthesized as part of a series of related compounds using a modified Eschenmoser-Claisen rearrangement reaction. The compound is racemic and the structure features a centrosymmetric hydrogenbonded dimerization along with some aromatic stacking stabilization. [ABSTRACT FROM AUTHOR]

Presents an update of docetaxel in the management of androgen-independent prostate cancer. Association of docetaxel with a reduction of more than half in serum prostate-specific antigen (PSA) level; Effectivity of docetaxel in terms of clinical benefit; Investigation on the combined regimens of docetaxel with novel agents.

Examines the direct hydrolysis of molecular oxo-hydroxo lanthanide complexes. Use of tyrosine as ligand in the synthesis; Absence of a tyrosine ligands in the oxo-hydroxo lanthanide cluster; Characterization of the lanthanide clusters; Structural determination of the complexes.

Background: Cancer clinical trial participation is low and inequitable. Partnering Around Cancer Clinical Trials (PACCT) addressed systemic and interpersonal barriers through an observational study of eligibility and an intervention to improve patient–physician communication and trial invitation rates. Methods: Physicians at two comprehensive cancer centers and Black and White men with prostate cancer participated. Patients were followed for 2 years to determine whether they became potentially eligible for an available therapeutic trial. Potentially eligible patients were randomized to receive a trials‐focused Question Prompt List or usual care. Patient–physician interactions were video‐recorded. Outcomes included communication quality and trial invitation rates. Descriptive analyses assessed associations between sociodemographic characteristics and eligibility and effects of the intervention on outcomes. Results: Only 44 (22.1%) of participating patients (n = 199) became potentially eligible for an available clinical trial. Patients with higher incomes were more often eligible (>$80,000 vs. <$40,000, adjusted OR = 6.06 [SD, 1.97]; $40,000–$79,000 vs. <$40,000, adjusted OR = 4.40 [SD, 1.81]). Among eligible patients randomized to the intervention (n = 19) or usual care (n = 25), Black patients randomized to the intervention reported participating more actively than usual care patients, while White intervention patients reported participating less actively (difference, 0.41 vs. −0.34). Intervention patients received more trial invitations than usual care patients (73.7% vs. 60.0%); this effect was greater for Black (80.0% vs. 30.0%) than White patients (80.0% vs. 66.7%). Conclusions: Findings suggest the greatest enrollment barrier is eligibility for an available trial, but a communication intervention can improve communication quality and trial invitation rates, especially for eligible Black patients. [ABSTRACT FROM AUTHOR]

Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes.Trial Registration: ClinicalTrials.gov identifier: NCT00465595. [ABSTRACT FROM AUTHOR]

Objective: This study described physicians' use of plain language during patient-physician cancer clinical trial discussions.Methods: Video-recorded clinical interactions and accompanying transcripts were taken from a larger study of communication and clinical trials (PACCT). Interactions (n = 25) were selected if they included invitations to participate in a clinical trial. We used descriptive, qualitative discourse analysis, a method that identifies language patterns at or above the sentence level. We first excerpted discussions of clinical trials, then identified instances of plain language within those discussions. Finally, we inductively coded those instances to describe physicians' plain language practices.Results: The analysis identified four plain language practices. Lexical simplification replaced medical terminology with simpler words. Patient-centered definition named, categorized, and explained complex medical terminology. Metaphor explained medical terminology by comparing it with known concepts. Finally, experience-focused description replaced medical terminology with descriptions of patients' potential physical experiences.Conclusion: These plain language practices hold promise as part of effective information exchange in discussions of cancer clinical trials. Testing is needed to identify patient preferences and the extent to which these practices address patient health literacy needs.Practice Implications: Pending further testing, these plain language practices may be integrated into physician clinical trial and other communication training. [ABSTRACT FROM AUTHOR]

The title compound, [Ni(C32H33N3O3)], crystallized as a minor product during the purification of its 2( R)-pent-4-enyl diastereomer. Mixtures of the title compound and its enanti­omer self-resolve. [ABSTRACT FROM AUTHOR]

Purpose: PRO-cision medicine refers to personalizing care using patient-reported outcomes (PROs). We developed and feasibility-tested a PRO-cision Medicine remote PRO monitoring intervention designed to identify symptoms and reduce the frequency of routine in-person visits. Methods: We conducted focus groups and one-on-one interviews with metastatic breast (n = 15) and prostate (n = 15) cancer patients and clinicians (n = 10) to elicit their perspectives on a PRO-cision Medicine intervention's design, value, and concerns. We then feasibility-tested the intervention in 24 patients with metastatic breast cancer over 6-months. We obtained feedback via end-of-study surveys (patients) and interviews (clinicians). Results: Focus group and interview participants reported that remote PRO symptom reporting could alert clinicians to issues and avoid unneeded/unwanted visits. However, some patients did not perceive avoiding visits as beneficial. Clinicians were concerned about workflow. In the feasibility-test, 24/236 screened patients (10%) enrolled. Many patients were already being seen less frequently than monthly (n = 97) or clinicians did not feel comfortable seeing them less frequently than monthly (n = 31). Over the 6-month study, there were 75 total alerts from 392 PRO symptom assessments (average 0.19 alert/assessment). Patients had an average of 4 in-person visits (vs. expected 6.5 without the intervention). Patients (n = 19/24) reported high support on the end-of-study survey, with more than 80% agreeing with positive statements about the intervention. Clinician end-of-study interviews (n = 11/14) suggested that PRO symptom monitoring be added to clinic visits, rather than replacing them, and noted the increasing role of telemedicine. Conclusions: Future research should explore combining remote PRO symptom monitoring with telemedicine and in-person visits. [ABSTRACT FROM AUTHOR]

The article presents research that examines the effectiveness of androgen-deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancers The background on ADT as a backbone for metastatic hormone-sensitive prostate cancer treatment, the methods used in the study, its results and findings and its conclusion on the long survival of patients administered with docetaxel are discussed.

Based on PROfound, olaparib is approved for patients with metastatic castration-resistant prostate cancer following disease progression on at least enzalutamide or abiraterone and who carry relevant alterations in DNA repair genes. To facilitate continued olaparib treatment as long as the patient derives benefit, we describe further safety assessments from PROfound focusing on the four most common adverse events (AEs) and events of special interest. Patients were randomized (2:1) to olaparib tablets (300 mg bid) or control (enzalutamide or abiraterone) until disease progression or unacceptable toxicity. Safety was assessed through AE reporting and laboratory assessments. Safety data were also collected from all patients in the control group who experienced radiographic disease progression and subsequently crossed over to olaparib treatment. 256 patients received olaparib and 130 control. Incidence rates for the four most commonly occurring AEs in the olaparib group (all-causality) were anaemia 50%, nausea 43%, fatigue/asthenia 42% and decreased appetite 31%. All were mostly Grade 1 and 2 and all peaked within the first 2 months of treatment as the events were managed where appropriate, primarily with dose interruptions or dose reductions. The extent of bone metastases at baseline or prior taxane use was not associated with the rate of anaemia. Pneumonitis was reported in 2% and 1.5% of patients in the olaparib and control groups, respectively, and one patient (0.4%) in the olaparib group experienced an event of MDS/AML after a 30-day follow-up period. Venous thromboembolic events occurred in 8% of olaparib and 3% of control patients. The four most common AEs observed in PROfound were generally manageable without the need for treatment discontinuation, allowing patients to remain on treatment for as long as they were deriving clinical benefit. gov registration number : NCT02987543. [Display omitted] • The safety profile of olaparib in men with mCRPC was similar to other solid tumours. • Events of anaemia, nausea, decreased appetite and fatigue occurred most frequently. • Incidences of all four events peaked within the first 2 months of starting treatment. • All four were generally manageable through dose modifications and supportive therapies. • Baseline bone metastases or prior taxane use was unrelated to the rate of anaemia. [ABSTRACT FROM AUTHOR]

Introduction Drug development and clinical decision making for patients with metastatic prostate cancer (PC) have been hindered by a lack of quantitative methods of assessing changes in bony disease burden that are associated with overall survival (OS). Bone scan index (BSI), a quantitative imaging biomarker of bone tumor burden, is prognostic in men with metastatic PC. We evaluated an automated method for BSI calculation for the association between BSI over time with clinical outcomes in a randomized double-blind trial of tasquinimod (TASQ) in men with metastatic castration-resistant PC (mCRPC). Methods Bone scans collected during central review from the TASQ trial were analyzed retrospectively using EXINIbone BSI , an automated software package for BSI calculation. Associations between BSI and other prognostic biomarkers, progression-free survival, OS, and treatment were evaluated over time. Results Of 201 men (57 TASQ and 28 placebo), 85 contributed scans at baseline and week 12 of sufficient quality. Baseline BSI correlated with prostate-specific antigen and alkaline phosphatase levels and was associated with OS in univariate (hazard ratio [HR] = 1.42, P = 0.013) and multivariate (HR = 1.64, P <0.001) analyses. BSI worsening at 12 weeks was prognostic for progression-free survival (HR = 2.14 per BSI doubling, P <0.001) and OS (HR = 1.58, P = 0.033) in multivariate analyses including baseline BSI and TASQ treatment. TASQ delayed BSI progression. Conclusions BSI and BSI changes over time were independently associated with OS in men with mCRPC. A delay in objective radiographic bone scan progression with TASQ is suggested; prospective evaluation of BSI progression and response criteria in phase 3 trials of men with mCRPC is warranted. [ABSTRACT FROM AUTHOR]

Purpose: AZD7762 is a Chk1 kinase inhibitor which increases sensitivity to DNA-damaging agents, including gemcitabine. We evaluated the safety of AZD7762 monotherapy and with gemcitabine in advanced solid tumor patients. Experimental design: In this Phase I study, patients received intravenous AZD7762 on days 1 and 8 of a 14-day run-in cycle (cycle 0; AZD7762 monotherapy), followed by AZD7762 plus gemcitabine 750-1,000 mg/m on days 1 and 8, every 21 days, in ascending AZD7762 doses (cycle 1; combination therapy). Results: Forty-two patients received AZD7762 6 mg ( n = 9), 9 mg ( n = 3), 14 mg ( n = 6), 21 mg ( n = 3), 30 mg ( n = 7), 32 mg ( n = 6), and 40 mg ( n = 8), in combination with gemcitabine. Common adverse events (AEs) were fatigue [41 % (17/42) patients], neutropenia/leukopenia [36 % (15/42) patients], anemia/Hb decrease [29 % (12/42) patients] and nausea, pyrexia and alanine aminotransferase/aspartate aminotransferase increase [26 % (11/42) patients each]. Grade ≥3 AEs occurred in 19 and 52 % of patients in cycles 0 and 1, respectively. Cardiac dose-limiting toxicities occurred in two patients (both AZD7762 monotherapy): grade 3 troponin I increase (32 mg) and grade 3 myocardial ischemia with chest pain, electrocardiogram changes, decreased left ventricular ejection fraction, and increased troponin I (40 mg). AZD7762 exposure increased linearly. Gemcitabine did not affect AZD7762 pharmacokinetics. Two non-small-cell lung cancer patients achieved partial tumor responses (AZD7762 6 mg/gemcitabine 750 mg/m and AZD7762 9 mg cohort). Conclusions: The maximum-tolerated dose of AZD7762 in combination with gemcitabine 1,000 mg/m was 30 mg. Although development of AZD7762 is not going forward owing to unpredictable cardiac toxicity, Chk1 remains an important therapeutic target. [ABSTRACT FROM AUTHOR]

Emerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical. To characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC. This was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease. We measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC). The frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p < 0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio [HR] 1.59; p = 0.03) and the development of CRPC (HR 1.71; p = 0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined. Somatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration. Oligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions. The frequency of putative driver mutations increases across the metastatic hormone-sensitive prostate cancer spectrum and can stratify clinical outcomes. Somatic mutational profiles help in redefining oligometastasis beyond simple lesion enumeration by providing a biological definition. [ABSTRACT FROM AUTHOR]

Abstract: Background: This study was designed to evaluate toxicity and preliminary efficacy of 2 cycles of concomitant standard dose/schedule of 153Sm-lexidronam plus Q 3 weeks schedule escalating doses of docetaxel in metastatic castration-resistant prostate cancer (mCRPC). Methods: mCRPC patients with progressive bone metastases were treated in 4 cohorts. Docetaxel doses were escalated from 50, 50, 0 mg/m2 (on days 1, 22, 43, per 12-week cycle) to 75, 75, 75 mg/m2. 153Sm-lexidronam was administered on days 2 (Q 12 weeks) at dose of 1 mCi/kg/cycle (maximum of 2 cycles). Results: Thirteen patients received an average of 3.6 doses of docetaxel (range, 2–6 doses, median 4) and 1.5 doses of 153Sm-lexidronam (range, 1–2, median 2). Toxicity was primarily hematologic. There were total 35 episodes grade 3/4 neutropenia with a median 7 (range 7–14) days to recovery to ≤grade 1. One dose limiting grade 3 thrombocytopenia occurred on cohorts 3 and 4. Eight of 13 (62%) patients had PSA > 50% decrease as best response during the treatment. Median time to bone disease progression was 5.2 months (range 91 days–10 months+); 6/13 (46%) patients had stable/improved bone scans at 6 months and 6/6 (100%) symptomatic patients had improvement in pain. Conclusions: Concurrent 6-month administration of 4 doses (75 mg/m2) of standard Q 3 weeks schedule of docetaxel with 2 Q 3 months infusions of 1 mCi/Kg 153Sm-lexidronam is feasible with reversible bone marrow suppression, and deserves further testing in mCRPC patients with extensive bone metastasis. [Copyright &y& Elsevier]

Abstract: Context: Prostate cancer (PCa) is the most common noncutaneous malignancy and the second leading cause of cancer mortality amongst men in the Western world. Up to 40% of men diagnosed with PCa will eventually develop metastatic disease, and although most respond to initial medical or surgical castration, progression to castration resistance is universal. The average survival for patients with castration-resistant prostate cancer (CRPC) is 2–3 yr. Objective: To discuss the biologic rationale and evidence supporting current management of patients with CRPC and to review promising novel agents. Evidence acquisition: Electronic databases (PubMed, ClinicalTrials.gov), relevant journals, and conference proceedings were searched manually for preclinical studies, clinical trials, and biomarker analyses focused on the treatment of CRPC. Keywords included castrate resistant prostate cancer and: targeted therapy, novel therapy, immunotherapy, androgen therapy, bone therapy, mechanisms, biomarkers, and trial endpoints; no time range was specified. Information pertaining to current studies was discussed with key opinion leaders. Evidence synthesis: We focus on the efficacy and safety of approved agents, promising therapies that have proceeded to phase 3 evaluation, and those that have enhanced our understanding of the biology of CRPC. Biomarkers are considered in the context of novel targeted agents and immunotherapy. Conclusions: CRPC has many targets. Four new agents with different mechanisms of action have recently been shown to have positive results in large phase 3 randomized trials, and have already been approved in the United States for CRPC: cabazitaxel, sipuleucel-T, denosumab, and abiraterone acetate. With our improved understanding of tumor biology and the incorporation of new prognostic and molecular biomarkers into clinical trials, we are making progress in the management of patients with CRPC. [Copyright &y& Elsevier]

Combination of two differentiation agents such as phenylbutyrate (PB) and 13- cis-retinoic acid (CRA) has been shown to have an additive inhibitory effect on tumor growth in preclinical studies. In this report we explored the hypotheses that these “cytostatic” agents may have a greater antitumor activity in combination with “cytotoxic” compounds and their biological effect may be sequence-dependent. The antitumor activity of combination of PB and CRA with paclitaxel (TX ) and doxorubicin (DOXO) on human prostate and colon carcinoma cell lines was assessed both in vitro and in vivo. The effect on cell cycle, apoptotic rate, cycline expression and induction of p21 expression was also determined. Following treatment of tumor cells with PB + CRA + TX or DOXO, inhibition of tumor cell growth was greatly enhanced as compared to PB + CRA, TX or DOXO alone, with >90% growth inhibition. However, when the cells were pretreated with PB + CRA followed by TX or DOXO, the enhanced inhibition was abolished suggesting a protective effect to this sequence. Interestingly treatment with PB + CRA restored sensitivity to DOXO in PC-3 human prostate cancer cell line. PB + CRA induced p21 expression and cell-cycle arrest in G1 phase, while TX and DOXO induced G2/M arrest. p21 and p53-deficient colon carcinoma cell lines were more sensitive to the effect of PB + CRA and TX as single agents and in combination, as compared to the wild type cells. When p21-deficient cells were pretreated with PB + CRA followed by TX the protective effect was still observed. Treatment of tumor cells with combination of these drugs induced cell cycle delay at multiple mitotic checkpoints before undergoing apoptosis. Tumor growth was significantly inhibited and delayed in animals treated with either TX or concomitantly with TX and PB + CRA as compared to control. Animals treated with all three agents demonstrated further growth inhibition or delay than the TX alone or PB + CRA arm. These results suggest a rational therapeutic approach for combination of differentiation-inducing agents with cytotoxic drugs given concomitantly, but not sequentially. [ABSTRACT FROM AUTHOR]

The preparation, EPR spectra, and crystal structures of octaethyltetraphenylporphyrinatoiron(llI) having two imidazole, N-benzylimidazole, and N-methylimidazole axial ligands are reported, [(OETPP)Fe(Hlm)2]Cl, [(OETPP)Fe(N-Bzlm)2]-Cl, and [(OETPP)Fe(N-MeIm)2]Cl. Despite large variation in axial ligand size, the unit cell parameters for all complexes are very similar; each structure has the same basic motif, with large voids formed by the extended porphyrin framework (filled by ordered or disordered axial ligands and disordered solvent), which allows differently sized ligands to fit within the same cell dimensions. Each porphyrin core adopts a saddled conformation with ∣ΔCβ∣I = 1.13-1.15 Å. The dihedral angles between axial ligand planes, Δφ, are far from being either ideal parallel or perpendicular: 30.1°, 57.2° for [(OETPP)Fe(Hlm)2]Cl (molecules 1 and 2), 56.8° for [(OETPP)Fe(N-Bzlm)2]Cl, and 16.00, 44.6°, 59.6°, and 88.1° for [(OETPP)Fe(N-Melm)2]Cl, which has disordered axial ligands. Among the complexes of this study, an axial ligand Δφ of 56.8° is found to be the largest "parallel" angle (as defined by the observation of a normal rhombic or Type II EPR signal (N-Bzlm, g = 3.08, 2.19, 1.31)), while 57.2° is found to be the smallest "perpendicular" Δφ (as defined by the observation of a "large gmax" or Type I EPR signal (Hlm, gmax = 3.24)). From the results of this study, it is clear that the size of the largest g for Types I and II complexes varies continuously, with no break between the two. While the switch in EPR signal type, from Type Ito Type I, appears to be very sharp in this study, this may be somewhat artificial based upon limited numbers of examples and the required saddle distortion of the (OETPP)FeII complexes. However, in comparison to several proteins with dihedral angles near 60° and Type II EPR spectra, we may conclude that the switch in EPR signal type occurs near 57° ± 3-5°. [ABSTRACT FROM AUTHOR]

A novel Eu(III) complex featuring three dibenzoylmethanate (DBM) ligands and a Lewis base ligand 2,4,6-tri(2-pyridyl)-1,3,5-triazine (TPTZ) was synthesized. This novel complex was characterized by 1H NMR, FAB-MS, and elemental analyses. The structure of the complex was established by single crystal X-ray diffraction. The nonacoordinate europium ion features six oxygen atoms of the three DBM ligands and three nitrogen atoms from the TPTZ ligand, forming a distorted monocapped square antiprism. Spectroscopic studies revealed that the electronic absorption of the complex is essentially ligand-based, while the emission is characteristic of a Eu(III) ion. It is concluded that the metal-centered red emission is promoted by the ligand-assisted energy transfer, namely the antenna effects. [Copyright &y& Elsevier]