Enhanced Treatment Strategies Research Articles

A Novel Biosignature to Assess Residual Risk in Early Stage Invasive Breast Cancer after Standard Breast Conserving Surgery

Despite continually improving outcomes for women diagnosed with early stage breast cancer, there is an unmet need to identify those with elevated risk after standard treatment for whom enhanced treatment strategies should be considered. A poor response-type (RSt) signature has been assessed in women treated with breast conserving surgery. This study includes patients from two separate hospitals in Sweden diagnosed with early stage breast cancer (tumor size 20 mm or less) and treated with breast conserving therapy between 1987 and 2004. Women with positive margins, lymph node metastases, or those treated with mastectomy or chemotherapy were excluded. The RSt biosignature was calculated using biomarkers (ER, p16/INK4A, Ki-67, COX-2, PgR, HER2, FOXA1, SIAH2) scored by board certified pathologists in a CLIA certified laboratory. Pathology and clinical data were collected from medical records. There were 284 eligible patients with biomarker data and 102 received hormone therapy. Multivariate Cox proportional hazards and survival analysis were used to assess cumulative incidence risk differences, hazard ratios, and 10-year risks. Women with a poor RSt remained at particularly elevated risk after treatment with breast conserving surgery and radiation therapy with a 17% 10-yr risk and HR = 3.7 (95%CI 2.0-7.10), p<0.00001 (Table 1). The distribution of size and grade were similar for good versus poor RSt. Patients with a poor RSt had an elevated risk of disease-specific death; HR = 2.9 (95%CI 1.3-6.7), p = 0.01. A novel biosignature identified women diagnosed with early stage invasive breast cancer with a low risk and a poor RSt. Women with a poor RSt remained at particularly elevated risk even after RT, and thus enhanced treatment strategies should be considered for these women.Abstract 2041; TableRSt GroupPatientsEvents10-Year Event Risk (95% CI)Local Regional Events10-Year Specific Death (95% CI)Breast Cancer DeathsLow Risk16574% (1-8)52% (0-5)2Poor RSt681117% (7-25)513% (5-21)9 Open table in a new tab

Enhanced treatment strategies and distinct disease outcomes among autoantibody-positive and -negative rheumatoid arthritis patients over 25 years: A longitudinal cohort study in the Netherlands.

Based on different genetic and environmental risk factors and histology, it has been proposed that rheumatoid arthritis (RA) consists of 2 types: autoantibody-positive and autoantibody-negative RA. However, until now, this remained hypothetical. To assess this hypothesis, we studied whether the long-term outcomes differed for these 2 groups of RA patients. In the Leiden Early Arthritis Clinic cohort, 1,285 consecutive RA patients were included between 1993 and 2016 and followed yearly. Treatment protocols in routine care improved over time, irrespective of autoantibody status, and 5 inclusion periods were used as instrumental variables: 1993-1996, delayed mild disease-modifying antirheumatic drug (DMARD) initiation (reference period); 1997-2000, early mild DMARDs; 2001-2005, early methotrexate; 2006-2010, early methotrexate followed by treat-to-target adjustments; 2011-2016, similar to 2006-2010 plus additional efforts for very early referral. Three long-term outcomes were studied: sustained DMARD-free remission (SDFR) (persistent absence of clinical synovitis after DMARD cessation), mortality, and functional disability measured by yearly Health Assessment Questionnaire (HAQ). Treatment response in the short term (disease activity) was measured by Disease Activity Score-28 with erythrocyte sedimentation rate (DAS28-ESR). Linear mixed models and Cox regression were used, stratified for autoantibody positivity, defined as IgG anti-CCP2 and/or IgM rheumatoid factor positivity. In total, 823 patients had autoantibody-positive RA (mean age 55 years, 67% female); 462 patients had autoantibody-negative RA (age 60 years, 64% female). Age, gender, and percentage of autoantibody-positive patients were stable throughout the inclusion periods. Disease activity significantly decreased over time within both groups. SDFR rates increased after introduction of treat-to-target (hazard ratio [HR] 2006-2010 relative to 1993-1996: 3.35 [95% CI 1.46 to 7.72; p = 0.004]; HR 2011-2016: 4.57 [95% CI 1.80 to 11.6; p = 0.001]) in autoantibody-positive RA, but not in autoantibody-negative RA. In autoantibody-positive RA, mortality decreased significantly after the introduction of treat-to-target treatment adjustments (HR 2006-2010: 0.56 [95% CI 0.34 to 0.92; p = 0.023]; HR 2011-2016: 0.33 [95% CI 0.14 to 0.77; p = 0.010]), but not in autoantibody-negative RA (HR 2006-2010: 0.79 [95% CI 0.40 to 1.56; p = 0.50]; HR 2011-2016: 0.36 [95% CI 0.10 to 1.34; p = 0.13]). Similarly, functional disability improved in autoantibody-positive RA for the periods after 2000 relative to 1993-1996 (range -0.16 [95% CI -0.29 to -0.03; p = 0.043] to -0.32 [95% CI -0.44 to -0.20; p < 0.001] units of improvement), but not in autoantibody-negative RA (range 0.10 [95% CI -0.12 to 0.31; p = 0.38] to -0.13 [95% CI -0.34 to 0.07; p = 0.20] units of improvement). Limitations to note were that treatment was not randomized-but it was protocolized and instrumental variable analysis was used to obtain comparable groups-and that a limited spread of ethnicities was included. Although disease activity has improved in both autoantibody-positive and autoantibody-negative RA in recent decades, the response in long-term outcomes differed. We propose that it is time to subdivide RA into autoantibody-positive RA (type 1) and autoantibody-negative RA (type 2), in the hope that this leads to stratified treatment in RA.

A novel biosignature to assess residual risk in ductal carcinoma in situ (DCIS) patients after standard treatment.

548 Background: There is an unmet need to identify women diagnosed with DCIS with elevated risk after standard treatment for whom enhanced treatment strategies should be considered. A response type (RSt) signature has been assessed in women treated with breast conserving surgery (BCS) with or without radiotherapy (RT), or with mastectomy. Methods: Women diagnosed with pure DCIS and treated with BCS or, BCS with whole breast RT were consecutively collected in Sweden, 1986-2004 and the USA, 1999-2008. A third cohort treated with mastectomy was collected in Sweden from 1986-2004. Patients with FFPE tissue were included unless they had prior or simultaneous invasive breast cancer (IBC). The RSt and DCISionRT biosignatures were calculated using biomarkers (p16/INK4A, Ki-67, COX-2, PgR, HER2, FOXA1, SIAH2), scored by board certified pathologists. Pathology and clinical data were collected from medical records. Only women at elevated risk by DCISionRT (DS &gt; 3) and negative margins were included in analysis. Total breast event risk included either ipsilateral DCIS or IBC. Multivariate Cox proportional hazards and survival analysis were used to assess cumulative incidence risk differences, hazard ratios, and 10-year risks adjusted for year of diagnosis. Results: Women with a poor RSt were all HER2 positive and remained at particularly elevated risk after BCS and RT (23% 10-yr risk, p &lt; 0.0001, Table), with a risk profile similar to women treated with BCS without RT (RSt not evaluated). The distribution of age and size were not statistically different for good versus poor RSt, but poor RSt were more commonly Grade 3. In a small cohort of women treated with mastectomy, those women with a poor RSt were still at elevated risk after surgery, comparered to women with a good RSt (HR = 5.4, p = 0.014). The 10-year risk profile for women with a good RSt treated with BCS plus RT or mastectomy, was low (table). Conclusions: A novel biosignature identified women with a good and poor RSt, where the good RSt identified women with an apparent substantial benefit from RT, as well as women with a poor RSt who remained at particularly elevated risk after RT, and for whom enhanced treatment strategies should be considered. Additional validation studies are ongoing. [Table: see text]

SUN-747 Steroid Hormone Metabolism Mediated Racial Disparity in Men with Benign Prostatic Hyperplasia

Introduction and Objective: Racial disparity in prostate cancer has been well established, with African American (AA) men having higher rates of diagnoses and death from the disease compared to Caucasian American (CA) men. AA men also have a high incidence of benign prostatic hyperplasia (BPH), a disease associated with lower urinary tract symptoms (LUTS) that affect >210 million men worldwide. Furthermore, AA men with BPH have an increased incidence of non-surgical treatment failure, larger prostates at time of surgery, and surgery occurring at a younger age. The use of selective estrogen receptor modulators (SERMs) in the treatment of BPH has been proposed, as an increase in ERα has been associated with disease progression. AA men have higher levels of circulating estrogens as compared to CA leading to an increased prenatal exposure to estrogens. Estrogen exposure has been shown to alter the epigenetic landscape of genes, and this prenatal exposure to estrogens could sensitize the AA men to altered steroid homeostasis leading to an increase susceptibility to BPH and an altered response to treatment. In this study, we examine the prostate expression and localization changes in estrogen receptors (ERα, ERβ) as well as steroid metabolism genes in AA and CA with or without BPH. Methods: To examine the impact of race on BPH, we examined prostate tissue from 66 men. We utilized 21 normal transition zone controls from radical prostatectomies, 8 normal transition zone controls from organ donors, and 37 BPH samples divided between CA and AA men. Using multispectral quantitative multiplex IHC, we examined the steroid hormone related protein expression of ERα, ERβ, CYP7B1, and AKR1C1 on each FFPE tissue section. We quantified the optical density of each protein of interest as well as examined colocalization and coexpression through cell and tissue segmentation. Results: In CA men, there is a dysregulation of ERα:ERβ homeostasis with BPH relative to normal as an increase in ERα and a decrease in ERβ expression was observed. Furthermore, an increase in CYP7B1, an enzyme that degrades ERβ ligands, was also observed. In AA men, we observed no difference between normal and BPH states, however in both normal and BPH prostate tissues, ERα and ERβ were increased relative to CA men. In addition, there is a decrease in AKR1C1, the enzyme that metabolizes DHT to an ERβ ligand. Conclusions: Our study supports the concept that differences in hormone pathways exist between AA and CA men. Understanding how these racial difference in steroid metabolism enzymes as well as ERs between CA and AA men with BPH could enhance treatment strategies for men with BPH.

Obesity Alters the Expression of Suppressive Factors in Intra‐Tumoral Dendritic Cells Following Combinatorial Immunotherapy

A growing literature suggests that obesity induces dysregulated antitumor immunity. We found previously that diet‐induced obesity (DIO) increases the abundance of intra‐tumoral regulatory dendritic cells (DCs) in a murine model of renal cancer. Furthermore, DIO reduces the efficacy of an immunotherapy consisting of intra‐tumoral delivery of replication‐deficient adenovirus (Ad) encoding tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) (AdT) plus class B oligonucleotides (CpG1826). This therapy primes endogenous T cells by targeting DCs that process and present tumor‐derived antigens released by TRAIL‐mediated tumor cell death. Our current study evaluated the efficacy of AdT/CpG combined with either anti‐PD‐1 or anti‐CTLA‐4 immune checkpoint blockade, in the absence or presence of DIO. BALB/c mice (7–8‐weekold) were randomized to standard chow or high‐fat diet for 20 weeks prior to the orthotopic injection of Renca‐Luc renal cancer cells into the left kidney and were maintained on diets until day 28 post‐tumor injection. At day seven post‐tumor injection, mice were re‐injected in the left kidney with saline or AdT/CpG. Mice were further randomized to receive intra‐peritoneal isotype control, anti‐PD‐1, or anti‐CTLA‐4. Both AdT/CpG+anti‐PD‐1 (p&lt;0.001) and AdT/CpG+anti‐CTLA‐4 (p&lt;0.001) resulted in a significant reduction in renal tumor outgrowth and spontaneous lung metastasis in lean mice on standard chow. AdT/CpG increased the accumulation of intra‐tumoral DCs independent of dietary or immunotherapy intervention, with the conventional DC two (cDC2) subset favored over the conventional DC one (cDC1) subset. Expression of PD‐1 and PD‐L1 on DC subsets was unchanged in response to diet or immunotherapy intervention; however, untreated tumor‐bearing DIO mice had elevated PD‐1 expression on cDC1s (p=0.022) compared to untreated lean mice or lean mice receiving AdT/CpG+anti‐PD‐1. Lastly, Arginase‐1 expression in cDC1s was not significantly different between groups; however, Arginase‐1 expression was elevated in response to DIO on cDC2s (p=0.006) compared to both lean and DIO AdT/CpG+anti‐PD‐1 treated mice. Future studies are needed to characterize the suppressive function of intra‐tumoral DC populations, as well as the T cell priming capacity of DCs within tumor‐draining lymph nodes in response to immunotherapy in the absence or presence of DIO. In conclusion, the differential response to immunotherapy and alteration in suppressive factors in intra‐tumoral DCs in DIO mice warrants further investigation, as targeting these pathways may ultimately enhance treatment strategies in overweight and obese cancer patients.Support or Funding InformationRO1CA181088 and T32DK062710This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

New prognostic biomarkers and therapeutic effect of bevacizumab for patients with non-small-cell lung cancer.

BackgroundSeveral biomarkers have emerged as potential prognostic and predictive markers for non-small-cell lung cancer (NSCLC). Successful inhibition of angiogenesis with the antivascular endothelial growth factor antibody, bevacizumab, has improved the efficacy seen with standard cytotoxic therapy of NSCLC. However, despite such enhanced treatment strategies, the prognosis for patients with advanced NSCLC remains poor.Patients and methodsWe assessed potential biomarkers in 161 NSCLC patients and 42 control patients. Enzyme-linked immunosorbent assay methods were used to evaluate three biomarkers: platelet-derived microparticle (PDMP), high-mobility group box-1 (HMGB1), and plasminogen activator inhibitor-1 (PAI-1). We studied the effects of bevacizumab on the expression of these markers. We also analyzed the relationship of the newly designed risk factor (NDRF) to overall survival and disease-free survival. The NDRF classification of patients was determined from the levels of PDMP, HMGB1, and PAI-1. To determine the individual prognostic power of PDMP, HMGB1, and PAI-1, we evaluated associations between their levels and patient outcomes by Kaplan–Meier survival analysis in a derivation cohort.ResultsPDMP, HMGB1, and PAI-1 levels were higher in NSCLC patients compared with control patients. Notably, the difference in PDMP levels exhibited the strongest statistical significance (p<0.001). Multivariate analysis showed that HMGB1 and PAI-1 levels were significantly correlated with PDMP levels. Patients who received standard chemotherapy with bevacizumab exhibited significantly reduced levels of all three markers compared with patients who received standard chemotherapy. NDRF3 status (high levels of all three markers) was significantly correlated with a poor prognosis (p<0.05 for overall survival and disease-free survival).ConclusionOur results demonstrate that abnormal levels of PDMP, HMGB1, and PAI-1 are related to each other in NSCLC. Moreover, our findings suggest that the vascular complications associated with these markers may contribute to a poor prognosis for NSCLC patients.

Single center experience of urinary bladder malignancy: a 10-year retrospective analysis of hospital data

Background: Albeit the EAU, NCCN and AUA guidelines provide an excellent evidence-based protocol for the management of MIBC and NMIBC, these guidelines differ with respect to critical issues such as risk level definitions and management strategies. The NE part of the country has always bore the brunt of heavy oncological catastrophe like urinary bladder carcinoma related to extensive tobacco and pesticide usage. MIBC treatment usually encompasses RC with AC/NAC (Level I evidence for NAC use in MIBC exist) but the majority of patients seen at our center have already progressed to advanced stage at presentation and could not undertake full treatment.Methods: Cancer registry of the last 10 yrs at Dept. of Urology and Renal Transplant Gauhati Medical College Hospital was searched for demographic, clinical, pathological and prognostic data and results summarized using statistical parameters of univariate analysis.Results: There were a total of 168 patients in the NMIBC group with a majority in the 60-70-year age group. The most common grade was G2 and all DM type 2 and CKD were significantly associated in all the patients analyzed. Chemical exposure in the form of pesticide and smoking was a constant phenomenon in all patients of NMIBC and MIBC (n=66) population. CKD was significantly associated in the MIBC population along with positive urine cytology.Conclusions: Despite a paucity of high level evidence regarding the majority of management topics in Urinary Bladder cancer in NE part of the country, there was general agreement among the various guideline panels and management guidelines at our institution. Identification of the upfront clinical parameters suggesting severity of disease and time to progression are the two most important domains which will decide the future of UB carcinoma treatment in this part of the world. Categories of evidence synthesized and grades of recommendations will have to be constantly gazed upon to modify and enhance treatment strategies.

A Self-Report Measure to Detect Neurocognitive Impairment among Incarcerated People Living with HIV in Malaysian Context: An Exploratory Factor Analysis.

While neurocognitive impairment (NCI) among people living with HIV (PLWH) who use drugs and its impact on HIV treatment outcomes continue to be widely investigated, there remains a critical gap in NCI assessment among HIV-infected people who use drugs (PWUD) in Malaysian context. The present study, therefore, sought to improve the utility of the existing Neuropsychological Impairment Scale (NIS) as a screening tool for assessing NCI by establishing its psychometric properties in the Malaysian context. The NIS is a brief, self-report measure originally designed to assess NCI by having individuals rate a range of items that may influence cognitive functioning. HIV-infected male prisoners (N=301) administered the full 95-item NIS. An exploratory factor analysis (EFA) was conducted using principal axis factoring and orthogonal varimax rotation. Reliability was measured using Cronbach's alpha. The EFA resulted in an abbreviated, psychometrically sound, eight-factor structure (54-item) revised NIS - now referred to as the Brief Inventory of Neuro-cognitive Impairment-Malaysia (BINI-M). It is better designed to detect NCI in PLWH, ranging from generalized neurocognitive symptoms to more specific forms of impairment with excellent to average reliability. The BINI-M may serve as a useful tool for clinicians and researchers to assess NCI in PLWH and can inform enhanced treatment strategies in the Malaysian context.

Growth and development in children with classic congenital adrenal hyperplasia.

Final height outcome in classic congenital adrenal hyperplasia (CAH) has been of interest for many years. With analysis of growth patterns and used glucocorticoid regimens, enhanced treatment strategies have been developed and are still under development. Most of the current reports on final height outcome are confirmative of previous results. Final height data is still reported in cohorts that were diagnosed clinically and not by newborn screening. Clinical diagnosis of CAH leads to delayed diagnosis especially of simple virilizing CAH with significantly advanced bone age resulting in early pubertal development and reduced final height. In contrast salt-wasting CAH is diagnosed at an earlier stage in most cases resulting in better final height outcome in some cohorts. Nevertheless, final height outcome in patients with CAH treated with glucocorticoids is lower than the population norm and also at the lower end of genetic potential. Achievement of regular adult height is still a challenge with conventional glucocorticoid treatment in patients with CAH, which is why new hydrocortisone formulations and new treatment options for CAH are underway.

Novel circulating- and imaging-based biomarkers to enhance the mechanistic understanding of human drug-induced liver injury

Liver safety biomarkers in current clinical practice are recognized to have certain shortcomings including their representation of general cell death and thus lacking in indicating the specific underlying mechanisms of injury. An informative panel of circulating- and imaging-based biomarkers, will allow a more complete understanding of the processes involved in the complex and multi-cellular disease of drug-induced liver injury; potentially preceding and therefore enabling prediction of disease progression as well as directing appropriate, existing or novel, therapeutic strategies. Several putative liver safety biomarkers are under investigation as discussed throughout this review, informing on a multitude of hepatocellular mechanisms including: early cell death (miR-122), necrosis (HMGB1, K18), apoptosis, (K18), inflammation (HMGB1), mitochondrial damage (GLDH, mtDNA), liver dysfunction (MRI, MSOT) and regeneration (CSF1). These biomarkers also hold translational value to provide important read across between in vitro-in vivo and clinical test systems. However, gaps in our knowledge remain requiring further focussed research and the ultimate qualification of key exploratory biomarkers. Relevance for patients: this novel multi-modal approach of assessing drug-induced liver injury could potentially enable better patient stratification and enhance treatment strategies. Ultimately, this could reduce unnecessary treatment, also decreasing hospital bed occupancy, whilst ensuring early and accurate identification of patients needing intervention.

Comparing desferrioxamine and light fractionation enhancement of ALA-PpIX photodynamic therapy in skin cancer.

Background:Aminolevulinic acid (ALA)-based photodynamic therapy (PDT) provides selective uptake and conversion of ALA into protoporphyrin IX (PpIX) in actinic keratosis and squamous cell carcinoma, yet large response variations in effect are common between individuals. The aim of this study was to compare pre-treatment strategies that increase the therapeutic effect, including fractionated light delivery during PDT (fPDT) and use of iron chelator desferrioxamine (DFO), separately and combined.Methods:Optical measurements of fluorescence were used to quantify PpIX produced, and the total amount of PpIX photobleached as an implicit measure of the photodynamic dose. In addition, measurements of white light reflectance were used to quantify changes in vascular physiology throughout the PDT treatment.Results:fPDT produced both a replenishment of PpIX and vascular re-oxygenation during a 2 h dark interval between the first and second PDT light fractions. The absolute photodynamic dose was increased 57% by fPDT, DFO and their combination, as compared with PDT group (from 0.7 to 1.1). Despite that light fractionation increased oedema and scab formation during the week after treatment, no significant difference in long-term survival has been observed between treatment groups. However, outcomes stratified on the basis of measured photodynamic dose showed a significant difference in long-term survival.Conclusions:The assessment of implicit photodynamic dose was a more significant predictor of efficacy for ALA-PDT skin cancer treatments than prescription of an enhanced treatment strategy, likely because of high individual variation in response between subjects.

Discovery, Optimization, and Biological Evaluation of Sulfonamidoacetamides as an Inducer of Axon Regeneration.

Axon regeneration after injury in the central nervous system is hampered in part because if an age-dependent decline in the intrinsic axon growth potential, and one of the strategies to stimulate axon growth in injured neurons involves pharmacological manipulation of implicated signaling pathways. Here we report phenotypic cell-based screen of chemical libraries and structure-activity-guided optimization that resulted in the identification of compound 7p which promotes neurite outgrowth of cultured primary neurons derived from the hippocampus, cerebral cortex, and retina. In an animal model of optic nerve injury, compound 7p was shown to induce growth of GAP-43 positive axons, indicating that the in vitro neurite outgrowth activity of compound 7p translates into stimulation of axon regeneration in vivo. Further optimization of compound 7p and elucidation of the mechanisms by which it elicits axon regeneration in vivo will provide a rational basis for future efforts to enhance treatment strategies.

Rhythms and blues: modulation of oscillatory synchrony and the mechanism of action of antidepressant treatments.

Treatments for major depressive disorder (MDD) act at different hierarchical levels of biological complexity, ranging from the individual synapse to the brain as a whole. Theories of antidepressant medication action traditionally have focused on the level of cell-to-cell interaction and synaptic neurotransmission. However, recent evidence suggests that modulation of synchronized electrical activity in neuronal networks is a common effect of antidepressant treatments, including not only medications, but also neuromodulatory treatments such as repetitive transcranial magnetic stimulation. Synchronization of oscillatory network activity in particular frequency bands has been proposed to underlie neurodevelopmental and learning processes, and also may be important in the mechanism of action of antidepressant treatments. Here, we review current research on the relationship between neuroplasticity and oscillatory synchrony, which suggests that oscillatory synchrony may help mediate neuroplastic changes related to neurodevelopment, learning, and memory, as well as medication and neuromodulatory treatment for MDD. We hypothesize that medication and neuromodulation treatments may have related effects on the rate and pattern of neuronal firing, and that these effects underlie antidepressant efficacy. Elucidating the mechanisms through which oscillatory synchrony may be related to neuroplasticity could lead to enhanced treatment strategies for MDD.

Angiogenic inhibition in high-grade gliomas: past, present and future

High-grade gliomas, especially glioblastoma (GBM), are among the most aggressive and vascularized tumors. Angiogenesis plays a significant role in tumor growth and survival, and thus offers a target for anticancer treatment. Bevacizumab, a humanized monoclonal antibody against VEGF, was approved by the US FDA as a single agent for the treatment of recurrent glioblastoma. Significant radiographic response and progression-free survival were seen with bevacizumab treatment. However, benefits to overall survival remain undetermined. Other antiangiogenic strategies targeting VEGF, VEGF receptor (VEGFR) and other angiogenic factors have also been examined. Tumor progression after antiangiogenic treatment is inevitable, and effective salvage therapy is yet to be identified. Mechanisms of resistance to antiangiogenic therapy include activation of alternative proangiogenic pathways and increased tumor invasion. Strategies targeting these escape mechanisms are currently being investigated. The use of antiangiogenic drugs is generally well tolerated, although rare and potentially life-threatening adverse effects have been identified. With the striking antipermeability effect of anti-VEGF inhibitors, assessment of true tumor response has become a challenge. The Response Assessment in Neuro-Oncology Working Group has developed new criteria for clinical trials in patients with high-grade glioma. Identification of neuroimaging advances and biologic markers will greatly enhance treatment strategies for these patients.

Binding of huperzine A and galanthamine to acetylcholinesterase, based on ONIOM method

Binding energy calculations of huperzine A (HUP A) and galanthamine (GAL) to the binding pocket of the acetylcholinesterase enzyme (AChE) were studied. It was found that hydrogen bond formation and particular hydrogen π interactions exhibit the most significant contributions to the binding interaction of HUP A with Trp84 (W84) and Tyr130 (Y130), whereas no hydrogen bond was detected with Y130 of GAL binding. The interaction energies, calculated at the MP2 level between drugs and residues, demonstrate that the attractive interactions between GAL and residues at positions 84 and 130 were less than those for HUP A by 1.6 and 7.7 kcal·mol –1, respectively. In addition, ONIOM3 results show that the binding energies of HUP A per pocket (–28.4 kcal mol –1) are higher than for GAL per pocket (–17.0 kcal·mol –1). The detailed understanding of these interactions can be useful for the design of specific inhibitors for the AChE binding site. From the Clinical Editor The more efficient and specific inhibition of acetylcholinesterase may provide an enhanced treatment strategy in Alzheimer’s disease compared to the currently available inhibitors. This study discusses interactions of the enzyme binding site with two ligands. The results may pave the way to the development of more potent inhibitors.

Secondary prophylaxis treatment versus on‐demand treatment for patients with severe haemophilia A: comparisons of cost and outcomes in Taiwan

This study compared secondary prophylaxis treatment with on-demand treatment for severe haemophilia A in Taiwan. Fifty patients from one medical centre were evaluated over a 5-year period. Differences in annual bleed rates and factor VIII (FVIII) utilization were assessed between patients receiving secondary prophylaxis and patients receiving FVIII concentrates on-demand. Results were then used as inputs in a pharmacoeconomic model to predict outcomes of future haemophilia therapy strategies in Taiwan. The median annual number of total bleeding episodes was significantly lower in the 13 (26%) patients who received secondary prophylaxis than in the 37 patients who received FVIII on-demand (7.76 vs. 31.91, P < 0.0001). The between-group difference in median annual factor VIII utilization was statistically significant (1824.41 IU kg(-1) for the prophylaxis group and 1324.81 IU kg(-1) for the on-demand group, P < 0.01). It was estimated that approximately $2 million (USD) per year would be added to the cost of treatment by having all severe haemophilia A patients in Taiwan receive secondary prophylaxis instead of on-demand therapy while 12,566 bleeding will be prevented. It is recommended that National Health Insurance officials utilize these data to evaluate the benefits of enhanced treatment strategies and before making substantial policy changes to haemophilia care in Taiwan.

Management of Vascular Endothelial Growth Factor and Multikinase Inhibitor Side Effects

The availability of vascular endothelial growth factor and multikinase inhibitors (MKIs) has enhanced treatment strategies for patients with advanced kidney cancer. Side effects associated with the agents include dermatologic toxicities, gastrointestinal toxicities, and hematologic and metabolic abnormalities that may interfere with treatment adherence. Nurses play a key role in managing side effects associated with emerging therapies. This article presents a case study to illustrate side-effect management strategies for patients receiving MKIs for the treatment of advanced renal cell carcinoma.

Frontline Treatment in Elderly Patients With Multiple Myeloma

Melphalan-prednisone-thalidomide (MPT) and melphalan-prednisone-bortezomib (MPV) currently appear to be the treatments of choice for a large proportion of elderly multiple myeloma (MM) patients ineligible for autologous stem cell transplantation (ASCT). It seems certain that in the near future cyclophosphamide-thalidomide-dexamethasone, with an attenuated dose of dexamethasone (CTDa), and melphalan-prednisone-lenalidomide (MPR) will also be proved superior to MP, thus providing four therapeutic options in this patient group. These options could lead to more personalized treatment approaches, based on patient comorbidities, as the three novel agents have somewhat different toxicity profiles. MP would be appropriate for only a minority of patients with poor performance status and/or significant comorbidities. Questions regarding the relative efficacy of different melphalan-based regimens or melphalan-based regimens versus dexamethasone-based regimens with low-dose dexamethasone will require further trials. Additionally, the important issue of maintenance treatment needs to be investigated. These new and emerging therapies provide multiple effective treatment options for MM patients and greatly enhanced treatment strategies for clinicians, all offering promise that has been sorely lacking over the past four decades.

Bim is reversibly phosphorylated but plays a limited role in paclitaxel cytotoxicity of breast cancer cell lines

The chemotherapeutic drug, paclitaxel, induces mitotic arrest and then activates the cellular apoptotic program. Although paclitaxel has been in clinical use for over 10 years for the treatment of breast, ovarian, and lung cancer, the molecular mechanisms of paclitaxel-induced cytotoxicity are ill defined. We decided to investigate the regulatory mechanism of the pro-apoptotic BH3-only protein Bim, which is known to play a role in paclitaxel cytotoxicity. We discovered that paclitaxel induces reversible phosphorylation of Bim. Bim initially displays enhanced phosphorylation during paclitaxel-induced mitotic arrest, and then undergoes de-phosphorylation as cells become apoptotic. This dynamic phosphorylation is dependent on mitotic checkpoint signaling. However, while these results suggest that reversible phosphorylation of Bim may contribute to the transmission of a mitotic checkpoint-to-apoptosis signal, we did not observe a strong correlation between Bim protein levels and cellular sensitivity to paclitaxel. Indeed, in contrast to the well-defined role of Bim in paclitaxel-induced cell death in mouse model cells, our depletion studies demonstrate that Bim is not absolutely required for paclitaxel cytotoxicity in breast cancer cell lines. Clearly it is imperative to define the contribution of Bim in paclitaxel-induced apoptosis of clinically relevant targets in order to rationally develop enhanced treatment strategies.

Daily Tobacco Smoking in Treatment-Seeking Pathological Gamblers: Clinical Correlates and Co-occurring Psychiatric Disorders

Tobacco smoking and pathological gambling (PG) frequently co-occur. Little is known, however, about the clinical correlates and co-occurring psychiatric disorders in treatment-seeking pathological gamblers with and without daily tobacco smoking. Among a sample of 465 consecutive treatment-seeking subjects with current DSM-IV PG, those with daily tobacco smoking were compared to those without daily tobacco smoking on measures of gambling symptom severity (South Oaks Gambling Screen [SOGS] and the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling [PG-YBOCS]), types of gambling, social and legal problems, and co-occurring disorders. Two hundred and nine (44.9%) of the 465 subjects with PG reported current daily tobacco smoking. Gamblers with daily tobacco smoking as compared to those without had higher SOGS scores, had more severe PG-YBOCS behavior scores, endorsed more DSM-IV PG criteria, lost more money gambling, and were more likely to engage in non-strategic gambling, and were less likely to have a co-occurring mood disorder. Gamblers with daily tobacco smoking and a current substance use disorder reported a greater percentage of income lost to gambling during the past year. Daily tobacco smoking in PG is common and associated with multiple important clinical features including more severe gambling and financial problems. These findings suggest that pathological gamblers with daily tobacco smoking might need unique or enhanced treatment strategies.