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Decreases in total LSAS scores were significantly greater for paroxetine- compared to placebo-treated patients (53% compared with 32% generic hydrochlorothiazide 25mg without a prescription blood pressure chart hypotension, P=0 12.5 mg hydrochlorothiazide free shipping heart attack is recognized by a severe pain. A higher percentage of paroxetine-treated patients were CGI responders (defined as improvement score of 1 or 2) compared to placebo-treated patients (55% compared with 27%) purchase hydrochlorothiazide 25mg visa blood pressure numbers what do they mean. The mean reductions in Social Phobia Inventory (SPIN) results were greater in the paroxetine group but did not reach statistical significance (46% compared with 31% cheap hydrochlorothiazide 12.5 mg without a prescription heart attack facts, P=0. Three specific adverse events occurred significantly more frequently in paroxetine-treated patients: tremor (45% compared with 14%, P=0. Second-generation antidepressants 97 of 190 Final Update 5 Report Drug Effectiveness Review Project Sertraline compared with placebo Three fair RCTs compared sertraline and placebo in the treatment of patients with depression and 317-319 co-occurring alcohol dependence. A 24-week study compared sertraline (50-150 mg/d) with placebo in recently detoxified 317 alcohol-dependent patients with current depressive symptoms. Response (> 50% decrease in MADRS score) was slightly higher in sertraline- than placebo-treated patients (44% compared with 39%). Both groups experienced significant improvements in HAM-D and MADRS scores during the study, but the two groups did not differ significantly. Relapse rates were higher in sertraline- than placebo-treated patients (31. Adverse event rates were similar for both treatment groups. The overall attrition rate was greater than 40 percent; however, there was not a significant difference in withdrawal between groups (sertraline, 45% compared with placebo, 44%). In this fair study, 82 currently depressed, actively drinking alcohol-dependent subjects were randomized to sertraline (50-200 mg/d) or placebo. There was no significant difference between groups in depression symptoms. However, in women, treatment with sertraline was associated with less depression at the end of treatment than those receiving placebo based on HAM-D scores (P=0. There was no difference between groups in time to first heavy drinking day (P=0. Sertraline-treated subjects had fewer drinks per drinking day compared to placebo-treated subjects; the difference was significant (P=0. Less drinking during the study was associated with improved depression outcomes. Serious adverse events occurred in four subjects: three treated with sertraline and one treated with placebo. Loss to follow-up was twice as high in the placebo group (33%) compared to the sertraline group (16%); however, details were not reported on withdrawals due to tolerability or lack of efficacy. This study randomized 328 patients with co-occurring MDD and alcohol dependence to sertraline (50-200 mg/d) or placebo for 10 weeks. After the run-in period, two groups of patients were randomized separately based on HAM-D scores: Group A scores were > 17 while Group B scores were < 16. Mean reduction in HAM-D scores did not differ significantly between all sertraline-treated (-10. There were significant differences in HAM- D response rates by group stratification. In Group A, sertraline led to significantly higher response rate than placebo (64% compared with 47%, P=0. However, in Group B, sertraline patients had a significantly lower response rate than placebo patients (58% compared with 77%, P=0. There were no significant differences between medication groups in the reduction in BDI score from baseline to endpoint nor within Group A or Group B. No significant differences were detected between medication groups in drinking measures. Overall, the incidence of adverse events was similar between medication groups; however, significantly more sertraline-treated patients discontinued due to adverse events than placebo-treated patients (P<0. Alzheimer’s disease/dementia Two randomized trials compared sertraline and placebo for patients with depression and 320, 321 comorbid Alzheimer’s disease. More patients treated with sertraline responded to treatment (full responders, 38%; partial responders, 46%) than did patients treated with placebo (full responders, 20%; partial responders, 15%) (P<0. A second fair 12-week trial which randomized 133 patients with mild-to-moderate Alzheimer’s disease and depression to either sertraline (100mg/d) or placebo did not replicate the above findings. Mood was assessed by the modified Alzheimer Disease Cooperative Study- Clinical Global Impression of Change index and the CSDD. At the end of week 12, CSDD scores and remission rates did not differ between sertraline and placebo (OR 2. Treatment with sertraline, however, was associated with more adverse events, specifically gastrointestinal adverse events than with placebo. Serious adverse events occurred in 321 20 percent of patients in the sertraline group compared with 11 percent in the placebo group. Arthritis Our searches yielded only one trial that evaluated the efficacy of an antidepressants in depressed 322 patients with comorbid arthritis. This study is a subgroup analysis of a larger placebo- 323 controlled trial in elderly patients randomized to duloxetine (60 mg/d) or placebo. The subgroup analysis analyzed 233 subjects with MDD and co-occurring arthritis, diabetes and/or vascular disease; 55 percent of patients had diabetes. There were no statistically significant treatment-by-comorbidity interactions for any comorbidity (P < 0. Results must be interpreted with caution as this was the only study addressing this topic. Cancer Fluoxetine compared with placebo 324 We detected only one trial that studied the efficacy of fluoxetine in cancer patients; however, this placebo-controlled trial failed to meet our inclusion criteria because the duration of the study was less than 6 weeks. We mention it here because it was the only trial on this topic. This 5- week trial studied the efficacy of fluoxetine in 91 cancer patients with depression or adjustment disorder. The majority of the patients were female; 13 percent in the fluoxetine group and 5 percent in the placebo group had metastatic disease. Efficacy according to the main, observer-rated outcome measures (HADS, MADRS, HAS) did not differ significantly between the active drug and placebo groups. Improvements were generally greater in the fluoxetine group but statistically significant only for the SCL90-R (33% compared with 15%; P=0. No statistically significant difference in quality of life was reported. However, study duration was short and a substantially greater percentage of patients in the fluoxetine group had a more advanced stage of cancer at baseline. Fluoxetine-treated patients had a significantly greater drop-out rate than placebo-treated patients (33% compared with 15%; P=0. Paroxetine compared with placebo A 6-week randomized trial compared paroxetine (20 mg/d) and placebo in depressed breast cancer patients who were receiving at least four cycles of chemotherapy to evaluate whether the 325 use of an antidepressant can alleviate symptoms of depression and reduce fatigue. Although Second-generation antidepressants 99 of 190 Final Update 5 Report Drug Effectiveness Review Project this study was rated poor because of lack of ITT analysis and inadequate description of study duration, we included it because it was the only study conducted in cancer patients that satisfied our inclusion criteria. Paroxetine was more effective in reducing depression during chemotherapy, as measured by the Center for Epidemiological Studies of Depression (CES-D) (P=0. No differences between treatment groups were apparent with respect to fatigue. Diabetes Our searches yielded two trials that evaluated the efficacy of an antidepressants in depressed 322, 326 patients with comorbid diabetes. One fair-rated study randomized 89 depressed, low- income Hispanics and African Americans with diabetes to sertraline (50-100 mg/day) or placebo 326 for 6 months. HAM-D scores decreased significantly in both groups but there was no significant difference between sertraline-treated and placebo-treated patients.

Overall generic 25 mg hydrochlorothiazide visa arrhythmia heart disease, relapse and therefore are receiving intensified therapy 25mg hydrochlorothiazide fast delivery arteria gastroduodenalis. Over the past decade buy hydrochlorothiazide 25mg pulse pressure 42, many different subtypes of childhood ALL have been identified through molecular biology techniques 12.5mg hydrochlorothiazide visa arteria coronaria dextra. These subtypes bear several features, such as iAMP21, CRLF2 rearrange- Identification of new genomic alterations with ments, IKZF1 alteration, JAK1/2 mutations, BCR-ABL1-like signa- potential prognostic relevance ture, and early T-cell precursor (ETP), which are associated with Ikaros (IKZF1) and B-cell development gene deletions poorer outcome and therefore have been given particular attention. Furthermore, their independent value with respect development, including PAX5, EBF1, and IKZF1. Among them, to MRD as measured currently in the AIEOP-BFM ALL2009 study IKZF1 deletions are frequently associated with the BCR-ABL1 (PCR FCM) remains difficult to be defined considering fusion gene (70%-80% of BCR-ABL1–positive ALL),17,18 whereas that also treatment is different from the previous AIEOP-BFM in BCR-ABL1–negative ALL they occur at lower frequency (10%- ALL2000 study. Estimated frequency of specific genotypes in childhood ALL. In green are the genetic lesions associated with BCP-ALL, in blue are lesions associated with T-ALL. Darker green or blue colors indicate subtypes associated with poor prognosis. The sum of percentages does not take into account the possible coexistence of different lesions. Although the IKZF1 alteration itself is an indepen- include activating mutations in JAK1, JAK2,orSH2B3 or activating dent prognostic factor of the hazard of relapse in childhood mutations of either the CRLF2 or IL7RA chains of TSLP receptor BCR-ABL1–negative ALL, its impact is largely reduced when MRD itself (for review, see Izraeli et al;14 Palmi et al;12 Roberts et al26). In contrast, Kuiper et al24 have shown that patients, currently stratified as MRD medium risk, could be integration of both MRD and IKZF1 can provide a stronger considered for treatment intensification, their outcome and overall prognostic value than each of the established risk factors alone, survival did not prompt clinicians to allocate them to the high-risk allowing prediction of 79% of all the relapses with a 93% category. It is highly likely that over the next few years, the specificity. Based on this study, the current Dutch Childhood relevance of aberrant JAK-STAT signaling for risk stratification Oncology Group (DCOG) clinical protocol requires a longer will be clarified. To date, this is the first example of the integrated use of genomics and MRD data (R. Alterations of the TP53 gene Interestingly, in high-risk relapse patients, deletion of IKZF1 is Copy number and sequence alterations of TP53 were observed in strongly predictive of a second relapse after SCT and therefore 12. Furthermore, multivariate analysis identified CRLF2-JAK-STAT signaling IKZF1 deletion and TP53 alteration as independent predictors of 14 inferior outcome. A high frequency of negative childhood and adult ALL and in approximately 60% of TP53 alterations can occur in both pediatric and adult low- children with Down syndrome ALL. Although of either chromosomal translocations of CRLF2 into the IGH locus or limited clinical relevance due to the very low incidence, a signifi- from deletions at the pseudo-autosomal region of chromosomes X cant proportion of the TP53 mutations identified in pediatric and Y fusing the coding region of CRLF2 with the first exon of the low-hypodiploid ALL were present as heterozygous mutations in constitutively expressed P2RY8 gene. CRLF2 is normally associ- remission BM or peripheral blood and in purified normal T-cell ated with the IL7 receptor alpha (IL7Ra) to form the heterodimeric populations, suggesting that in these cases, TP53 mutations are receptor of the inflammatory cytokine TSLP. Aberrant expression of inherited as Li-Fraumeni syndrome and that low hypodiploidy could CRLF2 in B-cell precursor (BCP)–ALL is associated with addi- be a manifestation of this disease. The first is whether these genotypes can be used to ferase domain. Functionally, the mutations impaired histone acetyla- improve patient stratification. For example, in a frontline protocol tion and transcriptional regulation of CREBBP targets, including stratified into 3 groups (low, intermediate, and high risk), adding a glucocorticoid-responsive genes. Therefore, this finding raises the new stratification factor would be worthwhile only if this increased possibility of using epigenetic treatment (eg, DNA methyltrans- the separation between risk groups while decreasing the within- ferase and histone deacetylase inhibitors) in these BCP-ALL group heterogeneity in terms of outcome. This evaluation should also be performed to avoid ABL1 like”) was reported by 2 independent studies. This unnecessary complexity in the stratification system, which is subgroup was associated with a significantly inferior prognosis in relevant for trial design, feasibility, and generalizability of the independent clinical protocols. Whether it may actually and molecular biology in determining specific treatment modalities. Among could provide the rationale for the creation of a new separate genetic abnormalities identified in BCR-ABL1–like cases, EBF1- subgroup of patients. This would then lead to a redefinition of the PDGFRB or NUP214-ABL1 fusion responded to ABL1 tyrosine specific treatment protocol for this subgroup regardless of how kinase inhibitors (which also inhibit PDGFRB) and BCR-JAK2 or 26 rare it might be. Refining treatment stratification and defining subgroups for targeted ETP-ALL treatments are just the tip of the iceberg of a more complex reality A stem cell-like gene expression signature was identified in 12% of we have to face in study design. We know that patient stratification T-ALL cases treated in 3 consecutive clinical trials at St. Jude’s is also influenced by available treatment options and that the Hospital and validated in an AIEOP series. Altogether, the progress in genetics and of CD1a and CD8 expression and weak CD5 expression, with biology (and biotechnology) that drives the “personalized” treat- expression of stem cell and/or myeloid markers. The risk of relapse ment approach makes it more and more difficult to gain sufficient in this subgroup was 72% compared with 19% of the other T-ALL evidence regarding new treatments unless these are markedly patients. Because ETP T-ALL can be easily diagnosed by FCM, it is superior to those used routinely. With this latter exception, when likely to be translated into clinical practice. An example is the subpopulation of children with ALL Ongoing pharmacogenomics studies hold great promise to yield who, after the induction and consolidation phases, still show genetic polymorphisms that could be used to individualize the persistence of the disease either at the molecular or morphological dosages of antileukemic agents. This high-risk subpopulation is small and has a dismal clinical effect refers to mercaptopurine and the genetic polymor- prognosis after transplantation. For all of these reasons, this phism status of the thiopurine methyltransferase (TPMT) gene. For example, these patients may be eligible preemptive testing for thiopurine methyltransferase status will for phase 2 or 3 studies, which would include novel drugs that have likely decrease the risk of mercaptopurine-induced toxicities associ- already gone through early phases of clinical development in adults. This, in turn, might reduce An example of a rare subpopulation specifically identified in the likelihood of acute myelosuppression (without compromising relationship with a targeted therapy is that of Ph ALL patients, disease control) and the risk for the development of mercaptopurine- accounting for only 3% of the ALL population. However, the increased risk of developing hepatic venoocclusive disease. It is sample size needed in the framework of a traditional study is possible that, in the near future, genetic guidance might ensure a difficult to achieve in a reasonable time frame considering that 616 American Society of Hematology high-risk leukemias often represent a small subset and that, in controlled trials should only be considered when completely general, lymphoblastic leukemia is not regarded as a common unavoidable and justified. For this reason, mainly in childhood leukemia, many countries have developed national study groups that design and run A final consideration is concerning the clinical use of MRD multicenter clinical trials. In addition to that, they have developed assessment. Although we can assume that MRD provides relevant international collaborations to address therapeutic questions in trials additional information on the activity of new drugs because it for rare subgroups, including Ph ALL. Formal validation of a surrogate end point is that is sufficient for driving changes in treatment practice. Further- usually carried out by performing a meta-analysis of all of the more, it should be taken into account that relatively large trials are randomized trials in which a new drug (or a class of drugs) was also needed to optimize treatment modalities by aiming at modest studied, with the aim of assessing whether the treatment effects on differences that nonetheless are clinically important for outcome MRD are strongly related to the treatment effects on the clinical improvement (efficacy), together with a more efficient definition of benefit end point. This would be necessary before using MRD as a therapeutic strategies that use existing chemotherapeutic agents. These studies are generally powered to detect less than 10% Conclusions absolute increase (or difference) in EFS in a subpopulation of The remarkable advances in the treatment of childhood ALL have patients, usually of relevant size, who have a relatively good become a paradigm of success in modern oncology. In childhood ALL, these studies typically address the still have to deal with a treatment failure rate of 10%-15% and the so-called intermediate-risk patients, accounting for approximately need to minimize long-term health complications in a large popula- 50% of the ALL population, who have a 4-year EFS of 70% to 80%. To face these challenges and to keep These studies may ask a randomized question on intensification or making progress against childhood ALL, we need new drugs and inclusion of new formulations of existing drugs such as, for transnational collaborations across large and well-characterized example, pegylated L-asparaginase instead of the native product. Treatment optimization may also be achieved by testing strategies that are at least as efficacious as those currently used, but carry a Acknowledgments lower burden of toxicity and complications. Typically, this gener- This work was supported by the Associazione Italiana Ricerca sul ates studies of noninferiority targeted to subpopulations of patients Cancro (IG-8666 to A. We thank Maria EFS, for whom the attempt is to de-intensify certain therapy Grazia Valsecchi and Valentino Conter for conceiving, writing, and elements with known short- or long-term side effects without revising the manuscript. In addition, in these 2 settings, international cooperation is needed in addition to innovative ap- proaches of study design and conduct. Tettamanti progressive availability of new targeted therapy will make the ONLUS.

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