Dosimetry of 90Y-ibritumomab tiuxetan as consolidation of first remission in advanced-stage follicular lymphoma: results from the international phase 3 first-line indolent trial.

The objective of this analysis was to assess the radiation exposure associated with (90)Y-ibritumomab tiuxetan when used as consolidation therapy in adults with low or minimal tumor burden after first-line therapy of advanced follicular lymphoma (FL). METHODS: The patients who were enrolled in the phase 3 first-line indolent trial were 18 y or older, with CD20(+) grade 1 or 2 stage III or IV FL, and a partial response, complete response, or unconfirmed complete response to first-line chemotherapy. The patients were allocated randomly to receive a single infusion of unlabeled rituximab 250 mg/m(2) on day -7 and consolidation on day 0 with a single dose of (90)Y-ibritumomab tiuxetan, 14.8 MBq/kg, immediately after unlabeled rituximab, 250 mg/m(2), or no further treatment. On day -7, a subset of patients received an injection of 185 MBq of (111)In-ibritumomab tiuxetan immediately after unlabeled rituximab, 250 mg/m(2), for central dosimetry analysis. Correlations were assessed between organ radiation absorbed dose and toxicity, body weight, body mass index, and progression-free survival. RESULTS: Central dosimetry evaluations were available from 57 of 70 patients. Median radiation absorbed doses were 100 cGy (range, 28-327 cGy) for the red marrow and 72 cGy (range, 46-106 cGy) for the whole body. Radiation absorbed doses did not differ significantly between patients who had a partial response or complete response to initial therapy. Progression-free survival correlated significantly with the whole-body (r = 0.4401; P = 0.0006) and bone marrow (r = 0.2976; P = 0.0246) radiation dose. Body weight was significantly negatively correlated with whole-body radiation dose (r = -0.4971; P < 0.0001). Neither the whole-body radiation dose nor the bone marrow radiation dose correlated with hematologic toxicity. CONCLUSION: In patients with low or minimal residual tumor burden after first-line chemotherapy of advanced FL, whole-body and bone marrow exposure after (90)Y-ibritumomab tiuxetan consolidation showed a significant positive correlation with progression-free survival, whereas dosimetric data could not predict hematologic toxicity.

ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment.

BACKGROUND AND OBJECTIVE: The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment. METHODS: Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. RESULTS: The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. CONCLUSION: In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.

Prevalence, awareness and treatment of type 2 diabetes mellitus in Switzerland: the CoLaus study.

ABSTRACT: Aims To assess the prevalence, awareness and treatment levels of Type 2 diabetes in a Swiss city. Methods Population-based cross-sectional study of 6181 subjects (3246 women) aged 35-75 years living in Lausanne, Switzerland. Type 2 diabetes was defined as fasting plasma glucose >/= 7 mmol/l and/or oral hypoglycaemic treatment and/or insulin. Results Total prevalence of Type 2 diabetes was 6.3% (95% confidence interval: 5.7-7.0%), higher in men (9.1%) than in women (3.8%, P < 0.001) and increased with age. Two-thirds (65.3%; 60.4-70.0%) of participants with Type 2 diabetes were aware of their status and among those aware 86.0% (81.5-90.3%) were treated. Treatment was more frequent in men (91.3%) than in women (75.9%, P < 0.001). Two-thirds of those treated for Type 2 diabetes were on monotherapy. Biguanides were prescribed in 65.0% of Type 2 diabetes patients and represented 48% of all antidiabetic drugs. Multivariable analysis showed male gender, increasing age, waist or BMI to be positively associated with prevalence of Type 2 diabetes, while leisure-time physical activity and alcohol consumption were negatively associated. Among participants presenting with Type 2 diabetes, increasing age was positively associated with awareness of Type 2 diabetes. Among subjects diagnosed with Type 2 diabetes, male gender and increasing age were positively associated with treatment. Conclusion Prevalence of Type 2 diabetes in Switzerland is estimated to be between 5.7% and 7.0%. Two-thirds of patients with Type 2 diabetes are aware of their status, and over three quarters of those aware are treated.

Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment.

BACKGROUND AND OBJECTIVE: Recent in vitro studies have suggested an important role of cytochrome P450 (CYP) 2B6 and CYP2C19 in methadone metabolism. We aimed to determine the influence of CYP2B6, CYP2C9, and CYP2C19 genetic polymorphism on methadone pharmacokinetics and on the response to treatment. METHODS: We included 209 patients in methadone maintenance treatment on the basis of their response to treatment and their daily methadone dose. Patients were genotyped for CYP2B6, CYP2C9, and CYP2C19. Steady-state trough and peak (R)-, (S)-, and (R,S)-plasma levels and peak-to-trough plasma level ratios were measured. RESULTS: CYP2B6 genotype influences (S)-methadone and, to a lesser extent, (R)-methadone plasma levels, with the median trough (S)-methadone plasma levels being 105, 122, and 209 ng . kg/mL . mg for the noncarriers of allele *6, heterozygous carriers, and homozygous carriers (*6/*6), respectively (P = .0004). CYP2C9 and CYP2C19 genotypes do not influence methadone plasma levels. Lower peak and trough plasma levels of methadone and higher peak-to-trough ratios were measured in patients considered as nonresponders [median (R,S)-methadone trough plasma levels of 183 and 249 ng . kg/mL . mg (P = .0004) and median peak-to-trough ratios of 1.82 and 1.58 for high-dose nonresponders and high-dose responders, respectively (P = .0003)]. CONCLUSION: Although CYP2B6 influences (S)-methadone plasma levels, given that only (R)-methadone contributes to the opioid effect of this drug, a major influence of CYP2B6 genotype on response to treatment is unlikely and has not been shown in this study. Lower plasma levels of methadone in nonresponders, suggesting a higher clearance, and higher peak-to-trough ratios, suggesting a shorter elimination half-life, are in agreement with the usual clinical measures taken for such patients, which are to increase methadone dosages and to split the daily dose into several intakes.

Preemptive treatment approach to cytomegalovirus (CMV) infection in solid organ transplant patients: relationship between compliance with the guidelines and prevention of CMV morbidity.

Cytomegalovirus (CMV) remains a major cause of morbidity in solid organ transplant patients. In order to reduce CMV morbidity, we designed a program of routine virological monitoring that included throat and urine CMV shell vial culture, along with peripheral blood leukocyte (PBL) shell vial quantitative culture for 12 weeks post-transplantation, as well as 8 weeks after treatment for acute rejection. The program also included preemptive ganciclovir treatment for those patients with the highest risk of developing CMV disease, i.e., with either high-level viremia (>10 infectious units [IU]/106 PBL) or low-level viremia (<10 IU/106 PBL) and either D+/R- CMV serostatus or treatment for graft rejection. During 1995-96, 90 solid organ transplant recipients (39 kidneys, 28 livers, and 23 hearts) were followed up. A total of 60 CMV infection episodes occurred in 45 patients. Seventeen episodes were symptomatic. Of 26 episodes managed according to the program, only 4 presented with CMV disease and none died. No patient treated preemptively for asymptomatic infection developed disease. In contrast, among 21 episodes managed in non-compliance with the program (i.e., the monitoring was not performed or preemptive treatment was not initiated despite a high risk of developing CMV disease), 12 episodes turned into symptomatic infection (P=0.0048 compared to patients treated preemptively), and 2 deaths possibly related to CMV were recorded. This difference could not be explained by an increased proportion of D+/R- patients or an increased incidence of rejection among patients with episodes treated in non-compliance with the program. Our data identify compliance with guidelines as an important factor in effectively reducing CMV morbidity through preemptive treatment, and suggest that the complexity of the preemptive approach may represent an important obstacle to the successful prevention of CMV morbidity by this approach in the regular healthcare setting.

Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial.

BACKGROUND: The outcome of diffuse large B-cell lymphoma has been substantially improved by the addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy regimens. We aimed to assess, in patients aged 18-59 years, the potential survival benefit provided by a dose-intensive immunochemotherapy regimen plus rituximab compared with standard treatment plus rituximab. METHODS: We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18-59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00140595. FINDINGS: One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75-86) in the R-ACVBP group and 67% (59-73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38-0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81-91] vs 73% [66-79]; HR 0·48 [0·30-0·76]; p=0·0015) and overall survival (92% [87-95] vs 84% [77-89]; HR 0·44 [0·28-0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3-4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183]). INTERPRETATION: Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18-59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable. FUNDING: Groupe d'Etudes des Lymphomes de l'Adulte and Amgen.

Long-term antiretroviral treatment initiated at primary HIV-1 infection affects the size, composition, and decay kinetics of the reservoir of HIV-1-infected CD4 T cells.

Initiation of antiretroviral therapy during the earliest stages of HIV-1 infection may limit the seeding of a long-lasting viral reservoir, but long-term effects of early antiretroviral treatment initiation remain unknown. Here, we analyzed immunological and virological characteristics of nine patients who started antiretroviral therapy at primary HIV-1 infection and remained on suppressive treatment for >10 years; patients with similar treatment duration but initiation of suppressive therapy during chronic HIV-1 infection served as controls. We observed that independently of the timing of treatment initiation, HIV-1 DNA in CD4 T cells decayed primarily during the initial 3 to 4 years of treatment. However, in patients who started antiretroviral therapy in early infection, this decay occurred faster and was more pronounced, leading to substantially lower levels of cell-associated HIV-1 DNA after long-term treatment. Despite this smaller size, the viral CD4 T cell reservoir in persons with early treatment initiation consisted more dominantly of the long-lasting central-memory and T memory stem cells. HIV-1-specific T cell responses remained continuously detectable during antiretroviral therapy, independently of the timing of treatment initiation. Together, these data suggest that early HIV-1 treatment initiation, even when continued for >10 years, is unlikely to lead to viral eradication, but the presence of low viral reservoirs and durable HIV-1 T cell responses may make such patients good candidates for future interventional studies aiming at HIV-1 eradication and cure. IMPORTANCE: Antiretroviral therapy can effectively suppress HIV-1 replication to undetectable levels; however, HIV-1 can persist despite treatment, and viral replication rapidly rebounds when treatment is discontinued. This is mainly due to the presence of latently infected CD4 T cells, which are not susceptible to antiretroviral drugs. Starting treatment in the earliest stages of HIV-1 infection can limit the number of these latently infected cells, raising the possibility that these viral reservoirs are naturally eliminated if suppressive antiretroviral treatment is continued for extremely long periods of time. Here, we analyzed nine patients who started on antiretroviral therapy within the earliest weeks of the disease and continued treatment for more than 10 years. Our data show that early treatment accelerated the decay of infected CD4 T cells and led to very low residual levels of detectable HIV-1 after long-term therapy, levels that were otherwise detectable in patients who are able to maintain a spontaneous, drug-free control of HIV-1 replication. Thus, long-term antiretroviral treatment started during early infection cannot eliminate HIV-1, but the reduced reservoirs of HIV-1 infected cells in such patients may increase their chances to respond to clinical interventions aiming at inducing a drug-free remission of HIV-1 infection.

Normative Topographic ERP Analyses of Speed of Speech Processing and Grammar Before and After Grammatical Treatment.

Typically developing (TD) preschoolers and age-matched preschoolers with specific language impairment (SLI) received event-related potentials (ERPs) to four monosyllabic speech sounds prior to treatment and, in the SLI group, after 6 months of grammatical treatment. Before treatment, the TD group processed speech sounds faster than the SLI group. The SLI group increased the speed of their speech processing after treatment. Posttreatment speed of speech processing predicted later impairment in comprehending phrase elaboration in the SLI group. During the treatment phase, change in speed of speech processing predicted growth rate of grammar in the SLI group.

Transsexualisme: enjeux et spécificités liés à la prise en charge d'une demande de réassignation sexuelle [Gender identity disorder: challenges and specificity in the treatment of requests for sexual reassignment].

Gender identity disorder is defined as a permanent desire to relieve one's own sexual features to acquire the sexual features and line to life of the opposite sex. The diagnosis is based on the psychiatric evaluation and treatment on an interdisciplinary approach by endocrinologists, surgeons and psychiatrists, and can be conceptualized into distinct phases: diagnostic evaluation, real life experience, hormonal treatment and surgery. Multiples challenges have to be faced, especially by the psychiatrist who follows the patient during the whole process.

Coping with an HIV infection. A multicenter qualitative survey on HIV positive adolescents' perceptions of their disease, therapeutic adherence and treatment.

HIV-positive adolescents face a number of challenges in dealing with their disease and its treatment. In this qualitative study, twenty-nine HIV-positive adolescents aged 13 to 20 years (22 girls), who live in Switzerland, were asked, in a semi-structured interview (duration of 40-110 minutes), to describe their perceptions and experiences with the disease itself and with therapeutic adherence. While younger adolescents most often thought of their disease as fate, older adolescents usually knew that they had received it through vertical transmission, although the topic appeared to be particularly difficult to discuss for those living with their HIV-positive mothers. Based on their attending physician's assessment, 18 subjects were judged highly adherent, 4 fairly and 7 poorly adherent. High adherence appeared linked with adequate psychological adjustment and effective coping mechanisms, as well as with the discussion and adoption of explicit medication-taking strategies. The setting and organisation of health care teams should allow for ongoing discussions with HIV-positive adolescents that focus on their perceptions of their disease, how they cope with it and with the treatment, and how they could improve their adherence.

Neuropeptide Y and corticotropin-releasing hormone in CSF mark response to antidepressive treatment with citalopram.

Neuropeptides appear to play a role in the pathophysiology of depression and electroconvulsive treatment and lithium affect these compounds in human cerebrospinal fluid (CSF) and rodent brain. Consequently, we investigated whether long-term treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram (Cit) would also affect neuropeptides in CSF of depressed patients. Changes in CSF monoamine metabolites were also explored. CSF concentrations of corticotropin-releasing hormone (CRH)-like immunoreactivity (-LI), neuropeptide Y (NPY)-LI, and Cit were determined in 21 patients with major depression. Lumbar puncture was performed in the morning at baseline and was repeated after at least 4 wk of Cit treatment (40 mg/d). The severity of depression was assessed by the Hamilton Rating Scale for Depression (HAMD). Cit treatment was associated with a significant increase in NPY-LI and decrease in CRH-LI. An evaluation of the relationship between changes in concentrations of NPY-LI, CRH-LI, and the clinical response showed significant correlations between these parameters. Significant NPY and CRH changes in CSF following treatment as well as correlations to changes in HAMD support the hypothesis that these two peptides play a role in affective disorders and are markers of therapeutic response.

The potential impact of new effervescent alendronate formulation on compliance and persistence in osteoporosis treatment.

Osteoporotic fractures are a public health problem and their incidence and subsequent economic and social costs are expected to rise in the next future. Different drugs have been developed to reduce osteoporosis and the risk of osteoporotic fractures, and among them, antiresorptive agents, and in particular oral alendronate, are the most widely utilized. However, one of the most common problems with antiresorptive drugs is poor adherence to treatment, which is associated with a high fracture incidence and with an increase in hospitalization costs. One of the main reasons of poor adherence to these treatments is the occurrence of adverse events, mainly at gastrointestinal (GI) level, including dyspepsia, dysphagia, and esophageal ulcers. In light of these considerations the aim of this paper is to perform a literature review to show the pathophysiologic bases of GI alendronate-induced adverse events and how new bisphosphonate formulations like effervescent alendronate can improve compliance and persistence to treatment and decrease the fracture rate incidence in osteoporotic patients.

Gaining momentum: New options and opportunities for the treatment of advanced melanoma.

Before 2011, patients with advanced or metastatic melanoma had a particularly poor long-term prognosis. Since traditional treatments failed to confer a survival benefit, patients were preferentially entered into clinical trials of investigational agents. A greater understanding of the epidemiology and biology of disease has underpinned the development of newer therapies, including six agents that have been approved in the EU, US and/or Japan: a cytotoxic T-lymphocyte antigen-4 inhibitor (ipilimumab), two programmed cell death-1 receptor inhibitors (nivolumab and pembrolizumab), two BRAF inhibitors (vemurafenib and dabrafenib) and a MEK inhibitor (trametinib). The availability of these treatments has greatly improved the outlook for patients with advanced melanoma; however, a major consideration for physicians is now to determine how best to integrate these agents into clinical practice. Therapeutic decisions are complicated by the need to consider patient and disease characteristics, and individual treatment goals, alongside the different efficacy and safety profiles of agents with varying mechanisms of action. Long-term survival, an outcome largely out of reach with traditional systemic therapies, is now a realistic goal, creating the additional need to re-establish how clinical benefit is evaluated. In this review we summarise the current treatment landscape in advanced melanoma and discuss the promise of agents still in development. We also speculate on the future of melanoma treatment and discuss how combination and sequencing approaches may be used to optimise patient care in the future.

Epidemiology and outcome of fungemia in a cancer Cohort of the Infectious Diseases Group (IDG) of the European Organization for Research and Treatment of Cancer (EORTC 65031).

BACKGROUND: Anti-cancer treatment and the cancer population have evolved since the last European Organisation for Research and Treatment of Cancer (EORTC) fungemia survey, and there are few recent large epidemiological studies. METHODS: This was a prospective cohort study including 145 030 admissions of patients with cancer from 13 EORTC centers. Incidence, clinical characteristics, and outcome of fungemia were analyzed. RESULTS: Fungemia occurred in 333 (0.23%; 95% confidence interval [CI], .21-.26) patients, ranging from 0.15% in patients with solid tumors to 1.55% in hematopoietic stem cell transplantation recipients. In 297 evaluable patients age ranged from 17 to 88 years (median 56 years), 144 (48%) patients were female, 165 (56%) had solid tumors, and 140 (47%) had hematological malignancies. Fungemia including polymicrobial infection was due to: Candida spp. in 267 (90%), C. albicans in 128 (48%), and other Candida spp. in 145 (54%) patients. Favorable overall response was achieved in 113 (46.5%) patients by week 2. After 4 weeks, the survival rate was 64% (95% CI, 59%-70%) and was not significantly different between Candida spp. Multivariable logistic regression identified baseline septic shock (odds ratio [OR] 3.04, 95% CI, 1.22-7.58) and tachypnoea as poor prognostic factors (OR 2.95, 95% CI, 1.66-5.24), while antifungal prophylaxis prior to fungemia (OR 0.20, 95% CI, .06-.62) and remission of underlying cancer (OR, 0.18; 95% CI, .06-.50) were protective. CONCLUSIONS: Fungemia, mostly due to Candida spp., was rare in cancer patients from EORTC centers but was associated with substantial mortality. Antifungal prophylaxis and remission of cancer predicted better survival.

Present standards and future perspectives in the treatment of metastatic non-small cell lung cancer.

The development of novel effective immunotherapeutic agents and early clinical data hinting at significant activity in non-small cell lung cancer (NSCLC) has introduced yet another player in the field of management of advanced disease. At present, first-line cytotoxic chemotherapy is generally withheld pending results of molecular testing for any actionable genetic alteration that could lead to targeted treatment, and in their absence chemotherapy is prescribed as a default therapy. Phase III trials comparing head-to-head immune checkpoint inhibitors with standard platinum-based doublet chemotherapy are underway. Second-line chemotherapy is likewise being challenged in phase III trials, one of which having recently reported positive results in advanced squamous cell carcinoma. In tumors harboring actionable transforming genetic alterations such as EGFR mutations and ALK rearrangements, second- and third-generation inhibitors allow for multiple lines of targeted treatment beyond initial resistance, postponing the use of cytotoxic chemotherapy to very late lines of therapy. Chemotherapy as a longstanding but still present standard of care capable of prolonging survival, improving quality of life, and relieving symptoms sees its role increasingly restricted to clinical, immunological, and molecular subsets of patients where its activity and efficacy have never been tested prospectively.