Phase I study of emactuzumab single agent or in combination with paclitaxel in patients with advanced/metastatic solid tumors reveals depletion of immunosuppressive M2-like macrophages.

BACKGROUND: Emactuzumab is a monoclonal antibody against the colony-stimulating factor-1 receptor and targets tumor-associated macrophages (TAMs). This study assessed the safety, clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD) of emactuzumab, as monotherapy and in combination with paclitaxel, in patients with advanced solid tumors. PATIENTS AND METHODS: This open-label, phase Ia/b study comprised two parts (dose escalation and dose expansion), each containing two arms (emactuzumab, every 2 or 3 weeks, as monotherapy or in combination with paclitaxel 80 mg/m2 weekly). The dose-escalation part explored the maximum tolerated dose and optimal biological dose (OBD). The dose-expansion part extended the safety assessment and investigated the objective response rate. A PK/PD analysis of serial blood, skin and tumor biopsies was used to explore proof of mechanism and confirm the OBD. RESULTS: No maximum tolerated dose was reached in either study arm, and the safety profile of emactuzumab alone and in combination does not appear to preclude its use. No patients receiving emactuzumab monotherapy showed an objective response; the objective response rate for emactuzumab in combination with paclitaxel was 7% across all doses. Skin macrophages rather than peripheral blood monocytes or circulating colony-stimulating factor-1 were identified as an optimal surrogate PD marker to select the OBD. Emactuzumab treatment alone and in combination with paclitaxel resulted in a plateau of immunosuppressive TAM reduction at the OBD of 1000 mg administered every 2 weeks. CONCLUSIONS: Emactuzumab showed specific reduction of immunosuppressive TAMs at the OBD in both treatment arms but did not result in clinically relevant antitumor activity alone or in combination with paclitaxel. (ClinicalTrials.gov Identifier: NCT01494688).

Sequential research-related biopsies in phase I trials: acceptance, feasibility and safety.

BACKGROUND: Sequential tumour biopsies are of potential interest for the rational development of molecular targeted therapies. PATIENTS AND METHODS: From June 2004 to July 2009, 186 patients participated in 14 phase I clinical trials in which sequential tumour biopsies (13 trials) and/or sequential normal skin biopsies (6 trials) were optional. All patients had to sign an independent informed consent for the biopsies. RESULTS: Tumour biopsies were proposed to 155 patients and 130 (84%) signed the consent while normal skin biopsies were proposed to 70 patients and 57 (81%) signed the consent. Tumour biopsies could not be carried out in 41 (31%) of the 130 consenting patients. Tumour biopsies were collected at baseline in 33 patients, at baseline and under treatment in 56 patients. Tumour biopsies were obtained using an 18-gauge needle, under ultrasound or computed tomography guidance. Only nine minor complications were recorded. Most tumour biopsy samples collected were intended for ancillary molecular studies including protein or gene expression analysis, comparative genomic hybridization array or DNA sequencing. According to the results available, 70% of the biopsy samples met the quality criteria of each study and were suitable for ancillary studies. CONCLUSIONS: In our experience, the majority of the patients accepted skin biopsies as well as tumour biopsies. Sequential tumour and skin biopsies are feasible and safe during early-phase clinical trials, even when patients are exposed to anti-angiogenic agents. The real scientific value of such biopsies for dose selection in phase I trials has yet to be established.

A prospective registry of European haemophilia B patients receiving nonacog alfa, recombinant human factor IX, for usual use.

Nonacog alfa, a recombinant factor IX (FIX) used for the treatment of haemophilia B, was approved in Europe in 1998. In accordance with European Medicines Agency requirements, a registry study was conducted from 2002 to 2009. A reformulated iso-osmotic version was approved for European use in 2007. This study was conducted to evaluate the safety of nonacog alfa in a usual care setting, and provide clinical trial and postmarketing surveillance data support. This open-label, non-interventional, prospective observational cohort study (registry) comprised 52 sites in nine European countries. Patients with haemophilia B receiving nonacog alfa in either formulation for prevention or treatment were followed on a usual care schedule. A total of 218 patients were enrolled, of whom 66 (30.3%) were <18 years of age. Haemophilia severity was evenly distributed, with baseline FIX activity of <1%, 1-5% and >5% in 33.3%, 36.6% and 30.1% of patients, respectively. One hundred thirty-eight patients received the original formulation alone; 80 switched to or received only the new formulation. There was a low incidence of events of special interest (ESIs), with less-than-expected therapeutic effect in five patients (2.2%), inhibitor development in two (0.9%), thrombosis in one (0.5%) and allergic events in eight (3.7%). These accounted for the majority of the 15 serious AEs reported in six patients. Six patients discontinued because of AEs, primarily related to hypersensitivity. Nonacog alfa was shown to be safe for the treatment of haemophilia B, with a low incidence of serious AEs and ESIs.

Estrogen replacement in perimenopause-related depression: a preliminary report.

OBJECTIVES: We examined the efficacy of estrogen in the treatment of depression in perimenopausal women with and without hot flushes. STUDY DESIGN: Women with perimenopause-related depression were randomized in a double-blind parallel design to receive either 17beta-estradiol or placebo for 3 weeks. Subsequently, women receiving estradiol during the first 3 weeks continued receiving estradiol for an additional 3 weeks, whereas women who had received placebo crossed over to estradiol for 3 weeks. Outcome measures included standardized mood rating scales and a visual analog scale self-report instrument. RESULTS: Of 34 female subjects, 16 received estradiol first and 18 received placebo first. After 3 weeks of estradiol, standardized mood rating scale scores and visual analog scale symptom scores (eg, sadness, anhedonia, and social isolation) were significantly decreased compared with baseline scores (P <.01) and were significantly lower than scores in women receiving placebo (P <.01), who showed no significant improvement. Neither the presence of hot flushes nor the duration of treatment (3 weeks vs 6 weeks) influenced outcome. A full or partial therapeutic response was seen in 80% of subjects receiving estradiol and 22% of those receiving placebo. CONCLUSION: In this preliminary study estradiol replacement effectively treats perimenopausal depression independent of its salutary effects on vasomotor symptoms.

A follow-up study of premenstrual syndrome.

BACKGROUND: Previous data suggest that premenstrual syndrome (PMS) and affective disorder are related. The purpose of this preliminary study was to ascertain (1) whether women with PMS have an increased risk for future major depressive episodes compared with controls and (2) whether PMS is a stable diagnosis over time. METHOD: Patients with prospectively confirmed PMS, along with retrospective DSM-IV premenstrual dysphoric disorder, and asymptomatic controls were studied at 5- to 12-year follow-up using a structured clinical interview. Additionally, those women who still had regular cycles and were medication-free were asked to complete 2 months of prospective daily ratings. RESULTS: Women with PMS (N = 27) had a nonsignificantly higher incidence of new-onset depressive episodes (DSM-III-R and Schedule for Affective Disorders and Schizophrenia-Lifetime Version [SADS-L] criteria) during a 5- to 12-year follow-up compared with controls (N = 21). Differences in incidence disappeared when patients and controls without prior history of depression were compared. Prospective ratings completed during follow-up confirmed original diagnoses of PMS patients (N = 7) and controls (N = 11). CONCLUSION: While preliminary, these results suggest that the higher rate of major depression in patients with PMS during follow-up reflects the higher risk attendant to the history of major depression that existed at baseline. Additionally, at least in a small subsample, PMS appears to be a stable diagnosis over time.

Cerebrospinal fluid somatostatin, mood, and cognition in multiple sclerosis.

BACKGROUND: Cerebrospinal fluid (CSF) somatostatin (SS) levels have been shown to be decreased in multiple sclerosis (MS) during relapse as well as in disorders characterized by depression or cognitive impairment. Since MS is often associated with depression and cognitive impairment, we examined both the effect of course of illness on CSF SS as well as the variance in SS attributable to associated features (e.g., depression or cognitive impairment). METHODS: Fifteen patients with chronic progressive MS participating in a 2-year cyclosporine trial underwent lumbar punctures for CSF SS at baseline and at 12 and 24 months. Additionally, patients were evaluated by neuropsychological testing, and physical disability and mood ratings. Baseline CSF SS levels were also obtained in a group of control subjects (n = 10). RESULTS: At baseline, CSF SS levels were lower in MS patients than control subjects (p < .001). Decreased CSF SS at 24 months was correlated with decreased cognitive performance on several measures and was best and significantly predicted by cognitive deterioration at 24 months. CONCLUSIONS: Our data support those from previous studies that found lower levels of CSF SS in MS during relapse and suggest that changes in CSF SS are related to the process responsible for diminished cognitive function in MS.

Hormone measures in reproductive endocrine-related mood disorders: diagnostic issues.

Mood disturbances have been identified in association with changes in levels of reproductive hormones. The use of hormonal measures in the diagnosis of reproductive endocrine-related mood disorders is highly variable, ranging from necessary in perimenopausal depression to irrelevant in premenstrual syndrome. This article describes our view of the use of hormonal measures for diagnostic and research purposes in perimenopausal depression and premenstrual syndrome. We suggest that the understanding of these disorders lies in as yet unidentified contextual factors rather than in hormonal excesses or deficiencies.

Clinical evaluation in studies of perimenopausal women: position paper.

In some women, the perimenopause is associated with the onset of depressive illness, and it is possible that the changes in gonadal steroids accompanying the perimenopause increase an individual's vulnerability to mood destabilization. This article reviews selected aspects of the literature on the relationship between the perimenopause and depression, outlines the evaluation of depression occurring in the context of the perimenopause from a clinical research perspective, and emphasizes methodologic issues to be considered in future studies.

Estrogen-serotonin interactions: implications for affective regulation.

A burgeoning literature documents the convergence of reproductive endocrine and central serotonergic systems in the regulation of a variety of behaviors. This review will focus on one element of this interaction, the modulation of serotonergic function by estrogen. After describing the manifold neuroregulatory effects of gonadal steroids, we summarize the effects of estrogen on central serotonin systems in animals and humans as inferred from studies demonstrating the impact of gender, estrus (or menstrual) cycle, or hormone manipulation. Finally, we summarize the putative roles of estrogen and serotonin in two reproductive-endocrine-related mood disorders: premenstrual syndrome and perimenopausal depression.

The perimenopause and affective disorders.

A variety of epidemiologic studies have identified that the majority of postmenopausal women do not experience a depression during the perimenopause. In contrast, results of several epidemiologic studies and clinic-based surveys suggest that a substantial number of perimenopausal women, in fact, do experience a clinically significant depression. In this article, we review these studies. Case examples are described to introduce a discussion of the characteristics of perimenopause-related depression, and we identify several factors occurring during midlife in women that may potentially contribute to mood dysregulation at this time. Finally, we provide suggestions for the evaluation and management of women presenting with perimenopause-related depression.