Phase I trial of thalidomide and Interleukin-2 in patients with metastatic renal cell carcinoma

Summary Background: The treatment of advanced renal cell cancer remains unsatisfactory, therefore new combination regimens such as thalidomide and IL-2 are of interest. A phase I trial of SC IL-2 and oral thalidomide was performed to identify the toxicity, maximum tolerated dose (MTD) and preliminary clinical activity of this regimen. Methods: 33 patients with advanced/metastatic RCC were enrolled. An established 8-week outpatient schedule of subcutaneously administered IL-2 in escalating doses, days 1–5, for 6 weeks with a 2 week rest was utilized with daily oral thalidomide. Cohorts of 4–6 patients were treated at 4 dose levels. Results: Toxicity was moderate to severe and related to dose level. All patients developed fever, chills and fatigue. 29/33 patients developed ≤ Grade 2 desquamation of hands and feet and/or rash. Dose limiting toxicity (DLT) included Grade 3 neutropenia and pulmonary embolus. The maximum tolerated dose (MTD) of IL-2 and thalidomide was 9.0 MIU/m² SC days 1–5, weeks 1 to 6 and 100 mg po daily, respectively. A median of 2 cycles of therapy was administered (range 1–9). 2/33 patients responded (1 CR—prior IL-2 therapy, 1 PR—no prior therapy) with an overall response of 6% (95% CI, 1–20%). One minimal response was converted to a surgical CR (remains disease free at 24 + months). Conclusion: Outpatient administration of IL-2 and thalidomide is possible with acceptable toxicity. Further evaluation of this regimen is underway.     

Structural and functional models of depression: from sub-types to substrates

OBJECTIVE: To present a functional model of depression facilitating research and clinical understanding. METHOD: The authors conducted a systematic literature search and reviewed articles pertaining to the neurochemistry and pathophysiology of depressive disorders, focusing on the contribution made by the principal monoamines to three differing depressive structural sub-types (i.e. psychotic, melancholic and non-melancholic). RESULTS: We suggest that the three structural depressive subtypes appear functionally underpinned by differential contributions of serotonergic, noradrenergic and dopaminergic neurotransmitters, so influencing phenotypic distinction (our structural model) and allowing an aetiological model to be derived with treatment specificity implications. CONCLUSION: The functional model logically iterates with the structural model of depression and provides a useful framework for conceptualizing the depressive disorders. This model provides a logic for distinguishing between principal depressive subtypes, pursuing their functional underpinnings and explaining treatment differential effects across the three sub-types.     

Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma.

PURPOSE: To validate the Motzer et al prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma (RCC) and to identify additional independent prognostic factors. PATIENTS AND METHODS: Data were collected on 353 previously untreated metastatic RCC patients enrolled onto clinical trials between 1987 and 2002. RESULTS: Four of the five prognostic factors identified by Motzer were independent predictors of survival. In addition, prior radiotherapy and presence of hepatic, lung, and retroperitoneal nodal metastases were found to be independent prognostic factors. Using the number of metastatic sites as surrogate for individual sites (none or one v two or three sites), Motzer's definitions of risk groups were expanded to accommodate these two additional prognostic factors. Using this expanded criteria, favorable risk is defined as zero or one poor prognostic factor, intermediate risk is two poor prognostic factors, and poor risk is more than two poor prognostic factors. According to Motzer's definitions, 19% of patients were favorable risk, 70% were intermediate risk, and 11% were poor risk; median overall survival times for these groups were 28.6, 14.6, and 4.5 months, respectively (P < .0001). Using the expanded criteria, 37% of patients were favorable risk, 35% were intermediate risk, and 28% were poor risk; median overall survival times of these groups were 26.0, 14.4, and 7.3 months, respectively (P < .0001). CONCLUSION: These data validate the model described by Motzer et al. Additional independent prognostic factors identified were prior radiotherapy and sites of metastasis. Incorporation of these additional prognostic factors into the Motzer et al model can help better define favorable risk, intermediate risk, and poor risk patients.     

Recognizing the anxious face of depression

"Anxious depression" is used variably both by researchers and clinicians to describe admixtures of anxiety and depressive symptoms. The authors sought to determine the best model for conceptualizing anxious depression by studying a sample of depressed patients referred to a tertiary referral unit. Anxiety and depression were assessed using a comprehensive set of mixed symptoms that were subsequently refined to provide separate anxiety and depressive factors, and patients were trichotomized into groups of low, medium, and high anxiety on the basis of their total anxiety factor scores. Associations between the constructs of anxiety and depression in different depressive subgroups were explored, and the severity of depressive symptoms and other clinical variables across the three anxiety groupings was assessed. Depression variables were not linearly associated in a consistent pattern with anxiety-defined groups, arguing against a simple interdependence model driven by a higher-order variable such as depression severity. By contrast, the state anxiety categories were linked strongly with lifetime anxiety disorder prevalence, with some associations linear and with others evidencing a trend break association. The authors found support for a model of anxious depression, whereby anxiety both predisposes to nonmelancholic depression and contributes to its presentation by shaping its clinical features. Such a model and its definition assist in clarifying the cause of anxious depression and its treatment.     

Novel physical treatments for the management of neuropsychiatric disorders

OBJECTIVE: To briefly describe the novel non-drug physical interventions currently in use in the investigation and treatment of neuropsychiatric disorders regarding their efficacy and potential future applications. METHODS: A systematic review of the literature concerning transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), vagus nerve stimulation (VNS) and neurosurgery for mental disorders (NMD) was conducted using Medline and literature known to the authors. RESULTS: A summary of each procedure is provided giving a succinct overview of efficacy, current applications and possible future indications. CONCLUSION: Novel and innovative physical interventions are currently being used to study brain function in health and disease. In particular, TMS has quickly established itself as a useful investigational tool and is emerging as a possible antidepressant therapy. Similarly, VNS has been applied successfully in the management of intractable epilepsy and is undergoing evaluation in the management of patients with treatment-resistant depression. DBS has shown significant promise in the treatment of Parkinson's disease and may have use in the management of obsessive-compulsive disorder. Finally, neurosurgical procedures for the treatment of mental disorders have been sufficiently refined to stage a comeback, although rigorous scientific study of their efficacy and indications is still necessary.     

Kupffer cells participate in early clearance of syngeneic hepatocytes transplanted in the rat liver

BACKGROUND & AIMS: Kupffer cells are activated shortly after deposition of hepatocytes in liver sinusoids, with clearance of a significant fraction of transplanted cells, especially when cells are entrapped in portal spaces. We determined whether perturbation of Kupffer cells would improve transplanted cell engraftment. METHODS: Dipeptidyl peptidase IV-deficient rats were used as recipients of syngeneic Fischer 344 rat hepatocytes. Kupffer cell function was analyzed by measuring phagocytic activity with carbon particle or (99m)Tc-sulfur colloid incorporation. Transplanted cell survival and integration in the liver parenchyma was determined by histochemical analysis of tissues. Transplanted cell proliferation was analyzed in rats conditioned with retrorsine and partial hepatectomy. RESULTS: Gadolinium chloride significantly impaired Kupffer cell function, especially in periportal areas, where transplanted cells were localized. Transplanted cell survival increased by approximately 2-fold in animals treated with gadolinium chloride 24 hours before cell transplantation. In gadolinium-treated rats, more transplanted cells were observed in portal vein radicles, as well as in liver sinusoids, albeit integration of cells in the liver parenchyma was slower in gadolinium-treated rats and cells separated from other hepatocytes in portal vein radicles that failed to exhibit bile canalicular reconstitution. Finally, hepatocyte transplantation in rats primed with retrorsine and partial hepatectomy showed accelerated kinetics of liver repopulation in animals pretreated with gadolinium chloride. CONCLUSIONS: Perturbation of Kupffer cell activity will benefit liver repopulation with cells and further analysis of clinically suitable approaches to exploit this mechanism will be appropriate.     

Double-blind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression

BACKGROUND: The efficacy and safety of bilateral prefrontal repetitive transcranial magnetic stimulation (rTMS) for treating resistant major depression were examined in a double-blind, placebo-controlled study. METHOD: Nineteen medication-resistant depressed subjects were randomly assigned to 3 weeks of active or sham rTMS. Effects on mood and neuropsychological function were assessed. RESULTS: Both groups improved significantly in mood over the 3 weeks, but there was no significant difference between active and sham treatments. There were no significant neuropsychological effects. CONCLUSIONS: Bilateral rTMS was not superior to sham in treating resistant depression in this pilot study, but caused no neuropsychological impairment.     

High (15 Hz) and low (1 Hz) frequency transcranial magnetic stimulation have different acute effects on regional cerebral blood flow in depressed patients

BACKGROUND: High and low frequency repetititve transcranial magnetic stimulation (rTMS) are both effective in treating depression but have contrary effects on motor cortical activity. This study aimed to understand further the mechanisms of action of high and low frequency rTMS by examining their acute effects on regional cerebral blood flow (rCBF) in depressed patients. METHOD: Eighteen depressed subjects underwent brain single photon emission computerized tomography (SPECT) scanning using split-dose 99mTc-HMPAO, and were examined during sham and active rTMS to the left prefrontal cortex, at 15 Hz or 1 Hz (N=9 each). Relative rCBF changes were examined by statistical parametric mapping and by regions of interest analysis. RESULTS: High (15 Hz) frequency rTMS resulted in relative rCBF increases in the inferior frontal cortices, right dorsomedial frontal cortex, posterior cingulate and parahippocampus. Decreases occurred in the right orbital cortex and subcallosal gyrus, and left uncus. Low (1 Hz) frequency rTMS led to increased relative rCBF in the right anterior cingulate, bilateral parietal cortices and insula and left cerebellum. High frequency rTMS led to an overall increase, whereas low frequency rTMS produced a slight decrease, in the mean relative rCBF in the left dorsolateral prefrontal cortex. CONCLUSIONS: High (15 Hz) and low (1 Hz) frequency rTMS led to different frontal and remote relative rCBF changes, which suggests different neurophysiological and possibly neuropsychiatric consequences of a change in frequency of rTMS.     

Reduced growth, increased vascular area, and reduced response to cisplatin in CD13-overexpressing human ovarian cancer xenografts.

PURPOSE: Expression of aminopeptidase N/CD13 can be detected in several solid tumor types. Thus far, the role of CD13 in ovarian cancer has not been studied. We have investigated the expression pattern and biological function of CD13 in ovarian cancer. EXPERIMENTAL DESIGN: First, we studied the expression of CD13 in ovarian cancer tissue of 15 patients representing three different histological types (5 patients each) by immunohistochemistry. We then stably transfected the IGROV-1 human ovarian cancer cell line with a CD13 expression vector and examined the biological effect of CD13 in vitro and in vivo. RESULTS: The expression of CD13 in ovarian cancer was associated with the histological subtype: CD13 expression in tumor cells was observed in 80-100% of the patients with a serous or mucinous carcinoma and in only 20% of the clear cell carcinoma patients. In all patients' tumor samples, CD13-positive blood vessels were present. CD13 overexpression in IGROV-1 cells did not affect in vitro cell growth and sensitivity to doxorubicin, cisplatin, or gemcitabine. CD13 overexpression reduced invasion in Matrigel, which appeared to be independent of the aminopeptidase activity of CD13. Furthermore, the growth rate of IGROV-1/CD13 xenografts was reduced. The area of the vessel lumens was enlarged in a small percentage of vessels in the CD13-overexpressing xenografts. In addition, the CD13-overexpressing tumors were less sensitive to cisplatin. CONCLUSIONS: CD13 is expressed in tumor as well as endothelial cells in human ovarian cancer. Our results suggest that CD13 overexpression affects ovarian cancer growth, vascular architecture, and response to chemotherapy. Further elucidation of the mechanism of the observed effects of CD13 is warranted to better understand its role in the pathophysiology of ovarian cancer.