Untreated Control Patients Research Articles

Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial

Metachromatic leukodystrophy (a deficiency of arylsulfatase A [ARSA]) is a fatal demyelinating lysosomal disease with no approved treatment. We aimed to assess the long-term outcomes in a cohort of patients with early-onset metachromatic leukodystrophy who underwent haemopoietic stem-cell gene therapy (HSC-GT). This is an ad-hoc analysis of data from an ongoing, non-randomised, open-label, single-arm phase 1/2 trial, in which we enrolled patients with a molecular and biochemical diagnosis of metachromatic leukodystrophy (presymptomatic late-infantile or early-juvenile disease or early-symptomatic early-juvenile disease) at the Paediatric Clinical Research Unit, Ospedale San Raffaele, in Milan. Trial participants received HSC-GT, which consisted of the infusion of autologous HSCs transduced with a lentiviral vector encoding ARSA cDNA, after exposure-targeted busulfan conditioning. The primary endpoints of the trial are safety (toxicity, absence of engraftment failure or delayed haematological reconstitution, and safety of lentiviral vector-tranduced cell infusion) and efficacy (improvement in Gross Motor Function Measure [GMFM] score relative to untreated historical controls, and ARSA activity, 24 months post-treatment) of HSC-GT. For this ad-hoc analysis, we assessed safety and efficacy outcomes in all patients who had received treatment and been followed up for at least 18 months post-treatment on June 1, 2015. This trial is registered with ClinicalTrials.gov, number NCT01560182. Between April, 2010, and February, 2013, we had enrolled nine children with a diagnosis of early-onset disease (six had late-infantile disease, two had early-juvenile disease, and one had early-onset disease that could not be definitively classified). At the time of analysis all children had survived, with a median follow-up of 36 months (range 18-54). The most commonly reported adverse events were cytopenia (reported in all patients) and mucositis of different grades of severity (in five of nine patients [grade 3 in four of five patients]). No serious adverse events related to the medicinal product were reported. Stable, sustained engraftment of gene-corrected HSCs was observed (a median of 60·4% [range 14·0-95·6] lentiviral vector-positive colony-forming cells across follow-up) and the engraftment level was stable during follow-up; engraftment determinants included the duration of absolute neutropenia and the vector copy number of the medicinal product. A progressive reconstitution of ARSA activity in circulating haemopoietic cells and in the cerebrospinal fluid was documented in all patients in association with a reduction of the storage material in peripheral nerve samples in six of seven patients. Eight patients, seven of whom received treatment when presymptomatic, had prevention of disease onset or halted disease progression as per clinical and instrumental assessment, compared with historical untreated control patients with early-onset disease. GMFM scores for six patients up to the last follow-up showed that gross motor performance was similar to that of normally developing children. The extent of benefit appeared to be influenced by the interval between HSC-GT and the expected time of disease onset. Treatment resulted in protection from CNS demyelination in eight patients and, in at least three patients, amelioration of peripheral nervous system abnormalities, with signs of remyelination at both sites. Our ad-hoc findings provide preliminary evidence of safety and therapeutic benefit of HSC-GT in patients with early-onset metachromatic leukodystrophy who received treatment in the presymptomatic or very early-symptomatic stage. The results of this trial will be reported when all 20 patients have achieved 3 years of follow-up. Italian Telethon Foundation and GlaxoSmithKline.

Chemotherapy with BCNU in recurrent glioma: Analysis of clinical outcome and side effects in chemotherapy-naïve patients.

BackgroundTo date, standardized strategies for the treatment of recurrent glioma are lacking. Chemotherapy with the alkylating agent BCNU (1,3-bis (2-chloroethyl)-1-nitroso-urea) is a therapeutic option even though its efficacy and safety, particularly the risk of pulmonary fibrosis, remains controversial. To address these issues, we performed a retrospective analysis on clinical outcome and side effects of BCNU-based chemotherapy in recurrent glioma.MethodsSurvival data of 34 mostly chemotherapy-naïve glioblastoma patients treated with BCNU at 1st relapse were compared to 29 untreated control patients, employing a multiple Cox regression model which considered known prognostic factors including MGMT promoter hypermethylation. Additionally, medical records of 163 patients treated with BCNU for recurrent glioma WHO grade II to IV were retrospectively evaluated for BCNU-related side effects classified according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 2.0.ResultsIn recurrent glioblastoma, multiple regression survival analysis revealed a significant benefit of BCNU-based chemotherapy on survival after relapse (p = 0.02; HR = 0.48; 95 % CI = 0.26–0.89) independent of known clinical and molecular prognostic factors. Exploratory analyses suggested that survival benefit was most pronounced in MGMT-hypermethylated, BCNU-treated patients. Moreover, BCNU was well tolerated by 46 % of the 163 patients analyzed for side effects; otherwise, predominantly mild side effects occurred (CTCAE I/II; 45 %). Severe side effects CTCAE III/IV were observed in 9 % of patients including severe hematotoxicity, thromboembolism, intracranial hemorrhage and injection site reaction requiring surgical intervention. One patient presented with a clinically apparent pulmonary fibrosis CTCAE IV requiring temporary mechanical ventilation.ConclusionIn this study, BCNU was rarely associated with severe side effects, particularly pulmonary toxicity, and, in case of recurrent glioblastoma, even conferred a favorable outcome. Therefore BCNU appears to be an appropriate alternative to other nitrosoureas although the efficacy against newer drugs needs further evaluation.

23.4% Saline Decreases Brain Tissue Volume in Severe Hepatic Encephalopathy as Assessed by a Quantitative CT Marker.

Cerebral edema is common in severe hepatic encephalopathy and may be life threatening. Bolus 23.4% hypertonic saline improves surveillance neuromonitoring scores, although its mechanism of action is not clearly established. We investigated the hypothesis that bolus hypertonic saline decreases cerebral edema in severe hepatic encephalopathy utilizing a quantitative technique to measure brain and cerebrospinal fluid volume changes. Retrospective analysis of serial CT scans, and clinical data for a case-control series were performed. ICUs of a tertiary care hospital. Patients with severe hepatic encephalopathy treated with 23.4% hypertonic saline and control patients who did not receive 23.4% hypertonic saline. 23.4% hypertonic saline bolus administration. We used clinically obtained CT scans to measure volumes of the ventricles, intracranial cerebrospinal fluid, and brain using a previously validated semiautomated technique (Analyze Direct, Overland Park, KS). Volumes before and after 23.4% hypertonic saline were compared with Wilcoxon signed rank test. Associations among total cerebrospinal fluid volume, ventricular volume, serum sodium, and Glasgow Coma Scale scores were assessed using Spearman rank correlation test. Eleven patients with 18 administrations of 23.4% hypertonic saline met inclusion criteria. Total cerebrospinal fluid (median, 47.6 mL [35.1-69.4 mL] to 61.9 mL [47.7-87.0 mL]; p < 0.001) and ventricular volumes (median, 8.0 mL [6.9-9.5 mL] to 9.2 mL [7.8-11.9 mL]; p = 0.002) increased and Glasgow Coma Scale scores improved (median, 4 [3-6] to 7 [6-9]; p = 0.008) after 23.4% hypertonic saline. In contrast, total cerebrospinal fluid and ventricular volumes decreased in untreated control patients. Serum sodium increase was associated with increase in total cerebrospinal fluid volume (r = 0.83, p < 0.001), and change in total cerebrospinal fluid volume was associated with ventricular volume change (r = 0.86; p < 0.001). Total cerebrospinal fluid and ventricular volumes increased after 23.4% hypertonic saline, consistent with a reduction in brain tissue volume. Total cerebrospinal fluid and ventricular volume change may be useful quantitative measures to assess cerebral edema in severe hepatic encephalopathy.

Does Laser Work for Treating Onychomycosis? Maybe, Sometimes

Two new studies examine different laser approaches to treating onychomycotic nails. Hollmig and colleagues enrolled 27 patients with a total of 125 nails needing treatment to evaluate the effectiveness of 1064-nm Nd:YAG laser for mycologic cure and clinical improvement (defined as proximal nail-plate clearance). Patients randomized to treatment received two laser treatments, 2 weeks apart. Among the 22 study completers, treatment recipients and untreated control patients had no statistically significant differences in mycologic cure (33% and 20%, …

Diaphragm Fiber Strength Is Reduced in Critically Ill Patients and Restored by a Troponin Activator

Diaphragm Fiber Strength Is Reduced in Critically Ill Patients and Restored by a Troponin Activator

Open-Label, Exploratory Phase II Trial of Oral Itraconazole for the Treatment of Basal Cell Carcinoma

Itraconazole, a US Food and Drug Administration-approved antifungal drug, inhibits the Hedgehog (HH) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis, and reduces BCC growth in mice. We assessed the effect of itraconazole on the HH pathway and on tumor size in human BCC tumors. Patients with ≥ one BCC tumor > 4 mm in diameter were enrolled onto two cohorts to receive oral itraconazole 200 mg twice per day for 1 month (cohort A) or 100 mg twice per day for an average of 2.3 months (cohort B). The primary end point was change in biomarkers: Ki67 tumor proliferation and HH activity (GLI1 mRNA). Secondary end points included change in tumor size in a subset of patients with multiple tumors. A total of 29 patients were enrolled, of whom 19 were treated with itraconazole. Itraconazole treatment was associated with two adverse events (grade 2 fatigue and grade 4 congestive heart failure). Itraconazole reduced cell proliferation by 45% (P = .04), HH pathway activity by 65% (P = .03), and reduced tumor area by 24% (95% CI, 18.2% to 30.0%). Of eight patients with multiple nonbiopsied tumors, four achieved partial response, and four had stable disease. Tumors from untreated control patients and from those previously treated with vismodegib showed no significant changes in proliferation or tumor size. Itraconazole has anti-BCC activity in humans. These results provide the basis for larger trials of longer duration to measure the clinical efficacy of itraconazole, especially relative to other HH pathway inhibitors.

Use of escitalopram to prevent depression and cognitive impairments in the acute phase of stroke

The purpose of the study was to comparatively analyze the rate of post-stroke depression and cognitive impairments in escitalopram (cipralex)-treated and untreated (control) patients. Emotional and affective cognitive symptoms, neurological deficit, and day-to-day activity were evaluated over time 1, 3, and 6 months after treatment. The results of the study indicated that escitalopram used to prevent depression in the acute phase of stroke provided a good effect. This drug caused a prompter recovery of cognitive impairments and reduced the pace of development of neurodegenerative disorders underlying the post-stroke 2D (depression and dementia) syndrome. The study group was recorded to have more favorable functional outcomes of stroke and patient mobility indicators associated with lower disability rates.

Treatment of Disseminated Granuloma Annulare with Oral Vitamin E: ‘Primum Nil Nocere'

Background: Disseminated granuloma annulare (DGA) is a benign and usually asymptomatic skin disease. However, many patients feel aesthetically disfigured and ask for treatment. Until today, no standard therapy is recommended. Objective: To evaluate the safety and efficacy of oral vitamin E treatment compared to the natural course of DGA. Methods: This single-centre observational cohort study included 38 consecutive patients with histologically confirmed DGA. 21 patients underwent treatment with oral vitamin E, whereas 17 patients preferred a wait-and-see approach. Results: Complete healing (40%) and improvement (30%) were frequently seen under oral vitamin E therapy. However, DGA also spontaneously disappeared in 31% and improved in 25% of untreated control patients. Vitamin E therapy was very well tolerated. Conclusions: Oral vitamin E treatment is a safe and probably effective therapy for DGA. As the natural course of DGA leads to complete healing or significant improvement in many cases, ‘primum nil nocere' should be the maxim.

Effects of the Anti-CD20 Antibody Rituximab on B Cells in Human Secondary Lymphoid Organs

Introduction: A single dose of the anti-CD20 monoclonal antibody rituximab (RTX) induces a nearly complete B-cell depletion in peripheral blood. However, there remains a residual B-cell population in secondary lymphoid organs, such as spleen and lymph nodes. An intriguing question that remains to be answered is whether these remaining B cells are modified due to binding by RTX. Methods: To mimic the in vivo situation, where B cells are exposed to RTX but only partially depleted, spleen cells obtained from organ donors were incubated in vitro with RTX and a low concentration of complement. The distribution of B-cell subsets was analyzed after 3 days of culture in the presence or absence of CpG-B. Results: Incomplete B-cell depletion followed by culture in the absence of CpG-B resulted in a IgD+CD27- (naïve): IgD-CD27+ (switched memory) B-cell ratio that was comparable to the non-depleted condition. However, after culture in the presence of CpG-B, the B cells that survived the depletion procedure showed a reduced naïve: switched memory ratio. In contrast to the total splenic B-cell population, the depletion surviving B cells did not contain IL-10 producing cells after culture with CpG-B. Moreover, B cells were also characterized ex vivo in peripheral blood and lymph nodes obtained during renal transplant surgery from patients (n=4) who had received RTX 4 weeks before transplantation. As described in literature, a complete depletion of B cells in the peripheral blood was obtained after a single dose of RTX, however in the lymph nodes the frequency of B cells was comparable to that of untreated control patients. Remarkably, the remaining lymph node B cells from RTX-treated patients showed a lower percentage of IgD+CD27- and a higher percentage of IgD-CD27+ B cells compared to lymph node B cells of untreated patients. Conclusion: Exposure of both spleen and lymph node B cells to RTX results in a shift of B cells from a naïve to a switched memory phenotype.

Breast Cancer Risk Reduction: No Pain, No Gain?

Breast Cancer Risk Reduction: No Pain, No Gain?

Remote Ischemic Preconditioning Is Redundant in Patients Undergoing Coronary Artery Bypass Graft Surgery Who Are Already Protected by Volatile Anesthetics

To the Editor: We have read with interest the article by Heusch et al1 showing that troponin I levels of 12 coronary artery bypass patients treated with remote ischemic preconditioning (rIPC) performed under isoflurane anesthesia were reduced when compared with those of 12 untreated control patients. In that study, phosphorylation of the transcription factor STAT5 was also increased after reperfusion in left ventricular tissue samples of patients treated with rIPC. These findings are promising and the researchers should be commended for their analysis of human ventricular tissue samples. However, from the article, it is unclear whether data from these patients were also published in a report recently published by the same group,2 which was conducted under the same ClinicalTrials identifier number. A comparison of the perioperative …

Topical Nerve Growth Factor as a Visual Rescue Strategy in Pediatric Optic Gliomas

Background. To date, no specific therapy is available for optic glioma (OG)–induced visual loss. Objective. To evaluate the effects on visual function of murine nerve growth factor (NGF) eye drop administration in children with severe visual impairment due to low-grade OGs. Methods. Five patients with OGs and advanced optic nerve atrophy were assessed before and after a single 10-day course of 1 mg murine NGF topical administration by clinical evaluation, visual evoked potentials (VEPs), and brain magnetic resonance imaging (MRI). VEPs, the main functional outcome measure, were recorded at baseline and 1, 30, 45, 90, and 180 days posttreatment. MRI examinations were performed at baseline and at 180 days after NGF treatment. Six untreated control patients with OGs also underwent serial VEPs, clinical testing, and MRI assessments. Results. After NGF treatment, median VEPs amplitude showed a progressive increase from the baseline values (P < .01). VEPs reached a maximum amplitude at 90 days (170% increase) and declined at 180 days, still remaining above the baseline level. Perception of spontaneous visual phosphenes was noted in all patients after NGF administration. MRI showed stable tumor size. In controls, clinical findings and VEPs did not show any significant change over the observation period. Conclusions. The findings from the study show that NGF administration may be an effective and safe adjunct therapy in children with optic atrophy due to OGs. The beneficial effect on optic nerve function suggests a visual rescuing mechanism exerted by murine NGF on the residual viable optic pathways.

Effects of glycine on auditory evoked potentials among diabetic patients with auditory pathway neuropathy

Glycine inhibits the formation of advanced glycation end products that may cause central and peripheral neuronal damage, affecting also the auditory nerve. To evaluate the effect of glycine on auditory nerve conduction and hearing level among patients with type 2 diabetes mellitus and auditory neuropathy. Twenty grams of oral glycine per day were administered during 6 months to 28 type 2 diabetic patients aged 58 ± 6 years, with auditory pathway neuropathy. Hearing tests and evoked otoacustic potentials were performed regularly. Fifteen diabetic patients aged 49 ± 8 years, without auditory nerve neuropathy did not receive glycine and were followed as a control group. Among patients receiving glycine, a significant improvement in left ear audiometry at 125, 250 and 500 Hz and right ear audiometry at 500 Hz, was observed. Waves I, III and V (p= 0.02) of evoked otoacustic potentials improved significantly in the left ear and wave I in the right ear. Among controls, waves V and III of evoked otoacoustic potentials had a significant impairment in the left ear. There was an improvement in auditory evoked potentials in patients receiving glycine and an impairment in untreated control patients.

Chronic Treatment With Losartan Results in Sufficient Serum Levels of the Metabolite EXP3179 for PPARγ Activation

The losartan metabolite EXP3174 exhibits angiotensin II receptor 1 (AT1R)-blocking properties, whereas the metabolite EXP3179 potently induces the activity of the insulin-sensitizing peroxisome proliferator-activated receptor gamma (PPARgamma) as a partial agonist in vitro. We investigated whether chronic treatment with losartan leads to sufficient serum levels of EXP3179 to activate PPARgamma in monocytes derived from losartan-treated patients. Hypertensive patients (n=15) treated with losartan (100 mg/daily for at least the past 2 months) and untreated control patients (n=7) were included. Monocytes were extracted by negative isolation using a Dynal Monocyte Kit, followed by analysis of PPARgamma target gene expression (CD36, ABC transporter G1 [ABCG1]) by quantitative real-time RT-PCR. Serum was prepared before, 2, 4, and 6 hours after losartan (100 mg) ingestion for HPLC-based determination of losartan, EXP3174, and EXP3179. Chronic treatment with losartan resulted in basal levels of losartan, EXP3174, and EXP3179 of 348.3+/-101.8 ng/mL, 115.3+/-56.1 ng/mL, and 176.2+/-143.4 ng/mL, respectively. Levels of both EXP3174 and EXP3179 were time-dependently increased in serum with a maximum 2 hours after drug intake (1706.0+/-760.1 ng/mL, 808.9+/-618.2 ng/mL, respectively). In consonance with detectable PPARgamma-activating EXP3179 serum levels, monocytic PPARgamma target gene expression was significantly upregulated in patients treated with losartan by 3.75+/-0.95- and 252.02+/-46.86-fold for CD36 and ABCG1 (P=0.043, P=0.0045 versus control patients, respectively). This is the first clinical description of monocytic PPARgamma-target gene regulation by chronic treatment with losartan, which likely is mediated by its metabolite EXP3179. Our data show that sufficient serum levels of EXP3179 are present under losartan treatment. PPARgamma activation by AT1R-blockers may translate into synergistic beneficial actions in monocytes.

Suppression of the postoperative neutrophil leucocytosis following neoadjuvant chemoradiotherapy for rectal cancer and implications for surgical morbidity

The extent to which neoadjuvant chemoradiotherapy for rectal cancer influences postoperative morbidity is controversial. This study investigated whether this treatment suppresses the normal perioperative inflammatory response and explored the clinical implications. Prospective databases were queried to identify 37 consecutive study patients undergoing definitive surgery following 5-FU/capecitabine-based chemoradiotherapy and 34 consecutive untreated control patients operated upon for rectal or rectosigmoid cancer. Preoperative (< 10 days) and postoperative (< 24 h) neutrophil counts, along with morbidity data, were confirmed retrospectively. Univariate and multivariate analyses assessed the apparent effect of chemoradiotherapy on change in neutrophil count. The latter's association with postoperative morbidity was then examined. Sufficient data were available for 34 study and 27 control patients. Repeated-measures ANCOVA revealed significant differences between their perioperative neutrophil counts (P = 0.02). Of the other characteristics which differed between the groups, only age and tumour location were prognostically significant regarding perioperative change in neutrophil count. Accounting for relevant covariates, chemoradiotherapy was significantly associated with a suppressed perioperative neutrophil leucocytosis. Local postoperative complications affected 25 of 61 patients, who had lower perioperative neutrophil increases than their counterparts (P = 0.016). Chemoradiotherapy appears to suppress the perioperative inflammatory response, thereby increasing susceptibility to local postoperative complications.

Chronic hyperplastic candidosis: a pilot study of the efficacy of 0.18% isotretinoin

Management of oral candidiasis depends on an accurate diagnosis, identification and elimination of predisposing factors, and, often, use of antifungal agents. Chronic hyperplastic candidosis (CHC) is considered a premalignant lesion of the oral mucosa, occurring as speckled or homogeneous white lesions. If the lesions are untreated, a minor proportion may become dysplastic and progress to carcinoma. The traditional treatment of this lesion is based on the use of antifungal agents. The aim of this study was to examine the efficacy of 0.18% isotretinoin for treatment of nystatin-resistant candidiasis. Isotretinoin was administered topically twice a day for one month to six patients affected by nystatin-resistant CHC. In all six patients, daily antimycotic topical therapy with nystatin for 30 days had failed to resolve the candidal stomatitis. After one month of isotretinoin treatment, five of the six patients were negative for Candida, whereas in untreated control patients the situation was unchanged. Only one patient with suspected sicca syndrome was found to have oral Candida 15 days after the last administration of isotretinoin. None of the patients had any complaints about the medication. These findings suggest that 0.18% isotretinoin applied twice a day for one month is able to suppress nystatin-resistant candidiasis.

Exacerbation of cataplexy following gradual withdrawal of antidepressants: Manifestation of probable protracted rebound cataplexy

Background A double-blind, placebo-controlled sodium oxybate trial provided a unique opportunity to compare changes in cataplexy following gradual withdrawal from antidepressants in narcolepsy patients. Methods Of 228 enrolled patients, 71 discontinued antidepressant therapy. Data from 57 patients were available for analysis: 37 patients discontinued tricyclic antidepressants (TCAs) and 20 discontinued selective serotonin reuptake inhibitors (SSRIs). The trial included a 21-day withdrawal phase followed by 18-day washout and 14-day single-blind treatment phases. Two additional weeks were permitted for withdrawal from fluoxetine due to its long half-life. Weekly cataplexy attacks were recorded throughout the trial. No historical data on the frequency of cataplexy prior to treatment with antidepressants was available. Results Among the patients who were and were not withdrawn from antidepressants treatment, the median frequency of baseline weekly cataplexy was similar (17.5 vs. 14.0, respectively). As expected, significant between-group differences emerged by the end of the washout period (52.04 vs. 15.25, respectively; p < 0.05); however, the frequency of cataplexy events became similar again by the end of the trial (16.5 vs. 17.5, respectively). Conclusions Patients gradually withdrawn from antidepressants experienced a significant increase in cataplexy, but eventually returned to their baseline frequency, comparable to previously untreated control patients. Compared to SSRIs, discontinuation from TCAs was associated with a greater increase in cataplexy attacks.

Clinical Events in Prostate Cancer Lifestyle Trial: Results From Two Years of Follow-Up

Previous research has demonstrated that patients with prostate cancer participating in the Prostate Cancer Lifestyle Trial had a reduction in prostate-specific antigen (PSA) levels, inhibition of LNCaP cell growth, and fewer prostate cancer-related clinical events at the end of 1 year compared with controls. The aim of this study was to examine the clinical events in this trial during a 2-year period. The Prostate Cancer Lifestyle Trial was a 1-year randomized controlled clinical trial of 93 patients with early-stage prostate cancer (Gleason score <7, PSA 4-10 ng/mL) undergoing active surveillance. The patients in the experimental arm were encouraged to adopt a low-fat, plant-based diet, to exercise and practice stress management, and to attend group support sessions. The control patients received the usual care. By 2 years of follow-up, 13 of 49 (27%) control patients and 2 of 43 (5%) experimental patients had undergone conventional prostate cancer treatment (radical prostatectomy, radiotherapy, or androgen deprivation, P < .05). No differences were found between the groups in other clinical events (eg, cardiac), and no deaths occurred. Three of the treated control patients but none of the treated experimental patients had a PSA level of >or=10 ng/mL, and 1 treated control patient but no treated experimental patients had a PSA velocity of >2 ng/mL/y before treatment. No significant differences were found between the untreated experimental and untreated control patients in PSA change or velocity at the end of 2 years. Patients with early-stage prostate cancer choosing active surveillance might be able to avoid or delay conventional treatment for at least 2 years by making changes in their diet and lifestyle.

Neoadjuvant immunotherapy for prostate cancer with GM-CSF and tumor infiltration by antigen presenting cells

3063 Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth factor for antigen presenting cells that may enhance anti-tumor immune responses. Although this cytokine is being evaluated in immunotherapy trials for different malignancies, the impact of GM-CSF dose and schedule has not been directly addressed. Because systemic GM-CSF could potentiate anti-tumor immunity by enhancing presentation of endogenous tumor antigens, we examined whether increasing duration of GM-CSF treatment prior to radical prostatectomy could alter the composition of antigen presenting cells within the prostate tissue. Methods: A phase I trial in patients with localized prostate cancer was performed in subjects who were planned to undergo radical prostatectomy (RP). Two cohorts of 6 patients were sequentially accrued and treated with either 2 weeks or 3 weeks of daily GM-CSF (sargramostim, Bayer) 250 mg/m2/d SC. Patients were monitored for toxicity as well as for changes in circulating immune cells. RP tissues were assessed for immune cells by flow cytometry or immunohistochemistry (IHC) and digital slide scanning. In addition, IHC was also performed on RPs from untreated control Gleason grade- matched patients. Results: 12 patients were treated with neoadjuvant GM-CSF for either 2 weeks or 3 weeks. While significant leukocytosis was observed with treatment, no dose-limiting toxicities were encountered. As expected, circulating monocytes and dendritic cells (DC) were expanded following treatment. Compared to RPs from 11 untreated control patients, there was an increase in prostate-resident CD1a+ interstitial DC (Kruskal-Wallis test: p = 0.04). The increase was most pronounced in the 3-week treatment cohort. Moreover, tumor-resident DC expressed higher levels of the activation markers CD83 and 86 compared to DC residing in adjacent normal prostate and benign prostatic hypertrophy tissue. Conclusions: Systemically administered neoadjuvant GM-CSF can enhance the frequency of DC in prostate cancer. These effects appear to be dose dependent as they were most pronounced with 3 weeks of treatment. The composition of resident DC and monocytes also differs between malignant, benign, and hypertrophic prostate tissue. No significant financial relationships to disclose.

L-Carnitine Supplementation Decreases the Left Ventricular Mass in Patients Undergoing Hemodialysis

Patients on long-term hemodialysis become deficient in carnitine and are frequently treated with carnitine supplementation to offset their renal anemia, lipid abnormality and cardiac dysfunction. The therapeutic value of carnitine supplementation on left ventricular hypertrophy (LVH) in patients with normal cardiac systolic function remains uncertain. The cardiac morphology and function of 10 patients given 10 mg/kg of L-carnitine orally, immediately after hemodialysis sessions 3 times per week for a 12-month period were compared with 10 untreated control patients. Using echocardiography, left ventricular fractional shortening (LVFS) and left ventricular mass index (LVMI) were measured before and after the study period. As a result, amounts of serum-free carnitine increased from 28.4+/-4.7 to 58.5+/-12.1 micromol/L. The LVMI decreased significantly from 151.8+/-21.2 to 134.0+/-16.0 g/m(2) in treated patients (p<0.01), yet the LVMI in untreated control patients did not change significantly (ie, from 153.3+/-28.2 to 167.1+/-43.1 g/m(2)). However, LVFS values remained unchanged in both groups. Although L-carnitine promoted a 31% reduction in erythropoietin requirements, hematocrit and blood pressure did not change during the study period. Supplementation with L-carnitine induced regression of LVH in patients on hemodialysis, even for those with normal systolic function.