Roberto Serpe

A Phase II Study with Antioxidants, Both in the Diet and Supplemented, Pharmaconutritional Support, Progestagen, and Anti-Cyclooxygenase-2 Showing Efficacy and Safety in Patients with Cancer-Related Anorexia/Cachexia and Oxidative Stress

Purpose: To test the efficacy and safety of an integrated treatment based on a pharmaconutritional support, antioxidants, and drugs, all given orally, in a population of advanced cancer patients with cancer-related anorexia/cachexia and oxidative stress. Patients and Methods: An open early-phase II study was designed according to the Simon two-stage design. The integrated treatment consisted of diet with high polyphenols content (400 mg), antioxidant treatment (300 mg/d α-lipoic acid + 2.7 g/d carbocysteine lysine salt + 400 mg/d vitamin E + 30,000 IU/d vitamin A + 500 mg/d vitamin C), and pharmaconutritional support enriched with 2 cans per day (n-3)-PUFA (eicosapentaenoic acid and docosahexaenoic acid), 500 mg/d medroxyprogesterone acetate, and 200 mg/d selective cyclooxygenase-2 inhibitor celecoxib. The treatment duration was 4 months. The following variables were evaluated: (a) clinical (Eastern Cooperative Oncology Group performance status); (b) nutritional [lean body mass (LBM), appetite, and resting energy expenditure]; (c) laboratory [proinflammatory cytokines and leptin, reactive oxygen species (ROS) and antioxidant enzymes]; (d) quality of life (European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL-5D, and MFSI-SF). Results: From July 2002 to January 2005, 44 patients were enrolled. Of these, 39 completed the treatment and were assessable. Body weight increased significantly from baseline as did LBM and appetite. There was an important decrease of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α, and a negative relationship worthy of note was only found between LBM and IL-6 changes. As for quality of life evaluation, there was a marked improvement in the European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL-5DVAS, and multidimensional fatigue symptom inventory-short form scores. At the end of the study, 22 of the 39 patients were “responders” or “high responders.” The minimum required was 21; therefore, the treatment was effective and more importantly was shown to be safe. Conclusion: The efficacy and safety of the treatment have been shown by the study; therefore, a randomized phase III study is warranted. (Cancer Epidemiol Biomarkers Prev 2006;15(5):1030–4)

Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia.

PURPOSE A phase III, randomized study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia-lean body mass (LBM), resting energy expenditure (REE), and fatigue-and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines. PATIENTS AND METHODS Three hundred thirty-two assessable patients with cancer-related anorexia/cachexia syndrome were randomly assigned to one of five treatment arms: arm 1, medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day); arm 2, oral supplementation with eicosapentaenoic acid; arm 3, L-carnitine (4 g/day); arm 4, thalidomide (200 mg/day); and arm 5, a combination of the above. Treatment duration was 4 months. RESULTS Analysis of variance showed a significant difference between treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5; interleukin (IL)-6 decreased significantly in arm 5 and arm 4; GPS and Eastern Cooperative Oncology Group performance status (ECOG PS) score decreased significantly in arm 5, arm 4, and arm 3. Toxicity was quite negligible, and was comparable between arms. CONCLUSION The most effective treatment in terms of all three primary efficacy endpoints and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents.

Assessment of adiponectin and leptin as biomarkers of positive metabolic outcomes after lifestyle intervention in overweight and obese children.

BACKGROUND A number of metabolic changes are caused by childhood obesity, including insulin resistance, diabetes, and dyslipidemia. To counteract them, lifestyle modification with changes in dietary habits and physical activity is the primary intervention. Anthropometric parameters may not identify all positive changes associated with lifestyle modifications, whereas circulating adipokines may represent an alternative as biomarkers. The aim of this study was to evaluate adiponectin and leptin levels as markers of positive metabolic outcomes in childhood obesity. METHODS Changes in clinical, anthropometric, and metabolic parameters, including adiponectin and leptin, were assessed in 104 overweight and obese children before and after 1 yr of lifestyle intervention. Obesity and overweight were defined according to the Italian body mass index reference tables for age and sex. Fifty-four normal-weight children were evaluated as controls. Forty-eight of the children (47.5%) returned for follow-up at 1 yr. RESULTS Compared with normal-weight children, overweight and obese subjects differed significantly at baseline for glycemia, insulinemia, homeostasis model assessment for insulin resistance, adiponectinemia (5.8 vs. 18.2 microg/ml in controls), low-density lipoprotein-cholesterol, and triglycerides. These parameters were all higher in the overweight/obese children. At follow-up, most parameters improved in overweight/obese children. The most significant changes were observed in adiponectin concentration, which increased by 245% (P < 0.0001), reaching the levels observed in normal-weight children. Leptin levels showed changes unrelated to positive metabolic outcomes, remaining high at 1 yr of follow-up in overweight/obese children. Regardless of changes in weight status, children with lifestyle intervention reported changes in homeostasis model assessment for insulin resistance and in adiponectin that were associated with loss of fat mass. CONCLUSIONS After lifestyle intervention, adiponectin increased regardless of changes in weight, whereas no consistent changes was observed in serum leptin. Therefore, circulating adiponectin may represent a good biomarker to evaluate the efficacy of lifestyle intervention in overweight/obese children.

Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress

This study assessed in a wide population of advanced cancer patients the biological parameters relevant to cancer cachexia, such as serum levels of proinflammatory cytokines (IL-1β, IL-6, TNFα), IL-2, acute-phase proteins (C-reactive protein and fibrinogen), leptin, and relevant to oxidative stress (OS), such as ROS, body antioxidant enzymes GPx and SOD. We also studied the ability of effective antioxidant agents α-lipoic acid (ALA), N-acetyl cysteine (NAC), and amifostine (AMI) added into culture to induce lymphocyte progression through the cell cycle, namely to enter into S phase. Additionally, we assessed the most significant clinical indexes of nutritional status such as body mass index and disease progression such as stage and ECOG-PS in the same cancer patient population. Cell cycle analysis of cultured unstimulated or PHA-stimulated PBMCs isolated from 120 cancer patients and 60 controls, with or without ALA, NAC, or AMI, was studied. The biological parameters relevant to cancer cachexia and OS were also studied. The addition of antioxidants ALA, NAC and AMI, enhanced significantly the progression through the cell cycle, namely from G0/G1 to S phase, of PBMCs isolated from cancer patients (+132%, +150% and +141%, respectively). The percentage of PHA-stimulated PBMCs of cancer patients entering S phase, which was significantly lower than that of controls, increased significantly to more than physiological level after coculture with antioxidants. ROS levels were significantly higher and GPx and SOD activities significantly lower in cancer patients than controls. Serum levels of IL-1 β, IL-6, and TNFα were significantly higher and serum levels of IL-2 and leptin significantly lower in cancer patients than controls. Serum levels of C-reactive protein and fibrinogen were significantly higher in cancer patients than controls. A significant correlation was found in laboratory parameters only between serum levels of leptin and body mass index. Patients with advanced cancer thus exhibit both a high-grade OS and a chronic inflammatory condition. Antioxidant agents ALA, NAC, and AMI enhanced significantly the PBMCs progression through the cell cycle, thus providing evidence of their potential role in the functional restoration of the immune system in advanced cancer patients. Our data warrant further investigation with adequate clinical trials.

Randomized phase III clinical trial of five different arms of treatment for patients with cancer cachexia: interim results

OBJECTIVE In April 2005 a phase III randomized study was started to establish which was the most effective and safest treatment of cancer-related anorexia/cachexia syndrome and oxidative stress in improving identified primary endpoints: increase of lean body mass, decrease of resting energy expenditure (REE), increase of total daily physical activity, decrease of interleukin-6 and tumor necrosis factor-alpha, and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). METHODS All patients were given as basic treatment polyphenols plus antioxidant agents alpha-lipoic acid, carbocysteine, and vitamins A, C, and E, all orally. Patients were then randomized to one of the following five arms: 1) medroxyprogesterone acetate/megestrol acetate; 2) pharmacologic nutritional support containing eicosapentaenoic acid; 3) L-carnitine; 4) thalidomide; or 5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. Treatment duration was 4 mo. The sample comprised 475 patients. RESULTS By January 2007, 125 patients, well balanced for all clinical characteristics, were included. No severe side effects were observed. As for efficacy, an interim analysis on 125 patients showed an improvement of at least one primary endpoint in arms 3, 4, and 5, whereas arm 2 showed a significant worsening of lean body mass, REE, and MFSI-SF. Analysis of variance comparing the change of primary endpoints between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1, 3, and 5 versus arm 2. A significant inferiority of arm 2 versus arms 3, 4, and 5 for the primary endpoints lean body mass, REE, and MFSI-SF was observed on the basis of t test for changes. CONCLUSION The interim results obtained thus far seem to suggest that the most effective treatment for cancer-related anorexia/cachexia syndrome and oxidative stress should be a combination regimen. The study is still in progress and the final results should confirm these data.

Randomized phase III clinical trial of a combined treatment with carnitine + celecoxib ± megestrol acetate for patients with cancer-related anorexia/cachexia syndrome

BACKGROUND & AIMS A phase III, randomized non-inferiority study was carried out to compare a two-drug combination (including nutraceuticals, i.e. antioxidants) with carnitine + celecoxib ± megestrol acetate for the treatment of cancer-related anorexia/cachexia syndrome (CACS): the primary endpoints were increase of lean body mass (LBM) and improvement of total daily physical activity. Secondary endpoint was: increase of physical performance tested by grip strength and 6-min walk test. METHODS Sixty eligible patients were randomly assigned to: arm 1, L-carnitine 4 g/day + Celecoxib 300 mg/day or arm 2, L-carnitine 4 g/day + celecoxib 300 mg/day + megestrol acetate 320 mg/day, all orally. All patients received as basic treatment polyphenols 300 mg/day, lipoic acid 300 mg/day, carbocysteine 2.7 g/day, Vitamin E, A, C. Treatment duration was 4 months. Planned sample size was 60 patients. RESULTS The results did not show a significant difference between tre atment arms in both primary and secondary endpoints. Analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) increased significantly in both arms as well as physical performance assessed by 6MWT. Toxicity was quite negligible and comparable between arms. CONCLUSIONS The results of the present study showed a non-inferiority of arm 1 (two-drug combination) vs arm 2 (two-drug combination + megestrol acetate). Therefore, this simple, feasible, effective, safe, low cost with favorable cost-benefit profile, two-drug approach could be suggested in the clinical practice to implement CACS treatment.

Interleukin‐1B (IL1B) and interleukin‐6 (IL6) gene polymorphisms are associated with risk of chronic lymphocytic leukaemia

Common polymorphisms in genes encoding for cytokines implicated in the inflammatory response and Th1/Th2 balance might play a role in the development and prognosis of chronic lymphocytic leukaemia (CLL). To test the hypothesis, we investigated 13 single nucleotide polymorphisms (SNPs) in nine of such genes in a population‐based case‐control study, conducted in the Italian region of Sardinia in 1999–2003. Forty incident CLL cases and 113 population controls were available for study. The following SNPs were selected: IL1A‐889C > T, IL1RN 9589A > T, IL1B‐31C > T, IL1B‐511C > T, IL2‐384T > G, IL6‐174G > C, IL6‐597G > A, IL10‐1082A > G, IL10‐3575T > A, TNF‐308G > A, LTA‐ 91A > C, LTA 252A > G and CARD15 nt1007. After adjusting by age and gender, individuals homozygous for the IL1B‐511T allele run a lower risk of CLL (OR = 0.1, 95% CI 0.0, 0.8, p = 0.032), while risk showed a 4.5‐fold increase associated with the genotype homozygous for the IL6‐174C allele (OR = 4.5; 95% CI 1.1, 19.3, p = 0.041). Individuals homozygous for the IL6‐174C allele and carrying the homozygous IL1B‐511C allele showed an 11‐fold increase in CLL risk (OR = 11.4, 95% CI 1.9, 69.4, p = 0.008). None of the other interleukin SNPs evaluated showed any association with CLL risk. Large multicentre pooled studies are warranted, achieving the statistical power required to confirm whether IL6 and IL1B gene polymorphisms might play a role in CLL development and prognosis, as well as the null associations herein reported. Copyright

Persistence, Up to 18 Months of Follow-Up, of Epirubicin-Induced Myocardial Dysfunction Detected Early by Serial Tissue Doppler Echocardiography: Correlation with Inflammatory and Oxidative Stress Markers

A phase II, open, nonrandomized trial was carried out in a group of epirubicin-treated cancer patients with the aim of detecting early preclinical changes that are predictive of the risk for heart failure. Thirty-one patients (male/female ratio, 8/23; mean age +/- standard deviation, 59 +/- 14 years) with tumors at different sites and scheduled to be treated with an epirubicin-based chemotherapy regimen, were enrolled. We prospectively evaluated the acute (1 week after) and late (3, 6, 12, and 18 months of follow-up) effects of epirubicin administration. A significant impairment in systolic left ventricular (LV) function was observed at a cumulative epirubicin dose of 200 mg/m(2). This was shown by a reduction in the strain rate (SR) peak in comparison with baseline and persisted throughout the treatment and follow-up, up to 18 months; strain (Sigma) remained unchanged. The Sm wave showed a progressive reduction that became significant only at the 18-month follow-up. On TDI the E(m)/A(m) ratio declined at the 200-mg/m(2) cumulative epirubicin dose versus baseline and persisted throughout the treatment and up to the 18-month follow-up. On conventional echocardiography the E/A ratio declined significantly only at the 300-mg/m(2) cumulative epirubicin dose. Interleukin (IL)-6, soluble IL-6 receptor, and reactive oxygen species (ROS) increased significantly at the 200-mg/m(2) dose, and IL-6 was persistently high at the 300- and 400-mg/m(2) doses, returning to within baseline values during follow-up. ROS, after the peak reached at the 200-mg/m(2) dose, returned to within baseline values. A significant inverse correlation between DeltaSR and the increase in both IL-6 and ROS was observed. A multiple regression analysis showed that both the IL-6 and ROS variables were independent and strongly predictive of DeltaSR. The clinical meaningfulness of our findings warrants further investigations on a larger number of patients for a longer period of follow-up.

Effects of an adapted physical activity program on motor and non-motor functions and quality of life in patients with Parkinson's disease

BACKGROUND Several studies have clearly shown that strategies of health promotion, such as fitness and general exercise programs, may improve quality of life (QoL), motor and non-motor functions in Parkinsons disease (PD) patients. However, little is known about the effects of specific Adapted Physical Activity (APA) programs on PD patients. OBJECTIVE To determine the effects of an APA program on motor and non-motor symptoms, functional performances and QoL in PD patients. METHODS Nine consecutive PD patients (5 men, 4 women, 64.4 ± 6.8 years) able to ambulate independently (Hoehn and Yahr: from stage 1 to 3) and not demented, were enrolled. Patients performed an APA program, 3 sessions/week, for 9 weeks. Exercises focused on balance, walking, strength and functional activities. Functional effects were assessed by Six Minute Walking Test (6MWT), Five Time Sit to Stand Test (FTSST), Berg Balance Scale (BBS), Sit and Reach Test (SRT), and Timed Up and Go test (TUG). Motor impairment and disability were assessed using the Unified Parkinsons Disease Rating Scale - part III (UPDRS-III) and the Hoehn and Yahr Scale, respectively. Non-motor symptoms were evaluated by PD Fatigue Scale (PFS), Beck Depression Inventory II (BDI-II) and PD Quality of life scale, 8 items (PDQ-8). RESULTS A significant decrease in resting HR (67.55 ± 10.85 vs 70.22 ± 12.34 bpm, p < 0.05) and a significant increase in walked distance (p < 0.0005) were observed. A significant impairment of the muscles strength was noted (FTSST, p < 0.05). BBS showed a significant increase in balance abilities (p < 0.0005) and safety with mobility (TUG, p < 0.005) was enhanced. Finally, a significant improvement in motor and non-motor symptoms was detected: UPDRS-III (p < 0.00005), PFS (p < 0.005), BDI-II (p < 0.05) and PDQ-8 (p < 0.05). CONCLUSIONS A tailored exercise program in PD patients could be effective as an adjunct to conventional therapy on improving daily activities, motor and non-motor symptoms, with better QoL.

Effects of a Nordic Walking program on motor and non-motor symptoms, functional performance and body composition in patients with Parkinson’s disease

BACKGROUND Several studies have clearly shown that physical exercise can reduce the progression of motor symptoms in Parkinsons Disease (PD). However, little is known about the effects of a Nordic Walking (NW) program in PD patients. OBJECTIVE To determine the effects of a NW program on motor and non-motor symptoms, functional performances and body composition in PD patients. METHODS Twenty PD patients (16M, 4F, 67.3±7.8 years) were enrolled and randomly assigned to NW group (NWg, n = 10) and Control group (Cg, n = 10). The training consisted in 2 sessions per week for 12 weeks. Training effects were assessed by functional and instrumental tests and motor and non-motor symptoms were assessed by UPDRS-III, Hoehn and Yahr scale, PD Fatigue Scale, Beck Depression Inventory-II, Starkstein Apathy Scale, and Non-Motor Symptoms Scale. RESULTS Significant changes in resting HR, in walked distance (p <  0.05), and in lower limbs muscles strength (p <  0.005) were observed in NWg. Both balance abilities and safety with mobility were increased (p <  0.005). Significant variations in some circumferences and body composition were registered. Finally, a significant improvement in motor and non-motor symptoms was detected: UPDRS-III, HY scale, PFS-16, BDI-II, SAS, NMSS. CONCLUSIONS A tailored exercise program including NW proved to be an effective way to improve daily activities and both motor and non-motor symptoms in PD patients.