Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence.

PURPOSE: AE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis. METHODS: In this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated. RESULTS: 456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573 CI 0.275-1.193), HER2 under-expression (p = 0.181, HR 0.756 CI 0.499-1.145), and triple-negative breast cancer (p = 0.266, HR 0.443 CI 0.114-1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375 CI 0.142-0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG. CONCLUSIONS: This phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.

Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide AE37 vaccine in breast cancer patients to prevent recurrence.

BACKGROUND: AE37 is the Ii-Key hybrid of the MHC class II peptide, AE36 (HER2 aa:776-790). Phase I studies showed AE37 administered with granulocyte macrophage colony-stimulating factor (GM-CSF) to be safe and highly immunogenic. A prospective, randomized, multicenter phase II adjuvant trial was conducted to evaluate the vaccine's efficacy. METHODS: Clinically disease-free node-positive and high-risk node-negative breast cancer patients with tumors expressing any degree of HER2 [immunohistochemistry (IHC) 1-3+] were enrolled. Patients were randomized to AE37 + GM-CSF versus GM-CSF alone. Toxicity was monitored. Clinical recurrences were documented and disease-free survival (DFS) analyzed. RESULTS: The trial enrolled 298 patients; 153 received AE37 + GM-CSF and 145 received GM-CSF alone. The groups were well matched for clinicopathologic characteristics. Toxicities have been minimal. At the time of the primary analysis, the recurrence rate in the vaccinated group was 12.4% versus 13.8% in the control group [relative risk reduction 12%, HR 0.885, 95% confidence interval (CI) 0.472-1.659, P = 0.70]. The Kaplan-Meier estimated 5-year DFS rate was 80.8% in vaccinated versus 79.5% in control patients. In planned subset analyses of patients with IHC 1+/2+ HER2-expressing tumors, 5-year DFS was 77.2% in vaccinated patients (n = 76) versus 65.7% in control patients (n = 78) (P = 0.21). In patients with triple-negative breast cancer (HER2 IHC 1+/2+ and hormone receptor negative) DFS was 77.7% in vaccinated patients (n = 25) versus 49.0% in control patients (n = 25) (P = 0.12). CONCLUSION: The overall intention-to-treat analysis demonstrates no benefit to vaccination. However, the results confirm that the vaccine is safe and suggest that vaccination may have clinical benefit in patients with low HER2-expressing tumors, specifically TNBC. Further evaluation in a randomized trial enrolling TNBC patients is warranted.

Effects of olive oil wastes on river basins and an oligotrophic coastal marine ecosystem: a case study in Greece.

This work aims to contribute to the knowledge of the impacts of olive oil waste discharge to freshwater and oligotrophic marine environments, since the ecological impact of olive oil wastes in riverine and coastal marine ecosystems, which are the final repositories of the pollutants, is a great environmental problem on a global scale, mostly concerning all the Mediterranean countries with olive oil production. Messinia, in southwestern Greece, is one of the greatest olive oil production areas in Europe. During the last decade around 1.4×10(6)tons of olive oil mill wastewater has been disposed in the rivers of Messinia and finally entered the marine ecosystem of Messiniakos gulf. The pollution from olive oil mill wastewater in the main rivers of Messinia and the oligotrophic coastal zone of Messiniakos gulf and its effects on marine organisms were evaluated, before, during and after the olive oil production period. Elevated amounts of phenols (36.2-178 mg L(-1)) and high concentrations of ammonium (7.29-18.9 mmol L(-1)) and inorganic phosphorus (0.5-7.48 mmol L(-1)) were measured in small streams where the liquid disposals from several olive oil industries were gathered before their discharge in the major rivers of Messinia. The large number of olive oil units has downgraded the riverine and marine ecosystems during the productive period and a period more than five months is needed for the recovery of the ecosystem. Statistical analysis showed that the enrichment of freshwater and the coastal zone of Messiniakos gulf in ammonia, nitrite, phenols, total organic carbon, copper, manganese and nickel was directly correlated with the wastes from olive oil. Toxicity tests using 24h LC50 Palaemonidae shrimp confirm that olive mill wastewater possesses very high toxicity in the aquatic environment.

Estimation of maspin's subcellular localization in invasive ductal breast cancer via light microscopy and computerized image analysis: a comparative study.

PURPOSE: Contradictory results have been reported concerning the role of maspin and its cellular distribution in breast cancer. The purpose of this study was to examine the subcellular localization (nuclear-cytoplasmic) of maspin in breast cancer and to compare the evaluation of maspin immunostaining via light microscopy (LM) to the estimation via computerized image analysis (CIA) system. We also examined correlations between maspin expression and several clinicopathological parameters. METHODS: The sample consisted of 48 primary invasive ductal carcinomas (IDC) of the breast. Maspin immunostaining was quantified and graded via LM by two pathologists, separately in the nuclear and cytoplasmic compartments. Total maspin expression was also estimated via CIA system. Univariate non-parametric statistics and stepwise multivariate ordinal logistic regression were performed. RESULTS: Both maspin components (nuclear and cytoplasmic) were closely associated with each other (p<0.001). Total maspin score was positively and closely associated with nuclear maspin (p<0.001) and cytoplasmic maspin (p<0.001). Total maspin , nuclear maspin and cytoplasmic maspin did not correlate significantly with either age, grade, T, N and M status, stage, micro vessel density (MVD) (CD34), ki-67, p53, estrogen receptor (ER) and HER-2 status, or with any of the 4 groups of the molecular classification. The only factor that showed a borderline inverse correlation with nuclear maspin (p=0.059) was progesterone receptors (PR) positivity. CONCLUSION: The cytoplasmic and nuclear fractions of maspin seem to be closely interwoven. Evidently, both mutually intertwined counterparts were independently reflected upon the total maspin levels measured by CIA. Future studies should ideally encompass all three approaches (nuclear, cytoplasmic, total) adopted herein.

Cardiac rehabilitation effects on quality of life in patients after acute myocardial infarction.

Aim of this study was to investigate the significance of cardiac rehabilitation (CR) on Health Related Quality of Life ( HRQoL) in post acute myocardial infarction (AMI) patients. Methods. A total number off 110 individuals divided in 3 groups was included in the study. Group A consisted of 60 post-AMI pts participating in a CR program. It was a multidisciplinary rehabilitative approach including supervised bike exercise, with parallel education, counselling, psychological and social support, performed 3 times per week for 2 months after AMI . Group B consisted of 40 post-AMI pts not participating in any CR program while the control group C consisted of 10 apparently healthy people. HRQoL was evaluated by the Velasco-Del Barrio questionnaire. Questions on this questionnaire are reffered to 9 categories (health, sleep and rest, emotional behavior, concerns for the future, mobility, social interaction, alertness behavior, communication, work and leisure time). A 5-point scale (1=all of the time, 5=none of the time) and a special (1 to 8) coefficient for each parameter were used for the evaluation of each parameter. The highest score of 220 indicates the poorest QL. Results. Group A pts had better score of HRQoL as compared to Group B (94±3 vs 114±3, p<0.001) and slightly worse than Group C pts (94±4 vs 69±3, p<0.01).Significant difference was found among Group A and B pts regarding the most important evaluated parameters such as symptoms (17±6.8 vs 22±6.5, p<0.001) and social behavior (21±4.2 vs 23±5.5, p<0.0001).Conclusion. It is concluded that participation in a multidisciplinary CR program significantly improves HRQoL in post AMI pts. All these pts must urged to take part in such programs.

Relationship between isokinetic strength of the internal and external shoulder rotators and ball velocity in team handball.

BACKGROUND: The purpose of this study was to examine the relationship between the rotational strength of shoulder and ball velocity in team handball players from various levels. METHODS: Three groups of young healthy, male subjects took part in the experiments: one group of 15 handball players, the best of League A1 scorers, another group of 12 handball players, the best of League A2 scorers and a random sample of 15 physical education students. Each subject was tested on a Cybex II isokinetic dynamometer. The concentric action of the internal and external rotation of the dominant shoulder was examined at 60, 180 and 300 deg/sec. Ball velocity was examined in three types of throw: (a) on the spot, (b) with a cross-over step, and (c) with a vertical jump. Statistical analysis was performed using the Pearson product-moment correlation and one-way analysis of variance. RESULTS: The differences of peak torque values of the internal and external shoulder rotation between the three groups were not statistically significant. The differences between groups regarding ball velocity in all types of throw were statistically significant (p<0.001). The relationship between IR and ER rotation of the shoulder and ball velocity was not statistically significant, except the jump shot. CONCLUSIONS: The main finding of this study was that peak torque of IR and ER of the shoulder was not a good indicator of throwing velocity at any type of throw, except the jump shot, in all subjects, regardless of their throwing ability.

Personality disorders in drug abusers: prevalence and their association with AXIS I disorders as predictors of treatment retention.

A sample of 226 drug-dependent individuals consecutively admitted to treatment in the major therapeutic programmes in Greece were assessed at intake with the EuropASI and SCL-90-R. At 4 to 6 weeks, 173 who were continuing treatment were reassessed with the SCL-90-R and interviewed with the SCID-R and the CIDI. Mean age of the subjects was 28 years, and 82.3% were male. Heroin was the main substance of abuse for the large majority (89.8%). Prevalence of AXIS II personality disorders (PD) was 59.5% and the majority (61.2%) had more than one PD. Cluster B was diagnosed in almost half of the subjects (48.6%), Antisocial Personality Disorder (APD) being the most prevalent (33.5%) type of PD. Subjects with APD had an earlier age of initiation of illicit drug use than those without. Subjects with a PD had twice the odds of having a comorbid AXIS I diagnosis and three times the odds of having a mood disorder than those without a PD. SCL-90-R assessments showed that psychiatric symptoms were significantly reduced in the period between intake and the fourth week in treatment. Somatization, Depression and Anxiety symptoms were however less reduced in subjects with a PD than in those without PD. Dropping out from treatment was more strongly predicted by AXIS I than AXIS II disorders, with an increased probability of dropping out in the presence of current mood disorders, whereas current anxiety disorder predicted treatment retention.