Transcriptomic analysis and mutational status of IDH1 in paired primary-recurrent intrahepatic cholangiocarcinoma.

BACKGROUND: Effective target therapies for intrahepatic cholangiocarcinoma (ICC) have not been identified so far. One of the reasons may be the genetic evolution from primary (PR) to recurrent (REC) tumors. We aim to identify peculiar characteristics and to select potential targets specific for recurrent tumors. Eighteen ICC paired PR and REC tumors were collected from 5 Italian Centers. Eleven pairs were analyzed for gene expression profiling and 16 for mutational status of IDH1. For one pair, deep mutational analysis by Next Generation Sequencing was also carried out. An independent cohort of patients was used for validation. RESULTS: Two class-paired comparison yielded 315 differentially expressed genes between REC and PR tumors. Up-regulated genes in RECs are involved in RNA/DNA processing, cell cycle, epithelial to mesenchymal transition (EMT), resistance to apoptosis, and cytoskeleton remodeling. Down-regulated genes participate to epithelial cell differentiation, proteolysis, apoptotic, immune response, and inflammatory processes. A 24 gene signature is able to discriminate RECs from PRs in an independent cohort; FANCG is statistically associated with survival in the chol-TCGA dataset. IDH1 was mutated in the RECs of five patients; 4 of them displayed the mutation only in RECs. Deep sequencing performed in one patient confirmed the IDH1 mutation in REC. CONCLUSIONS: RECs are enriched for genes involved in EMT, resistance to apoptosis, and cytoskeleton remodeling. Key players of these pathways might be considered druggable targets in RECs. IDH1 is mutated in 30% of RECs, becoming both a marker of progression and a target for therapy.

Irinotecan and temozolomide in recurrent Ewing sarcoma: an analysis in 51 adult and pediatric patients.

BACKGROUND: Data on temozolomide (TEM) and irinotecan (IRI) activity in recurrent Ewing sarcoma (EWS), especially in adult patients, are limited. METHODS: Patients receiving TEM 100 mg/m2/day oral, and IRI 40 mg/m2/day intravenous, days 1-5, every 21 days, were included in this multi-institutional retrospective study. Disease control rate (DCR) [overall response rate (ORR) [complete response (CR) + partial response (PR)] + stable disease (SD)], 6-months progression-free survival (6-mos PFS) and 1-year overall survival (OS) were assessed. RESULTS: The median age of the 51 patients was 21 years (range 3-65 years): 34 patients (66%) were adults (≥18 years of age), 24 (48%) had ECOG 1 and 35 (69%) were presented with multiple site recurrence. TEMIRI was used at first relapse/progression in 13 (25%) patients, while the remainder received TEMIRI for second or greater relapse/progression. Fourteen (27%) patients had received prior myeloablative therapy with busulfan and melphalan. We observed five (10%) CR, 12 (24%) PR and 19 (37%) SD, with a DCR of 71%. 6-mos PFS was 49% (95% CI 35-63) and it was significantly influenced by ECOG (6-mos PFS 64% [95% CI 45-83] for ECOG 0, 34% [95% CI 14-54] for ECOG ≥1; p = .006) and LDH (6-mos PFS 62% [95% CI 44-79] for normal LDH, 22% [95% CI 3-42] for high LDH; p = .02), with no difference according to line of treatment, age and metastatic pattern. One-year OS was 55% (95% CI 39-70), with RECIST response (p = .001) and ECOG (p = .0002) independently associated with outcome. Grade 3 and 4 toxicity included neutropenia in 12% of patients, thrombocytopenia in 4%, diarrhea in 4%. CONCLUSIONS: This series confirms the activity of TEMIRI in both adults and pediatric patients. This schedule offers a 71% DCR, independently of the line of chemotherapy. Predictive factors of response are ECOG and LDH.

New European Clinical Trial Regulation: perception and expectations in Italy.

BACKGROUND: In July 2012, the European Commission formalized the proposal for a European Clinical Trial Regulation that should replace the European Clinical Trials Directive 2001/20/CE. The new Regulation 536/2014 entered into force in June 2014 and it was expected to be applied not earlier than May 2016. Indeed, at the time, all required central tools are not yet available and new forecasts indicate it will become effective at the end of 2018. The aims of the Regulation are the promotion of higher standards in patient's safety and increasing transparency in Clinical Trials, also by changing the application process. METHODS: An online survey was conducted among the Italian's Clinical Research Coordinators and Clinical Investigators to examine the perception and knowledge about the upcoming changes in Clinical Trials. A total of 190 Clinical Research Coordinators and 80 Clinical Investigators were surveyed. RESULTS: Clinicians are less aware of the content of the Regulation than Clinical Research Coordinators, who demonstrate an extensive expertise on the topic (84.4%), mainly reached through self-training. The majority of the Investigators (74%) believes that their site's facilities and staff already met all the requirements imposed by the Regulation while Clinical Research Coordinators are less optimistic: 65.2% of them believes that the site staff is not yet fully aware of changes associated to its implementation. CONCLUSIONS: The general opinion of the interviewed is that the new Regulation will strongly affect the trial management regardless of their type and phase, and the fulfillment of the imposed requirements represents an opportunity that Italy should not miss to increase its attractiveness to the pharmaceutical market.

Gemcitabine and docetaxel in relapsed and unresectable high-grade osteosarcoma and spindle cell sarcoma of bone.

BACKGROUND: Few new compounds are available for relapsed osteosarcoma. We retrospectively evaluated the activity of gemcitabine (G) plus docetaxel (D) in patients with relapsed high-grade osteosarcoma and high-grade spindle cell sarcoma of bone (HGS). METHODS: Patients receiving G 900 mg/m(2) d 1, 8; D 75 mg/m(2) d 8, every 21 days were eligible. Primary end-point: progression-free survival (PFS) at 4 months; secondary end-point: overall survival (OS) and response rate. RESULTS: Fifty-one patients were included, with a median age of 17 years (8-71), 26 (51%) were pediatric patients. GD line of treatment: 2nd in 14 patients, ≥3rd in 37. 25 (49%) patients had metastases limited to lungs, 26 (51%) multiple sites. HISTOLOGY: 40 (78%) osteosarcoma, 11 (22%) HGS. Eight (16%) patients achieved surgical complete response (sCR2) after GD. Four-month PFS rate was 46%, and significantly better for patients with ECOG 0 (ECOG 0: 54% vs ECOG 1: 43% vs ECOG 2: 0%; p = 0.003), for patients undergoing metastasectomy after GD (sCR2 75% vs no-sCR2 40 %, p = 0.02) and for osteosarcoma (osteosarcoma 56% vs HGS 18%; p = 0.05), with no differences according to age, line of treatment, and pattern of metastases. Forty-six cases had RECIST measurable disease: 6 (13%) patients had a partial response (PR), 20 (43%) had stable disease (SD) and 20 (43%) had progressive disease (PD). The 1-year OS was 30%: 67% for PR, 54% for SD and 20% for PD (p = 0.005). CONCLUSIONS: GD is an active treatment for relapsed high-grade osteosarcoma, especially for ECOG 0 patients, and should be included in the therapeutic armamentarium of metastatic osteosarcoma.

Listeria Monocytogenes: an uncommon pathogen of cervical necrotizing fasciitis.

The aim of this paper is to present a unique case of neck-necrotizing fasciitis caused by Listeria Monocytogenes in a young woman, successfully treated by surgery and IV antibiotic therapy. Necrotizing fasciitis is a rare, rapidly progressing and potentially life-threatening infection that infrequently occurs in the head and neck region. Pathogens involved in necrotizing fasciitis are heterogeneous and include aerobic and anaerobic bacteria. To the best of our knowledge, this is the only case of neck necrotizing fasciitis caused by Listeria Monocytogenes studied in literature so far.

[Usefulness of the MPB-INFURG-SEMES model to predict bacteremia in the patient with solid tumor in the Emergency Department]. / Utilidad del modelo MPB-INFURG-SEMES para predecir bacteriemia en el paciente con neoplasia sólida en el Servicio de Urgencias.

OBJECTIVE: To analyse a new risk score to predict bacteremia (MPB-INFURG-SEMES) in the patients with solid tumor attender for infection in the emergency departments (ED). METHODS: Prospective, multicenter observational cohort study of blood cultures (BC) obtained from adult patients with solid neoplasia treated in 63 EDs for infection from November 1, 2019, to March 31, 2020. The predictive ability of the model was analyzed with the area under the Receiver Operating Characteristic curve (AUC-ROC). The prognostic performance for true bacteremia was calculated with the chosen cut-off for getting the sensitivity, specificity, positive predictive value and negative predictive value. RESULTS: A total of 857 blood samples wered cultured. True cases of bacteremia were confirmed in 196 (22.9%). The remaining 661 cultures (77.1%) wered negative. And, 42 (4.9%) were judged to be contaminated. The model's area under the receiver operating characteristic curve was 0.923 (95% CI,0.896-0.950). The prognostic performance with a model's cut-off value of ≥ 5 points achieved 95.74% (95% CI, 94,92-96.56) sensitivity, 76.06% (95% CI, 75.24-76.88) specificity, 53.42%(95% CI, 52.60-54.24) positive predictive value and 98.48% (95% CI, 97.66- 99.30) negative predictive value. CONCLUSIONS: The MPB-INFURG-SEMES score is useful for predicting bacteremia in the adults patients with solid tumor seen in the ED.

LSD1 is an environmental stress-sensitive negative modulator of the glutamatergic synapse.

Along with neuronal mechanisms devoted to memory consolidation -including long term potentiation of synaptic strength as prominent electrophysiological correlate, and inherent dendritic spines stabilization as structural counterpart- negative control of memory formation and synaptic plasticity has been described at the molecular and behavioral level. Within this work, we report a role for the epigenetic corepressor Lysine Specific Demethylase 1 (LSD1) as a negative neuroplastic factor whose stress-enhanced activity may participate in coping with adverse experiences. Constitutively increasing LSD1 activity via knocking out its dominant negative splicing isoform neuroLSD1 (neuroLSD1KO mice), we observed extensive structural, functional and behavioral signs of excitatory decay, including disrupted memory consolidation. A similar LSD1 increase, obtained with acute antisense oligonucleotide-mediated neuroLSD1 splicing knock down in primary neuronal cultures, dampens spontaneous glutamatergic transmission, reducing mEPSCs. Remarkably, LSD1 physiological increase occurs in response to psychosocial stress-induced glutamatergic signaling. Since this mechanism entails neuroLSD1 splicing downregulation, we conclude that LSD1/neuroLSD1 ratio modulation in the hippocampus is instrumental to a negative homeostatic feedback, restraining glutamatergic neuroplasticity in response to glutamate. The active process of forgetting provides memories with salience. With our work, we propose that softening memory traces of adversities could further represent a stress-coping process in which LSD1/neuroLSD1 ratio modulation may help preserving healthy emotional references.

Denosumab in advanced/unresectable giant-cell tumour of bone (GCTB): For how long?

BACKGROUND: Giant-cell tumours of bone (GCTB) are RANK/RANK-ligand (RANKL) positive, aggressive and progressive osteolytic tumours. Denosumab, a RANKL inhibitor, was FDA-approved for adults and skeletally mature adolescents with unresectable GCTB or when surgical resection is likely to result in severe morbidity. Data on long-term toxicity and activity of denosumab monthly 'GCTB-schedule' (120 mg per 12/year, 1440 mg total dose/year) are lacking. METHODS: Patients with GCTB receiving denosumab, 120 mg on days 1, 8, 15, 29 and every 4 weeks thereafter, from 2006 to 2015 treated in two centres were included. Long-term toxicity was evaluated. RESULTS: Ninety-seven patients were identified. 43 patients underwent resection of the tumour with a median time on denosumab treatment of 12 months (range 6-45 months). Fifty-four patients had unresectable GCTB's (male/female 23/31, median age 35 years [range: 13-76 years], 26% presented with lung metastases, 31% had primary tumor located to the spine, 63% were relapsed after previous surgery) with a median time on denosumab of 54 months (9-115 months). In the unresectable GCTB group, tumour control and clinical benefits were observed in all patients undergoing denosumab, whereas 40% of patients discontinuing denosumab had tumour progression after a median of 8 months (range 7-15 months). ADVERSE EVENTS: Overall, six (6%) patients developed osteonecrosis of jaw (ONJ): 1/43 (2%) in the resectable group, 5/54 (9%) in the unresectable group, with a 5-year ONJ-free survival of 92% (95% CI 84-100). Only patients with prolonged treatment experienced mild peripheral neuropathy (6/54, 11%), skin rash (5/54, 9%), hypophosphataemia (2/54, 4%) and atypical femoral fracture (2/54, 4%). CONCLUSIONS: Prolonged treatment with denosumab has sustained activity in GCTB, with a mild toxicity profile. The dose-dependent toxicity observed recommends a careful and strict monitoring of patients who need prolonged treatment. Decreased dose-intensity schedules should be further explored in unresectable GCTB.

In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor.

BACKGROUND: The leukemia cells of approximately 95% of patients with chronic myeloid leukemia and 30%-50% of adult patients with acute lymphoblastic leukemia express the Bcr/Abl oncoprotein, which is the product of a fusion gene created by a chromosomal translocation [(9:22) (q34;q11)]. This oncoprotein expresses a constitutive tyrosine kinase activity that is crucial for its cellular transforming activity. In this study, we evaluated the antineoplastic activity of CGP57148B, which is a competitive inhibitor of the Bcr/Abl tyrosine kinase. METHODS: Nude mice were given an injection of the Bcr/Abl-positive human leukemia cell lines KU812 or MC3. Tumor-bearing mice were treated intraperitoneally or orally with CGP57148B according to three different schedules. In vitro drug wash-out experiments and in vivo molecular pharmacokinetic experiments were performed to optimize the in vivo treatment schedule. RESULTS: Treatment schedules administering CGP57148B once or twice per day produced some inhibition of tumor growth, but no tumor-bearing mouse was cured. A single administration of CGP57148B caused substantial (>50%) but short-lived (2-5 hours) inhibition of Bcr/Abl kinase activity. On the basis of the results from in vitro wash-out experiments, 20-21 hours was defined as the duration of continuous exposure needed to block cell proliferation and to induce apoptosis in these two leukemia cell lines. A treatment regimen assuring the continuous block of the Bcr/Abl phosphorylating activity that was administered over an 11-day period cured 87%-100% of treated mice. CONCLUSION: These data indicate that the continuous block of the oncogenic tyrosine kinase of Bcr/Abl protein is needed to produce important biologic effects in vivo.

Inhibition of promyelocytic leukemia (PML)/retinoic acid receptor-alpha and PML expression in acute promyelocytic leukemia cells by anti-PML peptide nucleic acid.

The fusion protein promyelocytic leukemia (PML)/retinoic acid receptor (RAR)alpha is tightly linked to the pathogenesis of acute promyelocytic leukemia (APL); hence, it represents a tumor-associated, transformation-related molecule. In this study, three anti-PML adamantyl-conjugated peptide nucleic acid (PNA) oligomers previously described as in vitro inhibitors of PML/RARalpha translation were combined and used to block PML/RARalpha synthesis in NB4 cells. Cationic liposomes were used to achieve sufficient delivery of PNAs into the cells. Upon treatment of cells with the liposome/PNA mixture, enhanced cellular uptake of PNA (approximately 5-fold compared with control) was obtained. Concomitantly, a substantial reduction (>90%) of the expression of PML/RARalpha was observed when all of the three PNAs were used together. This resulted in a dramatic effect on the number and viability of NB4 cells in culture after 48 h of treatment. This phenomenon was preceded by induction of apoptosis that could be observed 24 h after treatment. No sign of granulocytic differentiation was observed after treatment. These effects were also noted on other leukemic cell lines that express PML but not the fusion transcript. These results show that it is possible to deliver PNA into hematopoietic cells and obtain specific gene inhibition, and they suggest that a growth inhibitory effect on acute promyelocytic leukemia cells can be obtained through the block of PML/RARalpha and PML expression.

Differential recognition of a BCR/ABL peptide by lymphocytes from normal donors and chronic myeloid leukemia patients.

The BCR/ABL oncogenic fusion protein transforms normal bone marrow stem cells into neoplastic cells. It has been shown that peptides derived from the junctional region of this oncogenic fusion protein can be recognized by human T-lymphocytes obtained from normal donors. In this study, we investigated the immunogenicity in patients with chronic myeloid leukemia (CML) of a 17 mer b3/a2 Bcr/abl peptide (B/A1), which was shown to induce proliferative responses in lymphocytes from normal donors. A total of 56 CML patients in chronic phase were studied. Twenty-two patients were studied at diagnosis without any treatment (group I). Fourteen patients were receiving IFN (group II), 14 patients were being treated with hydroxyurea (group III), and 6 patients were on different regimens (group IV). Patients were initially assessed for general immunological competence using both in vivo and in vitro assays. Patients were also selected for the expression of HLA-DR0401, the HLA specificity known to present peptide B/A1 to CD4 lymphocytes. With the exception of the six patients in group IV, the results of all these assays (in vitro phytohemagglutinin/tetanus toxoid responses, in vivo skin reaction to ubiquitous antigens) in CML patients did not significantly differ from those obtained in normal donors, thus excluding the presence of generalized immunosuppression. Eight patients with HLA-DR0401 and a b3/a2 type of fusion were identified and further studied. In these eight patients dendritic cells were obtained from adherent peripheral blood mononuclear cells and used to stimulate CD4 lymphocytes. No patient developed a specific response to the bcr/abl peptide, although patients' lymphocytes proliferated in response to a promiscuous tetanus toxoid peptide in all but one case. In contrast, response to the bcr/abl peptide was observed in seven of eight HLA-DR0401 healthy donors tested. These data suggest that immunocompetent, HLA-DR0401+ CML patients are unable to respond to peptide B/A1, at difference from healthy donors. The implication of these results for the immunotherapy of CML is discussed.

Lack of T-cell-mediated recognition of the fusion region of the pml/RAR-alpha hybrid protein by lymphocytes of acute promyelocytic leukemia patients.

In previous studies, it was shown that the fusion region of the pml/RAR-alpha protein, expressed by acute promyelocytic leukemia (APL) cells, can be specifically recognized in vitro by donor (D. E. ) CD4 T cells in a HLA class II DR11-restricted fashion. We present here the results on the recognition of several pml/RAR-alpha peptides by APL patients expressing HLA DR11. The in vitro immunization of peripheral blood lymphocytes from four patients in remission (S. R., F. R., M. M., P. G.) with BCR1/25, a 25-mer pml/RAR-alpha, did not elicit either a polyclonal or a clonal immune response specific to the peptide. We then generated new donor anti-pml/RAR-alpha CD4(+) T-cell clones. These clones were tested for their recognition of BCR1/25. One clone (C3/5, CD3(+), CD4(+), CD8(-)) was selected for further analysis. Clone C3/5 showed specific proliferation, cytotoxicity, and cytokine (tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor) production when challenged with autologous lymphoblastic cell lines pulsed with peptide BCR1/25. C3/5 cells developed specific proliferation and cytotoxicity when challenged with peptide-pulsed lymphoblastic cell lines and peripheral blood lymphocytes from the four DR11(+) APL patients. APL blasts, available only from patients F. R. and P. G., were not lysed by C3/5 and were unable to present peptide BCR1/25. Incubation of APL cells with IFN-gamma failed to induce HLA class II molecules and recognition by the C3/5 clone. Since APL cells do not express HLA class II molecules, we tested in two donors (D. E. and C. H. R.) and in patients S. R. and P. G. whether the use of 9-mer peptides (BCR1/9) would generate a CD8/HLA class I-restricted response. No peptide-specific T-cell line or clone could be generated from both donors and patients. These findings are discussed in relation to possible therapeutic approaches to the immunotherapy of APL.

Cardiovascular autonomic modulation in essential hypertension. Effect of tilting.

To better understand the role played by the autonomic nervous system in essential hypertension, we used autoregressive power spectrum analysis to study the noncasual oscillations in RR interval, blood pressure, and skin blood flow in 40 subjects with mild to moderate hypertension and in 25 age-matched control subjects at low frequency (index of sympathetic activity to the heart and the peripheral circulation) and high frequency, respiratory related (index of vagal tone to the heart). RR interval, respiration, noninvasive systolic blood pressure, and skin arteriolar blood flow were simultaneously and continuously recorded with subjects in the supine position and immediately after tilting. The low-frequency component was not significantly different in the two groups either at the cardiac level (control versus hypertensive subjects: 39.1 +/- 4.3 versus 39.9 +/- 3.7 normalized units [NU]) or at the vascular level (1.52 +/- 0.17 versus 1.69 +/- 0.13 ln mm Hg2). After head-up tilting, the RR interval fluctuations were less in hypertensive subjects (low-frequency components from 39.9 +/- 3.7 to 48.4 +/- 4.1 NU, P < .05; high-frequency components from 53.9 +/- 3.7 to 44 +/- 4 NU, P < .05) than in control subjects (low-frequency components from 39.1 +/- 4.3 to 64.4 +/- 4.9 NU, P < .001; high-frequency components from 56.0 +/- 4.5 to 31.2 +/- 4.6 NU, P < .001); the low-frequency components in systolic blood pressure increased similarly in hypertensive subjects (to 2.43 +/- 0.17 ln mm Hg2, P < .0001) and in control subjects (to 2.44 +/- 0.21 ln mm Hg2, P < .01), but the low-frequency components in skin blood flow increased only in control subjects (from 5.34 +/- 0.45 to 6.55 +/- 0.53 mm Hg2, P < .01), not in hypertensive subjects (from 5.55 +/- 0.34 to 5.60 +/- 0.35 ln mm Hg2). In hypertensive subjects with left ventricular hypertrophy, the low-frequency components in systolic blood pressure did not increase after tilting (from 1.75 +/- 0.33 to 2.05 +/- 0.41 ln mm Hg2). Baroreflex sensitivity, as assessed by spectrum analysis, was significantly lower in hypertensive than in control subjects (5.17 +/- 0.49 versus 13.18 +/- 2.44 ms/mm Hg, P < .001. Power spectrum analysis did not reveal an increased sympathetic activity or reactivity either at the cardiac or at the vascular level. The decreased baroreceptor sensitivity in hypertensive subjects could explain the reduced change in sympathovagal balance in the tilt position at the cardiac level. In hypertensive subjects without left ventricular hypertrophy, cardiopulmonary reflex deactivation induced by tilting and/or amplification of sympathetic nervous tone by arteriolar structural change could have preserved the sympathetic activation at the vascular level.

Medium effects on the antioxidant activity of dipyridamole.

Very strong medium effects have been observed when testing the antioxidant activity of dipyridamole (DP) in different media such as benzene, tert-butanol, methanol solutions and egg yolk lecithin unilamellar and multilamellar vesicles. Actually, dipyridamole behaves as a very poor antioxidant in benzene while its ability to inhibit the lipid peroxidation reaction increases with increasing solvent polarity, being the highest in lipid vesicles. This behavior can not be rationalized on the basis of the classical chain breaking mechanism which operates in the case of phenolic and amine antioxidants and involving the transfer of a hydrogen atom to peroxyl radicals. An explanation is instead given in terms of an electron transfer reaction which leads to the oxidation of DP by the chain carrying peroxyl radical to give the dipyridamole cation radical, DP+*, and the peroxyl anion LOO-, and whose rate constant is expected to increase in strongly polar media. EPR and electrochemical data supporting this interpretation have been collected.

Photoreduction of the fluorescent dye 2'-7'-dichlorofluorescein: a spin trapping and direct electron spin resonance study with implications for oxidative stress measurements.

The photoreduction of 2'-7'-dichlorofluorescein (DCF) was investigated in buffer solution using direct electron spin resonance (ESR) and the ESR spin-trapping technique. Anaerobic studies of the reaction of DCF in the presence of reducing agents demonstrated that during visible irradiation (lambda > 300 nm) 2'-7'-dichlorofluorescein undergoes one-electron reduction to produce a semiquinone-type free radical as demonstrated by direct ESR. Spin-trapping studies of incubations containing DCF, 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and either reduced glutathione (GSH) or reduced NADH demonstrate, under irradiation with visible light, the production of the superoxide dismutase-sensitive DMPO/*OOH adduct. In the absence of DMPO, measurements with a Clark-type oxygen electrode show that molecular oxygen is consumed in a light-dependent process. The semiquinone radical of DCF, when formed in an aerobic system, is immediately oxidized by oxygen, which regenerates the dye and forms superoxide.

Perindopril versus captopril: efficacy and acceptability in an Italian multicenter trial.

The aim of this 3-month, double-blind, double-dummy, parallel group study was to compare the antihypertensive efficacy and acceptability of perindopril (4-8 mg/day) in 54 patients (30 males, 24 females, 25-68 years of age) and captopril (50-100 mg/day) in 54 patients (39 males, 15 females, 29-66 years of age) in the treatment of essential hypertension. In a subgroup of 38 patients a complete echocardiographic study was performed. The two groups had similar (ANOVA) blood pressure (BP), heart rate (HR), body mass index, and duration of hypertension. Supine and standing BP was significantly reduced by both drugs, without differences between them. Owing to poor control of BP, hydrochlorothiazide (25 mg/day) was added to 27% of patients on perindopril and to 41% of patients on captopril (p less than 0.05). Normalization of supine diastolic BP (less than or equal to 90 mm Hg) was obtained in 67% of patients on perindopril and in 47% of patients on captopril (p less than 0.01). No change in HR was detected. Only mild untoward effects were recorded. Left ventricular mass was significantly reduced by either drug, with no change in systolic function. In conclusion, perindopril and captopril, at these doses, were both well tolerated and on average reduced BP to a similar extent; however, treatment with perindopril showed that fewer patients needed the addition of a thiazide and BP became normal in a larger number of patients.

Presence of autoantibodies against oxidatively modified low-density lipoprotein in essential hypertension: a biochemical signature of an enhanced in vivo low-density lipoprotein oxidation.

OBJECTIVE: We have previously reported that low-density lipoproteins (LDL) isolated from patients with essential hypertension are more susceptible to in vitro oxidation than lipoproteins isolated from normotensive control subjects. In the present study we investigated the occurrence of in vivo LDL oxidation in hypertensive patients. DESIGN: The presence of antioxidatively modified LDL autoantibodies was taken as a suitable index of in vivo LDL oxidation because, after oxidative modifications, LDL express antigenic epitopes that elicit an immune response. The antibody titres were measured in plasma from untreated patients with newly diagnosed essential hypertension. METHODS: An enzyme-linked immunosorbent assay method was employed, using native LDL, Cu(2+)-oxidized LDL and malondialdehyde-derivatized LDL (MDA-LDL) as antigens. Human serum albumin and MDA human serum albumin were also used to monitor cross-reactivity with other oxidized molecules. The antibody titre was expressed as the ratio between anti-modified and anti-native antigen absolute values. RESULTS: The patients with essential hypertension had an antibody ratio significantly higher than control subjects with respect to anti-Cu(2+)-oxidized LDL immunoglobulins G and M, and with respect to anti-MDA-LDL immunoglobulins G and M. A significant positive correlation was found between anti-MDA-LDL and anti-Cu(2+)-oxidized LDL antibody titres. The anti-MDA human serum albumin antibody titre was not different in the two groups of patients. An inverse correlation was detected between the anti-MDA-LDL immunoglobulin M titre and the age of the patients. CONCLUSIONS: The results obtained are consistent with the view that, during the early phases of hypertension development, LDL undergo in vivo oxidation that is mirrored by the generation of autoantibodies against epitopes of oxidized LDL. The oxidation process appears specific for LDL and might be relevant both for the progression of hypertension and for the development of the atherosclerosis that often complicates hypertension itself.

Low-density lipoprotein oxidation in essential hypertension.

OBJECTIVES: To investigate the occurrence of enhanced low-density lipoprotein (LDL) oxidation as an additional factor promoting atherosclerosis progression in hypertensive patients. DESIGN: The oxidation of plasma LDL was investigated in a group of untreated patients with mild-to-moderate essential hypertension without clinically evident target organ damage and in a group of control subjects. METHODS: LDL oxidation was evaluated as both the susceptibility to oxidation in vitro and the presence of plasma anti-oxidized LDL antibodies (as an index for oxidation in vivo). RESULTS: LDL from hypertensive subjects exhibited enhanced susceptibility to oxidation in vitro as revealed by early and accelerated generation of conjugated dienes after exposure to CuSO4. Vitamin E concentration in LDL from hypertensive subjects was slightly but significantly decreased and its efficiency in protecting LDL from oxidation was impaired. Furthermore, a higher plasma anti-oxidized LDL titre was found in hypertensive patients. Subclass analysis revealed that the contemporary presence of hypercholesterolaemia did not significantly modify either the increased susceptibility of LDL to oxidation or the presence of plasma anti-oxidized LDL antibodies detected in hypertensive patients. Moreover, no correlation was found between LDL oxidation parameters and blood pressure values. CONCLUSIONS: LDL from hypertensive patients is more susceptible to oxidation in vitro and is more promptly oxidized in vivo. These findings suggest a possible participation of LDL oxidation in promoting and accelerating the atherosclerosis that often develops in hypertensive patients.

Effect of enalapril on left ventricular mass and performance in essential hypertension.

The effect of enalapril on left ventricular (LV) morphology and function was studied in 12 hypertensive patients. The subjects were evaluated after 2 weeks of placebo and after 4 months of treatment with enalapril (20 or 40 mg once daily), using M-mode digitized echocardiograms. The drug reduced arterial blood pressure in all patients. Systemic vascular resistance decreased significantly without changes in cardiac output and heart rate. No patient had significant side effects. After treatment LV mass decreased significantly (233 +/- 46 to 204 +/- 37 g, p less than 0.01); the reduction was due to a decrease in septal and posterior wall thickness, without changes in LV diameter. LV systolic function remained unchanged, whereas peak lengthening rate of LV dimension, an index of LV diastolic function, increased significantly (4.05 +/- 1.8 to 5.11 +/- 1.8 s-1, p less than 0.01). After treatment the basal inverse correlation between peak shortening rate and wall stress did not change, the inverse correlation between peak lengthening rate and wall stress became closer and the basal inverse correlation between peak lengthening rate and LV mass disappeared. In conclusion, antihypertensive treatment with enalapril led to a significant regression of LV hypertrophy associated with improvement in LV diastolic performance and no deterioration of LV systolic function.

Double-blind comparison of perindopril and captopril in hypertension. Effects on left ventricular morphology and function.

Using digitized M-mode echocardiograms, we compared, in a double-blind study, the effects of 4 to 8 mg perindopril given once daily and 25 to 50 mg captopril given twice daily on the left ventricle (LV) in 20 hypertensive patients. Both treatments significantly (P less than .001) lowered blood pressure, reducing systemic vascular resistances. After 3 months both drugs induced a comparable percentage of reduction in LV mass, with an increase in the peak rate of LV relaxation and no changes in the peak rate of LV contraction. Our results demonstrate that perindopril once daily is an effective antihypertensive agent; it is also able, like captopril, to induce regression of LV hypertrophy, with improvement in diastolic performance and no deterioration in ventricular systolic function.