Carboplatin-paclitaxel compared to Carboplatin-Paclitaxel-Bevacizumab in advanced or recurrent endometrial cancer: MITO END-2 - A randomized phase II trial.

OBJECTIVE: Increased Vascular Endothelial Growth Factor Receptor (VEGF) expression in endometrial cancer (EC) is associated with a poor prognosis. Preliminary clinical data reported Bevacizumab effectiveness in EC both as single agent and in combination with chemotherapy. METHODS: In a phase II trial, patients with advanced (FIGO stage III-IV) or recurrent EC were randomized to receive Carboplatin-Paclitaxel standard dose for 6-8 cycles vs Carboplatin-Paclitaxel and Bevacizumab 15 mg/kg in combination with chemotherapy and maintenance until disease progression or unacceptable toxicity. The primary endpoint was progression free survival (PFS). RESULTS: 108 patients were randomized; PFS (10.5 vs 13.7 months, HR 0.84 p = 0.43), overall response rate (ORR 53.1% vs 74.4%) and overall survival (OS) (29.7 vs 40.0 months, HR 0.71 p = 0.24) resulted in a non-significant increase in Bevacizumab treated patients. The PFS increase became significant when an exploratory analysis with the Breslow test was used. Moreover, patients treated with Bevacizumab experienced a significant increase in 6-month disease control rate (70.4% vs 90.7%). Cardiovascular events were more frequent in the experimental arm ("de novo" grade ≥2 hypertension 21% vs 0% and grade ≥2 thromboembolic events 11% vs 2% in the Bevacizumab vs standard treatment arm, respectively). CONCLUSIONS: Bevacizumab combined with chemotherapy in the treatment of advanced/recurrent EC failed to demonstrate a significant increase in PFS in the MITO END-2 trial. Nevertheless, these preliminary data suggests some effectiveness of the antiangiogenic agent which merits further exploration in a larger population with a better molecular characterization.

Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC.

BACKGROUND: RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points. PATIENTS AND METHODS: Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored. RESULTS: At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1-26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0-29.8) with sunitinib-everolimus [hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9-1.6]. Median OS was 22.4 months (95% CI 18.6-33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8-33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9-1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences. CONCLUSIONS: Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals. CLINICAL TRIALS NUMBER: ClinicalTrials.gov identifier, NCT00903175.

Prospective phase II trial of trabectedin in BRCA-mutated and/or BRCAness phenotype recurrent ovarian cancer patients: the MITO 15 trial.

BACKGROUND: Current evidence suggest that trabectedin is particularly effective in cells lacking functional homologous recombination repair mechanisms. A prospective phase II trial was designed to evaluate the activity of trabectedin in the treatment of recurrent ovarian cancer patients presenting BRCA mutation and/or BRCAness phenotype. PATIENTS AND METHODS: A total of 100 patients with recurrent BRCA-mutated ovarian cancer and/or BRCAness phenotype (≥2 previous responses to platinum) were treated with trabectedin 1.3 mg/mq i.v. q 3 weeks. The activity of the drug with respect to BRCA mutational status and to a series of polymorphisms [single-nucleotide polymorphisms (SNPs)] involved in DNA gene repair was analyzed. RESULTS: Ninety-four were evaluable for response; in the whole population, 4 complete and 33 partial responses were registered for an overall response rate (ORR) of 39.4. In the platinum-resistant (PR) and -sensitive (PS) population, an ORR of 31.2% and 47.8%, and an overall clinical benefit of 54.2% and 73.9%, respectively, were registered. In the whole series, the median progression-free survival (PFS) was 18 weeks and the median overall survival (OS) was 72 weeks; PS patients showed a more favorable PFS and OS compared with PR patients. BRCA gene mutational status was available in 69 patients. There was no difference in ORR, PFS and OS according to BRCA 1-2 status nor any association between SNPs of genes involved in DNA repair and NER machinery and response to trabectedin was reported. CONCLUSIONS: Our data prospectively confirmed that the signature of 'repeated platinum sensitivity' identifies patients highly responsive to trabectedin. In this setting, the activity of trabectedin seems comparable to what could be obtained using platinum compounds and the drug may represent a valuable alternative option in patients who present contraindication to receive platinum. EUDRACT NUMBER: 2011-001298-17.

No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients.

BACKGROUND: Outcomes of Ewing tumor (ET) patients treated with allogeneic stem cell transplantation (allo-SCT) were compared regarding the use of reduced-intensity conditioning (RIC) and high-intensity conditioning (HIC) regimens as well as human leukocyte antigen (HLA)-matched and HLA-mismatched grafts. PATIENTS AND METHODS: We retrospectively analyzed data of 87 ET patients from the European Group for Blood and Marrow Transplantation, Pediatric Registry for Stem Cell Transplantations, Asia Pacific Blood and Marrow Transplantation and MetaEICESS registries treated with allo-SCT. Fifty patients received RIC (group A) and 37 patients received HIC (group B). Twenty-four patients received HLA-mismatched grafts and 63 received HLA-matched grafts. RESULTS: Median overall survival was 7.9 months [±1.24, 95% confidence interval (CI) 5.44-10.31] for group A and 4.4 months (±1.06, 95% CI 2.29-6.43) for group B patients (P = 1.3). Death of complications (DOC) occurred in 4 of 50 (0.08) and death of disease (DOD) in 33 of 50 (0.66) group A and in 16 of 37 (0.43) and 17 of 37 (0.46) group B patients, respectively. DOC incidence was decreased (P < 0.01) and DOD/relapse increased (P < 0.01) in group A compared with group B. HLA mismatch was not generally associated with graft-versus-Ewing tumor effect (GvETE). CONCLUSIONS: There was no improvement of survival with RIC compared with HIC due to increased DOD/relapse incidence after RIC despite less DOC incidence. This implicates general absence of a clinically relevant GvETE with current protocols.

Detection of circulating tumor cells by reverse transcriptase polymerase chain reaction of maspin in patients with breast cancer undergoing conventional-dose chemotherapy.

PURPOSE: To establish, in patients with breast cancer subjected to primary conventional chemotherapy and enrolled in a prospective study, the mobilizing effect of therapy on potentially neoplastic cells by means of a reverse transcriptase polymerase chain reaction (RT-PCR) assay for mRNA of maspin, a protein related to the serpin family of protease inhibitors. PATIENTS AND METHODS: Peripheral-blood samples were collected from 30 patients with histologically proven breast cancer before and 4 and 8 days after conventional chemotherapy for three consecutive courses. A total of 216 samples were screened for the presence of maspin mRNA by RT-PCR. RESULTS: Before therapy, all samples but one were negative. After chemotherapy, 11 patients (38%) had positive samples. No difference in the rate of positivity was observed between groups defined according to initial stage, type of chemotherapy, Ki-67-related proliferative activity, or CA 15.3 expression. CONCLUSION: Our results confirm that RT-PCR for maspin mRNA is a sensitive assay for the study of circulating potentially neoplastic mammary cells in patients with breast cancer. Moreover, our findings indicate a marked effect of conventional-dose chemotherapy on the mobilization of these cells in breast tumors. In our series of patients, this phenomenon does not seem to be associated with other known risk factors. Finally, the data suggest, without proving, an association between the presence of circulating maspin positive cells and a higher risk of disease progression. If this association could be confirmed, then the assay could have prognostic significance. However, larger confirmatory studies are necessary.

One-year mortality prognosis in heart failure: a neural network approach based on echocardiographic data.

OBJECTIVES: This study sought to assess the usefulness and accuracy of artificial neural networks in the prognosis of 1-year mortality in patients with heart failure. BACKGROUND: Artificial neural networks is a computational technique used to represent and process information by means of networks of interconnected processing elements, similar to neurons. They have found applications in medical decision support systems, particularly in prognosis. METHODS: Clinical and Doppler-derived echocardiographic data from 95 consecutive patients with diffuse impairment of myocardial contractility were studied. After 1 year, data regarding survival or death were obtained and produced the prognostic variable. The data base was divided randomly into a training data set (47 cases, 8 deaths) and a testing data set (48 cases, 7 deaths). Results of artificial neural network classification were compared with those from linear discriminant analysis, clinical judgment and conventional heuristically based programs. RESULTS: The study group included 57 male (47 survivors) and 38 female patients (33 survivors). Linear discriminant analysis was not efficient for separating survivors from nonsurvivors because the accuracy at the ideal cutoff value was only 67.4%, with a sensitivity of 67.5%, positive predictive value of 27.8% and negative predictive value of 91.5%. In contrast, all artificial neural networks were able to predict outcome with an accuracy of 90%, specificity of 93% and sensitivity of 71.4%, for the best artificial neural network. Both clinical judgment and automatic heuristic methods were also inferior in performance. CONCLUSIONS: The artificial neural network method has proved to be reliable for implementing quantitative prognosis of mortality in patients with heart failure. Additional studies with larger numbers of patients are required to better assess the usefulness of artificial neural networks.

Epirubicin versus CMF as adjuvant therapy for stage I and II breast cancer: a prospective randomised study.

We compared a relatively short regimen of monochemotherapy with epirubicin versus polychemotherapy with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) as adjuvant treatment for stage I and II breast cancer patients. 348 patients with oestrogen receptor negative (ER-) node negative and ER- or ER+ node-positive with <10 nodes were accrued. CMF was given intravenously (i.v.) on days 1 and 8, every 4 weeks, for six courses; epirubicin was given weekly for 4 months. Postmenopausal patients received tamoxifen for 3 years. The primary endpoints were overall survival (OS), relapse-free survival (RFS) and event-free survival (EFS). Outcome evaluation was performed both in eligible patients and in all randomised patients according to the intention-to-treat principle. 8 randomised patients were considered ineligible. At a median follow-up of 8 years, there was no difference in OS (Hazard Ratio (HR)=1.11, 95% Confidence Interval (CI): 0.77-1.61, P=0.58), EFS (HR=1.14, 95% CI: 0.78-1.64, P=0.48), and RFS (HR=1.14, 95% CI: 0.8-1.64, P=0.48) between the two arms for all of the patients. At 8 years, the RFS percentages (+/-Standard Error (S.E.)) were 65.4% (+/-4%) in the CMF arm and 62.7% (+/-4%) in the epirubicin arm; for EFS these were 64.2% (+/-4%) for CMF and 60.8% (+/-4%) for epirubicin, respectively. A significant difference in RFS (P=0.015) was observed in patients with 4-9 positive nodes in favour of the CMF arm. Toxicity in the two arms was superimposable except for more frequent grade 3 alopecia in the epirubicin-treated patients (P=0.001). Overall, at a median follow-up of 8 years, there were no differences between the two arms in terms of OS, EFS and RFS.

A multicentre, double-blind, randomised trial comparing ondansetron versus ondansetron plus dexamethasone in the prophylaxis of cisplatin-induced delayed emesis.

The aim was to compare the efficacy of ondansetron and a combination of ondansetron plus dexamethasone in the prophylaxis of cisplatin-induced delayed emesis over three consecutive courses of chemotherapy. Cancer patients scheduled to receive for the first time cisplatin (>50 mg/m(2)) in combination with other cytotoxic agents, were recruited in a multicentre, randomised, double-blind study and treated with ondansetron 8 mg i.v. and dexamethasone 20 mg i.v. Twenty-four hours after the start of chemotherapy, patients were randomised to treatment either with oral ondansetron 8 mg bd plus placebo on days 2-5 (group A) or with oral ondansetron 8 mg bd plus oral dexamethasone 8 mg bd on days 2-3, and 4 mg bd on days 4 and 5 (group B). Two hundred and thirty-six cancer patients were recruited into the study. Complete protection from delayed vomiting/nausea in group A and group B was Obtained in 50/39% and in 63/42% of patients, respectively in the first course; in 55/34% and in 64/40% in the second and in 49/31% and 60/37% in the third. Logistic regression analysis reveals a statistically significant difference in incidence of emesis between the combination of ondansetron plus dexamethasone and ondansetron alone (P<0.05). The same model, however, shows no difference in incidence of nausea between the two treatment regimens. Ondansetron plus dexamethasone reduces the risk of delayed emesis following cisplatin chemotherapy as compared to ondansetron alone.

Neuroethological evaluation of audiogenic seizures in hemidetelencephalated rats.

Wistar-derived male rats were tested for audiogenic seizure (AS) susceptibility, and classified into sensitive (S) and resistant (R) groups. Rats from group R underwent unilateral ablation of the telencephalon, or were detelencephalated (HD), or sham-lesioned, and were tested for audiogenic susceptibility one month and one year after surgery. It was found that previously AS-resistant, HD-operated animals developed generalized tonic-clonic convulsions upon high intensity (110.8 dB) acoustic stimulation, with higher severity and shorter latencies than the susceptible, non-operated control animals. Sham-lesioned R animals maintained their previous resistance to AS. HD-lesioned R animals also presented asymmetric motor patterns, such as gyrating and barrel-rolling behavior, always oriented towards the side contralateral to the lesion. HD-lesioned S animals presented an increase in the severity of seizures, as well as a shortening of the latencies of the running (procursive) and convulsive phases of the seizures. This effect was more marked one year after surgery. Contralateral barrel-rolling behavior was also observed in these animals. The fact that seizure severity increases and latency decreases with time after lesion seems to indicate a role for denervation hypersensitivity and other cerebral plasticity phenomena in explaining the effects of HD lesions on AS. The fundamental neural structures involved appear to be those related to sensorimotor coordinating systems (substantia nigra/pontine-mesencephalic reticular formation and substantia nigra/superior colliculus), the acoustic pathways (inferior colliculus) and their projections to the superior colliculus and reticular formation.

Possible interaction between the inferior colliculus and the substantia nigra in audiogenic seizures in Wistar rats.

Male Wistar rats were tested for sensitivity to audiogenic seizures (AS; 110 dB), using an audiogenic severity index (SI). Sensitive (S) animals were subjected to bilateral lesion of the inferior colliculus (IC) and/or the lateral lemniscus (LL). Resistant (R) animals were subjected to bilateral lesions of the IC, unilateral sequential lesions of the substantia nigra reticulata (SN) and/or IC (contralateral to one another), and unilateral thalamic and sham lesions. Bilateral lesions of the IC and LL abolish AS in S rats. Lesion of the SN resulted in more pronounced sensitivity to AS than unilateral lesion of IC, in R rats. When the SN lesion was contralateral to a previous IC lesion, the effect was not only an increase in the SI, but also a reversal of the asymmetry generated by IC lesion. Although the behavioral effects resulting from IC lesions are due to alterations in the primary structures involved in the origin of AS, unilateral SN lesions can alter critical substrates of sensorimotor integration involved in the control and expression of AS.

A stereotaxic atlas for the telencephalon of the Siamese fighting fish (Betta splendens).

1. A stereotaxic technique for electrode positioning in the telencephalic nuclei of the Siamese Fighting fish (Betta splendens) is described. 2. The forebrain atlas was based on paraffin-embedded, in situ-sectioned, Nissl-stained material. Brain measurements were corrected for tissue shrinkage due to histological procedures. The atlas and methods have already been tested and have shown good accuracy and reproducibility.

Role of the substantia nigra in audiogenic seizures: a neuroethological analysis in the rat.

The audiogenic crisis (AC) includes an initial phase of bursts of circular, stereotyped running. Since it has been shown that the nigrostriatal system is important in the control of lesion- and drug-induced stereotyped rotational behavior, the effects of unilateral electrolytic lesions of the substantia nigra (SN) on the AC were investigated. Behavior was recorded using a detailed ethogram by means of systematic observational techniques and analyzed quantitatively in terms of sequential structure by multivariate statistical methods. An index of susceptibility was computed on the basis of the frequency and intensity of the convulsive behavioral patterns observed during 4 successive pre- and post-operative tests. The lesion caused an increase in the susceptibility to AC of previously insusceptible rats or of low-susceptibility rats (LI), in relation to rats with sham lesions. No other differences of this type were detected for the groups of susceptible lesioned (LS) or non-lesioned animals. The sequential analysis disclosed a degradation in the tonic-clonic convulsive pattern of LS animals, with decreased frequency and more random transitions between their constituent units, as well as in the appearance of characteristic running patterns in LI rats. It is concluded that the SN plays a general inhibitory role in the central neural mechanisms of AC, and is involved in the integration and control of stereotyped local movements and of tonic-clonic convulsions. However, the SN might play only a secondary role in the control of the laterality and elaboration of the rotational phase.

Discrete telencephalic lesions accelerate the habituation rate of behavioral arousal responses in Siamese fighting fish (Betta splendens).

Stereotaxic electrolytic lesions were made in the dorsomedial telencephalic area, laterally to the dorsal commissure, in male Siamese Fighting Fish (Betta splendens). The startle and orienting responses to regularly delivered taps on the side of the aquarium were recorded for lesioned, sham-operated and unoperated groups. Lesioned fish showed increased reactivity to environmental modifications, including tonic immobility and changes in body color. Although no changes in the arousal responses were detected, the lesioned fish showed an increased frequency of startle responses and habituated to the orienting responses faster than sham-operated and unoperated animals. The long-term inter-session retention of habituation was also decreased. The effects observed are the opposite of those obtained after complete or unilateral telencephalic ablation in teleosts and suggest the existence of antagonic telencephalic systems playing a modulatory role in arousal control.

Effects of previous REM sleep deprivation on the acquisition of different topographies of discriminated avoidance in the rat.

The effects of REM sleep deprivation (REMSD) for 96 h on discriminated avoidance learning were tested in rats using three different task topographies:in a jumping-box, in a shuttle-box and bar-pressing. The same stimulus relationship and the same methodological controls with regard to the avoidance schedules and to the platform technique were employed. REMSD facilitated the acquisition of the jumping-box response, which was detectable at the end of the third session. REMSD did not interfere in the acquisition of the shuttle-box response since both the experimental and control groups met the criterion by concluding the eighth session without any observable difference in the analyzed parameters. With bar-pressing, neither group reached the learning criterion (80% of avoidance responses throughout two consecutive sessions). We have related these results to the existing hypothesis that REM sleep stimulates the coding of all complex sequences of motor behavior which are necessary for innate behaviors and concluded that the reimbursement of the REM sleep debt after testing facilitated only the acquisition of the jumping-box response through a reprogramming of the motor organization of this innate behavior.

Prevention of cisplatin-induced vomiting in patients with cancer. A pilot study with a multiagent protocol.

Forty patients receiving a total of 102 courses of cisplatin (CDDP)-based treatment were observed in the present study. The patients received an antiemetic prophylaxis with metoclopramide (6 mg/kg), dexamethasone (12 mg/m2), lorazepam (2.5 mg), promethazine (50 mg), and diazepam (10 mg). Complete protection from acute vomiting was obtained in 77.5% of patients during the first course, and partial protection (1 to 3 episodes of vomiting) was observed in 10.1% additional cases. Complete protection was achieved in 84.6% of males vs 57.1% of females. Patients at their first course of chemotherapy had 80% complete protection compared to 66.7% in those who received prior chemotherapy. No differences in the response rate between patients treated with high versus patients receiving low doses of CDDP were noted. The same pattern of response was observed in subsequent courses of therapy. Side effects were minimal (mild sedation in almost all the cases and hiccups in a few cases). No major extrapyramidal reaction was observed. The regimen used in the study showed good efficacy in preventing acute CDDP-induced nausea and vomiting. Moreover, the very low incidence of major side effects makes this protocol safe and recommendable in patients undergoing CDDP chemotherapy.

Lack of lymph node reaction to subcutaneously injected silicone gel: histological and computer aided morphometric study in rats.

The gel of silicone implants may bleed through the elastomeric envelope or may come into contact with the body because of rupture of the implant. We have studied the effects of free silicone gel injected into the subcutaneous space in rats and analysed the morphological features of the axillary and inguinal lymph nodes. Ninety six Wistar rats had 3 cm3 of silicone gel injected into their subcutaneous space and 96 Wistar rats (the control group) had distilled water injected into their subcutaneous space. The animals were killed on days 1,3,7,9,15, 30,60,90,120,180,270, and 365 after the injection. There was no detectable silicone and no damage to the lymph nodes on routine histopathological analysis. Small amounts of silicone that could migrate to lymph nodes could result in hyperplasia. To evaluate this possibility, a morphometric study based on a computer aided system compared the area of lymph node sections between treated and control animals, and showed no difference between treated and control groups. If silicone did migrate, it did not provoke morphological signs or hyperplasia in the lymph nodes.

Gradual bone distraction in craniosynostosis. Preliminary results in seven cases.

Seven patients with craniosynostosis (mean age 8 years, Apert syndrome, n = 4, Crouzon's disease, n = 3) underwent lengthening of the skull by gradual bone distraction. Three patients (group A) were treated by coronal craniectomy reaching the orbital fissure and gradual bone distraction. The other four (group B) underwent monobloc craniofacial disjunction and gradual bone distraction. The patients' progress was monitored clinically as well as by radiographs and photographs. The results showed that craniofacial disjunction followed by gradual bone distraction produced complete correction of exophthalmus and an improvement in the functional and aesthetic aspects of the middle third of the face without the need for bone grafts.