Landscape of early clinical trials for childhood and adolescence cancer in Spain.

PURPOSE: Despite numerous advances, survival remains dismal for children and adolescents with poor prognosis cancers or those who relapse or are refractory to first line treatment. There is, therefore, a major unmet need for new drugs. Recent advances in the knowledge of molecular tumor biology open the door to more adapted therapies according to individual alterations. Promising results in the adult anticancer drug development have not yet been translated into clinical practice. We report the activity in early pediatric oncology trials in Spain. METHODS: All members of the Spanish Society of Pediatric Hematology Oncology (SEHOP) were contacted to obtain information about early trials open in each center. RESULTS: 22 phase I and II trials were open as of May 2015: 15 for solid tumors (68 %) and 7 for hematological malignancies (32 %). Fourteen (64 %) were industry sponsored. Since 2010, four centers have joined the Innovative Therapies For Children With Cancer, an international consortium whose aim is developing novel therapies for pediatric cancers. A substantial number of studies have opened in these 5 years, improving the portfolio of trials for children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents and their benefits. CONCLUSIONS: Clinical trials are the way to evaluate new drugs, avoiding the use of off-label drugs that carry significant risks. The Spanish pediatric oncology community through the SEHOP is committed to develop and participate in collaborative academic trials, to favor the advancement and optimization of existing therapies in pediatric cancer.

A randomized controlled trial of pegylated interferon alpha-2a (40 KD) or interferon alpha-2a plus ribavirin and amantadine vs interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C.

We determined whether triple therapy comprising amantadine (AMA), ribavirin (RBV) and either peginterferon (PEG-IFN) alpha-2a or conventional IFN alpha-2a would improve sustained virological response (SVR) rates over dual therapy with IFN alpha-2a and RBV in patients with chronic HCV infection. A total of 362 treatment-naïve patients were randomized to 48 weeks of treatment with: PEG-IFN alpha-2a 180 microg/week (group A) or IFN alpha-2a 3 MU tiw (groups B and C). All patients received RBV 1000 or 1200 mg/day and those in groups A and B received AMA 200 mg/day. SVR was defined as an undetectable HCV RNA after 24 weeks of untreated follow-up. At the end of therapy, 74.4% (95% CI 0.66-0.82) of patients in group A were HCV RNA-negative compared with 42.5% (95% CI 0.33-0.50) of those in group B (P = 0.0001) and 48.8% (95% CI 0.40-0.56) of those in group C. SVR was achieved in a significantly greater proportion of patients in group A compared with groups B and C: 65.3% (95% CI 0.53-0.56), 33.3% (95% CI 0.25-0.41) and 44.6% (95% CI 0.36-0.53; P = 0.0001) respectively. In patients with genotype 1, SVR rates were 55.2, 22.8 and 28.8% with the three regimens respectively. Factors independently associated with SVR were HCV genotype 2 or 3, therapy with PEG-IFN, female gender and age. In treatment-naive patients with chronic hepatitis C, triple therapy with PEG-IFN alpha-2a, RBV and AMA produces higher SVR than dual or triple therapy with conventional IFN alpha-2a.

Efficacy of 5 MU of interferon in combination with ribavirin for naïve patients with chronic hepatitis C virus: a randomized controlled trial.

BACKGROUND: In chronic hepatitis C the schedule of interferon (IFN), 3 MU thrice weekly (tiw) plus ribavirin (1000-1200 mg/daily) needs further evaluation, as IFN dosages >3 MU achieve better responses. AIMS: To compare the efficacy of 5 MU tiw of IFN with (96 patients) or without ribavirin (96 patients) for 12 months in naïve patients, to evaluate the effect of baseline features on the response to therapy, and to determine a reliable point in time during treatment to predict non-response. RESULTS: Sustained virologic response was 20.8% (95% CI 13-29) with IFN monotherapy and 54.2% (95% CI 44-64) with combination (P = 0.0001), the relapse rate 39.4% (95% CI 23-56) and 9% (95% CI 1-16) (P = 0.0007), and the combined rate of sustained biochemical and virologic response 22.7% (95% CI 14-31) and 60.5% (95% CI 50-71) (P = 0.0001), respectively. Patients given combination therapy were more likely to respond regardless of baseline features. Apart from genotype non-1, predictive factors for IFN monotherapy were ineffective in predicting response to combination therapy. Using logistic regression analysis, IFN-ribavirin was the strongest predictor of response (X2 = 21.3; P = 0.0001). Viral persistence at month 3 of therapy was a more accurate predictor than aminotransferase values for non-response to IFN monotherapy but not to combination therapy (positive predictive values of 98 and 82%, respectively). CONCLUSION: In this study, 5 MU of IFN combined with a standard dose of ribavirin has yielded the highest rate of sustained response reported to date. Further dose finding studies are warranted.

Clinical studies on daily low dose oxytocin in mares at term.

The aim of this study was to test whether low dose oxytocin i.v. injection once a day to mares diagnosed as being ready for birth by mammary secretion calcium strip test measurements could be used as a reliable method to induce parturition and/or predict the mare would not foal during the following night if parturition did not occur within 2 h of treatment. Fifty-one near-term Haflinger mares were used and a single injection of 2.5 iu oxytocin was given between 1700 and 1900 h, including 10 mares used as controls which were administered a placebo. Administration of oxytocin resulted in the delivery of a normal foal within 120 min in 95% of mares. Twenty-four out of 38 (63%) treated animals foaled in response to the first oxytocin injection, 9 out of 38 (24%) in response to the second injection and 3 out of 38 (8%) in response to the third treatment. Two out of 38 (5%) treated mares foaled during the night irrespective of treatment whereas 7 out of 10 (70%) control mares foaled during the night. It was concluded that the major advantage of injecting a daily low dose of oxytocin appears to be that such a low dose induces delivery only in mares carrying a mature fetus and which are ready to foal.

The use of early pregnant mares as embryo recipients.

Fourteen normal, cyclic mares, treated to synchronise oestrus and ovulation and inseminated artificially with fresh semen, were assigned to a donor or a recipient group after ovulation, with the aim of obtaining a degree of synchrony of > or =2 days. Ten embryos, collected on Day 6 or 7 after ovulation (Day 0), were transferred nonsurgically to inseminated recipient mares (IRM) that had ovulated up to 5 days after the respective donors, or to pregnant recipient mares (PRM) that had ovulated 2-7 days before the donors. Embryonic size and development, as determined by ultrasound examination, were used to distinguish embryos derived from the recipient (recipient embryo = RE) or from the donor (transferred embryo = TE) mare. In cases of twin pregnancy, the RE was manually squeezed on Days 14-16. Abortion was induced in all mares on Day 30. Three of 6 TE developed in IRM. Two of 6 IRM developed a twin pregnancy (RE+TE), while 4 of 6 IRM developed a singleton pregnancy (1 TE and 3 RE). None of 4 TE developed in Day 9-14 PRM and one of these PRM lost her own embryo following ET. The experiment demonstrated that a mare can carry her own embryo and a transferred embryo simultaneously. However, the status of pregnancy does not improve conception rate in recipient mares that ovulate prior to the donor.

Gamma delta T lymphocyte regeneration after T lymphocyte-depleted bone marrow transplantation from mismatched family members or matched unrelated donors.

The recovery of gamma delta T lymphocytes was studied in 31 recipients of T cell-depleted allogeneic bone marrow (BMT) to determine if the dynamics of reconstitution could be related to graft-versus-host disease (GVHD) or other complications of marrow transplantation. Two distinct patterns of regeneration were apparent. In 12 patients, there was a progressive rise in both the percentage and the absolute number of peripheral blood gamma delta T cells over the first year post-transplantation, but these increases never breached levels found in 14 healthy donors. Each of the 19 remaining patients had abnormally high proportions and numbers of gamma delta T cells on at least two occasions following transplantation. The clinical factor that best explained these observations was the frequency of intercurrent infections. Of 19 patients with abnormally increased percentages and numbers of gamma delta T lymphocytes, 18 had one or more episodes of confirmed viral or fungal infection, contrasted with only two of 12 in the comparison group (P < 0.001). There was no significant association of gamma delta T cell recovery patterns with the presence of GVHD (P = 0.33). We conclude that the recovery of gamma delta T lymphocytes after marrow transplantation may vary. Supranormal levels of this T cell subset are associated with infection and may contribute significantly to cellular immune defenses against fungal or viral disease.

Luteolytic effects of prostaglandin F2alpha on day 8 to 19 corpora lutea in the bitch.

Luteolysis was induced in 5 experimental Beagle (8 cycles) and 7 client-owned bitches treated with 150 to 200 microg/kg, sc of prostaglandin F2alpha administered twice daily for 4 d, starting on Days 8 to 19 after the onset of cytological diestrus. Five experimental Beagle bitches had been mated during the estrus preceding treatment, and copulation had been confirmed in 2/7 client-owned bitches presented for termination of unwanted pregnancy. Serum progesterone concentration (mean +/- SD) declined from 26.1 +/- 66 ng/ml before treatment to 0.3 +/- 0.4 ng/ml on the fourth day of treatment One of the 7 client-owned bitches maintained her pregnancy even though serum progesterone concentrations were less than 0.5 ng/ml on the third and fourth day of treatment. Mean (+/- SEM) inter-estrous intervals before and following prostaglandin-induced luteolysis were 207.3 +/- 12.4 (n = 11 cycles in 6 bitches) and 95.5 +/- 20.0 d (n = 6 cycles in the same 6 bitches; P < 0.0001), respectively These results suggest that effective prostaglandin-induced luteolysis can be achieved with administration of 180 microg/kg during the third week of diestrus in pregnant and nonpregnant bitches.

Clinical use of prostaglandin F2 alpha to induce early abortion in bitches: serum progesterone, treatment outcome and interval to subsequent oestrus.

Records of elective abortion in 27 bitches presented to the Veterinary Surgery and Reproduction Clinic of the University of Pisa were reviewed. Treatment consisted of twice-daily subcutaneous injections of 150-270 micrograms natural prostaglandin F2 alpha kg-1 for 4 consecutive days starting between cytological dioestrous days 5 and 19. None of the treated bitches whelped. Luteolysis appeared to be complete (serum progesterone < 3.2 nmol l-1) at the end of treatment in 22 of 25 bitches in which progesterone was assayed in serum obtained daily during therapy. Serum progesterone rose after treatment to a concentration consistent with pregnancy in four of 17 bitches in which progesterone was measured once between dioestrous days 23 and 51. The mean intercycle interval (pro-oestrus-pro-oestrus) of the cycle in which abortion was induced was 134 +/- 45 days for 15 dogs for which the interval could be determined, and was significantly shorter than the average preceding interoestrous intervals (210 +/- 40.0 days) for the same dogs (P < 0.001).

Barnices y adhesivos en el sellado de restauraciones con amalgama de plata / [Varnishes and adhesives in the seal of silver amalgam restorations]

The object of this paper is to evaluate the marginal filtration occurring between restoration/teeth in cavities filled with silver alloy when using different cavity varnish and adhesives. In 50 teeth removed as a result of decay, cavities were prepaired on vestibular faces and were divided into 5 equal groups: Group A: with no caviti varnish; Group B: two coats of a linkin agent (Scotch Bond 3M); Group C: an amalgam liner base (Voco); Group D; two coats of copal varnish: Group E: an amalgam bond base (Carl San Remo, Germany). All groups were filled with a silver alloy. The teeth were inmersed in a fuchsin solution at different temperatures (17.37 degrees C and 50 degrees C) for 20 minutes. Longitudinal cuts were made for visualization under a stereoscopic magnifying glass. Each group was observed by five odontologists and was classified according to four categories: Grade I: no filtration: Grade II: less than 1/3 wall filtration; Grade III: more than 1/3 wall filtration; Grade IV: filtration in walls and floor. Teeth with pulp filtration were discarded. Total and percentage values were determined for each analysed group. The results revealed that: Group A: 100

of samples corresponds to Grade IV. Group B: 40

of sample falls within Grade II while the rest corresponds to the highest grade. Group C: 30

belongs to Grade II, 60

to Grade III and the remaining 10

falls within Grade I, while the remaining 20

correspond to Grades III and IV, respectively. Group E: 50

for Grade I and the rest in Grade II.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of prostaglandin F2 alpha for early pregnancy termination in the mismated bitch.

Natural PGF administered at a dose of at least 250 micrograms/kg twice daily subcutaneously for at least 4 days starting no earlier than day 5 of cytologic diestrus induces luteolysis and pregnancy termination in the mated bitch. The resulting shortening of the luteal phase is associated with a shortening of the interestrous interval from 1 to 4 months. Bitches treated with PGF show emesis, diarrhea, and panting within 5 minutes and transient hypothermia which lasts 2 to 3 hours but generally have no further reaction. Bitches with cardiac or respiratory dysfunctions are not considered safe patients for early pregnancy termination with PGF because of the cardiovascular effects of this drug. Bitches treated with this regime early in diestrus resorb their conceptuses; those treated after days 35 to 40 show clinical abortion of viable fetuses.

[Varnishes and adhesives in the seal of silver amalgam restorations]. / Barnices y adhesivos en el sellado de restauraciones con amalgama de plata.

The object of this paper is to evaluate the marginal filtration occurring between restoration/teeth in cavities filled with silver alloy when using different cavity varnish and adhesives. In 50 teeth removed as a result of decay, cavities were prepaired on vestibular faces and were divided into 5 equal groups: Group A: with no caviti varnish; Group B: two coats of a linkin agent (Scotch Bond 3M); Group C: an amalgam liner base (Voco); Group D; two coats of copal varnish: Group E: an amalgam bond base (Carl San Remo, Germany). All groups were filled with a silver alloy. The teeth were inmersed in a fuchsin solution at different temperatures (17.37 degrees C and 50 degrees C) for 20 minutes. Longitudinal cuts were made for visualization under a stereoscopic magnifying glass. Each group was observed by five odontologists and was classified according to four categories: Grade I: no filtration: Grade II: less than 1/3 wall filtration; Grade III: more than 1/3 wall filtration; Grade IV: filtration in walls and floor. Teeth with pulp filtration were discarded. Total and percentage values were determined for each analysed group. The results revealed that: Group A: 100% of samples corresponds to Grade IV. Group B: 40% of sample falls within Grade II while the rest corresponds to the highest grade. Group C: 30% belongs to Grade II, 60% to Grade III and the remaining 10% to Grade IV; Group D: 30% falls within Grade I, while the remaining 20% and 50% correspond to Grades III and IV, respectively. Group E: 50% for Grade I and the rest in Grade II.(ABSTRACT TRUNCATED AT 250 WORDS)

Barnices y adhesivos en el sellado de restauraciones con amalgama de plata. / [Varnishes and adhesives in the seal of silver amalgam restorations]

The object of this paper is to evaluate the marginal filtration occurring between restoration/teeth in cavities filled with silver alloy when using different cavity varnish and adhesives. In 50 teeth removed as a result of decay, cavities were prepaired on vestibular faces and were divided into 5 equal groups: Group A: with no caviti varnish; Group B: two coats of a linkin agent (Scotch Bond 3M); Group C: an amalgam liner base (Voco); Group D; two coats of copal varnish: Group E: an amalgam bond base (Carl San Remo, Germany). All groups were filled with a silver alloy. The teeth were inmersed in a fuchsin solution at different temperatures (17.37 degrees C and 50 degrees C) for 20 minutes. Longitudinal cuts were made for visualization under a stereoscopic magnifying glass. Each group was observed by five odontologists and was classified according to four categories: Grade I: no filtration: Grade II: less than 1/3 wall filtration; Grade III: more than 1/3 wall filtration; Grade IV: filtration in walls and floor. Teeth with pulp filtration were discarded. Total and percentage values were determined for each analysed group. The results revealed that: Group A: 100

of samples corresponds to Grade IV. Group B: 40

of sample falls within Grade II while the rest corresponds to the highest grade. Group C: 30

belongs to Grade II, 60

to Grade III and the remaining 10

to Grade IV; Group D: 30

falls within Grade I, while the remaining 20

and 50

correspond to Grades III and IV, respectively. Group E: 50

for Grade I and the rest in Grade II.(ABSTRACT TRUNCATED AT 250 WORDS)

[New surgical treatment for laryngeal paralysis in the dog].

Laryngeal paralysis is reported in 2 dogs which showed symptoms of dispnoea at rest, and also choking and vomiting after short exercise. Surgical removal of the mucosa of the lateral ventricles resulted in restoration of normal function and resumption of the animals' normal activities.