Summary
Background
Progress in developing effective salvage therapies for UC is warranted. Alisertib is an orally available, selective inhibitor of the aurora kinase A.
Methods
A single-group, phase ...2 trial was conducted with alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT02109328). The primary endpoint (EP) was RECIST 1.1 objective response-rate (ORR, H
0
≤ 5 %, H
1
≥ 20 %, α = 10 % and β = 20 %). Eligibility included failure of at least one platinum-based regimen.
Results
From 10/2014 to 04/2015, 22 patients were enrolled (20 evaluable for response), 8 (36.4 %) in second-line and 14 (63.6 %) beyond the second-line. Eight (36.4 %) had an ECOG-performance status 1–2. Two partial responses (PR, ORR: 9.1 %), 7 stable disease (SD) and 11 PD were obtained. Median follow-up was 8.3 months (IQR: 7–10.3), 6-month progression-free survival (PFS) was 13.6 % (95%CI: 4.8–39.0). Two SD are still receiving treatment after 11.5 and 6.3 months. Median overall survival (OS) was not reached (6-month OS: 59.1 %, 95%CI: 41.7–83.7). Hb < 10 g/dl was significantly associated with shorter PFS and OS multivariably (
p
= 0.031 and
p
= 0.033). Tissue of the case with 11.5 month SD harbored a missense mutation of
mTOR
(E1813D), the nonsense mutation Q527STOP of
TSC1
,
HER3
and
TAF1L
missense mutations. Grade 3–4 adverse events (AE) were: 40.9 % mucositis, 36.4 % fatigue, 18.2 % neutropenia (13.6 % febrile neutropenia). There were 2 treatment-related deaths.
Conclusions
The study did not meet the primary EP, yet sustained disease control was obtained in about 14 % of patients. The incidence of AE and the issue of patient selection are two major concerns.
Transfer of excitation from cadmium to sodium atoms was investigated in anheat pipe oven illuminated by a pulsed laser tuned on the intercombinationtransition of cadmium. A rich emission spectrum ...with cadmium as well assodium lines was observed. Intramultiplet mixing distributes the initialexcited level population 5p@@u3@P@@d1@ to the nearby fine structurelevels 5p@@u3@P@@d0,2@ of the same multiplet. We have experimentalevidence that the energy transfer pathway is from Cd (5p@@u3@P@@dJ@) to Na(4p@@u2@P@@dJ@) which is collisionally rapidly converted toNa(3d@@u2@D@@dJ@), from which the strongest emission was observed.
Pubertal growth, sexual maturation, and final height in children with IDDM. Effects of age at onset and metabolic control.
M Salerno ,
A Argenziano ,
S Di Maio ,
N Gasparini ,
S Formicola ,
G De ...Filippo and
A Tenore
Department of Pediatrics, University Federico II, Naples, Italy.
Abstract
OBJECTIVE: To evaluate growth and pubertal development in children with IDDM and the influence of the age at onset of IDDM
and the degree of metabolic control on final height. RESEARCH DESIGN AND METHODS: We conducted a retrospective evaluation
of 62 subjects followed longitudinally both clinically and metabolically from the onset of IDDM until final height was reached.
RESULTS: Height at diagnosis was within the normal percentiles in boys (0.5 +/- 1.0 standard deviation score SDS) and girls
(0.4 +/- 1.0 SDS), but above the genetic target height (-1.0 +/- 0.9 SDS in boys and -1.1 +/- 0.6 SDS in girls; P = 0.0001
for both comparisons). Although a lesser height gain was observed during the ensuing years, the final height reached by boys
(-0.4 +/- 1.1 SDS) and girls (-0.4 +/- 0.9 SDS) was higher than the genetic target height. Blunted total pubertal growth was
observed both in boys (24.5 +/- 3.6 cm) and girls (20.1 +/- 4.2 cm). The decrease in height gain was independent of the duration
of IDDM, the degree of metabolic control, or the insulin requirement. The greater the height at diagnosis, with respect to
the genetic target height, the lesser was the subsequent height gain to reach final adult height (r = 0.34, p < 0.01). BMI
increased with age as normally occurs in healthy children, independent of the duration of disease and the degree of metabolic
control. Pubertal development began and progressed normally both in boys and girls. In boys, a testicular volume of 4 ml was
reached at a mean age of 12.1 +/- 0.9 years. In girls, breast enlargement occurred at a mean age of 10.4 +/- 1.2 years and
the mean age of menarche was 12.8 +/- 1.4 years. Pubertal development and progression occurred independent of the age at onset
of IDDM, the glycemic control, or the insulin requirement during the pubertal period. CONCLUSIONS: Children with IDDM have
normal onset of puberty and normal sexual maturation. Even though final height falls within the normal percentiles, the diminished
height gain after diagnosis requires further investigation.
Micro-Abstract MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) chemotherapy (classic or dose-dense) is one of the current choices of therapy for locally advanced and metastatic urothelial ...cancer. The poor safety profile and not significantly greater efficacy as compared with cisplatin/gemcitabine are major issues. The authors analyzed the outcomes of a series of modified MVAC schedules in these patients, all treated at their center over a 26-year period. A fairly good tolerability, coupled with efficacy seemingly equal to that of the original MVAC, was obtained.
NGR-hTNF exploits the tumor-homing peptide asparagine-glycine-arginine (NGR) for selectively targeting TNF-α to an aminopeptidase N overexpressed on cancer endothelial cells. Preclinical synergism ...with cisplatin was displayed even at low doses. This study primarily aimed to explore the safety of low-dose NGR-hTNF combined with cisplatin in resistant/refractory malignancies. Secondary aims included pharmacokinetics (PKs), pharmacodynamics, and activity.
NGR-hTNF was escalated using a doubling-dose scheme (0.2-0.4-0.8-1.6 μg/m(2)) in combination with fixed-dose of cisplatin (80 mg/m(2)), both given intravenously once every three weeks. PKs and circulating TNF-receptors (sTNF-Rs) were assessed over the first three cycles.
Globally, 22 patients (12 pretreated with platinum) received a range of one to ten cycles. Consistently with the low-dose range tested, maximum-tolerated dose was not reached. No dose-limiting toxicities (DLTs) were observed at 0.2 (n = 4) and 0.4 μg/m(2) (n = 3). One DLT (grade 3 infusion-related reaction) was observed at 0.8 μg/m(2). This dose cohort was expanded to six patients without further DLTs. No DLTs were noted also at 1.6 μg/m(2) (n = 3). NGR-hTNF exposure increased dose-proportionally without apparent PK interactions with cisplatin. No shedding of sTNF-Rs was detected up to 0.8 μg/m(2). At the dose level of 0.8 μg/m(2), expanded to 12 patients for activity assessment, a platinum-pretreated lung cancer patient achieved a partial response lasting more than six months and five patients maintained stable disease for a median time of 5.9 months.
The combination of NGR-hTNF 0.8 μg/m(2) with cisplatin 80 mg/m(2) showed favorable toxicity profile and promising antitumor activity.
Multiple symmetric lipomatosis (MSL, OMIM 151800), is a rare disease characterised by the growth of uncapsulated masses of abnormal adipose tissue around the neck, shoulders or other parts of the ...trunk and typically associated with high ethanol intake. We describe the case of a 33 year-old woman with MSL and secondary amenorrhea. Despite the presence of an ovarian failure confirmed by undetectable serum levels of inhibin B and anti-Müllerian hormone, the patient had normal serum levels of estrone and gonadotropins coexisting with a biological adrenal hyperandrogenism. We suggest that the adrenal hyperandrogenism observed in our patient could be attributed to an impairment of the cytochrome p450 function, inducing a relative 21-hydroxylase deficiency/insufficiency, related to alcohol abuse and that the increased peripheral aromatization of androgens in estrogens lead to normal circulating levels of estrone. The result is the absence of gonadotropin elevation despite primary ovarian failure. The peculiar functional pattern of brown adipocytes in patients with MSL may contribute to this biological phenomenon with an additive effect related to alcohol consumption. Altogether, these data could help to better define the peculiar pituitary-gonadal profile observed in this rare syndrome and in some cases of women with heavy alcohol consumption.
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