Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment naive advanced TC. They received ramucirumab, carboplatin and paclitaxel for 6 cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was ORR according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were PFS, OS and safety. Centralized radiologic review was performed. RESULTS: From 11/2018 to 06/2023, 52 patients were screened, 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. ECOG PS was 0 in 68.5%, 1 in 31.4% patients. At the present analysis carried out some months later the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95%CI 63.1-91.6]. At the centralized radiological review of 33/35 evaluable patients, ORR was 57.6% [95%CI 39.2-74.5]. After a median follow-up of 31.6 months, median PFS was 18.1 [95%CI 10.8-52.3] and median OS 43.8 [95%CI 31.9-NR] months. Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE≥G3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

Inferring recruitment history from spatial genetic structure within populations of the colonizing tree Albizia julibrissin (Fabaceae).

Comparative analyses of spatial genetic structure (SGS) among species, populations, or cohorts give insight into the genetic consequences of seed dispersal in plants. We analysed SGS of a weedy tree in populations with known and unknown recruitment histories to first establish patterns in populations with single vs. multiple founders, and then to infer possible recruitment scenarios in populations with unknown histories. We analysed SGS in six populations of the colonizing tree Albizia julibrissin Durazz. (Fabaceae) in Athens, Georgia. Study sites included two large populations with multiple, known founders, two small populations with a single, known founder, and two large populations with unknown recruitment histories. Eleven allozyme loci were used to genotype 1385 individuals. Insights about the effects of colonization history from the SGS analyses were obtained from correlograms and Sp statistics. Distinct differences in patterns of SGS were identified between populations with multiple founders vs. a single founder. We observed significant, positive SGS, which decayed with increasing distance in the populations with multiple colonists, but little to no SGS in populations founded by one colonist. Because relatedness among individuals is estimated relative to a local reference population, which usually consists of those individuals sampled in the study population, SGS in populations with high background relatedness, such as those with a single founder, may be obscured. We performed additional analyses using a regional reference population and, in populations with a single founder, detected significant, positive SGS at all distances, indicating that these populations consist of highly related descendants and receive little seed immigration. Subsequent analyses of SGS in size cohorts in the four large study populations showed significant SGS in both juveniles and adults, probably because of a relative lack of intraspecific demographic thinning. SGS in populations of this colonizing tree is pronounced and persistent and is determined by the number and relatedness of founding individuals and adjacent seed sources. Patterns of SGS in populations with known histories may be used to indirectly infer possible colonization scenarios for populations where it is unknown.

A method to calculate tissue impedance through a standard bipolar pacing lead.

UNLABELLED: The transthoracic impedance (T) and its variations may be estimated through the measurement of the electrical impedance between the can and the right ventricular coil of a defibrillation lead. This method may allow the monitoring of fluid overload before a heart failure attack. Aim of this study was to validate in vitro a method to calculate T in case of a standard bipolar pacing lead, by performing 3 measurements: standard unipolar impedance from the tip (Zuni-tip); unipolar impedance from the ring (Zuni-ring); standard bipolar impedance (Zbip). The formula we used is derived from the standard equivalent circuit of a pacing system: [Formula: see text] T represents the tissue impedance between the can and the electrodes of the lead. To validate the method we used a saline solution and 3 different pacing leads manufactured by Vitatron (Vitatron BV, Arnhem, The Netherlands): Impulse II (high impedance lead), Crystalline ActFix (screw-in lead), Brilliant S+ (VDD single-lead). The measured values of the saline solution impedance were compared to the values calculated through the formula. RESULTS: The calculated impedance of the solution, evaluated through the proposed formula, is reliable independently of the electrode used and highly correlated to the corresponding measured values (R>0.9). CONCLUSION: Tissue impedance may be calculated from standard unipolar and bipolar impedance measurements with a standard bipolar pacing lead.

Thyroid function differently affects serum cystatin C and creatinine concentrations.

Cystatin C (Cys C) is a cysteine protease inhibitor produced at a constant rate by nucleated cells, filtered through the glomerular membrane and reabsorbed by kidney tubular cells. Aim of this cross-sectional and longitudinal study was to assess serum Cys C and creatinine (Crea) concentrations in thyroid dysfunction. One hundred and eighty-one patients, 26 with untreated non-toxic nodular goiter, 58 with hyperthyroidism, 31 on L-T4 suppressive therapy for non-toxic nodular goiter, 35 with short-term hypothyroidism after L-T4 withdrawal to perform whole body scan for thyroid cancer, 11 with long-term hypothyroidism due to chronic autoimmune thyroiditis and 20 patients with mild hypothyroidism were enrolled in the study. Fifty-seven age- and sex-matched normal subjects served as controls. Serum Cys C, Crea, free T4 (FT4), FT3 and TSH were assessed. Thirty hyperthyroid patients and 35 short-term hypothyroid patients were followed prospectively until euthyroidism was reached by methimazole or L-T4 therapy. The cross-sectional study showed that mean serum Crea concentrations were significantly reduced in overt hyperthyroid or subclinical hyperthyroid patients, while it was increased in overt hypothyroid patients, but not in mild hypothyroidism. Conversely, serum Cys C levels were significantly increased in overt hyperthyroid patients compared to controls (p<0.05), and significantly decreased in short-term, long-term and mild hypothyroids (p<0.05, p<0.05, p<0.01, respectively). However, 36 (62%) hyperthyroid patients and 50 (76%) hypothyroid patients had normal serum Cys C values. In the prospective study, restoration of euthyroidism by either methimazole or L-T4 therapy was associated with normalization of mean serum Cys C concentrations. In conclusion, thyroid dysfunction affects serum Cys C concentration, possibly influencing the production rate of the protein. However, the observation that hyper- or hypothyroid patients have normal serum Cys C levels limits its use as a marker of peripheral thyroid hormone effect.

Serum haptoglobin: a novel marker of adiposity in humans.

Haptoglobin (Hp) is a glycoprotein involved in the acute phase response to inflammation. Our previous findings indicate that Hp mRNA and protein are present in the adipose tissue of rodents and that Hp gene expression is up-regulated in obese models. The aim of the present study was to establish whether Hp could be considered a marker of obesity in humans. In 312 subjects, serum Hp was correlated directly with body mass index (BMI), leptin, C-reactive protein (CRP), and age. In a multivariate stepwise regression analysis, BMI and CRP were independent determinants of serum Hp in females, with BMI having the strongest effect. CRP and age were independent determinants of serum Hp in males, although explaining only a modest percentage of the total variability. Serum Hp was positively associated with body fat, as assessed by dual-energy x-ray absorptiometry, both in female and in male groups. The level of significance improved when serum Hp was analyzed against fat mass adjusted for lean mass. Finally, Northern and Western blot analyses performed in biopsies of sc abdominal fat from 20 obese individuals showed the presence of Hp mRNA and protein in the human adipose tissue. In conclusion, serum Hp constitutes a novel marker of adiposity in humans, and the adipose tissue likely contributes to determine its levels.

Surgical research in orthotopic liver transplantation: experiences in the pig model.

Since the very beginning of liver transplantation in humans, research in animals has had close relationship with clinical practice. Results obtained in animals have been transferred to the clinics and problems borne in the clinics have been addressed again in animals for to be answered clearly. In this review the authors report their experience of transplantation in the pig model and discuss the significance of a team cooperation in the laboratory as a preparatory step for clinical practice.

Omega-3 fatty acid supplementation and lipoprotein(a) concentrations in patients with chronic glomerular diseases.

Renal disease patients often exhibit alterations in the lipid profile which may become an important risk of accelerated atherosclerosis and contribute to disease progression. Among such alterations, increased levels of lipoprotein(a) [Lp(a)] are common and may be related, in part, to the degree of proteinuria. Omega-3 polyunsaturated fatty acids (omega-3 FA) have been reported to decrease Lp(a) concentrations in nonrenal subjects. In addition, they have recently been shown to reduce proteinuria in patients with chronic glomerular disease. We therefore tested the hypothesis that omega-3 FA treatment in patients with chronic glomerular disease may reduce Lp(a) concentrations. Eight patients (2 with membranous glomerulonephritis, 6 with focal glomerular sclerosis) were submitted to a total of 13 six-week courses of treatment with omega-3 FA, at a dose of 3 g/day with a triglyceride preparation (n = 4) and of 7.7 g/day with an ethyl-ester preparation (n = 9). Both treatments significantly increased the proportions of omega-3 to omega-6 FA in total serum lipids, documenting compliance to treatment. Both treatments were also effective in decreasing serum thromboxane (from mean 490 +/- (SEM) 70 to 325 +/- 49 ng/ml, p < 0.05, in the high-dose group) and prolonging the bleeding time (from 5.8 +/- 0.4 to 7.7 +/- 0.5 min, p < 0.05, in the high-dose group), thus documenting the biological efficacy of treatment. However, despite a significant reduction in serum triglyceride levels (from 137 +/- 20 to 104 +/- 19 mg/dl in the high-dose group), Lp(a) concentrations did not change (292 +/- 120 U/l before, 315 +/- 130 U/l after the high-dose therapy). Treatment-related changes in proteinuria (from 2.9 +/- 0.5 to 2.1 +/- 0.7 g/24 h) were not related at all to changes in Lp(a) levels. We conclude that omega-3 FA do not decrease Lp(a) concentrations in renal patients with chronic glomerular diseases and that Lp(a) levels are unlikely to be related to the degree of proteinuria within the short-term modifications induced by omega-3 FA.

[A case of atrial paralysis during the use of intravenous flecainide acetate]. / Un caso di paralisi atriale durante impiego di flecainide acetato per via venosa.

The aim of the present study is to describe a case of complete temporary atrial standstill, following iv administration of flecainide during the course of an endocavitary electrophysiologic study (EES). The patient, 79 years old, with frequent anamnestic periods of flutter and atrial fibrillation, which was followed by heart failure and with conductory disturbances to the surface ECG (first degree A-V block and left axis deviation), underwent EES in order to evaluate the functional reserve of cardiac eccito-conduction. With electric programmed stimulation, during EES, we induced atrial flutter, with a cycle length of about 300 ms. The administration of flecainide, dosage 1.5 mg/Kg in 15 min, determined the complete disappearance of every atrial electric activity, confirmed by right and left (coronary sinus) atrial mapping, also after electrical stimulation, and the emergency of substitutional ventricular rhythm, to a frequency of about 30-40/min. After atropine, dosage 0.02 mg/Kg iv, we noted an increase in the frequency of added focus up to the value of about 110 b/min, without any evidence of atrial electric activity. With sulfate isoprenaline in venous infusion, dosing 2 gamma/min, we noted firstly a ventricular-atrial back-leading 1:1; and after an ectopic atrial rhythm, with a frequency of about 130 b/min. After 5 hours a sinusal rhythm appeared.

[Flecainide acetate in the acute and medium-term prophylactic treatment of 2 cases of ectopic atrial tachycardia]. / Trattamento acuto e profilassi a medio termine con flecainide acetato in 2 casi di tachicardia atriale ectopica.

The aim of this study is to evaluate the efficacy of flecainide acetate, which was administered intravenously, to induce cardioversion in 2 female patients of 48 and 76 years, with ectopic atrial tachycardia. Besides the clinical examination, ECG monitoring by radiotelemetry, chest x-ray, echocardiographic examination, thyroid tests and other routine hematochemical tests, we carried out an endocavitary electrophysiologic study, followed by pharmacologic tests in series: propranolol (5 mg/5 min iv), verapamil (5 mg/5 min iv) and flecainide (1.5 mg/kg/15 min iv). We confirmed the presumptive diagnosis of ectopic atrial tachycardia and that, among all the drugs tested, flecainide acetate was the only one restoring the sinus rhythm. In a medium-term follow-up, during which the patients were treated with flecainide, 100 mg twice-a-day, we didn't notice relapse of the tachycardia and the patients tolerated the drug well.