Efficacy of everolimus in second- and third-line therapy for metastatic renal cell carcinoma: A registry-based analysis

ObjectivesThe aim of the present study was to describe the efficacy and safety of everolimus in the treatment of metastatic renal cell carcinoma (mRCC) after administration of 1 vs. 2 prior tyrosine kinase inhibitors (TKIs).Patients and methodsA national renal information system database was used as the data source for the retrospective study. There were 483 patients who received everolimus as the second (n = 350) or the third (n = 112) targeted agent following TKIs.ResultsMedian progression-free survival (PFS) from the start of everolimus in the second or the third line of targeted therapy was 6.1 months for both subgroups (P = 0.863). Median total PFS from the start of the first targeted agent to progression on the third targeted agent for patients receiving 3 lines of therapy with TKI-TKI-everolimus (n = 112) and TKI-everolimus-TKI (n = 27) sequences was 28.3 months vs. 31.3 months, respectively (P = 0.16), and there was no significant difference in overall survival. PFS on everolimus was associated with PFS on previous TKIs in patients receiving 1 but not 2 previous TKIs. Only 13% of 352 patients starting targeted therapy for mRCC in 2010 had received 3 sequential targeted agents by the data cutoff in March 2013.ConclusionPFS on everolimus correlated with PFS on TKIs in patients pretreated with 1 but not 2 TKIs. Everolimus can be deferred to the third line without loss of efficacy or increased toxicity. However, only a minority of patients with mRCC starting targeted treatment can be expected to receive third-line therapy.     

Right ventricular function in rats with hypoxic pulmonary hypertension

The function of the hypertrophic right ventricle (RV) was studied in adult rats with hypoxic pulmonary hypertension induced by intermittent high-altitude (IHA) exposure. The isolated RV working heart preparation that was employed enabled us to estimate ventricular contractile and pump performance under controlled loading conditions. In rats exposed to IHA hypoxia the elevated RV systolic pressure and maximum rate of pressure development were observed at various levels of preload or afterload. The peak indices of mechanical performance were almost doubled in these animals when compared with the normoxic group, while the index of contractility remained unchanged. Maximum ventricular performance was found to be a linear function of the relative RV weight. No evidence of RV pump dysfunction was detected in rats exposed to IHA; moreover, the ability of the ventricle to maintain cardiac output against increased pulmonary resistance was markedly improved. The prevention of tricuspid regurgitation by using an artificial valve did not influence the functional curves and the peak ventricular performance. The regression of hypertrophy was accompanied by a reversal of ventricular function to control values, except for the persisting slight increase of peak RV pressure. It may be concluded that the increase of the RV mass in IHA-exposed rats serves to improve maximum ventricular performance, which aids in overcoming an elevated pulmonary resistance without disturbing the pump function.     

Pegylated liposomal doxorubicin in combination with hyperthermia in the treatment of a case of advanced hepatocellular carcinoma.

BACKGROUND: Currently, there is no standard treatment of inoperable advanced hepatocellular carcinoma. STUDY: A patient with advanced hepatocellular carcinoma was treated with intravenous infusion of pegylated liposomal doxorubicin (PLD, Caelyx) in combination with ultrasound hyperthermia of the liver. Each cycle consisted of infusion of 60 mg of PLD followed by two fractions of hyperthermia 41 degrees C to 43 degrees C for 45 minutes 1 and 48 hours after infusion, respectively. RESULTS: A substantial regression of the tumor was observed on computed tomography scans. No toxicity of combined treatment was noted. CONCLUSIONS: This may be the first report of the combination of PLD and hyperthermia in the treatment of advanced hepatocellular carcinoma. Our observation suggests that the combination of PLD with hyperthermia is technically feasible, well tolerated, and could have synergistic potential.     

Transduodenal intraluminal high dose rate brachytherapy in the treatment of carcinomas of the subhepatic region

BACKGROUND/AIMS: The prognosis of carcinomas of the subhepatic region is poor, and therapeutic efforts are limited mostly to palliation. The aim of this study was to retrospectively evaluate the effectiveness of transduodenal administration of intraluminal high dose rate brachytherapy in the palliative treatment of bile duct and pancreatic head carcinomas. METHODOLOGY: Twelve patients with inoperable bile duct and pancreatic head carcinomas were treated by transduodenal brachytherapy using high dose rate remote afterloading system. Eleven patients were treated by intraluminal brachytherapy inserted via a nasobiliary drain and one patient by intraluminal brachytherapy via a nasopancreatic drain inserted in the duct of Wirsung. RESULTS: After transduodenal intraluminal brachytherapy, a control of icterus was observed in all patients. The treatment was well tolerated with the mean survival of 284 days. CONCLUSIONS: Transduodenal intraluminal brachytherapy is technically feasible. The addition of intraluminal brachytherapy may be beneficial to patients in whom drainage can be established. Transduodenal insertion of brachytherapy is not competitive to the percutaneous approach but spreads the possibilities of the treatment of bile duct carcinoma. Intraluminal brachytherapy of pancreatic head carcinoma is feasible only via transduodenal approach.     

Preparation and preclinical evaluation of 177Lu-nimotuzumab targeting epidermal growth factor receptor overexpressing tumors

ObjectivesNimotuzumab (h-R3) is a humanized monoclonal antibody (mAb) which recognizes the external domain of the epidermal growth factor receptor (EGFR) with high specificity. It was demonstrated that h-R3 has a unique clinical profile for immunotherapy of adult gliomas and pediatric pontine gliomas. The aim of this work was to evaluate the conjugate ¹⁷⁷Lu-h-R3 as a potential radioimmunoconjugate for radioimmunotherapy (RIT) of tumors overexpressing EGFR.Methodsh-R3 was modified with the macrocylcic ligand S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA) and the acyclic ligand S-2-(4-Isothiocyanatobenzyl)-diethylenetriamine pentaacetic acid (p-SCN-Bn-DTPA); the immunoconjugates were labeled with no-carried added ¹⁷⁷Lu. Specificity and affinity were tested using radioimmunoassays in a cell line overexpressing EGFR. Biodistribution in mice, healthy or bearing A431 epithelial carcinoma xenografts, was performed for 11 days. Tumor uptake, the influence of the nature of the chelate and the way of administration were studied. Absorbed dose in tumor and selected organs was calculated using the OLINDA/EXM software; the data from the animals was extrapolated to humans.Results¹⁷⁷Lu-h-R3 conjugates were obtained with specific activity up to 915 MBq/mg without significant loss of immunoreactivity. The binding of ¹⁷⁷Lu-h-R3 conjugates to A431 cells showed to be EGFR specific, and the affinity was similar to native h-R3. Tumor uptake reached a maximum value of 22.4±3.1 %ID/g at 72 h and remained ～20% ID/g over 1 week. Locoregional application showed better tumor/nontumor ratios than intravenous application.Conclusions¹⁷⁷Lu-h-R3 should be considered for further evaluations as a potential radiopharmaceutical for RIT of tumors overexpressing EGFR.     

The effect of loop diuretics upon summating potentials in the guinea pig

Ototoxic diuretics, ethacrynic acid (50 mg/kg) and furosemide (80 mg/kg) were injected intravenously in guinea pigs. Cochlear microphonics (CM), summating potentials (SPs) and endocochlear potential (EP) were recorded with a microelectrode in scala media of the second turn. CM changes after the injection were comparable with changes in the EP: an initial decrease was followed by an increase which was significantly slower in the case of the ethacrynic acid. SP changes following either diuretic were different from the CM and EP changes. In the first phase, roughly corresponding with the EP decrease to negative values, all SPs irrespective of the original polarity, attained high positive values. The high positive SPs then decreased and 12–18 min after injection reversed polarity. In the late phase all sounds evoked high negative SPs. Approximately 90 min after injection of furosemide normal SPs were again recorded. The return of SPs to control values was very slow after ethacrynic acid; even 140 min after injection the SPs were abnormal. The observed changes in the SPs were compared with those found during asphyxia and anoxia and are considered to result from diuretic effects on the inner and outer hair cells.     

Psychologische Persönlichkeitsmerkmale, Operationsverlauf und Genesung bei Patienten mit Präferenz für Allgemein- oder Lokalanästhesie

Objective

This study addresses two questions concerning open inguinal hernia repair patients: (1) are there differences in psychological traits between patients opting for local vs. general anaesthesia and (2) assuming comparable operations, are there any differences between the two groups during surgery and postoperative recovery?

Methods

A total of 69 male patients aged between 18 and 80 took part in the study. After having been briefed about anaesthesia, they opted for either local (n=40) or general anaesthesia (n=29). In order to determine psychological traits, patients filled out questionnaires before the operation [NEO Five-Factor-Inventory (NEO-FFI) and the Stress Coping Questionnaire (SVF)] and the Anaesthesiological Questionnaire (ANP) after the operation. Data about the surgery (duration of anaesthesia and operation, blood pressure and heart rate) and the convalescence period (time spent in recovery room, length of stay in hospital) were also recorded. The patients’ information processing skills were measured preoperatively and postoperatively using the “Trail Making Test”.

Results

Patients preferring local anaesthesia were significantly older than those who chose general anaesthesia. Therefore two similar age groups were formed by using the method of matched samples (n=2×26). Between these groups no significant differences were found with reference to psychological traits, but markedly extraverted patients favoured local anaesthesia. There were no differences in the duration of anaesthesia and surgery. Local anaesthesia patients spent less time in the recovery room and in hospital than general anaesthesia patients. Postoperatively, the cognitive state and the satisfaction with the anaesthesia were comparable between both groups.

Conclusion

Psychological traits do not have a significant impact on the choice of either local or general anaesthesia. However, highly extraverted patients prefer local anaesthesia while extreme introverts prefer general anaesthesia. Our findings suggest that local anaesthesia will become more widely adopted for the repair of groin hernia. Future studies should focus on optimising the perioperative care for patients who choose local anaesthesia.     

Constrained non‐smooth optimization in dead‐beat control of linear servosystems

Motivated by the polynomial approach to the dead‐beat ripple‐free control of a continuous linear servosystem, the paper presents a new effective algorithm for non‐smooth constrained optimization with design objectives applicable to both control and process variables. Constraints on closed‐loop poles are introduced and their role in optimization and rejection of a finite‐length continuous plant disturbances is examined. The solution is based on a new way of parametrization of the set of all admissible dead‐beat ripple‐free controllers and the constrained non‐smooth optimization profits from its linear programming formulation. Copyright © 2005 John Wiley & Sons, Ltd.     

Characterization of marginal and Claudius' cells growing from cochlear explants in vitro.

Tissue specimens of stria vascularis together with spiral ligament were transferred from the guinea pig cochlea to tissue culture dishes. To characterize and identify cells growing out from the explants, indirect immunofluorescence microscopy was used. The expression of the intermediate-sized filaments vimentin and cytokeratin 18 in cells on the surface of tissue specimens and in cells growing out from the explants after different cultivation periods were compared. Basically, three types of cells grew from the explants during several days: marginal cells, Claudius' cells and fibroblast-like cells. In primary cultures of explants, growth of marginal cells was observed in 25% of the dishes. Their proliferative activity, estimated by the use of the BrdUrd-DNA antibody, started in the stria vascularis and continued across the attachment of Reissner's membrane down to the bottom of the cell culture dish. The newly-formed marginal cells expressed cytokeratin 18 in the same way that original marginal cells on the tissue specimen do. If the newly-formed marginal cells were in contact with fibroblast-like cells or were forming groups (domes) on the bottom, they expressed vimentin. In 3% of the dishes growth of Claudius' cells was observed. Proliferative activity of these cells was found at the point where the basilar membrane was attached to the spiral ligament. New Claudius' cells spread at the opposite side of an explant when compared with the location of new marginal cells. Original as well as newly-formed Claudius' cells contained cytokeratin 18. Fibroblast-like cells were commonly present in cultures and contained only vimentin.