Could Interferon Still Play a Role in Metastatic Renal Cell Carcinoma? A Randomized Study of Two Schedules of Sorafenib Plus Interferon-Alpha 2a (RAPSODY)

Background

Sorafenib has proven efficacy in metastatic renal cell carcinoma (mRCC). Interferon (IFN) has antiangiogenic activity that is thought to be both dose- and administration-schedule dependent.

Objective

To compare two different schedules of IFN combined with sorafenib.

Design, setting, and participants

Single-stage, prospective, noncomparative, randomized, open-label, multicenter, phase 2 study on previously untreated patients with mRCC and Eastern Cooperative Oncology Group performance status 0–2.

Intervention

Sorafenib 400 mg twice daily plus subcutaneous IFN, 9 million units (MU) three times a week (Arm A) or 3 MU five times a week (Arm B).

Outcome measurements and statistical analysis

Primary end points were progression-free survival (PFS) for each arm and safety. Data were evaluated according to an intent-to-treat analysis.

Results and limitations

A total of 101 patients were evaluated. Median PFS was 7.9 mo in Arm A and 8.6 mo in Arm B (p = 0.049) and the median duration of response was 8.5 and 19.2 mo, respectively (p = 0.0013). Nine partial responses were observed in Arm A, and three complete and 14 partial responses were observed in Arm B (17.6% vs 34.0%; p = 0.058); 24 and 21 patients (47% and 42%), respectively, achieved stable disease. The most common grade 3–4 toxicities were fatigue plus asthenia (28% vs 16%; p = 0.32) and hand-foot skin reactions (20% vs 18%).

Conclusions

Sorafenib plus frequent low-dose IFN showed good efficacy and tolerability. Further investigations should be warranted to identify a possible positioning of this intriguing regimen (6% complete response rate) in the treatment scenario of mRCC.     

Rehabilitation of spelling along the sub-word-level routine

Contemporary psycholinguistic models assume at least two routes in writing. These models have been verified on the basis of neuropsychological observations of patients suffering from acquired dysgraphia. Many studies have discussed the architecture of the phonological and graphemic lexicons, their relations to semantic knowledge, and their disruption following neuropsychological damage, but few have dealt with the nature of the sub-word level writing routine and its disruption. This may be due to the fact that, although this routine has importance in languages such as Italian, where orthography is much more regular and predictable, it appears to have a relatively reduced impact on the spelling abilities of educated English-speaking adults. The present paper describes the rehabilitation of dysgraphia along the sub-word-level route in Italian dysgraphic patients. Particular emphasis is given to the treatment of the unit that allows the phonological analysis of the auditory string to be written. The treatment procedure was tested on two patients (RO, and DR suffering from severe dysgraphia. After treatment, the spelling ability of the two subjects was restored to practically normal levels on most subsets of items. Both patients were also able to apply the restored skills to spontaneous writing and to written naming tasks. Results are discussed in relation to the contemporary writing models and the principles of cognitive neurorehabilitation.     

Exposure to di(2-ethyl-hexyl) phthalate (DEHP) in utero and during lactation causes long-term pituitary-gonadal axis disruption in male and female mouse offspring

The present study examined the effects in mice of exposure to di(2-ethyl-hexyl) phthalate (DEHP) throughout pregnancy and lactation on the development and function of the pituitary-gonadal axis in male and female offspring once they have attained adulthood. Groups of two to three dams were exposed with the diet from gestational d 0.5 until the end of lactation, at 0, 0.05, 5, and 500 mg DEHP/kg · d. The experiment was repeated three times (total: seven to 10 dams per treatment). The 500-mg dose caused complete pregnancy failure, whereas exposure to doses of 0.05 and 5 mg did not affect pregnancy and litter size. In total, about 30 male and 30 female offspring per group were analyzed. Offspring of the DEHP-treated groups, compared with controls, at sexual maturity showed: 1) lower body weight (decrease 20-25%, P < 0.001); 2) altered gonad weight (testes were ～13% lighter and ovaries ～40% heavier; P < 0.001); 3) poor germ cell quality (semen was ～50% less concentrated and 20% less viable, and ～10% fewer oocytes reached MII stage, P < 0.001); 4) significant lower expression of steroidogenesis and gonadotropin-receptor genes in the gonads; and 5) up-regulated gonadotropin subunit gene expression in the pituitary. In conclusion, our findings suggest that, in maternally exposed male and female mice, DEHP acts on multiple pathways involved in maintaining steroid homeostasis. Specifically, in utero and lactational DEHP exposure may alter estrogen synthesis in both sexes. This, in turn, induces dysregulation of pituitary-gonadal feedback and alters the reproductive performance of exposed animals.     

Treatment of Supra‐Alveolar‐Type Defects by a Simplified Papilla Preservation Technique for Access Flap Surgery With or Without Enamel Matrix Proteins

Background: In this study, we compare the effectiveness of enamel matrix derivative (EMD) associated with a simplified papilla preservation flap (SPPF) technique to SPPF alone when surgically treating supra‐alveolar‐type defects. Methods: Fifty patients, from 54 initially selected, presenting horizontal bone loss around ≥4 adjacent teeth, were treated by an SPPF technique; 25 participants also received EMD (test group) and 25 patients underwent flap surgery alone (control group). A complete clinical and radiographic examination was performed at baseline and 12 months after treatment. Pre‐ and post‐therapy probing depth (PD), clinical attachment level (CAL), gingival recession (GR), and radiographic bone level (BL) were compared between treatments. Results: After 12 months, PD, CAL, and GR in both groups showed significant differences from baseline (P <0.001). No differences in BL scores were observed within the groups at the 12‐month examination. After 1 year, the test group showed significantly (P <0.001) greater PD reduction (3.4 ± 0.7 mm) and CAL gain (2.8 ± 0.8 mm) and a smaller GR increase (0.6 ± 0.4 mm) compared to the control group (PD, 2.2 ± 0.8 mm; CAL, 1.0 ± 0.6 mm; GR, 1.2 ± 0.7 mm.) BL changes did not significantly differ between the experimental groups. Conclusion: The results of this study suggest that combining EMD and SPPF in the treatment of suprabony defects may lead to a greater clinical improvement compared to SPPF alone.     

DDD pacing and interatrial conduction block: importance of optimal AV interval setting

The case of a 83-year-old patient undergoing DDD pacemaker implantation for sick sinus syndrome with postimplant detection of advanced interatrial conduction block is described. At nominal AV interval programming values (175 ms), absence of P wave following an atrial spike was observed, and the presence of an interatrial conduction disturbance was demonstrated by a Doppler transmitral flow pattern analysis and transesophageal ECG recording. AV interval lengthening up to 300 ms resulted in proper timing of atrial and ventricular contractions. Awaiting for conclusive data about biatrial pacing, interatrial conduction blocks can be managed in some cases by proper programming of conventional DDD systems.     

Adjuvant Treatment for Resected Renal Cell Carcinoma: Are All Strategies Equally Negative? Potential Implications for Trial Design With Targeted Agents

BackgroundAlthough data from ongoing trials with targeted agents are awaited, we used a meta-analytical approach to explore whether cytokines (CK), vaccines (VAX), or other therapies may differentially influence patients′ outcomes.Materials and MethodsThe objective was to determine whether significant interactions exist according to treatment (CK vs. VAX vs. other), in the context of a literature-based meta-analysis. Fourteen trials (3380 patients) were identified, with 10 randomized clinical trials (RCTs) (2257 patients) providing data for the primary outcome—5-year relapse-free survival (RFS). The primary selected end point was 5-year RFS; secondary end points were 5- and 2-year overall survival (OS) and 2-year RFS. Event-based relative risk (RR) ratios with 95% confidence intervals (CI) were extracted and cumulated according to a random-effect model from articles/presentations. Testing for heterogeneity was performed as well.ResultsAlthough not statistically significant, an effect in favor of a qualitative interaction according to treatment was found for 5-year RFS, with a likely detrimental effect in CK (P = .42) in contrast to that found in VAX subpopulation (P = .76). For the secondary end points, a similar effect in favor of a quantitative significant interaction according to treatment was found for 5-year OS, regardless of the approach adopted, with a different magnitude of treatment effect. In addition, a borderline significant (P = .05) detrimental effect in terms of 2-year OS against the use of adjuvant treatment was determined in the CK subpopulation (RR, 1.24; 95% CI, 0.99, 1.54).ConclusionThe effect in favor of a qualitative interaction according to the adopted strategy is intriguing and suggests potential implications for trial design with targeted agents.     

Knochenneubildung in der Wand einer Ovariencyste

Ohne Zusammenfassung Hierzu Taf. V.