Phase II study of sorafenib in patients with relapsed or refractory lymphoma

The safety and activity of the multikinase inhibitor sorafenib were investigated in patients with relapsed or refractory lymphoproliferative disorders who received sorafenib (400 mg) twice daily until disease progression or appearance of significant clinical toxicity. The primary endpoint was overall response rate (ORR). Biomarkers of sorafenib activity were analysed at baseline and during treatment. Thirty patients (median age, 61 years; range, 18-74) received a median of 4 months of therapy. Grade 3-4 toxicities included hand/foot skin reactions (20%), infections (12%), neutropenia (20%) and thrombocytopenia (14%). Two patients achieved complete remission (CR), and two achieved partial remission (PR) for an ORR of 13%. Stable disease (SD) and progressive disease (PD) was observed in 15 (50%) and 11 patients (37%), respectively. The median overall survival (OS) for all patients was 16 months. For patients who achieved CR, PR and SD, the median time to progression and OS was 5 and 24 months, respectively. Compared with patients with PD, responsive patients had significantly higher baseline levels of extracellular signal-regulated kinase phosphorylation and autophagy and presented a significant reduction of these parameters after 1 month of therapy. Sorafenib was well tolerated and had a clinical activity that warrants development of combination regimens.     

Novel INF2 mutation p. L77P in a family with glomerulopathy and Charcot-Marie-Tooth neuropathy

Background

Mutations in inverted formin, FH2, and WH2 domain containing (INF2) are common causes of dominant focal segmental glomerulosclerosis. INF2 encodes a member of the diaphanous-related formin family, which regulates actin and microtubule cytoskeletons. Charcot-Marie-Tooth neuropathy (CMT) is a group of inherited disorders affecting peripheral neurons. Many reports have shown that glomerulopathy can associate with CMT. However, it has been unclear whether these two processes in the same individual represent one disorder or if they are two separate diseases.

Case diagnosis/treatment

Recently, INF2 mutations were identified in 12 of 16 patients with CMT-associated glomerulopathy, suggesting that these mutations are a common cause of the dual phenotype. In this study, we report two cases of CMT-associated glomerulopathy that both showed INF2 mutations. A novel INF2 mutation, p. L77P, was identified in a family in which the dual phenotype was inherited in a dominant fashion. The pathogenic effect of p. L77P was proposed using a structural homology model. In addition, we identified a patient with a sporadic CMT-associated glomerulopathy carrying a known INF2 mutation: p. L128P.

Conclusions

Our study confirms the link between INF2 mutations and CMT-associated glomerulopathy and widens the spectrum of pathogenic mutations.     

Outcomes of junctional ectopic tachycardia ablation in adult population—a multicenter experience

Purpose

Idiopathic junctional ectopic tachycardia (JET) is typically refractory to antiarrhythmic agents. Catheter ablation for JET is feasible but is associated with high risk of unintended atrioventricular (AV) block. There is limited data on the appropriate procedural technique and clinical outcomes with catheter ablation for idiopathic JET in adults.

Methods

This is a multicenter, retrospective study of all adult patients (age?≥?18 years) who underwent catheter ablation for idiopathic JET. Patient, procedural characteristics, and long-term outcomes were evaluated.

Results

Fifteen patients [radiofrequency ablation (RF)?=?14 and cryoablation?=?1) were treated with catheter ablation. The median age was 58 years with 67% males. All patients underwent mapping of the right atrium and the aortic cusps prior to energy delivery. The location of earliest activation in relation to the atrioventricular (AV) node was postero-superior in 73% (11/15), posterior in 13% (2/15), and superior in 13% (2/15) respectively. Acute success was 100%. Arrhythmia recurrence occurred in 53% (8/15) all of whom underwent a repeat ablation. High-grade AV block requiring permanent pacemaker occurred in 20% (3/15). At 12-month follow-up in the redo-ablation group, 37.5% (3/8) had recurrence of the arrhythmia two of which underwent a third ablation procedure.

Conclusion

Catheter ablation of idiopathic JET in adults is associated with a high rate of recurrence requiring multiple procedures and high risk of AV block requiring a permanent pacemaker. Mapping and ablation of the non-coronary cusp can be considered as the arrhythmia was controlled in 3 patients with no inadvertent AV block.