A novel hematopoietic progenitor cell mobilization regimen, utilizing bortezomib and filgrastim, for patients undergoing autologous transplant.

Adequate hematopoietic progenitor cell (HPC) collection is critical for patients undergoing autologous HPC transplant (AHPCT). Historically, 15 - 30% of patients failed HPC mobilization with granulocyte-colony stimulating factor (G-CSF) alone. Bortezomib, a proteasome inhibitor, has been shown to down regulate very late antigen-4 (VLA-4), an adhesion molecule expressed on HPCs. In this pilot study, bortezomib was administered on days -11 and -8 at a dose of 1.3 mg/m2 intravenously (IV) or subcutaneously (SQ), followed by G-CSF 10 mcg/kg SQ, on days -4 to -1 prior to HPC collection (Day 1). Nineteen patients, with multiple myeloma (n = 12) or non-Hodgkin lymphoma (n = 7) undergoing AHPCT for the first time, were enrolled. Patients were excluded if they had worse than grade II neuropathy or platelet count less than 100 x 109 /L. Bortezomib was well tolerated and all patients had adequate HPC collections with no mobilization failures. One patient (6%) had a CD34+ cell count of 3.9 cells/µL on Day 1 and received plerixafor per institutional algorithm. Eleven patients completed HPC collection in 1 day and eight in 2 days. All patients underwent AHPCT and had timely neutrophil and platelet engraftment. Comparison with a historical control group of 70 MM and lymphoma patients, who were mobilized with G-CSF, showed significantly higher CD 34+ cells/kg collected in the bortezomib mobilization study group. Bortezomib plus G-CSF is an effective HPC mobilizing regimen worth investigating further in subsequent studies. J. Clin. Apheresis 31:559-563, 2016. © 2015 Wiley Periodicals, Inc.

The roles of ethnicity, sex, and parental pain modeling in rating of experienced and imagined pain events.

To investigate the association of ethnicity, sex, and parental pain modeling on the evaluation of experienced and imagined painful events, 173 healthy volunteers (96 women) completed the Prior Pain Experience Questionnaire, a 79-question assessment of the intensity of painful events, and a questionnaire regarding exposure to parental pain models. Consistent with existing literature, greater ratings of experienced pain were noted among Black versus White participants. Parental pain modeling was associated with higher imagined pain ratings, but only when the parent matched the participant's sex. This effect was greater among White and Asian participants than Black or Hispanic participants, implying ethno-cultural effects may moderate the influence of pain modeling on the evaluation of imagined pain events. The clinical implications of these findings, as well as the predictive ability of imagined pain ratings for determining future experiences of pain, should be investigated in future studies.

Complete coverage of phantom limb and stump pain with constant current SCS system: a case report and review of the literature.

BACKGROUND: Spinal cord stimulator (SCS) technology has advanced over the past several years. However, our literature review revealed a lack of well-documented cases of successful treatment of phantom limb pain with percutaneous revision of previously placed systems. CASE REPORT: We present the case of a patient who suffered from debilitating bilateral lower extremity phantom limb pain despite having a SCS with a constant voltage system. We used fluoroscopy to successfully guide a percutaneous octapolar paddle lead to the right of the existing surgical paddle lead and a cylindrical quadrapolar lead in between. Finally, the older paddle lead was connected to an extension to make it compatible with the updated constant current system. The revised constant current SCS system provided bilateral coverage of the patient's pain, and at 1-year postoperative, the patient reported he had sustained coverage from his bilateral phantom limb pain. Our patient had complete coverage of his phantom limb pain after his previously placed SCS was changed from a constant voltage to a constant current system, and percutaneous leads were connected to his system. Adding percutaneous leads or switching generator types may benefit patients whose pain patterns have expanded since original SCS system placement. This case reports the complete coverage of phantom limb pain with a change from a constant voltage to a constant current SCS system and the addition of percutaneous leads to an existing SCS system.

Short interfering RNA against transient receptor potential vanilloid 1 attenuates cisplatin-induced hearing loss in the rat.

Cisplatin, a chemotherapeutic agent of choice for the treatment of solid tumors, produces hearing loss in approximately half a million new cancer patients annually in the United States. The hearing loss is due, in part, to increased generation of reactive oxygen species (ROS) in the cochlea, leading to lipid peroxidation and damage or death of outer hair cells in the organ of Corti. The cochlea expresses the transient receptor potential vanilloid 1 (TRPV1), which are normally expressed on small diameter neurons in the peripheral nervous system and mediate thermal sensitivity, but whose role in the cochlea is unclear. In this study, we show that TRPV1 is coregulated along with the NADPH oxidase isoform, NOX3, by cisplatin. Induction of these proteins by cisplatin is dependent on ROS generation, since it is reversed by systemic lipoic acid administration. In organ of Corti hair cell cultures (UB/OC-1 cells), cisplatin activates and induces TRPV1 and NOX3, leading to apoptosis of these cells. Inhibition of TRPV1 by capsazepine or ruthenium red reduced the apoptosis, implicating TRPV1 in this process. Treatment of UB/OC-1 cultures with short interfering RNA (siRNA) against either TRPV1 or NOX3 reduced cisplatin-induced apoptosis, while round window application of TRPV1 siRNA to rats reduced TRPV1 expression, decreased damage to outer hair cells and reduced cisplatin-induced hearing loss. These data provide a link between NOX3 and TRPV1 in cisplatin-induced hearing loss and suggest that targeting these proteins for knockdown by siRNA could serve as a novel approach in treating cisplatin ototoxicity.

NOX3 NADPH oxidase couples transient receptor potential vanilloid 1 to signal transducer and activator of transcription 1-mediated inflammation and hearing loss.

Transient receptor potential vanilloid 1 (TRPV1) is implicated in cisplatin ototoxicity. Activation of this channel by cisplatin increases reactive oxygen species generation, which contribute to loss of outer hair cells in the cochlea. Knockdown of TRPV1 by short interfering RNA protected against cisplatin ototoxicity. In this study, we examined the mechanism underlying TRPV1-mediated ototoxicity using cultured organ of Corti transformed cells (UB/OC-1) and rats. Trans-tympanic injections of capsaicin produced transient hearing loss within 24 h, which recovered by 72 h. In UB/OC-1 cells, capsaicin increased NOX3 NADPH oxidase activity and activation of signal transducer and activator of transcription 1 (STAT1). Intratympanic administration of capsaicin transiently increased STAT1 activity and expression of downstream proinflammatory molecules. Capsaicin produced a transient increase in CD14-positive inflammatory cells into the cochlea, which mimicked the temporal course of STAT1 activation but did not alter the expression of apoptotic genes or damage to outer hair cells. In addition, trans-tympanic administration of STAT1 short interfering RNA protected against capsaicin-induced hearing loss. These data suggest that activation of TRPV1 mediates temporary hearing loss by initiating an inflammatory process in the cochlea via activation of NOX3 and STAT1. Thus, these proteins represent reasonable targets for ameliorating hearing loss.