Current role of radiation therapy for multiple myeloma

BACKGROUND: Radiation therapy (RT) is a treatment modality traditionally used in patients with multiple myeloma (MM), but little is known regarding the role and effectiveness of RT in the era of novel agents, i.e., immunomodulatory drugs and proteasome inhibitors. METHODS: We retrospectively reviewed data from 449 consecutive MM patients seen at our institute in 2010-2012 to assess indications for RT as well as its effectiveness. Pain response was scored similarly to RTOG 0631 and used the Numerical Rating Pain Scale. RESULTS: Among 442 evaluable patients, 149 (34%) patients and 262 sites received RT. The most common indication for RT was palliation of bone pain (n = 109, 42%), followed by prevention/treatment of pathological fractures (n = 73, 28%), spinal cord compression (n = 26, 10%), and involvement of vital organs/extramedullary disease (n = 25, 10%). Of the 55 patients evaluable for pain relief, complete and partial responses were obtained in 76.4 and 7.2%, respectively. Prior RT did not significantly decrease the median number of peripheral blood stem cells collected for autologous transplant, even when prior RT was given to both the spine and pelvis. Inadequacy of stem cell collection for autologous stem cell transplant (ASCT) was not significantly different and it occurred in 9 and 15% of patients receiving no RT and spine/pelvic RT, respectively. None of the three cases of therapy-induced acute myelogenous leukemia/MDS occurred in the RT group. CONCLUSION: Despite the introduction of novel effective agents in the treatment of MM, RT remains a major therapeutic component for the management in 34% of patients, and it effectively provides pain relief while not interfering with successful peripheral blood stem cell collection for ASCT

Molecular expression and pharmacological evidence for a functional role of kv7 channel subtypes in Guinea pig urinary bladder smooth muscle.

Voltage-gated Kv7 (KCNQ) channels are emerging as essential regulators of smooth muscle excitability and contractility. However, their physiological role in detrusor smooth muscle (DSM) remains to be elucidated. Here, we explored the molecular expression and function of Kv7 channel subtypes in guinea pig DSM by RT-PCR, qRT-PCR, immunohistochemistry, electrophysiology, and isometric tension recordings. In whole DSM tissue, mRNAs for all Kv7 channel subtypes were detected in a rank order: Kv7.1~Kv7.2Kv7.3~Kv7.5Kv7.4. In contrast, freshly-isolated DSM cells showed mRNA expression of: Kv7.1~Kv7.2Kv7.5Kv7.3~Kv7.4. Immunohistochemical confocal microscopy analyses of DSM, conducted by using co-labeling of Kv7 channel subtype-specific antibodies and α-smooth muscle actin, detected protein expression for all Kv7 channel subtypes, except for the Kv7.4, in DSM cells. L-364373 (R-L3), a Kv7.1 channel activator, and retigabine, a Kv7.2-7.5 channel activator, inhibited spontaneous phasic contractions and the 10-Hz electrical field stimulation (EFS)-induced contractions of DSM isolated strips. Linopiridine and XE991, two pan-Kv7 (effective at Kv7.1-Kv7.5 subtypes) channel inhibitors, had opposite effects increasing DSM spontaneous phasic and 10 Hz EFS-induced contractions. EFS-induced DSM contractions generated by a wide range of stimulation frequencies were decreased by L-364373 (10 µM) or retigabine (10 µM), and increased by XE991 (10 µM). Retigabine (10 µM) induced hyperpolarization and inhibited spontaneous action potentials in freshly-isolated DSM cells. In summary, Kv7 channel subtypes are expressed at mRNA and protein levels in guinea pig DSM cells. Their pharmacological modulation can control DSM contractility and excitability; therefore, Kv7 channel subtypes provide potential novel therapeutic targets for urinary bladder dysfunction

Kv7 channel activators, L-364373 and retigabine, induced inhibition of the 10 Hz EFS-evoked contractions in guinea pig DSM isolated strips.

<p><b>A</b>) This original DSM tension recording illustrates L-364373 inhibitory effects on DSM 10 Hz EFS-induced contractions. <b>B</b>) Cumulative concentration-response curves for L-364373 summarize inhibitory effects on the amplitude and muscle force of EFS-induced contractions (n=6, N=4). <b>C</b>) This original DSM tension recording depicts an effect of retigabine on contractions induced by EFS (10 Hz). <b>D</b>) Cumulative concentration-response curves for retigabine demonstrate reduction of 10 Hz EFS-induced DSM contraction amplitude and muscle force (n=9, N=8). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075875#pone-0075875-t002" target="_blank">Table 2</a> summarizes the potency and maximum efficacy values.</p

Kv7.2-7.5 channel activator retigabine induced hyperpolarization and inhibition of spontaneous action potentials in freshly-isolated guinea pig DSM cells.

<p><b>A</b>) The original current-clamp membrane potential recording illustrates spontaneous action potentials exhibited by a DSM cell. Retigabine (10 µM) inhibited these spontaneous action potentials and caused membrane hyperpolarization. Upon washout, the electrical activity fully recovered. The insets in (<b>A</b>) depict the electrical activity on an expanded time scale for the time points indicated allowing for visualization of the action potentials. <b>B</b>) The original membrane potential recording from a DSM cell lacking spontaneous action potentials. Retigabine (10 µM) induced hyperpolarization and upon its washout membrane potential recovered. <b>C</b>) Summary data show statistically significant hyperpolarization of DSM cells by retigabine (10 µM) (n=12, N=11) and the recovery upon its washout (n=8, N=7). The bars depict actual mean membrane potential and SEM values for each condition. The indicated comparisons indicate statistical significance of ***P<0.001 and *<0.05 for the specified conditions, ns = non-significant (P>0.05).</p

Kv7.1-Kv7.5 inhibitors, XE991 and linopiridine, increased spontaneous phasic contractions in guinea pig DSM isolated strips.

<p><b>A</b>) This original DSM tension recording illustrates that XE991 enhances spontaneous phasic contractions in isolated DSM strips in a concentration-dependent manner. <b>B</b>) Cumulative concentration-response curves for XE991 show increases in DSM spontaneous phasic contractions amplitude and muscle force (n=8, N=5). <b>C</b>) This original DSM tension recording exemplifies that linopiridine increases DSM spontaneous phasic contractions in a concentration-dependent manner. <b>D</b>) Cumulative concentration-response curves for linopiridine depict increases in DSM spontaneous phasic contractions amplitude and muscle force (n=7, N=5). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075875#pone-0075875-t001" target="_blank">Table 1</a> provides a summary of potency and maximum efficacy values. TTX (1 µM) was present throughout the experiments.</p

Kv7.2-Kv7.5 channel opener retigabine decreased spontaneous phasic contractions in guinea pig DSM isolated strips.

<p><b>A</b>) This original DSM tension recording illustrates retigabine inhibitory effects on spontaneous phasic contractions of DSM isolated strips in a concentration-dependent manner. <b>B</b>) Cumulative concentration-response curves for retigabine summarize reduction in DSM spontaneous phasic contraction amplitude, muscle force, frequency, and duration (n=7, N=6); see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075875#pone-0075875-t001" target="_blank">Table 1</a> for potency and maximum efficacy values. TTX (1 µM) was present throughout the experiments.</p

Protein expression of Kv7 channel subtypes in guinea pig DSM.

<p>Confocal images illustrate the staining for Kv7.1 (<b>A</b>), Kv7.2 (<b>B</b>), Kv7.3 (<b>C</b>), Kv7.4 (<b>D</b>), and Kv7.5 (<b>E</b>) channel subtype proteins in mucosa-free whole DSM tissue. Kv7 channel subtype proteins were detected by immunohistochemistry using subtype-specific antibodies. In all panels, α-smooth muscle actin is shown in green; cell nuclei are illustrated in blue; the specific Kv7 channel subtype protein expression is represented by red staining. The merged images of α-smooth muscle actin, nuclei, and the Kv7 channel protein expression are illustrated in the quadrant labeled “Merge”. Images were captured with a Carl Zeiss LSM 700 META confocal microscope (63x objective). Experiments were conducted on DSM tissue samples isolated from 3 different guinea pigs.</p