Network meta-analysis of nivolumab plus ipilimumab in the second-line setting for advanced hepatocellular carcinoma.

Aims: To compare the efficacy of nivolumab 1 mg/kg + ipilimumab 3 mg/kg with regorafenib 160 mg, cabozantinib 60 mg and nivolumab 3 mg/kg monotherapy for second-line treatment of advanced hepatocellular carcinoma. Materials & methods: Indirect comparison using network meta-analysis and propensity score weighting. Results: Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had significantly higher objective response rate (median 31.2% [95% credible interval: 19.6-44.5%]) than cabozantinib (4.2% [2.0-6.5%]) and regorafenib (4.8% [1.1-8.3%]), and significantly longer overall survival (cabozantinib: hazard ratio: 0.46 [95% credible interval: 0.27-0.79]; regorafenib: 0.56 [0.32-0.97]). Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had significantly better objective response rate (difference 21.0% [4.5-37.5%]) and overall survival (hazard ratio: 0.58 [0.35-0.96]) than nivolumab monotherapy. Conclusion: Nivolumab 1 mg/kg + ipilimumab 3 mg/kg had a superior efficacy versus cabozantinib 60 mg, regorafenib 160 mg and nivolumab 3 mg/kg monotherapy as second-line therapy for advanced hepatocellular carcinoma.

Clinical and cost outcomes of pre-emptive plerixafor administration in patients with multiple myeloma undergoing stem cell mobilization.

PURPOSE: The stem cell mobilization agent plerixafor significantly improves CD34+ stem cell procurement in patients with multiple myeloma undergoing autologous stem cell transplant. We compared mobilization success rates and costs of two regimens of plerixafor administration: pre-emptive (P-PL, initiated the evening prior to the first day of stem cell collection) and standard (S-PL, initiated the evening prior to the second day of stem cell collection in the event of inadequate collection on the first day). METHODS: Patients with multiple myeloma undergoing mobilization were categorized as either P-PL or S-PL. Stem cell collection success was evaluated using logistic regression models. Associated costs were aggregated in terms of average collections per patient in each mobilization option (patient level), and escalated to a panel of 5000 patients (population level). RESULTS: 299 patients were evaluable; 241 received P-PL and 58 received S-PL. Patients receiving P-PL had higher median CD34+ count pre-collection and higher median total CD34+ cell harvest on the first collection (6.75 × 106/kg for P-PL, 1.96 × 106/kg for S-PL; P<0.01). In multivariable analyses, P-PL remained significantly associated with the ability to collect ≥2 × 106/kg CD34+ on the first day (OR = 4.05, 95% CI, 1.19-13.83, P = 0.03) and ≥5 × 106/kg CD34+ in total (OR = 3.09, 95% CI, 1.04-9.23, P = 0.04). P-PL saved $11,248 (46%) per patient compared with S-PL. CONCLUSION: P-PL significantly enhanced collection efficiency, with most patients completing collection in 1 day, resulting in substantial cost savings.

Fluoxetine administration potentiates the effect of olanzapine on locus coeruleus neuronal activity.

BACKGROUND: As many as 30% of individuals diagnosed with depression are nonresponsive to traditional antidepressant medication. Augmentation and combination strategies have emerged in an attempt to address this issue. Atypical antipsychotics (e.g., olanzapine), when added to a selective serotonin reuptake inhibitor (e.g., fluoxetine) have shown great promise in the treatment of these treatment-resistant patients. As of yet, the precise neural mechanisms responsible for the beneficial clinical effect of these combinations are not completely understood. METHODS: Separate groups of rats received either saline or fluoxetine (10 mg/kg/day) for 24 hours or 3 weeks via subcutaneously implanted osmotic pumps. The effects of either intravenous saline or olanzapine (.3, 1.0, or 3.0 mg/kg) on locus coeruleus (LC) neuronal activity were then assessed via extracellular single-unit recordings. RESULTS: Acute administration of olanzapine produced a significant elevation of the firing rate and burst firing of LC cells, and chronic, but not acute, administration of fluoxetine decreased baseline and burst firing of LC cells; however, when given in combination, an interaction of fluoxetine and olanzapine was observed, with olanzapine causing a significantly greater increase in LC firing rate and burst firing after acute and chronic administration of fluoxetine. CONCLUSIONS: These results provide a potential neural mechanism for the beneficial clinical effects of the olanzapine/fluoxetine combination. The increase in baseline and burst firing of LC neurons in the groups receiving both fluoxetine and olanzapine would result in enhanced norepinephrine release in projection areas (e.g., prefrontal cortex), which could lead to a reduction in depressive symptoms.

Differential mastication kinematics of the rabbit in response to food and water: implications for conditioned movement.

Analysis of naturalistic chewing patterns may provide insight into mapping the neural substrates of jaw movement control systems, including their adaptive modification during the classically conditioned jaw movement (CJM) paradigm. Here, New Zealand White rabbits were administered food and water stimuli orally to evaluate the influence of stimulus consistency on masticatory pattern. Chewing patterns were recorded via video camera and movements were analyzed by computerized image analysis. The mandibular kinematics, specifically the extent of dorsal/ventral, medial/lateral, and rostral/caudal movement, were significantly larger in food-evoked than water-evoked chewing. Water-evoked chewing frequency, however, was significantly higher than that of food-evoked movements. In light of known cortical mastication modulatory centers, our findings implicate different neural substrates for the responses to food and water stimuli in the rabbit. A detailed delineation of jaw movement patterns and circuitry is essential to characterize the neural substrates of CJM.