A phase 1 study of ruxolitinib, steroids and lenalidomide for relapsed/refractory multiple myeloma patients.

Ruxolitinib with lenalidomide and dexamethasone shows anti-myeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma (MM) cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. A phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory (RR)MM who had been treated with lenalidomide, steroids and a proteasome inhibitor and showed progressive disease at study entry. A traditional 3 + 3 dose escalation design was used to enroll subjects in four cohorts. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1-21 of a 28 day cycle and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Forty-nine patients were enrolled. The median age was 64 years and they had received a median of six prior treatments including lenalidomide and steroids to which 94% were refractory. No dose limiting toxicities occurred. The CBR and ORR were 49% and 36%, respectively. All responding patients were refractory to lenalidomide. Grade 3 or 4 adverse events (AEs) included anemia (17%), decreased lymphocyte count (15%), and hypophosphatemia (10%). Most common serious AEs included sepsis (9.8%) and pneumonia (7.8%). This Phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating MM. NCT03110822.

Psychotherapy in pain management: New viewpoints and treatment targets based on a brain theory.

The current paper provides an explanation of neurophysiological pain processing based the Dimensional Systems Model (DSM), a theory of higher cortical functions in which the cortical column is considered the binary digit for all cortical functions. Within the discussion, novel views on the roles of the basal ganglia, cerebellum, and cingulate cortex are presented. Additionally, an applied Clinical Biopsychological Model (CBM) based on the DSM will be discussed as related to psychological treatment with chronic pain patients. Three specific areas that have not been adequately addressed in the psychological treatment of chronic pain patients will be discussed based on the CBM. The treatment approaches have been effectively used in a clinical setting. Conclusions focus on a call for researchers and clinicians to fully evaluate the value of both the DSM and CBM.

A Phase I Study of Ruxolitinib, Lenalidomide, and Steroids for Patients with Relapsed/Refractory Multiple Myeloma.

PURPOSE: Ruxolitinib with lenalidomide and dexamethasone shows antimyeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. Therefore, a phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory multiple myeloma (RRMM) who had been treated with lenalidomide/steroids and a proteasome inhibitor and showed progressive disease at study entry. PATIENTS AND METHODS: A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment of 28 patients. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1-21 of a 28-day cycle, and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR), and overall response rate (ORR). RESULTS: Twenty-eight patients were enrolled. The median age was 67 years and received a median of six prior treatments including lenalidomide and steroids to which 93% were refractory. No dose-limiting toxicities occurred. The CBR and ORR were 46% and 38%, respectively. All 12 responding patients were refractory to lenalidomide. Grade 3 or grade 4 adverse events (AE) included anemia (18%), thrombocytopenia (14%), and lymphopenia (14%). Most common serious AEs included sepsis (11%) and pneumonia (11%). CONCLUSIONS: This phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating multiple myeloma (ClinicalTrials.gov number, NCT03110822).

Complexes and Negative Activation Energies in Arylhalocarbene/Alkene Additions: Activation Parameter Dependence on Alkane Solvent Chain Length.

Activation parameters for the additions of PhCCl, F5-PhCCl, and 3,5-dinitro-PhCCl to tetramethylethylene, cyclohexene, and 1-hexene have been determined in decane. With the exception of two carbene/alkene combinations, Arrhenius correlations of ln kaddn vs 1/T were unimodal and linear, affording negative activation energies and entropies. The additions of PhCCl or F5-PhCCl to 1-hexene gave bimodal Arrhenius correlations. Comparisons to the analogous experimental data obtained in pentane and computational studies help to elucidate the observed behavior. Activation entropies decrease in parallel with activation enthalpies going from pentane to decane solvent, suggesting that enthalpy-entropy compensation is operative in these carbene additions. The bimodal Arrhenius behavior is proposed to result from carbene-alkene additions taking place intrinsically or extrinsically to decane solvent cage assemblies.

Adventures in Reactive Intermediate Chemistry: A Perspective and Retrospective.

I review aspects of my research on reactive intermediates, specifically the physical organic chemistry of carbenes and carbocations. The topics treated include carbenoids, carbenic philicity, absolute rates of carbene/alkene additions, the diazirine exchange reaction and derived carbenes, carbene equilibria, carbocations from diazotates, and carbocations from alkoxychlorocarbenes. The essay concludes with observations on the protean nature of physical organic chemistry.

Neuropsychological assessment in two cases of adult mild traumatic brain injury with a history of childhood head trauma.

The existence of residual cognitive deficits following mild traumatic brain injury (MTBI) has been a topic of controversy. The current paper describes neuropsychological assessment in two cases of adulthood mild traumatic brain injury. Both patients showed objective results demonstrating cognitive impairment. The first patient experienced a head trauma around the age of 4 and the other patient had a head injury around the age of 7. Discussion focuses on the need for the systematic consideration of a history of childhood head injury as a moderating factor that may account for why a subgroup of patients show cognitive deficits following MTBI.

CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma.

Carfilzomib, a proteasome inhibitor, is approved in the United States as a single agent, and in combination with dexamethasone or lenalidomide/dexamethasone (KRd) for relapsed or refractory multiple myeloma (MM). Under the single-agent and KRd approvals, carfilzomib is administered as a 10-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (20 mg/m(2) [cycle 1, days 1-2]; 27 mg/m(2) thereafter). This multicenter, single-arm, phase 1/2 study, Community Harmonized Assessment of Myeloma Patients via an Integrated Oncology Network-1 (CHAMPION-1), evaluated once-weekly carfilzomib with dexamethasone in relapsed, or relapsed and refractory MM (1-3 prior therapies). Patients received carfilzomib (30-minute IV infusion) on days 1, 8, and 15 of 28-day cycles. The phase 1 portion used a 3 + 3 dose-escalation scheme to determine the maximum tolerated dose (MTD) of carfilzomib. During phase 2, patients received carfilzomib on the same schedule at the MTD. Patients received dexamethasone (40 mg) on days 1, 8, 15, and 22; dexamethasone was omitted on day 22 for cycles 9+. A total of 116 patients were enrolled. The MTD was 70 mg/m(2), and 104 patients (phase 1/2) received carfilzomib 70 mg/m(2) At 70 mg/m(2), the median number of prior regimens was 1; and 52% were bortezomib-refractory. At 70 mg/m(2), the most common grade ≥3 adverse events were fatigue (11%) and hypertension (7%). Overall response rate at 70 mg/m(2) was 77%. Median progression-free survival was 12.6 months. These findings merit additional evaluation of the once-weekly dosing regimen. This trial was registered at www.clinicaltrials.gov as #NCT01677858.

Two Equilibria of (N-Methyl-3-pyridinium)chlorocarbene, a Cationic Carbene.

Equilibrium constants and the associated thermodynamic parameters are reported for the equilibria established between the cationic carbene (N-methyl-3-pyridinium)chlorocarbene tetrafluoroborate (MePyr(+)CCl BF4(-), 3) and 1,3,5-trimethoxybenzene (TMB) to form a carbene-TMB complex, as well as between carbene 3 and chloride ion to form the zwitterion, N-methyl-3-pyridinium dichloromethide (10). These equilibrium constants and thermodynamic parameters are contrasted with analogous data for several related carbenes, and the influence of the pyridinium unit in carbene 3 is thereby highlighted. Computational studies augment and elucidate the experimental results.

Activation Parameters for Additions to Alkenes of Arylchlorocarbenes with Enhanced Electrophilicity.

Activation parameters are reported for additions of phenylchlorocarbene (PhCCl), pentafluorophenylchlorocarbene (F5-PhCCl), and 3,5-dinitrophenyl-chlorocarbene (3,5-DN-PhCCl) to tetramethylethylene (TME), cyclohexene, and 1-hexene. The order of activation enthalpies is F5-PhCCl > PhCCl > 3,5-DN-PhCCl. Activation enthalpies also increase as the degree of alkene alkylation decreases. In general, the entropies of activation increase in tandem with the enthalpies of activation.

Absolute reactivity of (N-methyl-3-pyridinium)chlorocarbene.

(N-Methyl-3-pyridinium)chlorocarbene tetrafluoroborate (MePyr(+)CCl BF4(-), 4) is generated by laser flash photolysis (LFP) of the corresponding diazirine (5) and reacted with tetramethylethylene, cyclohexene, 1-hexene, 2-ethyl-1-butene, methyl acrylate, and acrylonitrile. Absolute rate constants are measured for these carbene-alkene addition reactions, and activation parameters are obtained for additions of MePyr(+)CCl BF4(-) to tetramethylethylene, cyclohexene, and 1-hexene. MePyr(+)CCl BF4(-) is computed to be a highly reactive, electrophilic, singlet carbene, and experiments are in accord with expectations. Its activation parameters are compared with those of CF3CCl, CCl2, CClF, and CF2. In all cases, enthalpy-entropy compensation is observed, with ΔH(‡) and ΔS(‡) decreasing in tandem as carbenic stability decreases. A qualitative explanation is offered for this phenomenon.

Nucleophilic intermolecular chemistry and reactivity of dimethylcarbene.

Experimental and computational studies find that dimethylcarbene (DMC), the parent dialkylcarbene, is both predicted to be and functions as a very reactive nucleophilic carbene in addition reactions with five simple alkenes. Activation energies and enthalpies for DMC additions to 2-ethyl-1-butene and methyl acrylate are computed and observed to be negative.

Impact of mental health comorbidities on health care utilization and expenditure in a large US managed care adult population with ADHD.

OBJECTIVE: To estimate the health resource use (HRU) and expenditure of adult patients with attention deficit/hyperactivity disorder (ADHD) subsequently diagnosed with one or more mental health (MH) comorbidities. METHODS: Using Kaiser Permanente Southern California electronic medical records (January 1, 2006, to December 31, 2009), we identified adults with at least one ADHD diagnosis and at least two subsequent prescriptions fills for ADHD medication. The date of first MH comorbidity diagnosis after the index ADHD diagnosis was defined as the index transition date. Continuous eligibility 12 months before and after the index transition date was required. For patients with multiple transitions (≥2), the post-transition period reflected the 12 months after the second transition. HRU for all-cause inpatient, outpatient, emergency department, behavioral therapy, overall prescription fill counts, and ADHD-specific prescription fill counts and mean patient expenditure (2010 US $) were estimated. Generalized estimating equations were used to evaluate differences in HRU and expenditure between the pre- and post-transition periods, respectively. RESULTS: Of the 3809 patients with ADHD identified, 989 (26%) had at least one transition (n = 357 single and n = 632 multiple). From the pre- to the post-transition period, for single transition cohort, all HRU increased significantly except for behavioral therapy. In the multiple transition cohort, all HRU increased significantly. Total expenditure increased by mean ± SE of $1822 ± $306 and $4432 ± $301 (both P < 0.0001) in the single and multiple transition cohorts, respectively. CONCLUSIONS: Twenty-six percent of patients with ADHD transitioned to MH comorbid diagnoses. Increased HRU and expenditure were associated with MH transitions. Identifying of patients with ADHD at risk for MH comorbidities may help to improve their outcomes.

O-ylide and π-complex formation in reactions of a carbene with dibenzo and monobenzo crown ethers.

Reactions of p-nitrophenylchlorocarbene (PNPCC) with various dibenzo crown ethers produce O-ylides and π-complexes; the reactions can be followed via the spectral signatures of the carbene and the products. The O-ylides form most rapidly, but over time they decay in favor of the more stable π-complexes. Extensive computational studies support and refine appropriate structural and mechanistic conjectures. Reactions of PNPCC with monobenzo crown ethers afford only the spectral signatures of O-ylides; monobenzo π-complexes are either not formed in significant concentrations or are spectroscopically silent.

The nucleophilicity of a dialkylcarbene: unusual activation parameters for additions of adamantanylidene to simple alkenes.

Computational and experimental results demonstrate that adamantanylidene (1) behaves as a highly reactive nucleophile toward common alkenes. It is the only known saturated nucleophilic carbene that lacks direct or vinylogous heteroatomic substitution. The activation energy and enthalpy for addition of 1 to methyl acrylate are the most negative values yet encountered in any carbene-alkene addition.

Visualizing carbene equilibria.

Reviewed herein are equilibria between halocarbenes and halocarbanions, carbenes and carbene complexes and carbenes and O-ylides. The transient species were visualized by laser flash photolysis coupled with UV-Visible spectroscopy. This methodology enabled the determination of equilibrium constants and the extraction of associated thermodynamic parameters. Parallel computational studies provided anticipated structures and energies for the transient species, as well as electronic absorption wavelengths and oscillator strengths.

Reactivity of chlorotrifluoromethylcarbene: activation parameters for halocarbene-alkene addition reactions.

Activation parameters are reported for ClCCF3 additions to three alkenes (tetramethylethylene, cyclohexene, and 1-hexene). The results are compared to those for CCl2, CClF, and CF2. Activation enthalpies decrease as the carbene stability decreases and its electrophilicity increases, and also as alkene reactivity (degree of alkylation) increases. Activation entropies decrease in parallel with activation enthalpies, suggesting the operation of enthalpy-entropy compensation in these carbene additions.

Hammett analyses of halocarbene-halocarbanion equilibria.

Substituted arylchlorocarbenes (X = H, p-Cl, p-CF3, p-F, m-Cl) reacted reversibly with Cl(-) in dichloroethane to form the corresponding aryldichloromethide carbanions. Equilibrium constants and rate constants for the forward and reverse reactions were correlated by the Hammett equation. DFT methods were used to compute equilibrium constants and electronic absorption spectra.

Neuropsychological evaluation in an adolescent with cerebellar hypoplasia diagnosed with Asperger's Syndrome.

There is a growing body of literature describing cases of cognitive impairment associated with both acquired and developmental damage to the cerebellum. The current case study describes such a case involving a 17-year-old male with cerebellar hypoplasia, having incomplete formation of the vermis and atrophy of the interior cerebellar hemispheres. He had previously been diagnosed as having Asperger's Syndrome. A full neuropsychological evaluation was performed, including effort testing. This is followed by a comparison of the current results to previously reported cases, with a discussion of the heterogeneity of deficits associated with developmental cerebellum malformation.

Directly observed halocarbene-halocarbanion equilibration.

Equilibria between phenylhalocarbenes, halide ions, and phenyldihalomethide carbanions have been spectroscopically characterized and computationally investigated for the halogens Cl and Br. Equilibrium constants, forward and reverse rate constants, and associated thermodynamic parameters are reported.