Safety, tolerability and symptom outcomes associated with L-carnitine supplementation in patients with cancer, fatigue, and carnitine deficiency: a phase I/II study

Carnitine deficiency is among the many metabolic disturbances that may contribute to fatigue in patients with cancer. Administration of exogenous L-carnitine may hold promise as a treatment for this common symptom. Little is known about L-carnitine safety, tolerability, and dose-response in patients with cancer. We conducted a Phase I/II open-label trial to assess the safety and tolerability of exogenous L-carnitine and clarify the safe dose range associated with symptom effects for future controlled trials. Adult patients with advanced cancer, carnitine deficiency (free carnitine <35 for males or <25 microM/L for females, or acyl/free carnitine ratio >0.4), moderate to severe fatigue, and a Karnofsky Performance Status (KPS) score > or =50 were entered by groups of at least three into a standard maximum tolerated dose design. Each successive group received a higher dose of L-carnitine (250, 750, 1250, 1750, 2250, 2750, 3000 mg/day, respectively), administered in two daily doses for 7 days. To compare symptom outcomes before and after supplementation, patients completed validated measures of fatigue (Brief Fatigue Inventory [BFI]), depressed mood (Center for Epidemiologic Studies Depression Scale [CES-D]), quality of sleep (Epworth Sleeplessness Scale [ESS]), and KPS at baseline and 1 week later. Of the 38 patients screened for carnitine levels, 29 were deficient (76%). Twenty-seven patients participated ("intention to treat, ITT") (17 males, 10 females), and 21 completed the study ("completers"); 17 of these patients ("responders," mean+/-[SD] age=57.9+/-15) had increased carnitine levels at the end of the supplementation period. The highest dose achieved was 3000 mg/day. No patient experienced significant side effects and no toxicities were noted. Analysis of all the patients accrued (ITT, n=27) showed a total carnitine increase from 32.8+/-10 to 54.3+/-23 microM/L (P<0.001) and free carnitine increase from 26.8+/-8 to 44.1+/-17 microM/L (P<0.001). BFI decreased significantly, from 66+/-12 to 39.7+/-26 (P<0.001); ESS decreased from 12.9+/-12 to 9+/-6 (P=0.001); and CES-D decreased from 29.2+/-12 to 19+/-12 (P<0.001). A separate analysis of the 17 "responders" showed a dose-response relationship for total- (r=0.54, P=0.03), free-carnitine (r=0.56, P=0.02) levels, and fatigue (BFI) scores (r=-0.61, P=0.01). These findings suggest that l-carnitine may be safely administered at doses up to 3000 mg/day and that positive effects may be more likely at relatively higher doses in this range. This study provides the basis for the design of future placebo-controlled studies of l-carnitine supplementation for cancer-related fatigue.     

Specialized Inpatient Psychiatry for Serious Behavioral Disturbance in Autism and Intellectual Disability

Psychiatric hospitalization of children with autism spectrum disorder and/or intellectual disability is common, however, the effectiveness of this intervention is largely unknown. Thirty-eight clinically-referred children 8–19 years old admitted to a specialized inpatient psychiatry unit were assessed by a consistent caregiver on the Aberrant Behavior Checklist-Irritability (ABC-I) subscale at admission, discharge and 2 months post discharge. There was a decrease in the mean ABC-I score from admission (27.3, SD 7.4) to discharge (11.9, SD 8.8), which was sustained at 2 months post discharge (14.8, SD 9.3) (p < 0.001). Seventy-eight percent of the subjects were rated as “Improved” on the clinician Clinical Global Impressions Improvement scale at discharge. The study is limited by lack of a control group, but offers preliminary evidence for specialized inpatient psychiatry as an intervention for serious behavioral disturbance in this population.     

Cool Mist Irrigation Improves Heat Dissipation during Surgical Bone Drilling

Objective High-speed drilling generates heat in small cavities and may pose a risk for neurovascular tissues. We hypothesize that a continuous pressurized cold mist could be an alternative approach for better cooling during drilling of bone to access cranial lesions. This study aims to examine this idea experimentally. Design Ex-vivo drilling tests with controlled speed, feed, and depth were performed on cortical bone samples. Thermocouples were embedded underneath the drilling path to compare the temperature rises under mist cooling (at 3°C, < 300 mL/h) and flood irrigation (at 22°C, > 800 mL/h). Results A significant difference exists between these two systems (p value < 0.05). The measured temperature was ∼ 4°C lower for mist cooling than for flood irrigation, even with less than a third of the flow rate. Conclusion Experimental data indicate the capability of mist cooling to reduce heat generation while simultaneously enabling flow reduction and targeted cooling. An improved field of view in an extremely narrow access corridor may be achieved with this technology.     

The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity

The effect of the potent and selective poly(ADP-ribose) (PAR) polymerase-1 [and PAR polymerase-2] inhibitor CEP-8983 on the ability to sensitize chemoresistant glioblastoma (RG2), rhabdomyosarcoma (RH18), neuroblastoma (NB1691), and colon carcinoma (HT29) tumor cells to temozolomide- and camptothecin-induced cytotoxicity, DNA damage, and G(2)-M arrest and on the potentiation of chemotherapy-induced myelotoxicity was evaluated using in vitro assays. In addition, the effect of the prodrug CEP-9722 in combination with temozolomide and/or irinotecan on PAR accumulation and tumor growth was also determined using glioblastoma and/or colon carcinoma xenografts relative to chemotherapy alone. CEP-8983 sensitized carcinoma cells to the growth-inhibitory effects of temozolomide and/or SN38 increased the fraction of and/or lengthened duration of time tumor cells accumulated in chemotherapy-induced G(2)-M arrest and sensitized tumor cells to chemotherapy-induced DNA damage and apoptosis. A granulocyte-macrophage colony-forming unit colony formation assay showed that coincubation of CEP-8983 with temozolomide or topotecan did not potentiate chemotherapy-associated myelotoxicity. CEP-9722 (136 mg/kg) administered with temozolomide (68 mg/kg for 5 days) or irinotecan (10 mg/kg for 5 days) inhibited significantly the growth of RG2 tumors (60%) or HT29 tumors (80%) compared with temozolomide or irinotecan monotherapy, respectively. In addition, CEP-9722 showed "stand alone" antitumor efficacy in these preclinical xenografts. In vivo biochemical efficacy studies showed that CEP-9722 attenuated PAR accumulation in glioma xenografts in a dose- and time-related manner. These data indicate that CEP-8983 and its prodrug are effective chemosensitizing agents when administered in combination with select chemotherapeutic agents against chemoresistant tumors.     

A novel immune competent murine hypertrophic scar contracture model: A tool to elucidate disease mechanism and develop new therapies

Hypertrophic scar (HSc) contraction following burn injury causes contractures. Contractures are painful and disfiguring. Current therapies are marginally effective. To study pathogenesis and develop new therapies, a murine model is needed. We have created a validated immune‐competent murine HSc model. A third‐degree burn was created on dorsum of C57BL/6 mice. Three days postburn, tissue was excised and grafted with ear skin. Graft contraction was analyzed and tissue harvested on different time points. Outcomes were compared with human condition to validate the model. To confirm graft survival, green fluorescent protein (GFP) mice were used, and histologic analysis was performed to differentiate between ear and back skin. Role of panniculus carnosus in contraction was analyzed. Cellularity was assessed with 4′,6‐diamidino‐2‐phenylindole. Collagen maturation was assessed with Picro‐sirius red. Mast cells were stained with Toluidine blue. Macrophages were detected with F4/80 immune. Vascularity was assessed with CD31 immune. RNA for contractile proteins was detected by quantitative real‐time polymerase chain reaction (qRT‐PCR). Elastic moduli of skin and scar tissue were analyzed using a microstrain analyzer. Grafts contracted to ～45% of their original size by day 14 and maintained their size. Grafting of GFP mouse skin onto wild‐type mice, and analysis of dermal thickness and hair follicle density, confirmed graft survival. Interestingly, hair follicles disappeared after grafting and regenerated in ear skin configuration by day 30. Radiological analysis revealed that panniculus carnosus doesn't contribute to contraction. Microscopic analyses showed that grafts show increase in cellularity. Granulation tissue formed after day 3. Collagen analysis revealed increases in collagen maturation over time. CD31 stain revealed increased vascularity. Macrophages and mast cells were increased. qRT‐PCR showed up‐regulation of transforming growth factor beta, alpha smooth muscle actin, and rho‐associated protein kinase 2 in HSc. Tensile testing revealed that human skin and scar tissues are tougher than mouse skin and scar tissues.