The partial dopamine D2 receptor agonist aripiprazole is associated with weight gain in adolescent anorexia nervosa.

OBJECTIVE: Finding medication to support treatment of anorexia nervosa has been difficult. Neuroscience-based approaches may help in this effort. Recent brain imaging studies in adults and adolescents with anorexia nervosa suggest that dopamine-related reward circuits are hypersensitive and could provide a treatment target. METHODS: Here, we present a retrospective chart review of 106 adolescents with anorexia nervosa some of whom were treated with the dopamine D2 receptor partial agonist aripiprazole during treatment in a specialized eating disorder program. RESULTS: The results show that aripiprazole treatment was associated with greater increase in body mass index (BMI) during treatment. DISCUSSION: The use of dopamine receptor agonists may support treatment success in anorexia nervosa and should be further investigated.

The Transition of Academic Mental Health Clinics to Telehealth During the COVID-19 Pandemic.

OBJECTIVE: A consortium of 8 academic child and adolescent psychiatry programs in the United States and Canada examined their pivot from in-person, clinic-based services to home-based telehealth during the COVID-19 pandemic. The aims were to document the transition across diverse sites and to present recommendations for future telehealth service planning. METHOD: Consortium sites completed a Qualtrics survey assessing site characteristics, telehealth practices, service use, and barriers to and facilitators of telehealth service delivery prior to (pre) and during the early stages of (post) the COVID-19 pandemic. The design is descriptive. RESULTS: All sites pivoted from in-person services to home-based telehealth within 2 weeks. Some sites experienced delays in conducting new intakes, and most experienced delays establishing tele-group therapy. No-show rates and use of telephony versus videoconferencing varied by site. Changes in telehealth practices (eg, documentation requirements, safety protocols) and perceived barriers to telehealth service delivery (eg, regulatory limitations, inability to bill) occurred pre-/post-COVID-19. CONCLUSION: A rapid pivot from in-person services to home-based telehealth occurred at 8 diverse academic programs in the context of a global health crisis. To promote ongoing use of home-based telehealth during future crises and usual care, academic programs should continue documenting the successes and barriers to telehealth practice to promote equitable and sustainable telehealth service delivery in the future.

Phase II and gene expression analysis trial of neoadjuvant capecitabine plus irinotecan followed by capecitabine-based chemoradiotherapy for locally advanced rectal cancer: Hoosier Oncology Group GI03-53.

PURPOSE: We designed this study in locally advanced rectal cancer to determine the pathological response, toxicity, and disease-free survival (DFS) with induction capecitabine plus irinotecan followed by capecitabine-based chemoradiotherapy (CRT) and analyze the gene expression of enzymes involved in the metabolism of capecitabine and irinotecan for associations with response and toxicity. METHODS: Patients with T3/T4 or node positive rectal cancer were treated with capecitabine 1,000 mg/m(2) twice daily (BID) days 1-14, and irinotecan 200 mg/m(2) on day 1 every 21 days for 2 cycles, followed by capecitabine 825 mg/m(2) BID days 1-5 per week with concurrent radiotherapy 50.4 Gy in 28 fractions. Surgical resection occurred a median of 7.4 weeks after CRT. Gene expression levels or sequencing were used to analyze carboxylesterase-converting enzymes (CES1, CES2), thymidylate synthase (TS), thymidine phosphorylase (TP), dehydropyrimidine dehydrogenase (DPD), topoisomerase I (TOPO I), and uridine-diphosphate (UDP) glucuronosyl transferase 1A1 in pre- and post-treatment tumor and normal tissue samples. RESULTS: Twenty-two patients were enrolled, and 18 completed neoadjuvant therapy and underwent R0 resection. Two patients with UGT1A1 7/7 had grade 3 and 4 neutropenic fever and sepsis. Pathological complete response (pCR) occurred in 6 of 18 patients (33 %) and 10 (56 %) had tumor and/or nodal downstaging. The 3-year DFS was 75.5 % (95 % CI, 39.7-91.8 %). Locoregional control rate was 100 %. We observed higher TP gene expression in pCR patients, but no correlations with toxicity. CONCLUSIONS: This neoadjuvant regimen was safe and demonstrated significant antitumor activity. High TP tumor gene expression was associated with obtaining pCR.

Human carboxylesterases: an update on CES1, CES2 and CES3.

Carboxylesterases belong to Phase I group of drug metabolizing enzymes. They hydrolyze a variety of drug esters, amides, carbamates and similar structures. There are five 'carboxylesterase' genes listed in the Human Genome Organization database. In this review, we will focus on the CES1, CES2 and CES3 genes and their protein products that have been partially characterized. Several variants of these three CESs result from alternate splicing, single nucleotide polymorphisms and multiple copy variants. The three CESs, are largely localized to tissues that are major sites of drug metabolism like the mucosa of the gastrointestinal tract, lungs and liver but, they differ in tissue-specific expression. The amino acid alignment of the three CESs reveals important conserved catalytic and structural residues. There are interesting insertions and deletions that may affect enzymatic function as determined by homology modeling of CES3 using the CES1 three-dimensional structure. A comparison of the substrate specificity of CES1 versus CES2 reveals broad but distinct substrate preferences. There is little information on the substrate specificity of CES3 but it seems to have a lower catalytic efficiency than the other two CESs for selected substrates.

Expression and characterization of a human carboxylesterase 2 splice variant.

CPT-11 [7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin or Irinotecan] is a carbamate prodrug that is activated in vivo by carboxylesterase (CES)-2 to SN-38 (7-ethyl-10-hydroxycamptothecin), a potent topoisomerase I inhibitor. There is high interindividual variation when CPT-11 is used in the treatment of colorectal cancer. Several splice variants of CES2 are reported in the expressed sequence tag database. Real-time polymerase chain reaction was used to determine the abundance of the CES2 and splice variant of human carboxylesterase 2 (CES2Delta(458-473)) transcripts in 10 paired samples of human tumor and normal colon tissue. The results showed that the CES2Delta(458-473) transcript accounts for an average of 6% of total CES2 transcripts in colon tissue, and there is large interindividual variation in CES2 expression in both tumor and normal colon samples. The carboxylesterase activity of the colon samples was determined by 4-methylumbelliferyl acetate hydrolysis assays and nondenaturing polyacrylamide gel electrophoresis followed by activity staining. Significant, positive correlations were found between CES2 expression levels and both measures of carboxylesterase activity. We cloned and expressed the CES2Delta(458-473) protein in Sf9 insect cells. The purification profiles and preliminary characterization of the CES2Delta(458-473) protein indicated that the expressed protein is folded and glycosylated like CES2. However, in vitro assays show that the CES2Delta(458-473) protein lacks 4-methylumbelliferyl acetate and irinotecan hydrolase activities. In conclusion, we found that the CES2Delta(458-473) protein is an inactive splice variant of CES2 and that its transcript is spliced at a relatively constant rate in tumor and normal colon tissue.