Adapting Alzheimer Disease and Related Dementias Clinical Research Evaluations in the Age of COVID-19.

In March 2020, the novel coronavirus (COVID-19) became a global pandemic that would cause most in-person visits for clinical studies to be put on pause. Coupled with protective stay at home guidelines, clinical research at the Icahn School of Medicine at Mount Sinai Alzheimer's Disease Research Center (ISMMS ADRC) needed to quickly adapt to remain operational and maintain our cohort of research participants. Data collected by the ISMMS ADRC as well as from other National Institute on Aging (NIA) Alzheimer Disease centers, follows the guidance of the National Alzheimer Coordinating Center (NACC). However, at the start of this pandemic, NACC had no alternative data collection mechanisms that could accommodate these safety guidelines. To stay in touch with our cohort and to ensure continued data collection under different stages of quarantine, the ISMMS ADRC redeployed their work force to continue their observational study via telehealth assessment. On the basis of this experience and that of other centers, NACC was able to create a data collection process to accommodate remote assessment in mid-August. Here we review our experience in filling the gap during this period of isolation and describe the adaptations for clinical research, which informed the national dialog for conducting dementia research in the age of COVID-19 and beyond.

Impact of maternal stress, depression and anxiety on fetal neurobehavioral development.

Although postnatal psychologic distress has been widely studied for many years, particularly with a focus on postpartum depression, symptoms of maternal depression, stress, and anxiety are not more common or severe after childbirth than during pregnancy. This paper reviews the newer body of research aimed at identifying the effects of women's antenatal psychologic distress on fetal behavior and child development, and the biologic pathways for this influence. These studies are in line with the growing body of literature supporting the "fetal origins hypothesis" that prenatal environmental exposures--including maternal psychologic state-based alterations in in utero physiology--can have sustained effects across the lifespan.

Toxicology and pharmacokinetic study of orally administered 5-iodo-2-pyrimidinone-2'deoxyribose (IPdR) x 28 days in Fischer-344 rats: impact on the initial clinical phase I trial design of IPdR-mediated radiosensitization.

PURPOSE: A toxicology and pharmacokinetic study of orally administered (po) IPdR (5-3iodo-2-pyrimidinone-2'deoxyribose, NSC-726188) was performed in Fischer-344 rats using a once daily (qd) x 28 days dosing schedule as proposed for an initial phase I clinical trial of IPdR as a radiosensitizer. METHODS: For the toxicology assessment, 80 male and female rats (10/sex/dosage group) were randomly assigned to groups receiving either 0, 0.2, 1.0 or 2.0 g kg(-1)day(-1) of po IPdR x 28 days and one-half were observed to day 57 (recovery group). Animals were monitored for clinical signs during and following treatment with full necropsy of one-half of each dosage group at day 29 and 57. For the plasma pharmacokinetic assessment, 40 rats (10/sex/dosage group) were randomly assigned to groups receiving either 0.2 or 1.0 g kg(-1)day(-1) of po IPdR x 28 days with multiple blood samplings on days 1 and 28 and single blood sampling on days 8 and 15. RESULTS: No drug-related deaths occurred. Higher IPdR doses resulted in transient weight loss and transient decreased hemoglobins but had no effect on white cells or platelets. Complete serum chemistry evaluation showed transient mild decreases in total protein, alkaline phosphatase, and serum globulin. Necropsy evaluation at day 29 showed minimal to mild histopathologic changes in bone marrow, lymph nodes and liver; all reversed by day 59. There were no sex-dependent differences in plasma pharmacokinetics of IPdR noted and the absorption and elimination kinetics of IPdR were found to be linear over the dose range studied. CONCLUSIONS: A once-daily dosing schedule of po IPdR for 28 days with doses up to 2.0 g kg(-1)day(-1) appeared to be well tolerated in Fischer-344 rats. Drug-related weight loss and microscopic changes in bone marrow, lymph nodes and liver were observed. These changes were all reversed by day 57. IPdR disposition was linear over the dose range used. However, based on day 28 kinetics it appears that IPdR elimination is enhanced following repeated administration. These toxicology and pharmacokinetic data were used when considering the design of our initial phase I trial of po IPdR as a clinical radiosensitizer.

5-iodo-2-pyrimidinone-2'-deoxyribose-mediated cytotoxicity and radiosensitization in U87 human glioblastoma xenografts.

PURPOSE: 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is a novel orally administered (p.o.) prodrug of 5-iododeoxyuridine. Because p.o. IPdR is being considered for clinical testing as a radiosensitizer in patients with high-grade gliomas, we performed this in vivo study of IPdR-mediated cytotoxicity and radiosensitization in a human glioblastoma xenograft model, U87. METHODS AND MATERIALS: Groups of 8 or 9 athymic male nude mice (6-8 weeks old) were implanted with s.c. U87 xenograft tumors (4 x 10(6) cells) and then randomized to 10 treatment groups receiving increasing doses of p.o. IPdR (0, 100, 250, 500, and 1000 mg/kg/d) administered once daily (q.d.) x 14 days with or without radiotherapy (RT) (0 or 2 Gy/d x 4 days) on days 11-14 of IPdR treatment. Systemic toxicity was determined by body weight measurements during and after IPdR treatment. Tumor response was assessed by changes in tumor volumes. RESULTS: IPdR alone at doses of > or =500 mg/kg/d resulted in moderate inhibition of tumor growth. The combination of IPdR plus RT resulted in a significant IPdR dose-dependent tumor growth delay, with the maximum radiosensitization using > or =500 mg/kg/d. IPdR doses of 500 and 1000 mg/kg/d resulted in transient 5-15% body weight loss during treatment. CONCLUSIONS: In U87 human glioblastoma s.c. xenografts, p.o. IPdR given q.d. x 14 days and RT given 2 Gy/d x 4 days (days 11-14 of IPdR treatment) results in a significant tumor growth delay in an IPdR dose-dependent pattern. The use of p.o. IPdR plus RT holds promise for Phase I/II testing in patients with high-grade gliomas.

A Predictive Genetic Signature for Response to Fluoropyrimidine-Based Neoadjuvant Chemoradiation in Clinical Stage II and III Rectal Cancer.

PURPOSE: Pre-operative chemoradiation (CRT) is currently the standard of care for patients with clinical stage II and III rectal cancer but only about 45% of patients achieve tumor downstaging and <20% of patients achieve a pathologic complete response. Better methods to stratify patients according to potential neoadjuvant treatment response are needed. We used microarray analysis to identify a genetic signature that correlates with a pathological complete response (pCR) to neoadjuvant CRT. We performed a gene network analysis to identify potential signaling pathways involved in determining response to neoadjuvant treatment. PATIENTS AND METHODS: We identified 31 T3-4 N0-1 rectal cancer patients who were treated with neoadjuvant fluorouracil-based CRT. Eight patients were identified to have achieved a pCR to treatment while 23 patients did not. mRNA expression was analyzed using cDNA microarrays. The correlation between mRNA expression and pCR from pre-treatment tumor biopsies was determined. Gene network analysis was performed for the genes represented by the predictive signature. RESULTS: A genetic signature represented by expression levels of the three genes EHBP1, STAT1, and GAPDH was found to correlate with a pCR to neoadjuvant treatment. The difference in expression levels between patients who achieved a pCR and those who did not was greatest for EHBP1. Gene network analysis showed that the three genes can be connected by the gene ubiquitin C (UBC). CONCLUSION: This study identifies a 3-gene signature expressed in pre-treatment tumor biopsies that correlates with a pCR to neoadjuvant CRT in patients with clinical stage II and III rectal cancer. These three genes can be connected by the gene UBC, suggesting that ubiquitination is a molecular mechanism involved in determining response to treatment. Validating this genetic signature in a larger number of patients is proposed.

Outcomes of chemoradiotherapy with 5-Fluorouracil and mitomycin C for anal cancer in immunocompetent versus immunodeficient patients.

PURPOSE: Information is limited as to how we should treat invasive anal squamous cell carcinoma (SCC) in patients with chronic immunosuppression, since the majority of clinical studies to date have excluded such patients. The objective of this study is to compare treatment outcomes in immunocompetent (IC) versus immunodeficient (ID) patients with invasive anal SCC treated similarly with combined modality therapy. METHODS AND MATERIALS: Between January 1999 and March 2007, a total of 36 consecutive IC and ID patients received concurrent chemoradiotherapy using three-dimensional conformal radiotherapy with infusional 5-fluorouracil and mitomycin C. The IC and ID groups consisted of 19 and 17 patients, respectively, with 14 human immunodeficiency virus-positive (HIV+) and 3 post-solid organ transplant ID patients. There were no significant differences in tumor size, T stage, N stage, chemotherapy doses, or radiation doses between the two groups. RESULTS: With a median follow-up of 3.1 years, no differences were found in overall survival, disease-specific survival, and colostomy-free survival. Three-year overall survival was 83.6% (95% CI = 68.2-100) and 91.7% (95% CI = 77.3-100) in the IC and ID groups, respectively. In addition, there were no differences in acute and late toxicity profiles between the two groups. In the human immunodeficiency virus-positive patients, Cox modeling showed no difference in overall survival by pretreatment CD4 counts (hazard ratio = 0.994, 95% CI = 0.98-1.01). No correlation was found between CD4 counts and the degree of acute toxicities. CONCLUSION: Our data suggest that standard combined modality therapy with three-dimensional conformal radiotherapy and 5-fluorouracil plus mitomycin C is as safe and effective for ID patients as for IC patients.