Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer's disease (MCI and dementia) in primary care: a review and synthesis.

The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

A mid-treatment break and reassessment maintains tumor control and reduces toxicity in patients with hepatocellular carcinoma treated with stereotactic body radiation therapy.

BACKGROUND AND PURPOSE: Patients with hepatocellular carcinoma (HCC) commonly have underlying liver dysfunction with variable tolerance to liver stereotactic body radiation therapy (SBRT). We hypothesized that insertion of a 1-month mid-treatment break would allow us to adapt treatment to the individual patient response, thereby reducing toxicity without compromising local control (LC). MATERIALS AND METHODS: We analyzed HCC patients receiving 3-5 fraction SBRT at our institution from 2005 to 2017. Over this time, patients were offered enrollment on prospective trials assessing individualized adaptive SBRT. Based on normal tissue complication probability and modeling of changes in liver function following a 1-month treatment break between fractions 3 and 4, patients could receive a total of 3 or 5 fractions. Patients not on trial received 3 or 5 fractions without a break. Toxicity was defined as a ≥2 point rise in Child-Pugh (CP) score within 6 months of SBRT. RESULTS: 178 patients were treated with SBRT to 263 HCCs. Median follow-up was 23 months. 86 treatments had a 1-month break. 1-Year LC was 95.4%; this was not different between patients treated with or without a break (p = 0.14). Controlling for tumor size and dose a break was not associated with inferior LC (HR: 0.58, 95%CI: 0.1-3.34, p = 0.54). 54 patients experienced a ≥2 point rise in CP score. Controlling for the number of prior liver directed therapies and mean liver dose, a treatment break reduced the odds of toxicity (OR: 0.42, 95% CI: 0.17-1.03, p = 0.06). CONCLUSION: A one-month mid-treatment break and reassessment may reduce the odds of treatment related toxicity without compromising LC.

Independent validation of the prognostic capacity of the ISUP prostate cancer grade grouping system for radiation treated patients with long-term follow-up.

BACKGROUND: There has been a recent proposal to change the grading system of prostate cancer into a five-tier grade grouping system. The prognostic impact of this has been demonstrated in regards only to biochemical recurrence-free survival (bRFS) with short follow-up (3 years). METHODS: Between 1990 and 2013, 847 consecutive men were treated with definitive external beam radiation therapy at a single academic center. To validate the new grade grouping system, bRFS, distant metastases-free survival (DMFS) and prostate cancer-specific survival (PCSS) were calculated. Adjusted Kaplan-Meier and multivariable Cox regression analyses were performed to assess the independent impact of the new grade grouping system. Discriminatory analyses were performed to compare the commonly used three-tier Gleason score system (6, 7 and 8-10) to the new system. RESULTS: The median follow-up of our cohort was 88 months. The 5-grade groups independently validated differing risks of bRFS (group 1 as reference; adjusted hazard ratio (aHR) 1.35, 2.16, 1.79 and 3.84 for groups 2-5, respectively). Furthermore, a clear stratification was demonstrated for DMFS (aHR 2.03, 3.18, 3.62 and 13.77 for groups 2-5, respectively) and PCSS (aHR 3.00, 5.32, 6.02 and 39.02 for groups 2-5, respectively). The 5-grade group system had improved prognostic discrimination for all end points compared with the commonly used three-tiered system (that is, Gleason score 6, 7 and 8-10). CONCLUSIONS: In a large independent radiotherapy cohort with long-term follow-up, we have validated the bRFS benefit of the proposed five-tier grade grouping system. Furthermore, we have demonstrated that the system is highly prognostic for DMFS and PCSS. Grade group 5 had markedly worse outcomes for all end points, and future work is necessary to improve outcomes in these patients.

High-throughput transcriptomic analysis nominates proteasomal genes as age-specific biomarkers and therapeutic targets in prostate cancer.

BACKGROUND: Although prostate cancer (PCa) is hypothesized to differ in nature between younger versus older patients, the underlying molecular distinctions are poorly understood. We hypothesized that high-throughput transcriptomic analysis would elucidate biological differences in PCas arising in younger versus older men, and would nominate potential age-specific biomarkers and therapeutic targets. METHODS: The high-density Affymetrix GeneChip platform, encompassing >1 million genomic loci, was utilized to assess gene expression in 1090 radical prostatectomy samples from patients with long-term follow-up. We identified genes associated with metastatic progression by 10 years post-treatment in younger (age<65) versus older (age⩾65) patients, and ranked these genes by their prognostic value. We performed Gene Set Enrichment Analysis (GSEA) to nominate biological concepts that demonstrated age-specific effects, and validated a target by treating with a clinically available drug in three PCa cell lines derived from younger men. RESULTS: Over 80% of the top 1000 prognostic genes in younger and older men were specific to that age group. GSEA nominated the proteasome pathway as the most differentially prognostic in younger versus older patients. High expression of proteasomal genes conferred worse prognosis in younger but not older men on univariate and multivariate analysis. Bortezomib, a Food and Drug Administration approved proteasome inhibitor, decreased proliferation in three PCa cell lines derived from younger patients. CONCLUSIONS: Our data show significant global differences in prognostic genes between older versus younger men. We nominate proteasomeal gene expression as an age-specific biomarker and potential therapeutic target specifically in younger men. Limitations of our study include clinical differences between cohorts, and increased comorbidities and lower survival in older patients. These intriguing findings suggest that current models of PCa biology do not adequately represent genetic heterogeneity of PCa related to age, and future clinical trials would benefit from stratification based on age.

Amylophagia presenting as gestational diabetes.

Amylophagia, or the practice of consuming purified starch, is a particular expression of the more general phenomenon of pica. This compulsive dietary aberration, observed in many pregnant patients worldwide, is common among rural African American women in the southern United States. The effect this practice has on the course of gestational diabetes has not been examined. We report 2 cases of gestational diabetes, refractory to initial dietary management, in which the patients were consuming one-half to 1 box of cornstarch per day. Following cessation of amylophagia, the gestational hyperglycemia spontaneously resolved. Amylophagia is a complex behavioral phenomenon arising from the interplay of biochemical, hematological, psychological, and cultural factors. In some patient populations, it may represent an often overlooked etiologic or exacerbating factor in the condition of gestational diabetes. Family physicians practicing obstetrics should inquire about amylophagia in patients who are at risk for this behavior and in patients who present with gestational hyperglycemia.

Differential Effect of Tetrazolium Dyes upon Bacteriophage Plaque Assay Titers.

This study examined whether the practice of incorporating either tetrazolium red or tetrazolium violet dye into plaque assay medium deleteriously influences plaque assay titers. Representative members of six different virus families were studied: Cystoviridae (varphi6), Leviviridae (MS2), Microviridae (varphiX174), Myoviridae (T2), Podoviridae (P22), and Siphoviridae (Denver, T1, and VD13). Each of the members of the Podoviridae and Siphoviridae families appeared to be suppressed by either one or both dyes at a 300-mug/ml concentration. The chosen representatives of the other bacteriophage families were not suppressed by either dye at a 300-mug/ml concentration. Subsequent trials revealed no suppression of Podoviridae or Siphoviridae plaque assay titers when members of these virus families were tested with the same two dyes at the lower concentrations of 150 and 50 mug/ml. Interestingly, the bacteriophage families whose members were affected by the dyes have additional commonality in that they are the two bacteriophage families whose members possess both double-stranded DNA genomes and noncontractile tails.