Revisiting primary endocrine therapy versus surgery in older women with breast cancer: meta-analysis.

BACKGROUND: Old age is associated with increased co-morbidities, resulting in reduced life expectancy. Primary endocrine therapy is an alternative to primary surgical therapy for patients with breast cancer and increased co-morbidities. The aim was to review outcomes of primary endocrine therapy versus primary surgical therapy in older women with breast cancer. METHODS: PubMed, Embase (Ovid), Scopus, and the Cochrane Library were searched systematically from January 2000 to May 2022. Single-arm studies were excluded. Primary outcomes were overall survival and breast cancer-specific survival. Secondary outcomes were local and regional failure of primary endocrine therapy, recurrence after primary surgical therapy, and health-related quality of life. RESULTS: There were 14 studies including 14 254 patients (primary endocrine therapy 2829, 19.8 per cent; primary surgical therapy 11 425, 80.2 per cent), with the addition of four major studies (9538 patients) compared with the latest review in 2014. Seven studies defined primary surgical therapy as surgery plus adjuvant endocrine therapy, and six studies included patients with oestrogen receptor-positive tumours only. Patients in the primary endocrine therapy group were older than the primary surgical therapy group (mean difference 2.43 (95 per cent c.i. 0.73 to 4.13) years). Primary endocrine therapy led to worse overall survival than primary surgical therapy (HR 1.42, 95 per cent c.i. 1.06 to 1.91). Subgroup analysis of RCTs and prospective studies, however, showed comparable overall survival. Breast cancer-specific survival was also comparable (HR 1.28, 95 per cent c.i. 0.87 to 1.87). At 6 weeks, operated patients had significant arm symptoms and illness burden following major breast surgery compared with patients receiving primary endocrine therapy. Health-related quality of life, measured by the European Organization for Research and Treatment of Cancer QLQ-C30 and EuroQol EQ-5D-5L™, was comparable in the two treatment groups. CONCLUSION: Overall survival was worse among older women receiving primary endocrine therapy in an analysis including all studies, but comparable in RCTs and prospective studies. This may be due to confounding by age and co-morbidities in retrospective cohort studies of primary endocrine therapy.

Early-Onset Colorectal Cancer Is Associated with a Lower Risk of Metachronous Advanced Neoplasia than Traditional-Onset Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) incidence in the USA has increased in adults under age 50. Current CRC surveillance guidelines do not consider age at diagnosis, and there are limited data available on outcomes from surveillance colonoscopies in early-onset CRC (EO-CRC) to guide recommendations on surveillance intervals. AIMS: To compare surveillance outcomes between EO-CRC and traditional-onset colorectal cancer (TO-CRC). METHODS: In a retrospective cohort study in a large tertiary care academic medical center, we collected data on patients with a diagnosis of CRC between 2000 and 2014 who received surgery with curative intent. We used log-rank test and inverse probability of treatment weighted Cox regression analysis to compare the development of metachronous advanced neoplasia (MAN) in patients with EO-CRC (diagnosed ages 18-49) and TO-CRC (diagnosed ages 50-75). RESULTS: Patients with EO-CRC (n = 107) were more likely to present with advanced-stage disease (62% versus 35%, p < 0.0001), rectal tumors (45% versus 27%, p < 0.01), and a family history of CRC (30% versus 16%, p = 0.02) compared to those with TO-CRC (n = 139). Patients with EO-CRC had lower risk of MAN (adjusted HR 0.44, 95% CI 0.22-0.88) than TO-CRC patients. The 5-year event rate for MAN was lower for patients with EO-CRC compared to patients with TO-CRC (5.8% vs. 16.1%, p = 0.07). The presence of synchronous neoplasia or history of diabetes was also predictive of MAN. CONCLUSIONS: EO-CRC was independently associated with a lower risk of developing MAN compared to TO-CRC. Shorter surveillance intervals may not be warranted in EO-CRC; however, large prospective studies are needed.

Low-Value Proton Pump Inhibitor Prescriptions Among Older Adults at a Large Academic Health System.

BACKGROUND: Older adults are particularly vulnerable to complications from proton pump inhibitor (PPI) drugs. We sought to characterize the prevalence of potentially low-value PPI prescriptions among older adults to inform a quality improvement (QI) intervention. METHODS: We created a cohort of patients, aged 65 years or older, receiving primary care at a large academic health system in 2018. We identified patients currently prescribed any PPI using the electronic health record (EHR) medication list (current defined as September 1, 2018). A geriatrician, a gastroenterologist, a QI expert, and two primary care physicians (PCPs) created multidisciplinary PPI appropriateness criteria based on evidenced-based guidelines. Supervised by a gastroenterologist and PCP, two internal medicine residents conducted manual chart reviews in a random sample of 399 patients prescribed PPIs. We considered prescriptions potentially low value if they lacked a guideline-based (1) short-term indication (gastroesophageal reflux disease [GERD]/peptic ulcer disease/Helicobacter pylori gastritis/dyspepsia) or (2) long-term (>8 weeks) indication (severe/refractory GERD/erosive esophagitis/Barrett esophagus/esophageal adenocarcinoma/esophageal stricture/high gastrointestinal bleeding risk/Zollinger-Ellison syndrome). We used the Wilson score method to calculate 95% confidence intervals (CIs) on low-value PPI prescription prevalence. RESULTS: Among 69 352 older adults, 8729 (12.6%) were prescribed a PPI. In the sample of 399 patients prescribed PPIs, 63.9% were female; their mean age was 76.2 years, and they were seen by 169 PCPs. Of the 399 prescriptions, 143 (35.8%; 95% CI = 31.3%-40.7%) were potentially low value-of which 82% began appropriately (eg, GERD) but then continued long term without a guideline-based indication. Among 169 PCPs, 32 (18.9%) contributed to 59.2% of potentially low-value prescriptions. CONCLUSION: One in eight older adults were prescribed a PPI, and over one-third of prescriptions were potentially low-value. Most often, appropriate short-term prescriptions became potentially low value because they lacked long-term indications. With most potentially low-value prescribing concentrated among a small subset of PCPs, interventions targeting them and/or applying EHR-based automatic stopping rules may protect older adults from harm. J Am Geriatr Soc 67:2600-2604, 2019.

Novel Approach to Cardiovascular Outcome Prediction in Haemodialysis Patients.

BACKGROUND: Cardiovascular mortality is high in haemodialysis (HD) patients. Arterial stiffness and global longitudinal strain (GLS) are important non-atheromatous cardiovascular risk predictors. No study has encompassed both parameters in a combined model for prediction of outcomes in HD patients. This is important because left ventricular (LV) dysfunction can result from fibrotic remodelling secondary to increased arterial stiffness. METHODS: Two hundred and nineteen HD patients had pulse wave velocity (PWV) and echocardiography (including GLS) assessments. Patients were followed-up until death, transplantation or November 16, 2015, whichever happened first. Pearson's correlation coefficient was used to determine factors associated with PWV and GLS. A multivariable Cox regression model investigated factors associated with all-cause, cardiac death and events. RESULTS: One hundred and ninety eight HD patients had full datasets (median age 64.2, 68.7% males) with a mean LV ejection fraction (LVEF) of 61.7 ± 10.1% and GLS -13.5 ± 3.3%; 51% had LV hypertrophy. Forty eight deaths (15 cardiac) and 44 major cardiac events occurred during a median follow-up of 27.6 (25th-75th percentile, 17.3-32.7) months. In separate survival models, PWV and GLS were independently associated with all-cause mortality; however, in a combined model, LV mass indexed to height2.7 (LVMI/HT2.7; adjusted hazard ratio (HR) 1.02, 95% CI 1.00-1.04) and PWV (adjusted HR 1.23, 95% CI 1.03-1.47) were significant. PWV was neither associated with cardiac death nor associated with related cardiac events. However, GLS was associated with cardiac death (adjusted HR 1.24, 95% CI 1.00-1.54) and cardiac events (adjusted HR 1.13, 95% CI 1.03-1.25). CONCLUSIONS: PWV and LVMI/HT2.7 were superior to GLS in prediction of all-cause mortality. However, GLS was associated with cardiac death and events even when accounting for LVEF and LVMI/HT2.7.

Estimating the unmeasured membrane potential of neuronal populations from the EEG using a class of deterministic nonlinear filters.

We present a model-based estimation method to reconstruct the unmeasured membrane potential of neuronal populations from a single-channel electroencephalographic (EEG) measurement. We consider a class of neural mass models that share a general structure, specifically the models by Stam et al (1999 Clin. Neurophysiol. 110 1801-13), Jansen and Rit (1995 Biol. Cybern. 73 357-66) and Wendling et al (2005 J. Clin. Neurophysiol. 22 343). Under idealized assumptions, we prove the global exponential convergence of our filter. Then, under more realistic assumptions, we investigate the robustness of our filter against model uncertainties and disturbances. Analytic proofs are provided for all results and our analyses are further illustrated via simulations.

Mitochondrial DNA hypervariable region 1 polymorphism in Singapore Chinese population.

Sequence polymorphisms of hypervariable region 1 were analyzed in 100 unrelated Singaporean Chinese. Ninety-five different haplotypes resulting from 113 variable sites were found between nucleotide positions 16045 and 16364. Single nucleotide polymorphism at nucleotide positions 16223, 16045, 16129, 16362 and 16189 was amongst the five highest frequencies observed in the sequences, whilst the most frequent haplotype was 16045-16223. Based on polymorphic sites observed at HV1, haplogroups A, F1a, M7b1, B5a and D4b were the most commonly observed clusters. The haplotype, nucleotide diversity and the average number of nucleotide differences were found to be 0.999, 0.028 and 9.082, respectively. The cytosine-stretch region located around nucleotide position 16189 was observed in 22% of this population sample. Transitions were found to be more predominant than transversions.

Role of p21(Waf-1) in regulating the G1 and G2/M checkpoints in ultraviolet-irradiated keratinocytes.

This study examines the role of p21(Waf-1) , a p53-dependent protein, in regulating mechanisms that protect keratinocytes against ultraviolet-B-induced cellular damage. Keratinocytes from p21(Waf-1) or p53-deficient mice were irradiated with ultraviolet B, and examined for DNA repair, cell cycle progression, and cell death. Both p21(Waf-1) -deficient and p53-deficient cells failed to maintain G2 arrest, and p21(Waf-1) -deficient cells, and to a lesser extent p53-deficient cells, also failed to undergo G1 arrest. After exposure to ultraviolet B, p53-deficient cells were more susceptible to cell death than wild-type cells. p21(Waf-1) -deficient cells did not undergo apoptotic cell death more often, however, but did have an increased frequency of nuclear abnormalities, suggesting mitotic catastrophe. TUNEL assay showed DNA fragmentation in the p53 +/+, p21(Waf-1) +/+, and p53 -/- cells, but not in p21(Waf-1) -/- cells. This result is consistent with the suggestion that p21(Waf-1) -deficient keratinocytes undergo mitotic cell death (catastrophe) after exposure to ultraviolet B irradiation in the system. Western analysis demonstrated that p21(Waf-1) expression was upregulated in p53-proficient and -deficient keratinocytes, supporting the notion that a p53-independent mechanism contributes to the response to ultraviolet B in keratinocytes. Finally, p21(Waf-1) -deficient cells had slightly less efficient nucleotide excision repair. In summary, this study suggests that p21(Waf-1) regulates the ultraviolet-B-induced G2/M checkpoint through p53, and the G1 checkpoint partially through p53. p21(Waf-1) does not significantly regulate DNA repair in ultraviolet-irradiated keratinocytes, however.

GADD45 regulates G2/M arrest, DNA repair, and cell death in keratinocytes following ultraviolet exposure.

GADD45 is a multifunctional protein that is regulated by p53. p53 plays an important role in regulating DNA repair and in the response to ultraviolet light in keratinocytes. This study investigates the role of GADD45 in the response to ultraviolet B. Cell cycle analysis demonstrated that wild-type and Gadd45-deficient cells have transient G2/M arrest, but only in the wild-type cells was arrest sustained. Cdc2 kinase activity in immunoprecipitates from normal and Gadd45-deficient cells decreases after irradiation in normal cells but not in Gadd45-deficient cells. An immunofluorescent study with Cdc2 antibody demonstrated diffuse cellular fluorescence before ultraviolet irradiation in both Gadd45-deficient and wild-type cells, but upon ultraviolet irradiation only Gadd45-proficient cells showed Cdc2 sequestration in the cytoplasm. Gadd45-deficient cells also have a slower rate of nucleotide excision repair. The lack of G2/M arrest coupled with reduced DNA repair leads to a higher ultraviolet sensitivity of Gadd45-deficient cells. These results reveal that GADD45 promotes G2/M arrest via nuclear export and kinase activity of Cdc2, increases global genomic DNA repair, and inhibits cell death in keratinocytes. Thus, GADD45 plays an important role in maintaining genomic integrity in ultraviolet-exposed skin.