BACKGROUND. Lytic bone metastases occur frequently in cancer patients and present major clinical issues including lack of effective therapies. The mechanism of lytic bone metastases involves interactions between tumor cells, bone matrix, and bone cells. Both focal adhesion kinase (FAK) and Pyk2 are implicated in the biology and physiology of bone and cancer. METHODS. The efficacy of PF‐562,271 was evaluated using MDA‐MB‐231 cells implanted in the tibia of nude rats. The drug was administered orally at a dose of 5 mg/kg, 7 days per week for 28 days. Serum and urine biomarkers, imaging, and histologic techniques were deployed to monitor tumor take rate, disease progression, and response to therapy. RESULTS. The compound was well tolerated. Both compound‐treated groups demonstrated significant and similar increases in osteocalcin and cancellous bone parameters. Radiographic evaluation of tumor‐bearing tibiae revealed tumor expansion in nontreated rats compared with a decrease in tumor growth and signs of bone healing in rats treated with PF‐562,271. Tartrate‐resistant acid phosphatase and fluorescent in situ hybridization analysis revealed that the majority of bone resorption at the tumor site was performed by osteoclasts of rat origin. CONCLUSIONS. The oral administration of PF‐562,271 at a dose of 5 mg/kg suppressed the growth and local spread of intratibial tumors and restored tumor‐induced bone loss. The unique ability of PF‐562,271 to both curb tumor growth and safely increase bone formation may be an effective therapy for many cancer patients with bone metastases and cancer‐associated osteoporosis. Cancer 2008. © 2008 American Cancer Society.

Background: The aim of this study is to compare metrics specific for stressinduced hyperglycemia (SIH) with glucose for predicting ischemic stroke outcome.Methods: This observational retrospective study (n = 300) included patients acutely hospitalized for ischemic stroke over a 3.8-year period. We assessed the association between acute ischemic stroke outcome with the stress hyperglycemia ratio (SHR, relative increase in glycemia) and glycemic gap (GG, absolute increase in glycemia) using admission values and 5-day maximum values, along with incidence of poor outcome above recognized clinical thresholds of glucose 10 mmol/L, SHR 1.14, and GG 2.5 mmol/L.Results: At admission, only SHR was associated with outcome after adjustment for clinical covariates (odds ratio [OR] = 2.88; 95% CI: 1.05-7.91; P = .041), while glucose or GG were not. Admission SHR ≥ 1.14 was also an indicator of poor outcome (39.1% vs 23.4%, P = .016), but not glucose ≥10 mmol/L or GG ≥ 2.5 mmol/L. All 5-day maximum glucose metrics were associated with outcome, as was any SHR ≥ 1.14 (40.9% vs 20.1%, P < .001) or GG ≥ 2.5 mmol/L (42.9% vs 23.4%, P = .011), but not glucose ≥10 mmol/L.Increased comorbidity was strongly associated with worse outcome (P < .001) in all models.Conclusions: SHR provided the best prognostic insight at admission to assess the relationship between SIH and ischemic stroke outcome. Absolute glucose levels failed to account for natural interpatient variation in background glycemia and provided little prognostic insight. To assess the impact of SIH, future interventional studies need to be designed using designated markers of SIH such as SHR in preference to absolute glucose.

To determine the associations of relative hypoglycemia and hemoglobin A1c-adjusted time in blood glucose (BG) band (HA-TIB) with mortality in critically ill patients. DESIGN: Retrospective cohort investigation.SETTING: University-affiliated adult medical-surgical ICU. PATIENTS:Three thousand six hundred fifty-five patients with at least four BG tests and hemoglobin A1c (HbA1c) level admitted between September 14, 2014, and November 30, 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS:Patients were stratified for HbA1c bands of <6.5%; 6.5-7.9%; greater than or equal to 8.0% with optimal affiliated glucose target ranges of 70-140, 140-180, and 180-250 mg/dL, respectively. HA-TIB, a new glycemic metric, defined the HbA1c-adjusted time in band. Relative hypoglycemia was defined as BG 70-110 mg/dL for patients with HbA1c ≥ 8.0%. Further stratification included diabetes status-no diabetes (NO-DM, n = 2,616) and preadmission treatment with or without insulin (DM-INS, n = 352; DM-No-INS, n = 687, respectively). Severity-adjusted mortality was calculated as the observed:expected mortality ratio (O:EMR), using the Acute Physiology and Chronic Health Evaluation IV prediction of mortality. Among NO-DM, mortality and O:EMR, decreased with higher TIB 70-140 mg/dL (p < 0.0001) and were lowest with TIB 90-100%. O:EMR was lower for HA-TIB greater than or equal to 50% than less than 50% and among all DM-No-INS but for DM-INS only those with HbA1 greater than or equal to 8.0%.Among all patients with hba1c greater than or equal to 8.0% And no bg less than 70 mg/dl, mortality was 18.0% For patients with relative hypoglycemia (bg, 70-110 mg/dl) (p < 0.0001) And was 0.0%, 12.9%, 13.0%, And 34.8% For patients with 0, 0.1-2.9, 3.0-11.9, And greater than or equal to 12.0 Hours of relative hypoglycemia (p < 0.0001). CONCLUSIONS:These findings have considerable bearing on interpretation of previous trials of intensive insulin therapy in the critically ill. Moreover, they suggest that BG values in the 70-110 range may be deleterious for patients with HbA1c greater than or equal to 8.0% and that the appropriate target for BG should be individualized to HbA1c levels. These conclusions need to be tested in randomized trials.

Background: Patients from residential aged care facilities are commonly exposed to inappropriate polypharmacy. Unplanned inpatient admissions can provide an opportunity for review of complex medical regimens and deprescribing of inappropriate or nonbeneficial medications. The aim of this study was to assess the efficacy, safety and sustainability of in-hospital deprescribing. Methods: We followed a prospective, multi-centre, cohort study design, with enrolment of 106 medical inpatients age 75 years and older (mean age was 88.8 years) who were exposed to polypharmacy prior to admission and with a planned discharge to a nursing home for permanent placement. Descriptive statistics were calculated for relevant variables. The Short Form-8 (SF-8) health survey was used to assess changes in health-related quality of life (HRQOL) at 90-day follow up, in comparison with SF-8 results at day 30. Results: Deprescribing occurred in most, but not all patients. There were no differences between the groups in principal diagnosis, Charlson index, number of medications on admission or number of Beers list medications on admission. At 90 days, mortality and readmissions were similar, though the deprescribed group had significantly higher odds of better emotional wellbeing than the nondeprescribed group [odds ratio (OR) = 5.08, 95% confidence interval (CI): 1.93, 13.39; p = 0.001]. In the deprescribing group, 31% of the patients still alive at 90 days had medications restarted in primary care. One-year mortality rates were similar. Conclusions: Deprescribing medications during an unplanned hospital admission was not associated with mortality, readmissions, or overall HRQOL.