Is Admission to the Intensive Care Unit Associated With Chronic Opioid Use? A 4-Year Follow-Up of Intensive Care Unit Survivors.

PURPOSE: To describe opioid use before and after intensive care unit (ICU) admission and to identify factors associated with chronic opioid use upto 4 years after ICU discharge. METHODS: Retrospective review of adult patients admitted to the ICU at a tertiary care center between January 1, 2005, to December 31, 2008. We defined "nonuser," "intermittent," and "chronic" opioid status by abstinence, use in <70%, and >70% of days for a given time period, respectively. We assessed opioid use at 3 months prior to ICU admission, at discharge, and annually for upto 4 years following ICU discharge. RESULTS: A total of 2595 ICU patients were included for surgical (48.6%), medical (38.4%), and undetermined (13%) indications. The study population included both elective (26.9%) and emergent (73.1%) admissions. Three months prior to ICU admission, 76.9% were nonusers, 16.9% used opioids intermittently, and 6.2% used opioids chronically. We found an increase in nonuser patients from 87.8% in the early post-ICU period to 95.6% at 48-month follow-up. Consequently, intermittent and chronic opioid use dropped to 8.6% and 3.6% at discharge and 2.6% and 1.8% at 48-month follow-up, respectively. Prolonged hospital length of stay was associated with chronic opioid use. CONCLUSION: Admission to ICU and duration of ICU stay were not associated with chronic opioid use.

Piperine, an alkaloid from black pepper, inhibits growth of human colon cancer cells via G1 arrest and apoptosis triggered by endoplasmic reticulum stress.

Piperine, a piperidine alkaloid present in black pepper, inhibits the growth of cancer cells, although the mechanism of action is not well understood. In this study, we show that piperine (75-150 µM) inhibited the growth of several colon cancer cell lines but had little effect on the growth of normal fibroblasts and epithelial cells. Piperine inhibited HT-29 colon carcinoma cell proliferation by causing G1 phase cell cycle arrest that was associated with decreased expression of cyclins D1 and D3 and their activating partner cyclin-dependent kinases 4 and 6, as well as reduced phosphorylation of the retinoblastoma protein and up-regulation of p21/WAF1 and p27/KIP1 expression. In addition, piperine caused hydroxyl radical production and apoptosis that was partially dependent on the production of reactive oxygen species. Piperine-treated HT-29 cells showed loss of mitochondrial membrane integrity and cleavage of poly (ADP-ribose) polymerase-1, as well as caspase activation and reduced apoptosis in the presence of the pan-caspase inhibitor zVAD-FMK. Increased expression of the endoplasmic reticulum stress-associated proteins inositol-requiring 1α protein, C/EBP homologous protein, and binding immunoglobulin protein, and activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, as well as decreased phosphorylation of Akt and reduced survivin expression were also observed in piperine-treated HT-29 cells. Furthermore, piperine inhibited colony formation by HT-29 cells, as well as the growth of HT-29 spheroids. Cell cycle arrest and endoplasmic reticulum stress-associated apoptosis following piperine treatment of HT-29 cells provides the first evidence that piperine may be useful in the treatment of colon cancer.

Colonoscopy following nonoperative management of uncomplicated diverticulitis may not be warranted.

BACKGROUND: Following the nonoperative management of acute diverticulitis, guidelines recommend routine follow-up colonoscopy; however, evidence to support this recommendation are lacking. OBJECTIVE: This study aims to determine the diagnostic yield of endoscopy for clinically significant neoplasia following the successful nonoperative management of acute diverticulitis. DESIGN: This study is a retrospective review. SETTING: This study was conducted in a large urban health region. PATIENTS: Adult patients who were admitted with a diagnosis of acute diverticulitis confirmed by CT and who were successfully managed nonoperatively to hospital discharge were included. Patients who underwent colonoscopy within 2 years of presentation were excluded. MAIN OUTCOME MEASURE: The primary outcome measured was the incidence of clinically significant neoplasia (invasive malignancy or advanced adenoma) on follow-up endoscopy within 1 year of admission. RESULTS: Four hundred fifty-eight patients were selected for analysis, of which 249 patients (54%) underwent endoscopy within 1 year of admission. Seventy-seven (30.9%) patients were found to have polyps, 19 (7.6%) patients had advanced adenomas, and 4 (1.6%) patients had an invasive malignancy; 23 patients (9.2%) were found to have clinically significant neoplasia. On subgroup analysis, patients presenting with complicated diverticulitis (n = 74) had a significantly higher incidence of advanced adenoma (18.9% vs 5%, p = 0.001) and invasive malignancy (5.4% vs 0%, p = 0.007) in comparison with patients who presented with uncomplicated diverticulitis (n = 175). On multivariate analysis, patient age (OR 1.04 (1.01-1.08), p = 0.02) and the presence of abscess (OR 4.15 (1.68-10.3), p = 0.002) were identified as significant risk factors for clinically significant neoplasia. LIMITATIONS: The use of retrospective data was a limitation of this study; 54% of selected patients underwent endoscopic follow-up. CONCLUSIONS: The incidence of clinically significant neoplasia on endoscopic follow-up after the nonoperative management of acute diverticulitis is 9.2%. Those with complicated diverticulitis are at higher risk, whereas the incidence of clinically significant neoplasia in those with uncomplicated diverticulitis is equal to the incidence in average-risk individuals. Routine diagnostic colonoscopy following the nonoperative management of acute uncomplicated diverticulitis may not be warranted.

Piperine impairs cell cycle progression and causes reactive oxygen species-dependent apoptosis in rectal cancer cells.

Piperine, an alkaloid phytochemical found in the fruit of black and long pepper plants, is reported to inhibit the growth of cancer cells; however, the mechanism of action in human cancer cells is not clear. In this study we investigated the effect of piperine on the growth of HRT-18 human rectal adenocarcinoma cells. MTT assays showed that piperine inhibited the metabolic activity of HRT-18 cells in a dose- and time-dependent fashion, suggesting a cytostatic and/or cytotoxic effect. Flow cytometric analysis of Oregon Green 488-stained and propidium iodide-stained HRT-18 cells showed that piperine inhibited cell cycle progression. Piperine also caused HRT-18 cells to die by apoptosis, as determined by Annexin-V-FLUOS staining and characteristic changes in cell morphology. Flow cytometric analysis of dihydroethidium- and 2',7'-dichlorofluorescein diacetate-stained HRT-18 cells showed increased production of reactive oxygen species in piperine-treated cells. Furthermore, the antioxidant N-acetylcysteine reduced apoptosis in cultures of piperine-treated HRT-18 cells, indicating that piperine-induced cytotoxicity was mediated at least in part by reactive oxygen species. The cytostatic and cytotoxic effects of piperine on rectal cancer cells suggest that this dietary phytochemical may be useful in cancer treatment.

Piperine inhibits the growth and motility of triple-negative breast cancer cells.

Piperine, an alkaloid from black pepper, is reported to have anticancer activities. In this study, we investigated the effect of piperine on the growth and motility of triple-negative breast cancer (TNBC) cells. Piperine inhibited the in vitro growth of TNBC cells, as well as hormone-dependent breast cancer cells, without affecting normal mammary epithelial cell growth. Exposure to piperine decreased the percentage of TNBC cells in the G2 phase of the cell cycle. In addition, G1- and G2-associated protein expression was decreased and p21(Waf1/Cip1) expression was increased in piperine-treated TNBC cells. Piperine also inhibited survival-promoting Akt activation in TNBC cells and caused caspase-dependent apoptosis via the mitochondrial pathway. Interestingly, combined treatment with piperine and γ radiation was more cytotoxic for TNBC cells than γ radiation alone. The in vitro migration of piperine-treated TNBC cells was impaired and expression of matrix metalloproteinase-2 and -9 mRNA was decreased, suggesting an antimetastatic effect by piperine. Finally, intratumoral administration of piperine inhibited the growth of TNBC xenografts in immune-deficient mice. Taken together, these findings suggest that piperine may be useful in the treatment of TNBC.

Curcumin causes superoxide anion production and p53-independent apoptosis in human colon cancer cells.

Curcumin from the rhizome of theCurcuma longa plant has chemopreventative activity and inhibits the growth of neoplastic cells. Since p53 has been suggested to be important for anticancer activity by curcumin, we investigated curcumin-induced cytotoxicity in cultures of p53(+/+) and p53(-/-) HCT-116 colon cancer cells, as well as mutant p53 HT-29 colon cancer cells. Curcumin killed wild-type p53 HCT-116 cells and mutant p53 HT-29 cells in a dose- and time-dependent manner. In addition, curcumin-treated p53(+/+) HCT-116 cells and mutant p53 HT-29 cells showed upregulation of total and activated p53, as well as increased expression of p53-regulated p21, PUMA (p53 upregulated modulator of apoptosis), and Bax; however, an equivalent cytotoxic effect by curcumin was observed in p53(+/+) and p53(-/-) HCT-116 cells, demonstrating that curcumin-induced cytotoxicity was independent of p53 status. Similar results were obtained when the cytotoxic effect of curcumin was assessed in wild-type p53 HCT-116 cells after siRNA-mediated p53 knockdown. Chromatin condensation, poly (ADP-ribose) polymerase-1 cleavage and reduced pro-caspase-3 levels in curcumin-treated p53(+/+) and p53(-/-) HCT-116 cells suggested that curcumin caused apoptosis. In addition, exposure to curcumin resulted in superoxide anion production and phosphorylation of oxidative stress proteins in p53(+/+) and p53(-/-) HCT-116 cells. Collectively, our results indicate that, despite p53 upregulation and activation, curcumin-induced apoptosis in colon cancer cells was independent of p53 status and involved oxidative stress. Curcumin may therefore have therapeutic potential in the management of colon cancer, especially in tumorsthatare resistant to conventional chemotherapydue todefects inp53 expression or function.