Health Care Resource Utilization and Total Costs of Care for Adult Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia in the United States: A Retrospective Claims Analysis.

PURPOSE: Although immunotherapies such as blinatumomab and inotuzumab have led to improved outcomes, financial burden and health resource utilization (HRU) have increased for adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). This study assessed real-world HRU and costs of care among adult patients with R/R B-ALL by line of therapy (LoT) in the United States. METHODS: We selected patients from the MarketScanⓇ Database (January 1, 2016 through December 31, 2020) as follows: ≥1 claims of ALL-indicated first-line (1L) therapies, ≥1 diagnosis of ALL before the index date (1L initiation date), 6-month continuous enrollment before the index date, second-line (2L) therapy initiation, ≥18 years old at 2L, no clinical trial enrollment, no diagnosis of other forms of non-Hodgkin's lymphoma, and no claim for daratumumab or nelarabine during the study period. Outcome measures included claim-based time to next treatment (TTNT), all-cause and adverse event (AE)-related HRU, and all-cause and AE-related costs. FINDINGS: The R/R B-ALL cohort (N = 203) was 60% male, median age of 41 years, and median Charlson Comorbidity Index score of 3.0. Mean (SD) follow-up was 17.8 (11.8) months. Of those who received 2L, 55.7% (113/203) required 3L, and 15% (30/203) initiated 4L+. Patients relapsed quickly, with a median TTNT of 170 days, 169 days, and 205 days for 2L, 3L, and 4L+, respectively. Hospitalization rates were high across each LoT (2L, 88%; 3L, 73%; 4L+, 73%), and the mean (SD) inpatient length of stay increased by LoT as follows: 8.6 (6.8) days for 2L, 10.6 (13.3) for 3L, and 11.6 (13.6) for 4L+. Mean (SD) overall costs were substantial within each LoT at $513,279 ($599,209), $340,419 ($333,555), and $390,327 ($332,068) for 2L, 3L, and 4L+, respectively. The mean (SD) overall/per-patient-per-month AE-related costs were $358,676 ($497,998) for 2L, $202,621 ($272,788) for 3L, and $210,539 ($267,814) for 4L+. Among those receiving blinatumomab or inotuzumab within each LoT, the mean (SD) total costs were $566,373 ($621,179), $498,070 ($376,260), and $512,908 ($159,525) for 2L, 3L, and 4L+, respectively. IMPLICATIONS: These findings suggest that adult patients with R/R B-ALL relapse frequently with standard of care and incur a substantial HRU and cost burden with each LoT. Those treated with blinatumomab or inotuzumab incurred higher total costs within each LoT compared with the overall R/R B-ALL cohort. Alternative therapies with longer duration of remission are urgently needed, and HRU should be considered for future studies examining the optimal sequencing of therapy.

Matching-Adjusted Indirect Comparisons of Brexucabtagene Autoleucel with Alternative Standard Therapies for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Adult Patients.

INTRODUCTION: Brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, is approved for relapsed/refractory B-cell precursor acute lymphoblastic leukemia in adults aged 18+/26+ years in the US/European Union (EU), based on efficacy results from the single-arm ZUMA-3 trial. This study aimed to estimate the relative treatment effects of brexu-cel versus inotuzumab ozogamicin (InO), blinatumomab (blina), and chemotherapies using unanchored matching-adjusted indirect comparison (MAIC) methods. METHODS: Individual patient data from ZUMA-3 and published aggregate level data from two randomized controlled trials, INO-VATE (InO versus chemotherapy) and TOWER (blina versus chemotherapy), were used. Patient-level data from ZUMA-3 were weighted to match the mean of the following prognostic variables at baseline, which were pre-specified based on clinical input, for each comparator population: primary refractory disease, duration of first remission < 12 months, prior stem-cell transplantation, age, performance status, salvage status, bone marrow blast, complex karyotype, and Philadelphia chromosome status. The base case analysis was conducted using the modified intention-to-treat population (i.e., received brexu-cel) from ZUMA-3. Relative treatment effects for overall survival (OS) and event-free survival (EFS) were expressed as hazard ratios (HR) and differences in restricted mean survival time (RMST) with 95% confidence intervals (CI). RESULTS: The base case MAIC results suggested brexu-cel improved OS and EFS compared to blina (OS HR 0.46 [95% CI 0.28, 0.75]; EFS HR 0.37 [95% CI 0.25, 0.56]) and pooled INO-VATE/TOWER chemotherapy (OS HR 0.32 [95% CI 0.18, 0.56]; EFS HR 0.27 [0.18, 0.40]). Brexu-cel also improved OS compared to InO (HR 0.45 [95% CI 0.24, 0.85]). The point estimate for EFS favored brexu-cel over Ino but the difference was not statistically significant (HR 0.67 [95% CI 0.41, 1.10]). Findings were consistent between the HR and RMST analyses. CONCLUSION: Despite limitations, these MAIC results suggest that brexu-cel may improve OS and EFS versus currently used therapies in this population.

Alleviative Effect of Ruellia tuberosa L. on Insulin Resistance and Abnormal Lipid Accumulation in TNF-α-Treated FL83B Mouse Hepatocytes.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, and most patients with T2DM develop nonalcoholic fatty liver disease (NAFLD). Both diseases are closely linked to insulin resistance (IR). Our previous studies demonstrated that Ruellia tuberosa L. (RTL) extract significantly enhanced glucose uptake in the skeletal muscles and ameliorated hyperglycemia and IR in T2DM rats. We proposed that RTL might be via enhancing hepatic antioxidant capacity. However, the potent RTL bioactivity remains unidentified. In this study, we investigated the effects of RTL on glucose uptake, IR, and lipid accumulation in vitro to mimic the T2DM accompanied by the NAFLD paradigm. FL83B mouse hepatocytes were treated with tumor necrosis factor-α (TNF-α) to induce IR, coincubated with oleic acid (OA) to induce lipid accumulation, and then, treated with RTL fractions, fractionated with n-hexane or ethyl acetate (EA), from column chromatography, and analyzed by thin-layer chromatography. Our results showed that the ethyl acetate fraction (EAf2) from RTL significantly increased glucose uptake and suppressed lipid accumulation in TNF-α plus OA-treated FL83B cells. Western blot analysis showed that EAf2 from RTL ameliorated IR by upregulating the expression of insulin-signaling-related proteins, including protein kinase B, glucose transporter-2, and peroxisome proliferator-activated receptor alpha in TNF-α plus OA-treated FL83B cells. The results of this study suggest that EAf2 from RTL may improve hepatic glucose uptake and alleviate lipid accumulation by ameliorating and suppressing the hepatic insulin signaling and lipogenesis pathways, respectively, in hepatocytes.

Identification of Bioactive Components from Ruellia tuberosa L. on Improving Glucose Uptake in TNF-α-Induced Insulin-Resistant Mouse FL83B Hepatocytes.

Ruellia tuberosa L. (RTL) has been used as a folk medicine to cure diabetes in Asia. RTL was previously reported to alleviate hyperglycemia, insulin resistance (IR), abnormal hepatic detoxification, and liver steatosis. However, the potential bioactive compounds of RTL have still not been identified. The aim of this study was to investigate the bioactive compounds in RTL ethyl acetate (EA) fractions by using a glucose uptake assay in TNF-α-treated mouse FL83B hepatocytes to discover a mechanism by which to improve IR. The bioactive compounds were identified by the high-performance liquid chromatography (HPLC) assay. Using the Sephadex LH20 gel packing chromatography column, the EAF5 fraction was isolated from RTL and significantly increased glucose uptake in TNF-α-treated FL83B cells. Moreover, the MCI gel packing chromatography column separated EAF5 into five subfractions and had no significant cytotoxic effect in FL83B cells when treated at the concentration of 25 µg/ml. Among the subfractions, EAF5-5 markedly enhanced glucose uptake in TNF-α-treated FL83B cells. The possible bioactive compounds of the EAF5-5 fraction that were identified by the HPLC assay include syringic acid, p-coumaric acid, and cirsimaritin. The bioactive compound with the best effect of increasing glucose uptake was p-coumaric acid, but its effect alone was not as good as the combined effect of all three compounds of the EAF5-5 fraction. Thus, we speculate that the antidiabetic effect of RTL may be the result of multiple active ingredients.

Alleviative effect of Ruellia tuberosa L. on NAFLD and hepatic lipid accumulation via modulating hepatic de novo lipogenesis in high-fat diet plus streptozotocin-induced diabetic rats.

Ruellia tuberosa L. (RTL) exhibits phytochemical activities and has been used as a folk medicine for curing diabetes mellitus in East Asia for decades. This study investigated the effect of RTL aqueous and ethanolic extracts on nonalcoholic fatty liver disease (NAFLD) and hepatic lipid accumulation in high-fat diet (HFD) and streptozotocin (STZ)-induced type 2 diabetes mellitus (T2DM) rats. Administration of RTL aqueous extract (RTLW) or ethanolic extract (RTLE) at dosage of 100 or 400 mg/kg body weight for 4 weeks was carried out in HFD/STZ-induced T2DM rats. Liver weight, adipose (epididymal and perirenal adipose tissues) weight, hepatic triglyceride level, and de novo lipogenesis (DNL)-associated protein expression were monitored after scarification. The results revealed that RTLW and RTLE reduced relative liver weight and relative fat weights in HFD/STZ-induced T2DM rats. RTLW and RTLE also ameliorated NAFLD and hepatic triglyceride (TG) accumulation in diabetic rats. Moreover, hepatic DNL-regulated enzymes such as sterol regulatory element-binding protein-1 (SREBP1) and fatty acid synthase (FAS) expression were significantly suppressed by RTLE (100 and 400 mg/kg body weight) in diabetic rats. The evidences of this study suggest that RTL possesses potential on alleviating NAFLD and lipid accumulation via regulating DNL in the liver of HFD/STZ-induced T2DM rats.

Protective effect of Ruellia tuberosa L. extracts against abnormal expression of hepatic detoxification enzymes in diabetic rats.

Ruellia tuberosa L. (RTL) has been used as a folk medicine for curing diabetes mellitus in East Asia decades. This study investigated the effect of RTL on hepatic detoxification enzyme expression in diabetic rats. Male Wistar rats were fed a high fat diet (HFD) and intraperitoneally injected with streptozotocin (STZ) to induce diabetes. Subsequently, rats received oral administrations of 100 or 400 mg kg-1 body weight RTL extract, in either water (RTLW) or ethanol (RTLE), once a day for 4 weeks. The real-time PCR analyses showed that abnormality of hepatic phase I and II detoxification enzyme expression was observed in diabetic rats. However, both RTLW and RTLE significantly normalized the expression of hepatic phase I detoxification enzymes such as CYP 2E1, and expression of phase II detoxification enzymes such as UGT 1A7 and GST M1 in diabetic rats. Furthermore, we found that fasting serum glucose, hemoglobin A1C (HbA1C) and the area under the curve of oral glucose tolerance test (AUCOGTT) levels were significantly reduced in both RTLW and RTLE treated diabetic rats. Moreover, both RTLW and RTLE significantly increased the activity of hepatic anti-oxidative enzymes such as superoxide dismutase (SOD) in diabetic rats. The present study suggests that RTL may ameliorate abnormal hepatic detoxification function via alleviating hyperglycemia and enhancing hepatic antioxidant capacity in HFD/STZ-induced diabetic rats.

Vescalagin from Pink Wax Apple [Syzygium samarangense (Blume) Merrill and Perry] Alleviates Hepatic Insulin Resistance and Ameliorates Glycemic Metabolism Abnormality in Rats Fed a High-Fructose Diet.

This study investigates the ameliorative effect of vescalagin (VES) isolated from Pink wax apple fruit on hepatic insulin resistance and abnormal carbohydrate metabolism in high-fructose diet (HFD)-induced hyperglycemic rats. The results show that in HFD rats, VES significantly reduced the values of the area under the curve for glucose in an oral glucose tolerance test and the homeostasis model assessment of insulin resistance index. VES significantly enhanced the activity of hepatic antioxidant enzymes while reducing thiobarbituric acid-reactive substances in HFD rats. Western blot assay revealed that VES reduced hepatic protein expression involved in inflammation pathways while up-regulating expression of hepatic insulin signaling-related proteins. Moreover, VES up-regulated the expression of hepatic glycogen synthase and hepatic glycolysis-related proteins while down-regulating hepatic gluconeogenesis-related proteins in HFD rats. This study suggests some therapeutic potential of VES in preventing the progression of diabetes mellitus.

Gallic acid ameliorates hyperglycemia and improves hepatic carbohydrate metabolism in rats fed a high-fructose diet.

Herein, we investigated the hypoglycemic effect of plant gallic acid (GA) on glucose uptake in an insulin-resistant cell culture model and on hepatic carbohydrate metabolism in rats with a high-fructose diet (HFD)-induced diabetes. Our hypothesis is that GA ameliorates hyperglycemia via alleviating hepatic insulin resistance by suppressing hepatic inflammation and improves abnormal hepatic carbohydrate metabolism by suppressing hepatic gluconeogenesis and enhancing the hepatic glycogenesis and glycolysis pathways in HFD-induced diabetic rats. Gallic acid increased glucose uptake activity by 19.2% at a concentration of 6.25 µg/mL in insulin-resistant FL83B mouse hepatocytes. In HFD-induced diabetic rats, GA significantly alleviated hyperglycemia, reduced the values of the area under the curve for glucose in an oral glucose tolerance test, and reduced the scores of the homeostasis model assessment of insulin resistance index. The levels of serum C-peptide and fructosamine and cardiovascular risk index scores were also significantly decreased in HFD rats treated with GA. Moreover, GA up-regulated the expression of hepatic insulin signal transduction-related proteins, including insulin receptor, insulin receptor substrate 1, phosphatidylinositol-3 kinase, Akt/protein kinase B, and glucose transporter 2, in HFD rats. Gallic acid also down-regulated the expression of hepatic gluconeogenesis-related proteins, such as fructose-1,6-bisphosphatase, and up-regulated expression of hepatic glycogen synthase and glycolysis-related proteins, including hexokinase, phosphofructokinase, and aldolase, in HFD rats. Our findings indicate that GA has potential as a health food ingredient to prevent diabetes mellitus.

Effect of high pressure treatment on the survival of Shiga toxin-producing Escherichia coli in strawberry puree.

Most fresh produce, such as strawberries, receives minimal processing and is often eaten raw. Contamination of produce with pathogenic bacteria may occur during growth, harvest, processing, transportation, and storage (abuse temperature) and presents a serious public health risk. Strawberries have been implicated in an outbreak of Escherichia coli O157:H7 infection that sickened 15 people, including one death. Strawberries may also be contaminated by other serogroups of non-O157 Shiga toxin-producing E. coli (STEC), including O26, O45, O103, O111, O121 and O145, which have become known as the "Big Six" or "Top Six" non-O157 STECs. The objective of this research was to explore the potential application of high pressure processing (HPP) treatment to reduce or eliminate STECs in fresh strawberry puree (FSP). FSP, inoculated with a six-strain cocktail of the "Big Six" non-O157 STEC strains or a five-strain cocktail of E. coli O157:H7 in vacuum-sealed packages, were pressure-treated at 150, 250, 350, 450, 550, and 650 MPa (1 MPa = 10(6) N/m(2)) for 5, 15, and 30 min. HPP treatment, at 350 MPa for ≥5 min, significantly reduced STECs in FSP by about 6-log CFU/g from the initial cell population of ca. 8-log CFU/g. Cell rupture, observed by scanning electron microscopy (SEM), demonstrated that the HPP treatments can be potentially used to control both non-O157 and O157:H7 STECs in heat sensitive products.

Pectin methyl esterase treatment on high-methoxy pectin for making fruit jam with reduced sugar content.

BACKGROUND: Pectin methyl esterase (PME) has been postulated to catalyse the transacylation reaction between pectin molecules. The present study aimed to prove the occurrence of this reaction. The feasibility of applying PME-catalysed transacylation between high-methoxy pectin molecules in making fruit jam with reduced sugar content was also investigated. RESULTS: PME treatment increased the turbidity and particle size in pectin solution and the molecular weight of pectin, while it decreased the number of methoxy ester linkages and the intensity of the CH3 absorption peak in the Fourier transform infrared spectrum without changes in the number of total ester linkages in pectin molecules. These findings support the occurrence of PME-catalysed transacylation between pectin molecules. Higher values of hardness, gumminess and chewiness were found in a jam containing PME-treated citrus pectin (10 g L⁻¹) and sugar (350 g L⁻¹) as compared with either a jam containing untreated citrus pectin (10 g L⁻¹) and sugar (350 g L⁻¹) or strawberry jam containing pectin (10 g L⁻¹) from the fruit and sugar (650 g L⁻¹). CONCLUSION: The demand for sugar in jam making can be greatly reduced by the use of PME-treated high-methoxy pectin.

Evolution of continent ileostomy.

Continent ileostomy can be defined as a surgical procedure that facilitates planned intermittent evacuation of a bowel reservoir through an ileostomy. It was devised by Nils Kock in 1969. Subsequently, continent ileostomy (or Kock pouch) became a viable alternative in the management of patients who had traditionally required an end ileostomy. Kock pouch appeared to provide substantial physical and psychosocial benefits over a conventional ileostomy. The procedure became popular until ileal pouch anal anastomosis (IPAA) was introduced in 1980. Despite its benefits, continent ileostomy had many short term complications including intubation problems, ileus, anastomotic leaks, peritonitis and valve problems. Operative mortalities have also been reported in the literature. Most of these problems have been eliminated with increasing experience; however, valve-related problems remain as an "Achilles' heel" of the technique. Many modifications have been introduced to prevent this problem. Some patients have had their pouch removed because of complications mainly related to valve dysfunction. Although revision rates can be high, most of the patients who retain their reservoirs are satisfied with regard to their health status and quality of life. Today, this procedure is still appropriate for selected patients for whom pouch surgery is not possible or for patients who have failed IPAA. Both the patient and their physician must be highly motivated to accept the risk of failure and the subsequent need for revisional operations.

In vitro antitumor and immunomodulatory effects of the protein PCP-3A from mushroom Pleurotus citrinopileatus.

A nonlectin glycoprotein (PCP-3A) newly isolated from the fruit body of edible golden oyster mushroom Pleurotus citrinopileatus has been shown to be growth inhibitory against human myeloid leukemic U937 cells in a previous report. There is a well-recognized relation between antitumor activity and immunomodulation. The immunomodulatory activity of PCP-3A was therefore assessed in the present study. Human mononuclear cells (MNC) and the CD4(+) T lymphocytes isolated from them were stimulated separately with PCP-3A for various durations and then filtered to obtain the conditioned media (CM). The conditioned medium from MNC (MNC-CM) was proved effective in inhibiting the growth of U937 cells. Increased secretion of cytokines TNF-α, IL-2, and IFN-γ from the stimulated MNC and CD4(+) T cells was found in CM. The antibody neutralization test of MNC-CM revealed that the growth inhibition on leukemic U937 cells was related to the elevation in cytokine concentration. We propose that PCP-3A stimulated human MNC to secrete cytokines TNF-α, IL-2, and IFN-γ, which subsequently inhibit the growth of U937 cells, and that PCP-3A may be a possible material for developing into an antileukemia ingredient in health food.

Effect of guava (Psidium guajava L.) leaf extract on glucose uptake in rat hepatocytes.

People in oriental countries, including Japan and Taiwan, boil guava leaves (Psidium guajava L.) in water and drink the extract as a folk medicine for diabetes. The present study investigated the enhancement of aqueous guava leaf extract on glucose uptake in rat clone 9 hepatocytes and searched for the active compound. The extract was eluted with MeOH-H(2)O solutions through Diaion, Sephadex, and MCI-gel columns to separate into fractions with different polarities. The uptake test of 2-[1-(14)C] deoxy-D-glucose in rat clone 9 hepatocytes was performed to evaluate the hypoglycemic effect of these fractions. The active compound was identified by nuclear magnetic resonance analysis and high-performance liquid chromatography (HPLC). The results revealed that phenolics are the principal component of the extract, that high polarity fractions of the guava leaf extract are enhancers to glucose uptake in rat clone 9 hepatocytes, and that quercetin is the major active compound. We suggest that quercetin in the aqueous extract of guava leaves promotes glucose uptake in liver cells, and contributes to the alleviation of hypoglycemia in diabetes as a consequence.

Repeat pouch surgery by the abdominal approach safely salvages failed ileal pelvic pouch.

PURPOSE: : This study evaluated outcomes of patients with abdominal salvage operations for failed ileal pouch-anal anastomosis. METHODS: : Patients undergoing laparotomy for ileoanal pouch salvage were reviewed from a prospectively maintained pouch database and records. RESULTS: : From 1983 to 2007, 241 abdominal reconstructions were performed. The median follow-up was 5 years (range, 0.04-20.8). Diagnoses before primary ileal pouch-anal anastomosis were ulcerative colitis in 187, familial adenomatous polyposis in 22, indeterminate colitis in 20, Crohn's disease in 9, and other in 3. The most common indications for salvage were fistula (n = 67), leak (n = 65), stricture (n = 42) pouch dysfunction (n = 40), pelvic abscess (n = 25). Seventy-one cases had a new pouch constructed. One hundred and seventy cases had the original pouch salvaged. Twenty-nine cases had either pouch excision or ileostomy without pouch excision the result of failure after reconstruction. To assess functional results and quality of life, patients with reconstruction were matched to those with a primary ileal pouch-anal anastomosis. Significantly higher proportions of patients with reconstruction reported seepage during daytime (P = 0.002), at night (P = 0.015), and daytime pad usage (P = 0.02). Other parameters and quality of life were similar between groups. CONCLUSIONS: : Repeat abdominal surgery was a good alternative for pouch failure. Functional and quality of life outcomes were encouraging.

Antimutagenic and antiproliferative effects of roasted and defatted peanut dregs on human leukemic U937 and HL-60 cells.

The antimutagenic effects on Salmonella typhimurium TA98 and TA100 strains and antiproliferative effects on leukemia cell lines (U937 and HL-60) of peanut protein isolate (PPI), peanut protein isolate enzyme hydrolysate (PPIEH), roasted and defatted peanut dregs (RDPD), and roasted and defatted peanut dregs enzyme hydrolysate (RDPDEH) were investigated. The antimutagenic effects on B(a)P and 4-NQO toward the TA98 and TA100 strains were found to follow a diminishing order: RDPD > RDPDEH >> PPI = PPIEH with dose-dependency. Antiproliferative effects on leukemia cells U937 and HL-60 were also detected. RDPD was found to be the most effective of all the peanut preparations. At 100 microg/mL concentration, RDPD inhibited the proliferation of U937 and HL-60 cells by 56% and 52%, respectively. We propose to consider RDPD and RDPDEH in the development of natural chemotherapeutic or chemopreventive dietary supplements against leukemia and to upgrade the utilization of these by-products in peanut oil production.

Establishment of a sandwich ELISA using commercial antibody for plasma or serum 3-nitrotyrosine (3NT). Elevation in inflammatory diseases and complementary between 3NT and myeloperoxidase.

BACKGROUND: Amino acid tyrosine residue of a protein can be nitrated to form 3-nitrotyrosine (3NT), which is now being considered as a marker of inflammation, oxidative and nitrosative stress. METHOD: An in-house ELISA has been established using the same commercial antibody for both binding and detection of 3NT containing proteins. RESULTS: The sensitivity of the in-house ELISA was 1.8 nmol/l. The imprecision was <10% at all concentrations. The in-house assay correlates well with a commercial kit (r=0.89). In addition to EDTA plasma, we found that both heparinized plasma and serum can also be used to quantify 3NT concentration. Using the in-house ELISA we have detected increased concentrations of 3NT in diseases known to be associated with inflammation and also in subjects with polyps. As marker of oxidative stress and inflammation, both 3NT and myeloperoxidase are complementary to each other in test sensitivity. CONCLUSION: This ELISA can be used in the clinical laboratories to monitor the inflammatory disease activity and assess early risks that are associated with inflammation, oxidative and nitrosative stress.

Long-term outcome and quality of life after continent ileostomy.

INTRODUCTION: This study was designed to evaluate long-term outcomes for patients undergoing Kock continent ileostomy, identify factors associated with adverse outcomes, and compare changes in quality of life after removal of the reservoir. METHODS: The records of all patients (n = 330) undergoing continent ileostomy at the Cleveland Clinic Foundation between 1974 and 2001 were reviewed. Patient-related, intraoperative, and postoperative factors were evaluated as predictor variables of long-term pouch survival. Quality of life was evaluated using the continent ileostomy surgery follow-up questionnaire and the Cleveland Global Quality of Life scale (n = 216). These were compared between patients with continent ileostomy (n = 181) and patients who underwent removal of the continent ileostomy and conversion to an end stoma (n = 35). RESULTS: The median patient follow-up was 11 (range, 1-27) years. The median revision-free pouch interval was 14 (95 percent confidence interval, 11-17) months. The 10-year and 20-year pouch survival was 87 and 77 percent, respectively. Patients had an average of 3.7(range, 1-28) complications and 2.9 (range, 1-27) pouch revisions during follow-up. On multivariate analysis, Crohn's disease (hazard ratio = 4.5), female gender (hazard ratio = 2.4), fistula development (hazard ratio = 3), and body mass index (hazard ratio = 2.4 per 5 unit increase) were independent predictors of pouch failure. Quality of life measurements for patients with a continent ileostomy were higher on all scales in comparison with patients who had the Kock reservoir and then reverted to a Brooke ileostomy. CONCLUSIONS: Despite the associated morbidity with continent ileostomy surgery, long-term results and quality of life were encouraging. Continent ileostomy may be offered as an attractive long-term option to select patients whose only alternative is an end ileostomy.

Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1.

The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, survival, and tumor angiogenesis and represents a promising target for anticancer drugs. Here, we describe three potent PDK1 inhibitors, BX-795, BX-912, and BX-320 (IC(50) = 11-30 nm) and their initial biological characterization. The inhibitors blocked PDK1/Akt signaling in tumor cells and inhibited the anchorage-dependent growth of a variety of tumor cell lines in culture or induced apoptosis. A number of cancer cell lines with elevated Akt activity were >30-fold more sensitive to growth inhibition by PDK1 inhibitors in soft agar than on tissue culture plastic, consistent with the cell survival function of the PDK1/Akt signaling pathway, which is particularly important for unattached cells. BX-320 inhibited the growth of LOX melanoma tumors in the lungs of nude mice after injection of tumor cells into the tail vein. The effect of BX-320 on cancer cell growth in vitro and in vivo indicates that PDK1 inhibitors may have clinical utility as anticancer agents.

Functional outcome and quality of life after repeat ileal pouch-anal anastomosis for complications of ileoanal surgery.

PURPOSE: Disconnection of an ileal pouch-anal anastomosis with repeat ileal pouch-anal anastomosis has been proposed for treatment of ileal pouch-anal anastomosis failure caused by septic or functional complications. We report our experience with repeat ileal pouch-anal anastomosis, and document functional outcome and quality of life. METHODS: Of 101 patients undergoing laparotomy, ileoanal disconnection, and repeat ileal pouch-anal anastomosis, 80 were referred from other institutions. Indications included: chronic anastomotic leak (n=27), perineal or pouch-vaginal fistula (n=47), anastomotic stricture (n=22), dysfunction/long efferent limb of S-pouch (n=36), and previous ileal pouch-anal anastomosis excision or exclusion (n=6). In 64 cases a "septic" indication was observed. Pathologic features of Crohn's disease were present in 4 patients preoperatively and 15 more after repeat ileal pouch-anal anastomosis. Four patients had clinical features of Crohn's disease. RESULTS: Three patients had no ileostomy, and 82 patients had temporary ileostomy closure. Of these, 82 percent have a functioning pouch, with a median follow-up of 32 functioning months. Two were rediverted and 13 had the pouch excised. Five-year pouch survival was 74 percent, higher for ulcerative colitis (79 percent) than Crohn's disease (53 percent; P=0.06). No differences were seen between those having repeat ileal pouch-anal anastomosis for septic or nonseptic indications, or whether using a new or repaired pouch. Patients defecated 6.3 +/- 2.8 (mean +/- standard deviation) times per day, and 2 +/- 1.9 per night. Thirty-five percent of patients never described urgency. Fecal seepage occurred in 50 percent during the day and 69 percent at night. Using the Cleveland Global Quality of Life Score to assess the patient's quality of life, health, level of energy, and happiness with surgery (each scored from 0-10), quality of life was 8.2 +/- 1.6, and happiness with surgery was 9 +/- 2. Ninety-seven percent would undergo repeat ileal pouch-anal anastomosis again, and 99 percent would recommend it to others. CONCLUSIONS: Repeat ileal pouch-anal anastomosis is a valid alternative for patients with ileal pouch-anal anastomosis failure. A controlled septic condition should not preclude salvage surgery. Although pouch failure occurs more frequently than after primary ileal pouch-anal anastomosis, patient satisfaction and quality of life are high.