Baseline Alkaline Phosphatase Research Articles

Evaluating abiraterone responses in African Americans with metastatic CRPC.

244 Background: A disparity between African American (AA) and other racial groups is documented in prostate cancer incidence and mortality. For metastatic CRPC, abiraterone (Abi) showed improvement in overall survival and gained FDA approval. However, Phase III trials enrolled mostly Caucasian (CA) patients. Documentation of Abi response rates in AA men is scant. Further characterization of Abi responses in AA men was the objective of this study. Methods: Age at diagnosis, prior enzalutamide (Enza) and/or docetaxel (Doc), and duration of Abi treatment were assessed. Baseline values at Abi initiation for alkaline phosphatase (ALP), hemoglobin (Hgb), and lactate dehydrogenase (LDH) were recorded. PSA values at baseline and throughout treatment were also logged. The velocity of PSA decline was determined by the PSA half-life (PSAHL) based on time to nadir. PCWG2 criteria were used to define PSA response and progression. Results: This was a single institution, retrospective cohort of 103 patients with mCRPC treated with Abi (n = 24 AA; n = 79 CA). Median age at diagnosis was 61.8 years and 62.4 years for AA and CA respectively. Prior Enza/Doc was 4.2%/33.3% for AA and 6.3%/29.1% for CA. Median duration of Abi therapy in AA was 207 days and 253 days for CA; neither median age or duration were statistically distinct. Median AA baseline ALP, Hgb, LDH, and PSA was 136 (range (r) = 59-653), 11.8 (r = 8.9-15.4), 256 (r = 157-401), and 59.9 (r = 4.8-1658) respectively. Median CA baseline ALP, Hgb, LDH, and PSA were 88 (r = 51-1600), 12.4 (r = 8.4-15.0), 204 (r = 100-528), and 40.6 (r = 2.5-2890) respectively. The difference in baseline lab values between AA and CA were insignificant. No statistical difference was seen in median PSAHL (AA = 55 days; CA = 64 days), or PSA decline of > 30% (AA = 50%; CA = 52%), > 50% (AA = 46%; CA = 39%), or > 90% (AA = 21%; CA = 14%). Finally, neither the median time to nadir (AA = 119 days; CA = 137 days) or progression (AA = 157 days; CA = 131 days) were significantly different. Conclusions: Comparison between AA men and CA men in mCRPC patients being treated with Abi showed no statistical difference in response rates, duration of response, or time to progression. Prospective, multi-institutional studies are needed to further assess these findings.

Application of abiraterone acetate (AA) in chemo-naïve metastatic castration-resistant prostate cancer (mCRPC) patients who did not fulfil the patient inclusion criteria in the COU-AA-302 study.

317 Background: Visceral metastases or poor performance status (ECOG 2 or above) were the major exclusion criteria in the COU-AA-302 study, and hence the efficacy of abiraterone acetate (AA) in chemo-naïve mCRPC patients with these characteristics remain undetermined. Our study compares the clinical efficacy of AA in chemo-naïve mCRPC patients with or without the aforementioned characteristics. Methods: The clinical records of chemo-naïve mCRPC patients from all 6 public oncology centers in Hong Kong between August 2011 and December 2014 were reviewed. Patients with visceral disease who were medically unfit for, or who declined, chemotherapy, were allowed for AA in the study period. The median overall survival (OS), progression-free survival (PFS), patient and disease characteristics were compared between groups which satisfied, and did not satisfy, the inclusion criteria of COU-AA-302 study. Results: Fifty-eight consecutive chemo-naïve mCRPC patients had received AA in the review period, of which 29 fulfilled the inclusion criteria for the COU-AA-302 study (Group Eligible). All the remaining patients (Group Ineligible) had ECOG 2 or above, including 3 who had non-nodal visceral metastases. Group Ineligible had higher baseline PSA, haemoglobin and alkaline phosphatase level than Group Eligible, but otherwise there was no significant difference in the baseline characteristics between the groups for age, Gleason score, and co-morbidities. Group Ineligible had significantly shorter OS than Group Eligible (7.7 vs 25.0 months, p = 0.0095) and also a shorter PFS that did not reach statistical significance (5.3 vs 9.8 months, p = 0.2936). The duration of use of AA, and frequency of employment of post-AA treatment were comparable between the groups. Conclusions: Our study demonstrated a poor efficacy of AA in chemo-naïve patients who did not fulfil the inclusion criteria for COU-AA-302 study, by virtue of poor performance status or presence of visceral metastases. The impact of AA in this group of patients warrants further examination in clinical trials before its routine clinical use in this subgroup.

Real-world experience of therapeutic sequencing and time to first anticancer intervention (ACI) following sipuleucel-T (sip-T): Initial data from the PROCEED registry.

194 Background: Sip-T is an autologous immunotherapy approved for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).Many therapeutic agents have been approved in a short time frame, and their optimal sequencing in mCRPC is under investigation. The sequencing of agents post–sip-T treatment on PROCEED (NCT01306890) and factors associated with a shorter time to first ACI (tACI) are described. Methods: The number of unique and most common sequences and sequence trends were analyzed. Post–sip-T ACIs evaluated were abiraterone (abi), enzalutamide (enz), docetaxel (D), and cabazitaxel (cbz), excluding radium-223 due to its late approval relative to PROCEED initiation. The tACI and factors associated with shorter tACI were assessed. Results: 1902 pts received ≥1 sip-T infusion, and an estimated 37.0% and 21.2%had not received an ACI at 1 and 2 y, respectively, post–sip-T. 1331 (70%) pts received abi, enz, D, or cbz after sip-T. 47 therapy sequences were recorded post–sip-T, with the most used therapies in order of prevalence: abi alone, enz alone, D alone, abi → enz, abi → D, D → enz, and D → abi. The most common post–sip-T sequences beginning with abi, enz, or D are below (Table). Only 25 pts received cbz as the first ACI post–sip-T. Pts who received abi prior to sip-T had a shorter median tACI (4.6 mos) compared with all pts (8.3 mos) or pts with D prior to sip-T (7.3 mos). Higher baseline alkaline phosphatase, lower hemoglobin, and prior radical prostatectomy were associated with shorter tACI. Conclusions: In the evolving mCRPC space, 47 unique ACI sequences were recorded post-sip-T. The most common sequences post–sip-T were abi, enz, and D as single agents. Prior abi was associated with a shorter tACI post–sip-T, which warrants longer follow-up. While many pts received subsequent therapy, ~20% had not received an ACI at 2 y post–sip-T. Clinical trial information: NCT01306890. [Table: see text]

Alkaline phosphatase predicts response in polycystic liver disease during somatostatin analogue therapy: a pooled analysis.

Somatostatin analogues reduce liver volumes in polycystic liver disease. However, patients show considerable variability in treatment responses. Our aim was to identify specific patient, disease or treatment characteristics that predict response in polycystic liver disease during somatostatin analogue therapy. We pooled the individual patient data of four trials that evaluated long-acting somatostatin analogues (120 mg lanreotide or 40 mg octreotide) for 6-12 months in polycystic liver disease patients. We performed uni- and multivariate linear regression analysis with preselected patient, disease and drug variables to identify independent predictors of response, defined as per cent change in liver or kidney volume (in ADPKD subgroup). All analyses were adjusted for baseline liver volume and centre. We included 153 polycystic liver disease patients (86% female, median liver volume 4974 ml) from three international centres, all treated with octreotide (n = 70) or lanreotide (n = 83). Mean reduction in liver volume was 4.4% (range -31.6 to +9.4%). Multivariate linear regression revealed that elevated baseline alkaline phosphatase was associated with increased liver volume reduction during therapy (-2.7%, 95% CI -5.1 to -0.2%, P = 0.04), independently of baseline liver volume. Somatostatin analogue type, underlying diagnosis and eGFR did not affect response. In our ADPKD subpopulation (n = 100), elevated alkaline phosphatase predicted liver volume reduction (-3.2%, P = 0.03) but did not predict kidney volume reduction (+0.1%, P = 0.97). Total gastro-intestinal symptom severity decreased with therapy in a subgroup analysis (n = 95; P < 0.001). Alkaline phosphatase is a liver-specific, independent predictor of response in polycystic liver disease during somatostatin analogue therapy.

Defining Criteria for Steroid Response to Distinguish Primary Sclerosing Cholangitis (PSC) From IgG4-Sclerosing Cholangitis (IgG4-SC)

Introduction: Elevated serum IgG4 levels are seen in 10-15% of PSC, raising suspicion of IgG4-SC. However, differentiating PSC from IgG4-SC is a challenge. While IgG4-SC responds to steroids, it is unknown if liver test response to steroid therapy can distinguish the two entities. We evaluated the performance characteristics of reduction in serum alkaline phosphatase (ALP) following steroid treatment to distinguish PSC from IgG4-SC. Methods: We retrospectively identified 40 patients with SC (PSC: n=38, 27 M, mean age 46 yrand IgG4-SC: n=18, 15 M, mean age 66 yr) who received steroid treatment (≥30 mg prednisone with slow taper) and had ALP measured before and after initiation of treatment. PSC patients were treated with steroids because of elevated serum IgG4 (n=18), or, in those with normal IgG4 (n=20), for concomitant inflammatory bowel disease (n=15) or other indications (n=5). Pre- and post-steroid (median 5 weeks) ALP values were analyzed as fold upper limit of normal (ULN) and percentage decrease from baseline. Results: The pre- and post-treatment ALP distribution is reported in Table 1. Post-treatment ALP decreased in 91% of PSC and 96% of IgG4-SC with abnormal baseline ALP regardless of serum IgG4 status. If baseline ALP was < 2X ULN, its decrease after treatment did not distinguish IgG4-SC from PSC. If baseline ALP was ≥2X ULN, 0/28 PSC and 8/12 (67%) IgG4-SC had post-treatment normalization of ALP (p < 0.0001), 11/28 (39%) PSC vs 4/12 (33%) IgG4-SC had post treatment ALP 1-2X ULN (p=0.33), and post-treatment ALP persisted at >2X ULN in 17/28 (61%) in PSC and 0/12 in IgG4-SC (p=0.0002). Among patients with baseline ALP ≥2X ULN, the sensitivity and specificity for IgG4-SC was 67% and 100%, respectively, for ALP normalization, 83% and 86%, respectively, for reduction in ALP to < 1.5X ULN, and 100% and 61%, respectively, for reduction in ALP to < 2X ULN after steroid treatment. ALP reduction of >50% had a sensitivity of 67% and specificity of 89% for IgG4-SC.Table 1: The pre- and post-treatment ALP distribution in PSC and IgG4-SC.Conclusion: Following steroid treatment ALP decreases in both PSC and IgG4-SC; if baseline ALP is < 2X ULN, this response is not useful in distinguishing between the two entities. In SC patients with baseline ALP ≥2 fold ULN, a 6 week steroid trial may be diagnostic in 60%; normalization of ALP is diagnostic of IgG4-SC and its persistence >2 fold ULN is diagnostic of PSC; an intermediate ALP response is non-discriminatory. Percentage decrease in ALP did not reliably distinguish the two entities.

Characterization of abiraterone responses in African American castrate-resistant prostate cancer.

203 Background: African American (AA) men have a higher incidence and mortality from prostate cancer (PCa) compared to other racial groups. Abiraterone acetate (Abi) is approved for treatment of mCRPC. While some AA patients were included in Abi trials, the majority of patients have been Caucasian (CA). To date, there have been no reports of Abi responses exclusively in AA men. This study evaluated Abi responses in AA men with mCRPC. Methods: PSA values during Abi treatment as well as baseline hemoglobin (Hgb), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were tabulated. Prior therapy with docetaxel (Doc) or enzalutamide (Enza) was recorded. PSA response, progression and duration were assessed and compared between racial groups. PSA response, duration of response, and progression were defined by PCWG2 criteria. PSA half-life (PSAHL) based on time to nadir was calculated to assess rate of PSA decline. Results: A total of 74 Abi patients with mCRPC (n = 20 AA; n = 54 CA) were assessed from a single institution. Median AA baseline Hgb, ALP, LDH, and PSA were 11.8 (r = 6.4-15.4), 220 (r = 88-713), 209 (r = 157-401), and 48.41 (r = 4.8-1460) respectively. Median CA baseline Hgb, ALP, LDH, and PSA were 12.35 (r = 7.6-15), 165.5 (r = 70-1699), 218 (r = 133-528), and 44.84 (r = 1.71-2890) respectively. There were no significant differences in baseline labs between AA and CA. Prior use of Doc or Enza was 30% and 5% for AA; 31% and 4% for CA. PSA response was not significant for PSA decline of &gt;30% (&gt;30%: AA = 40%; CA = 44%), &gt;50% (&gt;50%: AA = 35%; CA = 30%), or &gt;90% (&gt;90%: AA = 20%; CA = 9%). In addition, no significant differences between the time to nadir (AA median = 209 days; CA median = 218 days), rate of PSA decline (AA PSAHL median = 72.4 days; CA PSAHL median = 80.1 days), or time to progression was observed. The median treatment length was 278 days and median time to progression was 66 days for AA men; 264 days and 88 days for CA men. Conclusions: Abi response rates, duration of response, and time to progression were not statistically different in AA men compared to CA men in patients with mCRPC. Larger studies are needed to fully evaluate this observation.

Impact of crossover and baseline prognostic factors on overall survival (OS) with abiraterone acetate (AA) in the COU-AA-302 final analysis.

142 Background: AA + prednisone (P) significantly increased OS, time to opiate use, and was well tolerated at the COU-AA-302 final analysis. Here we further characterize OS benefit adjusting for crossover therapy and for baseline prognostic factors. Methods: Patients (N = 1,088) were randomized 1:1 to receive AA (1 g) + P (5 mg po BID) vs P. Co-primary end points were radiographic progression-free survival and OS. Median time to events with 95% CI was estimated using the Kaplan-Meier method. Stratified log-rank test was used to test the difference in treatment effect. Adjustment for crossover utilized the iterative parameter estimate (IPE) and impact of baseline prognostic factors was examined via the multivariate Cox proportional hazard model. Results: With a median follow-up of 49.2 months and 741 deaths (96% of required), AA + P significantly reduced the risk of death vs P (19%) and prolonged median OS (34.7 vs 30.3 months) (Table). 44% of patients initially receiving P alone subsequently received AA + P as crossover per protocol (17%) or as subsequent therapy (27%). IPE adjustment resulted in a 26% reduction in the risk of death (Table). By multivariate analysis, AA + P treatment led to a 21% reduction in the risk of death; baseline prostate-specific antigen (PSA), lactate dehydrogenase (LDH), hemoglobin, alkaline phosphatase (ALP), bone metastases, and age were significant OS prognostic factors (Table). Conclusions: AA + P yielded a statistically significant improvement in OS. Greater improvement in OS was observed after adjusting for the 44% of patients originally on P who ultimately received AA + P. Adjusting for baseline prognostic factors also demonstrated an AA + P OS benefit. Clinical trial information: NCT00887198. [Table: see text]

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Vitamin D treatment in calcium-deficiency rickets: a randomised controlled trial

ObjectiveTo determine whether children with calcium-deficiency rickets have a better response to treatment with vitamin D and calcium than with calcium alone.DesignRandomised controlled trial.SettingJos University Teaching Hospital, Jos, Nigeria.PopulationNigerian children...

What predicts adverse outcomes in untreated primary hyperparathyroidism? The Parathyroid Epidemiology and Audit Research Study (PEARS)

Objective This study aims to identify the best biochemical risk factors alongside other factors for predicting adverse outcomes seen in untreated primary hyperparathyroidism (PHPT). Design Population-based cohort study, 1997-2006. Setting Tayside, Scotland, UK. Patients Patients with untreated diagnosed PHPT. OUTCOME MEASURES AND METHODS: Outcomes considered were all-cause mortality, fatal and nonfatal cardiovascular disease (CVD). Models were derived using survival analysis. Potential biochemical predictors tested were baseline serum calcium, parathyroid hormone (PTH), creatinine and alkaline phosphatase (ALP), and other covariates considered were gender, age at diagnosis, deprivation, previous comorbidities and bisphosphonates usage. Results From 1997 to 2006, 2097 patients (mean age, 68·4 years; 69·9% women) with untreated PHPT were identified with a total follow-up of 7338 person years, in the population of Tayside, Scotland. The median baseline calcium was 2·61 mm, and PTH was 7·2 pm. PTH was the only statistically significant risk factor in all outcomes observed adjusting for other covariates. Serum creatinine and ALP predicted mortality outcomes in the short term (≤3 years), but not long term. Calcium was associated with increased risk of all-cause mortality in the short term but had no significant impact on other outcomes. Conclusion Baseline PTH, rather than calcium, best predicts long-term outcomes in untreated PHPT.

Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis

Among 97 postmenopausal women with primary osteoporosis, adequate calcium and vitamin D supplementation, and good compliance to a 36-month bisphosphonate treatment, the 25.8% of patients are inadequate responders. Current smoking and a bone turnover in the upper part of the normal range increase the risk of treatment failure. To evaluate the prevalence of the bisphosphonate treatment failure and its possible associated factors in women with primary osteoporosis (PO). We studied 97 previously untreated postmenopausal women with PO and fragility fractures and/or a FRAX® 10-year probability of a major osteoporotic fracture ≥ 7.5%, before and after a 36-month treatment with alendronate or risedronate and adequate vitamin D supplementation with good compliance. At baseline and after 36 months, lumbar spine (LS) and femoral bone mineral density (BMD) were assessed by Dual X-ray absorptiometry and vertebral fractures by spinal radiographs. Spinal deformity index (SDI) was calculated. Treatment failure was defined by the presence of ≥ 2 incident fragility fractures and/or a BMD decrease greater than the least significant change. Bisphosphonate treatment failure was observed in 25.8% of patients. Age, body mass index, years since menopause, familiar history of hip fracture, number of falls, type of bisphosphonate used, 25-hydroxyvitamin D levels (25OHVitD), BMD, SDI, and FRAX® score at baseline were not different between responders and inadequate responders. Treatment failure was associated with current smoking (OR 3.22, 95% CI 1.10-9.50, P = 0.034) and baseline alkaline phosphatase total activity levels ≥ 66.5 U/L (OR 4.22, 95% CI 1.48-12.01, P = 0.007), regardless of age, number of falls, LS BMD, and baseline SDI. The 25.8 % of PO postmenopausal women inadequately responds to bisphosphonates, despite a good compliance to therapy and normal 25OHVitD levels. The current smoking and bone turnover in the upper part of the normal range are associated with the inadequate response to bisphosphonates.

Association of alkaline phosphatase (ALP) with clinical outcomes in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302.

27 Background: Prognostic models have been developed for men with mCRPC. In this analysis we undertook a pragmatic approach to focus on commonly obtained markers. Baseline ALP and normalization of elevated ALP post-docetaxel have prognostic value for overall survival (OS). We examined the association between ALP and prostate-specific antigen (PSA) elevation at baseline and after 4 cycles of therapy (C5D1), when both markers were assessed, with long-term clinical outcomes in COU-AA-302, a randomized phase 3 study of abiraterone acetate (AA) in chemotherapy-naive mCRPC pts. Methods: 1,088 pts were randomized 1:1 to AA (1 g) + prednisone (P) (5 mg BID) or placebo + P. Radiographic progression-free survival (rPFS) and OS were co-primary end points. The study design, as well as primary and secondary end point results obtained at the time of a prespecified interim analysis at 55% OS events, have been described in detail previously. The effect of elevated ALP (above upper limit of normal) and PSA (above 106.2 µg/mL, baseline third quartile) status on rPFS and OS was assessed retrospectively using a stratified Cox regression model that included treatment and baseline factors log (lactate dehydrogenase), hemoglobin, whether patient had only bone metastasis, and age. Results: Elevated status of ALP and PSA were independent significant predictors of increased risk for outcomes at baseline as well as after 4 cycles of therapy (Table). Conclusions: These post hoc analyses of data from COU-AA-302 suggest that elevated ALP and PSA at baseline and during treatment confers individual and additive risk for adverse clinical outcomes in chemotherapy-naive mCRPC. Clinical trial information: NCT00887198. [Table: see text]

Liver enzymes and risk of all-cause mortality in general populations: a systematic review and meta-analysis

Gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), commonly used as markers of liver dysfunction, have been implicated with risk of all-cause mortality. The prospective evidence on the associations in general populations has not been reliably quantified. We conducted a systematic review and meta-analysis of published prospective cohort studies evaluating the associations of baseline levels of these enzymes with all-cause mortality in general populations. Relevant studies were identified in a literature search of MEDLINE, EMBASE and Web of Science up to March 2013. Authors of unpublished studies provided data on request. Nineteen unique cohort studies with aggregate data on over 9.24 million participants and 242 953 all-cause mortality outcomes were included. In a comparison of extreme thirds of baseline GGT and ALP levels, relative risks (RRs) (95% confidence intervals) for all-cause mortality were 1.60 (1.42-1.80) and 1.38 (1.17-1.63), respectively. The corresponding RRs for ALT were 0.82 (0.78-0.86) and 1.43 (1.08-1.90) in North American and Asian populations, respectively. There was no strong evidence of an association of AST with all-cause mortality: RR 1.23 (0.80-1.88). The pooled RRs per 5 U/l increment in GGT and ALP levels were 1.07 (1.04-1.10) and 1.03 (1.01-1.06), respectively. Available data indicate positive independent associations of baseline levels of GGT and ALP with all-cause mortality, consistent with linear dose-response relationships. There were geographical variations in the association of ALT with all-cause mortality which require further investigation. The potential incremental prognostic values of GGT and ALP in mortality risk assessment need evaluation.

Alkaline Phosphatase and Mortality in Patients on Peritoneal Dialysis

Elevated total serum alkaline phosphatase levels have been associated with higher mortality in the general population, CKD patients, and hemodialysis patients. However, in peritoneal dialysis patients, this association has received little attention. The aim of this study was to evaluate the association between alkaline phosphatase and all-cause and cardiovascular mortality in peritoneal dialysis patients. In this single center retrospective cohort study, 1021 incident peritoneal dialysis patients from January 1, 2006, to December 31, 2010 with baseline serum alkaline phosphatase values were enrolled. Collected baseline data included demographic characteristics and clinical and laboratory measurements. All patients were followed until December 31, 2012. The associations of total serum alkaline phosphatase levels with all-cause and cardiovascular mortality were assessed using multivariable-adjusted Cox models. Of 1021 patients, mean age was 47.5 (± 15.5) years, 59.1% of patients were men, and 22.8% of patients were diabetic. The median serum alkaline phosphatase level was 64 U/L (interquartile range=52-82 U/L). During a median 31-month (interquartile range=19-45 months) follow-up period, 203 patients died, of which 109 deaths were caused by cardiovascular disease. After adjusting for demographics, comorbid conditions, liver function, and bone metabolism parameters, the highest alkaline phosphatase quartile was significantly associated with a hazard ratio for all-cause mortality of 1.70 (95% confidence interval, 1.06 to 2.74, P=0.03) and a hazard ratio for cardiovascular mortality of 1.94 (95% confidence interval, 1.02 to 3.72, P=0.04). Each 10 U/L higher baseline alkaline phosphatase level was associated with 4% (95% confidence interval, 1.00 to 1.08, P=0.04) and 7% (95% confidence interval, 1.02 to 1.11, P=0.003) higher risk of all-cause and cardiovascular mortality, respectively. Higher total serum alkaline phosphatase levels at the commencement of peritoneal dialysis were independently associated with all-cause and cardiovascular mortality in peritoneal dialysis patients.

Serum Alkaline Phosphatase Level On Day 4 Of G-CSF Administration Could Be a Simple Yet Practical Surrogate Marker For CD34 Mobilization and Collection

Introduction Granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSCs) have become the primary source of stem cells in the majority of allogeneic stem cell transplantations, mainly because of ease of collection and rapid hematopoietic reconstitution. G-CSF for 4 days is the preferred stem cell mobilization method for normal donors. Peripheral blood CD34+ cell count on day 4 of G-CSF is used as a guide to initiate apheresis and PBSC collection. The actual cutoff for PBSC collection varies by institutional preferences. At our center, we collect PBSCs when the CD34+ cell count is greater than 15/ml. Since the turnaround time for CD34 count is about 3 hours; there is a delay in the start of apheresis which extends the PBSC collection to a second day. A reliable and faster method which estimates CD34+ cell count will enable us to avoid delays in collection to the next day. We report the data from our center on the utility of serum alkaline phosphatase (ALK.ph) level as a surrogate marker for the adequacy of peripheral blood CD 34+ cell count suitable for stem cell collection. Methods A retrospective chart review on normal PBSC donors for allogeneic stem cell transplant between January 1, 2009 and March 31, 2013, was performed after obtaining IRB approval. Data was collected at baseline to include sex, age, BMI, WBC, ALK.ph and day 4 ALK.ph, WBC and CD34 count. Results 51 PBSC donors were evaluated, 2 patients were excluded for baseline ALK.ph&gt; 200 which was due to undetermined causes. None of these donors had a history of hematologic malignancies or underwent previous apheresis procedures. Of the 49 evaluable patients (23 were males); the median age was 53 years (range 11-72), and the median body mass index (BMI) was 29.1 (range 14-78). Median baseline ALK.ph was 72 (range 42-150), the median day 4 ALk.ph was 164 (54-279). The median CD34 count on first day of collection was 47 (5-218) and there were no mobilization failures. A positive correlation was observed between CD34 count and increase in ALK ph levels 0.4171 (p=0.002). For every one unit/ liter increase in alkaline phosphatase there is 0.48 times (95% CI 0.17-0.78) increase in CD34 count. On univariate regression analysis, the factors that were correlated with CD34+ cell counts were day 4 alkaline phosphatase (p=0.015), day 4 WBC count (p&lt;0.001) and change in alkaline phosphatase as compared to baseline (p=0.002). However, on multivariate robust regression analysis, factors that were correlated with CD34 counts were gender (p=0.04), day 4 WBC count (p&lt;0.001) and baseline alkaline phosphatase (p=0.027). Conclusion Our analysis suggests a potential utility of the change in serum alkaline phosphatase level at day 4 after GCSF in predicting peripheral blood CD34+ cell count. Further studies are underway to utilize this information as part of an algorithm to improve efficiency and prevent delays in normal donors undergoing PBSC mobilization and harvesting. Disclosures: No relevant conflicts of interest to declare.

Serum liver enzymes are associated with all‐cause mortality in an elderly population

Little is known about the association of serum liver enzymes with long-term outcome in the elderly. We sought to clarify the association of serum gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with all-cause and cause-specific mortality in an elderly population. This study was embedded in the Rotterdam Study, a large population-based cohort of persons aged 55 years or older. Cox-regression analyses were performed to examine the association of baseline serum GGT, ALP, and aminotransferase levels with mortality, adjusted for age, sex, education, smoking status, alcohol intake, hypertension, diabetes mellitus, body mass index and total cholesterol levels. Liver enzyme levels were categorized according to sample percentiles; levels <25th percentile were taken as a reference. During a follow-up of up to 19.5 years, 2997 of 5186(57.8%) participants died: 672 participants died of causes related to cardiovascular diseases (CVD) and 703 participants died of cancer. All serum liver enzymes were associated with all-cause mortality (all P < 0.001). Moreover, GGT was associated with increased CVD mortality (P < 0.001), and ALP and AST with increased cancer-related mortality (P = 0.03 and P = 0.005 respectively). Participants with GGT and ALP in the top 5% had the highest risk for all-cause mortality (HR1.55; 95%CI 1.30-1.85 and HR1.49; 95%CI 1.25-1.78 respectively). AST and ALT <25th percentile were also associated with a higher risk of all-cause mortality. All serum liver enzymes were positively associated with long-term mortality in this elderly population. Why participants with low ALT and AST levels have higher risk of mortality remains to be elucidated.

Association of IL28B genotype with fibrosis progression and clinical outcomes in patients with chronic hepatitis C: A longitudinal analysis

Interleukin (IL)28B polymorphisms are associated with spontaneous clearance of hepatitis C virus (HCV) infection and response to therapy. Whether IL28B genotype affects fibrosis progression or clinical outcome is unclear. Our aim was to study the relationship between IL28B genotype and both histological and clinical outcomes in patients with chronic hepatitis C (CHC). Hepatic fibrosis was scored using the Ishak (0-6) scale; progression was defined as a 2-point increase in Ishak score between biopsies. Multiple logistic and Cox regressions were used to identify variables associated with fibrosis progression. In all, 1,483 patients were included in a baseline cross-sectional analysis, from which 276 were eligible for a paired biopsy analysis (median time between biopsies 4 years), and 400 for a clinical outcome analysis. At baseline biopsy, patients with IL28B CC genotype had significantly higher portal inflammation (2.4 versus 2.2) and alanine aminotransferase (ALT) levels (133 versus 105 U/L; P < 0.05 for all). In the paired biopsy analysis, there was no difference in the frequency of fibrosis progression between patients with IL28B CC and non-CC genotypes (17% versus 23%). In logistic regression, only higher baseline alkaline phosphatase, lower platelets, and greater hepatic steatosis were associated with fibrosis progression. Patients with IL28B CC were twice as likely to develop adverse clinical outcomes compared to non-CC (32% versus 16%; P = 0.007). IL28B CC genotype was associated with greater hepatic necroinflammation, higher ALT, and worse clinical outcomes in CHC patients. This suggests that IL28B CC is associated with a state of enhanced immunity that, on the one hand, can promote viral clearance, but alternately can increase necroinflammation and hepatic decompensation without enhancing fibrosis progression.

Survival analysis of patients with metastatic castration-resistant prostate cancer treated with docetaxel plus prednisone

Objective To explore the potential value of patient characteristics in predicting overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel plus prednisone.Methods We retrospectively analyzed the data of 115 consecutive Chinese patients with mCRPC received docetaxel chemotherapy in our institution from Nov.2005 to Sep 2011.The median age at diagnosis was 65 years old and median serum prostate-specific antigen (PSA) level at diagnosis was 100.0 μg/L.The Gleason score≤7 in 26 patients and ≥8 in 89 patients.The median age at chemotherapy was 68 years old,ranging from 51 to 82 years old.The median baseline PSA level was 90.5 μg/L,ranging from 0.8 to 4066.4 μg/L.The median baseline hemoglobin (Hb) concentration was 121 g/L and median baseline alkaline phosphatase (ALP) concentration was 110 U/L.The time to castration resistance ranged from 2 to 114 months and the median value was 23.All 115 patients have bone metastasis,and 16 cases were simultaneously observed the presence of visceral metastasis including lung (9 cases),bladder (4 cases),liver (2 cases) and brain (1 case).The average cycles of chemotherapy was 6,ranging from 1 to 16.We retrospectively collected the variables including patient characteristics at diagnosis and characteristics before the chemotherapy.All laboratory analyses were performed in the same laboratory.Survival analysis was performed using KaplanMeier curves,and the differences in overall survival rates were assessed using the log-rank test.Only variables that were statistically significant in the univariate analysis (P＜0.05) were included in the multivariate model.Results The follow-up was performed until April 30,2012,and median follow-up time was 45 months,ranging from 2 to 74 months.During the follow-up period,87 of 115 patients (75.7％) died and the median OS for the entire cohort was 17 months,ranging from 2 to 46 months.The univariate analysis identified a total of 8 statistically significant predictors of OS:baseline serum PSA level,baseline Hb concentration,baseline ALP concentration,baseline lactate dehydrogenase (LDH) concentration,baseline gamma-glutamyl transpeptidase (GGT) concentration,ECOG PS,time to castration resistance and cycles of chemotherapy.Subsequent multivariate analysis reserved baseline ALP≥110 U/L,baseline Hb＜110 g/L,time to castration resistance＜23 months and cycles of chemotherapy＜6 as independent prognostic factors for shorter OS.Conclusions This retrospective analysis has demonstrated that baseline ALP concentration,baseline Hb concentration,time to castration resistance and cycles of chemotherapy could provide independent prognostic information of OS in Chinese patients with mCRPC treated with docetaxel plus prednisone. Key words: Castration-resistant prostate cancer; Docetaxel; Prognosis ; ALP ; Time to castration resistance

Efficacy and safety of radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases who did or did not receive prior docetaxel (D) in the phase III ALSYMPCA trial.

5068 Background: Ra-223, a first-in-class α-emitter, significantly improved median overall survival (OS) by 3.6 mo vs placebo (Pbo) in CRPC patients (pts) with bone metastases (mets) receiving best standard of care (BSoC) in the ALSYMPCA study (HR = 0.695; 95% CI, 0.581-0.832; p = 0.00007), and had a highly favorable safety profile in the updated ALSYMPCA analysis (Parker et al. ASCO 2012). This predefined subgroup analysis assessed efficacy and safety of Ra-223 in pts who did or did not receive prior D (pD). Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets; had no known visceral mets; were receiving BSoC; and had received pD, or were unfit for or declined D (npD). Pts were randomized 2:1 to 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching Pbo and stratified by prior D use, baseline alkaline phosphatase level, and current bisphosphonate use. Survival data were compared using a log-rank test. Results: 395/921 (43%) randomized pts had npD (Ra-223, n = 262; Pbo, n = 133); 526/921 (57%) received pD (Ra-223, n = 352; Pbo, n = 174). Median ages were 74 y (npD) and 69 y (pD). In pts with npD, median OS was 16.1 mo in the Ra-223 group vs 11.5 mo in the Pbo group (HR = 0.745; 95% CI, 0.562-0.987; p = 0.039). In pts with pD, median OS was 14.4 mo vs 11.3 mo in the Ra-223 and Pbo groups, respectively (HR = 0.710; 95% CI, 0.565-0.891; p = 0.003). Overall, there was a low incidence of myelosuppression. Incidences of neutropenia and thrombocytopenia were higher in pts with pD vs pts with npD. Conclusions: Ra-223 significantly prolonged OS and had a highly favorable safety profile in CRPC pts with bone mets, regardless of whether they had pD or npD. pD pts had a slightly increased rate of grade 3 and 4 bone marrow suppression with Ra-223. Clinical trial information: NCT00699751. [Table: see text]

Updated analysis of radium-223 dichloride (Ra-223) impact on skeletal-related events (SRE) in patients with castration-resistant prostate cancer (CRPC) and bone metastases from the phase III randomized trial (ALSYMPCA).

11 Background: Ra-223 is a first-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy, short-range (&lt; 100 μm) alpha-particles. In the phase 3, double-blind, randomized, multinational ALSYMPCA study, Ra-223 significantly improved OS in CRPC patients (pts) with bone mets by a median increase of 3.6 months compared with placebo (median OS: 14.9 vs 11.3 mo; P &lt; 0.001; HR = 0.69; 95% CI: 0.58-0.83). An updated analysis of the SRE secondary endpoint is presented. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving best standard of care (BSoC); and either previously received docetaxel, or did not because they were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra‑223 (50 kBq/kg IV) q4wk or matching placebo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. Results: 921 pts were randomized (Ra-223, n = 614; placebo, n = 307); 40% had &gt;20 mets. Ra-223 significantly delayed time to first SRE versus placebo by a median increase of 5.8 months (median time to SRE: 15.6 vs 9.8 mo; P &lt; 0.001; HR = 0.66; 95% CI: 0.52-0.83). Ra-223 also reduced the risk of time to first event for all 4 SRE components versus placebo. Conclusions: Ra-223 significantly delayed time to first SRE with a reduction in risk observed for all 4 SRE components. Despite the longer time at risk, Ra-223 patients had an approximately 50% reduction in risk for SCC. Ra-223 is an effective therapy with a highly favorable safety profile and may provide a new standard of care for treatment of CRPC pts with bone mets. Clinical trial information: NCT00699751. [Table: see text]