Baseline Alkaline Phosphatase Research Articles

Prognostic biomarkers in men with metastatic castration-resistant prostate cancer receiving [177Lu]-PSMA-617.

We analysed quantitative biomarkers derived from both baseline whole-body imaging and blood serum to identify prognostic markers in patients treated within the lutetium-177 prostate-specific membrane antigen (LuPSMA) phase 2 trial. PET image analysis was carried out using whole-body segmentation quantifying molecular tumour volume (SUV > 3 threshold for PSMA, SUV > liver+2sd for fluorodeoxyglucose (FDG) including SUVmax and SUVmean. For baseline bone scans, EXINI bone scan index (BSI) was used to calculate the percentage of involved bone. Baseline alkaline phosphatase (ALP), lactate dehydrogenase (LDH), prostate specific antigen (PSA) and PSA doubling time were also used in this analysis. We used univariate cox regression analysis and log-rank comparison with optimised cut-offs to find suitable biomarkers prognostic of overall survival from time of enrolment. This analysis identified FDG-positive tumour volume (FDGvol; HR 2.6; 95% CI, 1.4-4.8), mean intensity of PSMA-avid tumour uptake (PSMAmean; HR 0.89; 95% CI, 0.8-0.98), bone scan index (BSI; HR 2.3; 95% CI, 1.2-4.4), ALP (HR 1.1; 95% CI, 1-1.2) and LDH (HR 1.2; 95% CI, 1-1.5) as biomarkers prognostic of overall survival. In addition to established biomarkers, both FDG and PSMA PET/CT parameters have prognostic significance for survival in men undergoing LuPSMA therapy.

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

PurposeTo assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate.MethodsIn the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression.ResultsSignificantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25–50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden.Conclusions177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion.Clinicaltrials.gov: NCT01578239, EudraCT: 2011-005049-11

Safety and activity of radium-223 in metastatic castration-resistant prostate cancer: the experience of Istituto Nazionale dei Tumori.

Therapeutic decision-making in metastatic castration-resistant prostate cancer (mCRPC) represents an open challenge. Radium-223 is approved for patients with symptomatic bone metastases, no visceral involvement, progressing after at least 2 lines of systemic therapy, or ineligible for any other systemic treatment. We performed a retrospective, observational study on patients with mCRPC treated with radium-223 at our institution outside of clinical trials, to assess the safety and activity in a real-world population. Data regarding baseline patient/disease characteristics and treatment outcomes (number of cycles, treatment-related adverse events [AEs], cause of discontinuation, and best response) were collected. Overall, 41 patients were treated from September 2015 to September 2018. Median age was 73 years; baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 0, 1, or 2 in 15%, 80%, and 5% of cases, respectively; and 3%, 41%, 44%, and 12% of patients had <6, 6-20, >20, and superscan bone lesions, respectively. A median number of 5 cycles (interquartile range 3-6) with median dose 19.52 MBq (interquartile range 12.87-24.83) was received. Treatment schedule was completed in 49% of cases; discontinuations due to AEs, disease-related death, or disease progression occurred in 24%, 33%, and 43% of patients, respectively. Any-grade AEs occurred in 73% and grade 3/4 treatment-related AEs occurred in 29% of patients, mainly anemia, decreased platelet count, and fatigue. No skeletal-related events or treatment-related deaths were recorded. After treatment, 66%, 2%, and 32% of patients had a stable, improved, or deteriorated ECOG PS versus baseline, respectively, and 24%, 61%, and 15% reported a stable, improved, or worsened pain symptom control. Post-treatment versus baseline alkaline phosphatase was reduced or stable in 46% and increased in 54% of patients, whereas prostate-specific antigen was decreased or stable in 83% and increased in 17% of patients. Our study provides clinically useful real-world data on radium-223, highlighting the importance of multidisciplinary patient management to guarantee the best continuum of care for patients with mCRPC.

3:54 PM Abstract No. 28 Predictors of survival in patients with advanced (Barcelona Clinic Liver Cancer C) hepatocellular carcinoma undergoing Yttrium-90 radioembolization therapy

To identify key clinical and imaging predictors of survival in patients undergoing Yttrium-90 radioembolization (Y90-RE) for advanced, Barcelona Clinic Liver Cancer (BCLC) C, hepatocellular carcinoma (HCC). In an IRB-approved study, patients with BCLC C HCC who underwent Y90-RE were retrospectively identified. Reason for BCLC C Status (i.e., Eastern Cooperative Oncology Group performance status (ECOG-PS), macrovascular invasion, and/or extrahepatic metastasis) and additional pre and post Y90-RE prognostic factors were recorded and analyzed. Median overall survival (OS) from first Y90-RE was calculated using Kaplan-Meier estimation and potential prognostic factors were tested for significance (p ≤0.05) using log-rank analysis. Between 2013 and 2018, 97 BCLC C HCC patients (79% male; 65 years mean age) underwent Y90-RE with a median OS (95% CI) of 13.7 months (10.8-16.9). Median OS for the 40 (41%) ECOG-PS driven BCLC C patients versus the 57 (59%) macrovascular invasion and/or extrahepatic metastasis driven BCLC C patients was 14.5 (10.8-20.5) versus 13.2 (6.9-16.9) months, respectively (p = 0.9). Prognostic factors associated with a prolonged median OS were absence of hepatic vein invasion (14.9 vs. 5.3; p = 0.0002), single hepatic lobe burden (15.4 vs. 7.2; p = 0.04), absence of anorexia (14.6 vs. 6.1; p = 0.004), normal baseline alkaline phosphatase (19.1 vs. 9.0; P <0.0001), normal baseline serum sodium (14.9 vs. 5.2; p = 0.01), greater post Y90-RS tumor shrinkage (14.9 vs. 5.2; p = 0.01), attainment of Milan eligibility status (20.8 vs. 9.6; p = 0.001), and complete/partial tumor response per mRECIST (17.5 vs. 7.3; p = 0.01). Y90-RE is an effective therapy for the treatment of BCLC C hepatocellular carcinoma patients, resulting in an overall survival that is equivalent, if not favorable, to currently allocated therapies per BCLC guidelines. Certain pre Y90-RE clinical and imaging characteristics are associated with an improved overall survival.Tabled 1Prognostic Factors, in median OS (95% CI) monthsPresentAbsentPHepatic vein invasion5.314.90.0002Single hepatic lobe burden15.47.20.04Anorexia6.114.60.004Normal baseline alkaline phosphatase19.19.00.0001Normal baseline sodium blood levels18.07.10.014Greater tumor shrinkage14.95.20.01Attained Milan eligibility status20.89.60.001Attained complete or partial tumor response, per mRECIST17.57.30.01 Open table in a new tab

Association between serum alkaline phosphatase and renal outcome in patients with type 2 diabetes mellitus

This retrospective study included 299 patients with type 2 diabetes mellitus and biopsy-confirmed diabetic nephropathy (DN) to investigate the prognostic value of alkaline phosphatase (ALP) for renal outcome. Cox proportional hazards models were used to estimate the hazard ratios (HRs) for the serum ALP level on renal outcome, which was defined as end-stage renal disease (ESRD) or a 50% decline in estimated glomerular filtration rate (eGFR) from baseline. The median baseline ALP was 80 IU/L with an interquartile range of 64–97 IU/L. Serum ALP was negatively associated with eGFR but positively associated with proteinuria and renal interstitial fibrosis. During a median follow-up period of 23 months, ESRD or a 50% declined in the eGFR occurred in 156 (52.2%) patients. The highest quartile of ALP was significantly associated with poor renal outcome, as defined above (HR 2.38, 95% confidence interval [CI] 1.09–5.17), when adjusted for sociodemographics, baseline eGFR, proteinuria, liver function parameters, parathyroid hormone levels, and renal pathological findings. Each standard deviation higher in the natural log-transformed ALP was associated with a 25% increased risk for poor renal outcome. Additionally, there was a graded increase in the risk for poor renal outcome with higher ALP in patients with nephrotic-range proteinuria. However, no significant associations were observed between serum ALP levels and renal outcome in patients with non-nephrotic-range proteinuria. In conclusion, an elevated ALP level was independently associated with poor renal outcome in patients with type 2 diabetes mellitus and nephrotic-range proteinuria after multivariate adjustment.

Assessing Radiographic Response to 223Ra with an Automated Bone Scan Index in Metastatic Castration-Resistant Prostate Cancer Patients.

For effective clinical management of patients being treated with 223Ra, there is a need for radiographic response biomarkers to minimize disease progression and to stratify patients for subsequent treatment options. The objective of this study was to evaluate an automated bone scan index (aBSI) as a quantitative assessment of bone scans for radiographic response in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: In a multicenter retrospective study, bone scans from patients with mCRPC treated with monthly injections of 223Ra were collected from 7 hospitals in Sweden. Patients with available bone scans before treatment with 223Ra and at treatment discontinuation were eligible for the study. The aBSI was generated at baseline and at treatment discontinuation. The Spearman rank correlation was used to correlate aBSI with the baseline covariates: alkaline phosphatase (ALP) and prostate-specific antigen (PSA). The Cox proportional-hazards model and Kaplan-Meier curve were used to evaluate the association of covariates at baseline and their change at treatment discontinuation with overall survival (OS). The concordance index (C-index) was used to evaluate the discriminating strength of covariates in predicting OS. Results: Bone scan images at baseline were available from 156 patients, and 67 patients had both a baseline and a treatment discontinuation bone scan (median, 5 doses; interquartile range, 3-6 doses). Baseline aBSI (median, 4.5; interquartile range, 2.4-6.5) was moderately correlated with ALP (r = 0.60, P < 0.0001) and with PSA (r = 0.38, P = 0.003). Among baseline covariates, aBSI (P = 0.01) and ALP (P = 0.001) were significantly associated with OS, whereas PSA values were not (P = 0.059). After treatment discontinuation, 36% (24/67), 80% (54/67), and 13% (9/67) of patients demonstrated a decline in aBSI, ALP, and PSA, respectively. As a continuous variable, the relative change in aBSI after treatment, compared with baseline, was significantly associated with OS (P < 0.0001), with a C-index of 0.67. Median OS in patients with both aBSI and ALP decline (median, 134 wk) was significantly longer than in patients with ALP decline only (median, 77 wk; P = 0.029). Conclusion: Both aBSI at baseline and its change at treatment discontinuation were significant parameters associated with OS. The study warrants prospective validation of aBSI as a quantitative imaging response biomarker to predict OS in patients with mCRPC treated with 223Ra.

The value of tumor markers in men with metastatic prostate cancer undergoing [177Lu]Lu‐PSMA therapy

Currently, prostate-specific membrane antigen-radioligand therapy (PSMA-RLT) is considered a last-line treatment option in advanced castration-resistant prostate cancer. Despite these patients' poor prognosis, accurate estimation of their overall survival (OS) is essential to determine whether benefits exist from the treatment and whether the loss of valuable time and unnecessary side effects can be avoided. The aim of the present study is to evaluate whether various biochemical markers can predict OS in men undergoing PSMA-RLT and whether the changes assessed after PSMA-RLT correlate with the OS. The tested tumor markers in this retrospective analysis were alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BAP), prostate-specific antigen (PSA), lactate dehydrogenase (LDH), chromogranin A, and pro-gastrin-releasing peptide (pro-GRP). For the evaluation, we performed blood tests before each PSMA-RLT cycle and during follow-up visits (which were 2-3 months apart). All patients were followed up until their deaths. To test the correlations between the tumor markers and survival, we conducted the logrank tests and the multivariate Cox proportional-hazards regression model. The significance level was set at P < .05. The study included 137 patients who received a total of 487 PSMA-RLT cycles between January 2015 and November 2017. Of the tested biochemical tumor markers, baseline ALP (120 U/L cut-off), LDH (248 U/L cut-off), and PSA (first quartile cut-off) correlated significantly with survival post-PSMA-RLT (P < .001 for ALP and LDH, and P = .007 for PSA). Stable and/or decreased values in most of the initially abnormal parameters were associated with significantly better OS; these parameters were ALP (P = .009), LDH (P = .005), PSA (P < .001), and pro-GRP (P = .013). The BAP and ALP responses also correlated significantly with survival in patients with bone metastases (P = .002 and P < .001, respectively). Furthermore, there was a strong correlation of the kinetic patterns of PSA, ALP, BAP, and LDH with the survival, showing that patients with steadily increasing markers had the shortest OS. Along with the established tumor marker PSA, ALP, LDH, BAP, and pro-GRP were correlated with the OS post-PSMA-RLT in the univariate and multivariate analyses.

1015 Fibroscan Is a Feasible and Useful Point-Of-Care Tool to Assess Nonalcoholic Fatty Liver Disease Severity in Children Texas Liver Institute, University of Texas (UT) Health San Antonio, San Antonio, TX

INTRODUCTION: Estimating the severity of liver steatosis by controlled attenuation parameter (CAP) and liver fibrosis by transient elastography (TE) using the FibroscanTM machine provides a noninvasive method to establish the presence of nonalcoholic fatty liver disease (NAFLD) and assess its severity. The use of CAP/TE is becoming routine practice in adults yet limited data exists in children with suspected NAFLD. The aim of this study was to assess the feasibility and utility of measuring CAP/TE by FibroscanTM in a cohort of children with suspected NAFLD. METHODS: All children referred with a clinical suspicion of NAFLD (elevated alkaline phosphatase (ALT) or fatty infiltration on ultrasonography) who had CAP/TE measured were included. FibroscanTM testing was performed on a standardized machine with an experienced operator utilizing a medium (M) or extra-large (XL) probe. Standard criteria for having valid measurements were applied (IQR &lt; 30% with &gt;70% success rate). Severity of steatosis was evaluated based on the following cutoffs for CAP: &lt;225 db/m (no steatosis), 225-250 db/m (mild steatosis), 250-300 db/m (moderate steatosis), &gt;300 db/m (severe steatosis). Severity of liver stiffness was evaluated using the following TE cutoffs: &lt;6 kPa (no fibrosis), 6-10 kPa (mild to moderate fibrosis), &gt;10 kPa (advanced fibrosis). Baseline clinical and laboratory parameters were also collected. RESULTS: 119 children with suspected NAFLD were referred to the clinic between May 2017 and April 2019. The mean age at time of assessment was 13.0 (± 3.0) years. The majority were males (68%), obese (87%) and of Hispanic ethnicity (77%). The M probe was used to successfully complete 64% of scans whereas the XL probe was required for 36% of scans. 4/116 (3%) had a CAP &lt; 225 indicating no steatosis. 15/116 (13%) of patients fell within the mild steatosis range (CAP 225-250), 31/116 (27%) with moderate steatosis (CAP 250-300) and the majority, 66/116 (57%), of patients having severe steatosis with CAP values &gt; 300. On TE, 50% had no fibrosis, 45% with mild to moderate fibrosis and 7% with advanced fibrosis. Linear regression analysis demonstrated a weakly positive correlation between baseline ALT and TE measurements (correlation coefficient (r) was 0.24; P value &lt; 0.05; Figure 1.1). CONCLUSION: CAP/TE provides a reliable way to confirm the diagnosis of NAFLD and assess its severity in children. Larger pediatric studies that assess the correlation with liver histology and disease progression are needed.

1014 The Majority of Patients With Primary Biliary Cholangitits Do Not Achieve the Ideal Treatment Response in a Real World Clinical Practice

INTRODUCTION: The currently accepted criteria to define therapeutic response to primary biliary cholangitis (PBC) consists of alkaline phosphatase (ALP) (&lt;180 U/L) and bilirubin (&lt;1.0 mg/dL). New data suggests that normalization of ALP (&lt;120 U/L) and bilirubin (&lt;0.5 mg/dL) is associated with better overall outcomes. PBC patients are usually maintained on first line therapy of ursodeoxycholic acid (UDCA), obeticholic acid (OCA) or combination of both agents. The aim of the study was to determine the percentage of PBC patients that achieve the accepted (ALP &lt; 180, bilirubin &lt; 1) and ideal (ALP &lt; 120, bilirubin &lt; 0.5) treatment responses in a real-world setting. METHODS: All adult patients in this multi-center study had a diagnosis of PBC via ICD-9 and ICD-10 codes. Other chronic liver disease cases and those with significant alcohol consumption were excluded. Baseline demographics, clinical characteristics and laboratory data were collected. Therapy starting time was noted, assessing their lab values at baseline compared to a recent workup. A two-sided t test was done to compare continuous variables and a P value &lt; 0.05 was considered statistically significant. RESULTS: 76 adult PBC patients were included in the final analysis. The mean age at the last follow up was 61.8 years (±11.3). 96% were female, 47% were White and 51% were of Hispanic ethnicity. 93% were on UDCA therapy alone with daily dosages between 750-1500 mg. Only 7% received both UDCA and OCA. The mean baseline ALP was 286 U/L and the mean follow up ALP was 172 U/L (±84.6), 52 U/L above the ideal value (P &lt; 0.05). The mean baseline bilirubin was 1.04 mg/dL and the mean follow up bilirubin was 0.8 mg/dL (±1.2), 0.3 mg/dL above the ideal value (P &lt; 0.05). 62% reached the accepted ALP value, 86% reached the accepted bilirubin value, and 57% reached the accepted level. 30% of patients achieved the ideal ALP value and 26% achieved the ideal bilirubin level with 20% reaching the ideal response. The rates for accepted and ideal responses were 80% and 40%, respectively, for those on UDCA and OCA. CONCLUSION: The majority of PBC patients in real-life settings did not achieve the ideal treatment response of ALP &lt; 120 U/L and bilirubin &lt; 0.5 mg/dL. Furthermore, a significant percentage did not achieve the accepted treatment response of ALP &lt; 180 U/L and bilirubin &lt; 1.0 mg/dL. Only a small percentage received combination therapy with UDCA/OCA. There's a need to increase awareness among healthcare providers on the optimal responses to PBC treatment.

SAT-066 EFFECTS OF PARATHYROIDECTOMY ON NOCTURNAL NON-DIPPING HEART RATE IN STAGE 5 CKD PATIENTS

In healthy population 24-hour heart rate (HR) displays a circadian pattern, peaking shortly after waking and falling during the night, a phenomenon known as “dipping”. Non-dipping HR is defined as nighttime HR decreased less than 10% as compared to daytime readings, which is an independent risk factor for increased cardiovascular diseases (CVD) and all-cause mortality. It is well known that patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) have high risk of CVD and mortality, however, the associations between CKD-MBD and non-dipping HR remain uncertain. Here we evaluated the features of 24-hour HR in stage 5 chronic kidney disease (CKD) and the effects of parathyroidectomy (PTX) on HR circadian rhythm in severe secondary hyperparathyroidism (SHPT) patients. The cross-sectional study included 213 stage 5 CKD patients and 96 controls. A prospective follow-up study was conducted in 47 PTX patients. Blood examinations and 24-hour Holter monitoring were measured. HR in each hour, daytime (8:00 AM-19:59 PM) and nighttime (20:00 PM-7:59 AM) mean HR values were recorded. Night/day HR ratio was calculated as nighttime/daytime ratio of heart rate, when greater than 0.90 could be considered as non-dipping HR. Stage 5 CKD patients and healthy controls were matched for age and sex. Compared with controls, CKD patients had higher blood pressure, lower body mass index (BMI), hemoglobin, hematocrit, serum albumin and total cholesterol values. In addition, stage 5 CKD group had higher circulating adjusted calcium (Ca), phosphorus (P), alkaline phosphatase (ALP) and intact parathyroid hormone (iPTH) levels. Stage 5 CKD patients display higher 24-hour, daytime and nighttime mean HR than controls. Night/day HR ratio in controls and CKD patients were 0.81±0.080, 0.91±0.075 respectively (P＜0.0001) (Table 1). Night/day HR ratio had closely positive correlations with baseline serum Ca, iPTH and ALP, while negatively related with serum urea and albumin levels. In CKD patients, the dipping patterns of 24-hour HR were shallower in both non-PTX and PTX group, especially in severe SHPT patients(Figure 1). After PTX (median follow-up interval: 11.84±11.33 months), the non-dipping HR pattern was reversed in severe SHPT patients, and Night/day HR ratio decreased from 0.92±0.077 to 0.88±0.075 (P=0.01) (Figure 2). Twenty four hour heart rate in stage 5 CKD patients displayed non-dipping pattern, mainly due to increased nighttime HR. Severe SHPT patients have more serious non-dipping HR, which could be reversed by parathyroidectomy. Rhythm abnormalities of heart rate are suggested to be taken seriously and treated effectively in order to decrease CVD and all-cause mortality in CKD-MBD patients.

Bone scan index as metastatic bone disease quantifier and predictor of radium-223-dichloride biochemical response.

This work aims to assess whether the biochemical response of radium-223-dichloride treatment can be predicted based on the pretherapy bone scan, and consequently if bone scan index (BSI) and maximum lesion intensity have a place as alternatives or as complements to extent of bone disease (EOBD) scoring in predicting biochemical response to treatment. Many cases of advanced prostate cancer have evidence of bone metastasis. Accurate EOBD quantification could help predict the response to radium-223-dichloride therapy. Current EOBD score is simple to use but does not consider size, intensity or localisation of lesion BSI might be more suitable for stratification of bone metastases. Bone scans (n=20) preceding radium-223-dichloride treatment for prostate cancer were assessed retrospectively using automated BSI software (EXINI) and by assessing maximum counts per lesion. Results were then compared to total alkaline phosphatase (ALP) as a measure of biochemical response to therapy using linear regressions and to their EOBD scores using box plot analysis. Moderate correlation was found between ALP response and maximum lesion intensity (R=0.41) and BSI (R=0.46). Strong correlation (R=0.71) was found between baseline ALP and BSI and between lesion number and BSI (R=0.60). Visual assessment of EOBD score was found to correlate well with baseline ALP and maximum ALP response. BSI is a useful asset in stratification of patients with metastatic bone disease. It may also have a place in prediction of biochemical response.

Identifying predictors of pathologic complete response to neoadjuvant chemotherapy for muscle invasive bladder cancer.

e16015 Background: Pathologic complete response (pCR) to neoadjuvant chemotherapy is associated with improved outcome in patients (pts) with muscle invasive and/or lymph node positive (LN+) bladder cancer. Although molecular predictors are currently being evaluated, limited information is available regarding purely clinical parameters offering predictive information regarding pCR to neoadjuvant chemotherapy. Methods: We identified 189 unique pts within Kaiser Permanente Northern California diagnosed with bladder cancer during 1/1/10 through 12/31/17 who underwent chemotherapy with neoadjuvant intent with a plan for subsequent radical cystectomy. All pts had disease that was ≥cT2 and/or ≥cN1 and M0. Fourteen variables were examined for their association with pCR at radical cystectomy, using bivariate analysis and multivariate models. Results: Of the 189 pts in our cohort, 141 (74.6%) were male, 162 (85.7%) were white and the mean age was 66.4 years. 76 (40.2%) pts achieved pCR; of these, 59 (77.6%) had pre-treatment hemoglobin (hg) ≥ 13 g/dL (p = 0.0087), 69 (90.8%) did not have hydronephrosis (p &lt; 0.0001), 66 (86.8%) had no lymphovascular invasion (LVI) on transurethral resection of bladder tumor (TURBT) (p = 0.0506) and 69 (90.8%) had cT2 disease at time of diagnosis (p &lt; 0.0001). Logistic regression analysis showed that pCR was associated with hg ≥ 13 (OR 2.736, 95% CI 1.188-6.657), absence of hydronephrosis (OR 4.672, 95% CI 1.820-13.554), age ≤ 75 years (OR 3.410, 95% CI 1.263-10.057), absence of LVI on TURBT (OR 2.592, 95% CI 1.055-6.829), and clinical stage T2 vs. ≥T3 and/or N+ (OR 6.480, 95% CI 2.645-17.858). There was no statistically significant relationship between pCR and the following variables: cumulative cisplatin dose, split dose chemotherapy, chemotherapy regimen, history of tobacco use, race, gender, Charlson comorbidity score, baseline alkaline phosphatase, and percentage body weight loss during therapy. Conclusions: Pathologic CR was predicted by Hg &lt; 13 g/dL, absence of hydronephrosis, age ≤ 75 yrs, absence of LVI on TURBT specimen, and stage at diagnosis. These factors may influence selection of pts with muscle invasive and/or LN+ bladder cancer for neoadjuvant chemotherapy.

Clinical Outcomes of 177Lu-PSMA Radioligand Therapy in Earlier and Later Phases of Metastatic Castration-Resistant Prostate Cancer Grouped by Previous Taxane Chemotherapy.

177Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy using PSMA-617 and PSMA-I&T ligands (177Lu-PRLT) is an emerging treatment in metastatic castration-resistant prostate cancer (mCRPC). This retrospective study evaluates clinical outcomes of 177Lu-PRLT in earlier and later phases of mCRPC grouped by previous taxane chemotherapy. Methods: A retrospective analysis was performed on 167 patients with mCRPC who underwent 177Lu-PRLT between March 2013 and December 2016. Patients were classified as either taxane chemotherapy pretreated (T-pretreated) or naïve (T-naïve) depending on whether they had received taxane-based chemotherapy prior to 177Lu-PRLT. Clinical outcome for T-pretreated and T-naïve patients was assessed by overall survival (OS), radiographic progression-free survival, and prostate-specific antigen (PSA) response rate. Univariate and multivariable analyses were performed for both T-pretreated and T-naïve patients to determine predictors of outcome. Toxicity was categorized by the Common Terminology Criteria for Adverse Events (version 4.03). Results: Of the 167 patients treated with 177Lu-PRLT, 83 were T-pretreated and 84 were T-naïve. At baseline, T-pretreated patients had overall poorer performance status, a higher prevalence of bone metastases, higher PSA levels, lower hemoglobin levels, higher alkaline phosphatase (ALP) levels and had received more additional therapies compared with T-naïve patients. Median OS was 10.7 mo for T-pretreated patients and 27.1 mo for T-naïve patients. Median radiographic progression-free survival was 6.0 mo for T-pretreated patients and 8.8 mo for T-naïve patients. PSA response assessment was evaluable in 132 patients and seen in 25 of 62 (40%) T-pretreated patients and 40 of 70 (57%) T-naïve patients. Significant determinates of inferior OS in multivariable analysis for T-pretreated patients were poorer performance status, lower cumulative administered activity, and lower baseline hemoglobin. Higher baseline alkaline phosphatase was the only significant determinate of inferior OS in multivariable analysis for T-naïve patients. Overall 177Lu-PRLT was safe, with minimal adverse effects evident during follow-up in both T-pretreated and T-naïve patients. Conclusion: 177Lu-PRLT is a promising therapy in mCRPC, with encouraging outcomes and minimal associated toxicity seen in both our T-naïve and heavily pretreated patient cohorts.

Radium-223 in patients with metastatic castration-resistant prostate cancer: Efficacy and safety in clinical practice.

Radium-223 has improved overall survival (OS) and reduced symptomatic skeletal events (SSE) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases (ALSYMPCA trial). Our aim was to assess clinical and biochemical factors related to survival, safety and survival outcomes of Radium-223 in a clinical practice setting. We retrospectively analysed 32 mCRPC patients treated with Radium-223, assessing bone scan, pain reduction, alkaline phosphatase (ALP) and prostate-specific antigen (PSA) response (≥30% reduction). At scintigraphic assessment, 41% had partial response with a disease control rate of 91%; 56% had ALP response and 25% had PSA response; 41% had pain reduction with pain control of 72%. Scintigraphic response and stability were correlated with longer median progression-free survival (mPFS) (13 and 12 vs. 6 months; P=0.002) and mOS (16 and 12 vs. 6 months; P=0.003). ALP response was associated with longer mPFS (13 vs. 12 months; P=0.2) and mOS (16 vs. 12 months; P=0.2). PSA response was associated with longer mPFS (13 vs. 12 months; P=0.02), whereas mOS could not be computed. Pain response and stability were associated with survival benefit according to mPFS (13 and 12 vs. 9 months) and mOS (both 16 vs. 12 months) without statistical significance. Baseline ALP <220 UI/l, Eastern Cooperative Oncology Group (ECOG) performance status 0 and absence of previous chemotherapy correlated with statistically significantly longer survival outcomes. Skeletal-related events (SRE) occurred in three patients and median time to first SRE was 9.5 months, mPFS was 12 months and mOS 14 months. G3-G4 toxicities developed in 16% of patients. Our results are in line with those reported in the pivotal trial and in other retrospective studies. In conclusion, Radium-223 was associated with high scintigraphic, biochemical and pain response rates and was tolerated well by most patients. Response to Radium-223 and better baseline factors correlated to longer survival in clinical practice experience as in the clinical trial setting.

Patient Selection for Radium-223 Therapy in Patients With Bone Metastatic Castration-Resistant Prostate Cancer: New Recommendations and Future Perspectives.

Radium-223 therapy was registered in 2013 as a new life-prolonging therapeutic option for patients with symptomatic bone metastatic castration-resistant prostate cancer after the phase 3 ALSYMPCA study. Postregistration reports on the use of radium-223 in real-world populations demonstrate that appropriate selection of patients for radium-223 therapy is challenging. While primarily retrospective and post hoc studies identified prognostic variables associated with overall survival, validated predictive biomarkers are still lacking. Important pretherapeutic prognostic variables include the number of prior therapies, baseline Eastern Cooperative Oncology Group performance status, baseline extent of bone metastatic disease, and baseline alkaline phosphatase, prostate-specific antigen, and lactate dehydrogenase levels. We reviewed the currently available literature to provide recommendations on patient selection for radium-223 therapy in patients with bone metastatic castration-resistant prostate cancer. In addition, the recent evidence from the report of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee regarding the restricted use of radium-223 after interim data analysis of the ERA-223 trial has been incorporated into our recommendations. Future perspectives are also discussed, including radium-223 re-treatment, the use of concomitant therapies, and the implementation of pretherapeutic molecular analysis for treatment stratification.

Risk Factors for Eye Disorders Caused by Paclitaxel: A Retrospective Study.

Paclitaxel and nanoparticle albumin-bound paclitaxel are known to cause adverse events of eye disorders, such as cystoid macular edema. However, at present, the risk factors remain unclear. Therefore, risk factors for eye disorders caused by paclitaxel and nanoparticle albumin-bound paclitaxel were studied. This retrospective study targeted patients who were newly administered paclitaxel or nanoparticle albumin-bound paclitaxel at Kyoto Okamoto Memorial Hospital between April 1, 2012, and March 31, 2017. Eye disorder occurrence was defined as an event in which the pharmacist confirmed the symptoms in a patient interview and the ophthalmologist diagnosed the disorder. To analyze the risk factors, logistic regression analysis using 41 factors was performed. Of 128 subjects, 13 (10.2%) had eye disorders with symptom degrees of Grades 1 and 2. The symptoms were conjunctivitis or subconjunctival hemorrhage (3.1%), visual acuity reduction (2.3%), blurred vision and eye pain (1.6% each), eye mucus, blepharitis, stye, watering eyes, photopsia, and muscae volitantes (0.8% each). In eight patients, the conditions patients improved with spontaneously or with medication use; no improvements were observed the cases of visual acuity reduction, blurred vision, or muscae volitantes. Multivariate logistic regression analysis revealed that a cumulative dose of ≥819 mg/m2 (odds ratio: 5.34, 95% confidence interval: 1.32-21.60, p=0.019) and baseline alkaline phosphatase ≥256 U/L (odds ratio: 3.74, 95% confidence interval: 1.02-13.70, p=0.046) were significant risk factors associated with eye disorders. In conclusion, it was determined that paclitaxel- and nanoparticle albumin-bound paclitaxel-related eye disorders might be influenced by cumulative dose and baseline alkaline phosphatase.

Results From a Large, Multicenter, Retrospective Analysis On Radium223 Use in Metastatic Castration-resistant Prostate Cancer (mCRPC) in the Triveneto Italian Region.

Radium 223 was introduced for metastatic castration-resistant prostate cancer based on the results of a randomized controlled trial showing risk reduction for death and skeletal events. Our aim was to evaluate the outcome of patients receiving radium 223 in a real-world setting. We conducted a multicenter retrospective analysis in the Triveneto region of Italy. One hundred fifty-eight patients received radium 223 in our region. After a median follow-up of 9.5 months, 75 patients died. The median overall survival (OS) was 14.2 months, and the median progression-free survival (PFS) was 6.2 months. Seventy-one (45%) patients achieved progression as best response. Thirty-seven (23%) patients stopped the treatment early because of progression. Eastern Cooperative Oncology Group performance status was prognostic for OS (18.4 vs. 12.3 vs. 7.5 months; 0 vs. 1, P= .0062; 0 vs. 2, P= .0002), whereas previous prostatectomy or docetaxel exposure were not. A neutrophil to lymphocytes ratio≥ 3 significantly impacted OS (18.1 vs. 9.7 months; P< .001) and slightly impacted PFS (6.6 vs. 5.6 months; P= .05). Patients with a baseline alkaline phosphatase (ALP) value≥ 220 U/L had worse OS and PFS (24.1 vs. 10.5 months; 7.2 vs. 5.5 months; P< .001). Patients with changes in ALP value achieved better OS (P= .029) and PFS (P= .002). There was no difference according to the line of therapy (0 vs.≥ 1; P= .490). The main grade 3/4 toxicities were anemia, asthenia, and thrombocytopenia. This large real-world report confirms comparable OS and PFS data when compared with the pivotal study, as well as the predictive role of ALP and neutrophil to lymphocytes ratio. The definition of the optimal position of radium 223 in the treatment of metastatic castration-resistant prostate cancer has still to be defined.

Biochemical and Haematological Predictors of Reduced Neutrophil Granulocyte Count associated with Intravenous Ceftriaxone Treatment.

Background: Intravenous treatment with ceftriaxone, a commonly used third-generation cephalosporin, is associated with a risk of the potentially fatal side-effect of neutropenia.Objective: The first systematic study to determine whether six to 12 days’ intravenous ceftriaxone treat-ment is associated with a reduction in the neutrophil count and the extent to which biochemical and/or haematological parameters routinely measured at baseline predict such a fall.Method: Baseline and follow-up haematological and biochemical blood indices were measured in 86 pa-tients (mean age 39.4 years; 55 female) receiving 2 g intravenous ceftriaxone daily.Results: At follow-up, the mean (standard error) neutrophil count had fallen from 3.93 × 109 (0.16 × 109) L-1 to 3.15 × 109 (0.15 × 109) L-1 (p < 0.000001). This reduction was predictable according to the following multifactor linear regression model: (baseline neutrophil count (× 109 L-1)) – (follow-up neu-trophil count (× 109 L-1)) = 76 + 159.2(baseline haematocrit) – 14.5(baseline red blood cell count (× 1012 L-1)) – 0.724(baseline mean corpuscular volume (fL)) + 0.474(baseline neutrophil count (× 109 L-1)) + 0.0448(baseline total iron binding capacity (μM)) + 7.15(baseline calcium ion concentration (mM)) – 13.2(baseline corrected calcium ion concentration (mM)) + 0.0166(baseline alkaline phosphatase (IU L-1)). The residuals were normally distributed and model testing by random partition of the original data into two parts, with training of the model using the first part and model testing with the second part, gave highly satisfactory results.Conclusion: Intravenous ceftriaxone treatment is associated with a fall in neutrophils, which can be pre-dicted by routine baseline blood indices

Change in alkaline phosphatase activity associated with intensive care unit and hospital length of stay in patients with septic acute kidney injury on continuous renal replacement therapy

BackgroundEvidence suggests that alkaline phosphatase attenuates inflammatory response in sepsis by lipopolysaccharide detoxification and adenosine triphosphate dephosphorylation. We sought to determine changes in alkaline phosphatase (AP) activity during septic acute kidney injury (AKI) and clinical parameters associated with AP activity.MethodsIn this retrospective study, we investigated baseline (when initiating CRRT) and follow-up AP activity on day 3, and associated outcomes in patients who underwent continuous renal replacement therapy (CRRT) due to septic AKI.ResultsWe analyzed the baseline AP activity of 155 patients and day 3 AP activity in 123 patients. Baseline AP activity was not associated with renal or inflammatory biomarkers, or outcomes. It did not significantly differ between the 75 survivors and 80 non-survivors (p = 0.155). AP activity was higher on day 3 than at baseline (105 U/L [interquartile range, 79–156] vs 90 U/L [interquartile range, 59–133]). In particular, liver and bone isoforms increased significantly (p < 0.05), but intestine isoforms did not reach statistical significance (p = 0.367). In addition, day 3 AP activity showed a weak correlation with length of ICU stay (r = 0.213, p = 0.018) and length of hospital stay (r = 0.216, p = 0.017), but not with survival (r = − 0.035, p = 0.698).ConclusionEndogenous AP activity significantly increased in patients with septic AKI. However, neither baseline nor follow-up AP activity was associated with survival.

Prognostic value of serum alkaline phosphatase in the survival of prostate cancer: evidence from a meta-analysis.

BackgroundMany studies have evaluated the relationship between alkaline phosphatase (ALP) and the prognosis for prostate cancer (PCa). But they have not reached a widespread consensus yet. Therefore, we completed a meta-analysis to ascertain the significance of ALP and the prognosis for PCa.MethodsA literature search was performed in the PubMed, Embase, and Web of Science databases. HRs concerning overall survival (OS), progression-free survival (PFS), and cancer-specific survival (CSS) were extracted to evaluate the impacts of ALP on the prognosis for PCa. Subgroup analyses were conducted on different study types, regions, sample sizes, and cutoff values. Sensitivity analysis was performed by removing one study in sequence.ResultsA total of 63 studies from 54 articles with 16,135 patients were included in this meta-analysis. The pooled results indicated that high baseline ALP was associated with obviously poor OS (HR=1.74, 95% CI: 1.47–2.06) and PFS (HR=1.60, 95% CI: 1.13–2.26) in patients with PCa. The pooled HR for bone-specific ALP and OS was 1.76 (95% CI: 1.45–2.15). However, no association between ALP and CSS (HR=1.002, 95% CI: 0.998–1.005) was found for PCa. The results of subgroup analyses were all in accordance with the main findings. Sensitivity analysis suggested that no single study could affect the stability of the results.ConclusionHigh serum ALP is significantly associated with poor OS and PFS except for CSS in PCa. ALP is an efficient and convenient biomarker for PCa prognosis.