Bone turnover biomarkers identify unique prognostic risk groups in men with castration resistant prostate cancer and skeletal metastases: Results from SWOG S0421.

BACKGROUND: Skeletal metastases often occur in men with castration-resistant prostate cancer (CRPC) where bone biomarkers are prognostic for overall survival (OS). In those with highly elevated markers, there is preferential benefit from bone-targeted therapy. In the phase IIIS0421 docetaxel +/- atrasentan trial, clinical covariates and bone biomarkers were analyzed to identify CRPC subsets with differential outcomes. SUBJECTS AND METHODS: Markers of bone resorption [N-telopeptide-NTx; pyridinoline-PYD] and formation [C-terminal collagen propeptide-CICP; bone alkaline phosphatase-BAP] were measured in pre-treatment sera. Bone biomarkers and clinical covariates were included in a Cox model for OS; bone markers were added in a stepwise selection process. Receiver operating characteristic (ROC) curves were constructed for risk factor models +/- bone markers. Significant variables were allowed to compete in a classification and regression tree (CART) analysis. Hazard ratios(HR) were calculated by comparing OS in each of the terminal nodes to a reference group in a Cox model. RESULTS: 750 patients were included. Each bone marker significantly contributed to the risk factor-adjusted OS Cox model, with higher levels associated with worse OS. BAP (HR = 1.15, p = 0.008), CICP (HR = 1.27, p < 0.001), and PYD (HR = 1.21, p = 0.047) in combination were significantly associated with OS. Prognostic accuracy was improved by addition of bone markers to clinical covariates. CART analysis selected CICP, BAP, hemoglobin, and pain score for the final OS model, identifying five prognostic groups. CONCLUSIONS: Elevated serum bone biomarker levels are associated with worse OS in bone-metastatic CRPC. Bone biomarkers can identify unique prognostic subgroups. These results further define the role of bone biomarkers in the design of CRPC trials.

Borealis-1: a randomized, first-line, placebo-controlled, phase II study evaluating apatorsen and chemotherapy for patients with advanced urothelial cancer.

BACKGROUND: Five-year survival of patients with inoperable, advanced urothelial carcinoma treated with the first-line chemotherapy is 5%-15%. We assessed whether the Hsp27 inhibitor apatorsen combined with gemcitabine plus cisplatin (GC) could improve overall survival (OS) in these patients. PATIENTS AND METHODS: This placebo-controlled, double-blind, phase II trial randomized 183 untreated urothelial carcinoma patients (North America and Europe) to receive GC plus either placebo (N = 62), 600 mg apatorsen (N = 60), or 1000 mg apatorsen (N = 61). In the experimental arm, treatment included loading doses of apatorsen followed by up to six cycles of apatorsen plus GC. Patients receiving at least four cycles could continue apatorsen monotherapy as maintenance until progression or unacceptable toxicity. The primary end point was OS. RESULTS: OS was not significantly improved in the single or combined 600- or 1000-mg apatorsen arms versus placebo [hazard ratio (HR), 0.86 and 0.90, respectively]. Exploratory study of specific statistical modeling showed a trend for improved survival in patients with baseline poor prognostic features treated with 600 mg apatorsen compared with placebo (HR = 0.72). Landmark analysis of serum Hsp27 (sHsp27) levels showed a trend toward survival benefit for poor-prognosis patients in 600- and 1000-mg apatorsen arms who achieved lower area under the curve sHsp27 levels, compared with the placebo arm (HR = 0.45 and 0.62, respectively). Higher baseline circulating tumor cells (≥5 cells/7.5 ml) was observed in patients with poor prognosis in correlation with poor survival. Treatment-emergent adverse events were manageable and more common in both apatorsen-treatment arms. CONCLUSIONS: Even though apatorsen combined with standard chemotherapy did not demonstrate a survival benefit in the overall study population, patients with poor prognostic features might benefit from this combination. Serum Hsp27 levels may act as a biomarker to predict treatment outcome. Further exploration of apatorsen in poor-risk patients is warranted.

Evaluation of the relationship between baseline autonomic tone and the vagotonic effect of a bolus dose of remifentanil.

Remifentanil stimulates the parasympathetic nervous system, and patients with increased parasympathetic tone may be at greater risk of bradycardia after its administration. We aimed to establish if adult patients with increased baseline parasympathetic tone were at higher risk of bradycardia and hypotension when given a bolus dose of remifentanil. Seventy adults (age 20-60 years and ASA physical status 1 or 2) were given remifentanil 1 µg.kg(-1) . A Holter ECG monitor was used to assess heart rate changes. Heart rate variability in the frequency domain during the 5 min after remifentanil administration was analysed. Multivariate analysis demonstrated that baseline heart rate was the only independent predictor of remifentanil-induced bradycardia [odds ratio (95% CI) 0.877 (0.796-0.966)]. The vagotonic action of remifentanil does not appear to be related to baseline autonomic tone in adult patients.

Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel.

BACKGROUND: Enzalutamide and abiraterone are new androgen-axis disrupting treatments for metastatic castration-resistant prostate cancer (mCRPC). We examined the response and outcomes of enzalutamide-treated mCRPC patients in the real-world context of prior treatments of abiraterone and/or docetaxel. METHODS: We conducted a seven-institution retrospective study of mCRPC patients treated with enzalutamide between January 2009 and February 2014. We compared the baseline characteristics, PSA declines, PSA progression-free survival (PSA-PFS), duration on enzalutamide and overall survival (OS) across subgroups defined by prior abiraterone and/or docetaxel. RESULTS: Of 310 patients who received enzalutamide, 36 (12%) received neither prior abiraterone nor prior docetaxel, 79 (25%) received prior abiraterone, 30 (10%) received prior docetaxel and 165 (53%) received both prior abiraterone and prior docetaxel. Within these groups, respectively, ⩾30% PSA decline was achieved among 67, 28, 43 and 24% of patients; PSA-PFS was 5.5 (95% CI 4.2-9.1), 4.0 (3.2-4.8), 4.1 (2.9-5.4) and 2.8 (2.5-3.2) months; median duration of enzalutamide was 9.1 (7.3-not reached), 4.7 (3.7-7.7), 5.4 (3.8-8.4) and 3.9 (3.0-4.6) months. Median OS was reached only for the patients who received both prior abiraterone and docetaxel and was 12.2 months (95% CI 10.7-16.5). 12-month OS was 78% (59-100%), 64% (45-90%), 77% (61-97%) and 51% (41-62%). Of 70 patients who failed to achieve any PSA decline on prior abiraterone, 19 (27%) achieved ⩾30% PSA decline with subsequent enzalutamide. CONCLUSIONS: The activity of enzalutamide is blunted after abiraterone, after docetaxel, and still more after both, suggesting subsets of overlapping and distinct mechanisms of resistance.

Ondansetron attenuates the decrease in blood pressure due to spinal anesthesia in the elderly: a double blind, placebo-controlled study.

BACKGROUND: Ondansetron was effectively used to prevent spinal anesthesia-induced hypotension in the general population and women anesthetised for cesarean section. The aim of this study was to test the hypothesis that blocking type 3 serotonin receptors with intravenous ondansetron administration reduces hypotension and bradycardia induced by spinal anesthesia in elderly patients. METHODS: Fifty-three patients participated in the study with 26 in the ondansetron group (received 8 mg intravenous ondansetron) and 27 in the placebo group (received 0.9% NaCl solution). The heart rate and arterial blood pressure were measured every 5 minutes after spinal anaesthesia, which was performed with 2.5 to 3 mL of 0.5% hyperbaric bupivacaine solution. RESULTS: Decreases in both the heart rate and mean systolic, as well as diastolic, arterial pressure compared to the baseline values were noted in both groups. The minimum diastolic and mean blood pressure values obtained over a 20-minute observation period were significantly higher in the ondansetron group. There were no significant differences in the systolic blood pressure and heart rate values between the groups. CONCLUSION: Administration of intravenous ondansetron prior to spinal anesthesia in geriatric patients attenuates the drop in the diastolic and mean arterial pressure without substantially affecting the systolic blood pressure.

Long-term survival after high-dose chemotherapy followed by peripheral stem cell rescue for high-risk, locally advanced/inflammatory, and metastatic breast cancer.

Patients with high-risk locally advanced/inflammatory and oligometastatic (≤3 sites) breast cancer frequently relapse or experience early progression. High-dose chemotherapy combined with peripheral stem cell rescue may prolong progression-free survival/relapse-free survival (PFS/RFS) and overall survival (OS). In this study, patients initiated high-dose chemotherapy with STAMP-V (carboplatin, thiotepa, and cyclophosphamide), ACT (doxorubicin, paclitaxel, and cyclophosphamide), or tandem melphalan and STAMP-V. Eighty-six patients were diagnosed with locally advanced/inflammatory (17 inflammatory) breast cancer, and 12 were diagnosed with oligometastatic breast cancer. Median follow-up was 84 months (range, 6-136 months) for patients with locally advanced cancer and 40 months (range, 24-62 months) for those with metastatic cancer. In the patients with locally advanced cancer, 5-year RFS and OS were 53% (95% CI, 41%-63%) and 71% (95% CI, 60%-80%), respectively, hormone receptors were positive in 74%, and HER2 overexpression was seen in 23%. In multivariate analysis, hormone receptor-positive disease and lower stage were associated with better 5-year RFS (60% for ER [estrogen receptor]/PR [progesterone receptor]-positive versus 30% for ER/PR-negative; P < .01) and OS (83% for ER/PR-positive versus 38% for ER/PR-negative; P < .001). In the patients with metastatic cancer, 3-year PFS and OS were 49% (95% CI, 19%-73%) and 73% (95% CI, 38%-91%), respectively. The favorable long-term RFS/PFS and OS for high-dose chemotherapy with peripheral stem cell rescue in this selected patient population reflect the relative safety of the procedure and warrant validation in defined subgroups through prospective, randomized, multi-institutional trials.

A phase I study of bortezomib and temozolomide in patients with advanced solid tumors.

PURPOSE: The primary objective was to determine the maximum tolerated doses (MTDs) of the combination of bortezomib and temozolomide in patients with solid tumors. The secondary objective was to evaluate the pharmacokinetics (PK) of bortezomib with and without concurrent hepatic enzyme-inducing anticonvulsants (HEIAs). METHODS: Bortezomib was administered on days 2, 5, 9, and 12; temozolomide on days 1-5 of a 28-day cycle. Dose escalation proceeded using a standard 3+3 design. Patients with primary or metastatic brain tumors were eligible and were stratified based on whether they were taking HEIAs or not. RESULTS: Of the 25 patients enrolled, 22 were not taking HEIAs. MTDs were only given to patients not receiving HEIAs. Dose-limiting toxicities (DLTs) consisted of grade-3 constipation, hyponatremia, fatigue, elevated hepatic enzymes, and grade-4 neutropenia, thrombocytopenia, constipation, and abdominal pain. Stable disease (>8 weeks) was observed in 5 patients. Bortezomib systemic clearance (CL(sys)) on day 9 was 51% of the CL(sys) on day 2 (P < 0.01) Similarly, the normalized area under the concentration-time curve (norm AUC) on day 9 was 1.9 times the norm AUC on day 2 (P < 0.01). The median bortezomib CL(sys) on days 2 and 9 was significantly higher (P < 0.04) in patients taking HEIAs, and the median norm AUC was correspondingly lower (P < 0.04). CONCLUSIONS: The MTDs for the combination of bortezomib and temozolomide in patients not taking HEIAs are 1.3 and 200 mg/m(2), respectively. The rate of bortezomib elimination in patients taking HEIAs was increased twofold. Additional trials are needed to better define the optimal dosing in such patients.

Influence of promethazine on cardiac repolarisation: a double-blind, midazolam-controlled study.

Drugs used in anaesthesia may provoke torsadogenic changes in cardiac repolarisation. The aim of this study was to assess the effect of promethazine on the parameters of ventricular repolarisation: QTc interval and transmural dispersion of repolarisation. Forty patients were randomly allocated to receive promethazine (25 mg) or midazolam (2.5 mg). Changes in the ECG and arterial blood pressure were recorded. Correction of QT interval was calculated using Bazett's formula and Fridericia's correction; transmural dispersion of repolarisation was determined as T(peak)-T(end) time. Significant prolongation of QT interval, corrected with both formulae, was detected in patients receiving promethazine, while no change in the QTc value was observed in the midazolam group. There were no significant differences in T(peak)-T(end) time either between or within the groups. In conclusion, promethazine induces significant QTc prolongation but the lack of influence on transmural dispersion of repolarisation makes the risk of its torsadogenic action very low.

Control of the myopic shift in modified Badal optometer.

Refractive error measurements made with the Badal optometer typically register more myopia than is actually present. In this paper we measured the influence of the image size on the endpoint of a Badal optometer's refractive error measurement. The optometer was modified with a camera's zoom lens in such a way that the retinal image size could be controlled. It was found that retinal image size is a major factor in controlling the subjective endpoint. When retinal image size is diminished rather than increased as the target approaches the subject, as is the case under normal circumstances, the perceived endpoint more closely agrees with the actual refractive error.

Clinical trials of antiangiogenic agents.

Acquisition of new blood vessels is a required step in malignant transformation, tumor growth, and metastasis. Inhibition of angiogenesis is one of the most promising new strategies for the treatment of malignant neoplasms. In recent years, several antiangiogenic compounds, including TNP-470, matrix metalloproteinase inhibitors, carboxyamidotriazole, and tecogalan sodium, have entered clinical trials. In this we review, we look at the results of early clinical trials of these agents and discuss the new angiogenesis inhibitors in preclinical development.

The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin.

Angiostatin, a potent naturally occurring inhibitor of angiogenesis and growth of tumor metastases, is generated by cancer-mediated proteolysis of plasminogen. Human prostate carcinoma cells (PC-3) release enzymatic activity that converts plasminogen to angiostatin. We have now identified two components released by PC-3 cells, urokinase (uPA) and free sulfhydryl donors (FSDs), that are sufficient for angiostatin generation. Furthermore, in a defined cell-free system, plasminogen activators [uPA, tissue-type plasminogen activator (tPA), or streptokinase], in combination with one of a series of FSDs (N-acetyl-L-cysteine, D-penicillamine, captopril, L-cysteine, or reduced glutathione] generate angiostatin from plasminogen. An essential role of plasmin catalytic activity for angiostatin generation was identified by using recombinant mutant plasminogens as substrates. The wild-type recombinant plasminogen was converted to angiostatin in the setting of uPA/FSD; however, a plasminogen activation site mutant and a catalytically inactive mutant failed to generate angiostatin. Cell-free derived angiostatin inhibited angiogenesis in vitro and in vivo and suppressed the growth of Lewis lung carcinoma metastases. These findings define a direct mechanism for cancer-cell-mediated angiostatin generation and permit large-scale production of bioactive angiostatin for investigation and potential therapeutic application.

Human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor, angiostatin.

Angiostatin is an inhibitor of angiogenesis and metastatic growth that is found in tumor-bearing animals and can be generated in vitro by the proteolytic cleavage of plasminogen. The mechanism by which angiostatin is produced in vivo has not been defined. We now demonstrate that human prostate carcinoma cell lines (PC-3, DU-145, and LN-CaP) express enzymatic activity that can generate bioactive angiostatin from purified human plasminogen or plasmin. Affinity purified PC-3-derived angiostatin inhibited human endothelial cell proliferation, basic fibroblast growth factor-induced migration, endothelial cell tube formation, and basic fibroblast growth factor-induced corneal angiogenesis. Studies with proteinase inhibitors demonstrated that a serine proteinase is necessary for angiostatin generation. These data indicate that bioactive angiostatin can be generated directly by human prostate cancer cells and that serine proteinase activity is necessary for angiostatin generation.

Fatal pulmonary embolism in spinal cord injury.

Fatal pulmonary embolism (PE) is a major cause of mortality in patients with spinal cord injury. In order to ascertain those characteristics that might predict this event, we reviewed the records of all patients with autopsy-proven massive PE admitted to a regional spinal cord care center over a 5-year period. The information analyzed included patient age, sex, race, height, weight, type of accident, prior use of tobacco, alcohol, or narcotic drugs, level of injury, presence of spasticity, surgical procedures, infections, transfusions, and type of anticoagulant prophylaxis. Forty-two concurrently hospitalized patients with spinal cord injury served as control subjects. Significant differences between cases and control subjects were observed for level of injury (fewer thoracic and lumbar injuries in cases, p = 0.04), less spasticity in cases (p = 0.01), and greater body mass index in cases (p = 0.01). There was also a trend toward more advanced age in the cases (p = 0.1) and more frequent serious infections (p = 0.08). Lastly, low molecular weight heparin had been used as thromboprophylaxis in a greater proportion of control subjects than cases (60 percent vs 22 percent, p = 0.07), suggesting that low molecular weight heparin may be more effective in preventing fatal PE than unfractionated heparin.