Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era.

Acute promyelocytic leukemia (APL) is commonly complicated by a complex coagulopathy. Uncertainty remains as to which markers of bleeding risk are independent predictors. Drawing from 5 large clinical trials that included all-trans retinoic acid (ATRA) as part of induction, we assessed known determinants of bleeding at baseline and evaluated them as potential predictors of hemorrhagic death (HD) in the first 30 days of treatment. The studies included were ALLG APML3 (single arm of ATRA + idarubicin ± prednisone), ALLG APML4 (single arm of ATRA + idarubicin + arsenic trioxide + prednisone), CALGB C9710 (single arm of ATRA + cytarabine + daunorubicin), Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E2491 (intergroup I0129, consisting of daunorubicin + cytarabine vs ATRA), and SWOG S0521 (single-arm induction of ATRA + cytarabine + daunorubicin). A total of 1009 patients were included in the original trials, of which 995 had sufficient data to be included in our multivariate analysis. In this final cohort, there were 37 HD cases during the first 30 days following induction, for an estimated cumulative incidence of 3.7% (95% confidence interval [CI], 2.6% to 5.0%). Using multivariate Cox proportional hazards regression, the hazard ratio of HD in the first 30 days was 2.17 (95% CI, 0.84-5.62) for an ECOG performance status of 3-4 vs 0-2 and 5.20 (95% CI, 2.70-10.02) for a white blood cell count of ≥20 000/µL vs <20 000/µL. In this large cohort of APL patients, high white blood cell count emerged as an independent predictor of early HD.

Acute myeloid leukaemia relapsing after allogeneic haemopoietic stem cell transplantation: prognostic factors and impact of initial therapy of relapse.

BACKGROUND/AIMS: We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft-versus-host disease (GVHD) on OSR. METHODS: Data on 386 patients from nine Australian centres with relapsed AML post-alloHSCT were collected retrospectively. OSR was calculated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the log-rank test and proportional hazards modelling, respectively and a prognostic index for OSR was derived from multivariate modelling. RESULTS: On multivariate analysis, relapse within 6 months (hazard ratio (HR) 2.4, P < 0.001) and grade 3-4 acute GVHD preceding relapse (HR 2.0, P = 0.004), were associated with inferior OSR. Patients with 1-2 factors had inferior OSR compared to those with zero factors (all patients: HR 2.3, P < 0.001, patients given salvage: HR 1.8, P < 0.001). The first salvage therapy used post-relapse was donor cell therapy (DCT) (second alloHSCT or donor lymphocyte infusion) in 75, re-induction chemotherapy (CT) in 103, radiotherapy in 8 and interferon-α in 6. Although re-induction CT death rate was low (2%), survival after CT was inferior to DCT (HR 1.9, P < 0.001). No survival benefit was seen for patients who developed GVHD following salvage therapy (P = 0.405). CONCLUSION: Patients with AML who relapse beyond 6 months from alloHSCT without prior grade 3-4 acute GVHD have a better outcome from salvage therapy. Salvage treatments employing DCT as the initial treatment of AML relapse confer a survival advantage over CT.

Differential mechanisms of CDKN2A (p16) alteration in oral tongue squamous cell carcinomas and correlation with patient outcome.

CDKN2A (p16) disruption is reported as a frequent event in head and neck squamous cell carcinomas that confers poor prognosis. We investigated the frequency of different potential mechanisms of CDKN2A inactivation in oral tongue squamous cell carcinomas (OTSCC) and their impact on patient outcome. From a cohort of 153 OTSCC patients, 131 formalin fixed paraffin embedded blocks of pre-treatment primary tumours were suitable for further molecular analysis. We assessed CDKN2A (p16) levels by immunohistochemistry (IHC), promoter methylation status by methylation-sensitive high resolution melting, mutation status by Sanger sequencing, gene copy number variation by fluorescence in situ hybridisation, and correlated these with patient outcome. We found that the majority of OTSCC did not overexpress p16 (110/116, 95%), assessed by IHC. The frequency of CDKN2A mutations was 20% (21/103), homozygous loss was 7% (7/97), hemizygous loss 31% (30/97), and promoter methylation was 18% (20/113). We found no evidence of these mechanisms in 24/106 (23%) p16 IHC negative tumours. No significant correlation was identified between any potential mechanism of CDKN2A inactivation and clinical features, including smoking status and age. There was a non-significant trend for worse overall survival for p16 IHC negative patients versus positive patients (HR = 1.81, 95% CI = 0.44-7.47, p = 0.40). No relationship was found between mechanisms of CDKN2A disruption and patient outcome. In conclusion, we demonstrate that CDKN2A alteration is a frequent event in OTSCC tumourigenesis. However, no correlation was identified between different potential mechanisms of CDKN2A disruption and clinical characteristics or patient outcome.

A randomized trial of prophylactic palifermin on gastrointestinal toxicity after intensive induction therapy for acute myeloid leukaemia.

Gastrointestinal toxicity, including oral mucositis, is a frequent complication of intensive combination chemotherapy for acute myeloid leukaemia (AML) and contributes substantially to treatment-related mortality. We conducted a placebo-controlled randomized trial to evaluate the efficacy of palifermin (keratinocyte growth factor), given at 60 µg/kg per daily IV for 3 d before and after chemotherapy, for mucosal protection in adult patients with previously untreated AML receiving induction therapy with idarubicin, high-dose cytarabine and etoposide. Among 155 randomized patients, there was no statistically significant difference in the rate of grade 3 and 4 oral mucositis (primary study endpoint) between the two treatment arms (three in palifermin arm (4%), 8 in placebo arm (10%; P = 0·21); however, when considering the severity of oral mucositis (World Health Organization grade 0-4), there was evidence of reduced rates of higher grades of oral mucositis in the palifermin arm (P = 0·0007, test for trend). There was a statistically significantly lower rate of grades 3 and 4 gastrointestinal adverse events in the palifermin arm (21% vs. 44% in placebo arm; P = 0·003), mainly due to a reduction in severe diarrhoea (8% palifermin, 26% placebo; P = 0·01). Palifermin has activity as a mucosal protectant in AML patients receiving intensive chemotherapy. This trial is registered at ACTRN012605000095662.

All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4).

The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.

Weight and fat distribution in patients taking valproate: a valproate-discordant gender-matched twin and sibling pair study.

OBJECTIVES: Chronic treatment with valproate (VPA) is commonly associated with weight gain, which potentially has important health implications, in particular increased central fat distribution. We utilized a VPA-discordant same-sex, twin and matched sibling pair study design to primarily examine for differences in fat distribution between patients with epilepsy treated with VPA compared to their matched twin or sibling control. Weight, blood pressure, and leptin levels were assessed. METHODS: Height, weight, waist and hip measurements, exercise, blood pressure (BP), and serum leptin levels were measured. Body composition was measured using dual-energy x-ray absorptiometry (DXA). Abdominal fat was expressed as a percentage of the abdominal region (AFat%); and of whole body fat (WBF); (AFat%WBF). Mean within-pair differences were assessed (VPA-user and nonuser). Restricted maximum likelihood (REML) linear mixed model analysis was fitted to examine associations of anthropometrics, zygosity, gender, menopausal status, VPA dose and duration, with weight and AFat%. RESULTS: We studied 19 pairs of VPA-discordant, gender-matched (five male, 14 female) twins and siblings. Mean (standard deviation, SD) duration of therapy for VPA users was 11.0 (7.4) years. There were no statistically significant within-pair differences in age, height, weight, body mass index (BMI), BP, leptin level, WBF, AFat%, or AFat%WBF. For pairs in which VPA-user was treated for >11 years there were statistically significant mean within-pair differences in AFat%, (+7.1%, p = 0.03, n = 10 pairs), mean BP (+11.0 mm Hg, p = 0.006, n = 8 pairs); but not in AFat%WBF. VPA duration was positively associated with weight (estimate +0.98 kg/per year of VPA, p = 0.03); VPA treatment duration and dose were not significantly associated with AFat%. SIGNIFICANCE: This study demonstrated a relationship between long-term VPA use and abdominal adiposity (AFat%), which could have significant health implications. We recommend ongoing monitoring of weight, BMI, and blood pressure for patients taking VPA.

The operating surgeon is an independent predictor of chest tube drainage following cardiac surgery.

OBJECTIVES: Bleeding into the chest is a major cause of blood transfusion and adverse outcomes following cardiac surgery. The authors investigated predictors of bleeding following cardiac surgery to identify potentially correctable factors. DESIGN: Data were retrieved from the medical records of patients undergoing cardiac surgery over the period of 2002 to 2008. Multivariate analysis was used to identify the independent predictors of chest tube drainage. SETTING: Tertiary hospital. PARTICIPANTS: Two thousand five hundred seventy-five patients. INTERVENTIONS: Cardiac surgery. RESULTS: The individual operating surgeon was independently associated with the extent of chest tube drainage. Other independent factors included internal mammary artery grafting, cardiopulmonary bypass time, urgency of surgery, tricuspid valve surgery, redo surgery, left ventricular impairment, male gender, lower body mass index and higher preoperative hemoglobin levels. Both a history of diabetes and administration of aprotinin were associated with reduced levels of chest tube drainage. CONCLUSIONS: The individual operating surgeon was an independent predictor of the extent of chest tube drainage. Attention to surgeon-specific factors offers the possibility of reduced bleeding, fewer transfusions, and improved patient outcomes.

The association of blood transfusion with mortality after cardiac surgery: cause or confounding? (CME).

BACKGROUND: Bleeding into the chest is a life-threatening complication of cardiac surgery. Blood transfusion has been implicated as an important cause of harm associated with bleeding, based largely on studies demonstrating an independent association between transfusion and mortality. These studies did not, however, consider the possibility that bleeding may in itself be harmful, inasmuch as drains are inefficient at clearing blood from the chest and retained blood may compromise cardiac and lung function. STUDY DESIGN AND METHODS: We undertook a multivariate logistic regression analysis of the risk factors associated with mortality in 2599 consecutive patients undergoing cardiac surgery. Unlike previous studies the risk factors examined included the volume of chest tube drainage at 24 hours. A stratified analysis was also undertaken that compared the adjusted risk of death for patients exposed or not exposed to a postoperative blood transfusion. RESULTS: Blood transfusion was not an independent predictor of mortality (p=0.4). Chest tube drainage was the strongest independent predictor of mortality (p<0.001). In the stratified analysis, chest tube drainage remained an independent predictor of mortality for patients not exposed to a blood transfusion (p<0.01). Furthermore, the risk of death of these patients was no different from patients exposed to a blood transfusion (p=0.7 for interaction). CONCLUSIONS: Our results argue that for patients undergoing cardiac surgery bleeding contributes to mortality through mechanisms unrelated to blood transfusion.

Results of the APML3 trial incorporating all-trans-retinoic acid and idarubicin in both induction and consolidation as initial therapy for patients with acute promyelocytic leukemia.

BACKGROUND: Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols. DESIGN AND METHODS: In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine. RESULTS: Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P<0.001) and disease-free survival (hazard ratio 0.290, P<0.001). CONCLUSIONS: The combination of all-trans-retinoic acid and just two cycles of idarubicin followed by triple maintenance produced durable remissions in most patients, but patients with high-risk disease, especially those with FLT3 mutations, require additional agents or alternative treatment approaches. The significant reduction in relapse seen after the addition of maintenance to the protocol supports a role for maintenance in the context of relatively low chemotherapy exposure during consolidation. (actr.org.au identifier: ACTRN12607000410459).

Pathophysiological determinants of worse stroke outcome in atrial fibrillation.

BACKGROUND: The reasons for worse outcome following ischemic stroke in patients with atrial fibrillation (AF) remain unclear. We aimed to elucidate the pathophysiological determinants of poorer stroke outcome in patients with AF using systematic MRI data from the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). METHODS: Comparisons of infarct size, hypoperfusion volume, infarct growth, arterial occlusion, recanalization, reperfusion, hemorrhagic transformation and stroke severity were made between patients with and without AF enrolled in the EPITHET study. RESULTS: AF was present in 42 of 101 patients. At baseline, AF patients were older (79 vs. 73 years, p = 0.02), had more severe neurological impairment (National Institutes of Health Stroke Scale score 16 vs. 11, p = 0.006), larger infarcts (29 vs. 15 ml, p = 0.04) and greater volumes of more severe hypoperfusion (T(max) > or =8 s, perfusion-weighted imaging volume 70 vs. 43 ml, p = 0.01) compared to patients without AF. There were no significant differences in arterial occlusion site, infarct growth, recanalization or reperfusion. At outcome, AF patients had larger infarcts (52 vs. 16 ml, p = 0.05), more severe hemorrhagic transformation (29 vs. 5%, p = 0.002 for parenchymal hematomas), greater disability (modified Rankin Scale score 4 vs. 3, p = 0.03) and higher mortality rates (31 vs. 12%, p = 0.04). AF was an independent predictor of parenchymal hematoma (OR = 6.90, 95% CI = 1.57-30.25), but not mortality (OR = 2.56, 95% CI = 0.83-7.85). CONCLUSIONS: Patients with AF have worse clinical and imaging outcomes following ischemic stroke. This study suggests that the adverse effect of AF is due to greater volumes of more severely hypoperfused tissue, leading to larger infarct size and greater risk of severe hemorrhagic transformation.

Enamel microhardness and bond strengths of self-etching primer adhesives.

The aim of this study was to determine the relationship between enamel surface microhardness and microshear bond strength (microSBS). Buccal and lingual mid-coronal enamel sections were prepared from 22 permanent human molars and divided into two groups, each comprising the buccal and lingual enamel from 11 teeth, to analyze two self-etching primer adhesives (Clearfil SE Bond and Tokuyama Bond Force). One-half of each enamel surface was tested using the Vickers hardness test with 10 indentations at 1 N and a 15-s dwell time. A hybrid resin composite was bonded to the other half of the enamel surface with the adhesive system assigned to the group. After 24 h of water storage of specimens at 37 degrees C, the microSBS test was carried out on a universal testing machine at a crosshead speed of 1 mm min(-1) until bond failure occurred. The mean microSBS was regressed on the mean Vickers hardness number (VHN) using a weighted regression analysis in order to explore the relationship between enamel hardness and microSBS. The weights used were the inverse of the variance of the microSBS means. Neither separate correlation analyses for each adhesive nor combined regression analyses showed a significant correlation between the VHN and the microSBS. These results suggest that the microSBS of the self-etch adhesive systems are not influenced by enamel surface microhardness.

Density and shape as CT predictors of intracerebral hemorrhage growth.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) growth predicts mortality and functional outcome. We hypothesized that irregular hematoma shape and density heterogeneity, reflecting active, multifocal bleeding or a variable bleeding time course, would predict ICH growth. METHODS: Three raters examined baseline sub-3-hour CT brain scans of 90 patients in the placebo arm of a Phase IIb trial of recombinant activated Factor VII in ICH. Each rater, blinded to growth data, independently applied novel 5-point categorical scales of density and shape to randomly presented baseline CT images of ICH. Density and shape were defined as either homogeneous/regular (Category 1 to 2) or heterogeneous/irregular (Category 3 to 5). Within- and between-rater reliability was determined for these scales. Growth was assessed as a continuous variable and using 3 binary definitions: (1) any ICH growth; (2) >or=33% or >or=12.5 mL ICH growth; and (3) radial growth >1 mm between baseline and 24-hour CT scan. Patients were divided into tertiles of baseline ICH volume: "small" (0 to 10 mL), "medium" (10 to 25 mL), and "large" (25 to 106 mL). RESULTS: Inter- and intrarater agreements for the novel scales exceeded 85% (+/-1 category). Median growth was significantly higher in the large-volume group compared with the small group (P<0.001) and in heterogeneous compared with homogeneous ICH (P=0.008). Median growth trended higher in irregular ICHs compared with regular ICHs (P=0.084). Small ICHs were more regularly shaped (43%) than medium (17%) and large (3%) ICHs (P<0.001). Small ICHs were more homogeneous (73%) compared with medium (37%) and large (17%) ICHs (P<0.001). Adjusting for baseline ICH volume and time to scan, density heterogeneity, but not shape irregularity, independently predicted ICH growth (P=0.046) on a continuous growth scale. CONCLUSIONS: Large ICHs were significantly more irregular in shape, heterogeneous in density, and had greater growth. Density heterogeneity independently predicted ICH growth using some definitions.

Clinical-diffusion mismatch and benefit from thrombolysis 3 to 6 hours after acute stroke.

BACKGROUND AND PURPOSE: The clinical-diffusion mismatch (CDM) model has been proposed as a simpler tool than perfusion-diffusion mismatch (PDM) to select acute ischemic stroke patients for thrombolytic therapy. We hypothesized that in the 3- to 6-hour time window, the effect of tPA was significantly greater in patients with CDM than in patients without CDM. METHODS: This is a substudy of EPITHET, a double-blind multi-center study of 100 patients randomized to tPA or placebo 3 to 6 hours after stroke onset. MRI was obtained before treatment, and at 3 to 5 days and 90 days after treatment. Presence of PDM (perfusion deficit/DWI(volume) >1.2 and perfusion deficit at least 10 mL>DWI(volume)) and CDM (NIHSS >or=8 and DWI(volume) or=8 points between baseline and 90 days, or a 90-day NIHSS

Medication use across transition points from the emergency department: identifying factors associated with medication discrepancies.

BACKGROUND: As patients move across transition points of care, medication discrepancies are likely to occur. In the emergency department (ED), patients are vulnerable to medication discrepancies because they are in an environment in which rapid decisions need to be made under high levels of stress. OBJECTIVE: To identify the patient-, environment-, and medication-related factors involving unexplained medication discrepancies across transition points after ED presentation. METHODS: Using a retrospective chart review design, a stratified, random sampling of data was undertaken over a 12-month period. Information was obtained from an electronic administrative database and medical records as patients moved from the ED to another transition point of care. Medication discrepancies were classified into 2 outcome groups: (1) no discrepancies and situations in which discrepancies were adequately explained and (2) discrepancies that had no adequate explanation. RESULTS: For the 12-month period, 210 randomly selected patients were included; 73 (34.8%) had at least one unexplained medication discrepancy. Binary logistic regression modeling showed 4 factors that were statistically significant in determining the incidence of at least one unexplained medication discrepancy. Benefit card holders (individuals who receive benefits from government insurance programs comparable to the US-based Medicare and Medicaid initiatives, which include the elderly, the disabled, low income earners, and unemployed persons) had 3.73 greater odds of experiencing an unexplained medication discrepancy (95% CI 1.72 to 8.07; p = 0.001). Patients prescribed 5 or more drugs at discharge from the ED had 12.22 greater odds of having at least one unexplained medication discrepancy (95% CI 5.52 to 27.08; p < 0.001). Patients who were first seen by a physician within 1 hour of a change in working shift had 3.70 greater odds of having an unexplained medication discrepancy (95% CI 1.67 to 8.18; p = 0.001). For each additional minute of wait time for a physician, the odds of having an unexplained medication discrepancy increased by a factor of 1.01 (95% CI 1.00 to 1.01; p = 0.042). CONCLUSIONS: Patient-, environment-, and drug-related factors contribute to the risk of medication discrepancies across transition points from the ED.

Postoperative Concurrent Chemoradiotherapy Versus Postoperative Radiotherapy in High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck: The Randomized Phase III TROG 05.01 Trial.

Purpose To report the results of the Trans Tasman Radiation Oncology Group randomized phase III trial designed to determine whether the addition of concurrent chemotherapy to postoperative radiotherapy (CRT) improved locoregional control in patients with high-risk cutaneous squamous cell carcinoma of the head and neck. Patients and Methods The primary objective was to determine whether there was a difference in freedom from locoregional relapse (FFLRR) between 60 or 66 Gy (6 to 6.5 weeks) with or without weekly carboplatin (area under the curve 2) after resection of gross disease. Secondary efficacy objectives were to compare disease-free survival and overall survival. Results Three hundred twenty-one patients were randomly assigned, with 310 patients commencing allocated treatment (radiotherapy [RT] alone, n = 157; CRT, n = 153). Two hundred thirty-eight patients (77%) had high-risk nodal disease, 59 (19%) had high-risk primary or in-transit disease, and 13 (4%) had both. Median follow-up was 60 months. Median RT dose was 60 Gy, with 84% of patients randomly assigned to CRT completing six cycles of carboplatin. The 2- and 5-year FFLRR rates were 88% (95% CI, 83% to 93%) and 83% (95% CI, 77% to 90%), respectively, for RT and 89% (95% CI, 84% to 94%) and 87% (95% CI, 81% to 93%; hazard ratio, 0.84; 95% CI, 0.46 to 1.55; P = .58), respectively, for CRT. There were no significant differences in disease-free or overall survival. Locoregional failure was the most common site of first treatment failure, with isolated distant metastases as the first site of failure seen in 7% of both arms. Treatment was well tolerated in both arms, with no observed enhancement of RT toxicity with carboplatin. Grade 3 or 4 late toxicities were infrequent. Conclusion Although surgery and postoperative RT provided excellent FFLRR, there was no observed benefit with the addition of weekly carboplatin.

Safety and cost analysis of an (18)FDG-PET-CT response based follow-up strategy for head and neck cancers treated with primary radiation or chemoradiation.

BACKGROUND: Prognostic information can rationalise clinical follow-up after radical cancer treatment. This retrospective cohort study of radical head and neck (chemo)radiotherapy patients examines the clinical safety and cost implications of stratifying follow-up intensity by post-treatment (18)FDG-PET-CT response. METHODS: In 2008 clinical review after radical head and neck radiotherapy was reduced from 3- to 6-monthly for patients with complete (18)FDG-PET-CT response at 3months. 184 patients treated after this change ("PET Stratified", 2009-11) were compared to 178 patients treated before ("Standard", 2005-7). Clinical safety was assessed by the time to detection of recurrence, overall survival and potential for radical treatment of recurrence. A hospital cost analysis was performed using individual patient data. RESULTS: 127 of 178 Standard and 148 of 184 PET Stratified patients achieved complete response on post-treatment imaging. Baseline clinical characteristics were comparable. Median follow-up from response assessment was 4.8years in the Standard cohort and 2.1years for PET Stratified. PET Stratified patients had a mean 4.4 outpatient visits in 2years, compared to 7.0 among Standard patients. Over 90% of patients remained free of recurrence at 2years in both cohorts. Time to detection of recurrence was similar between two cohorts (HR1.05, 95%CI 0.45-2.52), as was overall survival (HR0.91, 95%CI 0.36-2.29). The proportion of radically treatable recurrences was also similar (42% Standard vs. 47% PET Stratified). The hospital cost savings per patient from reduced review were AUD$2606 over 2years, AUD$5012 over five. CONCLUSION: (18)FDG-PET-CT to stratify follow-up intensity after radical radiotherapy for head and neck cancer reduces costs with no apparent clinical detriment.

68Ga-EDTA PET/CT imaging and plasma clearance for glomerular filtration rate quantification: comparison to conventional 51Cr-EDTA.

UNLABELLED: Glomerular filtration rate (GFR) can accurately be determined using (51)Cr-ethylenediaminetetraacetic acid (EDTA) plasma clearance counting but is time-consuming and requires technical skills and equipment not always available in imaging departments. (68)Ga-EDTA can be readily available using an onsite generator, and PET/CT enables both imaging of renal function and accurate camera-based quantitation of clearance of activity from blood and its appearance in the urine. This study aimed to assess agreement between (68)Ga-EDTA GFR ((68)Ga-GFR) and (51)Cr-EDTA GFR ((51)Cr-GFR), using serial plasma sampling and PET imaging. METHODS: (68)Ga-EDTA and (51)Cr-EDTA were injected concurrently in 31 patients. Dynamic PET/CT encompassing the kidneys was acquired for 10 min followed by 3 sequential 3-min multibed step acquisitions from kidneys to bladder. PET quantification was performed using renal activity at 1-2 min (PETinitial), renal excretion at 2-10 min (PETearly), and, subsequently, urinary excretion into the collecting system and bladder (PETlate). Plasma sampling at 2, 3, and 4 h was performed, with (68)Ga followed by (51)Cr counting after positron decay. The level of agreement for GFR determination was calculated using a Bland-Altman plot and Pearson correlation coefficient (PCC). RESULTS: (51)Cr-GFR ranged from 10 to 220 mL/min (mean, 85 mL/min). There was good agreement between (68)Ga-GFR and (51)Cr-GFR using serial plasma sampling, with a Bland-Altman bias of -14 ± 20 mL/min and a PCC of 0.94 (95% confidence interval, 0.88-0.97). Of the 3 methods used for camera-based quantification, the strongest correlation was for plasma sampling-derived GFR with PETlate (PCC of 0.90; 95% confidence interval, 0.80-0.95). CONCLUSION: (68)Ga-GFR agreed well with (51)Cr-GFR for estimation of GFR using serial plasma counting. PET dynamic imaging provides a method to estimate GFR without plasma sampling, with the additional advantage of enabling renal imaging in a single study. Additional validation in a larger cohort is warranted to further assess utility.

Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial.

BACKGROUND: Initial treatment of acute promyelocytic leukaemia traditionally involves tretinoin (all-trans retinoic acid) combined with anthracycline-based risk-adapted chemotherapy, with arsenic trioxide being the treatment of choice at relapse. To try to reduce the relapse rate, we combined arsenic trioxide with tretinoin and idarubicin in induction therapy, and used arsenic trioxide with tretinoin as consolidation therapy. METHODS: Patients with previously untreated genetically confirmed acute promyelocytic leukaemia were eligible for this study. Eligibilty also required Eastern Cooperative Oncology Group performance status 0-3, age older than 1 year, normal left ventricular ejection fraction, Q-Tc interval less than 500 ms, absence of serious comorbidity, and written informed consent. Patients with genetic variants of acute promyelocytic leukaemia (fusion of genes other than PML with RARA) were ineligible. Induction comprised 45 mg/m(2) oral tretinoin in four divided doses daily on days 1-36, 6-12 mg/m(2) intravenous idarubicin on days 2, 4, 6, and 8, adjusted for age, and 0·15 mg/kg intravenous arsenic trioxide once daily on days 9-36. Supportive therapy included blood products for protocol-specified haemostatic targets, and 1 mg/kg prednisone daily as prophylaxis against differentiation syndrome. Two consolidation cycles with tretinoin and arsenic trioxide were followed by maintenance therapy with oral tretinoin, 6-mercaptopurine, and methotrexate for 2 years. The primary endpoints of the study were freedom from relapse and early death (within 36 days of treatment start) and we assessed improvement compared with the 2 year interim results. To assess durability of remission we compared the primary endpoints and disease-free and overall survival at 5 years in APML4 with the 2 year interim APML4 data and the APML3 treatment protocol that excluded arsenic trioxide. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12605000070639. FINDINGS: 124 patients were enrolled between Nov 10, 2004, and Sept 23, 2009, with data cutoff of March 15, 2012. Four (3%) patients died early. After a median follow-up of 4·2 years (IQR, 3·2-5·2), the 5 year freedom from relapse was 95% (95% CI 89-98), disease-free survival was 95% (89-98), event-free survival was 90% (83-94), and overall survival was 94% (89-97). The comparison with APML3 data showed that hazard ratios were 0·23 (95% CI 0·08-0·64, p=0·002) for freedom from relapse, 0·21 (0·07-0·59, p=0·001) for disease-free survival, 0·34 (0·16-0·69, p=0·002) for event-free survival, and 0·35 (0·14-0·91, p=0·02) for overall survival. INTERPRETATION: Incorporation of arsenic trioxide in initial therapy induction and consolidation for acute promyelocytic leukaemia reduced the risk of relapse when compared with historical controls. This improvement, together with a non-significant reduction in early deaths and absence of deaths in remission, translated into better event-free and overall survival. FUNDING: Phebra.