Regular, sustained-release morphine for chronic breathlessness: a multicentre, double-blind, randomised, placebo-controlled trial.

INTRODUCTION: Morphine may decrease the intensity of chronic breathlessness but data from a large randomised controlled trial (RCT) are lacking. This first, large, parallel-group trial aimed to test the efficacy and safety of regular, low-dose, sustained-release (SR) morphine compared with placebo for chronic breathlessness. METHODS: Multisite (14 inpatient and outpatient cardiorespiratory and palliative care services in Australia), parallel-arm, double-blind RCT. Adults with chronic breathlessness (modified Medical Research Council≥2) were randomised to 20 mg daily oral SR morphine and laxative (intervention) or placebo and placebo laxative (control) for 7 days. Both groups could take ≤6 doses of 2.5 mg, 'as needed', immediate-release morphine (≤15 mg/24 hours) as required by the ethics review board. The primary endpoint was change from baseline in intensity of breathlessness now (0-100 mm visual analogue scale; two times per day diary) between groups. Secondary endpoints included: worst, best and average breathlessness; unpleasantness of breathlessness now, fatigue; quality of life; function; and harms. RESULTS: Analysed by intention-to-treat, 284 participants were randomised to morphine (n=145) or placebo (n=139). There was no difference between arms for the primary endpoint (mean difference -0.15 mm (95% CI -4.59 to 4.29; p=0.95)), nor secondary endpoints. The placebo group used more doses of oral morphine solution during the treatment period (mean 8.7 vs 5.8 doses; p=0.001). The morphine group had more constipation and nausea/vomiting. There were no cases of respiratory depression nor obtundation. CONCLUSION: No differences were observed between arms for breathlessness, but the intervention arm used less rescue immediate-release morphine. TRIAL REGISTRATION NUMBER: ACTRN12609000806268.

Small increases in enhancement on MRI may predict survival post radiotherapy in patients with glioblastoma.

To assess impact of volumetric changes in tumour volume post chemoradiotherapy in glioblastoma. Patients managed with chemoradiotherapy between 2008 and 2011 were included. Patients with incomplete MRI sets were excluded. Analyses were performed on post-operative MRI, and MRIs at 1 month (M+1), 3 months (M+3), 5 months (M+5), 7 months (M+7), and 12 months (M+12) post completion of RT. RANO definitions of response were used for all techniques. Modified RANO criteria and two volumetric analysis techniques were used. The two volumetric analysis techniques involved utility of the Eclipse treatment planning software to calculate the volume of delineated tissue: surgical cavity plus all surrounding enhancement (Volumetric) versus surrounding enhancement only (Rim). Retrospective analysis of 49 patients with median survival of 18.4 months. Using Volumetric analysis the difference in MS for patients who had a <5 % increase versus ≥5 % at M+3 was 23.1 versus 15.1 months (p = 0.006), and M+5 was 26.3 versus 15.1 months (p = 0.006). For patients who were classified as progressive disease using modified RANO criteria at M+1 and M+3 there was a difference in MS compared with those who were not (M+1: 13.1 vs. 19.4 months, p = 0.017, M+3: 13.2 vs. 20.1 months, p = 0.096). An increase in the volume of cavity and enhancement of ≥5 % at M+3 and M+5 post RT was associated with reduced survival, suggesting that increases in radiological abnormality of <25 % may predict survival.

EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial.

BACKGROUND: Existing treatments for postherpetic neuralgia, and for neuropathic pain in general, are limited by modest efficacy and unfavourable side-effects. The angiotensin II type 2 receptor (AT2R) is a new target for neuropathic pain. EMA401, a highly selective AT2R antagonist, is under development as a novel neuropathic pain therapeutic agent. We assessed the therapeutic potential of EMA401 in patients with postherpetic neuralgia. METHODS: In this multicentre, placebo-controlled, double-blind, randomised, phase 2 clinical trial, we enrolled patients (aged 22-89 years) with postherpetic neuralgia of at least 6 months' duration from 29 centres across six countries. We randomly allocated 183 participants to receive either oral EMA401 (100 mg twice daily) or placebo for 28 days. Randomisation was done according to a centralised randomisation schedule, blocked by study site, which was generated by an independent, unmasked statistician. Patients and staff at each site were masked to treatment assignment. We assessed the efficacy, safety, and pharmacokinetics of EMA401. The primary efficacy endpoint was change in mean pain intensity between baseline and the last week of dosing (days 22-28), measured on an 11-point numerical rating scale. The primary efficacy analysis was intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000822987. FINDINGS: 92 patients were assigned to EMA401 and 91 were assigned to placebo. The patients given EMA401 reported significantly less pain compared with baseline values in the final week of treatment than did those given placebo (mean reductions in pain scores -2.29 [SD 1.75] vs -1.60 [1.66]; difference of adjusted least square means -0.69 [SE 0.25]; 95% CI -1.19 to -0.20; p=0.0066). No serious adverse events related to EMA401 occurred. Overall, 32 patients reported 56 treatment-emergent adverse events in the EMA401 group compared with 45 such events reported by 29 patients given placebo. INTERPRETATION: EMA401 (100 mg twice daily) provides superior relief of postherpetic neuralgia compared with placebo at the end of 28 days of treatment. EMA401 was well tolerated by patients. FUNDING: Spinifex Pharmaceuticals.

A review of the treatment options for skin rash induced by EGFR-targeted therapies: Evidence from randomized clinical trials and a meta-analysis.

BACKGROUND: Agents targeting the epidermal growth factor receptor (EGFR) are amongst the most extensively used of the targeted agents in the therapy of some of the most common solid tumors. Although they avoid many of the classic side effects associated with cytotoxic chemotherapy, they are associated with unpleasant cutaneous toxicities which can affect treatment compliance and impinge on patient quality of life. To date, despite a plethora of consensus recommendations, expert opinions and reviews, there is a paucity of evidence-based guidance for the management of the skin rash that occurs in the treatment of patients receiving EGFR-targeted therapies. METHODS: A literature search was conducted as a first step towards investigating not only an evidence-based approach to the management of skin rash, but also with a view to designing future randomized trials. RESULTS: The literature search identified seven randomized trials and a meta-analysis was conducted using the data from four of these trials involving oral antibiotics. The meta-analysis of the data from these four trials suggests that prophylactic antibiotics might reduce the relative risk of severe rash associated with EGFR-targeted agents by 42-77%. Vitamin K cream was also identified as having a potential role in the management EGFR-targeted agent induced rash. CONCLUSIONS: This review and meta-analysis clearly identify the need for further randomized studies of the role of oral antibiotics in this setting. The results of the ongoing randomized trials of the topical application of vitamin K cream plus or minus doxycycline and employing prophylactic versus reactive strategies are eagerly awaited.

Living With Hereditary Angioedema in Australia: Findings From a National Observational Study Using Short Message Service to Monitor the Burden of Disease.

BACKGROUND: To understand the impact and burden of disease experienced by patients with hereditary angioedema (HAE). OBJECTIVE: To determine whether the use of short message service (SMS) to communicate with patients with HAE facilitates the collection of attack rate, medication use, and quality of life measurements. METHODS: Patients aged 12 years and older with doctor-confirmed HAE C1-inhibitor deficiency types I and II were invited to participate. We devised a novel method for monitoring attacks by using questions weekly via SMS to gain a more accurate picture of the burden of HAE in Australian patients in real time. RESULTS: A total of 2,648 weekly SMS messages were sent to 47 participants; 1,892 responses were received (71%). Participants reported 463 attacks across all treatment groups. Sixty percent of attacks were treated. Icatibant and C1-inhibitor concentrate were administered IV for 210 and 67 attacks, respectively. Of the 463 recorded attacks, 23 necessitated presentation to the hospital (5%), predominantly for facial and/or throat swelling. Several participants reported attacks (n = 186), which they chose not to treat. Most of those attacks were rated mildly severe. Twenty-one participants reported lost days owing to HAE attacks (44.7%). Fifty-eight attacks (17%) resulted in time away from work or school, equating to a total of 85.5 days lost. CONCLUSIONS: This study was a first of its kind, real-world, prospective, observational study of Australian patients living with HAE. Despite the availability of effective on-demand therapies, HAE remains burdensome. Wider access to safe and effective prophylactic therapies is needed for patients living with HAE.

Astodrimer sodium antiviral nasal spray for reducing respiratory infections is safe and well tolerated in a randomized controlled trial.

Astodrimer sodium is a dendrimer molecule with antiviral and virucidal activity against SARS-CoV-2 and other respiratory viruses in vitro, and has previously been shown to be safe and well tolerated, and not systemically absorbed, when applied to the vaginal mucosa. To investigate its potential utility as a topical antiviral, astodrimer sodium has been reformulated for application to the nasal mucosa to help reduce viral load before or after exposure to respiratory infection. The current investigation assessed the safety, tolerability and absorption of astodrimer sodium 1% antiviral nasal spray. This was a single-centre, double-blinded, randomized, placebo-controlled, exploratory clinical investigation. Forty healthy volunteers aged 18 to 65 years with no clinically significant nasal cavity examination findings were randomized 3:1 to astodrimer sodium nasal spray (N = 30) or placebo (N = 10) at an Australian clinical trials facility. An initial cohort of participants (N = 12 astodrimer, N = 4 placebo) received a single application (one spray per nostril) to assess any acute effects, followed by a washout period, before self-administering the spray four times daily for 14 days to represent an intensive application schedule. Extent of absorption of astodrimer sodium via the nasal mucosa was also assessed in this cohort. A second cohort of participants (N = 18 astodrimer, N = 6 placebo) self-administered the spray four times daily for 14 days. The primary endpoint was safety, measured by frequency and severity of treatment emergent adverse events (TEAEs), including clinically significant nasal cavity examination findings, in the safety population (all participants randomized who administered any spray). Participants were randomized between 6 January 2021 and 29 March 2021. TEAEs occurred in 8/10 (80%) participants in the placebo arm and 19/30 (63.3%) participants in the astodrimer sodium arm; all were of mild intensity. TEAEs considered potentially related to study product occurred in 5/10 (50%) participants receiving placebo and 10/30 (33.3%) of participants receiving astodrimer sodium. No participants experienced serious AEs, or TEAEs leading to withdrawal from the study. No systemic absorption of astodrimer sodium via the nasal mucosa was detected. Astodrimer sodium nasal spray was well tolerated and is a promising innovation warranting further investigation for nasal administration to potentially reduce infection and spread of community acquired respiratory virus infections.Trial Registration: ACTRN12620001371987, first registered 22-12-2020 (Australia New Zealand Clinical Trials Registry, https://anzctr.org.au/ ).

Prescribed Water Intake in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Arginine vasopressin promotes kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). Increased water intake reduces arginine vasopressin and urine osmolality and may slow kidney cyst growth. METHODS: In this randomized controlled 3-year clinical trial, we randomly assigned adults with ADPKD who had a height-corrected total kidney volume in Mayo imaging subclass categories 1B to 1E and an estimated glomerular filtration rate of 30 ml/min/1.73 m2 or greater to (1) water intake prescribed to reduce 24-hour urine osmolality to 270 mOsmol/kg or less or (2) ad libitum water intake irrespective of 24-hour urine osmolality. The primary end point was the percentage annualized rate of change in height-corrected total kidney volume. RESULTS: A total of 184 patients participated in either the ad libitum water intake group (n=92) or the prescribed water intake group (n=92). Over 3 years, there was no difference in the annualized rate of change in height-corrected total kidney volume between the ad libitum (7.8% per year; 95% confidence interval [CI], 6.6 to 9.0) and prescribed (6.8% per year; 95% CI, 5.8 to 7.7) water intake groups (mean difference, −0.97% per year; 95% CI, −2.37 to 0.44; P=0.18). The difference in mean 24-hour urine osmolality between the ad libitum and prescribed water intake groups was −91 mOsmol/kg (95% CI, −127 to −54 mOsmol/kg), with 52.3% of patients achieving adherence to the target 24-hour urine osmolality and no reduction in serum copeptin over 3 years. The frequency of adverse events was similar between groups. CONCLUSIONS: For patients with ADPKD, prescribed water intake was not associated with excess adverse events and achieved the target 24-hour urine osmolality for half of the patients but did not reduce copeptin or slow the growth of total kidney volume over 3 years compared with ad libitum water intake. (Funded by the National Health and Medical Research Council of Australia [grant GNT1138533], Danone Research, PKD Australia, the University of Sydney, and the Westmead Medical Research Foundation; Australian New Zealand Clinical Trials Registry number, ACTRN12614001216606).

A phase 3, randomized, controlled trial of Astodrimer 1% Gel for preventing recurrent bacterial vaginosis.

OBJECTIVE: The objective of the study was to confirm the efficacy and safety of Astodrimer 1% Gel to prevent recurrence of bacterial vaginosis. STUDY DESIGN: 864 women with a diagnosis of bacterial vaginosis and a history of recurrent bacterial vaginosis were enrolled in North America and first received oral metronidazole (500 mg twice daily for 7 days). Women successfully treated with metronidazole were randomly assigned 1:1 to Astodrimer 1% Gel (N = 295) or placebo (N = 291) at a dose of 5 g vaginally every second day for 16 weeks, and followed for a further 12 weeks off-treatment. The primary endpoint was recurrence of bacterial vaginosis (presence of ≥3 Amsel criteria) at or by Week 16. Secondary endpoints included time to recurrence, and recurrence of subject-reported symptoms. Adverse events were monitored throughout the study. RESULTS: Astodrimer 1% Gel was superior to placebo for the primary and many secondary efficacy measures. At or by Week 16, bacterial vaginosis recurred in 44.2 % (130/294) of women receiving astodrimer and 54.3 % (158/291) receiving placebo (P = .015). Time to recurrence of bacterial vaginosis was significantly longer for women receiving astodrimer compared with placebo (Kaplan-Meier survival curves, P = .007). Recurrence of subject-reported symptoms at or by Week 16 was also significantly lower in the astodrimer arm compared with placebo (vaginal odor and/or discharge, 27.9 % [75/269] vs 40.6 % [108/266], P = .002). A significantly lower proportion of patients receiving astodrimer compared with placebo had recurrence of bacterial vaginosis at or by Week 16 by other secondary measures, including individual Amsel criteria (vaginal discharge and clue cells) and Nugent score 7-10. Recurrence of subject-reported vaginal odor and/or discharge was significantly lower in the astodrimer arm compared with placebo up to 8 weeks after cessation of therapy (36.1 % [97/269] vs 45.5 % [121/266], P = .027).Adverse events were infrequent, and rates were generally similar between placebo and astodrimer groups. Vulvovaginal candidiasis and urinary tract infection occurred more often in women receiving astodrimer. CONCLUSIONS: Astodrimer 1% Gel, administered every second day for 16 weeks, was effective and superior to placebo for prevention of recurrent bacterial vaginosis in women with a history of recurrent BV, and was well-tolerated.

Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B.

UNLABELLED: We investigated the relationship between hepatitis B virus surface antigen (HBsAg) serum level decline and posttreatment response in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B from a large multinational study of pegylated interferon alfa-2a (peginterferon alfa-2a), with or without lamivudine, versus lamivudine alone. Serum HBsAg was quantified using the Architect assay (Abbott Diagnostics) at pretreatment, end of treatment (week 48), and 6 months after the end of treatment (week 72) in sera from 386 of the 537 patients who participated in the multinational study (peginterferon alfa-2a, 127; peginterferon alfa-2a plus lamivudine, 137; lamivudine monotherapy, 122). Pretreatment HBsAg levels varied according to genotype, with the highest levels present in patients infected with genotypes A (median, 4.11 log(10) IU/mL) and D (median, 3.85 log(10) IU/mL). Significant on-treatment decline in HBsAg was observed during treatment with peginterferon alfa-2a (alone or combined with lamivudine; mean decline at week 48, -0.71 and -0.67 log(10) IU/mL, respectively, P < 0.001), but not during treatment with lamivudine alone (-0.02 log(10) IU/mL). Significantly more patients treated with peginterferon alfa-2a (21%) or peginterferon alfa-2a plus lamivudine (17%) achieved HBsAg levels <100 IU/mL at the end of treatment compared with lamivudine (1%) (both P < 0.001 versus lamivudine). End-of-treatment HBsAg level correlated strongly with HBV DNA suppression to 1 log(10) IU/mL were significantly associated with sustained HBsAg clearance 3 years after treatment (both P < 0.0001). CONCLUSION: On-treatment quantification of HBsAg in patients with HBeAg-negative chronic hepatitis B treated with peginterferon alfa-2a may help identify those likely to be cured by this therapy and optimize treatment strategies.

Early impact of the Australian national shingles vaccination program with the herpes zoster live attenuated vaccine.

Herpes zoster (shingles) is a painful condition resulting from reactivation of latent varicella zoster virus (VZV). The Australian National Shingles Vaccination Program (commenced November 2016) provides free herpes zoster vaccination for eligible adults aged 70 years, with a 5-year catch-up program (until October 2021) for adults aged 71-79 years. Patterns and impact of the program were evaluated by analysis of vaccine distribution and delivery data and specific antiviral prescription data from the Pharmaceutical Benefits Scheme. During the first 2 years, uptake of funded live attenuated shingles vaccine ZOSTAVAX® (Zoster Virus Vaccine Live; ZVL) was high across the ongoing and catch-up programs. Before program implementation (2006-2016), herpes zoster coded antiviral prescription rates increased by 2.2% per year (95% CI: 1.5, 2.9) in the 70-79 years age group. In the two years since program launch, herpes zoster antiviral prescription rates declined substantially in this age group, by an average of 13.6% per year (95% CI: 1.5, 24.2). These results indicate that the National Shingles Vaccination Program has been highly successful in vaccinating a considerable proportion of Australian adults aged 70-79 years against herpes zoster and suggest that vaccine uptake was associated with decreased incidence of herpes zoster.

A phase 2, double-blind, multicenter, randomized, placebo-controlled, dose­ranging study of the efficacy and safety of Astodrimer Gel for the treatment of bacterial vaginosis.

BACKGROUND: Astodrimer Gel contains a novel dendrimer intended to treat and prevent bacterial vaginosis. We assessed the efficacy and safety of Astodrimer Gel for treatment of bacterial vaginosis. METHODS: 132 women with bacterial vaginosis were randomized 1:1:1:1 to Astodrimer 0.5% (N = 34), 1% (N = 33), or 3% (N = 32) Gel or hydroxyethyl cellulose placebo gel (N = 33) at a dose of 5 g vaginally once daily for 7 days at 6 centers in the United States. The primary endpoint was clinical cure (no bacterial vaginosis vaginal discharge and no more than one of 1) vaginal pH ≥4.5; 2) ≥20% clue cells; or 3) positive whiff test) at study days 21-30. Secondary analyses included clinical cure at study days 9-12, patient-reported symptoms, acceptability and adverse events. RESULTS: The Astodrimer 1% Gel dose was superior to placebo for the primary and selected secondary efficacy measures in the modified intent-to-treat population. Clinical cure rates at day 9-12 were superior to placebo for the Astodrimer 3%, 1% and 0.5% Gel groups (62.5% [15/24; P = .002], 74.1% [20/27; P < .001], and 55.2% [16/29; P = .001], respectively, vs. 22.2% [6/27]). At day 21-30, clinical cure rates were 46.2% (12/26) for the 1% dose vs. 11.5% for placebo (3/26; P = .006). A greater proportion of patients reported absence of vaginal discharge and vaginal odor at day 9-12 and day 21-30 for Astodrimer Gel groups compared with placebo. Adverse events considered potentially treatment-related occurred in only 25% of Astodrimer Gel-treated patients vs. 22% of placebo patients. CONCLUSION: Astodrimer Gel once daily for 7 days was superior to placebo for treatment of bacterial vaginosis and was well-tolerated. The 1% dose consistently showed the strongest efficacy across endpoints. These results support a role for Astodrimer Gel, 1%, as an effective treatment for bacterial vaginosis.

Controlled-Release Oxycodone vs. Placebo in the Treatment of Chronic Breathlessness-A Multisite Randomized Placebo Controlled Trial.

CONTEXT: Chronic breathlessness is a clinical syndrome that results in significant distress and disability. Morphine can reduce chronic breathlessness when the contributing etiologies are optimally treated. OBJECTIVES: Does oxycodone reduce chronic breathlessness compared with placebo? METHODS: A multisite, randomized, placebo-controlled, double-blind, parallel-arm, fixed-dose trial of oral controlled-release oxycodone 15 mg (5 mg, eight hourly) or placebo (ACTRN12609000806268 at www.anzctr.org.au). As-needed immediate-release morphine (2.5 mg per dose; six and less doses/day) was available for both arms as required by one ethics committee overseeing the trial. Recruitment occurred from 2010 to 2014 in 14 inpatient and outpatient respiratory, cardiology, and palliative care services across Australia. Participants were adults, with chronic breathlessness (modified Medical Research Council Scale 3 or 4), who were opioid naive. The primary end point was the proportion of people with greater than 15% reduction from baseline in the intensity of breathlessness now (0-100 mm visual analogue scale) comparing arms Days 5-7. Secondary end points were average and worst breathlessness, quality of life, function, and harms. RESULTS: Of 157 participants randomized, 155 were included (74 oxycodone and 81 placebo), but the study did not reach target recruitment. There was difference in neither between groups for the primary outcome (P = 0.489) nor any of the prespecified secondary outcomes. Placebo participants used more as-needed morphine (mean 7.0 vs. 4.2 doses; P ≤ 0.001). Oxycodone participants reported more nausea (P < 0.001). CONCLUSION: There was no signal of benefit from oxycodone over placebo. Future research should focus on investigating the existence of an opioid class effect on the reduction of chronic breathlessness.

Two phase 3, double-blind, placebo-controlled studies of the efficacy and safety of Astodrimer 1% Gel for the treatment of bacterial vaginosis.

OBJECTIVE: Astodrimer is a dendrimer formulated in a vaginal gel to treat bacterial vaginosis (BV) and prevent recurrence. The objective of these studies was to confirm the efficacy and safety of Astodrimer 1 % Gel for treatment of BV. STUDY DESIGN: Women with bacterial vaginosis were randomized 1:1 to Astodrimer 1 % Gel (Study 1 conducted in the United States, N = 127; Study 2 conducted in the United States, Germany and Belgium, N = 128) or placebo gel (Study 1, N = 123; Study 2, N = 123) at a dose of 5 g vaginally once daily for 7 days. The primary endpoint was clinical cure, defined as i) absence of bacterial vaginosis vaginal discharge; ii) <20 % clue cells; and iii) negative whiff test at day 9-12. Secondary efficacy analyses included clinical cure at day 21-30. Other endpoints at days 9-12 and 21-30 included Nugent cure (Nugent score ≤3), absence of symptoms, and adverse events. The primary analysis in the modified intent-to-treat population used the Cochran Mantel Haenszel test stratified by analysis center with a two-sided significance level of α = .05. RESULTS: Astodrimer 1 % Gel was superior to placebo for the primary and selected secondary efficacy measures. Clinical cure rates at day 9-12 were 50.4 % (59/117) vs 16.5 % (19/115, P < .001) (Study 1) and 56.7 % (68/120) vs 21.4 % (25/117, P < .001) (Study 2) for astodrimer vs placebo. At day 21-30, clinical cure results showed a similar trend but the difference to placebo was not statistically significant. Nugent cure rates at day 9-12 were 12.8 % (15/117) vs 2.6 % (3/115, P = .004) (Study 1) and 13.3 % (16/120) vs 5.1 % (6/117, P = .030) (Study 2) for astodrimer vs placebo. A greater proportion of women receiving astodrimer reported absence of vaginal discharge and absence of vaginal odor at day 9-12 and day 21-30 compared with placebo. Adverse events were generally mild and self-limiting. For the combined studies, adverse events potentially related to treatment occurred in 14.7 % (37/252) of astodrimer patients vs 9.4 % (23/244) for placebo, including vulvovaginal candidiasis reported for 2.4 % (6/252) of astodrimer patients. CONCLUSION: These results support a role for Astodrimer 1 % Gel as an effective, safe and well-tolerated treatment for women with bacterial vaginosis.

A simple algorithm to predict non-compliance with organ at risk dose-volume constraints when planning intensity modulated post-prostatectomy radiation treatment: 'Why we should put the CART before the horse'.

INTRODUCTION: It is not always apparent when the optimal IMRT/VMAT plan for post-prostatectomy radiotherapy (PPRT) has been achieved. Individual variation in patient anatomy is a key contributor. This study aimed to create a model to determine the probability of rectum and/or bladder doses exceeding planning goals based on individual patient anatomy prior to planning. METHODS: The IMRT/VMAT PPRT plans from 200 men were randomly and evenly allocated into the Training Cohort and the Validation Cohort. Univariate and multivariate analysis of the Training Cohort identified variables which impacted bladder and rectal doses. Significant variables were included in a Classification and Regression Tree (CART) analysis. The resultant algorithm was then applied to the Validation Cohort. RESULTS: On multivariate analysis, prescription dose; bladder and rectal volume; lymph node treatment; and percentage of bladder and rectal overlap with the PTV were significant variables. Following CART analysis, the overlap volume (OV) for both rectum (rectum overlap > 20%) and bladder (bladder overlap > 20%) were the key drivers of meeting planning goals. Treatment of pelvic lymph nodes was included as the secondary driving factor for bladder (but not rectal) dose. On application to the Validation Cohort, CART analysis predicted 95% and 87% of patients who would meet bladder and rectal planning goals respectively. CONCLUSIONS: A simple algorithm was developed to predict plan quality by using the OV of the bladder and rectum with the PTV. This algorithm may be used a priori to assess the planning process in the context of variable anatomy, and to optimise planning quality and efficiency.

Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.

BACKGROUND: Current treatments for chronic hepatitis B are suboptimal. In the search for improved therapies, we compared the efficacy and safety of pegylated interferon alfa plus lamivudine, pegylated interferon alfa without lamivudine, and lamivudine alone for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. METHODS: A total of 814 patients with HBeAg-positive chronic hepatitis B received either peginterferon alfa-2a (180 microg once weekly) plus oral placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), or lamivudine alone. The majority of patients in the study were Asian (87 percent). Most patients were infected with hepatitis B virus (HBV) genotype B or C. Patients were treated for 48 weeks and followed for an additional 24 weeks. RESULTS: After 24 weeks of follow-up, significantly more patients who received peginterferon alfa-2a monotherapy or peginterferon alfa-2a plus lamivudine than those who received lamivudine monotherapy had HBeAg seroconversion (32 percent vs. 19 percent [P<0.001] and 27 percent vs. 19 percent [P=0.02], respectively) or HBV DNA levels below 100,000 copies per milliliter (32 percent vs. 22 percent [P=0.01] and 34 percent vs. 22 percent [P=0.003], respectively). Sixteen patients receiving peginterferon alfa-2a (alone or in combination) had hepatitis B surface antigen (HBsAg) seroconversion, as compared with 0 in the group receiving lamivudine alone (P=0.001). The most common adverse events were those known to occur with therapies based on interferon alfa. Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients receiving peginterferon alfa-2a monotherapy, combination therapy, and lamivudine monotherapy, respectively. Two patients receiving lamivudine monotherapy had irreversible liver failure after the cessation of treatment--one underwent liver transplantation, and the other died. CONCLUSIONS: In patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a offers superior efficacy over lamivudine, on the basis of HBeAg seroconversion, HBV DNA suppression, and HBsAg seroconversion.

Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality.

To investigate the role of androgens in increasing bone density and improving low libido in postmenopausal women, we have studied the long-term effects of estradiol and testosterone implants on bone mineral density and sexuality in a prospective, 2 year, single-blind randomised trial. Thirty-four postmenopausal volunteers were randomised to treatment with either estradiol implants 50 mg alone (E) or estradiol 50 mg plus testosterone 50 mg (E&T), administered 3-monthly for 2 years. Cyclical oral progestins were taken by those women with an intact uterus. Thirty-two women completed the study. BMD (DEXA) of total body, lumbar vertebrae (L1-L4) and hip area increased significantly in both treatment groups. BMD increased more rapidly in the testosterone treated group at all sites. A substantially greater increase in BMD occurred in the E&T group for total body (P < 0.008), vertebral L1-L4 (P < 0.001) and trochanteric (P < 0.005) measurements. All sexual parameters (Sabbatsberg sexual self-rating scale) improved significantly in both groups. Addition of testosterone resulted in a significantly greater improvement compared to E for sexual activity (P < 0.03), satisfaction (P < 0.03), pleasure (P < 0.01), orgasm (P < 0.035) and relevancy (P < 0.05). Total cholesterol and LDL-cholesterol fell in both groups as did total body fat. Total body fat-free mass (DEXA, anthropometry, impedance) increased in the E&T group only. We concluded that in postmenopausal women, treatment with combined estradiol and testosterone implants was more effective in increasing bone mineral density in the hip and lumbar spine than estradiol implants alone. Significantly greater improvement in sexuality was observed with combined therapy, verifying the therapeutic value of testosterone implants for diminished libido in postmenopausal women. The favourable estrogenic effects on lipids were preserved in women treated with T, in association with beneficial changes in body composition.

Contemporary salvage post prostatectomy radiotherapy: Early implementation improves biochemical control.

INTRODUCTION: The optimal time to commence salvage radiotherapy (SRT) for a rising PSA post radical prostatectomy is not known. We wished to assess the impact of index PSA (iPSA) level prior to SRT on rates of biochemical failure (BCF) post treatment. METHODS: Patients referred to our institution for SRT for a rising PSA post surgery were accrued onto a prospective database. Baseline demographic data, tumour and treatment factors were collected including pathologic T and N stage, margin status, Gleason score (GS), lymphovascular space invasion (LVSI), use of androgen deprivation therapy (ADT) and time from surgery to salvage radiotherapy. Our endpoint was time to BCF. RESULTS: Between January 2008 and December 2013, 189 patients received SRT to a mean dose of 69.8 Gy in 34 fractions using Intensity Modulated Radiotherapy (IMRT). Median follow-up was 50 months. For patients with an iPSA of <0.2 ng/mL (n = 92), iPSA ≥ 0.2 to <1.0 ng/mL (n = 75) and ≥ 1.0 ng/mL (n = 22), rates of BCF at 5 years were 28.3%, 44.3% and 73.7% respectively. Compared to the iPSA <0.2 ng/mL group, the hazard ratios for time to BCF for an iPSA ≥ 0.2 to <1.0 ng/mL was 1.73 (P = 0.05) and >1.0 ng/mL was 3.1 (P = 0.002). Factors predicting time to BCF on univariate analysis included iPSA, GS, T stage, PSA nadir post surgery and LVSI. On multivariate analysis, GS, iPSA, use of ADT, T stage, PSA post surgery nadir and margin status remained significant. CONCLUSION: Rising iPSA levels are associated with an increasing risk of biochemical failure after adjusting for known prognostic factors and early salvage post prostatectomy radiotherapy is recommended.

Correlating Ki67 and other prognostic markers with Oncotype DX recurrence score in early estrogen receptor-positive breast cancer.

AIM: Decisions regarding adjuvant chemotherapy for early breast cancer are complex. Ki67 is increasingly used, in conjunction with conventional prognostic markers, to help decide the use of adjuvant chemotherapy for early breast cancer. Ki67 has been proposed as an economical alternative to Oncotype DX recurrence score (RS), which is a validated prognostic marker for disease recurrence and predictive marker for benefit from chemotherapy. This study aimed to determine in patients where conventional prognostic markers did not provide a clear recommendation for adjuvant chemotherapy, whether Ki67 could be a substitute for RS. METHODS: We reviewed all cases of luminal-type node-negative early breast cancer (T1-2, N0-1mi, M0, estrogen receptor positive, HER2 negative) referred for Oncotype DX testing by the multidisciplinary team at an Australian tertiary private hospital from 14th December 2006 to 31st December 2013, when conventional prognostic markers did not provide a clear recommendation for adjuvant chemotherapy. RS was correlated with Ki67, along with other conventional prognostic markers including tumor size, grade, mitotic rate and lymphovascular invasion. Spearman's rank order correlation coefficient and Pearson product-moment correlation coefficient (r) were used for ordinal and continuous variables, respectively. RESULTS: A total of 58 patients were analyzed, median Ki67 was 15% (range 2-50%) and the median RS was 16 (range 3-65). There was no positive correlation between Ki67 and RS (r = 0.01, P = 0.93). No single conventional prognostic marker was shown to significantly correlate with RS, including tumor size (r = -0.02, P = 0.88), grade (r = 0.10, P = 0.44), mitotic rate (r = -0.07, P = 0.69) and lymphovascular invasion (r = -0.12, P = 0.39). CONCLUSION: Ki67 and conventional prognostic markers do not correlate with Oncotype DX RS. In the setting where conventional prognostic markers do not show a clear indication for or against adjuvant chemotherapy as determined by consensus in a multidisciplinary team, Ki67 is not a substitute for Oncotype DX testing. RS may provide additional information to aid decision making for adjuvant chemotherapy.

Randomised controlled trial to determine the efficacy and safety of prescribed water intake to prevent kidney failure due to autosomal dominant polycystic kidney disease (PREVENT-ADPKD).

INTRODUCTION: Maintaining fluid intake sufficient to reduce arginine vasopressin (AVP) secretion has been hypothesised to slow kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). However, evidence to support this as a clinical practice recommendation is of poor quality. The aim of the present study is to determine the long-term efficacy and safety of prescribed water intake to prevent the progression of height-adjusted total kidney volume (ht-TKV) in patients with chronic kidney disease (stages 1-3) due to ADPKD. METHODS AND ANALYSIS: A multicentre, prospective, parallel-group, open-label, randomised controlled trial will be conducted. Patients with ADPKD (n=180; age ≤65 years, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2) will be randomised (1:1) to either the control (standard treatment+usual fluid intake) or intervention (standard treatment+prescribed fluid intake) group. Participants in the intervention arm will be prescribed an individualised daily fluid intake to reduce urine osmolality to ≤270 mOsmol/kg, and supported with structured clinic and telephonic dietetic review, self-monitoring of urine-specific gravity, short message service text reminders and internet-based tools. All participants will have 6-monthly follow-up visits, and ht-TKV will be measured by MRI at 0, 18 and 36 months. The primary end point is the annual rate of change in ht-TKV as determined by serial renal MRI in control vs intervention groups, from baseline to 3 years. The secondary end points are differences between the two groups in systemic AVP activity, renal disease (eGFR, blood pressure, renal pain), patient adherence, acceptability and safety. ETHICS AND DISSEMINATION: The trial was approved by the Human Research Ethics Committee, Western Sydney Local Health District. The results will inform clinicians, patients and policy-makers regarding the long-term safety, efficacy and feasibility of prescribed fluid intake as an approach to reduce kidney cyst growth in patients with ADPKD. TRIAL REGISTRATION NUMBER: ANZCTR12614001216606.

Longitudinal study of clinical prognostic factors in patients with early rheumatoid arthritis: the PREDICT study.

AIM: To assess the association between baseline clinical prognostic factors and subsequent Disease Activity Score of 28 joints (DAS28) remission in early rheumatoid arthritis (RA). METHODS: Data were collected using point of care clinical software from participating rheumatology centres. Patients aged 18 years or over whose date of clinical onset of RA was within the previous 12-24 months, who had at least 6 months of follow-up data and a DAS28-ESR (erythrocyte sedimentation rate) score recorded between 12 and 24 months from first being seen for RA were included. Data collected included baseline demographics, mode of disease onset, pattern of joint involvement at onset, smoking status, DAS28, rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPA), time from symptom onset to presentation and disease activity at baseline. Univariate and multivariate logistic regression of DAS28-ESR remission between 12 and 24 months after first assessment were performed. RESULTS: Data from 1017 patients were analyzed: 70% female; mean age 60 years (SD: 14.7); 70% RF-positive, 58% ACPA-positive. The strongest age and sex adjusted baseline predictors of DAS28-ESR remission at 12-24 months were remission at baseline (odds ratio [OR]: 4.49, 95% CI: 2.17-9.29, P < 0.001), being male (OR: 2.42, 95% CI: 1.46-4.01, P < 0.001), abstaining from alcohol (P < 0.001) and being lower weight (OR: 0.98, 95% CI: 0.97-1.00, P = 0.015). There was no statistically significant association between joint onset patterns, mode of onset, RF, ACPA or smoking status. CONCLUSION: In this observational study, patients with early RA at risk of not achieving remission include those with high disease activity at baseline, women, those who drink alcohol and those with higher body weight.