Gaps in completion and timeliness of breast surgery and adjuvant therapy: a retrospective cohort of Haitian patients with nonmetastatic breast cancer.

BACKGROUND: There are limited data on breast surgery completion rates and prevalence of care-continuum delays in breast cancer treatment programs in low-income countries. METHODS: This study analyzes treatment data in a retrospective cohort of 312 female patients with non-metastatic breast cancer in Haiti. Descriptive statistics were used to summarize patient characteristics; treatments received; and treatment delays of > 12 weeks. Multivariate logistic regressions were performed to identify factors associated with receiving surgery and with treatment delays. Exploratory multivariate survival analysis examined the association between surgery delays and disease-free survival (DFS). RESULTS: Of 312 patients, 249 (80%) completed breast surgery. The odds ratio (OR) for surgery completion for urban vs. rural dwellers was 2.15 (95% confidence interval [CI]: 1.19-3.88) and for those with locally advanced vs. early-stage disease was 0.34 (95%CI: 0.16-0.73). Among the 223 patients with evaluable surgery completion timelines, 96 (43%) experienced delays. Of the 221 patients eligible for adjuvant chemotherapy, 141 (64%) received adjuvant chemotherapy, 66 of whom (47%) experienced delays in chemotherapy initiation. Presentation in the later years of the cohort (2015-2016) was associated with lower rates of surgery completion (75% vs. 85%) and with delays in adjuvant chemotherapy initiation (OR [95%CI]: 3.25 [1.50-7.06]). Exploratory analysis revealed no association between surgical delays and DFS. CONCLUSION: While majority of patients obtained curative-intent surgery, nearly half experienced delays in surgery and adjuvant chemotherapy initiation. Although our study was not powered to identify an association between surgical delays and DFS, these delays may negatively impact long-term outcomes.

PRIME-HCC: phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma.

BACKGROUND: After liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC. Emerging data from cohort 4 of the CA209-040 study, which investigated the safety and preliminary efficacy of nivolumab/ipilimumab co-administration in advanced HCC, suggest that the combination can be delivered safely with an acceptable proportion of reversible grade 3-4 toxicities (27.1%) and a low discontinuation rate (2%) in patients with HCC. Here, we describe the design and rationale of PRIME-HCC, a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab/ipilimumab combination prior to LR in early-stage HCC. METHODS: The study involves an initial safety run-in phase (Part 1) to allow for preliminary safety characterisation within the first 6 patients enrolled and a subsequent expansion (Part 2). Ipilimumab will be administered once only on Day 1. Nivolumab will be administered on Day 1 and Day 22 (± 3 days) for a total of two 21-day cycles (i.e. 6 weeks of treatment). The primary objective of the study is to determine the safety and tolerability of the nivolumab/ipilimumab combination prior to LR. The secondary objective is to preliminarily characterize the efficacy of the combination prior to LR, including objective response rate (ORR) and pathologic response rates. Additional exploratory objectives include preliminary evidence of long-term disease control and to identify predictive correlates of response to the nivolumab/ipilimumab combination in HCC. DISCUSSION: The results of this study will help define the positioning of neoadjuvant nivolumab/ipilimumab combination in the perioperative management of HCC, with potential to improve survival outcomes in this patient population. TRIAL REGISTRATION: EudraCT Number: 2018-000987-27 Clinical trial registry & ID: ClinicalTrials.gov : NCT03682276 .

Phase 1/2a trial of intravenous BAL101553, a novel controller of the spindle assembly checkpoint, in advanced solid tumours.

BACKGROUND: BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents. METHODS: This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D). RESULTS: Seventy-three patients received BAL101553 at doses of 15-80 mg/m2 (phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2 were reversible Grade 2-3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population. CONCLUSIONS: The RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent's vascular-disrupting properties. CLINICAL TRIAL REGISTRATION: EudraCT: 2010-024237-23.

Advanced Imaging Modalities to Monitor for Cardiotoxicity.

OPINION STATEMENT: Early detection and treatment of cardiotoxicity from cancer therapies is key to preventing a rise in adverse cardiovascular outcomes in cancer patients. Over-diagnosis of cardiotoxicity in this context is however equally hazardous, leading to patients receiving suboptimal cancer treatment, thereby impacting cancer outcomes. Accurate screening therefore depends on the widespread availability of sensitive and reproducible biomarkers of cardiotoxicity, which can clearly discriminate early disease. Blood biomarkers are limited in cardiovascular disease and clinicians generally still use generic screening with ejection fraction, based on historical local expertise and resources. Recently, however, there has been growing recognition that simple measurement of left ventricular ejection fraction using 2D echocardiography may not be optimal for screening: diagnostic accuracy, reproducibility and feasibility are limited. Modern cancer therapies affect many myocardial pathways: inflammatory, fibrotic, metabolic, vascular and myocyte function, meaning that multiple biomarkers may be needed to track myocardial cardiotoxicity. Advanced imaging modalities including cardiovascular magnetic resonance (CMR), computed tomography (CT) and positron emission tomography (PET) add improved sensitivity and insights into the underlying pathophysiology, as well as the ability to screen for other cardiotoxicities including coronary artery, valve and pericardial diseases resulting from cancer treatment. Delivering screening for cardiotoxicity using advanced imaging modalities will however require a significant change in current clinical pathways, with incorporation of machine learning algorithms into imaging analysis fundamental to improving efficiency and precision. In the future, we should aspire to personalized rather than generic screening, based on a patient's individual risk factors and the pathophysiological mechanisms of the cancer treatment they are receiving. We should aspire that progress in cardiooncology is able to track progress in oncology, and to ensure that the current 'one size fits all' approach to screening be obsolete in the very near future.

Smoking, alcohol consumption, diet and physical activity following stoma formation surgery, stoma-related concerns, and desire for lifestyle advice: a United Kingdom survey.

BACKGROUND: Adherence to smoking, alcohol consumption, diet and physical activity (PA) guidelines may improve outcomes for people with a stoma. A better understanding of these behaviours following stoma formation surgery and their experiences and attitudes towards receiving lifestyle advice, could help identify specific gaps and inform interventions going forward. The aim of this study was to describe changes in current lifestyle following stoma formation and to explore concerns, desire for lifestyle information, advice and support among people who have or have had a stoma. METHODS: A sample of adults who currently had or in the past had a stoma for treatment for any medical condition was recruited online through relevant charities and companies, and invited to complete a cross-sectional, online survey. Consenting participants (n = 425) provided demographic information and completed brief, validated questionnaires about their lifestyle, alongside questions around their concerns regarding permanent stoma and experiences of lifestyle information and advice. Responses were summarised using descriptive statistics, and associations between reported concerns about stoma and changes in health behaviours were explored. RESULTS: Most respondents (93%) still had a stoma at the time of completing the survey. The majority (80%) had not consumed at least 5 portions of fruit and vegetables on the previous day and 20% reported they had not participated in at least 30 min of physical activity on any day in the previous week. Most respondents were non-smokers (84%) and did not exceed recommendations for alcohol intake (60%). Most (56%) felt their PA had decreased following stoma formation. Frequencies of concerns about a permanent stoma were high, and appeared to be associated with reported decreases in PA. Of those reporting nausea, 40% felt their diet had worsened since having their stoma. A large proportion of respondents had not received PA (42%) or dietary (30%) advice, and of these > 90% would have liked guidance. CONCLUSIONS: Few respondents to this survey were eating the recommended amount of fruit and vegetables, and most reported a decrease in their PA following stoma surgery. Lifestyle advice would be welcomed by this population, which professionals should take into account when addressing stoma- related concerns.

Development of a Multivariate Prognostic Model for Pain and Activity Limitation in People With Low Back Disorders Receiving Physiotherapy.

OBJECTIVE: To identify predictors for back pain, leg pain, and activity limitation in patients with early persistent low back disorders (LBDs). DESIGN: Prospective inception cohort study. SETTING: Primary care private physiotherapy clinics in Melbourne, Australia. PARTICIPANTS: Individuals (N=300) aged 18-65 years with low back and/or referred leg pain of ≥6 weeks and ≤6 months duration. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Numeric rating scales for back pain and leg pain as well as the Oswestry Disability Scale. RESULTS: Prognostic factors included sociodemographics, treatment related factors, subjective/physical examination, subgrouping factors, and standardized questionnaires. Univariate analysis followed by generalized estimating equations were used to develop a multivariate prognostic model for back pain, leg pain, and activity limitation. Fifty-eight prognostic factors progressed to the multivariate stage where 15 showed significant (P<.05) associations with at least 1 of the 3 outcomes. There were 5 indicators of positive outcome (2 types of LBD subgroups, paresthesia below waist, walking as an easing factor, and low transversus abdominis tone) and 10 indicators of negative outcome (both parents born overseas, deep leg symptoms, longer sick leave duration, high multifidus tone, clinically determined inflammation, higher back and leg pain severity, lower lifting capacity, lower work capacity, and higher pain drawing percentage coverage). The preliminary model identifying predictors of LBDs explained up to 37% of the variance in outcome. CONCLUSIONS: This study evaluated a comprehensive range of prognostic factors reflective of both the biomedical and psychosocial domains of LBDs. The preliminary multivariate model requires further validation before being considered for clinical use.

Research priorities about stoma-related quality of life from the perspective of people with a stoma: A pilot survey.

BACKGROUND: There is a recognized need to include patients in setting research priorities. Research priorities identified by people with a stoma are rarely elicited. OBJECTIVES: To improve the quality of life of people with a stoma through use of evidence-based practice based on research priorities set by patients. DESIGN AND METHODS: Online pilot survey publicized in 2016 via United Kingdom stoma charities. People ranked nine stoma-related quality of life topics in order of research priority. PARTICIPANTS: People 16 years of age and over who currently have or have had a stoma for treatment for any medical condition. ANALYSIS: Distributions of the priority scores for each of the nine research topics were examined. Group differences were explored using either the Mann-Whitney U-test or the Kruskal-Wallis test depending on the number of groups. RESULTS: In total, 225 people completed the survey. The most important research priority was pouch leak problems and stoma bag/appliance problems followed by hernia risk. There were statistically significant differences in ranking research priorities between males and females, age, underlying disease that led to a stoma, stoma type and length of time with a stoma. CONCLUSION: People with a stoma are willing to engage in and set research priorities. The results should contribute towards future research about setting the research agenda for the study of stoma-related concerns that impact quality of life.

Individualised physiotherapy as an adjunct to guideline-based advice for low back disorders in primary care: a randomised controlled trial.

BACKGROUND: Many patients with low-back disorders persisting beyond 6 weeks do not recover. This study investigates whether individualised physiotherapy plus guideline-based advice results in superior outcomes to advice alone in participants with low-back disorders. METHODS: This prospective parallel group multicentre randomised controlled trial was set in 16 primary care physiotherapy practices in Melbourne, Australia. Random assignment resulted in 156 participants receiving 10 sessions of physiotherapy that was individualised based on pathoanatomical, psychosocial and neurophysiological barriers to recovery combined with guideline-based advice, and 144 participants receiving 2 sessions of physiotherapist-delivered advice alone. Primary outcomes were activity limitation (Oswestry Disability Index) and numerical rating scales for back and leg pain at 5, 10, 26 and 52 weeks postbaseline. Analyses were by intention-to-treat using linear mixed models. RESULTS: Between-group differences showed significant effects favouring individualised physiotherapy for back and leg pain at 10 weeks (back: 1.3, 95% CI 0.8 to 1.8; leg: 1.1, 95% CI 0.5 to 1.7) and 26 weeks (back: 0.9, 95% CI 0.4 to 1.4; leg: 1.0, 95% CI 0.4 to 1.6). Oswestry favoured individualised physiotherapy at 10 weeks (4.7; 95% CI 2.0 to 7.5), 26 weeks (5.4; 95% CI 2.6 to 8.2) and 52 weeks (4.3; 95% CI 1.4 to 7.1). Responder analysis at 52 weeks showed participants receiving individualised physiotherapy were more likely to improve by a clinically important amount of 50% from baseline for Oswestry (relative risk (RR=1.3) 1.5; 95% CI 1.2 to 1.8) and back pain (RR 1.3; 95% CI 1.2 to 1.8) than participants receiving advice alone. CONCLUSIONS: 10 sessions of individualised physiotherapy was more effective than 2 sessions of advice alone in participants with low-back disorders of ≥6 weeks and ≤6 months duration. Between-group changes were sustained at 12 months for activity limitation and 6 months for back and leg pain and were likely to be clinically significant. CLINICAL TRIAL REGISTRATION: ACTRN12609000834257.

Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.

BACKGROUND: EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. METHODS: In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. FINDINGS: Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥ 3 neutropenia 35 [13%] vs 74 [28%]). INTERPRETATION: Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. FUNDING: Amgen, UK National Institute for Health Research Biomedical Research Centre.

Predicting cardiovascular events with fluoropyrimidine chemotherapy using a standard cardiovascular risk calculator.

AIMS: Fluoropyrimidine chemotherapy is important for treatment of many solid tumours but is associated with cardiotoxicity. The relationship of fluoropyrimidine-associated cardiotoxicity (FAC) with conventional cardiovascular (CV) risk factors is poorly understood, and standard cardiovascular risk scores are not validated in this context. METHODS AND RESULTS: Single-centre retrospective study of patients treated with fluoropyrimidine chemotherapy using electronic health records for cardiovascular risk factors (and calculation of QRISK3 score), cancer treatment, and clinical outcomes. FAC was defined by cardiovascular events during or within 3 months of fluoropyrimidine treatment, and Cox regression was used to assess associations of CV risk and cancer treatment with FAC. One thousand eight hundred ninety-eight patients were included (45% male; median age 64 years), with median follow up 24.5 (11.5-48.3 months); 52.7% of patients were at moderate or high baseline CV risk (QRISK3 score >10%) Cardiovascular events occurred in 3.1% (59/1898)-most commonly angina (64.4%, 38/59) and atrial fibrillation (13.6%, 8/59), with 39% events during cycle one of treatment. In univariable analysis, QRISK3 score >20% was significantly associated with incident FAC (HR 2.25, 95% CI 1.11-4.93, P = 0.03). On multivariable analysis, beta-blocker use (HR 1.04, 95% CI 1.00-1.08, P = 0.04) and higher BMI (HR 2.33, 95% CI 1.04-5.19, P = 0.04) were independently associated with incident CV events. Thirty-two of the 59 patients with FAC were subsequently rechallenged with fluoropyrimidine chemotherapy, with repeat CV events in 6% (2/32). Incident FAC did not affect overall survival (P = 0.50). CONCLUSIONS: High BMI and use of beta-blockers are associated with risk of CV events during fluoropyrimidine chemotherapy. QRISK3 score may also play a role in identifying patients at high risk of CV events during fluoropyrimidine chemotherapy. Re-challenge with further fluoropyrimidine chemotherapy can be considered in patients following CV events during prior treatment.

Effect of Training on Physicians' Palliative Care-Related Knowledge and Attitudes in Vietnam.

CONTEXT: Palliative care remains largely inaccessible in low- and middle-income countries (LMICs), and efforts to increase access are impeded by lack of training of proven effectiveness for physicians. OBJECTIVES: To measure the effectiveness of palliative care training for Vietnamese physicians. METHODS: The palliative care-related knowledge, attitudes, and self-assessment of Vietnamese physicians were studied prior to a basic course in palliative care (baseline), just after the physicians completed the course (post), and 6-18 months later (follow-up). RESULTS: The self-assessment scores and knowledge scores increased significantly from baseline to post and decreased significantly from post to follow-up, but the follow-up scores remained significantly higher than baseline. There were significant interactions between changes over time of the knowledge scores and baseline age, degree, years of graduation, training, type of work, and whether participants had ever prescribed morphine for pain. Medically appropriate attitudes increased significantly from baseline to post and did not decrease significantly from post to follow-up. CONCLUSION: Our basic palliative care course in Vietnam resulted in significant and enduring improvements among physicians in palliative care-related knowledge, attitudes, and self-assessed competence. To respond to the enormous unmet need for palliative care in LMICs, primary care providers and physician-specialists in many fields, among others, should receive palliative care training of proven effectiveness, receive ongoing mentoring or refresher training, and be given the responsibility and opportunity to practice what they learn.

G-CSF rescue of FOLFIRINOX-induced neutropenia leads to systemic immune suppression in mice and humans.

BACKGROUND: Recombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic myelopoiesis and granulopoiesis in patients with cancer has been shown to induce immature monocytes and neutrophils that contribute to both systemic and local immunosuppression in the tumor microenvironment. The effect of recombinant G-CSF (pegfilgrastim or filgrastim) on the production of myeloid-derived suppressive cells is unknown. Here we examined patients with pancreatic cancer, a disease known to induce myeloid-derived suppressor cells (MDSCs), and for which pegfilgrastim is routinely administered concurrently with FOLFIRINOX but not with gemcitabine-based chemotherapy regimens. METHODS: Serial blood was collected from patients with pancreatic ductal adenocarcinoma newly starting on FOLFIRINOX or gemcitabine/n(ab)paclitaxel combination chemotherapy regimens. Neutrophil and monocyte frequencies were determined by flow cytometry from whole blood and peripheral blood mononuclear cell fractions. Serum cytokines were evaluated pretreatment and on-treatment. Patient serum was used in vitro to differentiate healthy donor monocytes to MDSCs as measured by downregulation of major histocompatibility complex II (HLA-DR) and the ability to suppress T-cell proliferation in vitro. C57BL/6 female mice with pancreatic tumors were treated with FOLFIRINOX with or without recombinant G-CSF to directly assess the role of G-CSF on induction of immunosuppressive neutrophils. RESULTS: Patients receiving FOLFIRINOX with pegfilgrastim had increased serum G-CSF that correlated with an induction of granulocytic MDSCs. This increase was not observed in patients receiving gemcitabine/n(ab)paclitaxel without pegfilgrastim. Interleukin-18 also significantly increased in serum on FOLFIRINOX treatment. Patient serum could induce MDSCs as determined by in vitro functional assays, and this suppressive effect increased with on-treatment serum. Induction of MDSCs in vitro could be recapitulated by addition of recombinant G-CSF to healthy serum, indicating that G-CSF is sufficient for MDSC differentiation. In mice, neutrophils isolated from spleen of G-CSF-treated mice were significantly more capable of suppressing T-cell proliferation. CONCLUSIONS: Pegfilgrastim use contributes to immune suppression in both humans and mice with pancreatic cancer. These results suggest that use of recombinant G-CSF as supportive care, while critically important for mitigating neutropenia, may complicate efforts to induce antitumor immunity.

Treating the treatment: chemotherapy-induced multi-organ toxicity.

A 40-year-old man presented to a local hospital with a 2-day history of dyspnoea having been started on adjuvant chemotherapy consisting of oxaliplatin and capecitabine for mucinous adenocarcinoma of the colon. During his admission, he develops chest pain, worsening shortness of breath, and intermittent dysarthria and disorientation. Investigations reveal severely impaired left ventricular function on echocardiogram, bilateral acute pulmonary embolisms on CT pulmonary angiogragraphy, and diffused subcortical and callosal white matter signal change and restricted diffusion consistent with a toxic leukoencephalopathy on MRI of brain. This case highlights the pivotal role of the multidisciplinary cardio-oncology approach which enabled these challenging diagnoses to be made and ensured optimal patient outcome.

Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer.

Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.

Correction: BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration.

BRF1 is a rate-limiting factor for RNA Polymerase III-mediated transcription and is elevated in numerous cancers. Here, we report that elevated levels of BRF1 associate with poor prognosis in human prostate cancer. In vitro studies in human prostate cancer cell lines demonstrated that transient overexpression of BRF1 increased cell proliferation whereas the transient downregulation of BRF1 reduced proliferation and mediated cell cycle arrest. Consistent with our clinical observations, BRF1 overexpression in a Pten-deficient mouse (PtenΔ/Δ BRF1Tg) prostate cancer model accelerated prostate carcinogenesis and shortened survival. In PtenΔ/Δ BRF1Tg tumours, immune and inflammatory processes were altered, with reduced tumoral infiltration of neutrophils and CD4 positive T cells, which can be explained by decreased levels of complement factor D (CFD) and C7 components of the complement cascade, an innate immune pathway that influences the adaptive immune response. We tested if the secretome was involved in BRF1-driven tumorigenesis. Unbiased proteomic analysis on BRF1-overexpresing PC3 cells confirmed reduced levels of CFD in the secretome, implicating the complement system in prostate carcinogenesis. We further identify that expression of C7 significantly correlates with expression of CD4 and has the potential to alter clinical outcome in human prostate cancer, where low levels of C7 associate with poorer prognosis.

The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rapidly progressive invariably lethal tumor. Treatment options remain limited and the outcome in relapsed disease is poor warranting new therapeutic options. Following our previous experience in the first-line setting, we conducted a phase 2 open-label non-comparative study to assess the safety and efficacy of weekly vinorelbine chemotherapy, each cycle consisting of 30 mg/m(2) for 6 weeks, in patients with previous exposure to chemotherapy. In 63 individuals with relapsed MPM who had not received previous vinorelbine, we observed an objective response rate of 16% and an overall survival of 9.6 months (95% confidence interval 7.3-11.8 months). The main grade III/IV toxicity observed was neutropenia and toxicity was similar to weekly vinorelbine when used in the first-line setting. Weekly vinorelbine appeared to have a reasonable response rate with an acceptable toxicity profile in the second-line treatment of MPM. Its use should be prospectively evaluated in a randomised trial in the first or second-line therapy of MPM.

Individualised manual therapy plus guideline-based advice vs advice alone for people with clinical features of lumbar zygapophyseal joint pain: a randomised controlled trial.

OBJECTIVES: To determine whether individualised manual therapy plus guideline-based advice results in superior outcomes to advice alone in participants with clinical features potentially indicative of lumbar zygapophyseal joint pain. DESIGN: Multi centre parallel group randomised controlled trial. SETTING: 14 physiotherapy clinics in Melbourne, Australia. PARTICIPANTS: Sixty-four participants with clinical features potentially indicative of lumbar zygapophyseal joint pain. INTERVENTIONS: 10-weeks of physiotherapy comprising individualised manual therapy based on pathoanatomical, psychosocial and neurophysiological barriers to recovery plus guideline-based advice (10 sessions) or advice alone (two sessions). MAIN OUTCOME MEASURES: Primary outcomes were activity limitation (Oswestry Disability Index), and separate 0 to 10 numerical rating scales for leg pain and back pain. Measures were taken at baseline and 5, 10, 26 and 52-week. RESULTS: Between-group differences for back pain favoured individualised manual therapy over advice for back pain at 5 (1.0; 95% CI 0.6 to 2.0), 10 (1.5; 95% CI 0.5 to 2.4) and 26-weeks (1.4; 95% CI 0.4 to 2.3) as well as for activity limitation at 26 (8.3; 95% CI 2.6 to 14.2) and 52-weeks (8.2; 95% CI 2.3 to 14.2). There were no significant between-group differences for leg pain. Secondary outcomes and responder analyses also favoured individualised manual therapy at almost all time-points. CONCLUSIONS: In participants with clinical features potentially indicative of lumbar zygapophyseal joint pain, individualised manual therapy led to greater reduction in back pain at 5, 10 and 26-week follow-up as well as activity limitation at 26 and 52-weeks. Between-group differences were likely to be clinically important. TRIAL REGISTRATION: ACTRN12609000334202.

Palliative Care-Related Knowledge, Attitudes, and Self-Assessment Among Physicians in Vietnam.

CONTEXT: Palliative care is rarely accessible in low- and middle-income countries, and lack of adequate training for health care providers is a key reason. In Vietnam, the Ministry of Health, major hospitals and medical universities, and foreign physician-educators have partnered to initiate palliative care training for physicians. OBJECTIVES: To measure the baseline palliative care-related knowledge, attitudes, and self-assessment of Vietnamese physicians as a basis for curriculum development and to enable evaluation of training courses. METHODS: Before palliative care training courses in Vietnam from 2007 to 2014, we collected data on the participating physicians' demographics, self-assessed competence in palliative care, and palliative care-related knowledge and attitudes. Scores were calculated in three outcome categories-knowledge, attitudes, and self-assessment-and in two subcategories related to physical and psychological symptoms. Associations between the demographic, education, and practice factors and these scores were assessed using linear regression. RESULTS: Among the 392 physicians surveyed, concern about untreated suffering was highly prevalent. 85% felt that most patients with cancer in Vietnam die in pain. On self-assessment, only 8% felt adequately trained in palliative care and the mean knowledge assessment score was 44%. Although 77% had prescribed an opioid in the past year and most had appropriate attitudes toward the use of morphine for pain, the majority reported explicit or implicit restrictions on prescribing morphine. CONCLUSION: There is a great need among Vietnam's physicians for training in palliative care and especially in nonpain and psychological symptom control. Rational, balanced, and clear opioid-prescribing policies are needed to enable physicians to treat pain without fear of repercussions.