Overall survival with [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial.

BACKGROUND: The TheraP study reported improved prostate-specific antigen responses with lutetium-177 [177Lu]Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer progressing after docetaxel. In this Article, we report the secondary outcome of overall survival with mature follow-up, and an updated imaging biomarker analysis. We also report the outcomes of participants excluded due to ineligibility on gallium-68 [68Ga]Ga-PSMA-11 and 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) PET-CT. METHODS: TheraP was an open-label, randomised phase 2 trial at 11 centres in Australia. Eligible participants had metastatic castration-resistant prostate cancer progressing after docetaxel, and PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG that showed prostate-specific membrane antigen (PSMA)-positive disease and no sites of metastatic disease with discordant 2-[18F]FDG-positive and PSMA-negative findings. Participants were randomly assigned (1:1) to treatment with [177Lu]Lu-PSMA-617 (every 6 weeks for a maximum of six cycles; starting at 8·5 GBq, decreasing by 0.5 GBq to 6·0 GBq for the sixth cycle) versus cabazitaxel (20 mg/m2 every 3 weeks, maximum of ten cycles). Overall survival was analysed by intention-to-treat and summarised as restricted mean survival time (RMST) to account for non-proportional hazards, with a 36-month restriction time corresponding to median follow-up. This trial is registered with ClinicalTrials.gov, NCT03392428, and is complete. FINDINGS: 291 men were registered from Feb 6, 2018, to Sept 3, 2019; after study imaging, 200 were eligible and randomly assigned to treatment with [177Lu]Lu-PSMA-617 (n=99) or cabazitaxel (n=101). After completing study treatment, 20 (20%) participants assigned to cabazitaxel and 32 (32%) assigned to [177Lu]Lu-PSMA-617 were subsequently treated with the alternative regimen. After a median follow-up of 35·7 months (IQR 31·1 to 39·2), 77 (78%) participants had died in the [177Lu]Lu-PSMA-617 group and 70 (69%) participants had died in the cabazitaxel group. Overall survival was similar among those assigned to [177Lu]Lu-PSMA-617 versus those assigned to cabazitaxel (RMST 19·1 months [95% CI 16·9 to 21·4] vs 19·6 months [17·4 to 21·8]; difference -0·5 months [95% CI -3·7 to 2·7]; p=0·77). No additional safety signals were identified with the longer follow-up in this analysis. 80 (27%) of 291 men who were registered after initial eligibility screening were excluded after [68Ga]Ga-PSMA-11 and 2-[18F]FDG PET. In the 61 of these men with follow-up available, RMST was 11·0 months (95% CI 9·0 to 13·1). INTERPRETATION: These results support the use of [177Lu]Lu-PSMA-617 as an alternative to cabazitaxel for PSMA-positive metastatic castration-resistant prostate cancer progressing after docetaxel. We did not find evidence that overall survival differed between the randomised groups. Median overall survival was shorter for men who were excluded because of low PSMA expression or 2-[18F]FDG-discordant disease. FUNDING: Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, It's a Bloke Thing, CAN4CANCER, and The Distinguished Gentleman's Ride.

[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Enhancing circulatory myokines and extracellular vesicle uptake with targeted exercise in patients with prostate cancer (the MYEX trial): a single-group crossover study.

INTRODUCTION: Physical activity is associated with improved disease progression and cancer-specific survival in patients with prostate cancer (PCa). However, the mechanisms underlying these associations remain unclear, while the relative impact of exercise modes is unknown. This study aims to examine the differential impact of exercise mode on tumour-suppressive skeletal muscle-associated systemic molecules as well as their delivery mechanism. This study will compare the effects of the two main exercise modes, aerobic and resistance, on (1) circulatory myokine levels, (2) skeletal muscle-induced extracellular vesicle abundance and cargo contents, and (3) uptake of extracellular vesicles (EVs) in PCa cells in patients with localised or advanced PCa. METHODS: A single-group cross-over design will be used for patients at opposite ends of the disease spectrum. A total of 32 patients (localised PCa, n = 16; metastatic castrate-resistant PCa, n = 16) will be recruited while capitalising on two ongoing studies. Ethics amendment has been approved for two ongoing trials to share data, implement the acute exercise sessions, and collect additional blood samples from patients. The patients will undertake two exercise sessions (aerobic only and resistance only) in random order one week apart. Blood will be collected before, after, and 30 min post-exercise. Circulating/EV-contained myokine levels (irisin, IL-6, IL-15, FGF-21, and SPARC) and plasma skeletal muscle-induced EVs will be measured using ELISA and flow cytometry. PCa cell line growth with or without collected plasma will be examined using PCa cell lines (LNCaP, DU-145, and PC-3), while evaluating cellular uptake of EVs. Ethics amendments have been approved for two capitalising studies to share data, implement acute exercise sessions and collect additional samples from the patients. DISCUSSION: If findings show a differential impact of exercise mode on the establishment of an anti-cancer systemic environment, this will provide fundamental knowledge for developing targeted exercise prescriptions for patients with PCa across different disease stages. Findings will be reported in peer-reviewed publications and scientific conferences, in addition to working with national support groups to translate findings for the broader community. TRIAL REGISTRATION: The registration for the two capitalising studies are NCT02730338 and ACTRN12618000225213.

Loss of tumor-derived SMAD4 enhances primary tumor growth but not metastasis following BMP4 signalling.

BACKGROUND: Bone morphogenetic protein 4 (BMP4) is a potent inhibitor of breast cancer metastasis. However, a tumor-promoting effect of BMP4 is reported in other tumor types, especially when SMAD4 is inactive. METHODS: To assess the requirement for SMAD4 in BMP4-mediated suppression of metastasis, we knocked down SMAD4 in two different breast tumors and enforced SMAD4 expression in a third line with endogenous SMAD4 deletion. In addition, we assessed the requirement for SMAD4 in tumor cell-specific BMP signalling by expression of a constitutively active BMP receptor. Delineation of genes regulated by BMP4 in the presence or absence of SMAD4 was assessed by RNA sequencing and a BMP4-induced gene, MYO1F was assessed for its role in metastasis. Genes regulated by BMP4 and/or SMAD4 were assessed in a publicly available database of gene expression profiles of breast cancer patients. RESULTS: In the absence of SMAD4, BMP4 promotes primary tumor growth that is accompanied by increased expression of genes associated with DNA replication, cell cycle, and MYC signalling pathways. Despite increased primary tumor growth, BMP4 suppresses metastasis in the absence of tumor cell expression of SMAD4. Consistent with the anti-metastatic activity of BMP4, enforced signalling through the constitutively active receptor in SMAD4 positive tumors that lacked BMP4 expression still suppressed metastasis, but in the absence of SMAD4, the suppression of metastasis was largely prevented. Thus BMP4 is required for suppression of metastasis regardless of tumor SMAD4 status. The BMP4 upregulated gene, MYO1F, was shown to be a potent suppressor of breast cancer metastasis. Gene signature upregulated by BMP4 in the absence of SMAD4 was associated with poor prognosis in breast cancer patients, whereas gene signature upregulated by BMP4 in the presence of SMAD4 was associated with improved prognosis. CONCLUSIONS: BMP4 expression is required for suppression of metastasis regardless of the SMAD4 status of the tumor cells. Since BMP4 is a secreted protein, we conclude that it can act both in an autocrine manner in SMAD4-expressing tumor cells and in a paracrine manner on stromal cells to suppress metastasis. Deletion of SMAD4 from tumor cells does not prevent BMP4 from suppressing metastasis via a paracrine mechanism.

The SUB-urothelial DUrvalumab InjEction-1 (SUBDUE-1) trial: first-in-human trial in patients with bladder cancer.

OBJECTIVES: To assess the safety of sub-urothelial injection of durvalumab and examine the impact on tissue and circulating immune cell populations. PATIENTS AND METHODS: The patients were chemotherapy and immunotherapy naïve (bacille Calmette-Guérin allowed) with non-metastatic muscle-invasive bladder cancer or non-muscle-invasive bladder cancer planned for radical cystectomy (RC). The study was a Phase Ib 3 + 3 dose-escalation design with sub-urothelial injection of durvalumab at three pre-determined doses (25, 75, 150 mg) diluted in 25 mL normal saline, injected at 25 locations (25 × 1 mL injections), at least 2 weeks before RC. RESULTS: A total of 11 patients were recruited (10 male, one female). No significant changes were reported on American Urological Association Symptom Score or O'Leary Interstitial Cystitis Scale. In all, 14 adverse events (AEs) were reported (10 Grade 1, three Grade 2, one Grade 3), none considered immune-related. No Grade 4 or 5 AEs were recorded. All the patients underwent RC. Tissue immune populations changed following durvalumab injection (P = 0.012), with a statistically significant increase in M2-macrophage (CD163) when comparing the 25-150 mg dose (P = 0.021). Basal/mixed cancers showed a larger CD163 increase than luminal cancers (P = 0.033). CONCLUSION: Sub-urothelial injection of durvalumab is feasible and safe without immune-related AEs and shows local immunological effects.

A phase 1 study in healthy participants to characterize the safety and pharmacology of inclacumab, a fully human anti-P-selectin antibody, in development for treatment of sickle cell disease.

PURPOSE: We evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of intravenous (IV) inclacumab, a fully human IgG4 anti-P-selectin monoclonal antibody in development for the treatment of sickle cell disease, at doses up to and exceeding those previously tested in healthy individuals. METHODS: In this phase 1, open-label, single-ascending-dose study, 15 healthy participants were enrolled into cohorts receiving 20 mg/kg (n = 6) or 40 mg/kg (n = 9) IV inclacumab and observed for up to 29 weeks post-dose. Safety, PK parameters, thrombin receptor-activating peptide (TRAP)-activated platelet-leukocyte aggregate (PLA) formation, P-selectin inhibition, plasma soluble P-selectin, and anti-drug antibodies were characterized. RESULTS: Two inclacumab-related treatment-emergent adverse events were reported in 1 participant; no dose-limiting toxicities were observed. Plasma PK parameters were generally dose-proportional, with a terminal half-life of 13 to 17 days. Mean TRAP-activated PLA formation decreased within 3 h from the start of infusion, and inhibition was sustained for ~ 23 weeks. Mean P-selectin inhibition > 90% was observed up to 12 weeks post-dose. The mean ratio of free to total soluble P-selectin decreased rapidly from pre-dose to end of infusion, then increased gradually to 78% of the baseline ratio by week 29. Treatment-emergent anti-drug antibodies were observed in 2 of 15 participants (13%), without apparent impact on safety, PK, or PD. CONCLUSIONS: Inclacumab was well tolerated, with PK as expected for a monoclonal antibody against a membrane-bound target and a long duration of PD effects after both single IV doses, supporting a prolonged dosing interval. TRIAL REGISTRATION: ACTRN12620001156976; registered November 4, 2020.

Competencies of junior medical doctors in managing seriously ill and injured children: time to rethink our current training approach?

BACKGROUND: The correct treatment of very ill and injured children is critical, yet little is known about the competencies of South African (SA) junior doctors in managing these children. METHODS: This survey documents SA junior doctors' reported resuscitation training opportunities, experience, skills and knowledge. RESULTS: A total of 118 doctors (interns, medical officers and registrars) from paediatric departments affiliated with 7 medical schools, participated. Resuscitations were not rare events with 71% (84/118) reporting participation in >10 resuscitations during the preceding 2 years. Yet a third of doctors have not attended an accredited resuscitation training course within the last 2 years; 34% (12/35) medical officers and 29% (18/63) registrars, respectively, with 42% (49/118) of all participants never receiving any formal resuscitation training during employment. Feedback on performance is not standard practice with only 8% (10/118) reporting consistent debriefing after a resuscitation. Although 72% (85/118) reported their resuscitation knowledge as adequate, 56% (66/118) passed the knowledge test. CONCLUSION: This study recognized missed learning opportunities in junior doctors' training, assessment, debriefing and knowledge which may adversely affect the quality of care in managing paediatric emergencies. This has implications for departmental and post-graduate training programmes.

The correct treatment of very ill and injured children is critical, yet little is known about the competencies of South African (SA) junior doctors in managing these children. This study surveyed SA junior doctors' reported life-saving training opportunities, experience, skills and knowledge, with 118 doctors working at hospitals affiliated with 7 medical schools participating. Resuscitations were not rare events with 71% (84/118) reporting participation in >10 resuscitations during the preceding 2 years. Yet about one-third of medical officers (34%; 12/35) and paediatric registrars (29%; 18/63) have not attended an accredited resuscitation training course within the last 2 years, and 42% (49/118) of all participants reportedly did not receive any formal resuscitation training during employment. Feedback on performance after resuscitations is not standard practice and only 8% (10/118) reported consistent debriefing afterwards. Although 72% (85/118) reported their resuscitation knowledge as adequate, only 56% (66/118) passed the knowledge test. Inadequate knowledge of the treatment of very ill and injured children may adversely affect the quality of care provided in paediatric emergencies. There appear to be several missed formal and informal learning opportunities which may improve both quality of care and doctor wellbeing. This has implications for training programmes.

[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial.

BACKGROUND: Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers ß radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. METHODS: We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0-2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. FINDINGS: Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16-42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9-37]; p=0·0016). Grade 3-4 adverse events occurred in 32 (33%) of 98 men in the [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [177Lu]Lu-PSMA-617. INTERPRETATION: [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. FUNDING: Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.

Measuring and Modelling the Epithelial- Mesenchymal Hybrid State in Cancer: Clinical Implications.

The epithelial-mesenchymal (E/M) hybrid state has emerged as an important mediator of elements of cancer progression, facilitated by epithelial mesenchymal plasticity (EMP). We review here evidence for the presence, prognostic significance, and therapeutic potential of the E/M hybrid state in carcinoma. We further assess modelling predictions and validation studies to demonstrate stabilised E/M hybrid states along the spectrum of EMP, as well as computational approaches for characterising and quantifying EMP phenotypes, with particular attention to the emerging realm of single-cell approaches through RNA sequencing and protein-based techniques.

How much time do doctors spend providing care to each child in the ED? A time and motion study.

BACKGROUND: The total time per patient doctors spend providing care in emergency departments (EDs) has implications for the development of evidence-based ED staffing models. We sought to measure the total time taken by doctors to assess and manage individual paediatric patients presenting to two EDs in the Western Cape, South Africa and to compare these averages to the estimated benchmarks used regionally to calculate ED staffing allocations. METHODS: We conducted a cross-sectional, observational study applying time and motion methodology, using convenience sampling. Data were collected over a 5-week period from 11 December 2015 to 18 January 2016 at Khayelitsha District Hospital Emergency Centre and Tygerberg Hospital Paediatric Emergency and Ambulatory Unit. We assessed total doctor time for each patient stratified by acuity level using the South African Triage Scale. RESULTS: Care was observed for a total of 100 patients. Median age was 21 months (IQR 8-55). Median total doctor time per patient (95% CI) was 31 (22 to 38), 39 (31 to 63), 48 (32 to 63) and 96 (66 to 122) min for triage categories green, yellow, orange and red, respectively. Median timing was significantly higher than the estimated local benchmark for the lowest acuity 'green' triage category (31 min (22 to 38) vs 15 min; p=0.001) and the highest acuity 'red' category (96 min (66 to 122) vs 50 min; p=0.002). CONCLUSION: Doctor time per patient increased with increasing acuity of triage category and exceeded estimated benchmarks for the highest and lowest acuities. The distinctive methodology can easily be extended to other settings and populations.

Clinical Experience With Severe Acute Respiratory Syndrome Coronavirus 2-Related Illness in Children: Hospital Experience in Cape Town, South Africa.

BACKGROUND: Children seem relatively protected from serious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease, but little is known about children living in settings with high tuberculosis and human immunodeficiency virus (HIV) burden. This study reflects clinical data on South African children with SARS-CoV-2. METHODS: We collected clinical data of children aged <13 years with laboratory-confirmed SARS-CoV-2 presenting to Tygerberg Hospital, Cape Town, between 17 April and 24 July 2020. RESULTS: One hundred fifty-nine children (median age, 48.0 months [interquartile range {IQR}, 12.0-106.0 months]) were included. Hospitalized children (n = 62), with a median age of 13.5 months (IQR, 1.8-43.5 months) were younger than children not admitted (n = 97; median age, 81.0 months [IQR, 34.5-120.5 months]; P < .01.). Thirty-three of 159 (20.8%) children had preexisting medical conditions. Fifty-one of 62 (82.3%) hospitalized children were symptomatic; lower respiratory tract infection was diagnosed in 21 of 51 (41.2%) children, and in 11 of 16 (68.8%) children <3 months of age. Respiratory support was required in 25 of 51 (49.0%) children; 13 of these (52.0%) were <3 months of age. One child was HIV infected and 11 of 51 (21.2%) were HIV exposed but uninfected, and 7 of 51 (13.7%) children had a recent or new diagnosis of tuberculosis. CONCLUSIONS: Children <1 year of age hospitalized with SARS-CoV-2 in Cape Town frequently required respiratory support. Access to oxygen may be limited in some low- and middle-income countries, which could potentially drive morbidity and mortality. HIV infection was uncommon but a relationship between HIV exposure, tuberculosis, and SARS-CoV-2 should be explored.

The Critical Need for Pooled Data on Coronavirus Disease 2019 in African Children: An AFREhealth Call for Action Through Multicountry Research Collaboration.

Globally, there are prevailing knowledge gaps in the epidemiology, clinical manifestations, and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among children and adolescents; and these gaps are especially wide in African countries. The availability of robust age-disaggregated data is a critical first step in improving knowledge on disease burden and manifestations of coronavirus disease 2019 (COVID-19) among children. Furthermore, it is essential to improve understanding of SARS-CoV-2 interactions with comorbidities and coinfections such as human immunodeficiency virus (HIV), tuberculosis, malaria, sickle cell disease, and malnutrition, which are highly prevalent among children in sub-Saharan Africa. The African Forum for Research and Education in Health (AFREhealth) COVID-19 Research Collaboration on Children and Adolescents is conducting studies across Western, Central, Eastern, and Southern Africa to address existing knowledge gaps. This consortium is expected to generate key evidence to inform clinical practice and public health policy-making for COVID-19 while concurrently addressing other major diseases affecting children in African countries.

A phase I open label dose-escalation study to evaluate the tolerability, safety and immunological efficacy of sub-urothelial durvalumab injection in adults with muscle-invasive or high-risk non-muscle-invasive bladder cancer (SUBDUE-1, SUB-urothelial DUrvalumab injection-1 study): clinical trial protocol.

OBJECTIVES: This article presents the clinical trial protocol for a phase I open label dose-escalation study to evaluate the tolerability, safety and immunological efficacy of sub-urothelial durvalumab injection in adults with muscle-invasive or high-risk non-muscle-invasive bladder cancer (NMIBC), the SUB-urothelial DUrvalumab injection-1 study (SUBDUE-1). The primary objectives of this study are to assess the safety of sub-urothelial injection of durvalumab using patient reported outcome measures and observed local or systemic adverse events. The secondary objectives are to examine the local immunological efficacy of sub-urothelial administration of durvalumab. PATIENTS AND METHODS: The SUBDUE-1 trial will include adult patients with either high-risk NMIBC or MIBC, who are scheduled for radical cystectomy or who have refused or are unsuitable for systemic neoadjuvant chemotherapy. Three fixed total dose levels of durvalumab (25, 75, 150 mg) will be studied to identify a dose suitable to be taken forward into phase II trials. The primary endpoint is to evaluate the safety and tolerability of the trial intervention in terms of the incidence and severity of adverse events and the potential establishment of dose-limiting toxicities. The secondary efficacy endpoints include rates of pT0 status at resection, lymph node status, as well as the change in distribution of tumour-infiltrating lymphocytes and tumour-activated macrophages between pre- and post-injection bladder biopsies. Translational studies will focus on bladder tumour molecular sub-typing, immune infiltrate characterisation, and immune checkpoint protein expression relative to efficacy end-points. OUTCOME AND SIGNIFICANCE: If proven safe and effective, this novel strategy comprising sub-urothelial durvalumab injections aimed at promoting an anti-tumour immune reaction, will provide additional treatment options for reducing tumour recurrence and progression in treatment-naïve patients with high-risk NMIBC or in patients with bacille Calmette-Guérin-refractory NMIBC. Local administration of durvalumab may be associated with a reduced rate of immunological side-effects and lower costs when compared to systemic delivery.

Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer.

BACKGROUND: Retrospective analyses suggest that capecitabine may carry superior activity in hormone receptor-positive relative to hormone receptor-negative metastatic breast cancer. This review examined the veracity of that finding and explored whether this differential activity extends to early breast cancer. OBJECTIVES: To assess effects of chemotherapy regimens containing capecitabine compared with regimens not containing capecitabine for women with hormone receptor-positive versus hormone receptor-negative breast cancer across the three major treatment scenarios: neoadjuvant, adjuvant, metastatic. SEARCH METHODS: On 4 June 2019, we searched the Cochrane Breast Cancer Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 5) in the Cochrane Library; MEDLINE; Embase; the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials looking at chemotherapy regimens containing capecitabine alone or in combination with other agents versus a control or similar regimen without capecitabine for treatment of breast cancer at any stage. The primary outcome measure for metastatic and adjuvant trials was overall survival (OS), and for neoadjuvant studies pathological complete response (pCR). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. Hazard ratios (HRs) were derived for time-to-event outcomes, and odds ratios (ORs) for dichotomous outcomes, and meta-analysis was performed using a fixed-effect model. MAIN RESULTS: We included 26 studies with outcome data by hormone receptor: 12 metastatic studies (n = 4325), 6 neoadjuvant trials (n = 3152), and 8 adjuvant studies (n = 13,457). Capecitabine treatment was added in several different ways across studies. These could be classified as capecitabine alone compared to another treatment, capecitabine substituted for part of the control chemotherapy, and capecitabine added to control chemotherapy. In the metastatic setting, the effect of capecitabine was heterogenous between hormone receptor-positive and -negative tumours. For OS, no difference between capecitabine-containing and non-capecitabine-containing regimens was observed for all participants taken together (HR 1.01, 95% confidence interval (CI) 0.98 to 1.05; 12 studies, 4325 participants; high-certainty evidence), for those with hormone receptor-positive disease (HR 0.93, 95% CI 0.84 to 1.04; 7 studies, 1834 participants; high-certainty evidence), and for those with hormone receptor-negative disease (HR 1.00, 95% CI 0.88 to 1.13; 8 studies, 1577 participants; high-certainty evidence). For progression-free survival (PFS), a small improvement was seen for all people (HR 0.89, 95% CI 0.82 to 0.96; 12 studies, 4325 participants; moderate-certainty evidence). This was largely accounted for by a moderate improvement in PFS for inclusion of capecitabine in hormone receptor-positive cancers (HR 0.82, 95% CI 0.73 to 0.91; 7 studies, 1594 participants; moderate-certainty evidence) compared to no difference in PFS for hormone receptor-negative cancers (HR 0.96, 95% CI 0.83 to 1.10; 7 studies, 1122 participants; moderate-certainty evidence). Quality of life was assessed in five studies; in general there did not seem to be differences in global health scores between the two treatment groups at around two years' follow-up. Neoadjuvant studies were highly variable in design, having been undertaken to test various experimental regimens using pathological complete response (pCR) as a surrogate for disease-free survival (DFS) and OS. Across all patients, capecitabine-containing regimens resulted in little difference in pCR in comparison to non-capecitabine-containing regimens (odds ratio (OR) 1.12, 95% CI 0.94 to 1.33; 6 studies, 3152 participants; high-certainty evidence). By subtype, no difference in pCR was observed for either hormone receptor-positive (OR 1.22, 95% CI 0.76 to 1.95; 4 studies, 964 participants; moderate-certainty evidence) or hormone receptor-negative tumours (OR 1.28, 95% CI 0.61 to 2.66; 4 studies, 646 participants; moderate-certainty evidence). Four studies with 2460 people reported longer-term outcomes: these investigators detected no difference in either DFS (HR 1.02, 95% CI 0.86 to 1.21; high-certainty evidence) or OS (HR 0.97, 95% CI 0.77 to 1.23; high-certainty evidence). In the adjuvant setting, a modest improvement in OS was observed across all participants (HR 0.89, 95% CI 0.81 to 0.98; 8 studies, 13,547 participants; moderate-certainty evidence), and no difference in OS was seen in hormone receptor-positive cancers (HR 0.86, 95% CI 0.68 to 1.09; 3 studies, 3683 participants), whereas OS improved in hormone receptor-negative cancers (HR 0.72, 95% CI 0.59 to 0.89; 5 studies, 3432 participants). No difference in DFS or relapse-free survival (RFS) was observed across all participants (HR 0.93, 95% CI 0.86 to 1.01; 8 studies, 13,457 participants; moderate-certainty evidence). As was observed for OS, no difference in DFS/RFS was seen in hormone receptor-positive cancers (HR 1.03, 95% CI 0.91 to 1.17; 5 studies, 5604 participants; moderate-certainty evidence), and improvements in DFS/RFS with inclusion of capecitabine were observed for hormone receptor-negative cancers (HR 0.74, 95% CI 0.64 to 0.86; 7 studies, 3307 participants; moderate-certainty evidence). Adverse effects were reported across all three scenarios. When grade 3 or 4 febrile neutropenia was considered, no difference was seen for capecitabine compared to non-capecitabine regimens in neoadjuvant studies (OR 1.31, 95% CI 0.97 to 1.77; 4 studies, 2890 participants; moderate-certainty evidence), and a marked reduction was seen for capecitabine in adjuvant studies (OR 0.55, 95% CI 0.47 to 0.64; 5 studies, 8086 participants; moderate-certainty evidence). There was an increase in diarrhoea and hand-foot syndrome in neoadjuvant (diarrhoea: OR 1.95, 95% CI 1.32 to 2.89; 3 studies, 2686 participants; hand-foot syndrome: OR 6.77, 95% CI 4.89 to 9.38; 5 studies, 3021 participants; both moderate-certainty evidence) and adjuvant trials (diarrhoea: OR 2.46, 95% CI 2.01 to 3.01; hand-foot syndrome: OR 13.60, 95% CI 10.65 to 17.37; 8 studies, 11,207 participants; moderate-certainty evidence for both outcomes). AUTHORS' CONCLUSIONS: In summary, a moderate PFS benefit by including capecitabine was seen only in hormone receptor-positive cancers in metastatic studies. No benefit of capecitabine for pCR was noted overall or in hormone receptor subgroups when included in neoadjuvant therapy. In contrast, the addition of capecitabine in the adjuvant setting led to improved outcomes for OS and DFS in hormone receptor-negative cancer. Future studies should stratify by hormone receptor and triple-negative breast cancer (TNBC) status to clarify the differential effects of capecitabine in these subgroups across all treatment scenarios, to optimally guide capecitabine inclusion.

Fine Needle Aspiration Biopsy of Peripheral Lymph Nodes in Children: Practical Experience in a Tertiary Hospital.

BACKGROUND: Peripheral lymphadenopathy occurs often in children; fine needle aspiration biopsy (FNAB) is a commonly performed diagnostic procedure. We describe FNAB use and outcome for peripheral lymphadenopathy in children in a routine clinical setting. METHODS: A retrospective study done at Tygerberg Hospital, Cape Town of children (<13 years) who had an FNAB for lymphadenopathy from July 2012 to June 2014. Demographic, clinical, treatment and follow-up data were retrieved from patient folders; FNAB and special investigation results were obtained from the laboratory database. RESULTS: Of the 173 children, the median age was 37 (interquartile range 13-75) months; 20 (11.5%) were HIV positive. Most FNABs were done in the neck (131; 76%) and axillary areas (34; 20%). FNAB provided a result in 165 (95%) cases; in 8 (5%) children FNAB was insufficient for diagnosis. Mycobacterial aetiology was diagnosed in 84 (49%); 49 (58%) were culture-confirmed (37 Mycobacterium tuberculosis, 10 Mycobacterium bovis BCG, 1 both and 1 non-tuberculous mycobacterium). Reactive lymphadenopathy was diagnosed in 56 (32%), neoplastic disease in 6 (3.5%) and other pathology in 19 (11%) cases. Additional special investigations changed FNAB diagnosis or led to an additional diagnosis in 8 (5%) children. Overall, 70/84 (83%) with mycobacterial aetiology and all neoplastic disease cases received the correct treatment. Follow-up appointments were arranged in 144 (83%) patients. CONCLUSIONS: In a high tuberculosis burden area, a single FNAB provided a diagnosis in most cases in a routine referral setting; FNAB remains a safe and useful investigation. Follow-up of children to initiate appropriate treatment could improve. LAY SUMMARY: Large swollen lymph nodes, especially in the neck, are a common finding in children. Fine needle aspiration biopsy (FNAB) is a commonly used diagnostic procedure and we looked at how well this procedure works in everyday hospital practice. We identified all children <13 years of age over a 2-year period (2012-2014) who had an FNAB done at Tygerberg Hospital, Cape Town, South Africa, and looked how well this procedure performed and what the doctors did with these children. We found 173 children who had an FNAB done. They were generally young children of around 3 years old. With a single FNAB, we could make a diagnosis in 95% of these children. About half of the children had tuberculosis or complications of a BCG vaccine (both caused by mycobacteria), only 4% had a malignancy of some kind, about a third had reactive lymph nodes (usually other mainly local infectious causes) and the rest had other pathology like abscesses. All malignancies and >80% of the mycobacterial pathology cases were correctly managed; the latter could definitely improve.

Risk-Stratification of Children Presenting to Ambulatory Paediatrics with First-Onset Seizures: Should We Order an Urgent CT Brain?

INTRODUCTION: A computed tomography (CT) brain scan is an often-utilised emergency department imaging modality to detect emergent intra-cranial pathology in a child with a first seizure. Identifying children at low risk of having a clinically significant intra-cranial abnormality could prevent unnecessary radiation exposure and contrast/sedation-related risks. OBJECTIVES: To identify clinical variables which could predict clinically significant CT brain abnormalities and use recursive partitioning analysis to define a low-risk group of children in whom emergent CT brain can be deferred. METHODS: Retrospective cross-sectional review of 468 children who underwent emergent CT brain after presenting to a low- and middle-income paediatric emergency department following first seizure. RESULTS: In total 133/468 (28.4%) of CT brain scans had clinically significant abnormalities. Failure to return to neurological baseline and focal neurological deficit persisting >36 h had statistical significance in a multiple regression analysis. Recursive partitioning analysis, applied to a subgroup without suspected tuberculous meningitis (n = 414), classified 153 children aged between 6 months and 5 years, who had a normal neurological baseline, had returned to baseline post-seizure, and were not in status epilepticus, as non-clinically significant scans and 98% were correctly classified. CONCLUSION: Our study re-inforces the American Academy of Neurology recommendation that children with persistent post-ictal abnormal neurological status and/or post-ictal focal deficit be prioritised for emergent CT brain. Having excluded children with suspected tuberculous meningitis, the remaining subgroup aged 6 months to 5 years presenting with a non-status first seizure, normal neurological baseline and return to baseline post-seizure, are at very low risk of having a clinically significant CT brain abnormality.

The distribution and determinants of mammographic density measures in Western Australian aboriginal women.

BACKGROUND: Mammographic density (MD) is an established risk factor for breast cancer. There are significant ethnic differences in MD measures which are consistent with those for corresponding breast cancer risk. This is the first study investigating the distribution and determinants of MD measures within Aboriginal women of Western Australia (WA). METHODS: Epidemiological data and mammographic images were obtained from 628 Aboriginal women and 624 age-, year of screen-, and screening location-matched non-Aboriginal women randomly selected from the BreastScreen Western Australia database. Women were cancer free at the time of their mammogram between 1989 and 2014. MD was measured using the Cumulus software. Kolmogorov-Smirnov tests were used to compare distributions of absolute dense area (DA), precent dense area (PDA), non-dense area (NDA) and total breast area between Aboriginal and non-Aboriginal women. General linear regression was used to estimate the determinants of MD, adjusting for age, NDA, hormone therapy use, family history, measures of socio-economic status and remoteness of residence for Aboriginal and non-Aboriginal women separately. RESULTS: Aboriginal women were found to have lower DA and PDA and higher NDA than non-Aboriginal women. Age (p <  0.001) was negatively associated and several socio-economic indices (p <  0.001) were positively associated with DA and PDA in Aboriginal and non-Aboriginal women. Remoteness of residence was associated with both mammographic measures but for non-Aboriginal women only. CONCLUSIONS: Aboriginal women have, on average, less MD than non-Aboriginal women but the factors associated with MD are similar for both sample populations. Since reduced MD is associated with improved sensitivity of mammography, this study suggests that mammographic screening is a particularly good test for Australian Indigenous women, a population that suffers from high breast cancer mortality.

The association between mammographic density and breast cancer risk in Western Australian Aboriginal women.

PURPOSE: Mammographic density is an established breast cancer risk factor within many ethnically different populations. The distribution of mammographic density has been shown to be significantly lower in Western Australian Aboriginal women compared to age- and screening location-matched non-Aboriginal women. Whether mammographic density is a predictor of breast cancer risk in Aboriginal women is unknown. METHODS: We measured mammographic density from 103 Aboriginal breast cancer cases and 327 Aboriginal controls, 341 non-Aboriginal cases, and 333 non-Aboriginal controls selected from the BreastScreen Western Australia database using the Cumulus software program. Logistic regression was used to examine the associations of percentage dense area and absolute dense area with breast cancer risk for Aboriginal and non-Aboriginal women separately, adjusting for covariates. RESULTS: Both percentage density and absolute dense area were strongly predictive of risk in Aboriginal women with odds per adjusted standard deviation (OPERAS) of 1.36 (95% CI 1.09, 1.69) and 1.36 (95% CI 1.08, 1.71), respectively. For non-Aboriginal women, the OPERAS were 1.22 (95% CI 1.03, 1.46) and 1.26 (95% CI 1.05, 1.50), respectively. CONCLUSIONS: Whilst mean mammographic density for Aboriginal women is lower than non-Aboriginal women, density measures are still higher in Aboriginal women with breast cancer compared to Aboriginal women without breast cancer. Thus, mammographic density strongly predicts breast cancer risk in Aboriginal women. Future efforts to predict breast cancer risk using mammographic density or standardize risk-associated mammographic density measures should take into account Aboriginal status when applicable.

A review of the influence of mammographic density on breast cancer clinical and pathological phenotype.

PURPOSE: It is well established that high mammographic density (MD), when adjusted for age and body mass index, is one of the strongest known risk factors for breast cancer (BC), and also associates with higher incidence of interval cancers in screening due to the masking of early mammographic abnormalities. Increasing research is being undertaken to determine the underlying histological and biochemical determinants of MD and their consequences for BC pathogenesis, anticipating that improved mechanistic insights may lead to novel preventative or treatment interventions. At the same time, technological advances in digital and contrast mammography are such that the validity of well-established relationships needs to be re-examined in this context. METHODS: With attention to old versus new technologies, we conducted a literature review to summarise the relationships between clinicopathologic features of BC and the density of the surrounding breast tissue on mammography, including the associations with BC biological features inclusive of subtype, and implications for the clinical disease course encompassing relapse, progression, treatment response and survival. RESULTS AND CONCLUSIONS: There is reasonable evidence to support positive relationships between high MD (HMD) and tumour size, lymph node positivity and local relapse in the absence of radiotherapy, but not between HMD and LVI, regional relapse or distant metastasis. Conflicting data exist for associations of HMD with tumour location, grade, intrinsic subtype, receptor status, second primary incidence and survival, which need further confirmatory studies. We did not identify any relationships that did not hold up when data involving newer imaging techniques were employed in analysis.

Hypoxia as a signal for prison breakout in cancer.

PURPOSE OF REVIEW: We discuss recent discoveries in hypoxic cellular pathophysiology and explore the interplay between hypoxic malignant cells and other stromal elements. This review will provide an update on the effects of hypoxia on cancer outcomes and therapeutic resistance. RECENT FINDINGS: Hypoxia has been discovered to be a key driver for tumor progression, both because of impacts on tumor cells and separately on the wider tumor microenvironment. The latter effects occur via epithelial mesenchymal transition, autophagy and metabolic switching. Through epithelial mesenchymal transition, hypoxia both drives metastasis and renders key target tissues receptive to metastasis. Autophagy is a double-edged sword which requires greater understanding to ascertain when it is a threat. Metabolic switching allows tumor cells to access hypoxic survival mechanisms even under normoxic conditions.Every element of the malignant stroma contributes to hypoxia-driven progression. Exosomal transfer of molecules from hypoxic tumor cells to target stromal cell types and the importance of microRNAs in intercellular communication have emerged as key themes.Antiangiogenic resistance can be caused by hypoxia-driven vasculogenic mimicry. Beyond this, hypoxia contributes to resistance to virtually all oncological treatment modalities. SUMMARY: Recent advances have moved us closer to being able to exploit hypoxic mechanisms to overcome hypoxia-driven progression and therapy failure.