First-line Palliative Chemotherapy for Colorectal Cancer: a Population-based Analysis of Delivery and Outcomes in a Single-payer Health System.

AIMS: Clinical practice guidelines recommend palliative chemotherapy for most patients with metastatic colorectal cancer. However, outcomes observed in the real world compared with patients enrolled in clinical trials have not been sufficiently described. The objective of this study was to evaluate the delivery and outcomes of first-line palliative chemotherapy administered to patients with colorectal cancer in routine clinical practice compared with clinical trials. MATERIALS AND METHODS: Using linked health administrative data, we carried out a retrospective population-level cohort study on patients diagnosed with colorectal cancer in Ontario, Canada from 2010 to 2019. Patient, disease and treatment characteristics were summarised. The primary outcome was median overall survival, stratified by treatment prescribed and age. Demographics and outcomes in this real-world population were compared with those from pivotal clinical trials. A multivariable Cox regression model reporting hazard ratios and 95% confidence intervals was used to determine factors associated with survival in patients receiving systemic treatment. RESULTS: We identified 70 987 patients with a new diagnosis of colorectal cancer, of which 4613 received first-line chemotherapy for unresectable locally advanced or metastatic disease and formed the study cohort. Fifty-eight per cent were male and the mean age was 63 years. Most had colon cancer (69%), at least one comorbidity (73%) and lived in an urban location (79%). Less than half (47%) had surgery after diagnosis. The most common regimen prescribed was folinic acid, 5-fluorouracil and irinotecan (FOLFIRI) with bevacizumab or epidermal growth factor receptor inhibitors (EGFRi; n = 2784, 60%). Among all treated patients, the median overall survival was 17.1 months, with survival difference by regimen [median overall survival 18.3 for FOLFIRI with bevacizumab or EGFRi, 19.6 for folinic acid, 5-fluorouracil and oxaliplatin (FOLFOX)/capecitabine, oxaliplatin (XELOX) with bevacizumab or EGFRi, 13.6 for FOLFIRI alone and 7.8 for 5-fluorouracil or capecitabine]. Patients aged >80 years were most likely to have received single-agent 5-fluorouracil or capecitabine, and had inferior overall survival compared with their younger counterparts. Compared with pivotal clinical trials, patients in the real world had inferior overall survival outcomes despite similar demographic characteristics (including age and sex). CONCLUSIONS: In this real-world population-based analysis of patients receiving first-line chemotherapy for unresectable locally advanced or metastatic colorectal cancer, survival outcomes were inferior to those reported in randomised trials despite similarities in age and sex. This information can be used when counselling patients in routine practice about expected outcomes.

The current status of National Cancer Control Plans in Africa: Data from 32 countries.

BACKGROUND: Cancer incidence and mortality are rapidly rising in Africa. National Cancer Control Plans (NCCPs have contributed to a reduction in the burden of some preventable cancers, availing early diagnosis and adequate treatment modalities and palliative care, while sustaining them with sufficient monitoring systems. knowledge we undertook a cross-sectional survey across continental Africa to understand the presence of NCCPs, availability of early detection and screening policies and the status of health financing pertaining to cancer. METHODS: Through an online survey, we approached key cancer care staff in 54 countries. Questions were themed in 3 main areas - Cancer registries and national cancer control plans (NCCPs) availability in countries, Cancer screening, diagnosis and management capacity, Financing in cancer care. RESULTS: On 54 approached respondents, we received 32 responses. 88 % of responding countries have active national cancer registries, 75 % with NCCPs and 47 % with cancer screening policies and practices. Universal Health Coverage is available in 40 % of countries. CONCLUSION: Our study shows that there is a scarcity of NCCPs in Africa. Deliberate investment in cancer registry and clinical services is key to improving access to care and ultimately reduce cancer mortality in Africa.

Validation of personal protective equipment ensembles, incorporating powered air-purifying respirators protected from contamination, for the care of patients with high-consequence infectious diseases.

BACKGROUND: The UK High-Consequence Infectious Diseases (HCID) Network of high-level isolation units provides care for patients with contact- or airborne-transmissible highly infectious and highly dangerous diseases. In most HCID units, the healthcare workers (HCWs) wear personal protective equipment (PPE) ensembles incorporating a powered air-purifying respirator (PAPR) for head and respiratory protection. Some PAPRs have components worn outside/over other PPE, necessitating decontamination of re-usable elements. Two alternative PAPRs, with all re-usable elements worn under PPE, were trialled in this study. AIM: To undertake scenario-based testing of PAPRs and PPE to determine usability, comfort and ability to remove contaminated PPE without personal cross-contamination. METHODS: Trained healthcare volunteers (N=20) wearing PAPR/PPE ensembles were sprayed with ultraviolet fluorescent markers. They undertook exercises to mimic patient care, and subsequently, after doffing the contaminated PPE following an established protocol, any personal cross-contamination was visualized under ultraviolet light. Participants also completed a questionnaire to gauge how comfortable they found the PPE. FINDINGS AND CONCLUSIONS: The ensembles were tested under extreme 'worst case scenario' conditions, augmented by physical and manual dexterity tests. Participating volunteers considered the exercise to be beneficial in terms of training and PPE evaluation. Data obtained, including feedback from questionnaires and doffing buddy observations, supported evidence-based decisions on the PAPR/PPE ensemble to be adopted by the HCID Network. One cross-contamination event was recorded in the ensemble chosen; this could be attributed to doffing error, and could therefore be eliminated with further practice.

Kondo quasiparticle dynamics observed by resonant inelastic x-ray scattering.

Effective models focused on pertinent low-energy degrees of freedom have substantially contributed to our qualitative understanding of quantum materials. An iconic example, the Kondo model, was key to demonstrating that the rich phase diagrams of correlated metals originate from the interplay of localized and itinerant electrons. Modern electronic structure calculations suggest that to achieve quantitative material-specific models, accurate consideration of the crystal field and spin-orbit interactions is imperative. This poses the question of how local high-energy degrees of freedom become incorporated into a collective electronic state. Here, we use resonant inelastic x-ray scattering (RIXS) on CePd3 to clarify the fate of all relevant energy scales. We find that even spin-orbit excited states acquire pronounced momentum-dependence at low temperature-the telltale sign of hybridization with the underlying metallic state. Our results demonstrate how localized electronic degrees of freedom endow correlated metals with new properties, which is critical for a microscopic understanding of superconducting, electronic nematic, and topological states.

Gene Edited T Cell Therapies for Inborn Errors of Immunity.

Inborn errors of immunity (IEIs) are a heterogeneous group of inherited disorders of the immune system. Many IEIs have a severe clinical phenotype that results in progressive morbidity and premature mortality. Over 450 IEIs have been described and the incidence of all IEIs is 1/1,000-10,000 people. Current treatment options are unsatisfactory for many IEIs. Allogeneic haematopoietic stem cell transplantation (alloHSCT) is curative but requires the availability of a suitable donor and carries a risk of graft failure, graft rejection and graft-versus-host disease (GvHD). Autologous gene therapy (GT) offers a cure whilst abrogating the immunological complications of alloHSCT. Gene editing (GE) technologies allow the precise modification of an organisms' DNA at a base-pair level. In the context of genetic disease, this enables correction of genetic defects whilst preserving the endogenous gene control machinery. Gene editing technologies have the potential to transform the treatment landscape of IEIs. In contrast to gene addition techniques, gene editing using the CRISPR system repairs or replaces the mutation in the DNA. Many IEIs are limited to the lymphoid compartment and may be amenable to T cell correction alone (rather than haematopoietic stem cells). T cell Gene editing has the advantages of higher editing efficiencies, reduced risk of deleterious off-target edits in terminally differentiated cells and less toxic conditioning required for engraftment of lymphocytes. Although most T cells lack the self-renewing property of HSCs, a population of T cells, the T stem cell memory compartment has long-term multipotent and self-renewal capacity. Gene edited T cell therapies for IEIs are currently in development and may offer a less-toxic curative therapy to patients affected by certain IEIs. In this review, we discuss the history of T cell gene therapy, developments in T cell gene editing cellular therapies before detailing exciting pre-clinical studies that demonstrate gene editing T cell therapies as a proof-of-concept for several IEIs.

Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott-Aldrich syndrome.

Patients with Wiskott-Aldrich syndrome (WAS) lacking a human leukocyte antigen-matched donor may benefit from gene therapy through the provision of gene-corrected, autologous hematopoietic stem/progenitor cells. Here, we present comprehensive, long-term follow-up results (median follow-up, 7.6 years) (phase I/II trial no. NCT02333760 ) for eight patients with WAS having undergone phase I/II lentiviral vector-based gene therapy trials (nos. NCT01347346 and NCT01347242 ), with a focus on thrombocytopenia and autoimmunity. Primary outcomes of the long-term study were to establish clinical and biological safety, efficacy and tolerability by evaluating the incidence and type of serious adverse events and clinical status and biological parameters including lentiviral genomic integration sites in different cell subpopulations from 3 years to 15 years after gene therapy. Secondary outcomes included monitoring the need for additional treatment and T cell repertoire diversity. An interim analysis shows that the study meets the primary outcome criteria tested given that the gene-corrected cells engrafted stably, and no serious treatment-associated adverse events occurred. Overall, severe infections and eczema resolved. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. The results suggest that lentiviral gene therapy provides sustained clinical benefits for patients with WAS.

Framework for preliminary risk assessment of brownfield sites.

The complexity of hazards, risk and environmental legislation surrounding the reuse of brownfield sites necessitates a preliminary risk assessment prior to their redevelopment. Most prevailing efforts have been targeted at indepth site investigations, which are often costly, time-consuming, and may not be required at the early stages of a site development. However, there is a collective absence of knowledge, methods and computer models that can present a complete framework to carry out a preliminary risk assessment that is simpler, quicker and sufficient, not only for risk assessor but also effectively communicative for a diverse range of stakeholders with or without risk assessment expertise. Therefore, this study aims to bridge this gap by designing and creating a framework, by not only identifying hazards but also exposing the degree of presence. Sixty-five potential hazards have been identified from a comprehensive literature review. A questionnaire survey was then shared with brownfield site experts (n = 76) that asked then to rank the priority of the potential hazards. Kendall's W test and Kruskal-Wallis H test were subsequently conducted to determine the level of agreement among the respondents. Mean weightings were calculated by using the Voting Analytic Hierarchy Process (VAHP) to prioritize the potential hazards from 'more likely' to 'least likely'. Based on this information, the framework has been developed. It is anticipated that the framework can assist professionals to conduct a preliminary assessment of brownfield sites, which enables them to gain informative and rapid guidance on any potential liabilities or risks related to a site's suitability for acquisition or redevelopment. In this context, the framework outlines a systematic structure to collect appropriate data and information in the three main categories which are sources, pathways and receptors.

Industry Funding of Oncology Randomised Controlled Trials: Implications for Design, Results and Interpretation.

AIMS: Most randomised controlled trials (RCTs) in oncology are now funded by the pharmaceutical industry. We explore the extent to which RCT design, results and interpretation differ between industry-funded and non-industry-funded RCTs. MATERIALS AND METHODS: In this cross-sectional analysis, a structured literature search was used to identify all oncology RCTs published globally during 2014-2017. Industry funding was identified based on explicit statements in the publication. Descriptive statistics were used to compare elements of trial methodology and output between industry- and non-industry-funded RCTs. RESULTS: The study sample included 694 RCTs; 71% were funded by industry. Industry-funded trials were more likely to test systemic therapy (97% versus 62%; P < 0.001), palliative-intent therapy (71% versus 41%; P < 0.001) and study breast cancer (20% versus 12%; P < 0.001). Industry-funded trials were larger (median sample size 474 versus 375; P < 0.001) and more likely to meet their primary end point (49% versus 41%; P < 0.001). Among positive trials, there were no differences in the magnitude of benefit between industry- and non-industry-funded RCTs. Trials funded by industry were published in journals that had a significantly higher median impact factor (21, interquartile range 7, 28) than non-industry-funded trials (impact factor 12, interquartile range 5, 24; P = 0.005); this persisted when adjusted for whether a trial was positive or negative. CONCLUSIONS: The vast majority of oncology RCTs are now funded by industry. Industry-funded trials are larger, more likely to be positive, predominantly test systemic therapies in the palliative setting and are published in higher impact journals than trials without industry support.

Distribution of the workforce involved in cancer care: a systematic review of the literature.

BACKGROUND: A skilled health workforce is instrumental for the delivery of multidisciplinary cancer care and in turn a critical component of the health systems. There is, however, a paucity of data on the vast inequalities in cancer workforce distribution, globally. The aim of this study is to describe the global distribution and density of the health care workforce involved in multidisciplinary cancer management. METHODS: We carried out a systematic review of the literature to determine ratios of health workers in each occupation involved in cancer care per 100 000 population and per 100 cancer patients (PROSPERO: protocol CRD42018095414). RESULTS: We identified 33 eligible papers; a majority were cross-sectional surveys (n = 16). The analysis of the ratios of health providers per population and per patients revealed deep gaps across the income areas, with gradients of workforce density, highest in high-income countries versus low-income areas. Benchmark estimates of optimal workforce availability were provided in a secondary research analysis: mainly high-income countries reported workforce capacities closer to benchmark estimates. A paucity of literature was defined for critical health providers, including for pediatric oncology, surgical oncology, and cancer nurses. CONCLUSION: The availability and distribution of the cancer workforce is heterogeneous, and wide gaps are described worldwide. This is the first systematic review on this topic. These results can inform policy formulation and modelling for capacity building and scaleup.

Deletion of Cdh16 Ksp-cadherin leads to a developmental delay in the ability to maximally concentrate urine in mouse.

Ksp-cadherin (cadherin-16) is an atypical member of the cadherin superfamily of cell adhesion molecules that is ubiquitously expressed on the basolateral membrane of epithelial cells lining the nephron and the collecting system of the mammalian kidney. The principal aim of the present study was to determine if Ksp-cadherin played a critical role in the development and maintenance of the adult mammalian kidney by generating and evaluating a mouse line deficient in Ksp-cadherin. Ksp-null mutant animals were viable and fertile, and kidneys from both neonates and adults showed no evidence of structural abnormalities. Immunolocalization and Western blot analyses of Na+-K+-ATPase and E-cadherin indicated that Ksp-cadherin is not essential for either the genesis or maintenance of the polarized tubular epithelial phenotype. Moreover, E-cadherin expression was not altered to compensate for Ksp-cadherin loss. Plasma electrolytes, total CO2, blood urea nitrogen, and creatinine levels were also unaffected by Ksp-cadherin deficiency. However, a subtle but significant developmental delay in the ability to maximally concentrate urine was detected in Ksp-null mice. Expression analysis of the principal proteins involved in the generation of the corticomedullary osmotic gradient and the resultant movement of water identified misexpression of aquaporin-2 in the inner medullary collecting duct as the possible cause for the inability of young adult Ksp-cadherin-deficient animals to maximally concentrate their urine. In conclusion, Ksp-cadherin is not required for normal kidney development, but its absence leads to a developmental delay in maximal urinary concentrating ability.NEW & NOTEWORTHY Ksp-cadherin (cadherin-16) is an atypical member of the cadherin superfamily of cell adhesion molecules that is ubiquitously expressed on the basolateral membrane of epithelial cells lining the nephron and the collecting system. Using knockout mice, we found that Ksp-cadherin is in fact not required for kidney development despite its high and specific expression along the nephron. However, its absence leads to a developmental delay in maximal urinary concentrating ability.

Effectiveness of Trastuzumab in Routine Clinical Practice: A Population-based Study of Patients with HER-2-positive Oesophageal, Gastroesophageal and Gastric Cancer.

AIMS: In the pivotal Trastuzumab for Gastric Cancer (ToGA) trial, trastuzumab improved median survival in patients with advanced HER-2-positive gastric and gastroesophageal cancer from 11.1 to 13.8 months; however, its effectiveness in routine clinical practice has not been evaluated. Our objective was to evaluate the uptake and outcomes of trastuzumab in a population-based cohort of patients with oesophageal, gastroesophageal and gastric cancer in Ontario, Canada. MATERIALS AND METHODS: The Ontario Cancer Registry and linked treatment records were used to identify all patients with oesophageal, gastroesophageal and gastric cancer treated with trastuzumab during 2012-2017. Outcomes were analysed from the time of first trastuzumab cycle and included a primary outcome (survival) and secondary outcomes (uptake, delivery, 30-day hospital admission and 30-day mortality). Trends over the study period and survival were evaluated. RESULTS: In total, 476 patients with oesophageal, gastroesophageal and gastric cancer received trastuzumab during the study period. The mean age was 62 years, 78% (370/476) were male, and 65% (312/476) had gastric cancer. The annual number of patients receiving trastuzumab increased over the study period (53 in 2012 and 101 in 2017). The median number of cycles of trastuzumab delivered was six. Thirty-day hospital admission and mortality rates were 17% and 4%, respectively. The median overall survival was 282 days (9.3 months). CONCLUSIONS: The median survival of patients treated with trastuzumab for advanced oesophageal, gastroesophageal and gastric cancer in routine practice is substantially less than that observed in the pivotal clinical trial. Studies of comparative effectiveness using real-world data offer insight into outcomes achieved in routine practice.

A population-based study of pulmonary monitoring and toxicity for patients with testicular cancer treated with bleomycin.

Background: Bleomycin is commonly used to treat advanced testicular cancer and can be associated with severe pulmonary toxicity. The primary objective of the present study was to describe the use of pulmonary function tests (pfts) and chest imaging before, during, and after treatment with bleomycin. Methods: To identify all incident cases of testicular cancer treated with bleomycin-based chemotherapy in the Canadian province of Ontario during 2005-2010, the Ontario Cancer Registry was linked with chemotherapy treatment records. Health administrative databases were used to describe use of pfts, chest imaging, and physician visits for respiratory complaints. Results: Of 394 patients treated with orchiectomy and chemotherapy who received at least 1 dose of bleomycin, 93% had complete chemotherapy records available. In the 4 weeks before, during, and within 2 years after finishing bleomycin-based chemotherapy, pfts were performed in 17%, 17%, and 29% of patients respectively. Chest imaging was performed in 68%, 62%, and 98% of patients in the same time periods. In the 2 years after bleomycin-based chemotherapy, 23% of treated patients had a physician visit for respiratory symptoms. That rate was substantially higher for men with greater exposure to bleomycin: 40% (24 of 60) for 10-12 doses bleomycin compared with 21% (53 of 250) for 7-9 doses and with 14% (8 of 58) for 1-6 doses (p = 0.002). Conclusions: Quality improvement initiatives are needed to increase baseline rates of chest imaging within 4 weeks of starting chemotherapy for testicular cancer; to understand why such a high proportion of men have chest imaging during bleomycin-based chemotherapy; and to mitigate the excess pulmonary toxicity seen with increasing exposure to bleomycin.

A systematic review of risk assessment tools for contaminated sites - Current perspectives and future prospects.

Health and safety hazards associated with the redevelopment of contaminated sites can be complex and pose considerable risks. A systematic literature review was conducted on risk assessment tools for contaminated sites. These tools have been identified from searching through leading academic databases and other professional sources. For each of the identified tools the relevant risk assessment stages, harm type, hazard category, receptor type and pathways are reported. Findings reveal that despite growing interest in the development of risk assessment tools, there are persistent knowledge gaps identified in this study, which serve as a basis for future research direction to where more advanced practical tools could be invented. For instance, it is evidenced there is a shortfall in practical tools available to contaminated site assessors conducting investigations at the preliminary risk assessment stage. Addressing this opening can benefit the planning process, coordinated between relevant stakeholders and, moreover, reduce uncertainty in the decision-making of contaminated site developers.

Venous Thromboembolism During Chemotherapy for Testicular Cancer: A Population-Based Study.

AIMS: Venous thromboembolism (VTE) is a potential complication among germ cell tumour patients. We evaluated the incidence rate, timing and factors associated with VTE among patients with germ cell cancer in routine practice. MATERIALS AND METHODS: The Ontario Cancer Registry was linked to electronic records of treatment to identify all cases of testicular cancer treated in Ontario during 2000-2010. Administrative databases were used to identify VTE in the 3 months before and 5 years after orchiectomy. We explored patient-, disease- and treatment-related factors associated with VTE among all patients as well as those with detailed chemotherapy records available. RESULTS: During 2000-2010, 2650 patients underwent orchiectomy for testicular cancer; among this cohort, 920 (33%) received chemotherapy. The VTE rate was 8% (69/920) among patients treated with chemotherapy and 0.6% (11/1730) among those without chemotherapy. Among the patients treated with chemotherapy who had VTE, 13% (9/69) occurred in the month before starting chemotherapy, 62% (42/69) in the first 3 months after starting and 25% thereafter. For patients who received three and four cycles, VTE rates were 8% (21/258) and 16% (19/121), respectively. In adjusted analyses, the only factor independently associated with VTE was increasing number of cycles (odds ratio 3.91 for four cycles, odds ratio 1.63 for three cycles (P = 0.022) compared with one to two cycles). CONCLUSION: This population-based study confirms findings from institutional case series regarding the high rate of VTE among patients with germ cell tumours treated with chemotherapy. Future studies should evaluate the extent to which VTE prophylactic strategies might mitigate this risk.

Medical Oncology Workload in Europe: One Continent, Several Worlds.

AIMS: The workload pressure on medical oncologists will increase in the near future. There are no comprehensive data available about the current workload of medical oncologists in Europe. Here we report the European results of a global survey of the workload of medical oncologists. MATERIALS AND METHODS: An online survey was distributed through a snowball method via national oncology societies to chemotherapy-prescribing physicians in 21 European countries. We compared the workload of medical oncologists in Eastern European countries (EECs) and Western European countries (WECs). The primary measure of workload was the annual number of new cancer patient consults seen per oncologist. RESULTS: In total, 495 oncologists from 16 European countries completed our survey: 100 from seven EECs and 395 from nine WECs. The median number of annual consults per medical oncologist was 225 in EECs compared with 175 in WECs (P < 0.001). The proportion of medical oncologists seeing more than 300 consults/year was 35% (35/100) in EECs compared with 18% (68/395) in WECs. The median number of patients seen in a full day clinic was 25 in EECs and 15 in WECs (P < 0.001). Eastern European medical oncologists reported spending a median of 25 min per new consultation compared with 45 min in WECs (P < 0.001). The top two reported barriers in both EECs and WECs to patient care were high clinical volumes and insufficient time for reading. CONCLUSION: The clinical workload of medical oncologists in EECs was substantially higher than in WECs. European health policymakers and educators need to address existing disparities in the workload of medical oncologist, undertake plans for future workforce supply and consider alternative models of care.

Neurotoxicity Among Survivors of Testicular Cancer: A Population-based Study.

AIMS: Neurotoxicity may affect the quality of life of survivors of testicular cancer. Understanding the burden of neurotoxicity is important to guide survivorship care. A population-based study was undertaken to describe the proportion of patients in the 'real world' with neurotoxicity. MATERIALS AND METHODS: A population-based, retrospective, cohort study of patients with advanced testicular cancer treated in the province of Ontario. The Ontario Cancer Registry was linked to electronic treatment records to identify all incident cases of testicular cancer during 2000-2010. Administrative databases were used to describe health system visits for symptoms potentially related to neurotoxicity. Health system visit rates were explored by number of chemotherapy cycles among patients treated during 2005-2010 for whom complete chemotherapy details were available. RESULTS: During 2000-2010, 2650 patients underwent an orchiectomy for testicular cancer; 920 (33%) also received chemotherapy. The proportion of patients with health system visits for neurotoxicity in the 2 years before surgery compared with the 2 years after surgery remained stable among patients treated with orchiectomy alone (18% [303/1730] versus 18% [316/1730], P = 0.523); however, there was a substantial increase among patients treated with chemotherapy (16% [151/920] versus 25% [231/920], P < 0.001). Among patients treated with chemotherapy in 2005-2010 for whom complete details were available regarding number of treatment cycles there was a dose-response effect. The increase in health system visits for neurotoxicity from 2 years before compared with 2 years after orchiectomy was greater among patients treated with four cycles of chemotherapy (17% [21/121] versus 37% [45/121]) and three cycles of chemotherapy (17% [45/258] versus 28% [72/258]) compared with those treated with one to two cycles of chemotherapy (<13% [<6/45] versus 20% [9/45], P = 0.013). CONCLUSIONS: This population-based study suggests that symptoms of neurotoxicity are common among survivors of testicular cancer and that this seems to be driven by increasing exposure to chemotherapy. Clinicians should carefully evaluate patients for neurotoxicity during the survivorship phase of treatment.