Engineering approaches for innate immune-mediated tumor microenvironment remodeling.

Cancer immunotherapy offers transformative promise particularly for the treatment of lethal cancers, since a correctly trained immune system can comprehensively orchestrate tumor clearance with no need for continued therapeutic intervention. Historically, the majority of immunotherapies have been T cell-focused and have included immune checkpoint inhibitors, chimeric antigen receptor T cells, and T-cell vaccines. Unfortunately T-cell-focused therapies have failed to achieve optimal efficacy in most solid tumors largely because of a highly immunosuppressed 'cold' or immune-excluded tumor microenvironment (TME). Recently, a rapidly growing treatment paradigm has emerged that focuses on activation of tumor-resident innate antigen-presenting cells, such as dendritic cells and macrophages, which can drive a proinflammatory immune response to remodel the TME from 'cold' or immune-excluded to 'hot'. Early strategies for TME remodeling centered on free cytokines and agonists, but these approaches have faced significant hurdles in both delivery and efficacy. Systemic toxicity from off-target inflammation is a paramount concern in these therapies. To address this critical gap, engineering approaches have provided the opportunity to add 'built-in' capabilities to cytokines, agonists, and other therapeutic agents to mediate improved delivery and efficacy. Such capabilities have included protective encapsulation to shield them from degradation, targeting to direct them with high specificity to tumors, and co-delivery strategies to harness synergistic proinflammatory pathways. Here, we review innate immune-mediated TME remodeling engineering approaches that focus on cytokines, innate immune agonists, immunogenic viruses, and cell-based methods, highlighting emerging preclinical approaches and strategies that are either being tested in clinical trials or already Food and Drug Administration approved.

Heterogeneity in outcome selection, definition and measurement in studies assessing the treatment of cryptoglandular anal fistula: findings from a systematic review.

BACKGROUND: Treatment for cryptoglandular anal fistula (AF) is challenging and a lack of uniform outcomes in the literature prevents direct comparison of treatments. This can be addressed by developing a core outcome set, a standardised set of outcomes reported in all interventional studies for a specific condition. The aim of this systematic review is to assess the range of outcomes, their definitions, and the measurement instruments currently utilised in interventional studies for adult patients with AF. This will inform the development of an AF core outcome set. METHODS: Medline, Embase and The Cochrane Library were searched to identify all patient- and clinician-reported outcomes in studies assessing medical, surgical or combination treatment of adult patients with AF published from January 2008 to May 2020. The resulting outcomes were categorized according to the Core Outcome Measurement in Effectiveness Trials (COMET) taxonomy to better understand their distribution. RESULTS: In total, 155 studies were included, 552 outcomes were extracted, with a median of three outcomes (interquartile range 2-5) per study. Only 25% of studies demonstrated high-quality outcome reporting. The outcomes were merged into 52 unique outcomes and structured into four core areas and 14 domains, with the majority in the domain of physiological or clinical (gastrointestinal) outcomes. The most commonly reported outcomes were healing (77%), incontinence (63%), and recurrence (40%), with no single outcome assessed across all studies. There was a wide variation in outcome definitions and measurement instruments used. CONCLUSIONS: There is substantial heterogeneity in outcomes, definitions, and measurement instruments reported in interventional studies for cryptoglandular anal fistula. This emphasises the need for standardised outcome reporting and measurement.

A Risk Score Model for Locoregional Recurrence Following Upfront Surgery for Pancreatic Adenocarcinoma: Implications for Adjuvant Therapy.

AIMS: The aims of the study were to identify predictors of locoregional failure (LRF) following surgery for pancreatic adenocarcinoma, develop a prediction risk score model of LRF and evaluate the impact of postoperative radiation therapy (PORT) on LRF. MATERIALS AND METHODS: A retrospective review was conducted on patients with stages I-III pancreatic adenocarcinoma who underwent surgery at our institution (2005-2016). Univariable and then multivariable analyses were used to evaluate clinicopathological factors associated with LRF for patients who did not receive PORT. The risk score of LRF was calculated based on the sum of coefficients of the predictors of LRF. The model was applied to the entire cohort to evaluate the impact of PORT on the high- and low-risk groups for LRF. RESULTS: In total, 467 patients were identified (median follow-up 22 months). Among patients who did not receive PORT (n = 440), predictors of LRF were pN+, involved or close ≤1 mm margin(s), moderately and poorly differentiated tumour grade and lymphovascular invasion. After adding patients who received PORT, the 2-year LRF in the high-risk group was 57% for patients who did not receive PORT (n = 242) and 32% among patients who received PORT (n = 22), with an absolute benefit to LRF of 25% (95% confidence interval 5-52%, P = 0.07). The 2-year overall survival for the high-versus the low-risk group was 36% versus 67% (P < 0.001). CONCLUSION: This risk group classification could be used to identify pancreatic adenocarcinoma patients with higher risk of LRF who may benefit from PORT. However, validation and prospective evaluation are warranted.

Non-immunotherapy options for the first-line management of hepatocellular carcinoma: exploring the evolving role of sorafenib and lenvatinib in advanced disease.

The results of the sharp trial established sorafenib, a tyrosine kinase inhibitor (tki), as the sole first-line treatment option in advanced hepatocellular carcinoma (hcc) for more than a decade. In 2020, there has been a surge in new therapies for hcc, including immunotherapeutic strategies and the approval of a number of novel tkis. In addition to sorafenib, lenvatinib and combination atezolizumab-bevacizumab now represent standard first-line treatment options. As those systemic therapy options begin to be better utilized, assurance of adequate liver function and optimal timing are required to improve patient outcomes. Furthermore, sequencing of the agents will have to be carefully tailored, given the increasing armamentarium of choices. Here, we discuss the role of lenvatinib and sorafenib in the first-line management of hcc.

Longitudinal health utilities, symptoms and toxicities in patients with ALK-rearranged lung cancer treated with tyrosine kinase inhibitors: a prospective real-world assessment.

Background: Tyrosine kinase inhibitors (tkis) have dramatically improved the survival of patients with ALK-rearranged (ALK+) non-small-cell lung cancer (nsclc). Clinical trial data can generally compare drugs in a pair-wise fashion. Real-world collection of health utility data, symptoms, and toxicities allows for the direct comparison between multiple tki therapies in the population with ALK+ nsclc. Methods: In a prospective cohort study, outpatients with ALK+ recruited between 2014 and 2018, treated with a variety of tkis, were assessed every 3 months for clinico-demographic, patient-reported symptom and toxicity data and EQ-5D-derived health utility scores (hus). Results: In 499 longitudinal encounters of 76 patients with ALK+ nsclc, each tki had stable longitudinal hus when disease was controlled, even after months to years: the mean overall hus for each tki ranged from 0.805 to 0.858, and longitudinally from 0.774 to 0.912, with higher values associated with second- or third-generation tkis of alectinib, brigatinib, and lorlatinib. Disease progression was associated with a mean hus decrease of 0.065 (95% confidence interval: 0.02 to 0.11). Health utility scores were inversely correlated to multiple symptoms or toxicities: rho values ranged from -0.094 to -0.557. Fewer symptoms and toxicities were associated with the second- and third-generation tkis compared with crizotinib. In multivariable analysis, only stable disease state and baseline Eastern Cooperative Oncology Group performance status were associated with improved hus. Conclusions: There was no significant decrease in hus when patients with ALK+ disease were treated longitudinally with each tki, as long as patients were clinically stable. Alectinib, brigatinib, and lorlatinib had the best toxicity profiles and exhibited high mean hus longitudinally in the real-world setting.

Prognostic Importance of Pathological Fractures in Osteosarcomas.

Aims To investigate whether pathological fractures impact on osteosarcoma patient prognosis in Ireland. Methods This was a retrospective study over 22 years in a National Orthopaedic Oncology Centre. There were 117 nonfracture cases and 15 fracture cases. Outcome measures included 5 and 10 year event-free (EFS) and overall survival (OS). Kaplan-Meier curves assessed length of survival and time to death. Results Pathological fracture has no significant effect on 10 year EFS or 10 year OS. 3 factors strongly associate with 10 year OS rates: American Joint Committee on Cancer (AJCC) classification (p<0.001), Metastases site (p<0.001) and Distant recurrence (p<0.001). Fractures had poorer post-chemotherapeutic necrosis rates (p=0.005). Conclusion Pathological fractures have no significant effect on survival rates or length of survival in an Irish population. The effect of pathological fractures on necrosis rates must be explored in future research.

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors, T790M, and clinical trials.

Tumours with sensitizing mutations in the EGFR gene constitute a distinct molecular subgroup of non-small-cell lung cancers (nsclcs) that benefit from precision medicine. First- and second-generation epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) are recommended as upfront therapy for EGFR-mutated advanced nsclc and, compared with chemotherapy, have resulted in superior progression-free survival, improved tumour response rates, and improved quality of life. However, resistance inevitably develops, and the third-generation tki osimertinib has been approved to target the gatekeeper EGFR mutation T790M, which is responsible for resistance in 60% of cases. Multiple drivers of tki resistance have now been identified, and many new drugs are in development. With respect to this rapidly evolving field, our review highlights the current status of treatment options for patients with EGFR-mutated advanced nsclc, focusing especially on identified causes of resistance, challenges, and clinical trials aiming to improve outcomes in this patient population.

A Survey Exploring the Experiences & Attitudes of Dental Implant Clinicians in the Management of Peri-implantitis within the United Kingdom.

Peri-implantitis remains one of the most challenging complications that could threaten the long-term survival of implants. The aim of this survey is to explore the experiences, attitudes and challenges that face clinicians in the management of peri-implantitis. A validated online questionnaire was emailed to implant clinicians in the United Kingdom. 72 clinicians responded to the questionnaire, all of whom face many challenges during the treatment of peri-implantitis, with 79% finding difficulties due to lack of treatment consensus and 78% finding treatment outcomes unpredictable. This survey highlights the marked differences in opinion and attitudes of clinicians in the management of peri-implantitis.

Is chemotherapy always required for cancer in pregnancy? An observational study.

BACKGROUND: Cancer in pregnancy is relatively rare, but the incidence is increasing. Several studies show that cytotoxic agents are safe to use in pregnancy from the second trimester onwards. AIMS: This study assesses the maternal and foetal outcomes of cancers diagnosed during pregnancy. In particular, it focuses on a subset of women who elected to defer systemic chemotherapy until after delivery. This study examines if all cancers need to be treated during pregnancy or if, in certain cases, treatment can be safely deferred until after full-term delivery. METHODS: This is a retrospective observational study of women diagnosed with cancer during pregnancy in an Irish cancer centre over a 27-year period. All women diagnosed with cancer during pregnancy who were referred to the medical oncology department for consideration of chemotherapy were included in this study. Medical and pharmacy records were extensively reviewed. RESULTS: Twenty-five women were diagnosed with cancer in pregnancy and referred to medical oncology for consideration of systemic chemotherapy. Sixteen women (64%) commenced chemotherapy during pregnancy, seven women (28%) did not receive chemotherapy while pregnant, but commenced treatment immediately after delivery, and two (8%) did not receive any systemic chemotherapy at all. Of the seven women who commenced chemotherapy after delivery, six (85.7%) were diagnosed before 30/40 gestation. There were three cases of Hodgkin's lymphoma, two breast cancers and one ovarian cancer. After a median follow-up of 12 years, all six mothers remain disease-free. CONCLUSIONS: This study identified a select cohort of patients that did not receive chemotherapy during pregnancy. There were no adverse outcomes to mothers due to delayed treatment.

Osteosarcoma in a Patient Receiving Long-Term TNF Inhibitor Therapy.

Patients with inflammatory bowel disease (IBD) have an increased risk of developing malignancy. The use of immunosuppressive therapies and tumour necrosis factor (TNF) inhibitors in these patients may provide a further risk for the development of malignancy. We report the clinical and pathological findings of a high grade osteosarcoma in a patient with Crohns disease receiving TNF inhibitor therapy. In this case, a 32-year old female presented with a painful right knee after receiving maintenance adalimumab for Crohns disease for a period of six years. There is a substantial hypothetical link between TNF inhibitor regimens such as adalimumab and an increased risk of malignancy. TNF inhibitor therapy should be ceased and chemotherapy and surgery is an effective combined modality approach in these patients. The role of TNF inhibitors in patients after cancer diagnosis is uncertain and further research is required to assess efficacy and safety.

Perioperative chemotherapy in the treatment of osteosarcoma: a 26-year single institution review.

BACKGROUND: Chemotherapy in the multimodality treatment of osteosarcoma has improved survival. Reported outcomes on adult patients are limited. Poor necrosis rates post neoadjuvant chemotherapy (NAC) is considered an adverse prognostic factor and attempts have been made to improve survival in this group. PATIENTS AND METHODS: Adult and young adult patients diagnosed with osteosarcoma between January 1986 and August 2012 were retrospectively reviewed. Patients identified were stratified according to stage (localised or metastatic) and age (≤40 and >40 years). Event free survival (EFS) and overall survival (OS) outcomes were determined. In patients with localised disease ≤40 years, survival was assessed according to necrosis rates post NAC (<90 and ≥90%). NAC consisted of two cycles of methotrexate alternating with doxorubicin/cisplatin (MAP) followed by definitive surgery. Those with ≥90% tumour necrosis continued on MAP. Patients with <90% necrosis received ifosfamide and etoposide (IE) post operatively. RESULTS: A total of 108 patients were reviewed and 97 were included. Median age was 23 years (range 16-75) and 70% of patients were male. Five year EFS and OS across all groups was 57% and 63% respectively. Of the patients with localised disease (N = 81), 5-year overall survival (OS), with a median follow up of 7 years (2-26) was 70% (p < 0.0001). Patients aged 16-40 (N = 68) with localised osteosarcoma had a significantly improved 5-year OS (74%) compared to those >40 years (N = 13) (42%) (p = 0.004). Of the 68 patients with localised osteosarcoma ≤40 years, 62 were evaluated according to necrosis rates post MAP. In 33 patients who achieved ≥90% necrosis and continued MAP, 5-year OS was 82%. In 29 patients who had <90% tumour necrosis and received adjuvant IE, 5-year OS was 68% (p = 0.15). Multivariate analysis confirmed age and stage as prognostic factors but not poor necrosis rates in our treated population. CONCLUSIONS: Long-term survival outcomes in a predominantly adult Irish population are similar to large reported trials. Age and stage at diagnosis are prognostic. Postoperative ifosfamide/etoposide alone in patients with poor necrosis rates is a feasible regimen, but its role in the adjuvant setting remains uncertain.

Vismodegib in the treatment of advanced BCC.

Basal-cell carcinoma (BCC) is the most commonly diagnosed malignancy, comprising over 80 per thousand of non-melanoma skin cancers. Surgical excision is adequate treatment for most BCC's. Options are however limited for the minority of patients presenting with locally advanced inoperable or metastatic BCC. The Hedgehog signalling pathway is a critical driver in the pathogenesis of both sporadic and hereditary BCC. On 31st January 2012, based on a phase II clinical trial the US Food and Drug Administration approved Vismodegib (Erivedge, Roche) a first-in-class, small-molecule oral Hedgehog-inhibitor for the treatment of locally advanced inoperable and metastatic BCC. We present our experience treating the first Irish patient with this agent.

Has the practice of radiation oncology for locally advanced and metastatic non-small-cell lung cancer changed in Canada?

AIM: Previous surveys have revealed wide variations in the management by radiation oncologists of non-small-cell lung cancer (NSCLC) in Canada. The aim of the present study was to determine the current patterns of practice for locally advanced and metastatic NSCLC among Canadian radiation oncologists. MATERIALS AND METHODS: An online survey was distributed electronically to all members of the Canadian Association of Radiation Oncologists. Those who treat lung cancer were invited to participate. The survey consisted of three scenarios focusing on areas of nsclc treatment in which the radiotherapy (RT) regimen that provides the best therapeutic ratio is unclear. RESULTS: Replies from 41 respondents were analyzed. For an asymptomatic patient with stage IIIB NSCLC unsuitable for radical treatment, 22% recommended immediate RT, and 78% recommended RT only if the patient were to become symptomatic. Those who believed that immediate RT prolongs survival were more likely to recommend it (p = 0.028). For a patient with a bulky stage IIIB tumour and good performance status, 39% recommended palliative treatment, and 61% recommended radical treatment (84% concurrent vs. 16% sequential chemoradiation at 60-66 Gy in 30-33 fractions). Those who believed that chemoradiation has a greater impact on survival were more likely to recommend it (p < 0.001). For a symptomatic patient with stage IV NSCLC, 54% recommended external-beam RT (EBRT) alone, 41% recommended other modalities (brachytherapy, endobronchial therapy, or chemotherapy) with or without EBRT, and 5% recommended best supportive care. A majority (76%) prescribed 20 Gy in 5 fractions for EBRT. CONCLUSIONS: Compared with previous surveys, more radiation oncologists now offer radical treatment for locally advanced NSCLC. Management of nsclc in Canada may be evidence-based, but perception by radiation oncologists of the treatment's impact on survival also influences treatment decisions.

Update on the management of atherosclerotic renal artery disease.

Typically involving the renal artery ostium or proximal segment of the renal artery, atherosclerosis is the major cause of renal artery stenosis. While commonly without direct clinical consequences, the presence of renal artery atherosclerosis is associated with atherosclerotic disease in other vascular beds and in some subjects may give rise to systemic hypertension, progressive renal dysfunction and/or heart failure. Aggressive blood pressure control, atherosclerotic risk factor modification and use of anti-platelet therapy are indicated once diagnosed. The role for concomitant renal artery revascularization remains unclear and the decision should be individualized depending on patient preferences, co-morbidities, institutional expertise, and carefully weighed risks and benefits. Ongoing trials including CORAL and ASTRAL will hopefully provide critical evidence for or against this additive invasive strategy.

Riverina men's study: a preliminary exploration of the diet, alcohol use and physical activity behaviours and attitudes of rural men in two Australian New South Wales electorates.

INTRODUCTION: Discourses around men's health refer to greater risk-taking behaviour, the social construct of masculinity and differences between men's and women's rates of death and disease. These ways of describing 'men's health' may be inadequate, but many men, particularly rural men, experience health disadvantage. OBJECTIVE: To determine the reported eating, drinking and exercise behaviours of rural men and relationships between reported behaviours and attitudes to health and body image, age and occupation. METHOD: A written postal survey was used to collect demographic data, eating behaviours using the Food Habit Score, alcohol use, physical activity behaviours using an adaptation of the Pilot Study of the Fitness of Australians and attitudes to health and body image. SUBJECTS AND SETTING: The survey was sent to 2000 randomly selected men in two New South Wales Riverina federal electorates in June 2004, with 529 returns (27% response). MAIN OUTCOME MEASURES: Food Habit Scores; regularity of physical activity; frequency and amount of alcohol use; degree of agreement with statements about attitudes to health and body image. STATISTICAL ANALYSES: Descriptive statistics using frequencies and cross tabulations were performed with further univariate analyses conducted at a level of significance of 5%. RESULTS: Approximately one-third of the men achieved a poor Food Habit Score (< or =10 out of 20). Age was not significantly associated with diet quality, but those in higher skilled occupations had a better diet, compared with those in less skilled occupations (p<0.01). Eighty-seven percent of the respondents drank alcohol and of those, almost half consumed only one or two alcoholic drinks at each session. Nearly a quarter of the men reported that they had more than four drinks on each drinking occasion. Almost half the men did no 'vigorous' exercise, but 42% did heavy labouring/gardening at least three times a week. The men with poor dietary habits were more likely to agree with less desirable attitudes to health, such as needing a health scare before changing lifestyle behaviours (p<0.001). The low response rate (27%) limits the ability to generalise these results to the whole male population in the Farrer and Riverina federal electorates. CONCLUSION: This study describes the eating and physical activity behaviours of a sample of rural men and highlights the attitudes that are associated with poor lifestyle behaviours among this hard to reach group. IMPLICATIONS: Health promotion programs targeting men, especially rural men, should address existing attitudes to health which may impact on lifestyle behaviours.

K(ATP) channel pharmacogenomics: from bench to bedside.

Inheritance plays a significant role in defining drug response and toxicity. Advances in molecular pharmacology and modern genomics emphasize genetic variation in dictating inter-individual pharmacokinetics and pharmacodynamics. A case in point is the homeostatic ATP-sensitive potassium (K(ATP)) channel, an established drug target that adjusts membrane excitability to match cellular energetic demand. There is an increased recognition that genetic variability of the K(ATP) channel impacts therapeutic decision-making in human disease.

Parenting programmes: a systematic review and synthesis of qualitative research.

BACKGROUND: Parenting programmes are at the heart of intervention strategies for parents of children with emotional and behaviour problems. Systematic reviews and meta-analyses of randomized controlled trials have indicated that such programmes can improve many aspects of family life. However, there is currently a dearth of information concerning what it is that makes parenting programmes meaningful and helpful to parents. The aim of this paper was to examine parents' experience and perceptions of parenting programmes using the meta-ethnographic method, in order to sensitize policymakers and practitioners to the key factors that parents perceive to be of value. METHODS: Systematic searches of a number of electronic databases were undertaken using key search terms. Critical appraisal of included studies was conducted using standardized criteria, and the reports were synthesized using meta-ethnographic methods. RESULTS: Six reports were purposefully selected and critically appraised independently by two reviewers. Two were excluded. Based on the remaining four papers, five key concepts were identified as important when planning and delivering parenting programmes. A lines-of-argument synthesis was developed which suggests that the acquisition of knowledge, skills and understanding, together with feelings of acceptance and support from other parents in the parenting group, enabled parents to regain control and feel more able to cope. This led to a reduction in feelings of guilt and social isolation, increased empathy with their children and confidence in dealing with their behaviour. CONCLUSION: This evaluation provides an indication of the components that parents perceive to be necessary in the provision of parenting programmes, independent of the particular type of programme being provided. It may therefore aid policymakers in decisions about which programmes to provide.