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Objective The microbial dolomite of the second Member of the Dengying Formation（Deng 2 Member） in the Penglai area of the Sichuan Basin is widely distributed and considered a potential target for deep carbonate oil and gas exploration. Unlike conventional high-quality reservoirs characterized by porosity and karst fractures, the carbonate rocks of the Deng 2 Member mainly consist of microbial dolomite. The genesis and diagenetic evolution of these high-quality reservoirs remain unclear. Methods This study employed petrographic thin sections, scanning electron microscopy (SEM), cathodoluminescence, and computed tomography （CT）scanning to conduct a detailed analysis of the microbial dolomite reservoirs in the Dengying Formation, using field outcrop and core samples. The aim was to gain a deeper understanding of the effects of diagenesis on pore formation and the development of high-quality reservoirs. Results and Conclusion The microbial carbonate reservoirs in the study area were characterized by low porosity and very low permeability, predominantly consisting of fracture-porosity (cavity) type microbial dolomite. The reservoir space was primarily composed of intergranular dissolution pores, residual framework dissolution pores, intragranular dissolution pores, and small to medium-sized dissolution cavities, with minor occurrences of intercrystalline pores and intercrystalline dissolution pores. The Deng 2 Member has undergone multiple diagenetic processes; penecontemporaneous dissolution and early epigenetic dissolution were key factors in enhancing porosity. Significance These findings enhance the understanding of the genesis of high-quality microbial carbonate reservoirs in the Ediacaran System of the Sichuan Basin and provide valuable information for deep oil and gas exploration and development in the region.

Objective To explore the effect of zinc finger protein A20 on senescence and apoptosis in human degenerative nucleus pulposus cells. Methods Human degenerative nucleus pulposus cells were extracted and cultured. Small interference RNA (siRNA) decreased the expression of A20. Lipopolysaccharide (LPS) was used as an inflammatory inducing factor. Control group, LPS group, siRNA-A20 group and siRNA-A20+LPS group were set up. The protein expression levels of A20, P21, P16, BAX, BID, BCL2, P65 and P-P65 were detected by Western blotting. β-galactosidase was detected by aging β-galactosidase staining kit, and Annexin V-PI double labeling and TUNEL staining was employed to detect apoptosis and to explore the effect of zinc finger protein A20 on senescence and apoptosis of nucleus pulposus cells. Caffeic acid phenethyl ester (CAPE) was used in rescue experiment, and the protein expression levels of A20, P21, P16, BAX, BID, BCL2, P65 and P-P65 were detected to explore the possible pathway of cell senescence and apoptosis induced by down-regulation of zinc finger protein A20. Results Compared with the control group, there was no significant change in protein levels of P21 and P16 in LPS group, but P21 and P16 increased significantly in siRNA-A20 group and siRNA-A20+LPS group (P < 0.05). β-galactosidase staining test showed that the number of positive cells increased significantly in siRNA-A20 treated groups (P < 0.05). The proportion of apoptosis in LPS group and siRNA-A20 group was higher than that of control group (P < 0.05), but lower than that of siRNA-A20+LPS group (P < 0.05). The result of TUNEL staining was consistent with that of AnnexinV-PI double labeling(P < 0.05). Apoptosis related protein BID and BAX increased (P < 0.05), and BCL2 decreased in siRNA-A20+LPS group (P < 0.05), while P-P65 increased significantly in siRNA-A20+LPS group(P < 0.05). Compared with siRNA-A20+LPS group, through the pretreatment of CAPE, protein levels of P-P65, P21, P16, BID and BAX decreased (P < 0.05), and the protein levels of BCL2 increased (P < 0.05). Conclusion Through down-regulation of zinc finger protein A20, LPS induces senescence and apoptosis of human degenerative nucleus pulposus cells through NF-κB signal pathway.

The shortest path model is selected to evaluate the regional traffic accessibility. Three index factors, gross regional product, total retail sales of consumer goods, and the number of permanent residents in the region, were selected, and the weight sum was given by entropy weight method to evaluate the regional economic intensity. The gravity model adding the regional accessibility index considering traffic factors is selected to evaluate the regional linkages. By integrating the three indexes, an evaluation index system of rail transit benefits is formed to study the utility of rail transit to the economic development of surrounding areas, and to provide scientific theoretical basis and guidance for the government to carry out urban construction and rail transit management.

Abstract Background Studies examining the transmission of multidrug-resistant tuberculosis (MDR-TB) strains have yielded conflicting results. Methods We examined transmission of MDR-TB strains using contact tracing data from a low incidence setting. Contacts of MDR-TB cases diagnosed in British Columbia, Canada, from 1990-2008 were identified through a provincial tuberculosis (TB) registry. Tuberculin skin test (TST) results and TB disease incident rates were determined for contacts. For comparison, TB disease incident rates and TST results were measured in close contacts of isoniazid mono-resistant (HMR-TB) and drug susceptible TB (DS-TB) cases. Results Of 89 identified close contacts of MDR-TB patients, 5 patients (6%) developed TB disease and 42 (47%) were TST positive. The incidence rate of TB disease (3%, p = 0.31) and TST positivity (49%, p = 0.82) were similar in contacts of HMR-TB cases. Compared with MDR-TB contacts, DS-TB contacts had lower incidence rate of TB disease (2%, p = 0.04) and TST positivity (32%, p Conclusion Contacts of MDR-TB and HMR-TB patients in a low incidence setting show high rates of TST positivity and TB disease but low rates of drug resistance.

Abstract Background Pertussis continues to challenge medical professionals; recently described increases in incidence may be due to age-cohort effects, vaccine effectiveness, or changes in testing patterns. Toronto, Canada has recently experienced increases in pertussis incidence, and provides an ideal jurisdiction for evaluating pertussis epidemiology due to centralized testing. We evaluated pertussis trends in Toronto using all available specimen data, which allowed us to control for changing testing patterns and practices. Methods Data included all pertussis culture and PCR test records for Greater Toronto from 1993 to 2007. We estimated incidence trends using Poisson regression models; complex relationships between disease incidence and test submission were explored with vector autoregressive models. Results From 1993 to 2007, 26988 specimens were submitted for testing; 2545 (9.4%) were positive. Pertussis incidence was 2 per 100,000 from 1993 to 2004 and increased to 10 per 100,000 from 2005-2007, with a concomitant 6-fold surge in test specimen submissions after the introduction of a new, more sensitive PCR assay. The relative change in incidence was less marked after adjustment for testing volumes. Bidirectional feedbacks between test positivity and test submissions were identified. Conclusions Toronto's recent surge in pertussis reflects a true increase in local disease activity; the apparent size of the outbreak has likely been magnified by increasing use of pertussis testing by clinicians, and by improved test sensitivity since 2005. These findings may be applicable to changes in pertussis epidemiology that have been noted elsewhere in North America.

Abstract Background ATRX is a tightly-regulated multifunctional protein with crucial roles in mammalian development. Mutations in the ATRX gene cause ATR-X syndrome, an X-linked recessive developmental disorder resulting in severe mental retardation and mild alpha-thalassemia with facial, skeletal and genital abnormalities. Although ubiquitously expressed the clinical features of the syndrome indicate that ATRX is not likely to be a global regulator of gene expression but involved in regulating specific target genes. The regulation of ATRX expression is not well understood and this is reflected by the current lack of identified upstream regulators. The availability of genomic data from a range of species and the very highly conserved 5' regulatory regions of the ATRX gene has allowed us to investigate putative transcription factor binding sites (TFBSs) in evolutionarily conserved regions of the mammalian ATRX promoter. Results We identified 12 highly conserved TFBSs of key gene regulators involved in biologically relevant processes such as neural and testis development and alpha-globin regulation. Conclusions Our results reveal potentially important regulatory elements in the ATRX gene which may lead to the identification of upstream regulators of ATRX and aid in the understanding of the molecular mechanisms that underlie ATR-X syndrome.

Abstract Background Multidrug resistance (MDR) is frequently observed after prolonged treatment in human hepatoma with conventional anti-tumor drugs, and photodynamic therapy (PDT) is a recently suggested alternative to overcome MDR. The therapeutic potential of PDT was evaluated in a multidrug resistance (MDR) human hepatoma cell line R-HepG2 with photosensitizer pheophorbide a (Pa). Results Our results demonstrated that intracellular accumulation of Pa was not reduced by the overexpression of P-glycoprotein. Pa-based PDT (Pa-PDT) significantly inhibited the growth of R-HepG2 cells with an IC50 value of 0.6 μM. Mechanistic study demonstrated that genomic DNA fragmentation and phosphatidylserine externalization occurred where increase of intracellular singlet oxygen level triggers the phosphorylation of c-Jun N-terminal Kinase (JNK) and leads to activation of intrinsic apoptotic caspases cascade during the Pa-PDT treatment. The cytotoxicity of Pa-PDT, accumulation of sub-G1 population, and depolarization of mitochondrial membrane could be inhibited by JNK inhibitor in the Pa-PDT treated cells. Interestingly, the Pa-PDT induced JNK activation showed inhibitory effect on MDR by the down-regulation of P-glycoprotein in R-HepG2 cells in a dose-dependent manner. In addition, significant reduction of tumor size was obtained in Pa-PDT treated R-HepG2-bearing nude mice with no significant damages in liver and heart. Conclusion In summary, our findings provided the first evidence that PDT could inhibit the MDR activity by down-regulating the expression of P-glycoprotein via JNK activation using pheophorbide a as the photosensitizer, and our work proved that Pa-PDT inhibited the growth of MDR hepatoma cells by mitochondrial-mediated apoptosis induction.

Abstract Background Legionellosis is a common cause of severe community acquired pneumonia and respiratory disease outbreaks. The Ontario Public Health Laboratory (OPHL) has conducted most testing for Legionella species in the Canadian province of Ontario since 1978, and represents a multi-decade repository of population-based data on legionellosis epidemiology. We sought to provide a laboratory-based review of the epidemiology of legionellosis in Ontario over the past 3 decades, with a focus on changing rates of disease and species associated with legionellosis during that time period. Methods We analyzed cases that were submitted and tested positive for legionellosis from 1978 to 2006 using Poisson regression models incorporating temporal, spatial, and demographic covariates. Predictors of infection with culture-confirmed L. pneumophila serogroup 1 (LP1) were evaluated with logistic regression models. Results 1,401 cases of legionellosis tested positive from 1978 to 2006. As in other studies, we found a late summer to early autumn seasonality in disease occurrence with disease risk increasing with age and in males. In contrast to other studies, we found a decreasing trend in cases in the recent decade (IRR 0.93, 95% CI 0.91 to 0.95, P-value = 0.001); only 66% of culture-confirmed isolates were found to be LP1. Conclusion Despite similarities with disease epidemiology in other regions, legionellosis appears to have declined in the past decade in Ontario, in contrast to trends observed in the United States and parts of Europe. Furthermore, a different range of Legionella species is responsible for illness, suggesting a distinctive legionellosis epidemiology in this North American region.

Abstract Background Mycoplasma pneumoniae and Chlamydophila pneumoniae are major causes of lower and upper respiratory infections that are difficult to diagnose using conventional methods such as culture. The ProPneumo-1 (Prodesse, Waukesha, WI) assay is a commercial multiplex real-time PCR assay for the simultaneous detection of M. pneumoniae and/or C. pneumoniae DNA in clinical respiratory samples. Objective The aim of this study was to evaluate the sensitivity and specificity of the ProPneumo-1, a newly developed commercial multiplex real-time PCR assay. Methods A total of 146 clinical respiratory specimens, collected from 1997 to 2007, suspected of C. pneumoniae or M. pneumoniae infections were tested retrospectively. Nucleic acid was extracted using an automated NucliSense easyMag (bioMerieux, Netherlands). We used a "Home-brew" monoplex real-time assay as the reference method for the analysis of C. pneumoniae and culture as the reference method for the analysis of M. pneumoniae. For discordant analysis specimens were re-tested using another commercial multiplex PCR, the PneumoBacter-1 assay (Seegene, Korea). Results Following discordant analysis, the sensitivity of the ProPneumo-1 assay for pathogens, C. pneumoniae or M. pneumoniae, was 100%. The specificity of the ProPneumo-1 assay, however, was 100% for C. pneumoniae and 98% for M. pneumoniae. The limits of detection were 1 genome equivalent (Geq) per reaction for pathogens, M. pneumoniae and C. pneumoniae. Due to the multipex format of the ProPneumo-1 assay, we identified 5 additional positive specimens, 2 C. pneumoniae in the M. pneumoniae-negative pool and 3 M. pneumoniae in the C. pneumoniae-negative pool. Conclusion The ProPneumo-1 assay is a rapid, sensitive and effective method for the simultaneous detection of M. pneumoniae and C. pneumoniae directly in respiratory specimens.

Abstract Background Integrated personal health records (PHRs) offer significant potential to stimulate transformational changes in health care delivery and self-care by patients. In 2006, an invitational roundtable sponsored by Kaiser Permanente Institute, the American Medical Informatics Association, and the Agency for Healthcare Research and Quality was held to identify the transformative potential of PHRs, as well as barriers to realizing this potential and a framework for action to move them closer to the health care mainstream. This paper highlights and builds on the insights shared during the roundtable. Discussion While there is a spectrum of dominant PHR models, (standalone, tethered, integrated), the authors state that only the integrated model has true transformative potential to strengthen consumers' ability to manage their own health care. Integrated PHRs improve the quality, completeness, depth, and accessibility of health information provided by patients; enable facile communication between patients and providers; provide access to health knowledge for patients; ensure portability of medical records and other personal health information; and incorporate auto-population of content. Numerous factors impede widespread adoption of integrated PHRs: obstacles in the health care system/culture; issues of consumer confidence and trust; lack of technical standards for interoperability; lack of HIT infrastructure; the digital divide; uncertain value realization/ROI; and uncertain market demand. Recent efforts have led to progress on standards for integrated PHRs, and government agencies and private companies are offering different models to consumers, but substantial obstacles remain to be addressed. Immediate steps to advance integrated PHRs should include sharing existing knowledge and expanding knowledge about them, building on existing efforts, and continuing dialogue among public and private sector stakeholders. Summary Integrated PHRs promote active, ongoing patient collaboration in care delivery and decision making. With some exceptions, however, the integrated PHR model is still a theoretical framework for consumer-centric health care. The authors pose questions that need to be answered so that the field can move forward to realize the potential of integrated PHRs. How can integrated PHRs be moved from concept to practical application? Would a coordinating body expedite this progress? How can existing initiatives and policy levers serve as catalysts to advance integrated PHRs?

(1) Background: This observational cohort study describes the frequency, content, and satisfaction with advance care planning (ACP) conversations with healthcare providers (HCPs), as reported by patients with advanced colorectal cancer. (2) Methods: The patients were recruited from two tertiary cancer centers in Alberta, Canada. Using the My Conversations survey with previously validated questions, the patients were asked about specific ACP elements discussed, with which HCPs these elements were discussed, their satisfaction with these conversations, and whether they had a goals of care designation (GCD) order. We surveyed and analyzed data from the following four time points: enrollment, months 1, 2, and 3. (3) Results: In total, 131 patients were recruited. At enrollment, 24% of patients reported discussing at least one ACP topic. From enrollment to month 3, patients reported a high frequency of discussions (80.2% discussed fears, 71.0% discussed prognosis, 54.2% discussed treatment preferences at least once); however, only 44.3% of patients reported discussing what is important to them in considering health care preferences. Patients reported having ACP conversations most often with their oncologists (84.7%) and cancer clinic nurses (61.8%). Patients reported a high level of satisfaction with their ACP conversations, with over 80% of patients reported feeling heard and understood. From enrollment to month 3, there was an increase in the number of patients with a GCD order from 53% to 74%. (4) Conclusions: Patients reported more frequent conversations compared to the literature and clinical documentation. While the satisfaction with these conversations is high, there is room for quality improvement, particularly in eliciting patients' personal goals for their treatment.

Background: Information needs are one of the most common unmet supportive care needs of those living with cancer. Little is known about how existing tools for assessing information needs in the cancer context have been created or the role those with lived cancer experience played in their development., Objectives: This review aimed to characterize the development and intended use of existing cancer specific information needs assessment tools., Methods: A systematic scoping review was conducted using a peer-reviewed protocol informed by recommendations from the Joanna Briggs Institute and the Prefered Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist., Results: Twenty-one information needs assessment tools were included. Most tools were either breast cancer ( n  = 8) or primary tumor nonspecific ( n  = 8). Patients and informal carers participated in initial identification of questionnaire items in the minority of cases ( n  = 6) and were more commonly involved in reviewing the final questionnaire before use or formal psychometric testing ( n  = 9). Most questionnaires were not assessed for validity or reliability using rigorous quantitative psychometric testing., Significance of Results: Existing tools are generally not designed to provide a rigorous assessment of informational needs related to a specific cancer challenge and are limited in how they have been informed by those with lived cancer experience. Tools are needed that both rigirously address information needs for specific cancer challenges and that have been developed in partnership with those who have experienced cancer. Future directions should include understanding barriers and facilitators to developing such tools.

Background: Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient selection. TKI-induced hypertension is reportedly a surrogate marker for treatment benefit for some tumor types. Our objective was to determine whether hypertension was associated with benefit in the context of CRC treatment, and also to gain insight on the pathogenesis of TKI-induced hypertension by monitoring associated changes in the circulating metabolome., Patients and Methods: Clinical data were acquired from clinical trial patients with metastatic CRC randomized to cetuximab ± the TKI brivanib (N = 750). Outcomes were evaluated as a function of treatment-induced hypertension. For metabolomic studies, plasma samples were taken at baseline, as well as at 1, 4, and 12 weeks after treatment initiation. Samples were submitted to gas chromatography-mass spectrometry to identify treatment-related metabolomic changes associated with TKI-induced hypertension, compared to pre-treatment baseline. A model based on changes in metabolite concentrations was generated using orthogonal partial least squares discriminant analysis (OPLS-DA)., Results: In the brivanib treated group, 95 patients had treatment-related hypertension within 12 weeks of initiating treatment. TKI-induced hypertension was not associated with a significantly higher response rate, nor was it associated with improved progression-free or overall survival. In metabolomic studies, 386 metabolites were identified. There were 29 metabolites that changed with treatment and distinguished patients with and without TKI-induced hypertension. The OPLS-DA model for brivanib-induced hypertension was significant and robust (R 2 Y score = 0.89, Q 2 Y score = 0.70, CV-ANOVA = 2.01 e-7). Notable metabolomic features previously reported in pre-eclampsia and associated with vasoconstriction were found., Conclusion: TKI-induced hypertension was not associated with clinical benefit in metastatic CRC. We have identified changes in the metabolome that are associated with the development of worsening brivanib-induced hypertension that may be useful in future efforts of characterizing this toxicity., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The rusty grain beetle, Cryptolestes ferrugineus (Stephens) is one of the most economically important stored grain pests, and it has evolved the high resistance to phosphine. Cuticular proteins (CPs) are the major structural components of insect cuticle, and previous studies have confirmed that CPs were involved in insecticide resistance. However, the CPs of C. ferrugineus are still poorly characterized, and thus we conducted transcriptome-wide identification of CP genes and analyze their possible relationships with phosphine resistance in this pest. In this study, a total of 122 putative CPs were annotated in the C. ferrugineus transcriptome data by blasting with the known CPs of Tribolium castaneum. The analysis of conserved motifs revealed these CPs of C. ferrugineus belonging to 9 different families, including 87 CPR, 13 CPAP1, 7 CPAP3, 3 Tweedle, 1 CPLCA, 1 CPLCG, 5 CPLCP, 2 CPCFC, and 3 CPFL proteins. The further phylogenetic analysis showed the different evolutionary patterns of CPs. Namely, we found some CPs (CPR family) formed species-specific protein clusters, indicating these CPs might occur independently among insect taxa, and while some other CPs (CPAP1 and CPAP3 family) shared a closer correlation based on the architecture of protein domains. Subsequently, the previous RNA-seq data were applied to establish the expression profiles of CPs in a phosphine susceptible and resistant populations of C. ferrugineus, and a large amount of CP genes were found to be over-expressed in resistant insects. Lastly, an up-regulated CP gene (CPR family) was selected for the further functional analysis, and after this gene was silenced via RNA interference (RNAi), the sensitivity to phosphine was significantly enhanced in C. ferrugineus. In conclusion, the present results provided us an overview of C. ferrugineus CPs, and which suggested that the CPs might play the critical roles in phosphine resistance., (Copyright © 2023. Published by Elsevier Inc.)

Background: The internet is an important source of information for many informal caregivers and patients living with cancer. A better understanding of how individuals use the internet to meet their informational needs is important for guiding intervention development., Objective: The objectives of this study were to develop a theory describing why individuals living with cancer use the internet to find information, characterize the challenges faced with existing web-based content, and provide recommendations for web-based content design., Methods: Adults (≥18 years) with a history of being patients with cancer or informal caregivers were recruited from Alberta, Canada. After providing informed consent, participants were engaged through digitally recorded one-on-one semistructured interviews, focus groups, a web-based discussion board, and emails. Classic grounded theory guided the study procedures., Results: A total of 21 participants took part in 23 one-on-one interviews and 5 focus groups. The mean age was 53 (SD 15.3) years. Breast, gynecological, and hematological cancers were the most common cancer types (4/21, 19% each). In total, 67% (14/21) of patients, 29% (6/21) of informal caregivers, and 5% (1/21) of individuals reporting both roles participated. Participants experienced many new challenges in their cancer journey and used the internet to become better oriented to them. For each challenge, internet searching attempted to address one or more of 3 key orientation questions: why the challenge was happening, what to expect, and options for managing it. Better orientation resulted in improved physical and psychosocial well-being. Content that was well laid out, concise, free of distractions, and that addressed the key orientation questions was identified as the most helpful in assisting with orientation. Creators of web-based content are encouraged to 1) clearly identify the cancer challenge and population the content is addressing, as well as the presence of any potentially distressing information; 2) provide versions of the content in different formats, including printer-friendly, audio, video, and alternative languages; 3) state who created the content, including the individuals, organizations, and processes involved; 4) place hyperlinks after the key orientation questions have been addressed; and 5) ensure that the content is optimized for discovery by search engines (ie, Google)., Conclusions: Web-based content plays an essential role for many living with cancer. Clinicians are encouraged to take active steps to help patients and informal caregivers find web-based content that meets their informational needs. Content creators also have a responsibility to ensure that the content they create assists and does not hinder those navigating the cancer journey. Research is needed to better understand the many challenges that individuals living with cancer face, including how they are temporally related. In addition, how to optimize web-based content for specific cancer challenges and populations should be considered an important area for future research., (©Maclean Thiessen, Shelly Raffin Bouchal, Patricia A Tang, Shane Sinclair. Originally published in JMIR Cancer (https://cancer.jmir.org), 17.05.2023.)

Cucujiformia, the largest taxon in the order Coleoptera, exhibits extraordinary morphological, ecological, and behavioral diversity. This infraorder is currently divided into seven superfamilies, but considerably incongruent relationships among superfamilies have been reported by recent phylogenomic studies. Here, we combined the 21 newly sequenced transcriptomes representing six superfamilies with nine previously published cucujiform genomes/transcriptomes to elucidate the phylogeny and evolution of Cucujiformia. The monophyly of each of five superfamilies were consistently supported by all phylogenetic analyses based on the twelve datasets (matrix occupancy, amino acid and nucleotide data) and the two analytical methods (maximum likelihood method and Bayesian inference). Both the amino acid datasets and the RY recoded nucleotide datasets recovered the monophyly of Cucujoidea. Topology test results statistically supported the following robust superfamily-level phylogeny in Cucujiformia: (Coccinelloidea, (Cleroidea, (Tenebrionoidea, (Cucujoidea, (Chrysomeloidea, Curculionoidea))))). Our divergence time analyses recovered a Permian origin of Cucujiformia and a Jurassic-Cretaceous origin of most superfamilies. The diversification of phytophagous beetles that occurred in the Cretaceous can be attributed to its co-evolution with angiosperms, supporting the hypothesis of a Cretaceous Terrestrial Revolution., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Oncogenic KRAS mutations are absent in approximately 10% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and may represent a subgroup of mPDAC with therapeutic options beyond standard-of-care cytotoxic chemotherapy. While distinct gene fusions have been implicated in KRAS wildtype mPDAC, information regarding other types of mutations remain limited, and gene expression patterns associated with KRAS wildtype mPDAC have not been reported. Here, we leverage sequencing data from the PanGen trial to perform comprehensive characterization of the molecular landscape of KRAS wildtype mPDAC and reveal increased frequency of chr1q amplification encompassing transcription factors PROX1 and NR5A2. By leveraging data from colorectal adenocarcinoma and cholangiocarcinoma samples, we highlight similarities between cholangiocarcinoma and KRAS wildtype mPDAC involving both mutation and expression-based signatures and validate these findings using an independent dataset. These data further establish KRAS wildtype mPDAC as a unique molecular entity, with therapeutic opportunities extending beyond gene fusion events., (© 2022. The Author(s).)

Immunotherapy-based monotherapy treatment in metastatic pancreatic ductal adenocarcinoma (mPDAC) has shown limited benefit outside of the mismatch repair deficiency setting, while safety and efficacy of combining dual-checkpoint inhibitor immunotherapy with chemotherapy remains uncertain. Here, we present results from the CCTG PA.7 study (NCT02879318), a randomized phase II trial comparing gemcitabine and nab-paclitaxel with and without immune checkpoint inhibitors durvalumab and tremelimumab in 180 patients with mPDAC. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and objective response rate. Results of the trial were negative as combination immunotherapy did not improve survival among the unselected patient population (p = 0.72) and toxicity was limited to elevation of lymphocytes in the combination immunotherapy group (p = 0.02). Exploratory baseline circulating tumor DNA (ctDNA) sequencing revealed increased survival for patients with KRAS wildtype tumors in both the combination immunotherapy (p = 0.001) and chemotherapy (p = 0.004) groups. These data support the utility of ctDNA analysis in PDAC and the prognostic value of ctDNA-based KRAS mutation status., (© 2022. The Author(s).)

Background: Long-term response to HER2-targeted therapies is infrequent in metastatic breast cancer (MBC). We evaluated clinical characteristics of HER2-positive MBC patients with no evidence of disease (NED) vs residual disease (RES) experiencing long-term response to first-line HER2-targeted therapy., Methods: Patients receiving first-line chemotherapy-trastuzumab (CT) or taxane-trastuzumab-pertuzumab (THP) with response duration ≥2-fold higher than in phase II/III trials (CT [18.2 months]; THP [40.4 months]) were included. Clinical characteristics and radiographic review for NED or RES was evaluated by Cox-regression (hazard ratio; HR) or Kaplan-Meier (log-rank). Characteristics associated with NED were evaluated by logistic regression (Odds; OR)., Results: From 01/2005-01/2016, N = 103 (4.6%) patients were identified. In multivariate analyses, NED (N = 46) showed improved progression-free (PFS) and overall survival (OS) [p < 0.001] versus RES (N = 57), with high 5-year PFS/OS for NED (93.2%/97.4%) relative to RES (10.6%/61.3%). Premenopausal status (p = 0.006), de-novo metastases (p = 0.002), and no palliative radiotherapy (p = 0.01) were associated with NED. Overall, 6/7 (85.7%) patients with NED were alive and disease-free after discontinuing HER2 treatment (≥1 year) versus 1/17 (5.9%) with RES., Conclusions: Long-term responders with NED have better survival compared to RES. Premenopausal status and de novo metastatic disease are associated with NED. Prospective studies of HER2 therapy discontinuation with NED in MBC are warranted., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Aim: To assess the patterns of emergency department (ED) visits in the 3 months preceding a diagnosis of colorectal cancer (CRC) in a real-world, population-based context. Materials & methods: Linked provincial registries in Alberta, Canada, were accessed and patients with CRC diagnosed between 2004 and 2018 were identified. The National Ambulatory Care reporting system was used to identify patients who visited an ED within 3 months of a diagnosis of CRC. Multivariable logistic regression analysis was used to identify factors associated with any ED visits as well as frequent (≥3) ED visits. Results: A total of 25,310 patients with CRC were included in the current study. These include 10,126 patients (40%) who had at least one visit to the ED in the 3 months before a diagnosis of CRC diagnosis and 613 patients (2.4%) who visited the ED multiple (≥3) times. The following factors were associated with any visit to an ED: older age (odds ratio [OR]: 1.010; 95% CI: 1.008-1.012), female gender (OR: 1.23; 95% CI: 1.16-1.30), higher comorbidity index (OR: 1.38; 95% CI: 1.35-1.41), metastatic disease (OR: 2.37; 95% CI: 2.23-2.53), proximal tumors (OR: 1.59; 95% CI: 1.50-1.68) and North zone (OR vs south zone: 1.75; 95% CI: 1.55-1.98). Conclusion: It is not uncommon for CRC patients to visit the ED at least once in the 3 months prior to having such a diagnosis. Factors associated with frequent pre diagnosis emergency visits included female gender, higher burden of comorbid disease, advanced stage, proximal tumors and living in the North zone of Alberta (where there is limited access to specialist care).

Purpose: Chemotherapy options for treating CRC have rapidly expanded in recent years, and few have predictive biomarkers. Oncologists are challenged with evidence-based selection of treatments, and response is evaluated retrospectively based on serial imaging beginning after 2-3 months. As a result, cumulative toxicities may appear in patients who will not benefit. Early recognition of non-benefit would reduce cumulative toxicities. Our objective was to determine treatment-related changes in the circulating metabolome corresponding to treatment futility., Methods: Metabolomic studies were performed on serial plasma samples from patients with CRC in a randomized controlled trial of cetuximab vs. cetuximab + brivanib ( N = 188). GC-MS quantified named 94 metabolites and concentrations were evaluated at baseline, Weeks 1, 4 and 12 after treatment initiation. In a discovery cohort ( N = 68), a model distinguishing changes in metabolites associated with radiographic disease progression and response was generated using OPLS-DA. A cohort of 120 patients was used for validation of the model., Results: By one week after treatment, a stable model of 21 metabolites could distinguish between progression and partial response (R2Y = 0.859; Q2Y = 0.605; P = 5e-4). In the validation cohort, patients with the biomarker had a significantly shorter OS ( P < 0.0001). In a separate cohort of patients with HCC on axitinib, appearance of the biomarker also signified a shorter PFS (1.7 months vs. 9.2 months, P = 0.001)., Conclusion: We have identified changes in the metabolome that appear within 1 week of starting treatment associated with treatment futility. The novel approach described is applicable to future efforts in developing a biomarker for early assessment of treatment efficacy., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2022 Rattner et al.)

Background: The incidence of early-onset (<50) colorectal cancer (eoCRC) has been increasing in Canada. Little is known about treatment patterns and outcomes among this patient population in Canada., Patients and Methods: We conducted a retrospective population-based cohort study of CRC patients in Alberta (2010-2018) using electronic medical records and administrative claims data. Treatment patterns and CRC-specific mortality were compared between early-onset age groups (<40 and 40-49) and average age-at-onset (60-70) (aoCRC) patients with multivariable logistic regression and cox proportional hazard models., Results: There were 334 and 935 patients in the early-onset groups and 4606 in the aoCRC group. Compared with aoCRC, patients <40 were more likely to receive chemotherapy in stage II colon (OR 3.41, CI 1.75-6.47) and stage III rectal (OR 3.01, CI 1.18-10.21), and to receive systemic therapy (OR 2.40, CI 1.46-4.12) and radiation in stage IV CRC (OR 2.70, CI 1.48-4.92). The 40-49 age group was more likely to receive chemotherapy in stage II colon (OR 2.13, CI 1.25-3.56), and chemoradiation in stage II rectal (OR 2.16, CI 1.25-3.80) and stage III rectal (OR 1.63, CI 1.13-2.40), as well as systemic therapy in stage IV CRC (OR 2.46, CI 1.75-3.52). Survival did not differ between <40 and 60-70 age groups. Survival was significantly higher for the 40-49 age group, but only in stage IV (HR 0.79, CI 0.67-0.94)., Conclusions: EoCRC patients tended to receive more therapy than average age CRC patients with minimal survival gains. Additional research to identify optimal treatment strategies for eoCRC patients is required., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with chronic kidney disease are commonly excluded from clinical trials. The impact of chronic kidney disease on outcomes in patients with locally advanced rectal cancer has not been previously studied., Objective: This study aimed to investigate the impact of chronic kidney disease on outcomes in patients with locally advanced rectal cancer., Design: This is a multi-institutional, retrospective cohort study., Settings: This study was conducted at academic and community cancer centers participating in the Canadian Health Outcomes Research Database Consortium Rectal Cancer Database., Patients: Consecutive patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation before curative-intent surgery from 2005 to 2013 were selected., Main Outcome Measures: Disease-free survival, overall survival, pathologic complete response, and neoadjuvant chemotherapy/radiotherapy completion rate were the primary outcomes measured., Results: A total of 1254 patients were included. Median age was 62, and 29%/69% had clinical stage II and III disease. Median estimated creatinine clearance was 93 mL/min, with 11% <60 mL/min (n = 136). There was no significant difference in the completion rate of neoadjuvant chemotherapy (82% vs 85%, p = 0.36) or radiotherapy (93% vs 95%, p = 0.45) between patients with and without chronic kidney disease. Patients with chronic kidney disease were less likely to receive adjuvant chemotherapy (63% vs 77%, p < 0.01). On multivariate analysis, patients with chronic kidney disease had decreased disease-free survival (HR, 1.37; 95% CI, 1.03-1.82; p = 0.03) but not overall survival (HR, 1.23; 95% CI, 0.88-1.75; p = 0.23) or pathologic complete response (OR, 0.83; 95% CI, 0.50-1.39; p = 0.71)., Limitations: This study was limited by its retrospective design and by limited events for overall survival analysis., Conclusions: In patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation, baseline chronic kidney disease was associated with less use of adjuvant chemotherapy and decreased disease-free survival. Chronic kidney disease was not independently associated with neoadjuvant chemotherapy/radiotherapy completion rate, pathologic complete response, or overall survival. These data suggest that patients with locally advanced rectal cancer with chronic kidney disease may have distinct outcomes and, accordingly, the results of landmark clinical trials may not be generalizable to this population. See Video Abstract at http://links.lww.com/DCR/B694., La Repercusin De La Enfermedad Renal Crnica En Pacientes Con Cncer De Recto Localmente Avanzado Tratados Con Quimiorradioterapia Neoadyuvante: ANTECEDENTES:Los pacientes con enfermedad renal crónica generalmente se excluyen de los ensayos clínicos. La repercusión de la enfermedad renal crónica en el desenlace en pacientes con cáncer de recto localmente avanzado no se ha estudiado previamente.OBJETIVO:Investigar la repercusión de la enfermedad renal crónica en los desenlaces en pacientes con cáncer de recto localmente avanzado.DISEÑO:Estudio de cohorte retrospectivo multiinstitucional.ESCENARIO:Centros oncológicos académicos y comunitarios que participan en la base de datos de cáncer rectal del consorcio CHORD.PACIENTES:Pacientes consecutivos con cáncer de recto localmente avanzado, tratados con quimiorradioterapia neoadyuvante, previa a la cirugía con intención curativa del 2005 al 2013.PRINCIPALES VARIABLES EVALUADAS:Sobrevida libre de enfermedad, sobrevida global, respuesta patológica completa, tasa de conclusión de quimioterapia / radioterapia neoadyuvante.RESULTADOS:Se incluyeron 1254 pacientes. El promedio de edad fue de 62, y el 29% / 69% tenían enfermedad en estadio clínico II y III, respectivamente. El promedio de la depuración de creatinina estimada fue de 93 mililitros / minuto, con un 11% <60 mililitros / minuto (n = 136). No hubo diferencias significativas en la tasa de conclusión de la quimioterapia neoadyuvante (82% vs 85%, p = 0,36) o radioterapia (93% vs 95%, p = 0,45) entre pacientes con y sin enfermedad renal crónica. Los pacientes con enfermedad renal crónica tenían menos probabilidades de recibir quimioterapia adyuvante (63% contra el 77%, p <0,01). En el análisis multivariado, los pacientes con enfermedad renal crónica tenían una sobrevida libre de enfermedad menor (HR 1,37, IC 95% 1,03-1,82, p = 0,03) pero no en la sobrevida global (HR 1,23, IC 95% 0,88-1,75, p = 0,23) o respuesta patológica completa (OR 0,83, IC 95% 0,50-1,39, p = 0,71).LIMITACIONES:Diseño retrospectivo y acontecimientos limitados para el análisis de sobrevida global.CONCLUSIONES:En pacientes con cáncer de recto localmente avanzado tratados con quimiorradioterapia neoadyuvante, la enfermedad renal crónica de base se asoció con un menor uso de quimioterapia adyuvante y una menor sobrevida libre de enfermedad. La enfermedad renal crónica no se asoció de forma independiente con la tasa de conclusión de la quimioterapia / radioterapia neoadyuvante, la respuesta patológica completa o la sobrevida global. Estos datos sugieren que los pacientes con cáncer de recto localmente avanzado con enfermedad renal crónica pueden tener resultados distintos y, en consecuencia, los resultados de los ensayos clínicos de referencia pueden no ser generalizables a esta población. Consulte Video Resumen en http://links.lww.com/DCR/B694., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Colon and Rectal Surgeons.)

Objectives: The POLO (Pancreas Cancer Olaparib Ongoing) trial demonstrated improvement in progression-free survival (PFS) with olaparib maintenance in advanced pancreatic cancer (APC) patients with germline BRCA1/2 mutations who had disease control after 16 weeks of platinum-based first-line therapy. However, in the real-world, the first assessment is usually performed at 12 weeks. Therefore, this study aimed to identify the proportion of real-world patients with APC that have disease control at 12 weeks (DC12) after FOLFIRINOX, assess any associations of baseline variables with DC12, and to determine the effect of DC12 on PFS and overall survival (OS)., Methods: APC patients treated with first-line FOLFIRINOX from 2011 to 2018 in Alberta, Canada, were identified. We conducted an analysis of baseline characteristics to identify factors associated with DC12 and to compare the PFS and OS of patients with DC12 to those with earlier disease progression., Results: We identified 165 APC patients treated with FOLFIRINOX with unknown BRCA1/2 status, of which 56% were men, and the median age at diagnosis was 59 years (interquartile range, 38 to 75 y). Of these, 72 (44%) had DC12. Lower serum carbohydrate antigen 19.9 and normal serum albumin were associated with a higher likelihood of DC12. The PFS and OS of patients with DC12 was significantly higher than those with earlier progression (9.3 vs. 2.5 mo; hazard ratio, 0.22; 95% confidence interval, 0.15-0.32; P<0.001; 21.6 vs. 8.9 mo; hazard ratio, 0.35; 95% confidence interval, 0.25-0.49; P<0.0001)., Conclusion: Less than half of real-world patients treated with first-line FOLFIRINOX have DC12. Patients with APC who have higher carbohydrate antigen 19.9 and low albumin are less likely to have DC12. DC12 is significantly associated with longer PFS and OS., Competing Interests: W.Y.C. and P.A.T. were on the advisory board of AstraZeneca. A.B. declares no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To assess the patterns of hospitalizations among early-stage colon cancer patients receiving adjuvant chemotherapy and to identify high-risk groups that may benefit from more careful monitoring in a real-world, population-based context., Methods: This is a population-based study using linked administrative databases from the province of Alberta, Canada. Any events of hospitalization among patients with non-metastatic colon cancer undergoing upfront surgery followed by adjuvant chemotherapy were reviewed. Multivariable logistic regression analysis was used to examine factors associated with risk of hospitalization, and the impact of hospitalization on overall survival was assessed through Kaplan-Meier estimates and Multivariable Cox regression analysis., Results: A total of 2257 patients were considered eligible and were included in the current analysis, including 483 patients (21.4%) who were hospitalized within 6 months of the start of adjuvant chemotherapy, and 1774 patients (78.6%) who were not. The following factors were associated with a higher hospitalization risk: older age (OR: 1.02; 95% CI 1.01-1.03), higher comorbidity (OR: 1.48; 95% CI 1.31-1.67), women (OR for men versus women: 0.79; 95% CI 0.64-0.98), living in the North zone (OR for Edmonton zone versus North zone: 0.60; 95% CI 0.42-0.87), and CAPOX chemotherapy (OR for CAPOX versus FOLFOX: 1.50; 95% CI 1.12-2.00). Patients with a history of hospitalization during adjuvant chemotherapy had a worse overall survival compared to patients who were not hospitalized (P < 0.001)., Conclusion: In this study, one out of five colon cancer patients were hospitalized during adjuvant chemotherapy. Older individuals, women, those with higher comorbidity, and those receiving adjuvant CAPOX were more likely to be hospitalized., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: In resected colonic liver metastasis (CLM), randomized studies of oxaliplatin-based chemotherapy have demonstrated improvements in disease-free survival (DFS), but not overall survival (OS). Additionally, oxaliplatin regimens have not been compared to non-oxaliplatin chemotherapy. Despite limited evidence, perioperative chemotherapy is often used in the management of CLM. The primary aim of this study was to assess the impact of oxaliplatin chemotherapy regimens on OS in patients who have undergone resection of CLM in a real-world setting., Patients and Methods: Patients who underwent resection of CLM in the provinces of Alberta and British Columbia, Canada, were identified from 1996 to 2016. Perioperative (pre- and/or post-) systemic therapy was categorized as oxaliplatin or non-oxaliplatin-based chemotherapy or no chemotherapy. The primary and secondary outcomes were OS and DFS, respectively., Results: We identified 511 patients who underwent R0 resection of CLM. A significant difference in median OS was identified among the oxaliplatin, non-oxaliplatin, and no-chemotherapy groups of 100, 60, and 59 months, respectively (P = .009). In multivariate analysis, patients who received oxaliplatin regimens had a lower risk of death (hazard ratio, 0.68; 95% confidence interval, 0.51-0.92; P = .012), whereas the non-oxaliplatin chemotherapy group did not (hazard ratio, 0.88; 95% confidence interval, 0.65-1.20; P = .422) compared with no chemotherapy., Conclusions: In this multicenter, retrospective, population-based study, perioperative oxaliplatin-based chemotherapy was associated with improved OS in conjunction with R0 resection of CLM. Further studies should evaluate the optimal duration and sequencing of perioperative chemotherapy in relation to curative-intent surgical resection of CLM., (Copyright © 2021. Published by Elsevier Inc.)

Despite the known benefits, healthcare systems struggle to provide early, integrated palliative care (PC) for advanced cancer patients. Understanding the barriers to providing PC from the perspective of oncology clinicians is an important first step in improving care. A 33-item online survey was emailed to all oncology clinicians working with all cancer types in Alberta, Canada, from November 2017 to January 2018. Questions were informed by Michie's Theoretical Domains Framework and Behaviour Change Wheel (BCW) and queried (a) PC provision in oncology clinics, (b) specialist PC consultation referrals, and (c) working with PC consultants and home care. Respondents ( n = 263) were nurses (41%), physicians (25%), and allied healthcare professionals (18%). Barriers most frequently identified were "clinicians' limited time/competing priorities" (64%), "patients' negative perceptions of PC" (63%), and clinicians' capability to manage patients' social issues (63%). These factors mapped to all three BCW domains: motivation, opportunity, and capability. In contrast, the least frequently identified barriers were clinician motivation and perceived PC benefits. Oncology clinicians' perceptions of barriers to early PC were comparable across tumour types and specialties but varied by professional role. The main challenges to early integrated PC include all three BCW domains. Notably, motivation is not a barrier for oncology clinicians; however, opportunity and capability barriers were identified. Multifaceted interventions using these findings have been developed, such as tip sheets to enhance capability, reframing PC with patients, and earlier specialist PC nursing access, to enhance clinicians' use of and patients' benefits from an early PC approach.

The rusty grain beetle, Cryptolestes ferrugineus (Stephens), is a serious pest of stored grain, which has developed high levels of resistance to phosphine. In this study, five geographically distant populations of C. ferrugineus had been collected in China, specifically in granaries where phosphine fumigant is used for pest control, and they showed a high resistance ratio up to 1,907 (LC50 = 21.0 mg/liter). Then, a reference transcriptome was constructed to use as a basis for investigating the molecular mechanisms of phosphine resistance in this species, which consisted of 47,006 unigenes with a mean length of 1,090. Subsequently, the RNA-Seq analysis of individuals from the most susceptible and resistant populations led to the identification of 54 genes that are differentially expressed. GO and KEGG analysis demonstrated that genes associated with mitochondrial and respiration functions were significantly enriched. Also, the 'structural constituent of cuticle' term was annotated in the GO enrichment analysis and further qRT-PCR confirmed that the expression levels of nine cuticular protein genes were significantly increased in the resistant population. In conclusion, we present here a transcriptome-wide overview of gene expression changes between resistant and susceptible populations of C. ferrugineus, and this in turn documents that mitochondria and cuticular protein genes may play together a crucial role in phosphine resistance. Further gene function analysis should enable the provision of advice to expedite resistance management decisions., (© The Author(s) 2020. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: With the rising incidence of early-onset pancreatic cancer (EOPC), molecular characteristics that distinguish early-onset pancreatic ductal adenocarcinoma (PDAC) tumors from those arising at a later age are not well understood., Experimental Design: We performed bioinformatic analysis of genomic and transcriptomic data generated from 269 advanced (metastatic or locally advanced) and 277 resectable PDAC tumor samples. Patient samples were stratified into EOPC (age of onset ≤55 years; n = 117), intermediate (age of onset 55-70 years; n = 264), and average (age of onset ≥70 years; n = 165) groups. Frequency of somatic mutations affecting genes commonly implicated in PDAC, as well as gene expression patterns, were compared between EOPC and all other groups., Results: EOPC tumors showed significantly lower frequency of somatic single-nucleotide variant (SNV)/insertions/deletions (indel) in CDKN2A ( P = 0.0017), and were more likely to achieve biallelic mutation of CDKN2A through homozygous copy loss as opposed to heterozygous copy loss coupled with a loss-of-function SNV/indel mutation, the latter of which was more common for tumors with later ages of onset ( P = 1.5e-4). Transcription factor forkhead box protein C2 ( FOXC2 ) was significantly upregulated in EOPC tumors ( P = 0.032). Genes significantly correlated with FOXC2 in PDAC samples were enriched for gene sets related to epithelial-to-mesenchymal transition (EMT) and included VIM ( P = 1.8e-8), CDH11 ( P = 6.5e-5), and CDH2 ( P = 2.4e-2)., Conclusions: Our comprehensive analysis of sequencing data generated from a large cohort of PDAC patient samples highlights a distinctive pattern of biallelic CDKN2A mutation in EOPC tumors. Increased expression of FOXC2 in EOPC, with the correlation between FOXC2 and EMT pathways, represents novel molecular characteristics of EOPC. See related commentary by Lou, p. 8 ., (©2020 American Association for Cancer Research.)

Purpose: RNA-sequencing-based subtyping of pancreatic ductal adenocarcinoma (PDAC) has been reported by multiple research groups, each using different methodologies and patient cohorts. "Classical" and "basal-like" PDAC subtypes are associated with survival differences, with basal-like tumors associated with worse prognosis. We amalgamated various PDAC subtyping tools to evaluate the potential of such tools to be reliable in clinical practice., Experimental Design: Sequencing data for 574 PDAC tumors was obtained from prospective trials and retrospective public databases. Six published PDAC subtyping strategies (Moffitt regression tools, clustering-based Moffitt, Collisson, Bailey, and Karasinska subtypes) were used on each sample, and results were tested for subtype call consistency and association with survival., Results: Basal-like and classical subtype calls were concordant in 88% of patient samples, and survival outcomes were significantly different ( P < 0.05) between prognostic subtypes. Twelve percent of tumors had subtype-discordant calls across the different methods, showing intermediate survival in univariate and multivariate survival analyses. Transcriptional profiles compatible with that of a hybrid subtype signature were observed for subtype-discordant tumors, in which classical and basal-like genes were concomitantly expressed. Subtype-discordant tumors showed intermediate molecular characteristics, including subtyping gene expression ( P < 0.0001) and mutant KRAS allelic imbalance ( P < 0.001)., Conclusions: Nearly 1 in 6 patients with PDAC have tumors that fail to reliably fall into the classical or basal-like PDAC subtype categories, based on two regression tools aimed toward clinical practice. Rather, these patient tumors show intermediate prognostic and molecular traits. We propose close consideration of the non-binary nature of PDAC subtypes for future incorporation of subtyping into clinical practice., (©2020 American Association for Cancer Research.)

Background: Information has been identified as a commonly unmet supportive care need for those living with cancer (ie, patients and their friends and family). The information needed to help individuals plan their lives around the consequences of cancer, such as the receipt of health care, is an example of an important informational need. A suitable theory to guide the development of interventions designed to meet this informational need has not been identified by the authors., Objective: The aim of this study is to generate a grounded theory capable of guiding the development of interventions designed to assist those living with cancer in meeting their informational needs., Methods: Classic grounded theory was used to analyze data collected through digitally recorded one-on-one audio interviews with 31 patients with cancer and 29 friends and family members. These interviews focused on how the participants had accessed and used information to plan their lives and what barriers they faced in obtaining and using this information., Results: The theory that emerged consisted of 4 variables: personal projects, cancer as a source of disruption to personal projects, information as the process of accessing and interpreting cancer-related data (CRD) to inform action, and CRD quality as defined by accessibility, credibility, applicability, and framing. CRD quality as a moderator of personal project disruption by cancer is the core concept of this theory., Conclusions: Informational resources providing accessible, credible, applicable, and positively framed CRD are likely key to meeting the information needs of those affected by cancer. Web-based informational resources delivering high-quality CRD focused on assisting individuals living with cancer in maintaining and planning their personal projects are predicted to improve quality of life. Research is needed to develop and integrate resources informed by this theoretical framework into clinical practice., (©Maclean Thiessen, Shane Sinclair, Patricia A Tang, Shelley Raffin Bouchal. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 29.10.2020.)

Objective: The aim of this analysis is to evaluate the relative weight of different epidemiological risk factors on the development of different breast cancer subtypes (i.e. luminal, Her2+ overexpressed or triple negative)., Methods: De-identified datasets of female participants recruited within the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial were accessed. Multivariate Cox regression analysis was utilized to assess factors affecting the development of breast cancer (regardless of subtype). Additional multivariate analyses were conducted to assess factors affecting the development of the three principal subtypes of breast cancer (ER+/Her2- breast cancer; Her2 overexpressed breast cancer and ER-/Her2- breast cancer)., Results: A total of 73,570 eligible participants were evaluated in the current analysis of which 2370 participants subsequently developed breast cancer. The following factors were associated with a higher risk of ER+/Her2- breast cancer: white race (P < 0.001), nulliparity (P < 0.001), higher body mass index (P = 0.003), prior exposure to hormone treatment (P = 0.004) and breast cancer in first-degree female relatives (P < 0.001). The following factors were associated with a higher risk of Her2 overexpressed breast cancer: prior exposure to hormone treatment (P = 0.002) and breast cancer in first-degree female relatives (P = 0.001). The following factors were associated with a higher risk of ER-/Her2- breast cancer: black race (P = 0.013), younger age (P = 0.017) and breast cancer in first-degree female relatives (P 0.023)., Conclusions: There is considerable heterogeneity in risk factors among patients with different subtypes of breast cancer. In particular, factors associated with high estrogen levels seem to be associated with luminal breast cancer rather than other breast cancer subtypes.

Here we determined mitogenomes of three Bostrichiformia species. These data were combined with 51 previously sequenced Polyphaga mitogenomes to explore the higher-level relationships within Polyphaga by using four different mitogenomic datasets and three tree inference approaches. Among Polyphaga mitogenomes we observed heterogeneity in nucleotide composition and evolutionary rates, which may have affected phylogenetic inferences across the different mitogenomic datasets. Elateriformia, Cucujiformia, and Scarabaeiformia were each inferred to be monophyletic by all analyses, as was Bostrichiformia by most analyses based on two datasets with low heterogeneity. The large series Staphyliniformia was never recovered as monophyletic in our analyses. The Bayesian tree using a degenerated nucleotide dataset (P123&#95;Degen) and a site-heterogeneous mixture model in PhyloBayes was supported as the best Polyphaga phylogeny: (Scirtiformia, (Elateriformia, ((Bostrichiformia, Cucujiformia), (Scarabaeiformia + Staphyliniformia)))). For Cucujiformia, the largest series, we inferred a superfamily-level phylogeny: ((Cleroidea, Coccinelloidea), (Tenebrionoidea, (Cucujoidea + Curculionoidea + Chrysomeloidea)))., (Copyright © 2020 Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) have been reported to play indispensable roles in regulating various developmental processes via the posttranscriptional repression of target genes in insect species. In the present paper, we studied the miRNAs in Indian meal moth (Plodia interpunctella (Hübener)), one of the most economically important stored grains pests around the world. In total, 12 small RNA libraries from four developmental stages of P. interpunctella were constructed, and 178 known and 23 novel miRNAs were identified. In addition, the expression profiles of these miRNAs were assessed across different developmental stages and miRNAs that were highly expressed in eggs, larvae, pupae, and adults were identified. Specifically, 100, 61, and 52 miRNAs were differentially expressed between eggs and larvae, larvae and pupae, and pupae and adults, respectively. The KEGG and GO analysis of the predicted target genes suggested the essential roles of miRNAs in the regulation of complex development of P. interpunctella. Importantly, we also found a set of miRNAs might be involved in the larval metamorphic molting process, with their expressions increasing and then decreasing during the larva-pupa-adult stages of P. interpunctella. In conclusion, the current paper has discovered numerous miRNAs, and some key miRNAs that might be responsible for regulating development in P. interpunctella. To our knowledge, this is the first study to document miRNAs and their expression patterns in interpunctella, and those findings would lay an important molecular foundation for future functional analysis of these miRNAs in P. interpunctella., (© The Author(s) 2020. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Cancer patients experience disparities due to socioeconomic status (SES) factors. We assessed the impact of SES factors on outcomes in patients with locally advanced rectal cancer (LARC) who received neoadjuvant chemoradiation (nCRT) and surgery (Sx) in 3 Canadian provinces., Study Design: This study was a multi-institutional retrospective chart review., Methods: Associations among community characteristics (2016 Canadian Census data), distance and time to the cancer center (mapping software), and outcomes were evaluated using the CHORD multi-institutional database., Results: 1,064 patients were included. Median age 62, 68% male, 15% lived in a rural community, 19% with median community household income >$50,000 CAD, median community proportion with post-secondary education 66%, 12% lived >100km away, and 18% lived >1 ​h away.Factors predictive of worse disease-free survival (DFS) and overall survival (OS) in univariate analysis included driving time >1 ​h, median community income ≤$50,000 CAD, driving distance >100km, and lower median community proportion with post-secondary education. Driving time >1 ​h remained significant in multivariate analysis for worse DFS (HR 1.47; 95% CI 1.14-1.90; p ​= ​0.003) and OS (HR 1.60, 95% CI 1.19-2.16; p ​= ​0.002)., Conclusion: Outcomes of patients with LARC undergoing nCRT are negatively associated with increased driving time to the cancer centre., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Background: Cancer patients transitioning to survivorship after completing cancer treatments need psychosocial interventions to manage stressors such as anxiety, depression, and fear of cancer recurrence. Mindfulness-based interventions (MBIs) are effective for treating these symptoms; however, cancer survivors are often unable to participate in face-to-face interventions because of difficulties such as work and family commitments, treatment-related side-effects, scheduling conflicts, and geography. Smartphone app-based MBIs are an innovative way to deliver psychosocial cancer care and can overcome several such difficulties, since patients can participate at their own convenience., Objective: The SEAMLESS (Smartphone App-Based Mindfulness Intervention for Cancer Survivors) study aims to evaluate the efficacy of a tailored app-based mindfulness intervention for cancer survivors (the Am Mindfulness-Based Cancer Survivorship-MBCS-Journey) for treating (1) symptoms of stress (primary outcome), as well as (2) fear of cancer recurrence, anxiety, depression, fatigue, and overall physical functioning (secondary outcomes). This is the first Canadian efficacy trial of a tailored mindfulness app intervention in cancer survivors., Methods: This is a randomized waitlist-controlled trial, which will evaluate the effectiveness of Am MBCS for impacting the primary and secondary outcomes in cancer survivors who have completed all their cancer treatments. Outcomes will be assessed using web-based surveys with validated psychometric instruments at (1) baseline, (2) mid-intervention (2 weeks later), (3) immediately postintervention (4 weeks), (4) 3 months postbaseline, (5) 6 months postbaseline, and (6) 12 months postbaseline. The waitlist group will complete all assessments and will cross over to the intervention condition after the 3-month assessment. In addition, data will be obtained by the smartphone app itself, which includes users' engagement with the app-based intervention, their emotional state (eg, angry and elated) from a user-inputted digital emotion-mapping board, and psychobiometric data using photoplethysmography technology., Results: The study received ethics approval in September 2018 and recruitment commenced in January 2019. Participants are being recruited through a provincial cancer registry, and the majority of participants currently enrolled are breast (44/83, 53%) or colorectal (17/83, 20%) cancer survivors, although some survivors of other cancer are also present. Data collection for analysis of the primary outcome time-point will be complete by September 2019, and the follow-up data will be collected and analyzed by September 2020. Data will be analyzed to determine group differences using linear mixed modelling statistical techniques., Conclusions: Cancer care providers are uncertain about the efficacy of app-based mindfulness interventions for patients, which are available in great supply in today's digital world. This study will provide rigorously evaluated efficacy data for an app-based mindfulness intervention for cancer survivors, which if helpful, could be made available for psychosocial care at cancer centers worldwide., Trial Registration: ClinicalTrials.gov NCT03484000; https://clinicaltrials.gov/ct2/show/NCT03484000., International Registered Report Identifier (irrid): DERR1-10.2196/15178., (©Utkarsh B Subnis, Norman AS Farb, Katherine-Ann Laura Piedalue, Michael Speca, Sasha Lupichuk, Patricia A Tang, Peter Faris, Mark Thoburn, Bechara J Saab, Linda E Carlson. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 11.05.2020.)

Background: Small bowel adenocarcinoma (SBA) is a rare disease. Current recommendations are largely extrapolated from the colorectal literature. For node-negative (N -ve) cases, optimally stratifying cases into high or low risk, may help define optimal management. The objective of this analysis was to determine the importance of lymph node sampling for prognostication and to define what number of lymph nodes sampled is adequate., Methods: Cases of non-metastatic SBA with complete staging, pathologic, and demographic information were selected from the SEER database and SAS 9.4 software was used. Variables included age, gender, race, grade, TNM staging, and number of lymph nodes were examined. Comparisons were made between N -ve and N +ve cases. Survival analysis using N -ve cases was performed to characterize the impact of nodal sampling on survival and to determine which nodal cut-offs best predict survival., Results: A total of 523 cases from 2004 to 2014 were included in this analysis. Statistically significant differences identified included the median number of nodes sampled between the N -ve and N +ve groups, and the distribution of T stage and grade. Survival analysis in the N -ve cases demonstrated that the strongest predictor of survival was sampling of 16 or more lymph nodes., Conclusion: In this analysis, lymph node sampling was shown to be the most important pathologic predictor of survival in cases of N -ve SBA. Replicating these findings in a secondary dataset and determining whether a clinical benefit of adjuvant chemotherapy exists for SBA patients with inadequate sampling are both important next steps.

Dietary shifts can alter the relative availability of different nutrients and are therefore associated with metabolic adaptation in animals. The Coccinellidae (ladybirds) exhibits three major types of feeding habits and provides a useful model to study the effects of dietary changes on the evolution of mitogenomes, which encode proteins directly involved in energy metabolism. Here, mitogenomes of three coccinellid species were newly sequenced. These data were combined with other ten previously sequenced coccinellid mitogenomes to explore the relationship between mitogenome evolution and diets. Our results indicate that mitogenomic data can be effectively used to resolve phylogenetic relationships of Coccinellidae. Strong codon usage bias in coccinellid mitogenomes was predominantly determined by nucleotide composition. The 13 mitochondrial protein-coding genes (PCGs) globally evolved under negative constraints, with some PCGs showing a stronger purifying selection. Six PCGs ( nad3 , nad4L, and nad5 from Complex I; cox1 and cox3 from Complex IV; and atp6 from Complex V) displayed signs of positive selection. Of these, adaptive changes in cox3 were potentially associated with metabolic differences resulting from dietary shifts in Coccinellidae. Our results provide insights into the adaptive evolution of coccinellid mitogenomes in response to both dietary shifts and other life history traits., Competing Interests: None declared., (© 2020 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Background: Reductions in adjuvant chemotherapy dose <85% for historical regimens (ie, cyclophosphamide/methotrexate/fluorouracil) are known to affect breast cancer survival. This threshold, in addition to early versus late dose reductions, are poorly defined for third-generation anthracycline/taxane-based chemotherapy. In patients with breast cancer receiving adjuvant 5-fluorouracil/epirubicin/cyclophosphamide followed by docetaxel (FEC-D), we evaluated the impact of chemotherapy total cumulative dose (TCD), and early (FEC) versus late (D only) dose reductions, on survival outcomes., Patients and Methods: Women with stage I-III, hormone receptor-positive/negative, HER2-negative breast cancer treated with adjuvant FEC-D chemotherapy from 2007 through 2014 in Alberta, Canada, were included. TCD for cycles 1 to 6 of <85% or ≥85% was calculated. Average cumulative dose was also calculated for early (cycles 1-3) and late (cycles 4-6) chemotherapy. Survival outcomes (disease-free survival [DFS] and overall survival [OS]) were estimated using Kaplan-Meier and multivariate analysis. Cohorts were evaluated for uniformity., Results: Characteristics were reasonably balanced for all cohorts. Overall, 1,302 patients were evaluated for dose reductions, with 16% being reduced <85% (n=202) relative to ≥85% (n=1,100; 84%). Patients who received TCD ≥85% relative to <85% had superior 5-year DFS (P=.025) and OS (P<.001) according to Kaplan-Meier analysis, which remained significant on univariate and multivariate analyses. In stratified late and early dose reduction cohorts, DFS and OS showed a significant inferior survival trend for dose reduction early in treatment administration in 5-year Kaplan-Meier (P=.002 and P<.001, respectively) and multivariate analyses (hazard ratio [HR], 1.46; P=.073, and HR, 1.77; P=.011, respectively). Dose delays of <14 or ≥14 days and granulocyte colony-stimulating factor use did not affect outcomes., Conclusions: Chemotherapy TCD <85% for adjuvant FEC-D affects breast cancer survival. Late reductions (D only) were not shown to adversely affect DFS or OS. Conversely, early reductions (FEC±D) negatively affected patient outcomes.

Background: A standard therapy for locally advanced rectal cancer (LARC) includes fluoropyrimidine (FP)-based neoadjuvant chemoradiation (nCRT). Previous studies have inconsistently demonstrated that baseline neutrophil- and platelet-to-lymphocyte ratios (NLR and PLR) are predictive of response to nCRT or prognostic of outcomes in LARC., Methods: We reviewed patients with LARC undergoing nCRT followed by surgery from 2005 to 2013 across 8 Canadian cancer centres. Outcome measures of interest were pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Logistic regression and Cox proportional hazard models were used to assess for associations between baseline hematologic variables and outcomes., Results: Of 1527 identified patients, 1237 (81%) were included in the DFS/OS analysis. Median age was 62 (range 23-88), 69% were male, and 80% had performance status (PS) 0-1. Twenty-six percent had elevated NLR (≥ 4), and 66% had elevated PLR (≥ 150). Ninety-seven percent of patients received FP-based nCRT, with 96% receiving ≥44 Gy. 81% completed neoadjuvant chemotherapy and 95% completed neoadjuvant radiotherapy, with a pCR rate of 18%. After a median follow-up time of 71 months, 8% developed local recurrence, 22% developed distant recurrence and 24% died. 5-year DFS and OS were 69% (95% CI 66-72%) and 79% (95% CI 77-82%), respectively. In multivariate analyses, elevated baseline NLR and PLR were neither prognostic for DFS and OS nor predictive of pCR., Conclusions: NLR and PLR were not found to be independently prognostic for DFS or OS and did not predict for pCR in patients with LARC undergoing nCRT followed by surgery.

Assessment of the clinical benefit of cancer treatments can be highly subjective, influenced by both perspective and context. Such assessments are required in regulatory and policy decision-making, but consistency between jurisdictions is often lacking. Clear and consistent standards for determining when a treatment offers a meaningful benefit, relative to the current standard of care, can help to address issues of equity and transparency in health technology assessment. For metastatic colorectal cancer (mcrc), no standardized Canadian definition of clinically meaningful benefit has yet been proposed. Colorectal Cancer Canada therefore convened a group of medical oncologists expert in colorectal cancer to review the literature about clinical significance. The resulting consensus is intended to apply to any therapeutic agent being considered in the setting of chemotherapy-refractory mcrc. It was agreed that overall survival is the appropriate measure of clinical efficacy in chemorefractory mcrc. As quantitative targets for efficacy, an improvement of 2 months or more in median overall survival or a hazard ratio for survival of 0.75 or lower (or both) are proposed as the threshold for clinically meaningful benefit. That threshold could be influenced by a treatment's effect on quality of life. Treatment toxicity is also relevant to the assessment of clinical benefit in this setting, specifically when significant differences in treatment tolerability are evident., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: YJK has received honoraria for advisory or speaking roles from Taiho, Amgen, Servier, and Eli Lilly; MA has received honoraria for advisory or speaking roles from AstraZeneca, Boehringer Ingelheim, Bristol–Myers Squibb, Celgene, Ipsen, Janssen, Johnson and Johnson, Merck, NB Urology, Novartis, Pfizer, Roche, Sanofi, Shire, Taiho, and Yewtree Consulting; he is a co-investigator or principal investigator on industry trials sponsored by AbbVie, Amgen, Aragon Pharmaceuticals, Astex Pharmaceuticals, Astra-Zeneca, Bayer, Boehringer Ingelheim, Bristol–Myers Squibb, the Canadian Cancer Trials Group, Chiltern/Pfizer, Eisai, Exactis Innovation, GlaxoSmithKline, Merck and Co., Merck KGaA, Novartis, Odonate Therapeutics, Pharmacyclics, Picomole, Puma Biotechnology, Purdue Pharma, the Quebec Clinical Research Organization in Cancer, Roche, Sanofi Aventis, Takeda, Turnstone Biologics, and United Therapeutics; PK has received honoraria for advisory roles from Amgen, Taiho, and Merck; he has also received educational grants from Amgen, Bayer, Merck, Roche, and Taiho; HL has received honoraria for advisory roles from Roche, Amgen, Eisai, Taiho, Lilly, and Bristol–Myers Squibb; he has also received travel support from Eisai and is a co-investigator or principal investigator on industry trials sponsored by Bristol–Myers Squibb, AstraZeneca, Amgen, Roche, and Astellas; PAT has received honoraria for advisory or speaking roles from Novartis, Genomic Health International, Amgen, Merck, Taiho, and AstraZeneca; MV has received honoraria for advisory or speaking roles from Taiho, Merck, Bristol–Myers Squibb, Boehringer Ingelheim, Eli Lilly, Sanofi Aventis, Amgen, Novartis, Pfizer, Roche, Amgen, and AstraZeneca; SG has received honoraria for advisory or speaking roles from Amgen, Roche, Taiho, and Eli Lilly. The remaining authors have no conflicts of interest to disclose.

Background: The optimal management of hypomagnesemia (hMg) induced by epidermal growth factor receptor inhibitors (egfris) for advanced colorectal cancer is unclear. We surveyed gastrointestinal medical oncologists in Canada to determine practice patterns for the management of egfri-induced hMg., Methods: Based on distribution lists from the Eastern Canadian Colorectal Cancer Consensus Conference and the Western Canadian Gastrointestinal Cancer Consensus Conference, medical oncologists were invited to participate in an online questionnaire between November 2013 and February 2014., Results: From the 104 eligible physicians, 40 responses were obtained (38.5%). Panitumumab was more commonly prescribed than cetuximab by 70% of respondents, with 25% prescribing cetuximab and panitumumab equally. Most respondents obtain a serum magnesium level before initiating a patient on an egfri (92.5%) and before every treatment (90%). Most use a reactive strategy for magnesium supplementation (90%) and, when using supplementation, favour intravenous (iv) alone (40%) or iv and oral (45%) dosing. Magnesium sulfate was used for iv replacement, and the most common oral strategies were magnesium oxide (36.4%) and magnesium rougier (18.2%). Under the reactive strategy, intervention occurred at hMg grade 1 (70.3%) or grade 2 (27%). Of the survey respondents, 45% felt that 1-5 of their patients have ever developed symptoms attributable to hMg, and 35% have had to interrupt egfri therapy because of this toxicity, most commonly at grade 3 (30%) or grade 4 (45%) hMg. The most important question about egfri-induced hMg was its relevance to clinical outcomes (45%) and its symptoms (37.5%)., Conclusions: In Canada, various strategies are used in the management of egfri-induced hMg, including prophylactic and reactive approaches that incorporate iv, oral, or a combination of iv and oral supplementation. Clinicians are concerned about the effect of hMg on clinical outcomes and about the symptoms that patients experience as a result of this toxicity., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

Background: Cognitive impairment is commonly reported in patients receiving chemotherapy, but the acuity of onset is not known. This study utilized the psychomotor vigilance test (PVT) and trail-making test B (TMT-B) to assess cognitive impairment immediately post-chemotherapy., Methods: Patients aged 18-80 years receiving first-line intravenous chemotherapy for any stage of breast or colorectal cancer were eligible. Patient symptoms, peripheral neuropathy and Stanford Sleepiness Scale were assessed. A five-minute PVT and TMT-B were completed on a tablet computer pre-chemotherapy and immediately post-chemotherapy. Using a mixed linear regression model, changes in reciprocal transformed PVT reaction time (mean 1/RT) were assessed. A priori, an increase in median PVT reaction times by > 20 ms (approximating PVT changes with blood alcohol concentrations of 0.04-0.05 g%) was considered clinically relevant., Results: One hundred forty-two cancer patients (73 breast, 69 colorectal, median age 55.5 years) were tested. Post-chemotherapy, mean 1/RT values were significantly slowed compared to pre-chemotherapy baseline (p = 0.01). This corresponded to a median PVT reaction time slowed by an average of 12.4 ms. Changes in PVT reaction times were not correlated with age, sex, cancer type, treatment setting, or use of supportive medications. Median post-chemotherapy PVT reaction time slowed by an average of 22.5 ms in breast cancer patients and by 1.6 ms in colorectal cancer patients. Post-chemotherapy median PVT times slowed by > 20 ms in 57 patients (40.1%). Exploratory analyses found no statistically significant association between the primary outcome and self-reported anxiety, fatigue or depression. TMT-B completion speed improved significantly post-chemotherapy (p = 0.03), likely due to test-retest phenomenon., Conclusions: PVT reaction time slowed significantly immediately post-chemotherapy compared to a pre-chemotherapy baseline, and levels of impairment similar to effects of alcohol consumption in other studies was seen in 40% of patients. Further studies assessing functional impact of cognitive impairment on patients immediately after chemotherapy are warranted.

Background: To describe patterns of referral, consultation, and treatment of advanced pancreatic cancer patients in a population-based health care system and to evaluate the impact of these factors on outcomes., Methods: This is a retrospective analysis of population-based cancer data from the province of Alberta, Canada. We analyzed patients diagnosed with either locally advanced or metastatic pancreatic adenocarcinoma from 2009 to 2016 and evaluated their patterns of referral to a cancer center, consultation with oncology, and treatment with active anticancer therapies. Logistic regression models were constructed to determine the factors associated with referral, late oncology assessment, and late receipt of treatment., Results: We identified 1621 pancreatic cancer patients. Median age was 70 years, 50% were men, and 51% had a Charlson index of 2+. Within this cohort, only 884 (54%) patients were referred to one of the provincial cancer centers. Adjusting for confounders in logistic regression models, older age and worse comorbidity scores were associated with nonreferral (both P < 0.01). In multivariable analysis among treated patients, the following factors were associated with improved overall survival, including younger age, earlier stage, and better comorbidity scores (all P < 0.01). Neither referral to consultation times nor consultation to treatment times correlated with outcomes. Importantly, nonreferred patients were more likely to use acute care services, including longer total duration of hospitalizations and more frequent visits with physician specialists., Conclusion: A significant proportion of patients with advanced pancreatic cancer were never referred to a cancer center. Nonreferred patients were more likely to utilize specific health care resources., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Palliative care (pc) is part of the recommended standard of care for patients with advanced cancer. Nevertheless, delivery of pc is inconsistent. Patients who could benefit from pc services are often referred late-or not at all. In planning for improvements to oncology pc practice in our health care system, we sought to identify barriers to the provision of earlier pc, as perceived by health care providers managing patients with metastatic colorectal cancer (mcrc). We used the Michie Theoretical Domains Framework (tdf) and Behaviour Change Wheel (bcw), together with knowledge of previously identified barriers, to develop a 31-question survey. The survey was distributed by e-mail to mcrc health care providers, including physicians, nurses, and allied staff. Responses were obtained from 57 providers (40% response rate). The most frequently cited barriers were opportunity-related-specifically, lack of time, of clinic space for consultations, and of access to specialist pc staff or services. Qualitative responses revealed that resource limitations varied by cancer centre location. In urban centres, time and space were key barriers. In rural areas, access to specialist pc was the main limiter. Self-perceived capability to manage pc needs was a barrier for 40% of physicians and 30% of nurses. Motivation was the greatest facilitator, with 89% of clinicians perceiving that patients benefit from pc. Based on the Michie tdf and bcw model, interventions that best address the identified barriers are enablement and environmental restructuring. Those findings are informing the development of an intervention plan to improve oncology pc practices in a publicly funded health care system., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

Background: Oncolytic reovirus pelareorep might preferentially infect and destroy rat sarcoma (RAS)-activated cells, and has preclinical and early clinical activity against colorectal cancer (CRC)., Patients and Methods: After a 6-patient safety run-in, 103 patients with metastatic CRC were randomly assigned to standard first-line leucovorin/5-FU/oxaliplatin (FOLFOX6)/bevacizumab (FOLFOX/BEV) every 2 weeks with (n = 51) or without (n = 52) pelareorep 3 × 10 10 tissue culture infective dose 50 on days 1 to 5 (cycles 1, 2, 4, and alternate cycles thereafter). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), quality of life, and correlative analyses., Results: At 13 months' median follow-up, PFS was inferior in the pelareorep arm (median 7 vs. 9 months; hazard ratio [HR], 1.59 [80% confidence interval (CI), 1.18-2.15]; P = .046). There was no statistical difference in OS (median, 19.2 vs. 20.1 months; HR, 1.22; P = .38). An increased ORR was observed with pelareorep (adjusted odds ratio, 2.52 [80% CI, 1.44-4.41]; P = .03), but with a shorter median duration of response (5 vs. 9 months; P = .028). Pelareorep patients experienced more hypertension and proteinuria, and were more likely to omit bevacizumab before progression. A trend to lower dose intensity and shorter oxaliplatin and bevacizumab treatment duration was observed with pelareorep., Conclusion: Combination pelareorep with FOLFOX/BEV was tolerable with an increased ORR, but PFS was inferior. Subgroup analysis of baseline variables including Kirsten rat sarcoma oncogene did not identify subgroups with PFS benefit. Decreased treatment intensity with standard agents likely contributed to the lack of benefit with pelareorep. Future studies might consider alternate pelareorep/chemotherapy strategies or combination therapy with novel agents., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Use of adjuvant chemotherapy (AC) following neoadjuvant chemoradiation (nCRT) is controversial in rectal cancer (RC). We assessed a multi-institutional database to determine if there was benefit from AC for pathologic stage II RC patients and whether the addition of oxaliplatin to fluoropyrimidine (OXAC) therapy impacted outcomes., Materials and Methods: We included patients who underwent nCRT and had pathologic stage II (ypT3/4 ypN0) tumors. Disease-free survival and overall survival were assessed. Multivariate Cox models adjusting for age, sex, Eastern Cooperative Oncology Group, high-risk features (pT4, poor differentiation, <12 nodes removed, lymphovascular/perineural invasion, or obstruction/perforation), and clinical stage were constructed., Results: Of 485 patients, 73.6% received AC, of which 25.5% received OXAC. Patients receiving AC were younger (median age 61 vs. 64; P=0.003) and had higher rates of total mesorectal excision (81.5% vs. 78.9%; P=0.049), but had similar high-risk features, performance status, clinical stage, margin status, preoperative carcinoembryonic antigen, and nCRT regimen. In univariate analysis, overall survival was improved with fluoropyrimidine AC compared with no AC or OXAC (P=0.049), but not disease-free survival (P=0.33). In multivariate analysis, any AC, fluoropyrimidine AC, or OXAC did not improve outcomes. After stratifying patients by the presence of high-risk features, elevated carcinoembryonic antigen, margin status, or preoperative clinical stage, we did not identify a group with improved outcomes following AC., Conclusions: In this multi-institutional cohort of yp stage II RC patients, we failed to identify a group that derives benefit from AC following nCRT. The addition of oxaliplatin did not appear to improve outcomes when compared with fluoropyrimidine alone.