LncRNA-mediated ceRNA network reveals the mechanism of action of Saorilao-4 decoction against pulmonary fibrosis.

Introduction: Pulmonary fibrosis (PF), a type of interstitial pneumonia with complex etiology and high mortality, is characterized by progressive scarring of the alveolar interstitium and myofibroblastic lesions. In this study, we screened for potential biomarkers in PF and clarified the role of the lncRNA-miRNA-mRNA ceRNA network in the inhibitory effect of SRL-4 on PF. Methods: Healthy male SPF SD rats were randomly divided into three groups, namely, CON, MOD, and SRL-4. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to determine the biological functions of the target genes. A visualized lncRNA-miRNA-mRNA ceRNA network was constructed using Cytoscape, while key genes in the network were identified using the cytoNCA plugin. Results: Seventy-four differentially expressed lncRNAs and 118 differentially expressed mRNAs were identified. Gene Ontology analysis revealed that the target genes were mainly enriched in the cell membrane and in response to organic substances, while Kyoto Encyclopedia of Genes and Genomes analysis showed that the target genes were mainly enriched in the AMPK, PPAR, and cAMP signaling pathways. We elucidated a ceRNA axis, namely, Plcd3-OT1/rno-miR-150-3p/Fkbp5, with potential implications in PF. Key genes, such as AABR07051308.1-201, F2rl2-OT1, and LINC3337, may be important targets for the treatment of PF, while the AMPK, PPAR, and cAMP signaling pathways are potential key targets and important pathways through which SRL-4 mitigates PF. Conclusion: Our findings suggest that SRL-4 improves PF by regulating the lncRNA-miRNA-mRNA network.

Identification of Central Genes and Regulatory Pathways Associated with Hyperlipidemia in Rats.

Hyperlipidemia is an independent risk factor for cardiovascular and cerebrovascular diseases. The transcriptomic data and the gene regulatory networks of hyperlipidemia are largely unclear. We analyzed the changes in liver gene expression and the serum levels of biochemical indicators in rats with hyperlipidemia induced by high-fat diet (HFD). The body weight, liver weight, and the serum levels of TG, TC, HDL-C, LDL-C, ALT, and AST were significantly higher in the hyperlipidemic rats compared to the healthy controls (P < 0.05). In addition, HFD feeding decreased the antioxidant capacity of the liver tissues and significantly increased the arteriosclerosis index (AI) (P < 0.05). There were 584 differentially expressed genes (DEGs) in the hyperlipidemia model compared to the control, with |log2FC|≥ 1 and P-adjust ≤ 0.05 as the thresholds. GO analysis of the DEGs revealed significant enrichment of 382 biological processes (BP), 18 cellular components (CC), and 40 molecular functions (MF). In addition, pathways related to bile secretion, cholesterol metabolism, and steroid hormone biosynthesis were significantly associated with hyperlipidemia. The key genes potentially involved in the blood lipid changes were Agt, Src, Gnai3, Cyp2c7, Cyp2c11, Cyp2c22, Apoa1, Apoe, and Srebf1. The genes and pathways identified in this study are potential intervention targets for hyperlipidemia and warrant further investigation.

VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4/6 Inhibitors - Efficacy, Safety, and Biomarker Results.

PURPOSE: Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post-cyclin-dependent kinase (CDK) 4/6 inhibitor progression. PATIENTS AND METHODS: Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status. RESULTS: At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44-23.87); fulvestrant: 13.7% (7/51; 5.70-26.26); risk difference -1.96% (95% CI, -16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94-3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84-3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61-1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status. CONCLUSIONS: Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy-resistant, CDK4/6 inhibitor-refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.

Management of Pyrexia Associated with the Combination of Dabrafenib and Trametinib: Canadian Consensus Statements.

The combination of dabrafenib and trametinib is a well-established treatment for BRAF-mutated melanoma. However, the effectiveness of this approach may be hindered by the development of treatment-related pyrexia syndrome, which occurs in at least 50% of treated patients. Without appropriate intervention, pyrexia syndrome has the potential to worsen and can result in hypotension secondary to dehydration and associated organ-related complications. Furthermore, premature treatment discontinuation may result in a reduction in progression-free and overall survival. Despite existing guidance, there is still a wide variety of therapeutic approaches suggested in the literature for both the definition and management of dabrafenib and trametinib-related pyrexia. This is reflected in the practice variation of its prevention and treatment within and between Canadian cancer centres. A Canadian working group was formed and consensus statements were constructed based on evidence and finalised through a two-round modified Delphi approach. The statements led to the development of a pyrexia treatment algorithm that can easily be applied in routine practice. The Canadian working group consensus statements serve to provide practical guidance for the management of dabrafenib and trametinib-related pyrexia, hopefully leading to reduced discontinuation rates, and ultimately improve patients' quality of life and cancer-related outcomes.

Ten ways to get a grip on designing and implementing a competency-based medical education training program.

BACKGROUND: Globally there is a move to adopt competency-based medical education (CBME) at all levels of the medical training system. Implementation of a complex intervention such as CBME represents a marked paradigm shift involving multiple stakeholders. METHODS: This article aims to share tips, based on review of the available literature and the authors' experiences, that may help educators implementing CBME to more easily navigate this major undertaking and avoid "black ice" pitfalls that educators may encounter. RESULTS: Careful planning prior to, during and post implementation will help programs transition successfully to CBME. Involvement of key stakeholders, such as trainees, teaching faculty, residency training committee members, and the program administrator, prior to and throughout implementation of CBME is critical. Careful and selective choice of key design elements including Entrustable Professional Activities, assessments and appropriate use of direct observation will enhance successful uptake of CBME. Pilot testing may help engage faculty and learners and identify logistical issues that may hinder implementation. Academic advisors, use of curriculum maps, and identifying and leveraging local resources may help facilitate implementation. Planned evaluation of CBME is important to ensure choices made during the design and implementation of CBME result in the desired outcomes. CONCLUSION: Although the transition to CBME is challenging, successful implementation can be facilitated by careful design and strategic planning.

CONTEXTE: Partout dans le monde, on observe une tendance en faveur de l'éducation médicale axée sur les compétences (EMAC) à tous les niveaux du système d'éducation médicale. Une intervention complexe comme l'élaboration d'un programme d'EMAC représente un important changement de paradigme qui nécessite l'implication de plusieurs parties prenantes. MÉTHODE: L'objectif de cet article est de partager des conseils dégagés par les auteurs d'une revue de la littérature et de leur propre expérience afin d'aider les éducateurs à mieux s'orienter dans cette entreprise de taille qu'est la mise en œuvre de l'EMAC et à éviter les écueils. RÉSULTATS: Une planification minutieuse avant, pendant et après la transition des programmes vers l'EMAC contribue à garantir son succès. L'implication des principales parties prenantes, telles que les stagiaires, le corps enseignant, les membres du comité du programme de résidence et l'administrateur du programme, avant et pendant la mise en œuvre est essentielle. La sélection attentive des éléments clés, comme les activités professionnelles confiables, les évaluations et l'utilisation appropriée de l'observation directe, favorisera l'adoption de l'EMAC. Des tests pilotes peuvent permettre la participation du corps professoral et des apprenants, et à déceler les problèmes logistiques qui peuvent entraver la mise en œuvre. Les conseillers pédagogiques, le recours à la cartographie des programmes d'études et le repérage et la mobilisation de ressources locales peuvent faciliter la mise en œuvre des programmes d'EMAC. L'évaluation planifiée de ces programmes est importante pour garantir que les choix faits lors de leur conception et mise en œuvre aboutissent aux résultats souhaités. CONCLUSION: Puisque la transition vers l'EMAC peut comporter de nombreux défis, elle peut néanmoins être opérée avec succès grâce à une conception et une planification stratégique minutieuses.

Contemporary Neoadjuvant Therapies for High-Risk Melanoma: A Systematic Review.

Despite advances in adjuvant immuno- and targeted therapies, the risk of relapse for stage III melanoma remains high. With 43 active entries on clinicaltrials.gov (8 July 2020), there is a surge of interest in the role of contemporary therapies in the neoadjuvant setting. We conducted a systematic review of trials performed in the last decade evaluating neoadjuvant targeted, immuno- or intralesional therapy for resectable stage III or IV melanoma. Database searches of Medline, Embase, and the Cochrane Central Register of Controlled Trials were conducted from inception to 13 February 2020. Two reviewers assessed titles, abstracts, and full texts. Trials investigating contemporary neoadjuvant therapies in high-risk melanoma were included. Eight phase II trials (4 randomized and 4 single-arm) involving 450 patients reported on neoadjuvant anti-BRAF/MEK targeted therapy (3), anti-PD-1/CTLA-4 immunotherapy (3), and intralesional therapy (2). The safest and most efficacious regimens were dabrafenib/trametinib and combination ipilimumab (1 mg/kg) + nivolumab (3 mg/kg). Pathologic complete response (pCR) and adverse events were comparable. Ipilimumab + nivolumab exhibited longer RFS. Contemporary neoadjuvant therapies are not only safe, but also demonstrate remarkable pCR and RFS-outcomes which are regarded as meaningful surrogates for long-term survival. Studies defining predictors of pCR, its correlation with oncologic outcomes, and phase III trials comparing neoadjuvant therapy to standard of care will be crucial.

How Canadian Oncologists Use Oncotype DX for Treatment of Breast Cancer Patients.

BACKGROUND: The literature suggests that medical oncologists differ on how they use the Oncotype DX (ODX) genomic assay for making decisions about systemic therapy in breast cancer patients. Given the emergence of data supporting the use of genomic profiling for the prognosis and predicting benefit of chemotherapy, we surveyed medical oncologists in Canada to assess their usage and perception of the ODX assay. METHODS: A 34-item survey was distributed to Canadian medical oncologists via the Canadian Association of Medical Oncologists. Data was collected on physician demographics, ODX usage patterns, and physicians' perception of the impact clinical and pathologic characteristics make on ODX utilization. RESULTS: Response rate was 20.6% with 47 responses received from 228 survey sent. Forty-five responses were eligible for analysis. Sixty-two percent (28/45) of respondents treated predominantly breast cancer, and 60% (27/45) have been in practice for at least 10 years. The most cited reason for using ODX was to avoid giving patients unnecessary chemotherapy (64%; 29/45). Sixty-seven percent (30/45) deferred making treatment decisions until ODX testing was completed. Factors most strongly impacting ODX utilization included: patient request, medical comorbidities and tumor grade. In clinical scenarios, ODX was more frequently selected for patients aged 40-65 (vs. <40 or >65), grade 2 tumors (vs. grade 1 or 3), and Ki-67 index of 10-20% (vs. <10% or >20%). CONCLUSIONS: This survey demonstrated that Canadian medical oncologists are preferentially using ODX to avoid giving patients unnecessary chemotherapy. The utilization of ODX is mainly in patients with intermediate clinical and pathologic features.

A Contemporary Report of Clinical Outcomes in Patients with Melanoma Brain Metastases.

Background: Brain metastases are observed in more than 40% of all patients with stage 4 melanoma. In recent years, more extensive use of stereotactic radiation (STRT) and the advent of immune checkpoint inhibitors have positively impacted outcomes in patients with metastatic melanoma.brain metastases. Here, we examined real world clinical outcomes of patients presenting with melanoma brain metastases (MBMs). Methods: This retrospective review evaluated MBMs patients treated at The Ottawa Hospital from April 2000 to July 2017. Clinical, radiologic, pathologic and treatment information were gathered from the electronic medical records. The primary outcome was overall survival. The proportional Cox regression model was employed for survival data, while the Fisher's exact and Mann-Whitney U tests analyzed the relationship between categorical and continuous data, respectively. Results: This retrospective study included 276 patients. Brain metastases were detected symptomatically in 191 patients (69.2%); the rates of detection by routine screening were 4.6% in the pre-2012 era and 11.7% in the contemporary era (p = 0.029). Median survival was three months. Predictors of overall survival were age, higher lactate dehydrogenase (LDH) values, multiple brain lesions, more extensive extracranial disease, neurological symptoms, infratentorial lesions and treatment type. Multivariable analysis demonstrated that stereotactic radiotherapy (STRT) was associated with a hazard ratio of 0.401 (p < 0.001) for survival; likewise, immune checkpoint inhibitor therapy was associated with a hazard ratio of 0.375 (p < 0.001). Conclusion: The findings from this study as "real world" data are consistent with results of pivotal clinical trials in MBMs patients and support contemporary locoregional and immunotherapy practices.

CANDIED: A Pan-Canadian Cohort of Immune Checkpoint Inhibitor-Induced Insulin-Dependent Diabetes Mellitus.

Immune checkpoint inhibitor (ICI)-induced insulin-dependent diabetes mellitus (IDDM) is a rare but potentially fatal immune-related adverse event (irAE). In this multicentre retrospective cohort study, we describe the characteristics of ICI-induced IDDM in patients treated across five Canadian cancer centres, as well as their tumor response rates and survival. In 34 patients identified, 25 (74%) were male and 19 (56%) had melanoma. All patients received anti-programed death 1 (anti-PD1) or anti-programmed death ligand-1 (anti-PD-L1)-based therapy. From ICI initiation, median time to onset of IDDM was 2.4 months (95% CI 1.1-3.6). Patients treated with anti-PD1/PD-L1 in combination with an anti-cytotoxic T lymphocyte antigen 4 antibody developed IDDM earlier compared with patients on monotherapy (1.4 vs. 3.9 months, p = 0.05). Diabetic ketoacidosis occurred in 21 (62%) patients. Amongst 30 patients evaluable for response, 10 (33%) had a complete response and another 10 (33%) had a partial response. Median overall survival was not reached (95% CI NE; median follow-up 31.7 months). All patients remained insulin-dependent at the end of follow-up. We observed that ICI-induced IDDM is an irreversible irAE and may be associated with a high response rate and prolonged survival.

Correction to: Imaging Intensity and Survival Outcomes in High-Risk Resected Melanoma Treated by Systemic Therapy at Recurrence.

In the original article, the survival curves are missing in Fig. 1c, d.

Systemic adjuvant therapy for adult patients at high risk for recurrent melanoma: A systematic review.

Cutaneous melanoma is typically treated with wide local excision and, when appropriate, a sentinel node biopsy. Many patients are cured with this approach but for patients who have cancers with high risk features there is a significant risk of local and distant relapse and death. Interferon-based adjuvant therapy was recommended in the past but had modest results with significant toxicity. Recently, new therapies (immune checkpoint inhibitors and targeted therapies) have been found to be effective in the treatment of patients with metastatic melanoma and many of these therapies have been evaluated and found to be effective in the adjuvant treatment of high risk patients with melanoma. This systematic review of adjuvant therapies for cutaneous and mucosal melanoma was conducted for Ontario Health (Cancer Care Ontario) as the basis of a clinical practice guideline to address the question of whether patients with completely resected melanoma should be considered for adjuvant systemic therapy and which adjuvant therapy should be used.

Imaging Intensity and Survival Outcomes in High-Risk Resected Melanoma Treated by Systemic Therapy at Recurrence.

BACKGROUND: Intensive imaging in melanoma remains controversial because its survival impact is unknown. We investigated the impact of imaging intensity on the rates of asymptomatic surveillance-detected recurrence (ASDR) and subsequent treatment outcomes in patients with access to immune checkpoint inhibitors (ICIs) and targeted therapy (TT). METHODS: Patients with resected malignant melanoma undergoing imaging surveillance at a single center between 2006 and 2016 were identified. Surveillance and recurrence characteristics (imaging, symptom, treatment, and survival data) were retrospectively collected. Univariate (t test, Chi square test) and multivariate Cox regression analyses were conducted. RESULTS: Of 353 high-risk melanoma patients (stage IIB, 24%; IIC, 19%; IIIA, 27%; IIIB, 16%; IIIC, 14%), 71 (45%) had ASDR and 88 (55%) had symptomatic recurrence (SR). Shorter imaging intervals identified more ASDR (57%, 0-6 months; 34%, 6-12 months; 33%, > 12 months; p = 0.03). ASDR had better prognostic factors than SR [fewer than three metastatic sites (43 vs. 21%, p = 0.003), normal lactate dehydrogenase (LDH; 53 vs. 38%, p = 0.09), brain metastases (11 vs. 40%, p < 0.001)] and received more systemic treatment (72 vs. 49%, p = 0.003; ICIs 55 vs. 31%, p = 0.002; TT 8 vs. 13%, p = 0.41). ASDR had better survival outcomes on ICI treatment (2-year OS, 56 vs. 31%, p < 0.001). Median OS from surveillance start was 39.6 vs. 22.8 months (p < 0.001). ASDR was independently associated with survival (hazard ratio 0.47, 95% confidence interval 0.29-0.78, p = 0.003), adjusting for stage, sex, age, disease burden, LDH, era of recurrence, brain metastases, and ICI/TT treatment. CONCLUSIONS: These real-world data support further study on intensified imaging surveillance protocols for high-risk resected melanoma, as ASDR was associated with superior survival outcomes from ICI therapy.

Correction: Climatic and topographic variables control soil nitrogen, phosphorus, and nitrogen: Phosphorus ratios in a Picea schrenkiana forest of the Tianshan Mountains.

[This corrects the article DOI: 10.1371/journal.pone.0204130.].

Climatic and topographic variables control soil nitrogen, phosphorus, and nitrogen: Phosphorus ratios in a Picea schrenkiana forest of the Tianshan Mountains.

Knowledge about soil nitrogen (N) and phosphorus (P) concentrations, stocks, and stoichiometric ratios is crucial for understanding the biogeochemical cycles and ecosystem function in arid mountainous forests. However, the corresponding information is scarce, particularly in arid mountainous forests. To fill this gap, we investigated the depth and elevational patterns of the soil N and P concentrations and the N: P ratios in a Picea schrenkiana forest using data from soil profiles collected during 2012-2017. Our results showed that the soil N and P concentrations and the N: P ratios varied from 0.15 g kg-1 to 0.56 g kg-1 (average of 0.31 g kg-1), from 0.09 g kg-1 to 0.16 g kg-1 (average of 0.12 g kg-1), and from 2.42 g kg-1 to 4.36 g kg-1 (average of 3.42 g kg-1), respectively; additionally, values significantly and linearly decreased with soil depth. We did not observe a significant variation in the soil N and P concentrations and the N: P ratios with the elevational gradient. In contrast, our results revealed that the mean annual temperature and mean annual precipitation exhibited a more significant influence on the soil N and P concentrations and the N: P ratios than did elevation. This finding indicated that climatic variables might have a more direct impact on soil nutrient status than elevation. The observed relationship among the soil N and P concentrations and the N: P ratios demonstrated that the soil N was closely coupled with the soil P in the P. schrenkiana forest.

Testing a novel account of the dissociation between self-reported memory problems and memory performance in chemotherapy-treated breast cancer survivors.

BACKGROUND: A puzzling observation pertaining to the impact of breast cancer on memory is the frequently reported dissociation between breast cancer survivors' self-reported memory problems and memory performance. We evaluated the hypothesis that the dissociation is related to the fact that the objective memory measures previously used assessed retrospective memory (RM) and did not tap prospective memory (PM), a domain about which survivors are complaining. METHODS: In a case-healthy-control (N = 80) cross-sectional study, the Memory for Intention Screening Test was used to assess PM and the Wechsler Logical Memory Test was used to evaluate RM. Self-reported problems were assessed with the Prospective and Retrospective Memory Questionnaire. Measures of depression (Center for Epidemiologic Studies Depression Scale) and fatigue (Functional Assessment of Cancer Therapy: Fatigue) were also administered. RESULTS: Both groups reported more PM than RM problems (P < .001). Survivors reported more fatigue and depression symptoms and more memory problems than controls (all P < .001). Importantly, the group difference in self-reported problems was no longer observed after adjusting for depression and fatigue. Survivors performed worse than controls on both PM and RM tasks. In neither group, however, were associations between self-reported RM and PM problems and RM and PM objective performance observed. CONCLUSIONS: Breast cancer survivors exhibit PM and RM deficits, which do not correlate with self-reported memory problems. Although unrelated to performance, memory complaints should not be dismissed, as they are closely associated with depression and fatigue and reveal an important facet of the cancer experience.

The relationship between mindfulness, pain intensity, pain catastrophizing, depression, and quality of life among cancer survivors living with chronic neuropathic pain.

PURPOSE: This study aims to examine if mindfulness is associated with pain catastrophizing, depression, disability, and health-related quality of life (HRQOL) in cancer survivors with chronic neuropathic pain (CNP). METHOD: We conducted a cross-sectional survey with cancer survivors experiencing CNP. Participants (n = 76) were men (24 %) and women (76 %) with an average age of 56.5 years (SD = 9.4). Participants were at least 1 year post-treatment, with no evidence of cancer, and with symptoms of neuropathic pain for more than three months. Participants completed the Five Facets Mindfulness Questionnaire (FFMQ), along with measures of pain intensity, pain catastrophizing, pain interference, depression, and HRQOL. RESULTS: Mindfulness was negatively correlated with pain intensity, pain catastrophizing, pain interference, and depression, and it was positively correlated with mental health-related HRQOL. Regression analyses demonstrated that mindfulness was a negative predictor of pain intensity and depression and a positive predictor of mental HRQOL after controlling for pain catastrophizing, age, and gender. The two mindfulness facets that were most consistently associated with better outcomes were non-judging and acting with awareness. Mindfulness significantly moderated the relationships between pain intensity and pain catastrophizing and between pain intensity and pain interference. CONCLUSION: It appears that mindfulness mitigates the impact of pain experiences in cancer survivors experiencing CNP post-treatment. IMPLICATIONS FOR CANCER SURVIVORS: This study suggests that mindfulness is associated with better adjustment to CNP. This provides the foundation to explore whether mindfulness-based interventions improve quality of life among cancer survivors living with CNP.

Prospective memory impairment in chemotherapy-exposed early breast cancer survivors: Preliminary evidence from a clinical test.

We report the results of a secondary analysis of a cross-sectional study (Paquet et al., 2013 ) to evaluate the cognitive operations involved in prospective memory (PM) deficits exhibited by chemotherapy-exposed breast cancer (BC) survivors. PM was assessed with the memory for intentions screening test administered to 80 patients and 80 healthy controls. Patients performed worse than controls on the PM tasks and had more "omission" errors (indices of the prospective component of the tasks) than the controls. No group differences emerged on a recognition test. Although further studies will be needed to disentangle the multiple cognitive operations involved in PM, these findings are consistent with the notion that self-initiated retrieval processes rather than encoding are implicated in PM impairment among BC survivors.

Risk Model-Guided Antiemetic Prophylaxis vs Physician's Choice in Patients Receiving Chemotherapy for Early-Stage Breast Cancer: A Randomized Clinical Trial.

IMPORTANCE: Despite multiple patient-centered factors being associated with the risk of chemotherapy-induced nausea and vomiting (CINV), these factors are rarely considered when making antiemetic recommendations. OBJECTIVE: To compare risk model-guided (RMG) antiemetic prophylaxis with physician's choice (PC) in patients receiving chemotherapy for early-stage breast cancer. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial of 324 patients with early-stage breast cancer undergoing chemotherapy (cyclophosphamide and an anthracycline) for the first time at 2 specialty cancer care centers in Ottawa from April 10, 2012, to September 2, 2014. Patients were randomized to either the RMG arm (n = 154) or the PC control arm (n = 170). Prior to each cycle of chemotherapy patients in the RMG group were categorized as low or high risk for CINV, and their antiemetic treatments were adjusted accordingly. INTERVENTIONS: Patients considered to be at low risk received standard dexamethasone and a 5-HT3 antagonist, while those at high risk also received aprepitant with or without olanzapine, based on their risk level. The PC control group received antiemetic agents according to the treating physician's discretion. MAIN OUTCOMES AND MEASURES: The primary end points were control of both nausea and vomiting in the acute posttreatment period (first 24 hours after therapy) and in the delayed posttreatment period (days 2-5 after therapy). RESULTS: The total numbers of chemotherapy cycles delivered in the RMG and PC control groups were 497 and 551 respectively. In the acute period, significantly more patients in the RMG group reported no nausea (53.7% [95% CI, 49.2%-58.1%] vs 41.6% [95% CI, 37.4%-45.3%]; P < .001) and no vomiting (91.8% [95% CI, 89.0%-94.0%] vs 82.2% [95% CI, 78.8%-85.3%]; P < .001) compared with the PC control group. Similarly, significantly more patients in the RMG group reported no nausea (39.6% [95% CI, 35.3%-44.1%] vs 30.7% [95% CI, 26.8%-34.7%]; P = .01) and no vomiting (87.1% [95% CI, 83.8%-90.0%) vs 78.0% [95% CI, 74.3%-81.4%]; P < .001) in the delayed period respectively. CONCLUSIONS AND RELEVANCE: In this trial, the RMG antiemetic prophylaxis led to improved control of acute and delayed CINV compared with physician's choice of therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01913990.

Predicting OncoDX recurrence scores with immunohistochemical markers: effect of stromelysin.

Recent reports suggest that immunohistochemistry (IHC) markers can be used to give prognostic information in breast cancer that is similar to that contained in the Genomic Health Inc. OncoDX recurrence score (Onco-RS). Our own previous work confirmed that an IHC model based on estrogen receptor (ER), progesterone receptor (PR), and Ki67 predicts 62% of the Onco-RS variability. Other markers used in the Onco-RS include proteins thought to increase tumoral invasive potential, and one such marker is matrix metalloproteinase-11, also called stromelysin 3 (ST3). The goal of this study is to examine the additional value of including ST3 in an IHC-based model that also includes ER, PR, and Ki67 in predicting the Onco-RS, as compared with an IHC model based only on ER, PR, and Ki67 (IHC-RS). The patient population consists of a retrospectively identified cohort of 91 women with ER-positive, HER2neu-negative breast cancer who completed OncoDX testing. Using stepwise multiple regression incorporating Ki67 percentage and semiquantitative ER, PR, and ST3 scores, the ST3 score was not statistically significant.

Factors influencing Oncotype DX use in the management of early breast cancer: a single centre experience.

BACKGROUND: Oncotype DX recurrence score is a multi-gene assay which quantifies the risk of distant recurrence in patients with hormone receptor-positive (HR+) early breast cancer (EBC) treated with tamoxifen, and predicts the magnitude of clinical benefit of adjuvant chemotherapy. This retrospective study examined factors that were associated with use of Oncotype DX assay at a tertiary care cancer centre in Ottawa, Canada. METHODS: One hundred consecutive patients (pts) diagnosed with HR+, HER2/neu negative EBC (stage I-II), who underwent Oncotype DX testing (Test Group) between 1st April 2010, and 30th June 2011 were included in the study. A second cohort of 100 randomly selected patients with HR+, HER2/neu negative EBC diagnosed from the same time period who did not receive Oncotype DX testing were used as the control group (Control Group). Demographic and clinicopathologic data were obtained from review of charts. Logistic regression was performed to identify variables associated with Oncotype DX usage. FINDINGS: Median age was 58 years (r: 26-77) in Test Group and 63 years (r: 30-81) in Control Group. Sixty-two patients in the Test Group had T1 tumours, compared with 71 in the Control Group. The median 10-year recurrence risks from Adjuvant! Online were 19% and 12% in the Test Group and Control Group, respectively. Factors significantly associated with the utilisation of Oncotype DX assay on multivariate analysis include age 50-64 (p=0.049), tumour size 10.1-20mm (p=0.008) and grade 2 histological grade (p=0.004). INTERPRETATION: Usage of Oncotype DX assay is associated with several clinicopathological factors. These factors reflect the clinical uncertainty of benefit from chemotherapy in these subpopulations of patients and suggest how Oncotype DX assay could complement clinicopathological factors in helping clinicians on treatment selection.