British Columbia Cancer Agency Research Articles

Chinese clinical practice guidelines for the prevention and treatment of radiation‐induced dermatitis

AbstractRadiation‐induced dermatitis is one of the most prevalent complications in patients undergoing cancer radiotherapy and poses a significant challenge to cancer therapy. The symptoms include erythema, dry desquamation, and moist desquamation, which are frequently observed in patients with breast, head and neck, anal, and vulvar cancers. Early skin reactions typically manifest within 2–4 weeks following the initiation of radiotherapy. In severe cases, acute dermatitis can cause radiotherapy interruptions, prolong treatment time, and ultimately affect patient outcomes and quality of life. Currently, there are numerous guidelines on radiation dermatitis, including the Multinational Association of Supportive Care in Cancer (MASCC), British Columbia Cancer Agency (BCCA), Oncology Nursing Society (ONS), and UK Society of Radiographers (SCoR) guidelines. In China, dermatology experts have drafted a consensus. However, due to the differing backgrounds of experts, recommendations among guidelines vary. These guidelines were first developed by Chinese radiation oncologists. The evidence‐based guideline in this paper fully considers and adopts China's national conditions; hence, it can be easily applied in daily practice.

Genetic and Microenvironment Features Do Not Distinguish Follicular Lymphoma Patients Requiring Immediate or Deferred Treatment.

Genetic and Microenvironment Features Do Not Distinguish Follicular Lymphoma Patients Requiring Immediate or Deferred Treatment.

Development and application of decatungstate catalyzed C-H 18F- and 19F-fluorination, fluoroalkylation and beyond.

Over the past few decades, photocatalytic C-H functionalization reactions have received increasing attention due to the often mild reaction conditions and complementary selectivities to conventional functionalization processes. Now, photocatalytic C-H functionalization is a widely employed tool, supporting activities ranging from complex molecule synthesis to late-stage structure-activity relationship studies. In this perspective, we will discuss our efforts in developing a photocatalytic decatungstate catalyzed C-H fluorination reaction as well as its practical application realized through collaborations with industry partners at Hoffmann-La Roche and Merck, and extension to radiofluorination with radiopharmaceutical chemists and imaging experts at TRIUMF and the BC Cancer Agency. Importantly, we feel that our efforts address a question of utility posed by Professor Tobias Ritter in "Late-Stage Fluorination: Fancy Novelty or Useful Tool?" (ACIE, 2015, 54, 3216). In addition, we will discuss decatungstate catalyzed C-H fluoroalkylation and the interesting electrostatic effects observed in decatungstate-catalyzed C-H functionalization. We hope this perspective will inspire other researchers to explore the use of decatungstate for the purposes of photocatalytic C-H functionalization and further advance the exploitation of electrostatic effects for both rate acceleration and directing effects in these reactions.

Rewilding Play: Design Build Interventions

Research on physical interventions installed in outdoor environments and their impacts on children’s play and development is a growing area of study. This paper focuses on the design and installation of outdoor interventions at early childhood education centres in Vancouver, Canada and the impact that theses interventions had on play affordances. With the aim of intervening with inexpensive natural materials and loose parts, graduate students designed, built, and installed interventions and using the Seven Cs evaluation form they scored the play spaces pre- and post-installation. Design methods included the Seven Cs design guidelines and the Two-Eyed Seeing model. Students also sought the insights of Early Childhood Educators, maintenance staff, licensing officers, the British Columbia Cancer Agency, and an Indigenous herbalist/educator. They also examined and addressed solar modifications to create dappled light. To understand the impacts of the student interventions researchers compared the pre- and post-intervention Seven Cs scores, which increased by 20 to 30 points. Researchers seeking to replicate this type of project in their own institutions should carefully consider the impact of climate change on construction timing and material selection, and sensitivity to the diversity of socio-cultural values embedded in the community and within design decisions and the interventions themselves.

A bibliometric analysis of diffuse large B-cell lymphoma research from 2001 to 2020

Diffuse large B-cell lymphoma (DLBCL) is a subtype of non-Hodgkin lymphoma (NHL) with the highest incidence, accounting for approximately one-third of NHL cases. Given the accumulated scientific publications related to the DLBCL domain, this study aimed to provide a comprehensive review of DLBCL studies from this millennium using the bibliometric method. With a strict retrieval strategy applied in the Web of Science database, a total of 10,869 publications from 2001 to 2020 were obtained and exported. The temporal and geographical distribution of these publications and the performance of contributing countries, institutions, journals, and authors corresponding to these documents were investigated, as well as an in-depth content analysis through keyword co-occurrence. With regard to the most productive countries, the United States ranks first with 2344 (21.6%) publications and shows the most frequent collaborations with other countries. By contrast, China has demonstrated remarkable performance in the growth rate of publications over the years, and it ranks first in the number of publications in the last five years. The University of Texas System is the institution with the highest number of published articles (4.99%). Leukemia Lymphoma is the journal with the highest number of publications in this field which contributed 588 articles. Solid and close collaborations between scholars are becoming more frequent over the four five-year periods. Overall, the highest cooperation frequency in the last two decades happens to Gascoyne RD at the British Columbia Cancer Agency and British Columbia Cancer Research Center in Canada. By comparing the article citation and keyword co-occurrence in each five-year period, as well as the changes in keyword clusters over two decades, we conclude that the stage, evaluation, prognosis, and treatment of DLBCL have always been the research hotspots in this field. Meanwhile, the evolution of keyword co-occurrence over the years demonstrates that new clusters appear. For instance, the effect of ferroptosis mechanism in DLBCL, immunotherapy for DLBCL, and PDL-1, PDL-2, and CAR-T therapy have drawn increasing attention from academia. Our research highlights the key characteristics of DLBCL research and provides comprehensive insights into the research status and evolutions in this field.

ANALYSIS OF SPECIFIC PARAMETERS FOR SKIN TUMOR CLASSIFICATION

During the last years, computer vision-based diagnosis systems have been widely used in several hospitals and dermatology clinics, aiming mostly at the early detection of malignant melanoma tumor, which is among the most frequent types of skin cancer, versus other types of nonmalignant cutaneous diseases. They grow in melanocytes, the cells responsible for pigmentation. This type of cancer is increasing rapidly and its related mortality rate is increasing more modestly, and inversely proportional to the tumor’s thickness. The mortality rate can be decreased by earlier detection of suspicious lesions and better prevention. In this work, we are interested in extracting all specific attributes which can be used for computer-aided diagnosis of melanoma. In the first step of the proposed work, we applied the Dull Razor [Lee T et al., Dullrazor: A software approach to hair removal from images, Cancer Control Research, British Columbia Cancer Agency, Vancouver, Canada, Vol. 21, No. 6, pp. 533–543, 1997] technique to images to reduce the influence of small structures, hairs, bubbles, light reflection. In the second step, a new fuzzy level set algorithm is proposed in order to facilitate the medical image segmentation task. It is able to directly evolve from the initial segmentation proposed that uses a spatial fuzzy clustering approach. The controlling parameters of the level set evolution are also estimated from the results of the fuzzy clustering step. This step is essential to characterize the shape of the lesion and also to locate the tumor to be analyzed. In this paper, we have also treated the necessity to extract all the specific attributes used to develop a characterization methodology that enables specialists to take the best possible diagnosis. For this purpose, our proposal relies largely on visual observation of the tumor while dealing with some characteristics as color, texture or form. The method used in this paper is called ABCD. It requires calculating four factors: Asymmetry ([Formula: see text], Border ([Formula: see text], Color ([Formula: see text], and Diversity ([Formula: see text]. Finally, these parameters are used to construct a classification module based on artificial neural network for the recognition of malignant melanoma.

Comparison of clinical practice guidelines on radiation dermatitis: a narrative review.

Radiation dermatitis (RD) is a common side effect of radiation therapy (RT). While many different treatment strategies are currently used to address RD, there is a lack of consensus and RD prophylaxis and management guidelines have remained largely unchanged over the last 10years. This review aims to formulate unambiguous supportive care interventions by comparing RD clinical practice guidelines published between 2010 and 2021 by several organizations: Multinational Association for Supportive Care in Cancer (MASCC), British Columbia Cancer Agency (BCCA), Cancer Care Manitoba (CCMB), Oncology Nursing Society (ONS), Society and College of Radiographers (SCoR), and International Society of Nurses in Cancer Care (ISNCC). Areas of agreement and discordance were assessed among the MASCC, BCCA, CCMB, ONS, SCoR, and ISNCC guidelines. Treatment recommendations across guidelines for acute RD and chronic RT-induced skin toxicities have been summarized. The strongest agreement among the guidelines exists for the use of topical corticosteroids, silver sulfadiazine, washing, and deodorant. All guidelines recommend the use of topical corticosteroids, and washing with water and soap is consistently supported. There is minimal consensus on an optimal dressing or barrier film for RD prophylaxis or management. MASCC weakly recommends prophylactic use of silver sulfadiazine to reduce RD, while BCCA, CCMB, and SCoR recommend its use upon signs of infection. MASCC and CCMB recommend the use of a long-pulsed dye laser to manage telangiectasia, a late effect of RT. Given the extent of discordance among guideline recommendations, further research is recommended to establish optimal treatments for RD prophylaxis and management.

Time to Treatment With Nivolumab or Pembrolizumab for Patients With Advanced Melanoma in Everyday Practice.

BackgroundThe anti-programmed cell death one antibodies (Anti-PD-1 Ab) pembrolizumab or nivolumab are commonly prescribed to patients with advanced melanoma. The purpose of the current study is to identify baseline clinical characteristics associated with time to treatment initiation (TTI) of pembrolizumab or nivolumab for advanced melanoma and whether treatment delays are associated with differences in survival outcomes.MethodsAll patients receiving Anti-PD-1 Ab as a first-line treatment for advanced melanoma outside of clinical trials at British Columbia Cancer Agency between 10/2015 and 10/2019 were identified retrospectively. TTI was defined as the interval from pathologic diagnosis of advanced melanoma to first Anti-PD-1 Ab treatment. To determine the association between TTI and baseline characteristics, multivariable Cox proportional hazard regression analyses provided an estimate of the instantaneous relative risk of starting treatment at any time point (hazard ratio [HR] >1 indicates shorter TTI). To describe changes in overall survival (OS) observed for each four-week delay in treatment initiation, multivariable cox proportional hazard regression modelling was also performed.ResultsIn a cohort of 302 patients, the median TTI was 52 days (interquartile range 30.2-99.0). Pulmonary metastases (M1b)/non-central nervous system visceral metastases (M1c) vs. metastases to skin or non-regional lymph nodes (M1a)(HR=1.50, 95% CI=1.12-2.02; p=0.007) and pre-treatment Eastern Cooperative Oncology Group Performance Status (ECOG PS) >1 (vs 0/1, HR=1.50, 95% CI= 1.11-2.01; p=0.008) were associated with earlier TTI. An association between treatment delay and improved OS was observed.ConclusionPatients having visceral metastases and poor baseline ECOG PS were more likely to initiate Anti-PD-1 Ab sooner. The association of shorter TTI with worse OS likely represents confounding by indication (urgent treatment offered to patients with aggressive disease).

BCL2 Expression Identifies a Population with Unmet Medical Need in Previously Untreated (1L) Patients with DLBCL

▪Introduction.High BCL2 protein expression has been associated with inferior outcome in multiple studies in diffuse large B-cell lymphoma (DLBCL) (Gascoyne et al. 1997; Salles et al. 2011; Horn et al. 2013; Tsuyama et al. 2017). Patients with high levels of BCL2 expression may benefit from treatment with venetoclax, a first-in-class, highly selective BCL2 inhibitor with demonstrated activity in cell lines and xenograft models (Souers et al. 2013, Punnoose et al. 2016). The evaluation of BCL2 as a prognostic marker has been complicated by the variability in recognized immunohistochemistry (IHC) thresholds (de Jong et al. 2007; Tsuyama et al. 2017) and the impact of cell-of-origin (COO) (Iqbal et al. 2011). Using a BCL2 IHC scoring algorithm that was developed to identify cell lines that are sensitive to BCL2 inhibition, and that could potentially identify patients likely to benefit from venetoclax, we evaluated the prognostic capability of BCL2 IHC in three independent cohorts of 1L DLBCL patients. Cohorts included two Phase 3 studies (MAIN [NCT00486759] and GOYA [NCT01287741]), and a representative cohort from the British Columbia Cancer Agency (BCCA) registry-based population, in which subjects received chemoimmunotherapy (either rituximab or obinutuzumab, combined with cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP]).Patients and Methods. Pretreatment tumor samples were tested for BCL2 IHC using an algorithm that assesses both the percent of tumor cells stained and the intensity of staining, similar to the BCL2 algorithm proposed by Tsuyama et al. (Table 1).Whole-tissue slides from184 patients from MAIN were tested at Genentech , whole tissue slides from 366 patients from GOYA were tested at Hematogenex (Ventana assay) and tissue microarray slides from 310 patients from BCCA were tested at Ventana (Ventana assay). The NanoString Lymphoma Subtyping gene expression assay was used for classification of COO into germinal center B-cell (GCB), activated B-cell (ABC) or unclassified subtypes in MAIN (n=159), GOYA (n=353) and BCCA (n=302). Multivariate Cox regression analysis of progression-free survival (PFS) was performed in each study with the International Prognostic Index (IPI; The International NHL Prognostic Factors Project 1993) and/or COO as covariates. Given the similar treatment effect, patient data from both treatment arms in each study were merged for this analysis.Results. Baseline characteristics were similar for the BCL2 IHC evaluable and intent-to-treat (ITT) populations of these three cohorts. Prevalence of BCL2 positive patients was 48% in MAIN, 49% in GOYA and 58% in the BCCA cohort. The prevalence of BCL2 positive samples within the ABC subtype was 64%, 75% and 60% in the MAIN, GOYA and BCCA cohorts, respectively, and 40%, 38% and 56% within the GCB subtype, respectively. In univariate analysis, BCL2 positivity was associated with shorter PFS in all three cohorts (Figure 1, A-C). In the MAIN study, the prognostic effect of BCL2 appeared to be in the GCB subgroup, not ABC, as previously reported (Punnoose et al. ASH 2015). In the two largest studies of GOYA and BCCA cohorts, the prognostic effect of BCL2 was similar in ABC and GCB (not shown), and was independent of IPI (Table 2).Conclusions. Using a newly developed BCL2 IHC scoring algorithm, we demonstrate that DLBCL patients positive for BCL2 have a consistently inferior prognosis compared with patients negative for BCL2. The prognostic value of BCL2 IHC is independent of IPI and COO in GOYA and BCCA. The Ventana assay is currently being used in a Phase 2 study of venetoclax in combination with R-CHOP to evaluate the correlation (if any) of BCL2 expression with venetoclax + R-CHOP treatment (CAVALLI - NCT02055820). [Display omitted] DisclosuresSzafer-Glusman:Genentech: Employment. Peale:Genentech / Roche: Employment, Equity Ownership. Lei:Roche: Employment. Ray:Genentech/Roche: Employment. Farazi:Genentech: Employment. Kornacker:Roche: Equity Ownership; F. Hoffmann-La Roche: Employment. Oestergaard:F. Hoffmann-La Roche Ltd: Employment. Liu:F. Hoffmann-La Roche: Employment. Punnoose:Genentech: Employment.

A Phase II Intergroup Trial of PET-Directed Therapy for Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG Study S1001 (NCT01359592)

A Phase II Intergroup Trial of PET-Directed Therapy for Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG Study S1001 (NCT01359592)

Evaluation of the NCCN-IPI As a Prognostic Tool in PTCLs

Background: The majority of systemic peripheral T-cell lymphomas (PTCLs) have an aggressive behavior and compared to diffuse large B-cell lymphoma, survival is inferior using standard anthracycline-based treatment. Patient and disease factors impact survival, and the International Prognostic Index (IPI) is the most widely used clinical tool for prognostication for aggressive lymphomas. The IPI has shown prognostic utility in some PTCL entities such as systemic anaplastic large cell lymphoma (ALCL) and PTCL not otherwise specified (PTCL NOS), but less usefulness for others such as angioimmunoblastic T-cell lymphoma (AITL) as well as the rarer predominantly extranodal PTCL subtypes. T-cell specific prognostic indices such as the Prognostic Index for PTCL-U (PIT) have been explored but the IPI remains the most commonly used prognostic tool. The NCCN-IPI prognostic index has recently been developed for DLBCL. The NCCN-IPI builds on much the same parameters as the IPI, but with age stratified into four groups, lactate dehydrogenase (LDH) ratio using the upper limit of normal (ULN) separated into three categories (<1 ULN, 1-3 ULN, >3 ULN) and it also incorporates specific extranodal sites (CNS, gastrointestinal, lung or bone marrow involvement) but not absolute number of sites, with a maximum score of 8 points. In this study we evaluated the NCCN-IPI in comparison to the IPI and PIT in the three main nodal PTCL subgroups: ALK-neg ALCL, AITL, and PTCL NOS.Methods: A cohort of newly diagnosed adult PTCL patients treated with anthracyline-based or other curative intent chemotherapy regimens was assembled from the Swedish Lymphoma Registry (SWE), University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), and British Columbia Cancer Agency (BCCA). Patients with complete prognostic data and ALK-neg ALCL, AITL or PTCL NOS subtypes were included. Event-free survival (EFS) was defined as time from pathologic diagnosis to progression/relapse, retreatment, or death due to any cause. Kaplan-Meier curves and Cox proportional hazards models were used to examine prognostic utility of indices; concordance was measured via Harrell's c-index.Results: In total, 603 patients were included. The majority of AITL presented with advanced stage disease (92%) and elevated LDH (75%) while ALK-neg ALCL patients less often exhibited adverse factors (advanced disease [67%] and elevated LDH [50%]) and PTCL NOS patients showed characteristics in between. At a median follow-up of 81 months (range 1-185), 449 patients (75%) had an event and 400 patients (66%) had died. Kaplan-Meier curves for EFS by NCCN-IPI are shown in figure 1. In patients with AITL (N=145), the NCCN-IPI had limited prognostic utility (EFS c-index=0.580) which was worse than the IPI (c-index=0.597) and similar to the PIT (c=0.585). The number of AITL patients with low-risk disease by NCCN-IPI was very small (N=2 [1%]). The NCCN-IPI had excellent prognostic utility in N=152 patients with ALK-neg ALCL (c-index=0.683), which was superior to the IPI and PIT (both c-index=0.665). However, a limited number of patients were classified as low risk (15%) or high risk disease (8%). The NCCN-IPI had modest prognostic utility in 306 patients with PTCL, NOS (c-index=0.629), which was inferior to the IPI (c-index=0.645) and similar to the PIT (c-index=0.631). Similar to ALK-neg ALCL, a limited number of patients were classified as low risk (12%) or high risk (14%) disease.Conclusions: The NCCN-IPI performed similarly to the IPI with the exception of ALK-neg ALCL where it appeared to be better at defining low and very high risk patients. In AITL, the NCCN-IPI had very limited prognostic ability and performed even worse than the IPI (which also had limited prognostic ability). Better risk stratification is needed in this disease. For PTCL-NOS, the NCCN-IPI performed similarly to the IPI and PIT. While regrouping of scores could potentially improve this situation, the integration of other clinically defined prognostic factors and molecular characteristics is needed for more precise prognostic models in PTCLs. [Display omitted] DisclosuresEllin:CTI: Consultancy; ROCHE: Consultancy, Research Funding. Connors:NanoString Technologies, Amgen, Bayer, BMS, Cephalon, Roche, Genentech, Janssen, Lilly, Merck, Seattle Genetics, Takeda,: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding; Lilly: Research Funding; Merck: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Takeda: Research Funding; F Hoffmann-La Roche: Research Funding; Bayer Healthcare: Research Funding. Smedby:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding. Slack:Seattle Genetics: Consultancy. Cerhan:Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering . Savage:Celgene: Consultancy; Roche: Research Funding; Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Merck: Honoraria.

Impact of Immunohistochemistry-Defined Cell of Origin and MYC Rearrangements on Outcomes in Patients with PET-Defined Stage I/II Diffuse Large B-Cell Lymphoma Treated with R-CHOP ± Radiotherapy: An International Multi-Center Retrospective Study

Impact of Immunohistochemistry-Defined Cell of Origin and MYC Rearrangements on Outcomes in Patients with PET-Defined Stage I/II Diffuse Large B-Cell Lymphoma Treated with R-CHOP ± Radiotherapy: An International Multi-Center Retrospective Study

Genetic Characterization and Clinical Impact of Loss of MHC Class I and II Expression in De Novo Diffuse Large B-Cell Lymphoma

Introduction: Immune recognition by T cells requires the presentation of processed peptides in association with major histocompatibility complex class I (MHC-I) and class II (MHC-II) molecules. Among the tumor immune escape mechanisms described to date, alterations in the expression of MHC molecules play a crucial role in the development of diffuse large B-cell lymphoma (DLBCL). Loss of MHC-I or -II expression in DLBCL can occur through multiple mechanisms, including deletion of the MHC-I and -II locus, loss of function mutations of B2M, and genetic alterations of CIITA ; however, the role of additional genetic and epigenetic mechanisms remains largely unknown. With regard to clinical significance, a number of studies have reported that low MHC-II expression on tumor cells is associated with shorter survival in DLBCL, while the prognostic effect of MHC-I expression has not been systematically evaluated in a large, homogeneously treated cohort. In addition, although the frequency of loss of MHC-II expression differs between ABC- and GCB-DLBCL cell of origin (COO) subtypes, the prognostic impact remains ill-defined. Here, we conducted a comprehensive phenotypic and genetic analysis in a population-based DLBCL cohort to investigate the genetic background and clinical relevance of loss of MHC-I and -II expression.Method: We analyzed biopsies from 347 patients newly diagnosed with de novo DLBCL and uniformly treated with R-CHOP at the BC Cancer Agency. High-resolution copy number analysis was performed using Affymetrix SNP 6.0 arrays. Mutation status was determined using deep targeted re-sequencing of the coding exons of 57 genes with a Truseq Custom Amplicon assay (Illumina) and/or Fluidigm Access Array chips, and RNAseq. Immunohistochemical staining of MHC-I and -II was performed on tissue microarrays (n=332). COO was assigned by gene expression (Lymph2Cx assay) in 323 cases (183 GCB, 104 ABC and 36 unclassifiable).Results: We found the following MHC-I and -II staining patterns:membrane-positive (n=188 (57%) and n=233 (72%), respectively), cytoplasmic only-positive / membrane-negative (n=86 (26%) and 31 (10%), respectively) and negative staining for both membrane and cytoplasmic (n=55 (17%) and n=59 (18%), respectively). Overall, membranous MHC-I and -II expression was not detected in 141/329 (43%) and 90/323 (28%) cases, respectively. While the frequency of loss of MHC-I expression was not different between COO subtypes, loss of MHC-II expression occurred more often in ABC-DLBCL (36% vs 22%, p=0.026). This is consistent with previous observations showing that MHC-II expression is reduced during plasmacytic differentiation and in ABC-DLBCL. Loss of MHC-I expression was associated with B2M mutation and deletion as well as with HLA-C deletions (all p <0.001, Fisher's exact test). Interestingly, mutations of EZH2 and GNA13 were detected more frequently in cases that had loss of MHC-I expression (p <0.001 and p=0.004, respectively). Moreover, mutations of CIITA and RFXAP (components of the MHC-II enhanceosome), and mutations of PRDM1 and TNFAIP3, ABC-DLBCL-specific mutations, were significantly enriched in MHC-II negative cases. Of note, mutations of B2M and EZH2 were significantly associated with loss of MHC-II expression, as well (p=0.001 and p=0.016, respectively). The associations between EZH2 mutation and MHC-I and -II expression were also observed when the analysis was restricted to GCB-DLBCL (both p <0.0001).With a median follow up of 6.5 years for living patients, the loss of MHC-I expression was not associated with survival in the entire DLBCL cohort, as well as within each COO subtype. Although there was also no significant survival difference according to the MHC-II expression status in the entire DLBCL cohort, loss of MHC-II expression was associated with an inferior 5y-time to progression (TTP, 59% vs 79%, p=0.007) in the GCB subtype. Interestingly, in the ABC subtype, loss of MHC-II expression was associated with a superior 5y-TTP (64% vs 40%, p=0.03).Conclusion: Our approach using next generation sequencing and high resolution SNP arrays uncovered the genetic background, as well as the clinical impact of loss of MHC-I and-II expression in a uniformly R-CHOP-treated large population-based cohort of DLBCL patients. Our results warrant further studies investigating a potential mechanism of EZH2 mutations regulating MHC-I and -II expression in DLBCL. DisclosuresSavage:Bristol-Myers Squibb: Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche: Research Funding; Celgene: Consultancy; Merck: Honoraria. Sehn:Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Morin:Epizyme, Inc: Consultancy. Connors:Genentech: Research Funding; Bayer Healthcare: Research Funding; Lilly: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Amgen: Research Funding; Janssen: Research Funding; F Hoffmann-La Roche: Research Funding; NanoString Technologies: Research Funding; Bristol-Myers Squibb: Research Funding; Cephalon: Research Funding; Takeda: Research Funding; NanoString Technologies, Amgen, Bayer, BMS, Cephalon, Roche, Genentech, Janssen, Lilly, Merck, Seattle Genetics, Takeda,: Research Funding. Scott:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BCCA: Patents & Royalties: Patent describing molecular subtyping of DLBCL licensed to NanoString Technologies. Patent describing measurement of the proliferation signature in MCL.. Steidl:Affimed Therapeutics: Consultancy; Juno Therapeutics: Consultancy.

Cost Effectiveness of Nivolumab for the Treatment of Relapsed/Refractory Classical Hodgkin Lymphoma (cHL) after Failure of Autologous Stem Cell Transplantation (ASCT) and Treatment with Brentuximab Vedotin (BV) Treatment in Australia

IntroductionAustralian cHL patients who have failed ASCT and BV treatment have historically had poor outcomes; however, recent clinical trial evidence has shown promising efficacy for nivolumab, a cancer immunotherapy that breaks the tolerance of the immune system to tumour cells and antigens by modulating the programmed death-1 (PD-1) regulatory checkpoint of the immune system. This study presents a cost effectiveness analysis of nivolumab compared to standard of care (SoC) in a contemporary Australian setting.MethodsA life-time decision-analytic partitioned survival model was developed to compare nivolumab with SoC. The comparison was performed in multiple steps as no head to head data were available. Step 1 estimated costs and outcomes for SoC using pooled data from British Columbia Cancer Agency Lymphoid Cancer Database and pseudo-individual patient data (IPD) simulated from a study published by Cheah et al. Ann. Oncol. 2016 on patients with cHL who had received BV treatment. Quality of life (QoL) was sourced from the literature. Step 2 estimated costs and outcomes (incl. QoL) for nivolumab based on pooled IPD from two clinical trials (Phase II study CheckMate205 and Phase I study CheckMate039). Australian specific costs were applied in both scenarios and expressed in US dollars (US$). Outcomes were extrapolated beyond the clinical trial data by applying parametric functions over a lifetime horizon. In Step 3 the incremental cost effectiveness ratio (ICER) was estimated for life years (LY) and quality adjusted life years (QALY) utilizing the results from Step 1 and 2. Sensitivity analyses were undertaken to test the robustness of the results of the model.ResultsNivolumab resulted in more than double the survival from 3.8 LYs to 8.6 LYs when compared to SoC and added 4.5 quality adjusted life years (QALYs) per person at an additional cost of US$214k (discounted). These led to ICERs of US$47k per LY gained and US$45k per QALY gained. Sensitivity analyses showed that the result was most sensitive to the time horizon, duration of treatment and health state utilities. However, the ICER was stable and generally stayed within +/-10% of the base case for most of the scenarios tested.ConclusionsNivolumab represents a cost-effective alternative to current SoC, with potential to improve quality of life and survival for patients treated for relapsed/refractory cHL after failure of ASCT and BV in Australia. DisclosuresTan:Bristol Myers Squibb: Employment. Lozano-Ortega:Bristol Myers Squibb: Consultancy. Szabo:Bristol Myers Squibb: Consultancy. Johnston:Bristol Myers Squibb: Consultancy. Connors:Genentech: Research Funding; Amgen: Research Funding; Bayer Healthcare: Research Funding; Janssen: Research Funding; F Hoffmann-La Roche: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Lilly: Research Funding; Cephalon: Research Funding; NanoString Technologies, Amgen, Bayer, BMS, Cephalon, Roche, Genentech, Janssen, Lilly, Merck, Seattle Genetics, Takeda,: Research Funding; Takeda: Research Funding. Chen:Bristol-Myers Squibb: Employment. Kim:Bristol Myers Squibb: Employment.

FOXP1 Expression Is a Prognostic Biomarker in Follicular Lymphoma Treated with Immunochemotherapy and Is Associated with Distinct Molecular Features

Introduction: Follicular lymphoma (FL) is a clinically and molecularly highly heterogeneous disease, yet prognostication relies predominantly on clinical tools. We have recently demonstrated that integration of the mutation status of seven genes (including EZH2 and MEF2B) into a combined clinico-genetic risk model (m7-FLIPI) improves risk-stratification, and represents a promising approach to identify a subset of patients at highest risk of treatment failure. However, the mechanism underlying the association between mutations of the 7 genes included in the m7-FLIPI and outcome has thus far not been elucidated. We assessed whether downstream phenotypic commonalities of gene mutations predict outcome following immunochemotherapy and whether select genotypic and phenotypic alterations are associated with FOXP1 expression.Methods: We mined gene expression data to uncover genes that are differentially expressed in EZH2 - and MEF2B -mutated FLs. We focused on FOXP1 and assessed its protein expression by immunohistochemistry (IHC) in a total of 763 tissue biopsies. For outcome correlation, a population-based training cohort of 142 FL patients treated with R-CVP, and a clinical trial validation cohort comprising 395 patients treated with CHOP +/- rituximab were used. To differentiate cases with high vs. low FOXP1 expression, we chose the cut-off that maximized the log-rank test statistic for failure-free survival (FFS) in the training cohort. The effect of FOXP1 expression on FFS in the validation cohort was estimated using Cox regression analysis. In addition, for exploratory analyses, we used specimens from 350 BC Cancer Agency patients, 124 of whom overlapped with the above-mentioned training cohort.Results: We found FOXP1 to be significantly down-regulated in both EZH2 - and MEF2B -mutated cases. The cut-off value that best separated favorable from unfavorable FFS in the training cohort was determined to be >10% percent tumor cells expressing FOXP1 based on the log-rank test statistic. 76 specimens in the training cohort (54%) had high FOXP1 expression, which was associated with reduced 5-year failure-free FFS (55% vs. 70%, P=0.035). In the validation cohort, high FOXP1 expression status was observed in 248 patients (63%) and correlated with significantly shorter FFS in patients treated with R-CHOP (HR 1.95, P=0.017), but not in patients treated with CHOP (HR 1.15, P=0.44), demonstrating that FOXP1 is a predictive biomarker. In BCCA patients, high FOXP1 expression remained significantly associated with inferior FFS in a multivariate Cox regression model including rituximab maintenance (by intention to treat) and FLIPI high vs low/intermediate (HR 1.84, 95%-CI [1.10-3.08], P=0.021). Similarly, in the GLSG cohort, high FOXP1 expression was significantly associated with poor FFS in patients treated with R-CHOP, after adjusting for rituximab, FLIPI and the interaction of FOXP1 with rituximab (HR 1.84, 95%-CI [1.05-3.24], P=0.035). No significant association was observed in GLSG patients treated with CHOP (HR 1.06, 95%-CI [0.73-1.54], P=0.76). High FOXP1 expression was associated with distinct molecular features such as TP53 mutations, expression of IRF4, and gene expression signatures reminiscent of dark zone germinal centre or activated B cells. Conversely, low expression of FOXP1 was associated with - in addition to EZH2 and MEF2B mutations - GNA13 and TNFRSF14 mutations, as well as with expression of genes related to normal germinal centre light zone cells and germinal centre B cells. Taken together, these observations suggest that FOXP1 expression delineates FL cases with distinct genomic and phenotypic characteristics.Conclusion: In patients treated with immunochemotherapy, high FOXP1 expression identified patient populations with significantly shortened FFS. On the other hand, FOXP1 did not separate distinct outcome groups in patients treated without rituximab, suggesting that FOXP1 is a predictive biomarker. In multivariate analyses, high FOXP1 expression remained significantly associated with FFS in immunochemotherapy patients, after adjusting for the FLIPI. Moreover, FOXP1 high and low expression phenotypes are reflective of distinct sets of molecular alterations. Our results illustrate the value of understanding the intricate relationships between lymphoma biology and response to treatment. DisclosuresKlapper:Hoffmann La Roche: Other: Grant; Novartis: Other: Grant; Celgene: Other: Grant; Takeda Millenium: Other: Grant. Hiddemann:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Steidl:Affimed Therapeutics: Consultancy; Juno Therapeutics: Consultancy. Connors:Janssen: Research Funding; F Hoffmann-La Roche: Research Funding; Bayer Healthcare: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding; Merck: Research Funding; Lilly: Research Funding; Genentech: Research Funding; Cephalon: Research Funding; Amgen: Research Funding; Bristol-Myers Squibb: Research Funding; NanoString Technologies, Amgen, Bayer, BMS, Cephalon, Roche, Genentech, Janssen, Lilly, Merck, Seattle Genetics, Takeda,: Research Funding; Takeda: Research Funding. Sehn:Roche/Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Hoster:Roche: Other: Travel support, Research Funding.

Comparative Effectiveness of High-Dose Bendamustine-EAM Versus BEAM in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplantation

Comparative Effectiveness of High-Dose Bendamustine-EAM Versus BEAM in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplantation

Evaluating the intended and unintended consequences of opioid-prescribing interventions on primary care in British Columbia, Canada: protocol for a retrospective population-based cohort study.

IntroductionBetween 2015 and 2018, there were over 40 000 opioid-related overdose events and 4551 deaths among residents in British Columbia (BC). During this time the province mobilised a variety of policy levers to encourage physicians to expand access to opioid agonist treatment and the College of Physicians and Surgeons of British Columbia (CPSBC) released a practice standard establishing legally enforceable minimum thresholds of professional behaviour in the hopes of curtailing overdose events. Our goal is to conduct a comprehensive investigation of the intended and unintended consequences of these policy changes. Specifically, we aim to understand the effects of these measures on physician prescribing behaviours, identify physician characteristics associated with uptake of the new measures, and measure the effects of the policy changes on patients’ access to quality primary care.Methods and analysisThis is a population-level, retrospective cohort study of all BC primary care physicians who prescribed any opioid medication for opioid-use disorder or chronic non-cancer pain during the study period, and their patients. The study period is 1 January 2013–31 December 2018, with a 1-year wash-in period (1 January 2012–31 December 2012) to exclude patients who initiated long-term opioid treatment prior to our study period or whose pain type (ie, ‘chronic non-cancer’, ‘acute’, ‘cancer or palliative’, or ‘other’) cannot be confirmed. The project combines five administrative health datasets under the authority of the BC Ministry of Health, with the CPSBC’s Physician Registry, BC Cancer Agency’s Cancer Registry and Vital Statistics’ Mortality data. We will create measures of prescribing concordance, access, continuity, and comprehensiveness to assess primary care delivery and quality at both the physician and patient level. We will use generalised estimating equations, interrupted time series, mixed effects models, and funnel plots to identify factors related to changes in prescribing and evaluate the impact of the changes to prescribing policies. Results will be reported using appropriate Enhancing the QUAlity and Transparency Of health Research guidelines (eg, STrengthening the Reporting of OBservational studies in Epidemiology).Ethics and disseminationThis study has been approved by McGill University’s Institutional Review Board (#A11-M55-19A), and the University of British Columbia’s Research Ethics Board (#H19-03537). We will disseminate results via a combination of open access peer-reviewed journal publications, conferences, lay summaries and OpEds.

Impact of wait time from neoadjuvant chemotherapy to surgery in breast cancer: Does time to surgery affect patient outcomes? : Time from Neoadjuvant Chemotherapy to Surgery.

The optimal time interval from neoadjuvant chemotherapy (NAC) to surgery in patients with breast cancer has not been established. We investigated whether different time intervals impact the rate of pathologic complete response (pCR), disease free survival (DFS), overall survival (OS), surgical complications, and rates of conversion from mastectomy to breast conserving surgery (BCS) in this population. We identified patients who received NAC at the BC Cancer Agency followed by surgery from May 2012 to April 2018. Patients were grouped based on time interval between NAC and surgery: < 4weeks, 4-8weeks, and > 8weeks. Kaplan Meier method was used to estimate DFS and OS. Rates of pCR between the time intervals were also compared. Of the 343 patients, 78 (22.8%) received surgery < 4weeks, 233 (67.9%) received surgery between 4-8weeks, and 32 (9.3%) received surgery > 8weeks after NAC, with a median time to surgery (TTS) of 5.0weeks. pCR was observed in 32.1%, 32.2%, and 28.1%, respectively (p = 0.90). Median follow-up time was 3.3years. The 5-year DFS was 76%, 78%, and 70% (p = 0.89), respectively. The 5-year OS was 83%, 82%, and 78% (p = 0.33), respectively. No statistically significant differences were seen in surgical complications (p = 0.90), or rates of conversion from mastectomy to BCS (p = 0.19). There were no statistically significant differences in pCR, DFS, OS, surgical complications, and rates of conversion from mastectomy to BCS, among breast cancer patients receiving surgery < 4weeks, 4-8weeks, or > 8weeks after the last dose of NAC.

Sequential therapy for asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer

Abiraterone acetate (in combination with prednisone/prednisolone (abiraterone/P)), enzalutamide or docetaxel may all be used for the first-line treatment of asymptomatic or mildly symptomatic mCRPC. As treatment with docetaxel can result in the emergence of considerable adverse events, the less toxic substances abiraterone/P and enzalutamide are important alternatives. Apart from the safety and clinical effectiveness of these therapies, their optimal sequencing can play a significant role when choosing a mCRPC first-line therapy. Until recently, only retrospective trials were conducted, investigating the sequential use of abiraterone/P and enzalutamide in asymptomatic or mildly symptomatic mCRPC. However, the British Columbia Cancer Agency (BCCA) has now published results from a phase II randomised cross-over trial, which directly compared the safety and efficacy of abiraterone/P and enzalutamide in the first and second line.

Hypersensitivity reactions to biologics (part I): allergy as an important differential diagnosis in complex immune-derived adverse events*

Purpose: Biotechnological substances (BSs) are strongly relied upon to prevent rejection of transplanted organs, and to treat oncological, allergological, and other inflammatory diseases. Allergic reactions to partly foreign biologics can occur due to their potential immunogenicity. The severity of an immune response to a biological drug may range from no clinical significance to a severe, life-threatening anaphylactic reaction.Methods: Detailed searches were performed on Pubmed, Web of Science, and Google Scholar to include all available publications. In addition, the Food and Drug Administration, the European Medicines Agency, and British Columbia Cancer Agency Drug Manual databases were screened for hypersensitivity reaction (HSR), infusion reaction, injection site reaction, urticaria, and anaphylaxis for individual BSs.Results: Treatment with BSs can cause various types of HSR. These are mentioned in the literature with definitions such as allergic reactions, anaphylactoid reactions, anaphylaxis, HSR, infusion reactions, injection site reactions, cytokine release syndrome, and urticaria. Due to the overlap in signs and symptoms in the reported descriptions, it is not always possible to differentiate these reactions properly according to their pathomechanism. Similarly, many data reported as anaphylaxis actually describe severe anaphylactic reactions (grades III or IV).Conclusion: There is an urgent need for a simpler symptom- or system-based classification and scoring system to create an awareness for HSRs to BSs. A better understanding of the pathophysiology of HSRs and increased clinical experience in the treatment of side effects will provide timely control of unexpected reactions. As a result, immunotherapy with BSs will become safer in the future.Cite this as Gülsen A, Wedi B, Jappe U. Hypersensitivity reactions to biologics (part I): allergy as an important differential diagnosis in complex immune-derived adverse events. Allergo J Int 2020; 29:97-125https://doi.org/10.1007/s40629-020-00126-6.