Citations

The NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as “preferred interventions,” whereas others are categorized as either “other recommended interventions” or “useful under certain circumstances.”

AbstractDistal biliary strictures (DBS) are common and may be caused by both malignant and benign pathologies. While endoscopic procedures play a major role in their management, a comprehensive review of the subject is still lacking. Our consensus statements were formulated by a group of expert Asian pancreatico‐biliary interventional endoscopists, following a proposal from the Digestive Endoscopy Society of Taiwan, the Thai Association for Gastrointestinal Endoscopy, and the Tokyo Conference of Asian Pancreato‐biliary Interventional Endoscopy. Based on a literature review utilizing Medline, Cochrane library, and Embase databases, a total of 19 consensus statements on DBS were made on diagnosis, endoscopic drainage, benign biliary stricture, malignant biliary stricture, and management of recurrent biliary obstruction and other complications. Our consensus statements provide comprehensive guidance for the endoscopic management of DBS.

Objective IgG4‐related disease (IgG4‐ RD ) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serologic, radiologic, and pathologic data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4‐ RD . Methods An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology ( ACR ) and the European League Against Rheumatism ( EULAR ). Investigators used consensus exercises, existing literature, derivation and validation cohorts of 1,879 subjects (1,086 cases, 793 mimickers), and multicriterion decision analysis to identify, weight, and test potential classification criteria. Two independent validation cohorts were included. Results A 3‐step classification process was developed. First, it must be demonstrated that a potential IgG4‐ RD case has involvement of at least 1 of 11 possible organs in a manner consistent with IgG4‐ RD . Second, exclusion criteria consisting of a total of 32 clinical, serologic, radiologic, and pathologic items must be applied; the presence of any of these criteria eliminates the patient from IgG4‐ RD classification. Third, 8 weighted inclusion criteria domains, addressing clinical findings, serologic results, radiology assessments, and pathology interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% confidence interval [95% CI ] 97.2–99.8%) and a sensitivity of 85.5% (95% CI 81.9–88.5%). In the second, the specificity was 97.8% (95% CI 93.7–99.2%) and the sensitivity was 82.0% (95% CI 77.0–86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. Conclusion ACR / EULAR classification criteria for IgG4‐ RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiologic, and basic science investigations.

Key Points A mixed methods study of surveys, interviews, and focus groups raises concerns about the state of the adult hematology workforce. Hematology/oncology fellowship program directors, fellows, and practicing clinicians offer different strategies to address these problems.

Abstract Waldenströms Macroglobulinemia (WM) is a unique form of lymphoplasmacytic lymphoma, in which the tumor compartment is comprised of B-lymphocytes, plasmacytoid lymphocytes and plasma cells. The majority of WM cases are immunophenotypically characterized by expression of surface antigens that are present on both B-cells (CD19/20) and plasma cells (CD38/138). However, in advanced stage disease, which has been treated with various chemoimmunotherapeutics the molecular profile of WM cells can drastically shift resulting in a majority of the WM tumor compartment exhibiting loss of CD20 and concurrent upregulation of atypical surface antigens (Barakat et al, Am J Clin Pathol 2011; Morice et al Mod Pathol 2009). These external immunophenotypic changes are associated with underlying epigenetic and genomic alterations, whose integrated study may provide further insight into the biology of advanced stage WM. Moreover, such an analysis holds clinical potential by uncovering of therapeutic vulnerabilities, which can direct the selection of appropriate therapeutics for patients with CD20- WM. With this in mind, we conducted comprehensive molecular testing coupled with functional studies to understand if underlying genomic/epigenetic changes correlated with drug sensitivity using appropriate preclinical models of CD20+ WM (BCWM.1 cell line) and CD20- WM (RPCI-WM1 cell line). Importantly, the index patient from whom the CD20- cells were developed had received a total of 6 lines of treatment, two of which contained rituximab and was documented as being refractory to rituximab. Immunophenotyping of CD20- cells showed differential downregulation of 19 and upregulation of 7 CD antigens relative to CD20+ WM cells (cutoff at 1.5 fold; >20% gated expression). Upregulated antigens were associated with a phenotype reminiscent of a memory B-cell with plasmacytoid features. Next, we conducted RNA-Seq analysis (Illumina HiSeq), which revealed downregulation of 6,673 and upregulation of 4,594 genes (>1.5 fold cutoff) in CD20- WM cells compared with CD20+ cells. Gene pathway enrichment analysis (NextBio, Illumina Inc.) of mRNA differentially expressed in CD20- cells showed significant enrichment of upregulated genes corresponding to Protein Transport (p<1.8E-98) and Response to Unfolded Protein Gene Ontology groups (p<5.9E-20). Interestingly, pathway analysis of downregulated genes in CD20- WM cells showed enrichment within the B-cell receptor-signaling (BCR) pathway (Broad MSigDB) (p<6.1E-14) relative to CD20+ WM cells. BCR signaling has been linked to dysregulated expression of several micro-RNAs (miRs). Consistent with pathway analysis results, we observed decreased levels of numerous miRs (Exiqon qPCR) in CD20- vs. CD20+ WM cells, which target and regulate components involved in BCR activation. To examine further epigenetic changes that may account for decreased BCR signaling, we examined the global methylation profile (Infinium HumanMethylation 450K array) of CD20- and CD20+ WM cells and noted hypermethylation of the promoter sites (200 base pairs upstream) for a number of transcription factors involved in the BCR pathway. We therefore examined sensitivity of CD20- WM cells to the BTK inhibitor ibrutinib, which abrogates BCR signaling. As anticipated, CD20- WM cells retained >90% viability and demonstrated significantly less apoptosis in presence of ibrutinib (4uM) compared to CD20+ cells, suggesting decreased reliance on canonical BCR signaling for survival. In parallel and guided by pathway analysis results, we exposed both CD20- and CD20+ WM cells to a novel 19S proteasome inhibitor (VLX1570), which caused profound proteotoxicity and ER stress at concentrations ranging between 250 – 500nM. We noted CD20- cells were significantly more sensitive (p<0.01) to 19S proteasome inhibition than CD20+ WM cells indicating the formers critical dependence on tightly regulated protein homeostasis. In summary we describe for the first time, a comprehensive molecular and immunophenotypic investigation of CD20- WM cells compared to CD20+ WM cells, using validated preclinical models of the two disease phenotypes. Overall our data suggests significant architectural differences between CD20+ and CD20- WM, which can potentially impact the behavior of the cells and their sensitivity towards novel therapeutics being developed for treatment of advanced stage WM. Disclosures Martin: Janssen: Honoraria.

INTRODUCTION: Mucosal healing is a widely accepted target for ulcerative colitis (UC) treatment. Linked color imaging (LCI) is a novel endoscopic enhancement system that utilizes Light Emitting Diode (LED) sources to spectrally enhance subtle erythema and mucosal surface patterns which may improve endoscopic classification of IBD associated inflammation. We aimed to assess the accuracy of LCI in classifying UC-associated mucosal healing compared to a validated histological reference standard (Geboes score). METHODS: 22 patients with ulcerative colitis were prospectively enrolled and evaluated by LCI colonoscopy using the Fujifilm’s digital video Processor VP-7000 and LED light source BL-7000 (Fujifilm, Tokyo Japan). Interobserver agreement was reported as kappa values. Geboes score was reported as score range of 0 to 5.4. A Geboes score of ≥3.1 (presence of surface intraepithelial neutrophils or < 5% crypts) was used to define histologic activity and a score of < 2B (no increase in neutrophils in the lamina propria) was used to define histologic remission. Geboes score has been previously validated to predict clinical recurrence. We calculated the overall accuracy, positive predictive value (PPV) and negative predictive value (NPV) of the LCI classification identifying mucosal healing against the Geboes score using the Fisher’s exact test. RESULTS: Total of 62 endoscopic images were obtained for different parts of the colon, 43 of which were matched to a corresponding biopsy. Endoscopic images were scored by 2 endoscopists into LCI-A (no redness), LCI-B (redness with visible vessels) and LCI-C (redness without visible vessels). A final LCI score was given for images with discrepant scores based on a consensus vote from both endoscopists. The interobserver agreement between the two endoscopists was 81%, kappa of 0.71 (95% confidence interval [CI] 0.57- 0.86). Among regions scored ≥3.1 on Geboes score, 9.5%, 28.6% and 61.9 % were classified as LCI-A, LCI-B and LCI-C, respectively ( P < 0.0001). Among images scored < 2B on Geboes score, 81.8%, 13.6% and 4.6% were classified as LCI-A, LCI-B and LCI-C, respectively ( P < 0.0001). Analyzing data against histology with LCI-A representing mucosal healing and LCI-B and C representing active mucosal disease, the overall accuracy becomes 86%, with NPV of 82.6% and PPV of 90% for identifying UC patients with histological and endoscopic evidence of mucosal healing. CONCLUSION: LCI technology has a potential role in assessing mucosal healing in UC.