Citations

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of most lethal malignancies with few known risk factors and biomarkers. Identification of disease biomarkers is critical for understanding the pathogenesis of this cancer and identifying high risk individuals for close surveillance. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers usually in small samples. To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, by using genetic instruments. Protein quantitative trait loci (pQTLs) for 1,226 plasma proteins identified in a large INTERVAL study of 3,301 healthy European descendants were used as instruments to evaluate associations between genetically predicted protein levels and PDAC. For proteins showing a significant association, we further conducted conditional analysis with adjustments for previously identified risk variants to assess whether the observed associations between genetically predicted protein concentrations and PDAC risk were independent of the risk variants identified in genome-wide association studies (GWAS). Furthermore, for the proteins that were associated with PDAC risk, we performed an enrichment analysis of the genes encoding these proteins to examine whether they are enriched in specific pathways, functions or networks. We observed associations between predicted concentrations of 38 proteins and PDAC risk at a false discovery rate of < 0.05, including those of 23 proteins that showed a significant association even after Bonferroni correction (4.08 × 10−5). These include Histo-blood group ABO system transferase encoded by ABO, which has been previously implicated as a potential target gene of PDAC risk variant identified in GWAS. Eight of the identified proteins (Beta-crystallin B2, Dedicator of cytokinesis protein 9, VIP36-like protein, Erythrocyte band 7 integral membrane protein, Tensin-2, Transmembrane protease serine 11D, Alcohol dehydrogenase 1B, and C-X-C motif chemokine 10) were associated with PDAC risk after conditioning on previously reported pancreatic cancer risk variants (odds ratios ranged from 0.79 to 1.52, P-values from 1.28 × 10−3 to 6.47 × 10−4). Pathway enrichment analysis showed that the encoding genes for the implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL-15 production. In conclusion, we identified 38 protein biomarker candidates for PDAC risk, which if validated by additional studies, may contribute to the etiological understanding of PDAC tumor development. Citation Format: Jingjing Zhu, Xiang Shu, Xingyi Guo, Duo Liu, Jiandong bao, Roger Milne, Graham G Giles, Chong Wu, Mengmeng Du, Emily White, Harvey A Risch, Nuria Malats, Eric J. Duell, Phyllis J. Goodman, Donghui Li, Paige Bracci, Verena Katzke, Rachel E Neale, Steven Gallinger, Stephen Van Den Eeden, Alan Arslan, Federico Canzian, Charles Kooperberg, Brian Wolpin, Laura Beane-Freeman, Ghislaine Scelo, Kala Visvanatha, Christopher A. Haiman, Loïc Le Marchand, Herbert Yu, Gloria M Petersen, Rachael Stolzenberg-Solomon, Alison P Klein, Laufey T Amundadottir, Qiuyin Cai, Jirong Long, Xiao-Ou Shu, Wei Zheng, Lang Wu. Associations between genetically predicted blood protein biomarkers and pancreatic ductal adenocarcinoma risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1200.

Abstract Background It is unclear how the Health Insurance Portability and Accountability Act (HIPAA) should be interpreted in the context of sharing of genomic information between family members. Methods The authors analyzed the HIPAA Privacy Rule, reviewed the literature and constructed a clinical scenario to inform how HIPAA can be interpreted for multiple forms of patient- and provider-mediated genetic risk notification. Results Under HIPAA, healthcare providers can lawfully notify relatives to recommend genetic risk assessment using multiple approaches, including supporting the patient telling their own relatives, contacting relatives directly with the patient’s authorization, or contacting a relative’s provider directly. Conclusions Multiple forms of patient- or provider-mediated contact of relatives are already legally permissible under HIPAA, are consistent with ethical obligations of care to patients and their families, and could result in improved population health through identification of clinically actionable disease risk. Unanswered questions remain about implementation and impacts of provider-mediated programs.

This combined American Neurotology Society, American Otological Society, and American Academy of Otolaryngology – Head and Neck Surgery Foundation document aims to provide guidance during the coronavirus disease of 2019 (COVID-19) on 1) “priority” of care for otologic and neurotologic patients in the office and operating room, and 2) optimal utilization of personal protective equipment. Given the paucity of evidence to inform otologic and neurotologic best practices during COVID-19, the recommendations herein are based on relevant peer-reviewed articles, the Centers for Disease Control and Prevention COVID-19 guidelines, United States and international hospital policies, and expert opinion. The suggestions presented here are not meant to be definitive, and best practices will undoubtedly change with increasing knowledge and high-quality data related to COVID-19. Interpretation of this guidance document is dependent on local factors including prevalence of COVID-19 in the surgeons’ local community. This is not intended to set a standard of care, and should not supersede the clinician's best judgement when managing specific clinical concerns and/or regional conditions. Access to otologic and neurotologic care during and after the COVID-19 pandemic is dependent upon adequate protection of physicians, audiologists, and ancillary support staff. Otolaryngologists and associated staff are at high risk for COVID-19 disease transmission based on close contact with mucosal surfaces of the upper aerodigestive tract during diagnostic evaluation and therapeutic procedures. While many otologic and neurotologic conditions are not imminently life threatening, they have a major impact on communication, daily functioning, and quality of life. In addition, progression of disease and delay in treatment can result in cranial nerve deficits, intracranial and life-threatening complications, and/or irreversible consequences. In this regard, many otologic and neurotologic conditions should rightfully be considered “urgent,” and almost all require timely attention to permit optimal outcomes. It is reasonable to proceed with otologic and neurotologic clinic visits and operative cases based on input from expert opinion of otologic care providers, clinic/hospital administration, infection prevention and control specialists, and local and state public health leaders. Significant regional variations in COVID-19 prevalence exist; therefore, physicians working with local municipalities are best suited to make determinations on the appropriateness and timing of otologic and neurotologic care.

AbstractBackgroundSpinal cord stimulation (SCS) has been shown to provide pain relief for chronic back and leg pain due to failed back surgery syndrome. But many patients with chronic back pain have not had major back surgery or are not good candidates for surgery, and conventional medical management (CMM) provides limited relief. We have termed this condition nonsurgical refractory back pain (NSRBP). Level 1 evidence does not yet exist showing the therapeutic benefit of SCS for NSRBP.ObjectiveTo compare 10‐kHz SCS plus CMM (10‐kHz SCS + CMM) to CMM alone for treatment of NSRBP in terms of clinical and cost effectiveness.Study DesignMulticenter, randomized controlled trial (RCT), with subjects randomized 1:1 to either 10‐kHz SCS + CMM or CMM alone. Optional crossover occurs at 6 months if treatment does not achieve ≥50% pain relief.MethodsPatients with NSRBP as defined above may be enrolled if they are ineligible for surgery based on surgical consultation. Subjects randomized to 10‐kHz SCS + CMM will receive a permanent implant if sufficient pain relief is achieved in a temporary trial. Both groups will receive CMM per standard of care and will undergo assessments at baseline and at follow‐ups to 12 months. Self‐report outcomes include pain, disability, sleep, mental health, satisfaction, healthcare utilization, and quality of life.ResultsEnrollment was initiated on September 10, 2018. Prespecified independent interim analysis at 40% of the enrollment target indicated the sample size was sufficient to show superiority of treatment at the primary endpoint; therefore, enrollment was stopped at 211.ConclusionsThis large multicenter RCT will provide valuable evidence to guide clinical decisions in NSRBP.

Abstract Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65–1.04)] but not BRAF-wildtype tumors [1.09 (0.97–1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case–control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (Ptrend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. Significance: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.

Context.— One goal of the joint College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee is to ensure the accurate detection and description of chromosomal abnormalities in both constitutional and neoplastic specimens, including hematologic neoplasms. Objective.— To report a 20-year performance summary (1999–2018) of conventional chromosome challenges focusing on hematologic neoplasms. Design.— A retrospective review was performed from 1999 through 2018 to identify karyotype challenges specifically addressing hematologic neoplasms. The overall performance of participants was examined to identify potential recurring errors of clinical significance. Results.— Of 288 total conventional chromosome challenges from 1999–2018, 87 (30.2%) were presented in the context of a hematologic neoplasm, based on the provided clinical history, specimen type, and/or chromosomal abnormalities. For these 87 hematologic neoplasm challenges, 91 individual cases were provided and graded on the basis of abnormality recognition and karyotype nomenclature (ISCN, International System for Human Cytogenomic [previously Cytogenetic] Nomenclature). Of the 91 cases, 89 (97.8%) and 87 (95.6%) exceeded the required 80% consensus for grading of abnormality recognition and correct karyotype nomenclature, respectively. The 2 cases (2 of 91; 2.2%) that failed to meet the 80% consensus for abnormality recognition had complex karyotypes. The 4 cases (4 of 91; 4.4%) that failed to meet the 80% consensus for correct karyotype nomenclature were the result of incorrect abnormality recognition (2 cases), missing brackets in the karyotype (1 case), and incorrect breakpoint designation (1 case). Conclusions.— This 20-year review demonstrates clinical cytogenetics laboratories have been and continue to be highly proficient in the detection and description of chromosomal abnormalities associated with hematologic neoplasms.

View Video S1