Citations

AbstractAn unprecedented global pandemic caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) has quickly overwhelmed the health care systems worldwide. While there is an absence of consensus among the community in how to manage solid organ transplant recipients and donors, a platform provided by the American Society of Transplantation online community “Outstanding Questions in Transplantation,” hosted a collaborative multicenter, multinational discussions to share knowledge in a rapidly evolving global situation. Here, we present a summary of the discussion in addition to the latest published literature.

The early stages of the metagenomics era produced countless observational studies linking various human diseases to alterations in the gut microbiota. Only recently have we begun to decipher the causal roles that gut microbes play in many of these conditions. Despite an incomplete understanding of how gut microbes influence pathophysiology, clinical trials have tested empirically numerous microbiota-targeting therapies to prevent or treat disease. Unsurprisingly, these trials have yielded mixed results. Nonetheless, the consumer market for probiotics, prebiotics, and synbiotics continues to grow. This theme paper highlights recent discoveries of mechanisms underlying diet-microbial-host interactions as they pertain to growth and metabolism and discusses current and future applications of microbiota-targeting therapies in the context of child malnutrition as well as obesity and its metabolic comorbidities, including nonalcoholic fatty liver disease and cardiovascular disease. We also highlight current challenges and identify future directions to facilitate a more efficient and direct path to clinical impact.

PURPOSENRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375 ) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802.METHODSIDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates.RESULTSOf the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup.CONCLUSIONThis study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.

Abstract Background: Lung cancer remains the leading cause of cancer death worldwide, with 15% to 20% occurring in never smokers. To assess genetic determinants for prognosis among never smokers, we conducted a genome-wide investigation in the International Lung Cancer Consortium (ILCCO). Methods: Genomic and clinical data from 1,569 never-smoking patients with lung cancer of European ancestry from 10 ILCCO studies were included. HRs and 95% confidence intervals of overall survival were estimated. We assessed whether the associations were mediated through mRNA expression–based 1,553 normal lung tissues from the lung expression quantitative trait loci (eQTL) dataset and Genotype-Tissue Expression (GTEx). For cross-ethnicity generalization, we assessed the associations in a Japanese study (N = 887). Results: One locus at 13q22.2 was associated with lung adenocarcinoma survival at genome-wide level, with carriers of rs12875562-T allele exhibiting poor prognosis [HR = 1.71 (1.41–2.07), P = 3.60 × 10−8], and altered mRNA expression of LMO7DN in lung tissue (GTEx, P = 9.40 × 10−7; Lung eQTL dataset, P = 0.003). Furthermore, 2 of 11 independent loci that reached the suggestive significance level (P &lt; 10−6) were significant eQTL affecting mRNA expression of nearby genes in lung tissues, including CAPZB at 1p36.13 and UBAC1 at 9q34.3. One locus encoding NWD2/KIAA1239 at 4p14 showed associations in both European [HR = 0.50 (0.38–0.66), P = 6.92 × 10−7] and Japanese populations [HR = 0.79 (0.67–0.94), P = 0.007]. Conclusions: Based on the largest genomic investigation on the lung cancer prognosis of never smokers to date, we observed that lung cancer prognosis is affected by inherited genetic variants. Impact: We identified one locus near LMO7DN at genome-wide level and several potential prognostic genes with cis-effect on mRNA expression. Further functional genomics work is required to understand their role in tumor progression.

Abstract Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low‐density lipoprotein [LDL] and high‐density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels ( P < 5 × 10 −8 ) were identified as instrumental variables, and assessed using genome‐wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non‐endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non‐endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non‐endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non‐endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

Objective: Describe the outcomes of treatment for patients with cholesteatomas that are medially invasive to the otic capsule, petrous apex, and/or skull base. Study Design: Retrospective case series Setting: Two tertiary care academic centers. Patients: Patients surgically managed for medially-invasive cholesteatoma at two tertiary care institutions from 2001 to 2017. Interventions: Surgical management of medially-invasive cholesteatomas. Main Outcome Measures: The presenting symptoms, imaging, pre- and post-operative clinical course, and complications were reviewed. Results: Seven patients were identified. All patients had pre-operative radiographic evidence of invasive cholesteatoma with erosion into the otic capsule beyond just a lateral semicircular canal fistula. Five patients had a complex otologic history with multiple surgeries for recurrent cholesteatoma including three with prior canal wall down mastoidectomy surgeries. Average age at the time of surgery was 41.3 years (range 20-83). Two patients underwent a hearing preservation approach to the skull base while all others underwent a surgical approach based on the extent of the lesion. Facial nerve function was maintained at the pre-operative level in all but one patient. No patient developed cholesteatoma recurrence. Conclusions: The medially-invasive cholesteatoma demonstrates an aggressive, endophytic growth pattern, invading into the otic capsule or through the perilabyrinthine air cells to the petrous apex. Surgical resection remains the best treatment option for medially-invasive cholesteatoma. When CSF leak is a concern, a subtotal petrosectomy with closure of the ear is often necessary.

We performed a retrospective study of our large patient cohort aiming to examine the ability to predict postthyroidectomy hypocalcemia. A retrospective review of patients who underwent total or near-total thyroidectomy at our institution between 2008 and 2018 was performed. Postoperative hypocalcemia was defined as Ca level <8.0 mg/dL (reference range: 8.9–10.1 mg/dL) within 30 days of operation. Logistic regression was used to develop models for prediction of the occurrence of postoperative hypocalcemia. Inclusion criteria were met by 1463 patients. Hypocalcemia was documented in 223 patients (15%). Models based on parathyroid hormone (PTH) levels alone had an associated receiver operator characteristic with an areas under the curve (AUC) of 0.79. There was an inverse relationship between time of measurement and PTH levels within the first two hours after thyroidectomy ( P < 0.01). When measured two to six hours after closure, the predictive ability of PTH compared favorably (AUC = 0.82) with either earlier (within the first two hours after closure, AUC = 0.79) or later measurement (6–24 hours after closure, AUC = 0.77). When measured between two and six hours postoperatively, PTH < 19 pg/mL had a sensitivity of 90 per cent and negative predictive value of 96 per cent for postoperative hypocalcemia. The model that included the PTH level, concurrently measured total blood calcium level, and time of measurement had an improved predictive ability with an AUC of 0.87. PTH level of 19 pg/mL measured two to six hours after thyroidectomy had a sensitivity of 90 per cent and a negative predictive value of 96 per cent in our cohort. The model including postoperative PTH level, calcium level, and time of measurement may further improve the ability to predict postthyroidectomy hypocalcemia.

Primary hyperparathyroidism is the most common cause of hypercalcemia. Follow-up can be resource-intensive and costly. The aim of this study was to determine if there is a subset of patients who can be defined cured earlier than six months. This was a retrospective study of patients who underwent parathyroidectomy between January 2012 and March 2014. Patients with a history of multiple endocrine neoplasia syndrome, and secondary or tertiary hyperparathyroidism were excluded. Patients with normal preoperative calcium and parathyroid hormone (PTH) and those without six months follow-up were excluded. Patients were divided into two groups: cured and not cured. Data analysis was performed between the two groups. A total of 509 patients were screened, and 214 met our inclusion criteria: 202 in the cured category and 12 in the not cured category (94% cure rate). There was no significant difference between age, gland weight, or pre-operative PTH. There was a statistically significant difference between final intraoperative PTH (IOPTH) (37 vs 55, P = 0.008) and per cent PTH decrease (69 vs 43%, P < 0.0001). There was a significant difference between intraoperative cure rate (P < 0.0006), imaging concordance (P = 0.0115), and solitary versus multiglandular disease (P = 0.0151). Subgroup analysis in patients with concordant imaging, solitary parathyroid adenoma, and IOPTH decrease by 50 per cent to normal or near-normal correlated with a six-month cure rate of 97 per cent. Patients with primary hyperparathyroidism with concordant imaging, single-adenoma pathology, and IOPTH decrease by 50 per cent to normal or near-normal levels (15–65 pg/mL) can be considered cured and may need less frequent follow-up.

Abstract Background: Earlier cancer detection could identify tumors when they are more treatable and thus may improve clinical outcomes. A blood-based multicancer early detection test using circulating tumor cell-free DNA (cfDNA) offers the potential to address this unmet need. Our previous discovery work identified whole-genome bisulfite sequencing as outperforming whole-genome and targeted sequencing approaches for multicancer detection across stages. We thus developed a targeted methylation (TM) assay for multicancer detection and tissue-of-origin (TOO) localization. Methods: Participants were from the Circulating Cell-free Genome Atlas (CCGA; NCT02889978) and STRIVE (NCT03085888) studies, both prospective, multicenter, observational studies with longitudinal follow-up. cfDNA samples spanning &gt;20 cancer types of all stages were divided into a cross-validated training set and an independent validation set; there were 3,583 evaluable samples in training (1,530 cancer; 2,053 noncancer) and 1,803 in validation (678 cancer; 1,125 noncancer). Performance in a prespecified set of 12 high-signal cancers was also reported (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach). This multicancer early detection test evaluated cfDNA for the presence of cancer and localization of TOO; the TM classifier was trained to target &gt;99% specificity. Precision was defined as the fraction of correct calls. Results: Participants with and without cancer were similar in age. Specificity across all cancer types in the training and validation sets was 99.8% (95% CI, 99.2-99.9%) and 99.3% (98.3-99.8%), respectively, which reflects a consistent (P=0.292) false positive rate of &lt;1%. Across all cancer types, aggregate sensitivity was also consistent between the training and validation sets (55% [53-58%] and 55% [51-59], respectively; P=0.897). In the validation set, aggregate sensitivity in the prespecified group was 76% (73-78%); detection was 39% (27–52%) in stage I (n=62), 69% (56–80%) in stage II (n=62), 83% (75–90%) in stage III (n=102), and 92% (86–96%) in stage IV (n=130). Overall, the classifier assigned a TOO across &gt;20 cancer types in 96% of samples (344/359); of these, the TOO was correct in 93% (321/344) of cases, which was consistent with training set analyses. Conclusions: This multicancer early detection test detected cancer signal across &gt;20 cancer types with a single, fixed, low false positive rate and highly accurate TOO localization. Importantly, results in the independent validation set were consistent with the training set, demonstrating the robustness of machine learning classifier training, and confirms that data were not overfitted. These data support the feasibility of a single blood-based test that can detect multiple cancers, supporting further clinical development in preparation for the return of results. Citation Format: Anne-Renee Hartman, Geoffrey Oxnard, Eric Klein, Michael Seiden, Earl Hubbell, Oliver Venn, Arash Jamshidi, Nan Zhang, John Beausang, Samuel Gross, Kathryn Kurtzman, Eric Fung, Brian Allen, Alexander Fields, Hai Liu, Mikkael Sekeres, Donald Richards, Peter Yu, Alexander Aravanis, Minetta Liu. Multicancer detection of early-stage cancers with simultaneous tissue localization using a plasma cfDNA-based targeted methylation assay [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr IA02.

Purpose: Well-differentiated neuroendocrine or carcinoid tumors are found most commonly in the gastrointestinal tract. When metastatic to the orbit, they tend to have a propensity for the extraocular muscles. The purpose of this study was to better understand the diversity in presentation of orbital carcinoid disease and to determine predictors for survival. Methods: In this observational cross-sectional cohort study, data from 8 tertiary orbital practices were compiled. Demographic, clinical, pathologic, American Joint Committee on Cancer stage and grade, imaging, and management data were extracted for all the patients. Descriptive statistics were calculated. Subgroups were compared utilizing analysis of variance analyses and Kaplan–Meier curves. Time to progression and disease-specific and overall mortality were calculated. Comparisons were performed for the following a priori pairs: unknown versus known primary tumor, single versus multiple extraocular muscle involvement, unilateral versus bilateral orbital disease, extraocular muscle versus other orbital involvement, and excisional versus incisional surgery. Results: A total of 28 patients with carcinoid tumors of the orbit were identified. Of these, 57.1% of patients were female, the mean age at diagnosis of the primary tumor was 58.8 years and the mean age at diagnosis of orbital disease was 62.6 years. At primary presentation, all patients were American Joint Committee on Cancer stage III or IV and 21.4% demonstrated carcinoid syndrome. Muscle involvement was noted in 78.6% of patients, and of these, 72% were noted to have single muscle disease. Eight patients had no primary tumor identified; 3 of these 8 demonstrated disseminated disease at the time of diagnosis. The overall 5-year survival rate was 81.8% from diagnosis of primary tumor and 50% from diagnosis of orbital disease. Subgroup analysis revealed that patients with unilateral orbital disease when compared with bilateral orbital disease had a longer progression-free survival and time to death from all causes ( p = 0.025). Patients with disease localized to the orbit at presentation had longer time to death than those with disseminated disease. Treatment with surgery, radiation, or octreotide did not appear to affect survival. Patients managed with systemic chemotherapy had a shorter time of survival than the rest of the group. All other subgroup comparisons were not found to be statistically significant. Conclusions: Neuroendocrine tumors of the orbit represent a wide spectrum of disease, with some cases being part of disseminated disease, while others being localized presentations. This heterogeneity may be responsible for the slightly higher overall survival in these patients than others with metastatic carcinoid tumors in other locations.