Citations

Abstract Motivation Despite the increasing evidence of utility of genomic medicine in clinical practice, systematically integrating genomic medicine information and knowledge into clinical systems with a high-level of consistency, scalability and computability remains challenging. A comprehensive terminology is required for relevant concepts and the associated knowledge model for representing relationships. In this study, we leveraged PharmGKB, a comprehensive pharmacogenomics (PGx) knowledgebase, to formulate a terminology for drug response phenotypes that can represent relationships between genetic variants and treatments. We evaluated coverage of the terminology through manual review of a randomly selected subset of 200 sentences extracted from genetic reports that contained concepts for ‘Genes and Gene Products’ and ‘Treatments’. Results Results showed that our proposed drug response phenotype terminology could cover 96% of the drug response phenotypes in genetic reports. Among 18 653 sentences that contained both ‘Genes and Gene Products’ and ‘Treatments’, 3011 sentences were able to be mapped to a drug response phenotype in our proposed terminology, among which the most discussed drug response phenotypes were response (994), sensitivity (829) and survival (332). In addition, we were able to re-analyze genetic report context incorporating the proposed terminology and enrich our previously proposed PGx knowledge model to reveal relationships between genetic variants and treatments. In conclusion, we proposed a drug response phenotype terminology that enhanced structured knowledge representation of genomic medicine. Supplementary information Supplementary data are available at Bioinformatics online.

AbstractBackgroundParallel‐opposed lateral beams are the conventional beam arrangements in proton therapy for prostate cancer. However, when considering linear energy transfer (LET) and RBE effects, alternative beam arrangements should be investigated.PurposeTo investigate the dose and dose averaged LET (LETd) impact of using new beam arrangements rotating beams 5°–15° posteriorly to the laterals in prostate cancer treated with pencil‐beam‐scanning (PBS) proton therapy.MethodsTwenty patients with localized prostate cancer were included in this study. Four proton treatment plans for each patient were generated utilizing 0°, 5°, 10°, and 15° posterior oblique beam pairs relative to parallel‐opposed lateral beams. Dose‐volume histograms (DVHs) from posterior oblique beams were analyzed. Dose‐LETd‐volume histogram (DLVH) was employed to study the difference in dose and LETd with each beam arrangement. DLVH indices, , defined as the cumulative absolute volume that has a dose of at least d (Gy[RBE]) and a LETd of at least l (keV/µm), were calculated for both the rectum and bladder to the whole group of patients and two‐sub groups with and without hydrogel spacer. These metrics were tested using Wilcoxon signed‐rank test.ResultsRotating beam angles from laterals to slightly posterior by 5°–15° reduced high LETd volumes while it increased the dose volume in the rectum and increased LETd in bladders. Beam angles rotated five degrees posteriorly from laterals (i.e., gantry in 95° and 265°) are proposed since they achieved the optimal balance of better LETd sparing and minimal dose increase in the rectum. A reduction of V(50 Gy[RBE], 2.6 keV/µm) from 7.41 to 3.96 cc (p < 0.01), and a slight increase of V(50 Gy[RBE], 0 keV/µm) from 20.1 to 21.6 cc (p < 0.01) were observed for the group without hydrogel spacer. The LETd sparing was less effective for the group with hydrogel spacer, which achieved the reduction of V(50 Gy[RBE], 2.6 keV/µm) from 4.28 to 2.10 cc (p < 0.01).ConclusionsPosterior oblique angle plans improved LETd sparing of the rectum while sacrificing LETd sparing in the bladder in the treatment of prostate cancer with PBS. Beam angle modification from laterals to slightly posterior may be a strategy to redistribute LETd and perhaps reduce rectal toxicity risks in prostate cancer patients treated with PBS. However, the effect is reduced for patients with hydrogel spacer.

Abstract Purpose: In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors. Patients and Methods: ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 mg/kg nivolumab plus 3 mg/kg ipilimumab) in Ewing sarcoma and rhabdomyosarcoma. Tumor response was measured using RECIST v1.1. Pharmacokinetics and PD-L1 expression on archival tissues were assessed. Results: Fifty-five eligible patients enrolled. Based on safety, tolerability, and similar drug exposure to the same doses administered in adults, DL2 was defined as the pediatric RP2D. Among 41 patients treated at the RP2D, 2 patients experienced dose-limiting toxicities during cycle 1, and 4 patients experienced toxicities beyond that period. Two patients had clinically significant sustained partial responses (1 rhabdomyosarcoma, 1 Ewing sarcoma) and 4 had stable disease. Among 8 patients treated at DL3, 3 dose-limiting toxicities (DLT) occurred, all immune-related adverse events; no objective responses were observed. Conclusions: The RP2D of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) is well tolerated in children and young adults with solid tumors and shows some clinical activity. Increased dose of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) was associated with increased toxicity without clinical benefit.

AbstractBackgroundThe current risk stratification system defined by clinicopathological features does not identify the risk of recurrence in early-stage (stage I-II) colorectal cancer (CRC) with sufficient accuracy. We aimed to investigate whether DNA methylation could serve as a novel biomarker for predicting prognosis in early-stage CRC patients.MethodsWe analyzed the genome-wide methylation status of CpG loci using Infinium MethylationEPIC array run on primary tumor tissues and normal mucosa of early-stage CRC patients to identify potential methylation markers for prognosis. The machine-learning approach was applied to construct a DNA methylation–based prognostic classifier for early-stage CRC (MePEC) using the 4 gene methylation markers FAT3, KAZN, TLE4, and DUSP3. The prognostic value of the classifier was evaluated in 2 independent cohorts (n = 438 and 359, respectively).ResultsThe comprehensive analysis identified an epigenetic subtype with high risk of recurrence based on a group of CpG loci in the CpG-depleted region. In multivariable analysis, the MePEC classifier was independently and statistically significantly associated with time to recurrence in validation cohort 1 (hazard ratio = 2.35, 95% confidence interval = 1.47 to 3.76, P &lt; .001) and cohort 2 (hazard ratio = 3.20, 95% confidence interval = 1.92 to 5.33, P &lt; .001). All results were further confirmed after each cohort was stratified by clinicopathological variables and molecular subtypes.ConclusionsWe demonstrated the prognostic statistical significance of a DNA methylation profile in the CpG-depleted region, which may serve as a valuable source for tumor biomarkers. MePEC could identify an epigenetic subtype with high risk of recurrence and improve the prognostic accuracy of current clinical variables in early-stage CRC.

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of international experts to discuss new research opportunities for the prevention, detection, and intervention of myocarditis in May 2021. These experts reviewed the current state of science and identified key gaps and opportunities in basic, diagnostic, translational, and therapeutic frontiers to guide future research in myocarditis. In addition to addressing community-acquired myocarditis, the workshop also focused on emerging causes of myocarditis including immune checkpoint inhibitors and SARS-CoV-2 related myocardial injuries and considered the use of systems biology and artificial intelligence methodologies to define workflows to identify novel mechanisms of disease and new therapeutic targets. A new priority is the investigation of the relationship between social determinants of health (SDoH), including race and economic status, and inflammatory response and outcomes in myocarditis. The result is a proposal for the reclassification of myocarditis that integrates the latest knowledge of immunological pathogenesis to refine estimates of prognosis and target pathway-specific treatments.

Context.— Plasmablastic lymphoma (PBL) is a rare aggressive lymphoma, usually positive for CD138 and frequently occurring in the oral cavity of human immunodeficiency virus (HIV) patients. Up to 10% of cases are negative for CD138 and diagnostically very challenging. Objective.— To investigate the appropriate approach to diagnose CD138− plasmablastic lymphoma and avoid misdiagnosis. Design.— We studied 21 cases of CD138− PBL from multiple large institutes in the United States and 21 cases from the literature. Results.— CD138− PBLs were positive for different B/plasma cell markers at various percentages: MUM1 (94.4%; 34 of 36), OCT2 (70.6%; 12 of 17), immunoglobulin light chains (68.8%; 22 of 32), CD38 (68.4%; 13 of 19), CD79a (34.2%; 13 of 38), and PAX5 (15.6%; 5 of 32), suggesting that MUM1, OCT2, immunoglobulin light chains, and CD38 are useful markers to help establish the lineage. A total of 83% of cases (30 of 36) were extraoral lesions. Extraoral lesions showed much lower Epstein-Barr virus (EBV) infection rates (16 of 30; 53.3%) and had worse prognosis. MYC was positive in 80% (8 of 10) of EBV+ cases and 40% (2 of 5) EBV− cases, indicating the importance of MYC in pathogenesis, especially in EBV+ cases. Conclusions.— Our study emphasizes that CD138− PBLs tend to be extraoral lesions, with much lower EBV infection rates, and diagnostically very challenging. Accurate diagnosis requires a thorough investigation and workup by using appropriate markers.

Abstract Lisocabtagene maraleucel (liso-cel) has shown promising efficacy in clinical trials for patients with relapsed/refractory large B-cell lymphoma (LBCL). We present health-related quality of life (HRQOL) results from the TRANSFORM study, the first comparative analysis of liso-cel vs standard of care (SOC) as second-line therapy in this population. Adults with LBCL refractory or relapsed ≤12 months after first-line therapy and eligible for autologous stem cell transplantation were randomized 1:1 to the liso-cel or SOC arms (3 cycles of immunochemotherapy in which responders proceeded to high-dose chemotherapy and autologous stem cell transplantation). HRQOL was assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – 30 items and the Functional Assessment of Cancer Therapy-Lymphoma subscale. Patients with baseline and ≥1 postbaseline assessment were analyzed (liso-cel, n = 47; SOC, n = 43). The proportion of patients with meaningful improvement in global health status/quality of life (QOL) was higher, whereas deterioration was lower in the liso-cel arm vs SOC arm from day 126 to month 6. Mean change scores showed meaningful worsening in global health status/QOL at month 6, fatigue at day 29 and month 6, and pain at month 6 with SOC; mean scores for other domains were maintained or improved in both arms. Time to confirmed deterioration favored the liso-cel arm vs SOC arm in global health status/QOL (median: not reached vs 19.0 weeks, respectively; hazard ratio, 0.47; 95% confidence interval, 0.24-0.94). HRQOL was either improved or maintained from baseline in patients with relapsed/refractory LBCL in the liso-cel arm vs SOC arm as second-line treatment. This study is registered at clinicaltrials.gov as #NCT0357531.

AbstractIschemia‐reperfusion injury (IRI) refers to a syndrome in which tissue damage is further aggravated and organ function further deteriorates when blood flow is restored after a period of tissue ischemia. Acute myocardial infarction, stress ulcer, pancreatitis, intestinal ischemia, intermittent claudication, acute tubular necrosis, postshock liver failure, and multisystem organ failure are all related to reperfusion injury. AMP‐activated protein kinase (AMPK) has been identified in multiple catabolic and anabolic signaling pathways. The functions of AMPK during health and diseases are intriguing but still need further research. Except for its conventional roles as an intracellular energy switch, emerging evidence reveals the critical role of AMPK in IRI as an energy‐sensing signal molecule by regulating metabolism, autophagy, oxidative stress, inflammation, and other progressions. At the same time, drugs based on AMPK for the treatment of IRI are constantly being researched and applied in clinics. In this review, we summarize the mechanisms underlying the effects of AMPK in IRI and describe the AMPK‐targeting drugs in treatment, hoping to increase the understanding of AMPK in IRI and provide new insights into future clinical treatment.