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Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

BackgroundThere is significant interest in treatment de-escalation for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to risk stratify HPV+ OPSCC patients.MethodsWe created an immune score (UWO3) associated with survival outcomes in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes.FindingsA three-gene immune score classified patients into three immune classes (immune rich, mixed, or immune desert) and was strongly associated with disease-free survival in six datasets, including large retrospective and prospective datasets. Pooled analysis demonstrated that the immune rich group had superior disease-free survival compared to the immune desert (HR = 9.0, 95% CI: 3.2-25.5, P = 3.6 × 10-5) and mixed (HR = 6.4, 95% CI: 2.2-18.7, P = 0.006) groups after adjusting for age, sex, smoking status, and AJCC8 clinical stage. Finally, UWO3 was able to identify patients from two small treatment de-escalation cohorts who remain disease-free after aggressive de-escalation to 30 Gy radiation.InterpretationWith additional prospective validation, the UWO3 score could enable biomarker-driven clinical decision-making for patients with HPV+ OPSCC based on robust outcome prediction across six independent cohorts. Prospective de-escalation and intensification clinical trials are currently being planned.FundingCIHR, European Union, and the NIH.

Anaplastic thyroid cancer (ATC) is a rare, aggressive form of undifferentiated thyroid cancer, which exhibits rapid progression and is almost universally fatal. At least a subset of ATC is thought to arise from pre-existing well-differentiated thyroid cancer, most frequently papillary thyroid cancer (PTC). While PIK3CA mutations are rare in PTC, they are common in ATC and tend to co-occur with BRAF mutations. This provided the rationale for our study to identify the potential role of PIK3CA mutations in the progression from well-differentiated to undifferentiated thyroid cancer. We introduced PIK3CAE545K into the LAM1 PTC cell line, which carries a BRAFV600E mutation. In culture, the engineered cell line (LAM1:PIK3CAE545K) proliferated faster and demonstrated increased clonogenic potential relative to the parental line carrying an empty vector (LAM1EV). Both the LAM1EV and LAM1:PIK3CAE545K edited lines were implanted into hind flanks of athymic nude mice for in vivo determination of disease progression. While tumour weights and volumes were not significantly higher in LAM1:PIK3CAE545K mice, there was a decrease in expression of thyroid differentiation markers TTF-1, thyroglobulin, PAX8 and B-catenin, suggesting that introduction of PIK3CAE545K led to dedifferentiation in vivo. Collectively, this study provides evidence of a role for PIK3CAE545K in driving disease progression from a well-differentiated to an undifferentiated thyroid cancer; however, over-expression was not a determinant of an accelerated growth phenotype in ATC.

BackgroundNumerous studies of head and neck squamous cell carcinoma (HNSCC) have demonstrated disparate outcomes by race and ethnicity. Beyond known associations with socioeconomic variables, whether these are also associated with differences in tumor molecular composition has thus far been poorly explored.MethodsWe downloaded clinical and multiplatform molecular data from The Cancer Genome Atlas and other published studies. These were compared between non-Hispanic Black (n = 43) and White (n = 354) patients with non-HPV-related tumors, using multivariable models. Publicly available validation cohorts were used.ResultsBlack patients had poorer progression-free survival than White patients. Tumors of Black patients had greater copy number aberrations, and increased SFRP1 methylation and miRNA-mediated PRG4 silencing associated with poor survival. PI3K/AkT/mTOR pathway proteins were differentially expressed.ConclusionsThere are molecular differences between tumors of Black and White patients that may partially account for differences in survival. These may inform targeted treatment decisions to achieve equitable outcomes.

Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here, we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (Lepob/ob). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake but is instead associated with alterations in the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that gut microbial CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have potential as anti-obesity therapeutics.

Objectives: Homocysteine is an intermediary amino acid formed in methionine metabolism, with elevated total homocysteine (tHCY) being a biomarker of cardiovascular and cerebrovascular diseases. We evaluated the Abbott ARCHITECT tHCY immunoassay, compared it with the current established JEOL ion exchange chromatography (IEC) method and evaluated its clinical utility. Design and methods: Following immunoassay method verification, plasma samples of 91 patients were analysed for tHCY using immunoassay and IEC. Results: For the Abbott immunoassay, accuracy was assessed, with UK NEQAS EQA specimens, by the correlation of our Abbott immunoassay measurements to the Abbott ARCHITECT immunoassay mean (bias = 1.6%), and to the overall immunoassay mean (bias = 2.0%). The total imprecision was 2.7% (11.00 μmol/L), 2.4% (16.80 μmol/L) and 2.8% (24.30 μmol/L) respectively. Bias in linearity assessment was 0.12%–2.58%. The inter-method correlation was strong in Passing-Bablok regression: immunoassay = IEC x0.857 + 2.445 (95% CI: slope = [0.742,0.947], intercept = [1.340,3.582]), with Spearman correlation = 0.803 (p

We present the clinical course of a 4-year-old girl with neurofibromatosis type 1-associated, unresectable, symptomatic urinary bladder ganglioneuroma. She was initially trialed on sirolimus without response and subsequently responded to MEK inhibitor trametinib, with improvement clinically and radiographically over 10 months. This report broadens the repertoire of therapeutic strategies for MEK inhibition in diseases related to the MAPK pathway. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) is an aggressive primary malignant brain tumour with a dismal prognosis, despite the improvement from the new establishment of post-operative treatment protocol of concomitant chemoradiotherapy (CCRT) plus adjuvant chemotherapy. This study aimed to evaluate the health-related quality of life (HRQoL) in post-operative GBM patients treated with CCRT plus adjuvant chemotherapy with subjective standardised questionnaires at various time points. Methods: Patients with newly diagnosed GBM who were treated at our centre with post-operative CCRT plus adjuvant chemotherapy were included. Their HRQoL scales were measured with the European Organisation for Research and Treatment of Cancer (EORTC) CLC30 and BN20 questionnaires. Assessments were made before the beginning of post-operative CCRT, and at 0 (within 2 weeks), 3 and 6 months after the end of CCRT. A mixed-level linear model was used to analyse the change in each HRQoL scale over time. Results: 21 patients were recruited with a median overall survival of 27 months (range:4–55 months). There was no significant change in the global health status over time. An improvement in insomnia and an aggravation in communication deficit were found with statistical significance and clinical meaningfulness. Greater improvement in insomnia was associated with methylated MGMT gene promoter in the tumour while worse aggravation in communication deficit was associated with older age (≥65). Conclusions: The global health status did not worsen during post-operative CCRT plus adjuvant chemotherapy, while the severity of insomnia lessened and communication deficit worsened. This may provide insight for clinicians to formulate treatment plan for patients with GBM.

Introduction: While anterior cruciate ligament (ACL) tears are commonly managed with ACL reconstruction (ACL-R), 35% of ACL-R individuals fail to return to the preinjury elite sport level. Persistent neuromuscular deficits in the hamstrings and quadriceps have been observed. It has been proposed that aquatic therapy can be used to optimize neuromuscular control after ACL-R. Objectives: (1) To compare muscle activity in ACL-R individuals during aquatic treadmill (ATM) running at different water depths and (2) to compare muscle activity during ATM running between ACL-R and healthy individuals. Methods: A total of 38 participants, including 18 ACL-R individuals (mean postoperative time [SD] = 25.8 [25.0] mo) and 20 healthy individuals were recruited. Muscle activity of biceps femoris (BF), rectus femoris (RF), tibialis anterior, and medial gastrocnemius during land treadmill and ATM running at mid-shin, mid-thigh, and waist levels were recorded using surface electromyography (sEMG). The sEMG signals of the selected muscles were normalized and expressed in % Maximal Voluntary Contraction (%MVC). Muscle activity of the ACL-R, ACL-contralateral, and healthy control limbs at different water depths was compared. Results: Among the 3 groups, the ACL-R group demonstrated the most prominent percentage increase of 101.97% (P = .001) at mid-shin level, 139.66% (P = .001) at mid-thigh level, and 141.97% (P < .001) at waist level, respectively, in %MVC when compared to land. In the ACL-R group, muscle activity of BF in the stance phase (BFSt) was significantly higher than the control group on land at all water depths. Muscle activity of RF in the swing phase (RFSw) in the ACL-R group significantly increased in all water depths immersion when compared to land, respectively. Conclusion: This study showed an increasing trend in muscle activity of BFSt and RFSw in ACL-R individuals during ATM running at increased water depths. ATM running could be implemented as neuromuscular training in rehabilitation after ACL-R. [ABSTRACT FROM AUTHOR]

Background: We aimed to analyze and compare the timing and patterns of treatment failure, and survival after progression between HPV‐positive (HPV+) and HPV‐negative (HPV−) patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas (OPSCC). Methods: A retrospective review was performed of all patients undergoing primary chemoradiation for OPSCC between 2008 and 2021. Demographic and clinical data were collected. Kaplan–Meier estimates for overall survival (OS), and time to recurrence/metastases (TTR) were compared using the log‐rank test, with Cox regression used for multivariable modeling comparing HPV+ and HPV− patients. Results: HPV− patients developed recurrence or metastases at earlier time points than HPV+ patients (8.8 vs. 15.2 months, p < 0.05), due to earlier local/locoregional recurrence and distant metastases, but not isolated regional recurrences. HPV− distant metastases exclusively occurred in a single organ, most commonly the lungs or bone, while HPV+ metastases frequently had multi‐organ involvement in a wide variety of locations (p < 0.05). Once progression (recurrence/metastases) was diagnosed, HPV+ patients experienced superior survival to HPV− patients on univariate and multivariate analysis, largely due to improved outcomes after treatment of local/locoregional recurrences (p < 0.05). There were no differences in survival after isolated regional recurrences or distant metastases. Conclusion: HPV+ OPSCC patients relapse later compared to HPV− patients in local/locoregional and distant sites. HPV+ patients with local/locoregional recurrence experience superior survival after recurrence, which does not hold true for isolated regional recurrences or distant metastases. These data can be useful to inform prognosis and guide treatment decisions in patients with recurrent OPSCC. [ABSTRACT FROM AUTHOR]