Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions.

Many cancers are characterized by gene fusions encoding oncogenic chimeric transcription factors (TFs) such as EWS::FLI1 in Ewing sarcoma (EwS). Here, we find that EWS::FLI1 induces the robust expression of a specific set of novel spliced and polyadenylated transcripts within otherwise transcriptionally silent regions of the genome. These neogenes (NGs) are virtually undetectable in large collections of normal tissues or non-EwS tumors and can be silenced by CRISPR interference at regulatory EWS::FLI1-bound microsatellites. Ribosome profiling and proteomics further show that some NGs are translated into highly EwS-specific peptides. More generally, we show that hundreds of NGs can be detected in diverse cancers characterized by chimeric TFs. Altogether, this study identifies the transcription, processing, and translation of novel, specific, highly expressed multi-exonic transcripts from otherwise silent regions of the genome as a new activity of aberrant TFs in cancer.

A druggable copper-signalling pathway that drives inflammation.

Inflammation is a complex physiological process triggered in response to harmful stimuli1. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2-4. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

The lifetime risk of surgery in England: a nationwide observational cohort study.

BACKGROUND: The average number of times a person will have surgery in their lifetime, and the amount of surgical healthcare resources they use, is unknown. Lifetime risk is a measure of the risk of an average person having a specific event within their lifetime. We report the lifetime risk of surgery and the change observed during the first year of the COVID-19 pandemic. METHODS: We conducted a population cohort study using hospital episode statistics to identify all patients undergoing surgery between January 1, 2016, and December 31, 2020, in England. We calculated age- and sex-specific incidence rates of surgery and combined these with routinely available population and mortality data from the Office for National Statistics. We computed the probability of requiring surgery stratified by 5-yr epochs (age 0-4 to ≥90 yr). Our primary analysis calculated lifetime risk for all surgery using the life table method. We assessed the impact of the COVID-19 pandemic, comparing a pre-pandemic and a pandemic period. RESULTS: Between 2016 and 2020, 23 427 531 patients underwent surgery, of which 11 937 062 were first surgeries. The average denominator population for England was 55.9 million. The lifetime risk of first surgery was 60.2% (95% confidence interval 55.1-65.4%) for women and 59.1% (95% confidence interval 54.2-64.1%) for men. The COVID-19 pandemic decreased the lifetime risk of first surgery by 32.3% for women and by 31.7% for men. This estimated lifetime risk should only be applied to the English population. CONCLUSIONS: This population epidemiological analysis suggests that approximately 60% of people in England will undergo surgery in their lifetime.

MDM4 amplification in atypical lipomatous tumors/well-differentiated liposarcoma: Private event or alternative oncogenic mechanism?

Adipocytic tumors are the most common mesenchymal tumors in soft tissues. Among them, a diagnostic challenge relies in the distinction between lipoma and atypical lipomatous tumor (ALT)/well differentiated liposarcoma (WDLPS), as both entities are often undistinguishable not only from a radiological point of view, but also at the microscopic level and particularly when dealing with small tumor specimen. Thus, detection of recurrent MDM2 amplifications may be the only criteria to discriminate malignant tumors from lipomas. In this study, we report the case of a patient diagnosed with a well differentiated, adipocytic tumor located in the inferior limb and lacking MDM2 amplification, whose diagnosis was reclassified for ALT/WDLPS after identification of an alternative MDM4 amplification by comparative genomic hybridization profiling, whole exome sequencing and fluorescence in situ hybridization (FISH). Screening of a cohort of 37 large, deep-seated, well-differentiated adipocytic tumors previously classified as lipomas using RT-qPCR and FISH failed to detect other cases of MDM4-amplified ALT/WDLPS. This report shows that MDM4 amplification is an exceptional molecular event alternative to MDM2 amplification in ALT/WDLPS. This alteration should be considered and looked for in suspicious adipocytic tumors to optimize their surgical management.

Percutaneous Uterine Needle Biopsy with Microscopic and Array-CGH Analyses for Preoperative Sarcoma Diagnosis in Patients with Suspicious Myometrial Tumors on MRI: A Prospective Pilot Study (SARCGYN).

BACKGROUND: Unlike for soft tissue sarcomas, percutaneous biopsy is not validated for uterine myometrial tumors, leading to leiomyosarcoma inadvertent morcellation and overtreatment in childbearing patients. This study aimed to evaluate preoperative percutaneous uterine needle biopsy (PUB) with microscopic examination (M-PUB) and array-comparative genomic hybridization (MCGH-PUB). METHODS: This was a prospective single-center cohort study including all consecutive patients who were candidates for hysterectomy because of suspected uterine leiomyosarcoma on magnetic resonance imaging (MRI) who received PUB. Microscopic and array-CGH analyses with genomic index (GI) counts were performed to guide the therapeutic strategy. Smooth-muscle tumors with suspect features with a GI above 15 were deemed malignant, as were tumors without microscopic malignant features with a complex genomic profile (GI above 30 or malignant profile). Preoperative diagnoses based on M-PUB and MCGH-PUB were compared with the postsurgical pathological specimen or follow-up. RESULTS: From November 2016 to February 2022, 34 patients were included. Based on the surgical specimen (N = 23) or follow-up (N = 11), final diagnoses were 11 sarcomas and 23 non-sarcomas. The median follow-up was 12 months (IQR 6-37). The diagnostic accuracies of M-PUB and MCGH-PUB were 94% and 100%, respectively. The sensitivity, specificity, and negative predictive value of MCGH-PUB were 100%, 100%, and 100%, respectively. A high GI was significantly associated with malignancy (P < 0.001). Genomic analyses allowed malignancy upgrades for four tumors. There were no complications and no dissemination along the biopsy track. CONCLUSION: MCGH-PUB is safe and accurate for preoperatively diagnosing uterine sarcomas and should be used routinely after suspicious MRI to tailor surgery.

Initial Active Surveillance Strategy for Patients with Peripheral Sporadic Primary Desmoid-Type Fibromatosis: A Multicentric Phase II Observational Trial.

BACKGROUND: Stabilization or spontaneous regressions are demonstrated in more than half of patients affected by primary desmoid-type fibromatosis (DF) in retrospective studies. The objective of this phase II study was to prospectively assess the behavior of primary sporadic DT managed by active surveillance (AS). METHODS: This prospective, multicenter, observational study (NCT01801176) included patients ≥18 years of age with primary sporadic DF located in an extremity or the abdominal/thoracic wall. At inclusion, all patients were initially placed on AS. Follow-up was based on clinical and radiological evaluation by magnetic resonance imaging (MRI) performed at 1, 3, 6, 9, and 12 months, and then every 6 months for 3 years. The primary endpoint was progression-free survival (PFS) at 3 years according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as evaluated by a Central Review Board. RESULTS: Between 2012 and 2015, 100 patients were enrolled. The female/male ratio was 8 and the median age was 34 years (interquartile range [IQR] 30.8-43.9). Median follow-up was 46.6 months (IQR 36.8-61.1) and the 3-year PFS was 53.4% (95% confidence interval 43.5-63.1%). At progression (48 patients), 23 patients received active treatment. Fifty-eight patients (58%) presented with spontaneous tumor regression (decrease > 0% compared with the initial size) during the first 3 months (n = 35, 35%) or after an initial progression (n = 23, 23%), of whom 26 (26%) had partial responses (PRs). The median time to PR was 31.7 months (25.3-not available). CONCLUSIONS: These data support the use of AS as the primary approach to select patients with peripheral DF who require aggressive treatment.

Significant Predictors of Postoperative Morbidity After Radical Resection of Retroperitoneal Sarcoma in a Tertiary Center.

BACKGROUND: The safety of multivisceral resection of retroperitoneal sarcoma is an issue. Previous reports have investigated its associations with the pattern of resection and factors recognized mostly per operatively. METHODS: All consecutive RPS resections from May 2015 to April 2022 were studied retrospectively with respect to adverse events. Two univariate and multivariate logistic regression analyses were performed to investigate the associations between severe adverse events and factors recognized pre- and per operatively. Associations of adverse events with overall survival (OS) and local recurrence (LR) were investigated. RESULTS: A total of 265 surgical interventions corresponding to 251 patients were recorded (38 RPS surgeries/year). Severe postoperative adverse events (Clavien-Dindo ≥ 3) occurred in 50 patients (18.9%), 15 (5.6%) patients underwent an iterative laparotomy, and 6 patients (2.3%) died within 90 days. On multivariate analysis including all parameters known preoperatively, male sex, performance status, dedifferentiated liposarcoma histology, and low serum albumin level were found to be significant predictors of major complications, whereas the timing of surgery and preoperative treatment were not. On univariate analysis including all per operative parameters, transfusion requirement, operative time, number of digestive anastomoses, and pancreas and/or major arterial resection were found to entail higher operative risk. On multivariate analysis, only transfusion requirement was significant. There was no impact of postoperative adverse events on OS or LR. CONCLUSIONS: The recognition of preoperative parameters that impact safety could mitigate the extent of the surgery, specifically the resection of adherent organs not overtly invaded. For the best decision, this surgery should be performed in referral centers.

The fetal response to maternal inflammation is dependent upon maternal IL-6 in a murine model.

BACKGROUND: The induction of maternal inflammation in mice leads to fetal injury that is believed to be IL-6 dependent. The fetal inflammatory response, defined by elevated fetal or amniotic fluid IL-6, has been described as a potential mechanism for subsequent fetal injury. The role of maternal IL-6 production and signaling in the fetal IL-6 response is currently unclear. METHODS: Genetic and anti-IL-6 antibody strategies were used to systematically block the maternal IL-6 response during inflammation. Chorioamnionitis was induced using intraperitoneal injection of lipopolysaccharide (LPS) at mid gestation (E14.5) and late gestation (E18.5). This model was used in pregnant C57Bl/6 dams, IL6-/- dams, C57Bl/6 dams treated with anti-IL-6 (blocks both classical and trans-signaling) or anti-gp130 antibodies (blocks trans-signaling only) and IL6+/- dams. Six hours following LPS injection, maternal serum, placental tissue, amniotic fluid and fetal tissue or serum were collected. A bead-based multiplex assay was used to evaluate levels of IL-6, KC, IL-1ß, TNF, IL-10, IL-22, IFN-γ, IL-13 and IL-17A. RESULTS: Chorioamnionitis in C57Bl/6 dams was characterized by elevated maternal serum levels of IL-6, KC and IL-22 with litter loss during mid gestation. The fetal response to maternal inflammation in C57Bl/6 mice was primarily characterized by elevated levels of IL-6, KC and IL-22 in the placenta, amniotic fluid and fetus during both mid and late gestation. A global IL-6 knockout (IL6-/-) eradicated the maternal, placental, amniotic fluid and fetal IL-6 response to LPS during mid and late gestation and improved litter survival, while minimally influencing the KC or IL-22 responses. Blocking maternal classical IL-6 signaling in C57Bl/6 dams at the time of LPS exposure diminished the maternal, placental, amniotic fluid and fetal IL-6 response during mid and late gestation, while blocking maternal IL-6 trans-signaling only affected fetal IL-6 expression. To evaluate whether maternal IL-6 was crossing the placenta and reaching the fetus, IL-6+/- dams were utilized in the chorioamnionitis model. IL-6+/- dams mounted a systemic inflammatory response following injection with LPS, characterized by elevated IL-6, KC and IL-22. IL-6-/- pups born to IL6+/- dams had decreased amniotic fluid levels of IL-6 and undetectable levels of fetal IL-6 compared to IL-6+/+ littermate controls. CONCLUSION: The fetal response to systemic maternal inflammation is dependent upon maternal IL-6 signaling, but maternal IL-6 is not crossing the placenta and reaching the fetus at detectable levels.

Novel EWSR1::UBP1 fusion expands the spectrum of spindle cell rhabdomyosarcomas.

Over the last decade, the development of next-generation sequencing techniques has led to the molecular dismantlement of adult and pediatric sarcoma, with the identification of multiple gene fusions associated with specific subtypes and currently integrated into diagnostic classifications. In this report, we describe and discuss the identification of a novel EWSR1-UBP1 gene fusion in an adult patient presenting with multi-metastatic sarcoma. Extensive pathological, transcriptomic, and genomic characterization of this tumor in comparison with a cohort of different subtypes of pediatric and adult sarcoma revealed that this fusion represents a novel variant of spindle cell rhabdomyosarcoma with features of TFCP2-rearranged subfamily.

Desmoid tumors: who, when and how to treat?

PURPOSE OF REVIEW: The objective of this article is to summarize new treatment strategies of desmoid tumors. RECENT FINDINGS: Desmoid tumor has an unpredictable evolution that may spontaneously regress or stabilize. A shift toward an initial frontline active surveillance has been acknowledged by experts. Surveillance monitoring should be performed frequently after the diagnosis to avoid missing a significant progression and then spaced in case of stabilization. Treatment is based on significant tumor growth or symptoms. Recent guidelines recommend commencing medical treatment. Kinase inhibitors and cytotoxic agents are the two classes of drugs where studies included progressive desmoid tumors and should be selected to guide medical practice. In a randomized trial, 2 years progression-free survival (PFS) was significantly better in the sorafenib group (81 versus 36% in the placebo group). In another randomized phase 2, 6 months PFS was 83.7% with pazopanib versus 45% with methotrexate and vinblastine. In a retrospective study, including progressive desmoid tumors, methotrexate + vinca alkaloids achieved 75 months median PFS. Cryotherapy is an alternative option in desmoid tumors with compatible locations and tumor sizes. Following medical treatment or cryotherapy failure, superficial sites represent the best indications for surgery in cases of continuous progression. In the event of a contra-indication or failure of medical treatment, in locations where surgery would be mutilating and incomplete, radiotherapy is an effective option. SUMMARY: Active surveillance with planned imaging has become the first-line management in desmoid tumor.

A coordinated national UK liver transplant program response, prioritizing waitlist recipients with the highest need, provided excellent outcomes during the first wave of the COVID-19 pandemic.

INTRODUCTION: Healthcare provision has been severely affected by COVID-19, with specific challenges in organ transplantation. Here, we describe the coordinated response to, and outcomes during the first wave, across all UK liver transplant (LT) centers. METHODS: Several policy changes affecting the liver transplant processes were agreed upon. These included donor age restrictions and changes to offering. A "high-urgency" (HU) category was established, prioritizing only those with UKELD > 60, HCC reaching transplant criteria, and others likely to die within 90 days. Outcomes were compared with the same period in 2018 and 2019. RESULTS: The retrieval rate for deceased donor livers (71% vs. 54%; P < .0001) and conversion from offer to completed transplant (63% vs. 48%; P < .0001) was significantly higher. Pediatric LT activity was maintained; there was a significant reduction in adult (42%) and total (36%) LT. Almost all adult LT were super-urgent (n = 15) or HU (n = 133). We successfully prioritized those with highest illness severity with no reduction in 90-day patient (P = .89) or graft survival (P = .98). There was a small (5% compared with 3%; P = .0015) increase in deaths or removals from the waitlist, mainly amongst HU cohort. CONCLUSIONS: We successfully prioritized LT recipients in highest need, maintaining excellent outcomes, and waitlist mortality was only marginally increased.

Neoadjuvant Everolimus for Adult Giant Mesenteric Cystic Lymphangioma with mTOR Pathway Activation.

Cystic lymphangioma are rare benign vascular or lymphatic tumors, diagnosed mostly in newborns or children, that may become life-threatening because of local invasiveness. Surgical "en-bloc" resection with negative margins is the only curative treatment, but some patients are diagnosed with unresectable tumors. We describe the case of a young adult with giant unresectable mesenteric lymphangioma. Extensive pathological characterization as well as whole exome and transcriptome sequencing enabled us to identify mTOR pathway activation within endothelial tumor cells. The patient was treated with everolimus and experienced major partial response, leading to the surgical resection of the residual lesions. This case highlights the importance of molecular characterization of adult cystic lymphangioma for mTOR pathway activation because multidisciplinary therapeutic approaches, including neoadjuvant everolimus and secondary surgery, can lead to complete cure of this rare condition. KEY POINTS: The case of an adult patient diagnosed with giant unresectable mesenteric cystic lymphangioma, in which activation of the mTOR pathway was documented at both the pathological and transcriptomic levels, is reported. This patient showed major partial response to the mTOR inhibitor everolimus, which led to the successful resection of residual tumor lesions after 9 months of treatment. This report shows that mTOR targeting should be considered as neoadjuvant treatment in adult large cystic lymphangioma, as it can lead to complete surgery and cure of this rare condition.

How groove in music affects gait.

Rhythmic auditory stimulation (RAS) is a gait intervention in which gait-disordered patients synchronise footsteps to music or metronome cues. Musical 'groove', the tendency of music to induce movement, has previously been shown to be associated with faster gait, however, why groove affects gait remains unclear. One mechanism by which groove may affect gait is that of beat salience: music that is higher in groove has more salient musical beats, and higher beat salience might reduce the cognitive demands of perceiving the beat and synchronizing footsteps to it. If groove's effects on gait are driven primarily by the impact of beat salience on cognitive demands, then groove's effects might only be present in contexts in which it is relevant to reduce cognitive demands. Such contexts could include task parameters that increase cognitive demands (such as the requirement to synchronise to the beat), or individual differences that may make synchronisation more cognitively demanding. Here, we examined whether high beat salience can account for the effects of high-groove music on gait. First, we increased the beat salience of low-groove music to be similar to that of high-groove music by embedding metronome beats in low and high-groove music. We examined whether low-groove music with high beat salience elicited similar effects on gait as high-groove music. Second, we examined the effect of removing the requirement to synchronise footsteps to the beat (i.e., allowing participants to walk freely with the music), which is thought to remove the cognitive demand of synchronizing movements to the beat. We tested two populations thought to be sensitive to the cognitive demands of synchronisation, weak beat-perceivers and older adults. We found that increasing the beat salience of low-groove music increased stride velocity, but strides were still slower than with high-groove music. Similarly, removing the requirement to synchronise elicited faster, less variable gait, and reduced bias for stability, but high-groove music still elicited faster strides than low-groove music. These findings suggest that beat salience contributes to groove's effect on gait, but it does not fully account for it. Despite reducing task difficulty by equalizing beat salience and removing the requirement to synchronise, high-groove music still elicited faster, less variable gait. Therefore, other properties of groove also appear to play a role in groove's effect on gait.

Association Between Anesthetic Dose and Technique and Oncologic Outcomes After Surgical Resection of Non-Small Cell Lung Cancer.

OBJECTIVES: Because of the biologic effects of volatile anesthetics on the immune system and cancer cells, it has been hypothesized that their use during non-small cell lung cancer (NSCLC) surgery may negatively affect cancer outcomes compared with total intravenous anesthesia (TIVA) with propofol. The present study evaluated the relationship between anesthetic technique and dose and oncologic outcome in NSCLC surgery. DESIGN: Retrospective cohort study. SETTING: Surgical records collated from a single, tertiary care hospital and combined with the Scottish Cancer Registry and continuously recorded electronic anesthetic data. PARTICIPANTS: Patients undergoing elective lung resection for NSCLC between January 2010 and December 2014. INTERVENTIONS: The cohort was divided into patients receiving TIVA only and patients exposed to volatile anesthetics. MEASUREMENTS AND MAIN RESULTS: Final analysis included 746 patients (342 received TIVA and 404 volatile anesthetic). Kaplan-Meier survival curves with log-rank testing were drawn for cancer-specific and overall survival. No significant differences were demonstrated for either cancer-specific (p = 0.802) or overall survival (p = 0.736). Factors influencing survival were analyzed using Cox proportional hazards modeling. Anesthetic type was not a significant predictor for cancer-specific or overall survival in univariate or multivariate Cox analysis. Volatile anesthetic exposure was quantified using area under the end-tidal expired anesthetic agent versus time curves. This was not significantly associated with cancer-specific survival on univariate (p = 0.357) or multivariate (p = 0.673) modeling. CONCLUSIONS: No significant relationship was demonstrated between anesthetic technique and NSCLC survival. Whether a causal relationship exists between anesthetic technique during NSCLC surgery and oncologic outcome warrants definitive investigation in a prospective, randomized trial.

Prosecutor Preference for Forensic Nurse Testimony: Outcome of Expanding a Forensic Program.

INTRODUCTION: The objective was to evaluate the impact of using forensic nurse examiners for patients with trauma on prosecutors' preference for testimony in criminal court. METHODS: A retrospective chart review of a database of 562 subpoenas received from January 2012 to December 2017 was conducted for patients with trauma seen in a level 1 trauma center with a comprehensive forensic nursing program. RESULTS: The prosecutors' preferences in 453 of the 562 subpoenas received by the Forensic Nurse Examiners program involving a patient with trauma were analyzed. The prosecutors preferred the use of the forensic nurse examiner alone in 441 of the 453 cases (97.4%), with a decrease (100% to 2.7%) in preference for physicians testifying in criminal court after the expansion of our forensic nursing program compared with previous years before the program expansion. DISCUSSION: The quality of the expanded Forensic Nurse Examiner program was validated by an increased prosecutor preference for forensic nurse examiner testimony in criminal court as the program matured over the years.

Transcriptomic definition of molecular subgroups of small round cell sarcomas.

Sarcoma represents a highly heterogeneous group of tumours. We report here the first unbiased and systematic search for gene fusions combined with unsupervised expression analysis of a series of 184 small round cell sarcomas. Fusion genes were detected in 59% of samples, with half of them being observed recurrently. We identified biologically homogeneous groups of tumours such as the CIC-fused (to DUX4, FOXO4 or NUTM1) and BCOR-rearranged (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR, and BCOR internal duplication) tumour groups. VGLL2-fused tumours represented a more biologically and pathologically heterogeneous group. This study also refined the characteristics of some entities such as EWSR1-PATZ1 spindle cell sarcoma or FUS-NFATC2 bone tumours that are different from EWSR1-NFATC2 tumours and transcriptionally resemble CIC-fused tumour entities. We also describe a completely novel group of epithelioid and spindle-cell rhabdomyosarcomas characterized by EWSR1- or FUS-TFCP2 fusions. Finally, expression data identified some potentially new therapeutic targets or pathways. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Time to progression ratio in cancer patients enrolled in early phase clinical trials: time for new guidelines?

BACKGROUND: Reliable evaluation of treatment benefit in early phase clinical trials is necessary. The time to progression ratio (TTPr), which compares successive TTP in a single patient, is a powerful criteria for determining targeted or immune therapies efficacy. METHODS: We evaluated 205 TTPr in a large cohort of 177 advanced cancer patients enrolled in at least two Phase 1/1b trials (out of 2827 phase 1/1b-treated patients) at Gustave Roussy. RESULTS: This first wide description of TTPr showed that, under the hypothesis of overall absence of treatment line effect, the median TTPr was 0.7 and that 25% of patients presented a TTPr above the conventional efficacy threshold of 1.3. CONCLUSIONS: A higher median TTPr and a larger proportion of patients above the 1.3 threshold should therefore be achieved to conclude to drug efficacy. New guidelines for TTPr interpretation and calibration are proposed, which warrant independent prospective validation.