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Background Sarcopenia is a known risk factor for poor outcomes across many chronic diseases. The impact on outcomes of both pre‐existing sarcopenia and acute muscle wasting (AMW) in acute critical illness caused by sepsis remain unclear. Methods We conducted a prospective longitudinal cohort study of critically ill patients with intra‐abdominal sepsis utilizing abdominal computed tomography at sepsis onset to determine baseline skeletal muscle index (SMI). Biomarkers of inflammation and catabolism were measured through 28 days while hospitalized. We performed follow‐up evaluations of strength and physical function at 3, 6, and 12 months, with interval CT analyses at 3 and 12 months to evaluate changes in muscle mass. Measured clinical outcomes included development of chronic critical illness (≥14 days in intensive care with persistent organ dysfunction), long‐term functional status, and 1 year mortality. Results Among 47 sepsis patients enrolled (mean age 53 ± 14 years), half (n = 23; 49%) were sarcopenic at baseline. Overall, sepsis patients exhibited acute and persistent muscle wasting with an average 8% decrease in SMI from baseline at 3 months (P = 0.0008). Sarcopenic (SAR) and non‐sarcopenic (NSAR) groups were similar in regards to age and comorbidity burden. SAR patients had greater acute physiologic derangement (APACHE II, 18 vs. 12.5), higher incidence of multiple organ failure (57% vs. 17%), longer hospital (21 vs. 12 days) and intensive care unit length of stays (13 vs. 4 days), and higher inpatient mortality (17% vs. 0%; all P

Background As hospital sepsis mortality has decreased, more surgical ICU survivors are progressing into chronic critical illness (CCI). This study documents the incidence of CCI and long-term outcomes of patients with abdominal sepsis. We hypothesized that patients developing CCI would have biomarker evidence of immune and metabolic derangement, with a high incidence of poor 1-year outcomes. Methods Review of abdominal sepsis patients entered in a prospective longitudinal study of surgical ICU sepsis. Results Of the 144 study patients, only 6% died early, 37% developed CCI (defined as ICU days ≥14 with organ dysfunction) and 57% were classified rapid recovery (RAP). Compared to RAP, CCI patients a) were older (66 vs 58), males who were sicker at baseline (Charlson Comorbidity Index 4 vs 2), b) had persistently elevated biomarkers of dysregulated immunity/metabolism (IL-6, IL-8, sPDL-1, GLP1), c) experienced more secondary infections (4.9 vs 2.3) and organ failure (Denver MOF frequency 40 vs 1%), d) were much more likely to have poor dispositions (85 vs 22%) with severe persistent disabilities by Zubrod Score and e) had a notably higher 1-year mortality of 42% (all p Conclusion Over 1/3rd surgical ICU patients treated for abdominal sepsis progress into CCI and experience dismal long-term outcomes.

Background Older adults have worse outcomes after sepsis than young adults. Additionally, alterations of the gut microbiota have been demonstrated to contribute to sepsis-related mortality. We sought to determine if there were alterations in the gut microbiota with a novel sepsis model in old adult mice, which enter a state of persistent inflammation, immunosuppression, and catabolism (PICS), as compared with young adult mice, which recover with the sepsis model. Methods Mixed sex old (∼20 mo) and young (∼4 mo) C57Bl/6J mice underwent cecal ligation and puncture with daily chronic stress (CLP+DCS) and were compared with naive age-matched controls. Mice were sacrificed at CLP+DCS day 7 and feces collected for bacterial DNA isolation. The V3-V4 hypervariable region was amplified, 16S rRNA gene sequencing performed, and cohorts compared. α-Diversity was assessed using Chao1 and Shannon indices using rarefied counts, and β-diversity was assessed using Bray-Curtis dissimilarity. Results Naive old adult mice had significantly different α and β-diversity compared with naive adult young adult mice. After CLP+DCS, there was a significant shift in the α and β-diversity (FDR = 0.03 for both) of old adult mice (naive vs. CLP+DCS). However, no significant shift was displayed in the microbiota of young mice that underwent CLP+DCS in regards to α-diversity (FDR = 0.052) and β-diversity (FDR = 0.12), demonstrating a greater overall stability of their microbiota at 7 days despite the septic insult. The taxonomic changes in old mice undergoing CLP+DCS were dominated by decreased abundance of the order Clostridiales and genera Oscillospira. Conclusion Young adult mice maintain an overall microbiome stability 7 days after CLP+DCS after compared with old adult mice. The lack of microbiome stability could contribute to PICS and worse long-term outcomes in older adult sepsis survivors. Further studies are warranted to elucidate mechanistic pathways and potential therapeutics.

Objectives Sepsis has been called a "disease of the elderly," and as in-hospital mortality has decreased, more sepsis survivors are progressing into poorly characterized long-term outcomes. The purpose of this study was to describe the current epidemiology of sepsis in older adults compared with middle-aged and young adults. Design Prospective longitudinal study with young (≤45 years), middle-aged (46-64 years), and older (≥65 years) patient groups. Setting University tertiary medical center. Participants A total of 328 adult surgical intensive care unit (ICU) sepsis patients. Measurements Patients were characterized by (1) baseline demographics and predisposition, (2) septic event, (3) hospital outcomes and discharge disposition, (4) 12-month mortality, and (5) Zubrod Performance Status, physical function (Short Physical Performance Battery and handgrip strength), and cognitive function (Hopkins Verbal Learning Test, Controlled Oral Word Association, and Mini-Mental Status Examination) at 3-, 6-, and 12-month follow-up. Loss to follow-up was due to death (in 68), consent withdrawal (in 32), and illness and scheduling difficulties: month 3 (in 51), month 6 (in 29), and month 12 (in 20). Results Compared with young and middle-aged patients, older patients had (1) significantly more comorbidities at presentation (eg, chronic renal disease 6% vs 12% vs 21%), intra-abdominal infections (14% vs 25% vs 37%), septic shock (12% vs 25% vs 36%), and organ dysfunctions; (2) higher 30-day mortality (6% vs 4% vs 17%) and fewer ICU-free days (median = 25 vs 23 vs 20); (3) more progression into chronic critical illness (22% vs 34% vs 42%) with higher poor disposition discharge to non-home destinations (19% vs 40% vs 62%); (4) worse 12-month mortality (11% vs 14% vs 33%); and (5) poorer Zubrod Performance Status and objectively measured physical and cognitive functions with only slight improvement over 12-month follow-up. Conclusion Compared with younger patients, older sepsis survivors suffer both a higher persistent disability burden and 12-month mortality.

Background Although early survival from sepsis has improved with timely resuscitation and source control, survivors frequently experience persistent inflammation and develop chronic critical illness. We examined whether increased copy number of endogenous alarmins, mitochondrial DNA, and nuclear DNA are associated with the early “genomic storm” in blood leukocytes and the development of chronic critical illness in hospitalized patients with surgical sepsis. Methods A prospective, observational, cohort study of critically ill septic patients was performed at a United States tertiary health care center. Blood samples were obtained at multiple time points after the onset of sepsis. Droplet Digital polymerase chain reaction (Bio-Rad Laboratories, Hercules, CA) was performed to quantify RHO (nuclear DNA) and MT-CO2 (mitochondrial DNA) copies in plasma. Leukocyte transcriptomic expression of 63 genes was also measured in whole blood. Results We enrolled 112 patients with surgical sepsis. Two experienced early death, 69 recovered rapidly, and 41 developed chronic critical illness. Both mitochondrial DNA and nuclear DNA copy number were increased in all sepsis survivors, but early nuclear DNA, and not mitochondrial DNA, copy number was further increased in patients who developed chronic critical illness. Cell-free DNA copy number was associated with in-hospital but not long-term (180-day and 365-day) mortality and were only weakly correlated with leukocyte transcriptomics. Conclusion Increased cell-free DNA copy number persists in survivors of sepsis but is not strongly associated with leukocyte transcriptomics. Nuclear DNA but not mitochondrial DNA copy number is associated with adverse, short-term, clinical trajectories and outcomes.

Rearrangements involving neurotrophic receptor tyrosine kinase (NTRK) genes can generate fusion oncoproteins driving tumor development and survival.1 NTRK gene fusions have been identified across a range of adult and pediatric solid malignancies.2 B-cell acute lymphoblastic leukemia (ALL) can harbor an ETV6-NTRK3 gene fusion in ∼1% of the so-called “Philadelphia-like” cases.3 ETV6-NTRK3 fusion–positive B-cell ALL is characterized by rapid proliferation and infiltration of the central nervous system (CNS) in preclinical models.4 Previously published phase 1 data for larotrectinib ({"type":"clinical-trial","attrs":{"text":"NCT02637687","term_id":"NCT02637687"}}NCT02637687), a highly selective tropomyosin receptor kinase (TRK) inhibitor, has shown a 93% response rate and good tolerability in a cohort of pediatric patients with TRK-positive relapsed/refractory solid tumors, excluding leukemia patients.5 Adverse events included increased alanine and aspartate aminotransferase elevations, leucopenia, decreased neutrophil count, and vomiting, with no grade 4 or grade 5 events. Pharmacokinetics revealed that a dose of 100 mg/m2 (with a maximum dose of 100 mg) twice a day resulted in a similar exposure as in adults treated with the recommended phase 2 dose of 100 mg twice a day. Exposure in the CNS was also confirmed.5 Here, we report the successful use of larotrectinib in a child with a relapse of ETV6-NTRK3 fusion positive B-cell ALL early after hematopoietic allogeneic stem cell transplantation (HSCT).

Medullary thyroid carcinoma (MTC) is most commonly associated with RET gene mutations. ALK fusions have rarely been described, although not previously in pediatrics and not previously partnered wit...

BackgroundSepsis is an increasingly significant challenge throughout the world as one of the major causes of patient morbidity and mortality. Central to the host immunologic response to sepsis is the increase in circulating myeloid-derived suppressor cells (MDSCs), which have been demonstrated to be present and independently associated with poor long-term clinical outcomes. MDSCs are plastic cells and potentially modifiable, particularly through epigenetic interventions. The objective of this study was to determine how the suppressive phenotype of MDSCs evolves after sepsis in surgical ICU patients, as well as to identify epigenetic differences in MDSCs that may explain these changes.MethodsCirculating MDSCs from 267 survivors of surgical sepsis were phenotyped at various intervals over 6 weeks, and highly enriched MDSCs from 23 of these samples were co-cultured with CD3/CD28-stimulated autologous T cells. microRNA expression from enriched MDSCs was also identified.ResultsWe observed that MDSC numbers remain significantly elevated in hospitalized sepsis survivors for at least 6 weeks after their infection. However, only MDSCs obtained at and beyond 14 days post-sepsis significantly suppressed T lymphocyte proliferation and IL-2 production. These same MDSCs displayed unique epigenetic (miRNA) expression patterns compared to earlier time points.ConclusionsWe conclude that in sepsis survivors, immature myeloid cell numbers are increased but the immune suppressive function specific to MDSCs develops over time, and this is associated with a specific epigenome. These findings may explain the chronic and persistent immune suppression seen in these subjects.

Pediatric mesenchymal tumors harboring variant NTRK fusions (ETV6-negative) are being increasingly described; however, the histologic and clinical features of these variant NTRK tumors and their relationship to classic infantile fibrosarcoma are not well characterized. A better understanding of the clinicopathologic features of these tumors is necessary, and would aid in both early diagnosis and treatment. Therefore, the aim of this study was to characterize a series of pediatric NTRK-rearranged mesenchymal tumors, including classic ETV6-NTRK3 fused tumors and tumors with variant (non-ETV6) NTRK fusions. The clinical features, morphology, immunophenotype, and genetics of 12 classic ETV6-NTRK3 fused infantile fibrosarcoma and 18 variant NTRK-rearranged mesenchymal tumors were evaluated. For both classic and variant groups, the age at diagnosis ranged from birth to 15 years (median, 4 mo) with no sex predilection; the most common sites involved were the extremities and trunk. The rate of local recurrence and metastasis were not significantly different (recurrence rate: 11% classic, 40% variant; metastatic rate: 18% classic, 25% variant). Classic and variant NTRK tumors had an overlapping spectrum of histologic features, containing haphazardly arranged primitive cells in a myxoid background and/or spindle cells in long fascicles. Both groups showed diffuse pan-TRK expression by immunohistochemistry. Otherwise, the immunoprofile was nonspecific, but similar between both groups. No statistical difference was seen in any clinicopathologic feature between the classic ETV6-NTRK3 and variant fusion cohorts. Pediatric NTRK-rearranged mesenchymal tumors with both classic and variant fusions likely represent a spectrum of disease with shared, recognizable cliniopathologic features.

Surgical sepsis has evolved into two major subpopulations: patients who rapidly recover, and those who develop chronic critical illness (CCI). Our primary aim was to determine whether CCI sepsis survivors manifest unique blood leukocyte transcriptomes in late sepsis that differ from transcriptomes among sepsis survivors with rapid recovery. In a prospective cohort study of surgical ICU patients, genome-wide expression analysis was conducted on total leukocytes in human whole blood collected on days 1 and 14 from sepsis survivors who rapidly recovered or developed CCI, defined as ICU length of stay ≥ 14 days with persistent organ dysfunction. Both sepsis patients who developed CCI and those who rapidly recovered exhibited marked changes in genome-wide expression at day 1 which remained abnormal through day 14. Although summary changes in gene expression were similar between CCI patients and subjects who rapidly recovered, CCI patients exhibited differential expression of 185 unique genes compared with rapid recovery patients at day 14 (p &lt, 0.001). The transcriptomic patterns in sepsis survivors reveal an ongoing immune dyscrasia at the level of the blood leukocyte transcriptome, consistent with persistent inflammation and immune suppression. Furthermore, the findings highlight important genes that could compose a prognostic transcriptomic metric or serve as therapeutic targets among sepsis patients that develop CCI.

Background Increased circulating myeloid-derived suppressor cells (MDSCs) are independently associated with poor long-term clinical outcomes in sepsis. Studies implicate subsets of MDSCs having unique roles in lymphocyte suppression; however, characterization of these cells after sepsis remains incomplete. We performed a pilot study to determine the transcriptomic landscape in MDSC subsets in sepsis using single-cell RNAseq (scRNA-seq). Methods A mixture of whole blood myeloid-enriched and Ficoll-enriched PBMCs from two late septic patients on post-sepsis day 21 and two control subjects underwent Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq). Results We successfully identified the three MDSC subset clusters-granulocytic (G-), monocytic (M-), and early (E-) MDSCs. Sepsis was associated with a greater relative expansion of G-MDSCs versus M-MDSCs at 21 days as compared to control subjects. Genomic analysis between septic patients and control subjects revealed cell-specific and common differential expression of genes in both G-MDSC and M-MDSC subsets. Many of the common genes have previously been associated with MDSC proliferation and immunosuppressive function. Interestingly, there was no differential expression of several genes demonstrated in the literature to be vital to immunosuppression in cancer-induced MDSC. Conclusion This pilot study successfully demonstrated that MDSCs maintain a transcriptomic profile that is immunosuppressive in late sepsis. Interestingly, the landscape in chronic critical illness is partially dependent on the original septic insult. Preliminary data would also indicate immunosuppressive MDSCs from late sepsis patients appear to have a somewhat unique transcriptome from cancer and/or other inflammatory diseases.

Older adults have significantly worse morbidity and mortality after severe trauma than younger cohorts. The competency of the innate immune response decreases with advancing age, especially after an inflammatory insult. Subsequent poor outcomes after trauma are caused in part by dysfunctional leukocytes derived from the host's hematopoietic stem and progenitor cells (HSPCs). Our objective was to analyze the bone marrow (BM) HSPC transcriptomic [mRNA and microRNA (miR)] responses to trauma in older and younger adults. BM was collected intraoperatively

Background The highly selective oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib has demonstrated significant activity in adult and pediatric TRK fusion cancers. In the current study, the authors describe the clinical course of children with locally advanced TRK fusion sarcoma who were treated preoperatively with larotrectinib and underwent subsequent surgical resection. Methods A total of 24 children were treated on a pediatric phase 1 trial of larotrectinib (ClinicalTrials.gov identifier NCT02637687). Five children who had a documented TRK fusion sarcoma and underwent surgical resection were included in the current analysis. Tumor response (Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1) and surgical outcomes were collected prospectively. Results A total of 5 patients (median age, 2 years; range, 0.4-12 years) had locally advanced infantile fibrosarcoma (3 patients) or soft-tissue sarcoma (2 patients). Four patients had disease that was refractory to standard therapy. All 5 patients achieved a partial response to larotrectinib by version 1.1 of RECIST and underwent surgical resection after a median of 6 cycles (range, 4-9 cycles) of treatment. Surgical resections were R0 (negative resection margins with no tumor at the inked resection margin) in 3 patients, R1 (microscopic residual tumor at the resection margin) in 1 patient, and R2 (macroscopic residual tumor at the resection margin) in 1 patient. Three patients achieved complete (2 patients) or near-complete (>98% treatment effect; 1 patient) pathologic responses. These patients remained in follow-up and were no longer receiving larotrectinib for a minimum of 7 to 15 months postoperatively. Two patients had viable tumor at the time of surgical resection and positive resection margins and continued to receive adjuvant larotrectinib. No patients experienced postoperative complications or wound healing issues. Conclusions Children with locally advanced TRK fusion sarcomas may proceed to surgical resection after treatment with the selective TRK inhibitor larotrectinib, thereby sparing them the potentially significant morbidity noted with current approaches. These results support the evaluation of larotrectinib as presurgical therapy in children with newly diagnosed TRK fusion sarcomas.

Genes encoding TRK are oncogenic drivers in multiple tumour types including infantile fibrosarcoma, papillary thyroid cancer and high-grade gliomas (HGG). TRK fusions have a critical role in tumourigenesis in 40% of infant HGG. Here we report the first case of a TRK fusion-driven HGG treated with larotrectinib—the first selective pan-TRK inhibitor in clinical development. This 3-year-old girl had failed multiple therapies including chemotherapy and radiotherapy. Tumour profiling confirmed an ETV6–NTRK3 fusion. Treatment with larotrectinib led to rapid clinical improvement with near total resolution of primary and metastatic lesions on MRI imaging. This is the first report of a TRK fusion glioma successfully treated with a TRK inhibitor.

BackgroundGene fusions involving NTRK1, NTRK2, or NTRK3 (TRK fusions) are found in a broad range of paediatric and adult malignancies. Larotrectinib, a highly selective small-molecule inhibitor of the TRK kinases, had shown activity in preclinical models and in adults with tumours harbouring TRK fusions. This study aimed to assess the safety of larotrectinib in paediatric patients.MethodsThis multicentre, open-label, phase 1/2 study was done at eight sites in the USA and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion status; had a Karnofsky (≥16 years of age) or Lansky (

BackgroundFusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions.MethodsWe enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety.ResultsA total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.ConclusionsLarotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).

Background The role of site of infection in sepsis has been poorly characterized. Additionally, sepsis epidemiology has evolved. Early mortality has decreased, but many survivors now progress into chronic critical illness (CCI). This study sought to determine if there were significant differences in the host response and current epidemiology of surgical sepsis categorized by site of infection. Study design This is a longitudinal study of surgical sepsis patients characterized by baseline predisposition, insult characteristics, serial biomarkers, hospital outcomes, and long-term outcomes. Patients were categorized into five anatomic sites of infection. Results The 316 study patients were predominantly Caucasian; half were male, with a mean age of 62 years, high comorbidity burden, and low 30-day mortality (10%). The primary sites were abdominal (44%), pulmonary (19%), skin/soft tissue (S/ST, 17%), genitourinary (GU, 12%), and vascular (7%). Most abdominal infections were present on admission and required source control. Comparatively, they had more prolonged proinflammation, immunosuppression, and persistent organ dysfunction. Their long-term outcome was poor with 37% CCI (defined as > 14 in ICU with organ dysfunction), 49% poor discharge dispositions, and 30% 1-year mortality. Most pulmonary infections were hospital-acquired pneumonia. They had similar protracted proinflammation and organ dysfunction, but immunosuppression normalized. Long-term outcomes are similarly poor (54% CCI, 47% poor disposition, 32% 1-year mortality). S/ST and GU infections occurred in younger patients with fewer comorbidities, less perturbed immune responses, and faster resolution of organ dysfunction. Comparatively, S/ST had better long-term outcomes (23% CCI, 39% poor disposition, 13% 1-year mortality) and GU had the best (10% CCI, 20% poor disposition, 10% 1-year mortality). Vascular sepsis patients were older males, with more comorbidities. Proinflammation was blunted with baseline immunosuppression and organ dysfunction that persisted. They had the worst long-term outcomes (38% CCI, 67% poor disposition, 57% 1-year mortality). Conclusion There are notable differences in baseline predisposition, host responses, and clinical outcomes by site of infection in surgical sepsis. While previous studies have focused on differences in hospital mortality, this study provides unique insights into the host response and long-term outcomes associated with different sites of infection.

Background Older patients account for a significant proportion of patients undergoing colorectal cancer surgery and are vulnerable to a number of preoperative risk factors that are not often present in younger patients. Further, three preoperative risk factors that are more prevalent in older adults include frailty, sarcopenia, and malnutrition. Although each of these has been studied in isolation, there is little information on the interplay between them in older surgical patients. A particular area of increasing interest is the use of urine metabolomics for the objective evaluation of dietary profiles and malnutrition. Objective Herein, we describe the design, cohort, and standard operating procedures of a planned prospective study of older surgical patients undergoing colorectal cancer resection across multiple institutions in the United Kingdom. The objectives are to determine the association between clinical outcomes and frailty, nutritional status, and sarcopenia. Methods The procedures will include serial frailty evaluations (Clinical Frailty Scale and Groningen Frailty Indicator), functional assessments (hand grip strength and 4-meter walk test), muscle mass evaluations via computerized tomography morphometric analysis, and the evaluation of nutritional status via the analysis of urinary dietary biomarkers. The primary feasibility outcome is the estimation of the incidence rate of postoperative complications, and the primary clinical outcome is the association between the presence of postoperative complications and frailty, sarcopenia, and nutritional status. The secondary outcome measures are the length of hospital stay, 30-day hospital readmission rate, and mortality rate at days 30 and 90. Results Our study was approved by the National Health Service Research Ethics Committee (reference number: 19/WA/0190) via the Integrated Research Application System (project ID: 231694) prior to subject recruitment. Cardiff University is acting as the study sponsor. Our study is financially supported through an external, peer-reviewed grant from the British Geriatrics Society and internal funding resources from Cardiff University. The results will be disseminated through peer-review publications, social media, and conference proceedings. Conclusions As frailty, sarcopenia, and malnutrition are all areas of common derangement in the older surgical population, prospectively studying these risk factors in concert will allow for the analysis of their interplay as well as the development of predictive models for those at risk of commonly tracked surgical complications and outcomes. International Registered Report Identifier (IRRID) PRR1-10.2196/16846

Medullary thyroid carcinoma (MTC) is most commonly associated with

OBJECTIVE: We sought to compare traditional inpatient outcomes to long-term functional outcomes and mortality of surgical intensive care unit patients (SICU) with sepsis. SUMMARY BACKGROUND DATA: As inpatient sepsis mortality declines, an increasing number of initial sepsis survivors now progress into a state of chronic critical illness (CCI) and their post-discharge outcomes are unclear. METHODS: We performed a prospective, longitudinal cohort study of SICU patients with sepsis. RESULTS: Among this recent cohort of 301 septic SICU patients, 30-day mortality was 9.6%. Only 13 (4%) patients died within 14 days, primarily of refractory multiple organ failure (62%). The majority (n=189, 63%) exhibited a rapid recovery (RAP), while 99 (33%) developed CCI. CCI patients were older, with greater comorbidities, and more severe and persistent organ dysfunction than RAP patients (all p0.0001) and mortality was 20.9%. Of note at 12 months, the CCI cohort had persistent severely impaired performance status and a much higher mortality (41.4%) than those with RAP (4.8%) after controlling for age and comorbidity burden (Cox hazard ratio 1.27, 95% C.I. 1.14-1.41, p

PURPOSE: Targeted inhibition of NTRK-fusion proteins has shown promise in treatment of infantile fibrosarcoma in a phase 1 open-label study. Herein we report successful treatment of an NTRK-driven infantile glioblastoma with larotrectinib, a small molecule TRK inhibitor. RESULTS: A 2-month-old term female presented with hydrocephalus due to 10-cm right frontal lobe mass plus leptomeningeal (LM) dissemination to the posterior fossa and spinal cord. She underwent a sub-total resection of the supratentorial tumor, which harbored an in-frame TPM3-NTRK1 activating fusion as the solitary pathogenic alteration, absent alterations involving IDH1, IDH2, H3F3A, HIST1H3B, ATRX, TERT, TP53, SETD2, PPM1D, ACVR1, MET, EGFR, PTEN, NF1, BCOR, BCORL1, BRAF, RAF1, FGFR1, CIC, or INI1. She received 1 cycle of oral etoposide without response and then started larotrectinib (LOXO-101) 100 mg/m(2) BID (NCT03025360). Due to neutropenia, dose reductions were required to 25 mg/m(2)BID. Tumor responses noted were an initial decrease in the intensity of LM Gadolinium enhancement followed by measurable decrease in the frontal lobe tumor bulk after 6 cycles. At age 17 months, larotrectinib was held for a procedure (shunt revision) unrelated to the therapy during which time there was evidence of tumor growth. Upon restarting larotrectinib, decrease in the size of intracranial enhancing lesions and stabilization of LM disease was noted again. She is currently 22 months old with resolved neutropenia and is tolerating full dose (100mg/m(2)BID) larotrectinib. CONCLUSION: Our experience with targeted treatment for NTRK-driven infantile glioblastoma demonstrates favorable early results even in the setting of disseminated disease. However, long-term outcomes for TRK inhibitor therapy have not been established. Treatment with small molecule inhibitors targeting the kinase gene fusions that are frequent in infantile glioblastomas may allow for delaying radiation therapy during this critical developmental period. Genomic testing should be considered an essential screening study for this tumor population.

DAY101 (formerly TAK-580) is an oral, CNS-penetrant, selective small molecule pan-RAF kinase inhibitor that is equipotent against BRAF V600E, wildtype BRAF, and CRAF and can inhibit both RAF monomers and dimers, including BRAF fusions. KIAA1549:BRAF fusions have been identified as a key oncogenic driver for pilocytic astrocytoma (Jones et al. 2008). DAY101 has demonstrated significant activity against this fusion preclinically (Sun et al. 2017). Clinical data for DAY101 has shown a durable 63% response rate with good tolerability in children with low-grade glioma (LGG) harboring RAF fusions (Wright et al. 2020). To explore the potential impact of DAY101 in adult solid tumors harboring specific genomic alterations beyond BRAF V600E, a panel of tumor cell lines and PDX models harboring BRAF fusions, non V600 BRAF mutations or RAS mutations were assessed for anti-proliferative activity in response to DAY101. Furthermore, hypothesis-driven MAPK pathway node inhibitor combinations were explored for potential synergy. While performing favourably in preclinical in vivo studies, DAY101 does exhibit some technical challenges in long-term in vitro assays, particularly in those that extend for more than three days. Accordingly, the tool compound TAK-632, which exhibits comparable biochemical and cellular potency to DAY101, was used alternatively as needed for in vitro assays. Single-agent anti-proliferative activity was observed in a melanoma BRAF fusion PDX model treated with TAK-632 ex vivo, with less sensitivity observed in models beyond melanoma harboring other BRAF fusions. Ongoing combination studies with MEK inhibitors demonstrated strong synergy in PDX models harboring BRAF fusions ex vivo, as assessed by Bliss independence or other relevant scoring systems. In cell lines or PDX models harboring non V600 BRAF mutations, in vitro combination studies demonstrated strong synergy when DAY101 was combined with MEK inhibitors, as assessed by Bliss independence score. DAY101 exhibited modest single agent anti-proliferative activity in a panel of KRAS mutant cell lines in vitro and ongoing combination studies will assess potential synergy when combined with MAPK pathway node inhibitors. DAY101 is currently in clinical development for the treatment of patients under 25 years old with LGG harboring RAF alterations, including BRAF fusions and BRAF mutations. Inhibition of both RAF monomers and dimers by DAY101 enables a broader indication selection strategy, beyond LGG and BRAF alterations. Ongoing translational work will highlight the potential utility of DAY101 in adult tumors harboring RAS or RAF alterations, both as a single agent and in hypothesis-driven combinations. Citation Format: Eleni Venetsanakos, Mike Preigh, Jeannie Hou, Michael C. Cox, Jeremy Bender, Sam C. Blackman. DAY101, a potent pan-RAF inhibitor with activity in preclinical models harboring MAPK pathway alterations beyond BRAF V600E mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1481.

Background NTRK1, NTRK2 and NTRK3 gene fusions (NTRK gene fusions) occur in a range of adult cancers. Larotrectinib is a potent and highly selective ATP-competitive inhibitor of TRK kinases and has demonstrated activity in patients with tumours harbouring NTRK gene fusions. Patients and methods This multi-centre, phase I dose escalation study enrolled adults with metastatic solid tumours, regardless of NTRK gene fusion status. Key inclusion criteria included evaluable and/or measurable disease, Eastern Cooperative Oncology Group performance status 0–2, and adequate organ function. Larotrectinib was administered orally once or twice daily, on a continuous 28-day schedule, in increasing dose levels according to a standard 3 + 3 dose escalation scheme. The primary end point was the safety of larotrectinib, including dose-limiting toxicity. Results Seventy patients (8 with tumours with NTRK gene fusions; 62 with tumours without a documented NTRK gene fusion) were enrolled to 6 dose cohorts. There were four dose-limiting toxicities; none led to study drug discontinuation. The maximum tolerated dose was not reached. Larotrectinib-related adverse events were predominantly grade 1; none were grade 4 or 5. The most common grade 3 larotrectinib-related adverse event was anaemia [4 (6%) of 70 patients]. A dose of 100 mg twice daily was recommended for phase II studies based on tolerability and antitumour activity. In patients with evaluable TRK fusion cancer, the objective response rate by independent review was 100% (eight of the eight patients). Eight (12%) of the 67 assessable patients overall had an objective response by investigator assessment. Median duration of response was not reached. Larotrectinib had limited activity in tumours with NTRK mutations or amplifications. Pharmacokinetic analysis showed exposure was generally proportional to administered dose. Conclusions Larotrectinib was well tolerated, demonstrated activity in all patients with tumours harbouring NTRK gene fusions, and represents a new treatment option for such patients. ClincalTrials.gov number NCT02122913.

Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin secretion, cellular glucose uptake, and has immune-regulatory functions. Glucagon-like peptide-1 is markedly altered after trauma and sepsis, but the implications remain unclear.We performed an analysis of a prospective, longitudinal cohort study of critically ill surgical patients with sepsis. Patient characteristics and clinical data were collected, as well as peripheral blood sampling for biomarker analysis, out to 28 days after sepsis onset. We prospectively adjudicated sepsis diagnosis, severity, clinical outcomes, and 6-month follow-up.The cohort included 157 septic surgical patients with significant physiologic derangement (Maximum Sequential Organ Failure Assessment [SOFA] score 8, interquartile range [IQR] 4 to 11), a high rate of multiple organ failure (50.3%), and septic shock (24.2%). Despite high disease severity, both early death (14 days; n = 4, 2.9%) and overall inpatient mortality were low (n = 12, 7.6%). However, post-discharge 6-month mortality was nearly 3-fold higher (19.7%). Both GLP-1 and interleukin [IL]-6 levels were significantly elevated for 21 days (p ≤ 0.01) in patients who developed chronic critical illness (CCI) compared with patients with a rapid recovery. Elevated GLP-1 at 24 hours was a significant independent predictor for the development of CCI after controlling for IL-6 and glucose levels (p = 0.027), and at day 14 for death or severe functional disability at 6 months (WHO/Zubrod score 4-5, p = 0.014).Elevated GLP-1 within 24 hours of sepsis is a predictor of early death or persistent organ dysfunction. Among early survivors, persistently elevated GLP-1 levels at day 14 are strongly predictive of death or severe functional disability at 6 months. Persistently elevated GLP-1 levels may be a marker of a nonresolving catabolic state that is associated with muscle wasting and dismal outcomes after sepsis and chronic critical illness.

Genes encoding neurotrophin receptor kinases (TRK) have recently been implicated as an oncogenic driver in multiple tumor types including congenital fibrosarcoma, papillary thyroid cancer and adult glioblastoma. TRK fusions have been found in up to 40% of non-brainstem infant high grade gliomas (HGG), and play a critical role in tumorigenesis. Larotrectinib is the first and only selective pan-TRK inhibitor in clinical development. Larotrectinib is available as a liquid formulation and has been shown in a Phase 1 trial to be well tolerated in children, with high response rates in TRK fusion solid tumors. Here we report the first case of a pediatric HGG treated with larotrectinib. The patient was initially diagnosed at 5 months of age with a high-grade, right parietal tumor and treated in another institution as an ependymoma with intensive chemotherapy. Following a localized recurrence and resection at 2 years, the diagnosis of HGG was confirmed and treated with focal radiation therapy. By age 3, she developed further primary site tumor progression, and multiple metastatic subependymal nodules. Tumor profiling confirmed an ETV6-NTRK3 fusion. Compassionate access to larotrectinib treatment was provided, and led to rapid clinical improvement with gains in all developmental milestones over 4–6 weeks. After 2 cycles, MRI imaging confirmed near total resolution of primary and metastatic lesions. The patient continues on therapy and updated clinical and radiological results will be presented. This case represents a new paradigm for the treatment for pediatric patients with TRK fusion HGG. Enrolment to a global phase 2 trial is ongoing.

Background Genomic rearrangements involving NTRK1/2/3 result in constitutively active TRK fusion proteins that are oncogenic drivers in multiple pediatric and adult cancers. Larotrectinib is a selective TRK inhibitor approved by the FDA in 2018 for the treatment of any TRK fusion cancer based on a primary analysis in 55 patients from 3 clinical trials [Drilon et al. NEJM 2018]. For the first time, we now report median duration of response (DOR) data in this primary cohort, as well as updated data in an expanded cohort of 159 total TRK fusion patients treated with larotrectinib, with 153 (55 primary + 98 supplemental) evaluable for efficacy. Methods Patients with TRK fusion cancer detected by local molecular profiling were treated with larotrectinib across 3 studies (NCT02122913, NCT02637687, and NCT02576431). Disease status was assessed by investigators using RECIST 1.1. Data cut-off was 19 February 2019. Results In the primary cohort of 55 patients with a median follow-up of 26 months, the median DOR in 44 patients with complete or partial responses was 35.2 months (95% CI 21.2–NE), with 17 progression events and 27 responses ongoing (range 1.6–44 months). The median PFS in the primary cohort was 25.8 months (95% CI 9.9–NE), with 27 patients having progressed. In the expanded combined dataset, the most common tumor types included soft tissue sarcoma (n = 36), infantile fibrosarcoma (n = 29), thyroid carcinoma (n = 26), salivary gland carcinoma (n = 21), and lung cancer (n = 12). The median age was 43 years, ranging from Conclusions These data confirm the marked tissue-agnostic efficacy and long durability of response in patients with TRK fusion cancer treated with larotrectinib. Larotrectinib continued to demonstrate a favorable long-term safety profile. Screening patients for NTRK gene fusions should be actively considered. Clinical trial identification NCT02122913, NCT02637687, NCT02576431. Editorial acknowledgement Editorial assistance was provided by Michael Sheldon, PhD, of Scion, London, UK, funded by Bayer. Legal entity responsible for the study Bayer. Funding Bayer. Disclosure D.M. Hyman: Advisory / Consultancy: Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer Pharmaceuticals, Genentech / F. Hoffmann-La Roche; Research grant / Funding (self): Loxo Oncology, Bayer Pharmaceuticals, PUMA Biotechnology, AstraZeneca. C.M. van Tilburg: Advisory / Consultancy: Novartis, Bayer. D.S.W. Tan: Advisory / Consultancy: Novartis, Merck Loxo AstraZeneca Roche Pfizer; Travel / Accommodation / Expenses: Pfizer Boehringer Ingelheim Roche; Honoraria (self): BMS, Takeda, Novartis, Roche, Pfizer; Research grant / Funding (self): Novartis, GSK, AstraZeneca. A.F. Farago: Research grant / Funding (self): Bayer, Loxo Oncology; Advisory / Consultancy: Bayer, Loxo Oncology. T.W. Laetsch: Advisory / Consultancy: Novartis, Bayer, Loxo, Lill; Research grant / Funding (self): Pfizer Novartis Bayer Loxo Abbvie Amgen Atara Biotherapeutics BMS Lilly Epizyme GSK Janssen Jubilant Pharmaceuticals Novella Clinical, Servier. S. Kummar: Honoraria (self): Bayer; Advisory / Consultancy: Bayer; Travel / Accommodation / Expenses: Bayer. F. Doz: Research grant / Funding (institution): BMS, Celgene; Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Bayer, BMS, Celgene, Loxo Oncology, Servier. U.N. Lassen: Advisory / Consultancy: Bayer; Advisory / Consultancy: Pfizer. S.G. DuBois: Advisory / Consultancy: Loxo; Travel / Accommodation / Expenses: Loxo, Roche; Honoraria (self): Loxo; Research grant / Funding (self): Millennium, Merck, Novartis Roche Lilly Lilly Loxo BMS. R. McDermott: Travel / Accommodation / Expenses: Janssen-Cilag, Pfizer; Honoraria (self): Bayer, Sanofi, Janssen, Astellas, BMS, MSD, Pfizer, Novartis, Clovis; Research grant / Funding (self): Sanofi, Janssen, Bayer, Astellas. L. Mascarenhas: Research grant / Funding (institution): AstraZeneca, Eli Lilly. J.D. Berlin: Research grant / Funding (institution): PsiOxus, Bayer, EMD Serono, Symphogen, Roche/Genentech, Immunomedics, Novartis, Taiho, AbbVie (pharamcyclics), Boston Biomedical, FivePrime, Loxo, Incyte, Macrogenics; Honoraria (self): Nestle; Advisory / Consultancy: Rafeal, Seattle Genetics, EMD Serono, Bayer, eisai, Taiho, Armo,Gritstone, AstraZeneca, Celgene, Erytech. E.R. Rudzinski: Advisory / Consultancy: Bayer. M.C. Cox: Full / Part-time employment: Loxo Oncology. S. Nanda: Full / Part-time employment: Loxo Oncology. B.H. Childs: Full / Part-time employment: Bayer. A. Drilon: Advisory / Consultancy: Loxo Oncology/Bayer, Ignyta, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Takeda/Ariad/Millenium, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Bayer, Tyra; Research grant / Funding (self): Foundation Medicine; Licensing / Royalties: Wolters Kluwer; Honoraria (institution): Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho; Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: MORE Health. D.S. Hong: Research grant / Funding (self): AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seatt; Travel / Accommodation / Expenses: Loxo, MiRNA, ASCO, AACR, SITC, Genmab; Advisory / Consultancy: Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics; Shareholder / Stockholder / Stock options: Molecular Match, OncoResponse, Presagia Inc. All other authors have declared no conflicts of interest.

Infantile fibrosarcoma (IFS) is a rare pediatric cancer typically presenting in the first 2 years of life. Surgical resection is usually curative and chemotherapy is active against gross residual disease. However, when recurrences occur, therapeutic options are limited. We report a case of refractory IFS with constitutive activation of the tropomyosin‐related kinase (TRK) signaling pathway from an ETS variant gene 6–neurotrophin 3 receptor gene (ETV6–NTRK3) gene fusion. The patient enrolled in a pediatric Phase 1 trial of LOXO‐101, an experimental, highly selective inhibitor of TRK. The patient experienced a rapid, radiographic response, demonstrating the potential for LOXO‐101 to provide benefit for IFS harboring NTRK gene fusions.

Metamifop is an aryloxyphenoxypropionate herbicide under evaluation in the United States for annual grass control in cool-season turfgrasses. Insufficient information is available on the most effective metamifop application timings and mixtures for POST smooth crabgrass control. Field trials conducted in Blacksburg, VA, evaluated metamifop for smooth crabgrass control in existing stands of perennial ryegrass, Kentucky bluegrass, and tall fescue at three rates compared to fenoxaprop, metamifop applied twice at three application intervals, and metamifop in combination with the broadleaf herbicides carfentrazone, 2,4-D plus dicamba plus mecoprop (DDM), and mesotrione. Smooth crabgrass control was equivalent with metamifop at 400 g ai ha−1and fenoxaprop at 195 g ai ha−1. Smooth crabgrass cover was 2% or less, 12 wk after initial treatment, when treated twice with metamifop (300 g ha−1) at a 3-, 6-, or 8-wk interval and significantly better than metamifop applied once. Smooth crabgrass cover was significantly greater at every assessment date in plots treated with metamifop plus DDM than all other metamifop plus broadleaf herbicide admixtures. Metamifop did not appear to significantly injure any turfgrass in these studies, but conclusions about metamifop safety to cool-season turfgrasses cannot be made from these studies due to nonreplication of turfgrass species. According to these data, metamifop is an effective herbicide for controlling smooth crabgrass in cool-season turfgrasses when applied once at 300 or 400 g ha−1or twice at a 3-, 6-, or 8-wk interval. Although metamifop continues to control smooth crabgrass when added to some broadleaf herbicides, smooth crabgrass control was reduced when metamifop was combined with DDM.

Alligatorweed, waterhyacinth, and hydrilla are three nonnative aquatic species of concern in the Ross Barnett Reservoir near Jackson, MS. Point-intercept surveys were conducted on the reservoir from 2005 to 2010 to monitor native and nonnative species' distributions and assess herbicide treatment efficacy across the reservoir. Foliar applications of 2,4-D, glyphosate, imazapyr, and diquat were made during summer months for emergent and free-floating vegetation, whereas submersed applications of liquid copper and granular fluridone were applied in spring and late summer for subsurface hydrilla populations. American lotus is the native species that has been observed the most throughout the survey years, with occurrence frequencies averaging between 17 and 27%. Alligatorweed populations significantly decreased from 21% in 2005 to 4% in 2006; however, they consistently increased in the next 4 yr to 12% occurrence in 2010. Waterhyacinth occurrence has remained relatively constant over the study period, averaging below 10% occurrence. Hydrilla was discovered in the reservoir in late 2005 and has remained below 2% in frequency of occurrence since 2006. Suppression of these nonnative species has been attributed to rigorous monitoring and herbicide applications conducted on the reservoir since 2005. A logistic regression model indicated that as native species richness increased, the likelihood of a nonnative species occurring also increased.

TPS10066 Background: Genomic alterations in the RET kinase, including gene fusions and activating point mutations, are implicated in the pathogenesis of lung, thyroid, sarcoma and other cancers in both chidren and adults. Currently available multikinase inhibitors with anti-RET activity are non-selective and may be associated with less favorable toxicity profile. LOXO-292 is a novel, highly selective, ATP-competitive small molecule RET inhibitor. LOXO-292 has preclinical nanomolar potency against diverse RET alterations (e.g. fusions, activating mutations and anticipated acquired resistance mutations) and anti-tumor activity in the brain. LOXO-292 has demonstrated clinical activity in adult patients with RET-alterated solid tumors. Methods: LIBRETTO-121 (EudraCT 2019-000212-28) is an ongoing multicenter phase 1/2 dose escalation multicenter trial in patients 6 months-21 years of age with advanced, RET-altered solid and CNS tumors. Dose escalation follows a rolling 6 design starting at the equivalent of the adult recommended phase 2 dose. Enrollment began on 12 Feb 2019 and is ongoing. Key eligibility criteria include: solid or CNS tumor with a documented RET gene alteration refractory to standard therapy; age 6 months to 21 years of age; and adequate bone marrow, liver and kidney function. LOXO-292 is administered orally BID for continuous 28-day cycles. Both capsule and liquid suspension dosage forms are available. The primary objective of the phase 1 portion of the study is to determine safety and dose limiting toxicities. Key secondary objectives include characterization of pharmacokinetic properties, identification of the MTD and initial characterization of the anti-tumor activity of LOXO-292. Archival tissue will be used to further characterize molecular abnormalities. Clinical trial information: 2019-000212-28.

2006 Background: TRK fusions are oncogenic drivers of a variety of cancers, many of which can involve the central nervous system (CNS). Larotrectinib is an FDA-approved selective TRK inhibitor for the treatment of TRK fusion cancer (Drilon et al, NEJM 2018). While larotrectinib has been shown to cross the blood–brain barrier (Ziegler et al, Br J Cancer 2018), its clinical activity in a series of TRK fusion cancers with primary or metastatic intracranial disease has not been described. Methods: Patients (pts) with non-primary CNS solid tumors with brain metastases, or primary CNS tumors harboring a TRK fusion treated with larotrectinib in 2 clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression (PD), withdrawal, or unacceptable toxicity. Disease status was investigator-assessed (RANO and RECIST). Data cutoff: July 30, 2018. Results: 14 pts were identified: 5 non-primary CNS solid tumors (3 lung cancer, 2 thyroid cancer; fusion type: 2 ETV6-NTRK3, 2 SQSTM1-NTRK3, 1 EPS15-NTRK1; age range 25–79 y) and 9 primary CNS tumors (3 glioma, 2 glioblastoma, 1 astrocytoma, 3 NOS; fusion type: 3 BCR-NTRK2, 2 KANK-NTRK2, 1 each of AFAP1-NTRK1, AGTPBP1-NTRK2, ETV6-NTRK3, SPECC1L-NTRK2; age range 2–79 y). In the 5 pts with non-primary CNS tumors, the best objective response to therapy was PR in 3 (60%, 1 pending confirmation), SD in 1 (20%), and not evaluable (NE) in 1 (20%). Duration of response ranged from 9+ to 13 mo. In the 9 pts with primary CNS tumors, disease control was achieved in all evaluable pts (primary PD not observed; 1 pt required dose increase). The best objective response to therapy was PR in 1 (11%; pending confirmation, −55% tumor shrinkage, ongoing at 3.7 mo), SD in 7 (78%; tumor shrinkage range −1% to −24% for pts with measurable disease, 5 had SD > 4 mo), and NE in 1 (11%). Duration of treatment ranged from 2.8–9.2+ mo. Conclusions: Larotrectinib is active in pts with TRK fusion cancers with intracranial disease. Confirmed responses and durable disease control were seen in metastatic disease and primary CNS tumors of various histologies. These results further support expanded testing for TRK fusions across all cancers, including primary CNS tumors. Clinical trial information: NCT02637687 and NCT02576431.

10010 Background: TRK fusions involving NTRK1, NTRK2, and NTRK3 genes have been identified in a broad range of pediatric and adult malignancies. Larotrectinib, a highly-selective oral TRK inhibitor, was well tolerated and showed encouraging antitumor activity in 17 pediatric patients (pts) with TRK fusion cancer (Laetsch et al, Lancet Oncol 2018). Here, we present data on the clinical efficacy and safety of larotrectinib in 38 pediatric pts with TRK fusion cancer from an expanded dataset. Methods: Pediatric pts enrolled in two larotrectinib clinical trials (NCT02637687, NCT02576431) with TRK fusion cancer detected by local testing were included; pts with primary CNS tumors were excluded from this report. Larotrectinib was administered until complete surgical resection, disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator-assessed using RECIST v1.1. Data cutoff: July 30, 2018. Results: As of July 30, 2018, 38 children and adolescents < 18 y with TRK fusion cancer were enrolled. Median age was 2.3 y (range 0.1–14.0); 14 (37%) were < 1 y. 18 (47%) had infantile fibrosarcoma, 15 (39%) other soft tissue sarcoma, 2 (5%) thyroid cancer and 1 (3%) each had gastrointestinal stromal tumor, melanoma, or mesoblastic nephroma. TRK fusions involved NTRK1, 2, and 3 in 18 (47%), 2 (5%), and 18 (47%) pts, respectively. Half of the pts had metastatic disease and half locally advanced disease at entry. 26 pts (68%) had received prior systemic therapy (median lines: 1 [range 0–4]) and 6 were treatment-naïve. In 34 evaluable pts, the overall response rate was 94%: 12 CRs, 18 confirmed PRs, and 2 PRs pending confirmation; 2 had stable disease. Median duration of response had not been reached (range 1.6+ to 26.7+ months); 84% > 1 y. At data cutoff, 28 pts (74%) remained on treatment; 4 pts discontinued due to complete surgical resection and 4 due to disease progression while on therapy, 2 of whom initially responded (PR). Adverse events were mostly grade 1–2. Conclusions: Larotrectinib treatment resulted in a high and durable response rate in pediatric pts with TRK fusion cancer together with a favorable safety profile. Routine testing for NTRK gene fusions in pediatric cancer pts is recommended in the appropriate clinical context. Clinical trial information: NCT02637687 and NCT02576431.

10045 Background: Genomic alterations of RET kinase, including chromosomal fusions and activating point mutations, have been identified as oncogenic drivers in pediatric and adult cancers. Multikinase inhibitors have modest activity against RET-altered cancers and are associated with significant toxicity. LOXO-292 is a potent, ATP-competitive, small molecule RET inhibitor with high selectivity for RET, preclinical activity in the brain and excellent pharmacokinetic properties. In an ongoing phase 1/2 study of adult and adolescent patients with advanced RET-altered cancers, LOXO-292 demonstrated marked antitumor activity and was well tolerated. Methods: Pediatric patients with RET-altered cancers who were unable to access LOXO-292 through a phase 1/2 clinical trial were enrolled using FDA-allowed, IRB-approved single patient protocols . Patients received LOXO-292 (capsule/liquid formulation) orally, continuously, at a starting dose of 90 mg/m2 BID. Response was assessed locally by investigators. Results: As of January 31, 2019, 4 female patients aged 13 months–8 years were enrolled from the Republic of Korea (papillary thyroid cancer, n = 1) and the USA (infantile myofibroma/hemangiopericytoma, n = 1; congenital mesoblastic nephroma/infantile fibrosarcoma, n = 1; lipofibromatosis, n = 1). All tumors harbored RET gene fusions (5′ partners: CCDC6, MYH10, SPECC1L, and NCOA4, respectively), detected by next-generation sequencing. Previous therapies included surgery/iodine 131 (n = 1); vandetanib (n = 1); surgery/chemotherapy (n = 1); 1 patient was treatment-naïve. Duration of treatment ranged from 3–120 days and all patients remain on treatment. There were no dose modifications or discontinuations due to adverse events. There were no treatment-related adverse events ≥ grade 3. Two patients who were evaluable for response had partial responses (both ongoing, 1 confirmed, 1 pending confirmation). Conclusions: These preliminary data from a real-world setting suggest that LOXO-292 is effective and safe in pediatric patients whose tumors harbor RET gene fusions.

Mesoblastic nephroma is the most frequent renal tumor in newborns and young infants, and the cellular type is characterized by an ETV6-NTRK fusion, which constitutively activates the tropomyosin-related kinase (TRK) signaling pathway. Larotrectinib is a highly selective TRK inhibitor with activity in adult and pediatric patients who have TRK fusions. We present a rare case of a patient with mesoblastic nephroma metastatic to bone who had a dramatic response to larotrectinib.

Increasing knowledge of drug resistance and side effects of currently approved agents, and of the biology of breast cancer, has given way to new treatment options that improve on previously available agents, or medications that target specific kinases and proteins associated with an oncogenic phenotype. This paper discusses new agents, including improved formulations of paclitaxel and epothilones, and molecularly targeted agents such as bevacizumab, sunitinib malate, pertuzumab, lapatinib, the mTOR inhibitors and farnesyl transferase inhibitors. Although endocrine therapy is a targeted therapy, it is not covered in this paper. These agents have increased excitement in the treatment of breast cancer and stand on the forefront of a potential improvement in quality of life and treatment options for patients afflicted with this deadly disease.

Despite its controversial past, thalidomide is currently under investigation for the treatment of several disease types, ranging from inflammatory conditions to cancer. The mechanism of action of thalidomide is complex and not yet fully understood, but there is some evidence to suggest that metabolism may play a role. Consequently, there has been a considerable effort to characterize the metabolism of thalidomide in recent years. Thalidomide undergoes biotransformation by non-enzymatic hydrolysis and enzyme-mediated hydroxylation to form a multitude of metabolites. Metabolite identification and reaction phenotyping studies have been performed and will be discussed in this review in addition to interspecies differences in thalidomide metabolism.