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Tumor-resident lymphocytes can mount a response against neoantigens expressed in microsatellite-stable gastrointestinal (GI) cancers, and adoptive transfer of neoantigen-specific lymphocytes has demonstrated antitumor activity in selected patients. However, whether peripheral blood could be used as an alternative minimally invasive source to identify lymphocytes targeting neoantigens in patients with GI cancer with relatively low mutation burden is unclear. We used a personalized high-throughput screening strategy to investigate whether PD-1 expression in peripheral blood could be used to identify CD8+ or CD4+ lymphocytes recognizing neoantigens identified by whole-exome sequencing in 7 patients with GI cancer. We found that neoantigen-specific lymphocytes were preferentially enriched in the CD8+PD-1+/hi or CD4+PD-1+/hi subsets, but not in the corresponding bulk or PD-1- fractions. In 6 of 7 individuals analyzed we identified circulating CD8+ and CD4+ lymphocytes targeting 6 and 4 neoantigens, respectively. Moreover, neoantigen-reactive T cells and a T cell receptor (TCR) isolated from the CD8+PD-1+ subsets recognized autologous tumor, albeit at reduced levels, in 2 patients with available cell lines. These data demonstrate the existence of circulating T cells targeting neoantigens in GI cancer patients and provide an approach to generate enriched populations of personalized neoantigen-specific lymphocytes and isolate TCRs that could be exploited therapeutically to treat cancer.

A woman with KRAS -mutated colon cancer had a response to T cells derived from her tumor that were specific for mutant KRAS. A lesion recurring 9 months later had lost expression of the class I major histocompatibility complex molecule recognized by the T cells. Adoptive cell therapy using ex vivo expanded tumor-infiltrating lymphocytes has led to durable complete regression of tumors in 20 to 25% of patients with metastatic melanoma. 1 , 2 This effect is probably mediated by T cells that specifically target mutant peptides encoded by de novo somatic mutations, which are known as neoepitopes. 3 – 8 Correlative evidence suggests that clinical responses in patients with cancer after the administration of immune checkpoint inhibitors may also be mediated by neoepitope-reactive T cells. 9 – 14 Direct evidence of the therapeutic utility of the targeting of neoepitopes was observed in a patient with metastatic cholangiocarcinoma who had tumor . . .

BackgroundStaging laparoscopy (SL) with peritoneal lavage is usually performed on a separate day from the planned resection and is recommended in patients with gastric adenocarcinoma as it can identify radiographically occult metastases and malignant cytology, thus altering prognosis and treatment. SL can be done on the same day as planned resection (SLSR) or with delayed resection (SLDR). The purpose of this study was to determine utilization of SL and factors associated with SLSR and SLDR, among patients diagnosed with gastric adenocarcinoma.MethodsSEER-Medicare linked data were used to identify patients diagnosed with gastric adenocarcinoma from 2004 through 2013. SL were defined as a laparoscopy that occurred up to 3 months postdiagnosis. Multivariate logistic regression was used to identify factors associated with the utilization of SLSR and SLDR.ResultsOf the 5610 patients with gastric adenocarcinoma who underwent a surgical procedure, 733 (13%) had a SL. Utilization of SL increased annually from 6.4% to 22.2% (p < 0.01). Receipt of SL was associated with patient demographics, tumor location, and treatment at a National Cancer Institute (NCI) Designated Cancer Center (CC). Of the 733 patients who underwent SL, 475 (65%) received further surgical procedures; 367 (77%) underwent SLSR, while 108 patients (23%) underwent SLDR. Compared with SLSR, SLDR was more common among patients who were younger, treated at an NCI-Designated CC and had proximal tumors.ConclusionsSL for optimal preoperative staging remains underutilized in the management of gastric adenocarcinoma. Expanded use of laparoscopy as a distinct procedure could minimize unnecessary interventions.

Earlier reports showed that hyperplasia of sympathoadrenal cell precursors during embryogenesis in Nf1-deficient mice is independent of Nf1’s role in down-modulating RAS-MAPK signaling. We demonstrate in zebrafish that nf1 loss leads to aberrant activation of RAS signaling in MYCN-induced neuroblastomas that arise in these precursors, and that the GTPase-activating protein (GAP)-related domain (GRD) is sufficient to suppress the acceleration of neuroblastoma in nf1-deficient fish, but not the hypertrophy of sympathoadrenal cells in nf1 mutant embryos. Thus, even though neuroblastoma is a classical “developmental tumor”, NF1 relies on a very different mechanism to suppress malignant transformation than it does to modulate normal neural crest cell growth. We also show marked synergy in tumor cell killing between MEK inhibitors (trametinib) and retinoids (isotretinoin) in primary nf1a-/- zebrafish neuroblastomas. Thus, our model system has considerable translational potential for investigating new strategies to improve the treatment of very high-risk neuroblastomas with aberrant RAS-MAPK activation. Neuroblastoma is one of the most common childhood cancers and is responsible for about 15% of childhood deaths due to cancer. The neuroblastoma tumors arise in cells that develop into and form part of the body’s nervous system. Many researchers have studied the genetics of this disease and have recognised common patterns. In particular, neuroblastomas can occur when a protein called MYCN is over-produced and a tumor suppressor protein called NF1 is lost. NF1 is a large protein with several distinct parts or domains. The most studied domain of NF1 is called the GRD, and it is mainly responsible for dampening down signals that cause cells to grow, specialize and survive. However, experiments in mice have revealed that this protein uses its other domains to control the normal development of part of the nervous system. He et al. wanted to know which domains of NF1 are important for suppressing the growth of neuroblastomas. The experiments were conducted in zebrafish that had been engineered to produce an excess of the human version of MYCN. When He et al. also deleted the gene for the zebrafish’s version of NF1, the fish quickly developed neuroblastomas. Supplying the zebrafish with just the GRD of NF1 was enough to supress the growth of the tumors. These experiments show that NF1 uses different domains and signalling pathways to regulate the normal development of part of the nervous system and to prevent formation of neuroblastoma. These engineered zebrafish represent an animal model of neuroblastoma that mimics the human disease in many ways. This model will make it possible to test new drug combinations and to find more effective treatments for neuroblastoma patients.

Type I neurofibromatosis (NF1) is caused by mutations in the NF1 gene encoding neurofibromin. Neurofibromin exhibits Ras GTPase activating protein (Ras-GAP) activity that is thought to mediate cellular functions relevant to disease phenotypes. Loss of murine Nf1 results in embryonic lethality due to heart defects, while mice with monoallelic loss of function mutations or with tissue-specific inactivation have been used to model NF1. Here, we characterize previously unappreciated phenotypes in Nf1-/- embryos, which are inhibition of hemogenic endothelial specification in the dorsal aorta, enhanced yolk sac hematopoiesis, and exuberant cardiac blood island formation. We show that a missense mutation engineered into the active site of the Ras-GAP domain is sufficient to reproduce ectopic blood island formation, cardiac defects, and overgrowth of neural crest-derived structures seen in Nf1-/-embryos. These findings demonstrate a role for Ras-GAP activity in suppressing the hemogenic potential of the heart and restricting growth of neural crest-derived tissues. Messages are carried from the surface of a cell to the cell’s nucleus in order to regulate various processes such as how often the cell will divide. The Ras-signaling pathway carries some of these messages. A gene called Nf1 encodes a protein in this pathway that deactivates another protein called Ras when the message is no longer required. If a mutation in Nf1 prevents it from deactivating Ras, the pathway becomes hyperactivated. In humans, this results in a disorder called Neurofibromatosis type I, which is characterized by tumors that affect many parts of the body. When the expression of Nf1 is turned off in mice, the mice die as embryos because of cardiac defects. But a mouse in which Nf1 has been turned off in specific organs or tissues other than the heart can survive, and these mice are used to model Neurofibromatosis type I and to help to identify potential treatments. Yzaguirre et al. have now identified new roles for Nf1 during embryonic development. In the embryo, blood cells originate from the cells lining the blood vessels. The experiments revealed that, when the Nf1 gene was mutated in mice, fewer blood cells formed from the lining of the major blood vessel that leaves the embryonic heart. In contrast, these mutant mice formed more structures called cardiac blood islands than a normal mouse. These structures line the heart, and have the potential to generate new blood cells for the heart to pump. These results shed new light on how blood is originally formed from the lining of the heart and blood vessels, and show that Ras signaling must be tightly regulated to maintain normal blood development in the embryo. Furthermore, Yzaguirre et al. demonstrated that this excessive formation of cardiac blood islands resulted specifically from the loss of Nf1’s role in the Ras-signaling pathway. This was achieved by using gene targeting to generate a mouse that expresses Nf1 with a minor change that affects only the protein’s interaction with Ras. In the future, this new strain of mouse will be a useful tool in determining if specific aspects of Neurofibromatosis type I can be attributed to loss of Nf1’s role in Ras-signaling and could therefore be treated by medicines that target this pathway.

Trauma is a major cause of morbidity and mortality in the pediatric population. However, temporal variations of trauma have not been well characterized and may have implications for appropriate allocation of hospital resources. Data from patients evaluated at an ACS-verified Level I pediatric trauma center between 2011 and 2015 were retrospectively analyzed. Date and time of injury, type of injury (blunt vs penetrating), and postemergency department disposition were reviewed. To assess temporal trends, heatmaps were constructed and a mixed poisson regression model was used to assess statistical significance. Pediatric trauma from blunt and penetrating injuries occurred at significantly higher rates between the hours of 1800 and 0100, on weekends compared with weekdays, and from May to August compared with November to February. These data provide useful information for hospital resource utilization. The emergency department, operating room, and intensive care unit should be prepared for increased trauma-related volume between May and August, weekends, and evening hours by appropriately increasing staff volume and resource availability.

Background Declining incidence of gastric cancer in the USA has presumably resulted in lower rates of major gastrectomy for cancer. The impact on perioperative outcomes remains undefined. The aims of this study were to characterize national trends in frequency of major gastrectomy for cancer, identify factors associated with in-hospital mortality, and examine outcome disparities by race/ethnicity. Methods Nationwide inpatient sample data from 1993 to 2013 were queried for procedural and diagnostic codes (ICD-9) relating to total and partial gastrectomy procedures. Gastric resections for cancer were compared to those for peptic ulcer disease for reference. Patient demographics, comorbidity score, mortality, and hospital characteristics were recorded as covariates. Results A significant decrease in annual rates of partial and total gastrectomy was observed from 1993 to 2013 ( p  < 0.0001). The change in absolute number and percent decline was greater for partial gastrectomy (− 39.3%) than total gastrectomy (− 19%). There was a 34.0% decrease in gastrectomy for cancer in Whites and a 61.2% increase among Hispanic patients over two decades. In-hospital mortality also significantly decreased over the study period (7.7% to 2.7%). Factors associated with lower mortality rates included male sex and treatment at urban teaching hospitals. Analysis of trends revealed that gastrectomy for cancer was performed with increasing frequency at urban teaching hospitals. Conclusions The frequency of major gastric resections in the USA has declined over two decades. Overall, in-hospital mortality rates also have decreased significantly. Declining in-hospital mortality after gastrectomy for cancer is associated with more frequent treatment at urban teaching hospitals.

Neurofibromatosis type 1 (NF1) is a common, dominantly inherited genetic disorder that results from mutations in the neurofibromin 1 (NF1) gene. Affected individuals demonstrate abnormalities in neural crest-derived tissues that include hyperpigmented skin lesions and benign peripheral nerve sheath tumors. NF1 patients also have a predisposition to malignancies including juvenile myelomonocytic leukemia (JMML), optic glioma, glioblastoma, schwannoma, and malignant peripheral nerve sheath tumors (MPNSTs). In an effort to better define the molecular and cellular determinants of NF1 disease pathogenesis in vivo, we employed targeted mutagenesis strategies to generate zebrafish harboring stable germline mutations in nf1a and nf1b, orthologues of NF1. Animals homozygous for loss-of-function alleles of nf1a or nf1b alone are phenotypically normal and viable. Homozygous loss of both alleles in combination generates larval phenotypes that resemble aspects of the human disease and results in larval lethality between 7 and 10 days post fertilization. nf1-null larvae demonstrate significant central and peripheral nervous system defects. These include aberrant proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), dysmorphic myelin sheaths, and hyperplasia of Schwann cells. Loss of nf1 contributes to tumorigenesis as demonstrated by an accelerated onset and increased penetrance of high-grade gliomas and MPNSTs in adult nf1a+/-; nf1b-/-; p53e7/e7 animals. nf1-null larvae also demonstrate significant motor and learning defects. Importantly, we identify and quantitatively analyze a novel melanophore phenotype in nf1-null larvae, providing the first animal model of the pathognomonic pigmentation lesions of NF1. Together, these findings support a role for nf1a and nf1b as potent tumor suppressor genes that also function in the development of both central and peripheral glial cells as well as melanophores in zebrafish.

Tumor-resident lymphocytes can mount a response against neoantigens expressed in microsatellite-stable gastrointestinal (GI) cancers, and adoptive transfer of neoantigen-specific lymphocytes has demonstrated antitumor activity in selected patients. However, whether peripheral blood could be used as an alternative minimally invasive source to identify lymphocytes targeting neoantigens in patients with GI cancer with relatively low mutation burden is unclear. We used a personalized high-throughput screening strategy to investigate whether PD-1 expression in peripheral blood could be used to identify [CD8.sup.+] or [CD4.sup.+] lymphocytes recognizing neoantigens identified by whole-exome sequencing in 7 patients with GI cancer. We found that neoantigen-specific lymphocytes were preferentially enriched in the [CD8.sup.+]PD-[1.sup.+/hi] or [CD4.sup.+]PD-[1.sup.+/hi] subsets, but not in the corresponding bulk or PD-[1.sup.-] fractions. In 6 of 7 individuals analyzed we identified circulating [CD8.sup.+] and [CD4.sup.+] lymphocytes targeting 6 and 4 neoantigens, respectively. Moreover, neoantigen-reactive T cells and a T cell receptor (TCR) isolated from the [CD8.sup.+]PD-[1.sup.+] subsets recognized autologous tumor, albeit at reduced levels, in 2 patients with available cell lines. These data demonstrate the existence of circulating T cells targeting neoantigens in GI cancer patients and provide an approach to generate enriched populations of personalized neoantigen-specific lymphocytes and isolate TCRs that could be exploited therapeutically to treat cancer.

BackgroundThe use of tumor-infiltrating T lymphocytes (TIL) that recognize cancer neoantigens has led to lasting remissions in metastatic melanoma and certain cases of metastatic epithelial cancer. For the treatment of the latter, selecting cells for therapy typically involves laborious screening of TIL for recognition of autologous tumor-specific mutations, detected through next-generation sequencing of freshly resected metastatic tumors. Our study explored the feasibility of using archived formalin-fixed, paraffin-embedded (FFPE) primary tumor samples for cancer neoantigen discovery, to potentially expedite this process and reduce the need for resections normally required for tumor sequencing.MethodWhole-exome sequencing was conducted on matched primary and metastatic colorectal cancer samples from 22 patients. The distribution of metastatic tumor mutations that were confirmed as neoantigens through cognate TIL screening was evaluated in the corresponding primary tumors. Mutations unique to primary tumors were screened for recognition by metastasis-derived TIL and circulating T lymphocytes.ResultsWe found that 25 (65.8%) of the 38 validated neoantigens identified in metastatic tumors from 18 patients with colorectal cancer were also present in matched primary tumor samples. This included all 12 neoantigens encoded by putative cancer driver genes, which are generally regarded as superior targets for adoptive cell therapy. The detection rate for other neoantigens, representing mutations without an established role in cancer biology, was 50% (13/26). Gene products encoding neoantigens detected in the primary tumors were not more likely to be clonal or broadly distributed among the analyzed metastatic lesions compared with those undetected in the primary tumors. Additionally, we found that mutations detected only in primary tumor samples did not elicit recognition by metastatic tumor-derived TIL but could elicit specific recognition by the autologous circulating memory T cells.ConclusionsOur findings indicate that primary FFPE tumor-derived screening libraries could be used to discover most neoantigens present in metastatic tumors requiring treatment. Furthermore, this approach can reveal additional neoantigens not present in resected metastatic tumors, prompting further research to understand their clinical relevance as potential therapeutic targets.