Multiple Gastrointestinal Tumors Research Articles

Next generation sequencing (NGS) to identify relapsed gastrointestinal (GI) solid tumor patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) for future logic-gated CAR T therapy to reduce on target off tumor toxicity.

190 Background: Metastatic colorectal (CRC), pancreatic (PANC), and gastroesophageal (GE) cancers are the leading causes of GI cancer–related mortality (5-yr survival rate, 14%, 3% and ̃5-6%, respectively). T-cell immunotherapy targeting GI-associated tumor antigens has been attempted, but efficacy has been constrained by on-target off-tumor toxicity, limiting the therapeutic window. The Tmod (TM) platform is an AND-NOT logic-gated CAR T modular system, versions of which have a CEA- or MSLN-targeting CAR activator and a separate HLA-A*02-targeting blocker receptor to protect normal cells. Tmod CAR T exploits HLA LOH, common in GI malignancies (10-33% in primary solid tumors [TCGA]) and can kill tumor cells without harming healthy cells in vitro and in vivo. However, the prevalence of HLA LOH across GI tumors is unknown in the real-world setting. We utilized the Tempus xT oncology NGS database of patients with multiple GI tumors. From a standard-of-care NGS assay, GI cancer patients can be readily identified for HLA LOH and future treatment with Tmod CAR T therapy. Methods: The occurrence of HLA LOH in GI tumors of 1439 patients was assessed using paired germline and somatic DNA sequencing using a research assay [6]. CRC, PANC and GE patients with ≥ stage 3 were then extracted, and rates of HLA LOH were identified (ie, whether loss occurred across high-frequency HLA-A alleles). In addition, mutations in KRAS and BRAF, as well as MSI status were stratified to determine any association with HLA-A LOH. Results: HLA-A LOH was detected in 830 (17.3%) of all solid tumor records, and a similar proportion when all GI cancer records were analyzed (17.0%). For GI subtypes, these values ranged from 13.5% to 23.1% (Table). No high-frequency HLA-A allele (A*01, A*02, A*03, A*11) was more likely to be lost. Clinical biomarkers ( KRAS, BRAF and MSI status) were not associated with HLA-LOH. Conclusions: The frequency of HLA LOH among advanced solid tumor cancers in this dataset is 17.3%, with a range of 13.5-23% between CRC, PANC and GE. The HLA LOH frequency observed in these GI tumors is consistent with that in primary tumors from TCGA, which also used germline-matched and tumor samples. Clinical biomarkers were not associated with HLA LOH. Tempus NGS was able to identify HLA LOH, which can be used for Tmod CAR T therapy to an enhanced therapeutic window. Identification of these patients in BASECAMP-1 (NCT04981119) will enable novel Tmod CAR T therapy. [Table: see text]

Intensive surveillance endoscopy for multiple gastrointestinal tumors in a patient with constitutional mismatch repair deficiency: case report

BackgroundConstitutional mismatch repair deficiency (CMMRD) is an extremely rare autosomal recessive hereditary disease characterized by the absence of mismatch repair gene activity from birth, which results in brain tumors, colonic polyposis, gastrointestinal cancers, and lymphomas later in life. An aggressive approach, including colectomy or proctocolectomy, is recommended for the treatment of colorectal cancer. Additionally, partial colectomy with subsequent endoscopic surveillance may be an alternative strategy due to poor patient’s condition, although there is no evidence of surveillance endoscopy after partial colectomy for CMMRD.Case presentationA 13-year-old male patient with a history of T-lymphoblastic lymphoma underwent total gastrointestinal endoscopy, which revealed rectal cancer, colorectal polyposis, and duodenal adenoma. Differential diagnosis included constitutional mismatch repair deficiency according to its scoring system and microsatellite instability, and subsequent germline mutation testing for mismatch repair genes confirmed the diagnosis of constitutional mismatch repair deficiency based on a homozygous mutation in mutS homolog 6 (MSH6). The patient and his family refused colectomy due to the high risk of malignancies other than colorectal cancer, which could require radical surgery. Therefore, the patient underwent low anterior resection of the rectosigmoid colon for rectal cancer and intensive surveillance endoscopy for the remaining colon polyposis. During the 3-year period after initial surgery, 130 polyps were removed and the number of polyps gradually decreased during 6-months interval surveillance endoscopies, although only one polyp was diagnosed as invasive adenocarcinoma (pT1).ConclusionsOur experience of short surveillance endoscopy illustrates that this strategy might be one of options according to patient’s condition.

Synchronous Upper Intestinal Neurofibromas and Duodenal Periampullary Well-Differentiated Neuroendocrine Tumor Associated With Neurofibromatosis 1

Neurofibromatosis type I (NF1) is an autosomal dominant genetic disorder associated with characteristic skin findings, as well as a fourfold increase in risk of malignancy. NF1 patient malignancies commonly include the central and peripheral nervous system, but these patients are also at high risk of developing gastrointestinal (GI) tumors. While most often these GI tumors are benign upper GI neurofibromas; clinicians should have a high suspicion for malignant tumors, degeneration into a malignant peripheral nerve sheath tumor or less common associated malignancies such as well-differentiated neuroendocrine tumor (formerly carcinoid tumor), when patients present with multiple GI tumors. Our patient underwent a Whipple for symptomatic neurofibromas associated with NF1 and was unexpectedly discovered to have a metastatic duodenal well-differentiated neuroendocrine tumor. The patient is a 66-year-old man with NF1 who presented with hematemesis and was found to have large gastric neurofibromas and an ampullary neurofibroma based on endoscopy and radiological imaging. Another ostensive neurofibroma was noted distally. A pancreatoduodenectomy was performed. Pathological examination identified the neurofibromas but the tumor measuring 1.4cm and arising from the minor duodenal papilla was, in fact, a synchronous well-differentiated neuroendocrine tumor metastatic to regional lymph nodes, consistent with pT2 pN1, Stage IIIB cancer. NF1 patients with multiple GI tumors are at an increased risk for malignancy. Therefore, a high index of suspicion for malignancy in any patient with NF1 presenting with gastrointestinal symptoms has implications for a surgeon, warranting not only a further diagnostic investigation, but also an appropriate surgical intervention and sampling for nodal spread. Because of the possibility of a simultaneous cancer, it is crucial to assess all suspicious tumors even if the masses appear endoscopically benign.

Effect of miR-503 Down-Regulation on Growth and Invasion of Esophagus Carcinoma and Related Immune Function.

BackgroundMicroRNA (miR) has been proved to be an important biomarker for tumors because it can regulate occurrence, progression, invasion, and metastasis of cancer. A previous study has shown the involvement of miR-503 in multiple gastrointestinal tumors. Its detailed role and immune regulatory function in esophagus carcinoma, however, remains unknown. This study thus investigated the effect of miR-503 in regulating growth, proliferation, and invasion of esophagus cancer and its influence on cytokine secretion.Material/MethodsEsophagus carcinoma cell line EC9706 and normal esophageal epithelial cell line HEEC were transfected with miR-503 inhibitor. MTT assay was used to quantify the cell proliferation, and a Transwell chamber was used to evaluate cell invasion. Release of cytokines, including interleukin-2 (IL-2), IL-4, IL-10, and interferon-γ (IFN-γ), was measured by enzyme-linked immunosorbent assay (ELISA).ResultsMiR-503 expression was significantly elevated in esophagus carcinoma cells (p<0.05). The specific inhibition of miR-503 expression remarkably suppressed proliferation and invasion of tumor cells. It can also down-regulated IL-2 and IFN-γ expression and facilitate secretion of IL-4 and IL-10 when compared to the control group (p<0.05 in all ceases).ConclusionsThe inhibition of miR-503 can effectively inhibit tumor progression and improve immune function, suggesting its potency as a novel drug target for esophagus cancer treatment.

Neurofibroma of the appendix and multiple gastrointestinal stromal tumors of small bowel in neurofibromatosis type 1 patient

Neurofibromatosis type 1 (NF-1) is an autosomal dominant hereditary disease with association of tumorous condition of body. Although the pathogenesis of tumorous condition with NF-1 is unclear, there were several reports for gastrointestinal tumors (GISTs) of gastrointestinal tract or nervous system tumors. However, there are few reports of appendiceal neurofibroma in NF-1 patients. We report here a case of NF-1 patient with multiple jejunal GISTs and appendiceal neurofibroma. A 61-year-old man was referred to department of surgery for abnormal findings of appendix on abdominal computed tomography scan. He underwent the laparoscopic appendectomy and laparoscopy-assisted segmental resection of proximal jejunum and he had numerous masses on duodenum and proximal jejunum in the operative findings. The pathologic findings revealed the neurofibroma of appendix and multiple GISTs of the jejunum. Keywords: Neurofibromatoses, Jejunum, Gastrointestinal stromal tumors, Appendix, Neurofibroma

Multiple gastrointestinal stromal tumours presenting as a haemoperitoneum in a patient with Type 1 neurofibromatosis: MDCT findings

We report multidetector row CT images of multiple gastrointestinal tumours in a patient with Type 1 neurofibromatosis who presented with haemoperitoneum. The use of CT demonstrated multiple, variably sized, ovoid, relatively well-enhancing masses in the intramural or subserosal location of the jejunum. The largest mass that showed a haemorrhagic necrosis caused haemoperitoneum. These imaging features are unique and differ from previous imaging features that have been reported in the radiological literature.

Homozygous PMS2 Deletion Causes a Severe Colorectal Cancer and Multiple Adenoma Phenotype Without Extraintestinal Cancer

We report a patient of Indian descent with parental consanguinity, who developed 10 carcinomas and 35 adenomatous polyps at age 23 and duodenal adenocarcinoma at age 25. He also had dysmorphic features, mental retardation, and café-au-lait spots but no brain tumor. We aimed to establish his molecular diagnosis. Germ-line screening for APC and MYH/MUTYH mutations was normal as was immunohistochemistry for MLH1 and MSH2 proteins. Investigation by array-comparative genomic hybridization revealed deletion of a small region on chromosome 7. Using polymerase chain reaction, this region was refined to a 400-kilobase deletion, which included exons 9-15 of the PMS2 gene, and all coding regions of oncomodulin, TRIAD3, and FSCN1. The deletion was confirmed as homozygous, and both parents were carriers. Immunohistochemistry showed absent PMS2 expression in all tumors and normal tissue. Most tumors showed microsatellite instability, more marked at dinucleotide than mononucleotide repeats. The tumors harbored no somatic mutations in APC, BRAF, AXIN2, or beta-catenin, but KRAS2 and TGFBR2 mutations were found. Our patient represents a novel phenotype for homozygous PMS2 mutation and perhaps the most severe colorectal cancer phenotype-in terms of numbers of malignancies at an early age-described to date. PMS2 mutations-and perhaps other homozygous mismatch repair mutations-should be considered in any patient presenting with multiple gastrointestinal tumors, since our patient could not be distinguished clinically from cases with attenuated familial adenomatous polyposis or MUTYH-associated polyposis.

多彩な消化管腫ようを合併した腫りゅう形成型大腸アミロイドーシスの１例

症例は66歳男性.便潜血反応陽性のため当科受診し,盲腸腫瘍を指摘され入院した.諸検査にて胃前庭部腫瘍,十二指腸球部ポリープ,盲腸の結節集籏様病変およびS状結腸の黄白色調多発粘膜下腫瘤を指摘した.前3者には手術を,S状結腸病変には内視鏡的粘膜切除を施行した,病理組織学的には胃前庭部腫瘍は粘膜下層まで浸潤した早期胃癌があり,その直下に平滑筋腫が併存していた.十二指腸ポリープは粘膜下層に主座を置くカルチノイドであり,盲腸の結節集籏様病変は粘膜層にとどまる腺管腺腫であった.S状結腸では粘膜下層に塊状のアミロイド沈着があり,それが黄白色腫瘤を形成していたが,他の消化管にはアミロイド沈着を証明しえなかった.アミロイドーシスに4種類もの多彩な消化管腫瘍を合併し,大腸にのみアミロイド沈着による腫瘤形成を認めたきわめて稀な1例であった.

Effect of Embryonic Tissue Immunization on Chemically Induced Gastrointestinal Tumors in Rats. I. Can Embryonic Antigens Act as Rejection Antigens?2

Inbred WF rats were inoculated with crude suspensions prepared from liver and gut tissue of 12- to 15-day fetuses of the same strain. Rats previously unsensitized to syngeneic embryonic tissue were inoculated with fetal material sc three times during exposure to 1, 2-dimethylhydrazine dihydrochloride (DMH), a gastrointestinal (GI) carcinogen in rodents. Properly timed immunization inhibited the development, growth, and metastasis of primary GI tumors. This effects was observed in both sexes; however, it was more prounced in male rats. Nine WF rats with DMH-induced carcinoma of the GI tract were inoculated sc with syngeneic fetal tissue. Of 9 rats, 7 rejected the embryonal tissue implants, which thus demonstrated the presence of a concomitant immune response to embryonic antigen(s). Two rats in which fetal tissue grew out to palpable nodules had multiple GI tumors with metastasis and extra-GI tumors, i.e., a massive tumor load. Ten other rats with DMH-induced GI tumors were treated with unblocking serum. The unblocking serum was inoculated to counteract serum-blocking factors in vivo. These rats were inoculated intradermally with syngeneic fetal tissue. In all 10 rats, inflammation and necrosis were noted at the inoculation site after 24-72 hours, which thus demonstrated a delayed hypersensitivity reaction to embryonic antigens. Our experiments suggest that embryonic antigens common to fetal and tumor cells can induce immunity in an autochthonous host and can act as rejection antigens.