Symptom Burden and Time from Symptom Onset to Cancer Diagnosis in Patients with Early-Onset Colorectal Cancer: A Multicenter Retrospective Analysis.

Background: The incidence of colorectal cancer (CRC) is decreasing in individuals >50 years due to organised screening but has increased for younger individuals. We characterized symptoms and their timing before diagnosis in young individuals. Methods: We identified all patients diagnosed with CRC between 1990-2017 in British Columbia, Canada. Individuals <50 years (n = 2544, EoCRC) and a matched cohort >50 (n = 2570, LoCRC) underwent chart review to identify CRC related symptoms at diagnosis and determine time from symptom onset to diagnosis. Results: Across all stages of CRC, EoCRC presented with significantly more symptoms than LoCRC (Stage 1 mean ± SD: 1.3 ± 0.9 vs. 0.7 ± 0.9, p = 0.0008; Stage 4: 3.3 ± 1.5 vs. 2.3 ± 1.7, p < 0.0001). Greater symptom burden at diagnosis was associated with worse survival in both EoCRC (p < 0.0001) and LoCRC (p < 0.0001). When controlling for cancer stage, both age (HR 0.87, 95% CI 0.8-1.0, p = 0.008) and increasing symptom number were independently associated with worse survival in multivariate models. Conclusions: Patients with EoCRC present with a greater number of symptoms of longer duration than LoCRC; however, time from patient reported symptom onset was not associated with worse outcomes.

Artificial intelligence in endoscopy: Overview, applications, and future directions.

Since the emergence of artificial intelligence (AI) in medicine, endoscopy applications in gastroenterology have been at the forefront of innovations. The ever-increasing number of studies necessitates the need to organize and classify applications in a useful way. Separating AI capabilities by computer aided detection (CADe), diagnosis (CADx), and quality assessment (CADq) allows for a systematic evaluation of each application. CADe studies have shown promise in accurate detection of esophageal, gastric and colonic neoplasia as well as identifying sources of bleeding and Crohn's disease in the small bowel. While more advanced CADx applications employ optical biopsies to give further information to characterize neoplasia and grade inflammatory disease, diverse CADq applications ensure quality and increase the efficiency of procedures. Future applications show promise in advanced therapeutic modalities and integrated systems that provide multimodal capabilities. AI is set to revolutionize clinical decision making and performance of endoscopy.

Treatment Patterns and Outcomes of Preoperative Neoadjuvant Radiotherapy in Patients with Early-onset Rectal Cancer.

Preoperative radiotherapy for early-stage rectal cancer has risks and benefits that may impact treatment choice in young patients. We reviewed radiotherapy use and outcomes for rectal cancer by age. Patients with early-stage rectal cancer in the Canadian province of British Columbia from 2002 to 2016 were identified (n = 6,232). Baseline characteristics, treatment response, overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and locoregional recurrence rate (LRR) were compared between patients <50 (early-onset; n = 532) and ≥50 years old (average-onset; n = 5,700). Early-onset patients were more likely to receive preoperative chemoradiotherapy than short-course radiotherapy [OR, 2.20; 95% confidence interval (CI), 1.67-2.89; P < 0.0001], but also had higher nodal (P = 0.00096) and overall clinical staging (P = 0.033). Cancer downstaging and pathologic complete response rates were similar in those receiving neoadjuvant chemoradiotherapy by age. Early-onset and average-onset patients had similar DSS (P = 0.91) and DFS (P = 0.27) in multivariate analysis unless non-colorectal deaths, which were higher in older patients, were censored in the DFS model (HR, 1.30; 95% CI, 1.01-1.68; P = 0.042). LRR also did not differ between age groups (P = 0.88). Outcomes did not differ based on radiotherapy type. Young patients with rectal cancer are more likely to present with higher staging and receive long-course chemoradiotherapy. DSS did not differ by age group; however, young patients had worse DFS when we censored competing risks of death in older patients. Significance: This population-based study suggests younger patients are more likely to receive chemoradiotherapy, potentially due to higher stage at diagnosis, and response is comparable by age.

Inflammation-Induced Metastatic Colonization of the Lung Is Facilitated by Hepatocyte Growth Factor-Secreting Monocyte-Derived Macrophages.

A rate-limiting step for circulating tumor cells to colonize distant organ sites is their ability to locate a microenvironmental niche that supports their survival and growth. This can be achieved by features intrinsic to the tumor cells and/or by the conditioning of a "premetastatic" niche. To determine if pulmonary inflammation promotes the latter, we initiated models for inflammatory asthma, hypersensitivity pneumonitis, or bleomycin-induced sterile inflammation before introducing tumor cells with low metastatic potential into the circulation. All types of inflammation increased the end-stage metastatic burden of the lungs 14 days after tumor cell inoculation without overtly affecting tumor extravasation. Instead, the number and size of early micrometastatic lesions found within the interstitial tissues 96 hours after tumor cell inoculation were increased in the inflamed lungs, coincident with increased tumor cell survival and the presence of nearby inflammation-induced monocyte-derived macrophages (MoDM; CD11b+CD11c+). Remarkably, the adoptive transfer of these MoDM was sufficient to increase lung metastasis in the absence of inflammation. These inflammation-induced MoDM secrete a number of growth factors and cytokines, one of which is hepatocyte growth factor (HGF), that augmented tumor cell survival under conditions of stress in vitro. Importantly, blocking HGF signaling with the cMET inhibitor capmatinib abolished inflammation-induced early micrometastatic lesion formation in vivo. These findings indicate that inflammation-induced MoDM and HGF in particular increase the efficiency of early metastatic colonization in the lung by locally preconditioning the microenvironment. IMPLICATIONS: Inflammation preconditions the distant site microenvironment to increase the metastatic potential of tumor cells that arrive there.

Hereditary and Inflammatory Bowel Disease-Related Early Onset Colorectal Cancer Have Unique Characteristics and Clinical Course Compared with Sporadic Disease.

BACKGROUND: Early onset colorectal cancer (EoCRC), diagnosed in those <50 years old, is increasing in incidence. We sought to differentiate characteristics and outcomes of EoCRC in patients with sporadic disease or preexisting conditions. METHODS: We evaluated 2,135 patients with EoCRC in a population-based cohort from the Canadian province of British Columbia. Patients were identified on the basis of presence of hereditary syndromes (n = 146) or inflammatory bowel disease (IBD; n = 87) and compared with patients with sporadic EoCRC (n = 1,902). RESULTS: Proportions of patients with preexisting conditions were highest in the youngest decile of 18-29 (34.3%, P < 0.0001). Patients with sporadic EoCRC were older, more likely female, and had increased BMI (P < 0.05). IBD-related EoCRC had the highest rates of metastatic disease, poor differentiation, adverse histology, lymphovascular, and perineural invasion (P < 0.05). Survival was lower in patients with IBD (HR, 1.80; 95% CI, 1.54-3.13; P < 0.0001) and higher in hereditary EoCRC (HR, 0.47; 95% CI, 0.45-0.73; P < 0.0001) compared with sporadic. Prognosis did not differ between ulcerative colitis or Crohn's disease but was lower in those with undifferentiated-IBD (HR, 1.87; 95% CI, 1.01-4.05; P = 0.049). Lynch syndrome EoCRC had improved survival over familial adenomatous polyposis (HR, 0.31; 95% CI, 0.054-0.57; P = 0.0037) and other syndromes (HR, 0.43; 95% CI, 0.11-0.99; P = 0.049). In multivariate analysis controlling for prognostic factors, hereditary EoCRC was unchanged from sporadic; however, IBD-related EoCRC had worse overall survival (HR, 2.21; 95% CI, 1.55-3.16; P < 0.0001). CONCLUSIONS: EoCRC is heterogenous and patients with preexisting conditions have different characteristics and outcomes compared with sporadic disease. IMPACT: Prognostic differences identified here for young patients with colorectal cancer and predisposing conditions may help facilitate treatment planning and patient counseling.See related commentary by Hayes, p. 1775.

Pancreatic Gastrinoma, Gastrointestinal Stromal Tumor (GIST), Pheochromocytoma, and Hürthle Cell Neoplasm in a Patient with Neurofibromatosis Type 1: A Case Report and Literature Review.

BACKGROUND Neurofibromatosis type 1 (NF1) is a multi-tumor syndrome in which affected patients develop malignancies that are rare in the overall population, such as tumors of neural or endocrine origin. CASE REPORT A 67-year-old woman with a clinical diagnosis of NF1 presented with abdominal pain and pneumoperitoneum. She underwent small-bowel resections for a perforated jejunal lesion and a second lesion in the ileum; pathology showed a neurofibroma at the site of the perforation and a 1-cm low-grade GIST, respectively. Additional staging with cross-sectional imaging identified a 3.7-cm pancreatic head mass and a 1.7-cm left adrenal mass; biochemical studies revealed elevated serum gastrin and urinary free metanephrines and catecholamines consistent with pheochromocytoma. Initial surgical management was a left posterior retroperitoneoscopic adrenalectomy. Postoperatively, gallium-68-DOTATOC PET/CT showed uptake in the pancreatic head and a 28-mm left thyroid nodule. Months later, she had an open pancreaticoduodenectomy. Pathology showed pheochromocytoma and a low-grade (G1) gastrinoma involving 2/8 peripancreatic lymph nodes (pT3pN1M0), respectively. Fine-needle aspiration biopsy of the thyroid nodule showed features consistent with a Hürthle cell neoplasm. Genetic testing identified a pathogenic mutation in NF1 and no mutations in BRCA1/2, CDC72, MEN1, or PALB2. The patient continues surveillance, with no evidence of recurrent disease. CONCLUSIONS We report the fifth case of gastrinoma associated with NF1 and the first to arise from the pancreas. This case of a pancreatic neuroendocrine tumor was associated with multiple additional neoplasms. Neuroendocrine tumors found in NF1 should raise suspicion of other malignancies.

Efficacy of stomach-partitioning on gastric emptying in patients undergoing palliative gastrojejunostomy for malign gastric outlet obstruction.

BACKGROUND: Palliative efficacy of conventional gastrojejunostomy in palliation of malignant gastric outlet obstruction is debatable. This study aims to compare the outcomes of conventional gastrojejunostomy and stomach-partitioning gastrojejunostomy and to explore the factors influencing the delayed gastric emptying after surgery in patients with malignant gastric outlet obstruction. METHODS: The study subjects were divided into the following two groups based on whether the stomach was partitioned or not: Conventional gastrojejunostomy and stomach-partitioning gastrojejunostomy. All demographic data, patient characteristics, postoperative outcomes, including delayed gastric emptying grade and 30-day complications were collected. Following the comparison of the clinical outcomes, risk factors for delayed gastric emptying were determined by regression models. RESULTS: Fifty-three patients were included in this study. Of these, 37 patients underwent conventional gastrojejunostomy, whereas 16 patients underwent stomach-partitioning gastrojejunostomy. Patient demographics and baseline characteristics were comparable between groups. Although 10 (27%) patients in the conventional gastrojejunostomy group had delayed gastric emptying grade B-C, no patient in the stomach-partitioning gastrojejunostomy group experienced this condition. There was no difference between the groups concerning hospital stay and complications. In multivariate regression analysis, having distant metastasis (OR=0.156, 95%CI 0.034-0.720, p=0.017) and stomach-partitioning (OR=0.127, 95%CI 0.025-0.653, p=0.014) were found as independent factors for the delayed gastric emptying. CONCLUSION: In patients with malignant gastric outlet obstruction, compared with conventional gastrojejunostomy, stomach-partitioning may provide favorable clinical outcomes by improving gastric emptying.

Hyaluronan-binding by CD44 reduces the memory potential of activated murine CD8 T cells.

Expansion and death of effector CD8 T cells are regulated to limit immunopathology and cells that escape contraction go on to generate immunological memory. CD44, a receptor for the extracellular matrix component hyaluronan, is a marker of activated and memory T cells. Here, we show with a murine model that the increase in CD44 expression and hyaluronan binding induced upon CD8 T cell activation was proportional to the strength of TCR engagement, thereby identifying the most strongly activated T cells. When CD44-/- and CD44+/+ OT-I CD8 T cells were adoptively transferred into mice challenged with Listeria-OVA, there was a slight increase in the percentage of CD44+/+ cells at the effector site. However, CD44+/+ cells were out-competed by CD44-/- cells after the contraction phase in the lymphoid tissues, and the CD44-/- cells preferentially formed more memory cells. The hyaluronan-binding CD44+/+ CD8 effector T cells showed increased pAkt expression, higher glucose uptake, and were more susceptible to cell death during the contraction phase compared to non-binding CD44+/+ and CD44-/- OT-I CD8 T cells, suggesting that CD44 and its engagement with hyaluronan skews CD8 T cells toward a terminal effector differentiation state that reduces their ability to form memory cells.

Endotoxin free hyaluronan and hyaluronan fragments do not stimulate TNF-α, interleukin-12 or upregulate co-stimulatory molecules in dendritic cells or macrophages.

The extracellular matrix glycosaminoglycan, hyaluronan, has been described as a regulator of tissue inflammation, with hyaluronan fragments reported to stimulate innate immune cells. High molecular mass hyaluronan is normally present in tissues, but upon inflammation lower molecular mass fragments are generated. It is unclear if these hyaluronan fragments induce an inflammatory response or are a consequence of inflammation. In this study, mouse bone marrow derived macrophages and dendritic cells (DCs) were stimulated with various sizes of hyaluronan from different sources, fragmented hyaluronan, hyaluronidases and heavy chain modified-hyaluronan (HA-HC). Key pro-inflammatory molecules, tumour necrosis factor alpha, interleukin-1 beta, interleukin-12, CCL3, and the co-stimulatory molecules, CD40 and CD86 were measured. Only human umbilical cord hyaluronan, bovine testes and Streptomyces hyaluronlyticus hyaluronidase stimulated macrophages and DCs, however, these reagents were found to be contaminated with endotoxin, which was not fully removed by polymyxin B treatment. In contrast, pharmaceutical grade hyaluronan and hyaluronan fragments failed to stimulate in vitro-derived or ex vivo macrophages and DCs, and did not induce leukocyte recruitment after intratracheal instillation into mouse lungs. Hence, endotoxin-free pharmaceutical grade hyaluronan does not stimulate macrophages and DCs in our inflammatory models. These results emphasize the importance of ensuring hyaluronan preparations are endotoxin free.

Generation and Identification of GM-CSF Derived Alveolar-like Macrophages and Dendritic Cells From Mouse Bone Marrow.

Macrophages and dendritic cells (DCs) are innate immune cells found in tissues and lymphoid organs that play a key role in the defense against pathogens. However, they are difficult to isolate in sufficient numbers to study them in detail, therefore, in vitro models have been developed. In vitro cultures of bone marrow-derived macrophages and dendritic cells are well-established and valuable methods for immunological studies. Here, a method for culturing and identifying both DCs and macrophages from a single culture of primary mouse bone marrow cells using the cytokine granulocyte macrophage colony-stimulating factor (GM-CSF) is described. This protocol is based on the established procedure first developed by Lutz et al. in 1999 for bone marrow-derived DCs. The culture is heterogeneous, and MHCII and fluoresceinated hyaluronan (FL-HA) are used to distinguish macrophages from immature and mature DCs. These GM-CSF derived macrophages provide a convenient source of in vitro derived macrophages that closely resemble alveolar macrophages in both phenotype and function.

Hyaluronan Binding Identifies a Functionally Distinct Alveolar Macrophage-like Population in Bone Marrow-Derived Dendritic Cell Cultures.

Although classical dendritic cells (DCs) arise from distinct progenitors in the bone marrow, the origin of inflammatory DCs and the distinction between monocyte-derived DCs and macrophages is less clear. In vitro culture of mouse bone marrow cells with GM-CSF is a well-established method to generate DCs, but GM-CSF has also been used to generate bone marrow-derived macrophages. In this article, we identify a distinct subpopulation of cells within the GM-CSF bone marrow-derived DC culture based on their ability to bind hyaluronan (HA), a major component of the extracellular matrix and ligand for CD44. HA identified a morphologically distinct subpopulation of cells within the immature DC population (CD11c(+) MHC II(mid/low)) that were CCR5(+)/CCR7(-) and proliferated in response to GM-CSF, but, unlike immature DCs, did not develop into mature DCs expressing CCR7 and high levels of MHC II, even after stimulation with LPS. The majority of these cells produced TNF-α in response to LPS but were unable to activate naive T cells, whereas the majority of mature DCs produced IL-12 and activated naive T cells. This HA binding population shared many characteristics with alveolar macrophages and was retained in the alveolar space after lung instillation even after LPS stimulation, whereas the MHC II(high) mature DCs were found in the draining lymph node. Thus, HA binding in combination with MHC II expression can be used to identify alveolar-like macrophages from GM-CSF-treated bone marrow cultures, which provides a useful in vitro model to study alveolar macrophages.