tbuckley/cabot-search huggingface dataset:
Association of methylation silencing of <i>ULK2</i> via epithelial-mesenchymal transition and differentiated gastric cancers.
Authors: Iori Motoo, Sohachi Nanjo, Takayuki Ando, Ichiro Yasuda
Journal: Journal of Clinical Oncology (2024)

404 Background: Diffuse-type gastric cancers (DGC) typically have a poor prognosis related to their invasion and metastasis, in which the epithelial–mesenchymal transition (EMT) is the initiation step. ULK2 plays a role in the autophagy initiation, which might provide a survival advantage in cancer cells. Although knock-down of ULK2 reportedly induces autophagy and EMT in a lung cancer cell line, the mechanism of EMT via the downregulation of ULK2, as well as its clinical significance, remains yet unclear. The present study, therefore, aims at clarifying this mechanism and its clinical significance in gastric cancers. Methods: We examined ULK2 mRNA expression in gastric cancer tissues and normal gastric tissues of healthy people. The effects of knock-downed ULK2 were examined in two gastric cancer cells, which were investigated in terms of their gene expression changes by the mRNA microarray. Furthermore, to investigate the carcinogenic process from normal gastric epithelial cells, we used RGE cells, which were conditionally immortalized normal gastric epithelial cells developed from a transgenic rat. Results: ULK2 mRNA expression of gastric cancer tissues was significantly lower than H. pylori-negative normal tissues. ULK2 was strongly expressed in normal tissues and intestinal-type gastric cancers (IGC) but was scarcely expressed in DGC by immunohistochemical staining. Furthermore, we found that the ULK2 methylation level of gastric cancer tissues was higher than H. pylori-negative normal tissues and IGC. Then, we validated whether knock-down of ULK2 could induce autophagy, cell migration, and EMT in NUGC3 and MKN45 cells. Using mRNA microarray analysis, we confirmed that knock-down of ULK2 changed expressions of oncogenic genes associated with cell migration and EMT. Autophagy inhibitor suppressed cell migration and EMT induced by knock-down of ULK2 in NUGC3 and MKN45. Additionally, we found that knock-down of Ulk2 induced apoptosis in normal gastric epithelial cells. Conclusions: Methylation silencing of ULK2 in gastric cancer cells could induce cell migration and EMT by means of autophagy induction, causing transformation to poorly differentiated cancers.
Insulin resistance and impaired insulin secretion and gastrointestinal cancer risk in Korean adults: Preliminary results from Korean Genome and Epidemiology study.
Authors: Hyemin Jo, Cheol Min Shin, Soyeon Ahn, Jung Hun Ohn, Eunjeong Ji, Yonghoon Choi, Yu Kyung Jun, Hyuk Yoon, Young Soo Park, Nayoung Kim, Dong Ho Lee
Journal: Journal of Clinical Oncology (2024)

761 Background: To date, few studies conducted on the effect of insulin resistance or insulin secretory function on cancer risk in non-diabetic population. This study evaluated whether insulin resistance and/or insulin secretory function affect gastrointestinal cancer risk in the Korean population. Methods: We analyzed data from Korean Genome and Epidemiology Study, Korea Association Resource dataset. It consists of 10,030 participants aged 40-69y observed from 2001 to 2018. The risk of all cancers, and gastrointestinal cancers were assessed. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Homeostasis Model Assessment of Beta-cell function (HOMA-β) were used as indicators of insulin resistance and insulin secretory function. Results: In the final dataset, 8,649 individuals without previous history of any cancers were included. During an average follow-up of 15 years, 415 subjects (4.8%) developed cancers. Compared to the low HOMA-IR/high HOMA-β group (reference), diabetic patients had the highest risk of overall cancers, followed by high HOMA-IR/low HOMA-β group (Adjusted hazard ratio[95% confidence interval]: 1.74 [1.11 - 2.75] and 1.40 [0.96 – 2.06], respectively) Among gastrointestinal cancers, the risk of gastric cancer was higher in the low HOMA-IR/low HOMA-β and high HOMA-IR/high HOMA-β groups (1.92 [1.06 - 3.47] and 2.27 [1.26 - 4.06], respectively) When further analyzed by HOMA-β stratified by quartiles, the lowest quartile (Q1) showed an increased risk of gastric cancer compared to the highest-quartile (Q4; 1.84 [0.98 – 3.46], p = 0.06) In contrast, no significant results were observed regarding the colorectal cancer risk, when analyzed based on HOMA-IR and HOMA-β. However, when further analyzed by HOMA-IR stratified by quartiles, the highest quartile (Q4) exhibited a significantly elevated colorectal cancer risk compared to the lowest quartile (Q1; 2.14 [1.11 - 4.11], P for trend = 0.04). Conclusions: Insulin resistance and impaired insulin secretion function may increase the risk of cancer, but the underlying mechanisms may differ by cancer type.
Comparison of neoadjuvant treatment modalities for locally advanced intrahepatic cholangiocarcinoma.
Authors: Esteban Garita, Muhammad Mohid Tahir, Santiago Sucre, Juan Jose Juarez, Mary Linton Bounetheau Peters, Ammar Sarwar, Andrea J. Bullock
Journal: Journal of Clinical Oncology (2024)

510 Background: The only curative therapy available for intrahepatic cholangiocarcinoma (IHCC) is resection. Nonetheless, most patients (pts) are diagnosed at a more advanced stage. In this population, using neoadjuvant treatment—locoregional therapies, systemic chemotherapy, or a combination—may improve survival outcomes and downstage them to resectable. We present data comparing survival outcomes (median overall survival [mOS], median progression-free survival [mPFS]) and resection rate (RR) among pts with locally advanced IHCC who received chemotherapy (CT-only), Y90-TARE with chemotherapy (Y90+CT) or Y90-TARE alone (Y90-only) as neoadjuvant treatment. Methods: A retrospective chart review of all pts from October 2015 to December 2022 with biopsy-proven IHCC was completed. Exclusion criteria included ECOG ≥ 2, stage IV extrahepatic disease, and having received previous treatment for IHCC. We defined the Y90+CT arm as pts who received ≤ 4 cycles before Y90 or chemotherapy &lt; 8 weeks after Y90. Statistical analysis was performed with Chi-square, Fisher’s Exact, and Kruskal-Wallis tests. Kaplan-Meier analysis was used for survival calculations and a Log-rank test to compare the arms. Survival is reported as median and 95% confidence interval [CI]. Results: A total of 56 pts were included: 23 pts in the CT-only arm, 15 in the Y90+CT arm, and 18 in the Y90-only arm. The median age at diagnosis was 69 years (IQR 59-74), and 54% were male. There was no statistically significant difference in age at diagnosis or sex between the three arms. RR was 1/23 (4%), 5/10 (50%), and 7/11 (64%) in the CT-only, Y90+CT, and Y90-only arms, respectively (CT-only vs. Y90+CT, p&lt;0.03; CT-only vs. Y90-only, p=0.01). mOS and mPFS for the cohort were 16.3 months [15.3–17.3] and 7.4 months [5.1–9.6]. Per arm, the mOS were 12.4 months [10.1—14.6], 24.3 months [23.3—25.3], and 24.3 months [23.0—25.6] for CT-only, Y90+CT, and Y90-only arms, respectively (CT-only vs. Y90+CT, p&lt;0.03; CT-only vs. Y90-only, p&lt;0.01). The mPFS were 3.5 months [1.1—5.9], 6.2 months [3.8—8.6], and 10.5 months [8.3—12.6], respectively (CT-only vs. Y90-only, p&lt;0.01; Y90+CT vs. Y90-only, p&lt;0.02). Conclusions: In the neoadjuvant setting, including Y90 as a treatment modality may improve survival outcomes and resection rates compared to using chemotherapy alone. Further analysis will include running the Cox multivariate regression model to control for factors that may affect treatment selection in this population.
The distribution of human epidermal growth factor receptor 2 (HER2) expression and the efficacy and safety of treatments in HER2-expressing advanced or metastatic gastroesophageal cancer: A systematic literature review (SLR).
Authors: David Bing Zhen, Naomi RM Schwartz, Rachel Beckerman, Janicec Stricker-Shaver, Mingshu Zhu, Hemanth Gadikota, Emilie Scherrer
Journal: Journal of Clinical Oncology (2024)

405 Background: HER2 overexpression plays an important role in determining treatment options for patients with gastroesophageal cancer (GEC). HER2 overexpression has historically been defined dichotomously as HER2-positive (HER2+) or HER2-negative. An emerging potentially clinically relevant category is HER2-low, which could be targeted with HER2-directed antibody drug conjugates. However, data on the epidemiology and outcomes associated with HER2-low GEC are limited. Methods: An SLR of PubMed, Embase, and Cochrane Central Register of Controlled Trials databases was conducted to identify clinical trials, observational studies, and meta-analyses reporting clinical outcomes or distribution of HER2 expression by IHC and ISH in advanced or metastatic (a/m) GEC. Key inclusion criteria were: English language, published between 2013-2023, and sample size ≥100 HER2-expressing patients. HER2+ was defined as IHC score of 3+ or IHC 2+ and ISH+. HER2-low was defined as IHC 1+ or IHC 2+ and ISH-. Weighted averages were calculated for the proportion of patients who were HER2+ and HER2-low to estimate of the proportion of patients in each HER2 expression category. Results were categorized by patient population (all GEC or gastric cancer [GC] only). Results: Of 2,701 non-duplicated records screened, 174 studies met inclusion criteria. Distribution of HER2 expression was reported in 111 studies, 5 of which reported on the frequency of HER2 expression of IHC 1+ and/or IHC 2+ and ISH+. HER2 expression status varied by patient population, with a weighted average of 26.9% for HER2-low and 13.1-16.5% for HER2+ across groups (Table). Different cutoffs for HER2 amplification via ISH also affected the proportion of patients in each HER2 category across studies. Efficacy and safety outcomes were stratified by HER2 status or IHC results in 74 studies. However, only 3 observational studies reported outcomes separately for the HER2-low population, and results were inconclusive. Conclusions: The distribution of HER2 expression in a/m GEC in the identified studies is highly heterogenous, likely due to variability in IHC scoring and patient populations. Few studies with sufficient samples size (≥100 patients with HER2-expression a/mGEC) reported outcomes for HER2-low a/m GEC, and those that were identified were of low quality. The HER2-low a/m GEC population constitutes an unmet need for effective therapy. There is a need for consistent use of a standardized definition of HER2-low in a/mGEC and additional studies to better evaluate treatment options and outcomes for this patient population. [Table: see text]
Cardiometabolic risk comorbidities in exocrine pancreatic insufficiency compared to patients with cancer: A single centered observational retrospective cohort study.
Authors: James Peeples, James Gore, Karina G. Romo, Abdullah A. Noor, Gabriel I. Uwaifo
Journal: Journal of Clinical Oncology (2024)

642 Background: Exocrine pancreatic insufficiency (EPI) is characterized by inadequate secretion of digestive enzymes. EPI is associated with increased risk for pancreatic cancer as well as increased risk for diabetes and consequently cardiometabolic (CM) risk equivalents. Emerging data suggest patients with cancer also have increased CM risk equivalents. To explore the cardiovascular risk associated with both EPI and cancer, we sought to describe and compare CM comorbidities and surrogates in patients with EPI vs cancer. Methods: A retrospective observational electronic chart analysis was done at Ochsner Health, Louisiana, spanning records from January 2017-2020 comparing two cohorts: patients with EPI (n=677) and patients with Cancer (n=1432). Results: The Cancer cohort was older (65.1 ± 11.9 yrs) than the EPI cohort (54.2 ± 17.6 yrs) (p &lt; 0.05). The Cancer cohort had higher AST levels (63.2 ± 106.2 U/L [nl 8-33 U/L] at start, 84.9 ± 447.3 U/L at end) vs the EPI cohort (50.2 ± 86.9 U/L at start, 65.4 ± 368.9 U/L at end) (p &lt; 0.05). The Cancer cohort also had higher ALT levels (69 ± 111.4 U/L (nl 7-55 U/L) at start, 58.5 ± 141.2 U/L at end) vs the EPI cohort (48.7 ± 79.5 U/L at start, 41.4 ± 100.3 U/L at end) (p &lt; 0.05). No significant differences were seen in Cancer cohort vs EPI cohort for A1c, TG, amylase, lipase, cholesterol, uric acid, tobacco/alcohol use, or blood pressure levels. Within the Cancer cohort, there was an increase in neuropathy (11% at the start vs 26.9% at end [p &lt; 0.05]), CHF (3.63% at the start vs 11.5% at end [p &lt; 0.05]), and HTN prevalence (29.9% at the start vs 66.1% at end [p &lt; 0.05]). Cancer patients also had decreased weight (175.2 ± 46.5 lbs at start, 163.8 ± 43.4 lbs at end [p &lt; 0.05]) and BMI (27.3 ± 6.5 at start, 25.7 ± 6.4 at end [p &lt; 0.05]). Among the general cancer cohort, no statistically different changes were seen in hypoglycemia, DKA, retinopathy, nephropathy, ESRD, dialysis, HLD, NAFLD, OSA, CAD, CVD, PAD, hyperuricemia, or gout prevalence over the period of observation or in comparison to EPI cohort. Conclusions: Patients in the Cancer cohort in this study have some indices of greater CM risk compared to those with EPI. Though older, they had significantly higher AST and ALT levels compared to EPI cohort. Over the 3 years of observation, cancer patients developed a statistically significant increase in neuropathy, CHF, and HTN prevalence, and decrease in weight and BMI. These changes may reflect consequent morbidity related both to natural disease progression and/or effects of cancer treatments such as chemotherapy.
Histopathologic and genomic profile characteristics of biliary cancers related to pancreaticobiliary maljunction.
Authors: Shodai Tohyama, Hiroshi Ohyama, Izumi Ohno, Kenji Amemiya, Yosuke Hirotsu, Miho Sakai, Kazuki Watabe, Nana Yamada, Jihei Sugihara, Mayu Ohuchi, Motoyasu Kan, Hiroki Nagashima, Koji Takahashi, Kohichiro Okitsu, Takashi Mishima, Tsukasa Takayashiki, Hitoshi Mochizuki, Masayuki Ohtsuka, Naoya Kato, Masao Omata
Journal: Journal of Clinical Oncology (2024)

527 Background: Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic duct and bile duct anatomically merge outside the duodenal wall, and is associated with a high rate of biliary cancer. It has been reported that TP53 and KRAS mutations are found not only in the cancerous area but also in the noncancerous area. However, there is no report of precise mapping of genetic mutations throughout the gallbladder and bile ducts. Methods: Ninety-seven patients (including 31 patients with biliary cancer) who underwent cholecystectomy and cholangiectomy for PBM between 1990 and 2023 at our hospital and affiliated hospitals were included in the study, and consent forms were obtained from 36 patients. The panel targeting 60 genes frequently identified in biliary tract cancer was created in-house and deep sequenced to compare with clinicopathological features. To date, we have analyzed 4 patients with biliary tract cancer and 5 patients without it (with prophylactic resection). The same analysis was also performed on cancerous and noncancerous parts of patients of gallbladder cancer and cholangiocarcinoma without confluence abnormalities for comparison. Results: A total of 33 Samples (7 cancerous parts and 26 noncancerous parts) were examined for biliary tract cancer. We found a variety of functional gene abnormalities, including driver mutations such as TP53, ARID2, and BRCA2, in 9 non-cancerous areas including hyperplasia and normal bile duct mucosa. Some of these mutations were not shared with cancerous areas. On the other hand, in 46 samples from 5 patients who did not develop gallbladder cancer (prophylactic resection), Driver mutations were found in only 3 sites. Pathological findings of dysplasia/hyperplasia in these prophylactic resections were observed in 28 of the 46 sections. In addition, Driver mutations were rarely observed in noncancerous areas in patients with normal gallbladder or cholangiocarcinoma. Conclusions: Unlike conventional biliary tract cancers, the patients with PBM showed a great variety of genetic abnormalities in both cancerous and noncancerous areas. On the other hand, in patients of prophylactic resection without cancer, driver mutations were almost completely absent despite the presence of mucosal changes. We believe that these findings can develop better strategy for biliary cancers with PBM.
The impact of multidisciplinary care for locally advanced rectal cancer referrals: A systems perspective.
Authors: Victor Lo, Ranjeeta Mallick, Rachel Anne Goodwin, Joanna Gotfrit
Journal: Journal of Clinical Oncology (2024)

85 Background: Locally advanced rectal cancer patients require multidisciplinary care for treatment planning. We sought to determine whether the order of surgical and radiation oncology consultation in relation to medical oncology consultation affects the time from cancer diagnosis to treatment initiation and the requirement for additional pre-treatment visits with medical oncology. Methods: We conducted a retrospective chart review of adult patients referred to The Ottawa Hospital with locally advanced rectal adenocarcinoma, seen in consultation by a surgical, radiation, and medical oncologist between January 2018 and December 2022. Results: Of 195 patients, the median time from diagnosis to treatment was 55 days (IQR: 45-68). Both surgical and radiation oncology consultation preceded medical oncology consultation in a minority of patients (72; 37%), and 48 (25%) patients required multidisciplinary cancer conference (MCC) discussion. However, the time from cancer diagnosis to treatment initiation was not significantly different between patients who were and were not seen by the surgeon and radiation oncologist prior to the medical oncologist (56 vs. 55 days respectively), nor if MCC discussions were or were not required (55 vs. 55 days). However, almost half of all patients (93; 48%) required an additional pre-treatment visit with their medical oncologist, and patients who saw both surgical and radiation oncology prior were significantly less likely to require additional pre-treatment visits with medical oncology (25% vs. 61%; p&lt;0.0001). Conclusions: The time from cancer diagnosis to treatment initiation was not significantly impacted by the order of specialist consultations with the multidisciplinary team, nor if patients required MCC discussion or additional pre-treatment visits with medical oncology. However additional pre-treatment visits with medical oncology were significantly more likely to occur when patients were seen by medical oncology prior to surgical and/or radiation oncology, representing a logistical and financial inefficiency in the system, and a potential area for process improvement. [Table: see text]
Retrospective review of compliance with guideline-directed germline testing in microsatellite instability-high colorectal cancer treated at the Veterans Health Administration.
Authors: Karly Williams Silva, Stacey A. Cohen, M. Carmen Frias Kletecka, George Ioannou, Deniz Aslan, Daniel Jacob Becker, Avi Kenny, Robert Bruce Montgomery
Journal: Journal of Clinical Oncology (2024)

86 Background: Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome that confers an increased risk of colorectal cancer (CRC). As clinical and history features under-recognize LS cases (3-5% of CRC), universal screening of CRCs for LS is recommended. Patients whose CRCs are mismatch repair protein deficient (dMMR) and/or microsatellite instability high (MSI-H) are recommended to have subsequent genetics evaluation to screen for germline mutations. Confirmed LS changes cancer surveillance recommendations for affected patients and their relatives. Within Veterans Health Administration (VHA), GT is ordered by genetic counselors at genomic medicine telehealth centers (GMTC), after initial consultation. We aim to quantify rates at which CRC patients treated at the VHA complete germline testing (GT) when indicated. Methods: The electronic health records (EHRs) of VHA patients with known dMMR/MSI-H CRC were reviewed. Cases were extracted from both Veterans Affairs (VA) Puget Sound and referral VA MSI testing laboratories. Surgical pathology reports and clinical documentation were reviewed in Joint Longitudinal Viewer (JLV) to determine if GT was indicated and reason for non-testing, if not performed. Patients with known LS prior to development of CRC were excluded, and patients with dMMR in MLH1 or MSI-H with concurrent BRAFV600 mutation and/or MLH1 hypermethylation were considered to have sporadic CRC. Results: Of 110 patients with abnormal tumor LS screening; 39 (36%) patients’ tumor tissue underwent IHC for dMMR, 16 (14%) underwent PCR for MSI, and 55 (50%) had both. 45 (41%) patients were classified as somatic MSI-H. 65 (59%) patients met criteria for referral for GMTC and GT. Of these 65, 49 ultimately did not undergo GT and 16 did, which confirmed 4 cases of LS and revealed 1 variant of uncertain significance in the MLH1 gene. Reasons for non-testing were: 7 (14%) declined all cancer testing and treatment after CRC diagnosis or were lost to follow-up/declined establishment of cancer care, 3 (6%) declined referral to GMTC, 14 (29%) accepted referral to GMTC but never had consultation, 7 (14%) accepted referral to GMTC but declined GT when offered, and 18 (37%) were never offered GMTC referral or GT. Conclusions: A majority of dMMR/MSI-H cases with an indication for GT were referred for genetic counseling, but only a small subset completed testing. This analysis identified multiple areas for improvement, including a lack of recognition by providers for the need for GT, and lack of completion of testing by patients at multiple levels. Further evaluation of VHA-specific barriers is needed to improve the quality of delivered care.