bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world treatment patterns and outcomes in patients with mCRC by MMR/MSI status.
Authors: Crossland Victoria , Peng Jianling , Yin Yu , Huang Yu-Chung , Raizer Jeffrey , Parent Alexander A
Published: January 2024

52

Background: There are limited data on real-world (RW) treatment patterns and outcomes in patients (pts) with metastatic colorectal cancer (mCRC), especially those with deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) disease, as they progress through lines of therapy. Methods: Data were extracted from the Flatiron Health electronic health record-derived database. Pts aged ≥18 years diagnosed with mCRC and with ≥2 clinical visits between January 01, 2013 and October 31, 2022 were included. Treatment patterns by therapeutic category and specific agent/regimens were explored across 3 time periods anchored to the start date of first line (1L): years <2017, 2017–2019 and ≥2020 for pts both with dMMR/MSI-H and proficient mismatch repair (pMMR)/microsatellite stability (MSS) disease. Analyzed outcomes, by treatment category, included overall survival (OS), time to treatment discontinuation (TTD) and time to next treatment (TTNT). Descriptive statistics and Kaplan–Meier analyses were conducted. Results: A total of 34,853 pts with mCRC were identified; 24,622 pts (70.6%) were tested for MMR or MSI status, of whom 1,594 (6.5%) were dMMR or MSI-H. After applying key eligibility criteria, 938 dMMR/MSI-H and 12,305 pMMR/MSS pts were included. Overall, chemotherapy-based treatment was the most common treatment category given to pts, but the use of immuno-oncology (IO) agents increased over time. In the dMRR/MSI-H cohort, IO was the most commonly used treatment in 1L and 2L after 2020, driven largely by the use of pembrolizumab. The median OS (mOS) from start of 1L, irrespective of treatment type, was 30.30 months (95% confidence interval [CI]: 24.47, 34.41) in the dMMR/MSI-H cohort and 23.78 months (95% CI: 23.32, 24.34) in the pMMR/MSS cohort. For pts with dMMR/MSI-H, those receiving 1L IO had a mOS of 57.60 months (95% CI: 42.43, not reached [NR]). In pts who had IO after 1L-chemotherapy alone or chemotherapy + targeted treatment, mOS was 52.63 months (95% CI: 38.06, NR) and 59.61 months (95% CI: 34.41, NR), respectively. In pMMR/MSS pts, chemotherapy alone or chemotherapy + targeted treatment had the longest OS when received as 1L-therapy, at 23.88 months (95% CI: 22.89, 25.10) and 24.28 months (95% CI: 23.55, 25.10), respectively. The median TTD and TTNT from start date of 1L, irrespective of treatment type, were 4.90 months (95% CI: 4.28, 5.20) and 7.96 months (95% CI: 7.04, 8.78), respectively, in the dMRR/MSI-H cohort, and 5.79 months (95% CI: 5.72, 5.95) and 10.33 months (95% CI: 10.07, 10.59) in the pMMR/MSS cohort. Conclusions: These real-world data from over 10,000 pts with mCRC supplement findings from clinical trials and limited reported RW evidence. While IO demonstrates significant improvement for pts with dMMR/MSI-H, and mOS is similar regardless of whether IO is given in the 1L or later setting, there remains a high unmet need in pMMR/MSS for additional effective treatment options.
Safety and efficacy of external beam radiotherapy in hepatocellular carcinoma patients previously treated with yttrium-90 radioembolization.
Authors: Thonglert Kanokphorn , Tsai Joseph , Anderson August C , Nyflot Matthew J. , Bowen Stephen R. , Grassberger Clemens , Zaki Peter , He Yulun , Johnson Guy E. , Monsky Wayne L , Apisarnthanarax Smith
Published: January 2024

523

Background: Data on the safety and efficacy of external beam radiation (EBRT) after Yttrium-90 (Y-90) radioembolization for hepatocellular carcinoma (HCC) is limited. We report our experience using EBRT to treat HCC patients who were previously treated with Y-90. Methods: We analyzed 31 HCC patients who received EBRT following Y-90 treatment. Eighteen were treated with photon therapy (40-50 Gy in 5 fractions), and thirteen with proton therapy (42-67.5 Gy in 15 fractions). Twenty-four patients underwent Y-90 segmentectomies, while seven received Y-90 lobar treatment. The median administered Y-90 activity was 44.4 mCi (range 8.3-114.4). Results: Patients had received 1 (n=14), 2 (n=7), or ≥3 (n=10) prior Y-90 treatments. EBRT was administered for various reasons: poor Y-90 response in two patients, technical limitations in 25 patients, and other reasons in four patients. Ten patients had previously received Y-90 within the EBRT area, thirteen outside the EBRT area, and eight in both regions. The median tumor size was 3.8 cm (range 1.6-19.4). Twenty-seven patients had Child-Pugh (CP)-A score, three had CP-B, and one had CP-C baseline liver function. With a median follow-up of 21 months, the 2-year progression-free survival, and overall survival rates were 28%, and 43%, respectively. The 2-year cumulative incidence of local failure was 7%. CP+2 progression was observed in five patients (16%): three had Y-90 delivered outside the EBRT area and two within the EBRT area. Three patients had possible RILD-related deaths. Grade 3+ biliary complications occurred in three patients (10%): one biloma, one liver abscess, and one biliary stricture which resulted in a possible treatment-related death. All three patients had received at least two prior Y-90 treatment overlapping with the area treated with EBRT and had tumors located near the porta hepatis. Conclusions: EBRT for HCC patients previously treated with Y-90 is feasible and offers excellent local control. Hepatic function and biliary toxicities are potential complications and should be weighed against the clinical benefits.
Real-world treatment patterns and unmet need in patients with previously treated metastatic colorectal cancer that is not MSI-H or dMMR.
Authors: Desai Kaushal , Sura Sneha , Liu Zhimei , Amonkar Mayur , Jain Rishi , Niehoff Nicole , Wilson Thomas W , Patton Gregory A. , Cosgrove David
Published: January 2024

53

Background: Regorafenib and trifluridine/tipiracil (TAS-102) are standard of care (SoC) systemic anticancer treatments (SACT) for metastatic colorectal cancer (mCRC) patients perviously treated with fluoropyrimidine (5-FU), irinotecan, & oxaliplatin-based chemotherapy. However, evidence is limited on post-chemotherapy & later SACT for patients with mCRC that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This study assessed real-world patient characteristics and treatment patterns in community oncology practices among previously treated, not MSI-H/dMMR mCRC patients. Methods: This retrospective cohort study utilized The US Oncology Network (iKnowMed) electronic health record database, supplemented by chart review. The study cohort comprised adult, not MSI-H/dMMR mCRC patients treated with chemotherapy (5-FU/capecitabine, irinotecan, and oxaliplatin) who initiated subsequent SACT or received best supportive care (BSC) between 1/1/2016 & 12/31/2021. Index date for SACT users was the regimen start date. For patients on BSC and no subsequent SACT/BSC, index date was last chemotherapy administration date. Patients were followed from index date through 8/31/2022, date of death or last contact date, whichever occurred first. Descriptive statistics were used to report patient and treatment characteristics. Results: The study consisted of 292 mCRC patients, with a median age of 57 (range: 49, 68) years. The predominant histology was adenocarcinoma (n = 237, 81.2%) with 1.7% other histology and rest missing, 198 (67.8%) patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and 206 (70.5%) had primary tumors located in the colon. Liver (n = 207, 70.9%) and lung (n = 78, 26.7%) were the most common metastasis sites. Diabetes (n = 33, 11.3%) and peripheral vascular disease (n = 18, 6.2%) were the most common comorbidities. Eighty-seven (29.8%) patients received at least one chemotherapy in the adjuvant/neo-adjuvant setting, while majority (70.2%) patients received chemotherapies in the metastatic setting. Overall, 203 (69.5%) received SACT post-chemotherapy, 84 (28.8%) received BSC and 5 (1.7%) did not receive SACT/BSC. Among the SACT post-chemotherapy users, 30 (14.8%) received regorafenib, 25 (12.3%) received TAS-102 and 148 (72.9%) received other SACT. Other SACT included irinotecan-based (n = 76, 37.4%), oxaliplatin-based (n = 30, 14.8%), irinotecan and oxaliplatin-based (n = 6, 3.0%) chemotherapy, and anti-EGFR (n = 15, 7.4%) or anti-VEGF (n = 8, 3.0%) targeted therapies. Conclusions: Overall, only 27.1% of previously treated mCRC patients with tumors that were not MSI-H or dMMR received SoC. The real-world variability in choice of treatments and the high percentage of patients rechallenged with chemotherapy in subsequent lines, highlights an unmet need in this population.
Clinical characteristics of patients with advanced hepatocellular carcinoma who received long-term treatment with atezolizumab and bevacizumab for more than one year.
Authors: Kim Youngun , Kang Beodeul , Kim Jung Sun , Kim Il-Hwan , Kim Hyeyeong , Lee Won Suk , Sang Yun Beom , Jung Sanghoon , Kim Chan , Chon Hong Jae
Published: January 2024

532

Background: Atezolizumab plus bevacizumab (Ate/Bev) has become the standard of care since 2020 as a first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). However, studies on patients receiving long-term treatment with Ate/Bev are still lacking. In this study, we evaluated the clinical characteristics and impacts on patients receiving Ate/Bev treatment for more than one year. Methods: We prospectively enrolled 246 patients with unresectable HCC who received Ate/Bev treatment at three tertiary cancer centers in Korea between May 2020 and April 2022. Comparative analyses were performed between patients treated with Ate/Bev for more than one year and those treated for less than one year. Additionally, treatment-related adverse events (AEs), and changes in liver function were evaluated. Results: Of the 246 patients, 69 (28.0%) were treated with Ate/Bev for more than one year. The long-term treatment group showed better Eastern Cooperative Oncology Group performance status, liver function, and lower residual hepatic tumor burden at baseline, compared to the group treated for less than one year. Furthermore, the long-term treatment group had a higher incidence of atezolizumab-related thyroid dysfunction (30.4% vs. 10.7%, p ‹ 0.001), dermatologic toxicity (30.4% vs. 14.1%, p = 0.006), and bevacizumab-related hypertension (43.5% vs. 22.6%, p = 0.002) and proteinuria (68.1% vs. 39.0%, p ‹ 0.001), compared to the less than one-year treatment group. The median time to onset of thyroid dysfunction and dermatologic toxicity after Ate/Bev treatment was 2.8 months and 3.3 months, respectively, while the median time to onset of hypertension and proteinuria was 4.2 months and 6.8 months, respectively. In the long-term treatment group, 30 patients (43.5%) showed an increase in Child-Pugh score, 20 (29.0%) had an increase in Child-Pugh grade during Ate/Bev treatment. Conclusions: The Ate/Bev long-term treatment group had better performance status, liver function, and a lower residual hepatic tumor burden at baseline. Atezolizumab-related immunologic adverse events occurred mostly early in the course of treatment, whereas bevacizumab-related adverse events occurred relatively later. In addition, a fraction of patients experienced deterioration of liver function during long-term Ate/Bev treatment.
Prognostic effects of co-occurring TP53 and KRAS aberrations in patients with advanced biliary tract cancer.
Authors: Shibuki Taro , Nakamura Yoshiaki , Ueno Makoto , Furukawa Masayuki , Kawamoto Yasuyuki , Itoh Shinji , Umemoto Kumiko , Sudo Kentaro , Satoh Taroh , Mizuno Nobumasa , Asagi Akinori , Okano Naohiro , Shimizu Satoshi , Bekaii-Saab Tanios S. , Strickler John H , Fujisawa Takao , Bando Hideaki , Yoshino Takayuki , Morizane Chigusa , Ikeda Masafumi
Published: January 2024

538

Background: In biliary tract cancer (BTC), TP53 is the most commonly altered gene and may co-occur with KRAS alteration. The presence of a co-alterations in of TP53 and KRAS is associated with poor prognosis in many cancers. In patients (pts) with advanced BTC, the prognostic implications of such co-alterations have not been fully investigated. Methods: This is a pooled analysis of SCRUM-Japan GOZILA and MONSTAR-SCREEN-1 and -2 studies. Genomic profiling was conducted with Guardant360 for plasma in GOZILA, FoundationOne CDx for tissue and FoundationOne Liquid CDx for plasma in MONSTAR-SCREEN-1, and CARIS MI Profile for tissue in MONSTAR-SCREEN-2. Pts with advanced BTC receiving systemic therapy were included in this study. Results: Among 636 pts with advanced BTC, 85 had TP53/KRAS co-alteration, 293 had TP53, 44 had KRAS, and 214 had neither KRAS nor TP53 alteration (WT/WT). Tumors with TP53 alteration had significantly higher level of tumor mutation burden (TMB) compared to the other groups (3.8 mut/Mb for TP53/KRAS, 5.0 mut/Mb for TP53, 2.8 mut/Mb for KRAS, and 2.5 mut/Mb for WT/WT, respectively, P<0.001). In addition, the frequency of microsatellite instability-high (MSI-High) in the TP53/KRAS group (11.0%) was significantly higher compared to the TP53 group (3.1%, P<0.05), and the WT/WT group (0.6%, P<0.001), respectively. The objective response rate of first-line therapy in the TP53/KRAS group (8.2%) was significantly lower than in the other groups (20.8% for TP53, 23.3% for KRAS, and 19.7% for WT/WT groups, P=0.035). There was no pts treated with durvalumab plus gemcitabine and cisplatin. Two pts with TP53/KRAS alteration and MSI-High received pembrolizumab monotherapy, and partial response was achieved with a progression-free survival of 9.4 and 22.0 months. The median overall survival (OS) for pts treated with first-line therapy of the TP53/KRAS, KRAS, TP53, and WT/WT groups were 13.6 (95% confidence interval [CI], 11.5-15.5), 14.3 (95%CI, 9.7-25.9), 18.8 (95%CI, 16.9-20.6), and 22.7 months (95%CI, 20.4-25.9), respectively. Multivariate analysis identified TP53/KRAS alteration (hazard ratio [HR] 2.14, 95%CI 1.43-3.22, P<0.001), number of detected variants (≥2) (HR 1.50, 95%CI 1.04-2.16, P=0.029), locally advanced (HR 1.72, 95%CI 1.05-2.83, P=0.033), and metastatic status (HR 1.78, 95%CI 1.39-2.28, P<0.001) as independent prognostic factors for shorter OS. Conclusions: Patients with advanced BTC with co-occurring TP53/KRAS alterations have worse prognosis. Interestingly, the presence of these co-alterations was associated with a higher likelihood of MSI-High phenotype.
Peri-hilar cholangiocarcinoma (phCCA): A comparative comprehensive genomic profiling study.
Authors: Sampat Parth J , Pavlick Dean C. , Ross Jeffrey S. , Basnet Alina
Published: January 2024

542

Background: CCA is a heterogenous group of malignancies that arise from epithelium of the biliary tree. The comparison of the genomic landscapes that can influence therapy selection of phCCA from other types of intra- and extra-hepatic CCA (ih/ehCCA) are not well-known. We queried differences in comprehensive genomic profiles (CGP) of CCAs and comparing genomic alterations (GA) in phCCA and other types of CCA. Methods: DNA extracted from 110 cases of phCCA, 743 cases of common bile duct CCA (cbdCCA) and 9178 cases of intrihCCA underwent hybrid capture-based CGP to evaluate GA, MSI status, TMB levels, genomic ancestry, genomic signature, HRD score and germline status. phCCA cases were confirmed at surgery and pathology as originating from either the left, right or common hepatic ducts. cbdCCA cases were confirmed either by CBD biopsies or Whipple procedures. PD-L1 expression was determined by IHC using the Dako 22C3 assay using the tumor proportional score (TPS) system. Results: Patient characteristics were similar (Table). The GA/tumor and frequencies of European ancestry were similar. Both phCCA and cbdCCA featured significantly greater frequency of ERBB2 GA than ihCCA (P=.002) and lower frequencies of FGFR2 GA (P=.001) and IDH1 GA (P=.006). ihCCA featured significantly higher frequencies of FGFR2 (11.7%) and IDH1 (13.9%; P=.006) GA than either phCCA or cbdCCA. cbdCCA had a significantly higher frequency of KRAS GA than phCCA (P=.015) and ihCCA (P<.001). The KRAS G12C frequency reached 5.9% of KRAS mutated ihCCA. GA in BRAF, PIK3CA, CDKN2A and MTAP were not significantly different. TP53 GA were higher in cbdCCA than phCCA (P=0.011) and combined phCCA and cbdCCA (ehCCA) were higher than ihCCA (P=.071). MSI status, TMB levels and PD-L1 expression was similarly low in all 3 groups. Positive homologous recombination deficiency (HRD) scores based on %gLOH and high frequencies of MMR genomic signatures were similar in all 3 groups. Conclusions: phCCA appears to be a distinctive form of ehCCA featuring significantly higher frequencies of potentially targetable ERBB2 and lower frequencies of targetable FGFR2 and IDH1 mutations, when compared to ihCCA. Predictive IO markers were similarly low in both ihCCA and ehCCA.[Table: see text]
Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma.
Authors: Sun Yun-Fan , Zhang Zefan , Fan Jia
Published: January 2024

556

Background: Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Methods: Here, we generated genomic, transcriptomic, and T cell repertoire data coupled with digital pathology and digital spatial profiling of 257 primary, 28 relapsed, and 176 metastatic regions from 182 HCC patients. Results: Primary tumors rich in hypoxia signatures tended to give rise to polyclonal dissemination, which was associated with a poor clinical outcome. Genomic divergence between primary and metastatic HCC was high, and early dissemination was prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases was associated with decreased T cell reactivity, which may have resulted from disruptions to neoantigen presentation. We identified macroevolutionary somatic copy number alterations as highly selected events driving metastasis. Furthermore, we found that subclonal Wnt pathway mutations were not selected during spreading, whereas subclones without Wnt mutations showed a strong selective advantage for metastasis and were characterized by a reactive microenvironment rich in activated fibroblasts favoring an invasive tumor cell phenotype. Finally, metastases without Wnt mutations exhibited higher enrichment of immunosuppressive B cells that mediated terminal exhaustion of CD8+ T cells via HLA-E – NKG2A checkpoint axis. Conclusions: Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.
Agrin as a prognostic biomarker in hepatocellular carcinoma.
Authors: Kapoor Ankita , Sonti Sahithi , Patel Riya Jayesh , George Anthony , Attwood Kristopher , Thanikachalam Kannan , Iyer Renuka V. , Chakraborty Sayan
Published: January 2024

559

Background: Hepatocellular carcinoma (HCC), the predominant form of hepatic cancer is associated with high mortality rates, both in the United States & globally. Alpha-fetoprotein (AFP) & Glypican-3 have been proposed as biomarkers for HCC, although they do not offer any prognostic benefit to model disease progression. Immunotherapy combinations increase patient survival to ~18 months but are not selected based on biomarkers. Agrin, a secreted proteoglycan is frequently overexpressed & secreted in HCC & plays a prominent role in liver tumor microenvironment to promote hepatocarcinogenesis. In this single center, retrospective study using banked materials, we assessed the role of agrin as a prognostic biomarker in HCC. Methods: With IRB approval, we studied 90 newly diagnosed unresectable hepatobiliary cancer patients, & compared them to healthy controls matched for age, gender, & BMI between February 2006 & September 2013. Serum concentration (conc.) of agrin was assessed using enzyme-linked immunosorbent assay (ELISA). We correlated the level of agrin with AFP, a known biomarker in hepatocellular cancer. Comparisons between groups were made using Mann-Whitney U & Kruskal Wallis tests. Survival analysis used both univariate & multivariate Cox regression models to investigate the relationship between survival outcomes & agrin concentration, in comparison to AFP. Results: Mean circulatory plasma agrin levels were higher in HCC patients (n=79) (7.97 ng/ml, SD 5.8) when compared to controls (4.27 ng/ml, SD 1.03). ECOG PS > 2 was linked to higher agrin conc. (mean: 10.5 ng/ml, p 0.007). While agrin levels in healthy individuals did not change with smoking history, the mean agrin levels were significantly higher in smokers (9.49 ng/ml) vs non-smokers (6.84 ng/ml) (p 0.0001) amongst HCC patients. Agrin displayed a strong positive correlation with AFP (correlation coefficient (r) 0.31944, p 0.0137). Multivariate cox regression models indicated that agrin conc. of > 9.3 ng/ml had greater predictable survival outcomes (Hazard ratio (HR) 8.51, p <0.001) when compared to elevated AFP levels (HR 1.55, p 0.25) (Table). HCC patients with lower agrin conc. (4.9 to 6.3 ng/ml) exhibited a one-year survival rate of 63% & a median survival time of 16 months, while those with higher agrin conc. exceeding 9.3 ng/ml had significantly lower one-year survival rate of 14% & significantly shorter median survival time of 3 months (p 0.002). Conclusions: Our results suggest that agrin levels as a prognostic indicator fare better than AFP levels. Thus, further studies should be done to explore this as a therapeutic target and as a biomarker of response to targeted therapies. [Table: see text]
The effect of obesity in hospitalized patients with hepatocellular carcinoma: A nationwide analysis.
Authors: Turk Ekrem , Olafimihan Ayobami Gbenga , Ibrahim Muhammad Bilal , Nieto Dominguez Alejandro , Deenadayalan Vaishali
Published: January 2024

569

Background: Obesity, a prominent issue in global health, is known to increase the risk factors associated with a variety of cancers, including hepatocellular carcinoma (HCC), the most common type of primary liver cancer. While existing research affirms the heightened risk of developing HCC in individuals with obesity, there remains a significant gap in understanding the specific influences of obesity on the outcomes of patients admitted with primary HCC diagnosis during their index hospital admission. This study explores the mortality rate, length of stay (LOS), and healthcare utilization in HCC patients with and without obesity. Methods: Nationwide Inpatient Sample (NIS) was queried to determine adult hospitalized patients with a primary diagnosis of HCC using ICD-10 codes. The primary outcome was defined as the effect of obesity on inpatient mortality in those patients. Secondary outcomes included LOS, total hospital charge, health care utilization, ICU admission. We evaluated the baseline characteristics using the t-test and chi-square test. Multivariable logistic regression analysis was performed to assess the association of HCC with obesity and inpatient mortality adjusted by age, gender, race, Charlson index, insurance, and household income. Results: A total of 62,050 HCC patients were identified, and 10.9% of these patients had obesity. HCC patients with obesity were younger (64.7 vs. 65 years, p=0.220), more likely to be female (32.2% vs. 24%, p < 0.001), White (59.8% vs. 50.2% p < 0.001), and more likely to have no insurance (28.8% vs. 23.3%, p < 0.001) compared to HCC patients without obesity. HCC with obesity had higher mean Charlson Comorbidity index 5.9 vs. 5.5, p < 0.001). The overall inpatient mortality rate was 8.2% for all patients who are admitted for HCC; lower in HCC with obesity (5.6%) vs HCC without obesity (8.5%) (p < 0.001). Charlson index, Male gender, African–American race, Hospital teaching status, insurance status found to be associated with inpatient mortality among HCC hospitalizations. HCC with obesity had a lower odds ratio with decreased all-cause mortality of 25% compared to HCC without obesity (aOR 0.75, 95% CI 0.58-0.96, p = 0.023). In addition, HCC with obesity was associated with increased LOS mean 6.3 vs. 5.7 days (adjusted difference: 0.6 p < 0.001), and total hospital charges (mean $112,687 vs $88,481, adjusted difference: $21122 p < 0.0001). Also; ICU transfer rate and AKI development were found more in obese cohort and this different was statistically significant. Conclusions: Our study revealed that HCC patients with obesity had a lower inpatient mortality rate compared to those without obesity, despite longer hospital stays and higher costs. These findings hint at a complex interplay between obesity and HCC outcomes, necessitating further in-depth research.
Lifestyle factors, viral hepatitis, and hepatocellular carcinoma in Uganda.
Authors: Assefa Redeat , Aizire Jim , Nsibirwa Sara , Ocama Ponsiano , Kirk Gregory
Published: January 2024

571

Background: The effect of lifestyle factors, namely alcohol use, cigarette smoking, and other forms of tobacco use on hepatocellular carcinoma (HCC) remains unclear. We assessed the independent associations of lifestyle factors with HCC among individuals with and without viral hepatitis. Methods: In a hospital-based case-control study recruiting from Mulago and Lacor hospitals in Uganda from March 2015 to August 2021, HCC cases were confirmed by clinical and ultrasound criteria, with biochemical and pathology confirmation on a subset. Controls were frequency matched by age and sex and from the same hospitals. Demographic, clinical and lifestyle data were collected using standardized instruments. Alcohol content of local drinks was standardized, and intensity categorized as light, moderate, or heavy based on CDC definitions. We analyzed alcohol (use status (current, former, never), duration (years), frequency (drinks/week)), cigarette smoking (status (current, former, never), cumulative (pack‐years), duration (years), intensity (cigarettes/day), and time since cessation), other tobacco use (tobacco chewing and pipe-smoking), and viral hepatitis (HBV surface antigen (HBsAg) and HCV antibody (HCVAb)). We used logistic regression models (Stata 18.0) to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CIs) controlling for age, sex, family history of HCC, socioeconomic status, and Schistosomiasis (urine Circulating Cathodic Antigen (CCA)). Stratified analyses were performed separately by HBV and HCV status. Results: Among 596 HCC cases and 1,277 controls, the median age (IQR) was 43 (32-56) and 45 (31-54) years, 410 (68.8%) and 832 (65.0%) were males, 460 (24.6%) and 442 (23.7%) current or former alcohol users, 96 (5.1%) and 251 (13.4%) current or former cigarette smokers, and 177 (9.45%) and other tobacco users, respectively. Other tobacco users were more likely to be heavy (⩾10 pack-years) cigarette smokers (aOR=5.10; 95% CI: 2.41-10.79), heavy (>14 drinks/week for males and >7 drinks/week for females) alcohol drinkers (aOR=5.25; 95% CI: 2.84-9.68), farmers (aOR=1.61; 95% CI: 1.01-2.57) and lower socioeconomic status (aOR=3.23; 95% CI: 1.76-5.94). HCC risk was associated with HBV (aOR=18.66; 95% CI: 12.96-27.88), HCV (aOR= 4.03; 95% CI:2.31-7.02), and other tobacco use (aOR=1.86; 95%CI: 1.13-3.08). The observed HCC risk with other tobacco use, and the null associations with heavy alcohol use (aOR= 0.89; 95% CI: 0.60-1.31) and heavy cigarette smoking (aOR=0.74, 95% CI:0.34-1.60), were homogenous by HCV status (positive versus negative), and similarly by HBV status. Conclusions: Viral hepatitis (HBV and HCV), and lifestyle factors (tobacco chewing and pipe-smoking) were strongly associated with HCC. Further research should explore the role of tobacco chewing and pipe-smoking in HCC risk in Uganda and similar settings in Sub-Saharan Africa.
Survival benefit and clinical characteristics of patients with metastatic colorectal cancer (mCRC) receiving pulmonary metastasectomy.
Authors: Soto Alsar Javier , Jiménez Rodríguez Roberto , Bringas Beranek Marianela , Gutiérrez Alonso Natalia , Martín Lozano Rocío , Gonzalez Caraballo Irene , Pérez Pérez Sara , González Casaurrán Guillermo , Muñoz Andrés , Ortega Morán Laura , Calvo Aitana , Torres Pérez-Solero Gabriela , Martin Miguel , Simón Adiego Carlos María , Garcia-Alfonso Pilar
Published: January 2024

59

Background: The role of lung metastasectomy in mCRC remains a topic of particular controversy, being uncertain which patients benefit more from it and whether it leads to better survival outcomes. Our aim was to identify clinical and molecular differences and survival data in a cohort from a tertiary care hospital. Methods: We retrospectively analyzed 115 patients with lung metastases from colorectal cancer (CRC) in a tumor registry from 2015 to 2021, analyzing clinical and molecular characteristics, as well as overall survival (OS) data of patients who received lung metastasectomy versus patients who did not. Results: Among all patients, 36 (31.3%) received pulmonary metastases surgery. Patients undergoing metastases resection had more frequently ECOG 0 (51.4% vs 20.8%, p = 0.0011), resected primary tumor (100% vs 78.5%, p = 0.0026), metachronous metastatic disease (75% vs 46.8%, p = 0.0048) and a single metastatic location (79.4% vs 41%, p = 0.0002). In addition, none of them had BRAF mutation (0% vs 17.1%, p = 0.04); however, no statistically significant differences were found regarding KRAS, NRAS, PI3K, HER2 or presence of microsatellite instability (MSI). Patients who received lung metastasectomy had higher BMI (26.1 vs 24.4, p = 0.037) and lower mean levels of CEA (19.5 vs 142.9, p = 0.007), CA 19.9 (30.6 vs 244.9, p = 0.011) and LDH (159 vs 211.9, p = 0.018). We found an OS benefit in patients undergoing metastatic surgery (median not reached (NR) vs 41.4 months, HR for death 0.27, 95% CI, 0.14 - 0.53, p < 0.000); a multivariate analysis confirmed that this benefit was independent from the characteristics mentioned above. The median progression-free survival (PFS) after metastases resection was 53.3 months. Conclusions: In our study, patients who were more likely to receive lung metastasectomy were those with ECOG 0, resected primary tumor, metachronous disseminated disease, a single metastatic location, native BRAF mutation status and low CEA, CA 19.9 and LDH levels, with a significant OS benefit associated.
Quality of surveillance in patients with completely resected gastroenteropancreatic neuroendocrine tumors.
Authors: Moffat Gordon Taylor , Mesci Aruz , Chadi Sami A. , Jang Raymond Woo-Jun , Avery Lisa , Moulton Carol-Anne , Nathan Paul C. , Krzyzanowska Monika K.
Published: January 2024

591

Background: The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are increasing worldwide. Surgery remains the only curative modality. Because of limited data on patterns of recurrence, real-world surveillance practices and duration vary widely. In 2018, the Commonwealth Neuroendocrine Tumour Research Collaboration (CommNETs) published consensus surveillance guidelines for patients with completely resected GEP-NETs. Our aim was to assess adherence to the CommNETs guidelines for surveillance practices for this patient population at our center. Methods: We conducted a retrospective cohort study of patients with GEP-NETs seen for a new patient appointment at Princess Margaret Cancer Centre (PMCC) from 2019-2022. Patients were included if they had a completely resected GEP-NET and followed on surveillance at our center. Demographic and tumor characteristics, surveillance practices, and clinical outcomes were abstracted. Summary statistics and a descriptive comparison of surveillance practices were completed. Results: Out of the 374 new patient appointments, 87 met the inclusion criteria. The main reasons for exclusion were metastatic disease at presentation (n=128), primary tumor not resected (n=58), and patients not followed at PMCC (n=49) so their surveillance practices cannot be determined from our records. The primary tumor sites were pancreatic (n=50, 57%), appendiceal (n=15, 17%), small bowel (n=11, 13%), rectal (n=10, 12%), and colon (n=1, 1%). Thirty-eight patients (44%) had stage 1 disease, 21 patients (24%) had stage 2, and 28 patients (32%) had stage 3. Forty-six patients (53%) had a WHO tumor grade of 1, 36 patients (41%) had grade 2, and 5 patients (6%) had grade 3. The median duration of follow-up was 18.2 months. Adherence to ordering the recommended surveillance investigations was 23% (20/87). Within the adherent cases, there was a higher number of appendiceal, WHO grade 1, and stage 1 tumors. Sixty-six patients (76%) had at least one test that was not recommended by the guidelines. The most frequent unnecessary tests were CT chest in all patient groups and CT pelvis in pancreatic NETs (Table). Six patients were lost to follow up and none discharged from surveillance. Conclusions: Adherence to the CommNETs consensus guidelines was low at our center, suggesting the guidelines had a minor impact on surveillance practices and providing an area for improvement in process of care and resource utilization. [Table: see text]
Prognostic value of O6-methylguanine-DNA methyltransferase (MGMT) status in pancreatic neuroendrocrine tumors with capecitabine and temozolomide (CAPTEM).
Authors: Terán Brage Eduardo , Feito Pérez Jorge , Navarro Martín Luis Miguel , Escala Cornejo Roberto Andrés , Abad Hernández María Mar , Del Carmen Sofía , López Gutiérrez Álvaro , Cigarral García Belén , Vidal Tocino Rosario , Lozano Rebeca , Fonseca Sánchez Emilio
Published: January 2024

598

Background: Loss of MGMT expression has been suggested as a predictor of response to alkylating agents in pancreatic neuroendocrine tumors (pNET), however, its determination is controversial. We aim to analyze the prognostic value of MGMT status assessed by immunohistochemistry (IHC) or pyrosequencing (PSQ) in patients with pNET receiving CAPTEM. Methods: Retrospective and unicentric analysis in patients (p) with pNET treated with CAPTEM from April 2008 to February 2023. MGMTdeficiency was determined by IHC and MGMT promoter methylation by PSQ. We analyzed patients’ characteristics, progression-free survival (PFS) and overall survival (OS) according to MGMT status. Results: 20p were included. Age (median): 62 [46-77]. Males (45%). Tumor grade (G): G1 (15%), G2 (55%) and G3 (20%). MGMT deficiency was detected in 12p (60%) and promoter methylation in 10p (50%). Results by IHC were consistent with PSQ in 10p (50%), with mismatches in 4p (methylated MGMT and positive IHC) and 6p (unmethylated MGMT and negative IHC). We reported a higher response rate in MGMT-deficient and MGMT-methylated p (Table) . In MGMT-deficient p we observed significantly better PFS (88m vs 11.1m; p=0.02, HR=0.21) and OS (141.9m vs 35.8m; p=0.03, HR=0.20). Also, in MGMT-methylated p we detected better PFS (88m vs 17.7m; p=0.20, HR=0.44) and OS (188.7m vs 141.9m; p=0.11, HR=0.28). A subanalysis was performed based on G, showing better PFS (88m vs 6.2m; p=0.03, HR=0.11) and OS (188.7m vs 35.8m; p<0.01, HR=0.06) in those with G2 vs G3. There was a strong negative correlation between G and MGMT by PSQ; the higher G, the lower probability of promoter methylation r(16)= -0.62, p<0.01. Conclusions: Our results support MGMT status, deficiency by IHC or promoter methylation by PSQ, as a potential prognostic biomarker in pNET treated with alkylating agents. However, it is necessary to evaluate its prognostic value in prospective studies. [Table: see text]
Clinical characteristics and survival analysis in patients with isolated pulmonary metastases from colorectal cancer (CRC).
Authors: Soto Alsar Javier , Jiménez Rodríguez Roberto , Gutiérrez Alonso Natalia , Bringas Beranek Marianela , Martín Lozano Rocío , López Jiménez Carlos , Gonzalez Caraballo Irene , Juliao Caamaño David Salomon , Gutierrez Ana , Muñoz Andrés , Ortega Morán Laura , Calvo Ferrandiz Pilar Aitana , Torres Pérez-Solero Gabriela , Martin Miguel , Garcia-Alfonso Pilar
Published: January 2024

60

Background: Recent studies seem to indicate that patients with metastatic colorectal cancer (mCRC) with exclusive pulmonary metastatic disease have better outcomes than those with other metastatic sites. The aim of this study is to identify differences in clinical and survival characteristics between the two groups in a cohort of a third level hospital. Methods: We retrospectively analyzed a sample of 569 patients with mCRC in a tumor registry from 2015 to 2021, studying clinical and molecular characteristics, as well as overall survival data of patients with isolated pulmonary metastases, versus the rest of patients. Results: Of the total sample analyzed, 61 patients (10.7%) had isolated pulmonary metastases. In these patients, several clinical characteristics were more frequent: primary rectal tumor (52.5% vs 23.4%, p < 0.000), resected primary tumor (95.1% vs 78.9%, p = 0.0026), metachronous metastatic disease (62.3% vs 42%, p = 0.0025) and complete response rate to the first line of treatment (19.3% vs 9.9%, p = 0.026). Furthermore, analytically, these patients were more likely to have normal CEA (75% vs 38.3%, p < 0.000), CA 19.9 (84.3% vs 57.7%, p = 0.0002) and LDH (91.1% vs 66.5%, p = 0.0007) levels. In our cohort, we found no statistically significant differences in tumor mutational status (KRAS, NRAS, BRAF, PI3K and HER2). There were no patients with exclusive pulmonary metastatic disease and microsatellite instability (MSI). 70.3% of patients with isolated pulmonary metastases received lung metastasectomy, and up to 58.3% received a second metastases surgery. We also found a numerical benefit in terms of overall survival (OS) in patients with exclusive metastatic lung disease, although it did not reach statistical signification (median OS 77.3 vs 58.1 months, HR for death 0.70, 95% CI, 0.49 – 1.01, p = 0.083). Conclusions: In our cohort, patients with isolated pulmonary metastases were more likely to have rectal tumors, primary tumor resection, metachronous metastatic disease, higher rate of complete responses and normal CEA, CA 19.9 and LDH levels, with a possible benefit in terms of OS.
Clinical impact of KRAS mutations in metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Norton Carter , Smith Jarrod , Rubnitz Zach , Tan Grace H. , Nevala-Plagemann Christopher Duane , Soares Heloisa P. , Garrido-Laguna Ignacio , Florou Vaia
Published: January 2024

619

Background: Mutations in the KRAS oncogene occur in most PDAC and lead to the activation of the KRAS protein. Little is known about the differential impact of KRAS mutations on the outcomes of patients receiving standard of care cytotoxic treatments for metastatic disease. KRAS inhibitors are emerging as promising options for this disease and understanding the impact of distinct KRAS mutations in patient outcomes is needed. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database from 5,369 patients. Adult patients with diagnosis of metastatic PDAC who received at least one line of systemic therapy and had sufficient data available were included in this analysis. Median time to next treatment (TTNT) and overall survival (OS) time were calculated for three common first-line treatments and KRAS mutations. TTNT and OS were calculated for each permutation of treatment and each KRAS mutation. Hazard ratios (HR) were generated for each KRAS mutation and treatment, accounting for potentially confounding variables. Results: Of the 5,369 patients, 2,472 met the inclusion/exclusion criteria. G12C had the shortest median OS (7.5 mo) and G12R had the longest (9.1 mo). Overall, KRAS mutation-positive patients had a median OS of 8.6 mo, compared to 11.7 mo for KRAS Wild Type (WT) patients. A Cox Proportional Hazard analysis of OS across KRAS mutation status found that G12C, G12V, G12D, and Other Non G12/13 KRAS had significantly higher HR than KRAS WT. A comparison of the three common first-line interventions for metastatic PDAC showed that FOLFIRINOX had the longest median TTNT (5.3 mo) and the longest OS (10.2 mo), while Gemcitabine had the shortest TTNT (2.6 mo) and OS (5.9 mo). A Cox Proportional Hazard analysis of OS across all patients found that Gemcitabine and Gemcitabine with Nabpaclitaxel had significantly higher HR than FOLFIRINOX. FOLFIRINOX had the longest TTNT in the G12C, G12V, G12D, G12R, and other non-G12/G13 KRAS groups (see table). Conclusions: Our data suggest that FOLFIRINOX has a longer TTNT than other first-line regimens for KRAS G12C, G12V, G12D, and G12R. KRAS G12C was associated with the shortest OS among common KRAS mutations.[Table: see text]
Optimising utility of selective internal radiation therapy in metastatic pancreatic adenocarcinoma.
Authors: Cooray Prasad , Muralidharan Vijayaragavan , Spanger Manfred , Page Patrick , Fox Adrian , Mackay Sean , Thang Sue , Miller Lisa , Poh Ashleigh , Le Caroline
Published: January 2024

622

Background: Selective internal radiation therapy (SIRT) using Yttrium-90 containing microspheres has established benefit for a number of cancers but there is limited data available on the utility of SIRT for the treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). Methods: In this retrospective audit we identified 32 patients who received SIRT using Yttrium-90 microspheres for metastatic PDAC in 2 treatment centres. All patients received SIRT in combination with chemotherapy. Data was analysed from electronic medical records. Results: Thirty two patients with metastatic PDAC who had SIRT were identified. Patients received SIRT (median activity 1.6 GBq) in combination with chemotherapy (platinum-based; n = 23, non-platinum-based; n = 9). Three patients remain alive and 29 patients were included in the survival analysis. For the entire group, the median OS was 15 months (range 4-49), median survival from time of SIRT was 9 months (range 1-48) and median PFS from time of SIRT was 4 months (range 1-25). Median PFS (6 vs 2 months, p=0.0011) and OS (13 vs 4 months, p=0.0004) from SIRT was significantly better when SIRT was given with 1st-line therapy vs with 2nd-line and beyond. Median PFS from SIRT was significantly better (10 vs 2 months, p=0.0020) when combined with 1st line platinum-based chemotherapy (n=14) vs non-platinum based treatment (n=6). 18 month survival was 40% (n=13) with 9/13 patients having had SIRT with 1st line with platinum-based therapy. 24 month survival was 22% (n=7) with 7/7 patients having had SIRT with 1st line with platinum-based therapy. SIRT was well-tolerated with no associated 30-day all-cause mortality. Grade 3 adverse events were liver abscess (7%, n = 2), gastritis (7%, n = 2) and duodenitis (7%, n=2). Conclusions: This is the first report to analyse optimum utility of SIRT with chemotherapy in metastatic PDAC. Our data suggest SIRT in combination with 1st-line platinum agents contribute to the best outcomes in the setting and warrants further study.
Prognostic value of the CRM status in pancreatic ductal adenocarcinoma: Data from a regional cancer registry.
Authors: Morakis Philipp , Surovtsova Irina , Schuhbaur Jasmin , Kokh Daria , Winzler Claudia , Szotyori-Artz Gertrud , Schütz Juliane , Uhl Waldemar , Tannapfel Andrea , Seufferlein Thomas
Published: January 2024

632

Background: Ductal pancreatic adenocarcinoma (PDAC) still has a dismal prognosis even when deemed resectable. A cancer free resection margin (R0) is associated with a more favourable prognosis than the presence of tumour cells at resection margin (R1). However, the precise definition of the R0 status is still a matter of debate in PDAC. For a more accurate determination of R0 in PDAC the concept of circumferential resection margins (CRM) has been introduced. However, an international standardized nomenclature of CRM is still missing, and the clinical value of the CRM concept is not yet fully established. Here we evaluate whether the CRM status as defined in the national German S3 guideline is an independent prognostic factor in PDAC using data from the regional cancer registry of the State of Baden Württemberg in Germany. Methods: Data from the cancer registry of the State of Baden-Württemberg, Germany were collected, using documented patients diagnosed with invasive ductal adenocarcinoma of the pancreas between 2015 and 2020. The R-status was assessed according to the national German S3 guideline with R0 wide/CRM- when CRM is > 1mm, R0 narrow/CRM+ when CRM is £ 1 mm from the tumour and R1 when tumour cells are found at the resection margin. Progression free survival (PFS) as well as 3-year overall survival (OS) were assessed using Kaplan-Meier statistics and multivariable Cox regression models (adjusted for age, pN stage, primary tumor location and systemic treatment). Results: In total we identified 1098 cases surgically treated for pancreatic cancer and fulfilling the inclusion criteria. 340 patients had an R0 wide/CRM- resection, 410 patients an R0 narrow/CRM+ resection, and 348 patients an R1 resection. The R0 wide/CRM- status was associated with a significantly increased median 3-year OS rate compared to the other two groups (51,5%, 37,4% and 26,7% for R0 wide/CRM-, R0 narrow/CRM+ and R1, respectively). mPFS was also longer in the R0 wide/CRM- group. These findings were robust with regards to grading. 5-FU based adjuvant treatment was mainly mFOLFIRINOX and show better outcome as compared to gemcitabine-based treatments. Conclusions: The present study was performed using real world data reflecting actual clinical settings. The results obtained are in good agreement with data from clinical trials, including the prognostic role of the R- and N- Status as well as the efficacy of adjuvant chemotherapy protocols used.