bluuebunny/crossref_metadata_2025 huggingface dataset:
Adjuvant chemotherapy for resected intrahepatic cholangiocarcinoma confers no survival advantage.
Authors: Sharib Jeremy , Liu Annie , McIntyre Sarah Margaret Helena , Rhodin Kristen Elizabeth , Kemeny Nancy E. , Cercek Andrea , Harding James J. , Abou-Alfa Ghassan K. , Soares Kevin , Wei Alice Chia-chi , Drebin Jeffrey A. , Kingham T. Peter , D'Angelica Michael Ian , Uronis Hope Elizabeth , Strickler John H , Morse Michael , Zani Sabino , Allen Peter J , Jarnagin William R. , Lidsky Michael
Published: January 2023

560

Background: Randomized data suggest improved survival with adjuvant chemotherapy for biliary tract cancers, but subset analyses of intrahepatic cholangiocarcinoma (ICC) show limited survival benefit. This study uses a large bi-institutional cohort of resected ICC patients to evaluate the impact of adjuvant therapy on recurrence patterns and overall survival (OS) and compares these findings to data from a national cancer registry. Methods: Patients with resected ICC were identified within a bi-institutional cohort (Duke and Memorial Sloan Kettering, 1997-2020) and the National Cancer Database (NCDB, 2010-2018). Patients were stratified by treatment with adjuvant chemotherapy (adj). Site of first recurrence was categorized as local (liver only), regional (liver and perihepatic nodes), nodal (perihepatic nodes only), distant, or mixed (both liver and distant). OS was compared with Kaplan-Meier methods. Results: 367 patients underwent resection for ICC, and 163 (44%) patients received adjuvant therapy. Median follow-up was 33 vs. 44 months (adj vs observation (obs), p=0.15). 263 (72%) patients had recurrent disease, most commonly in the liver (72%). There was no difference in recurrence patterns stratified by treatment with adjuvant chemotherapy (% recurrence, adj vs obs; local: 42 vs 42; regional: 2 vs 2; nodal: 0 vs 3; distant only: 27 vs 26; mixed: 29 vs 27, p=0.5). OS was the same between groups (adj vs obs; 42 vs 49 months, p=0.3) and when stratified by recurrence site (p=0.5). Similarly, in an NCDB cohort of 1,159 ICC patients over the same time period, there was no association between adjuvant therapy and OS (adj vs obs; 49 vs 57 months, p=0.1). Conclusions: In this retrospective dual registry analysis, corroborated by national data, adjuvant chemotherapy was not associated with an improvement in OS in ICC patients subjected to curative intent resection. Further, adjuvant therapy had no impact on the high rate of hepatic recurrence, suggesting that alternative strategies, such as liver directed therapies, are needed to improve recurrence rates and OS.
The impact of peri-operative chemotherapy on the outcomes of patients with non-metastatic cholangiocarcinoma.
Authors: Baidoun Firas , Alhaj Moustafa Muhamad , Abdel-Rahman Omar
Published: January 2023

563

Background: Cholangiocarcinoma is a rare malignancy with poor prognosis and outcome despite therapy. It accounts for 2.2% of all new cancer cases and 5% of all cancer deaths. Surgical resection is still the main therapeutic approach, whereas the role of peri-operative chemotherapy is debatable. Methods: The National Cancer Database (NCDB) was queried for patients diagnosed with non-metastatic biliary adenocarcinoma at age 18 or older between 2004 and 2019. After excluding patients with unknown timing of surgery and chemotherapy, patients who died within 90 days of the most definitive primary site surgery and patients lost to follow-up, we split the cohort into three groups according to the clinical stage (stage I-III). Then, we evaluated the overall survival (OS) between the different treatment modalities (surgery only, adjuvant chemotherapy and neoadjuvant chemotherapy) in each group. We studied the OS using Kaplan-Meier estimates and multivariate cox regression analyses to evaluate factors associated with OS. Results: A total of 35,260 patients with non-metastatic cholangiocarcinoma were included in the analysis, of which 50.4% were females, 83% Caucasians, 9.5% African Americans. The median age at diagnosis was 70 (range 18-90). 14,757 (41.9%) were stage I, 12,472 (35.4%) stage II and 8,031 (22.8%) stage III. 7,286 (20.7%) had surgical resection only, 8,144 (23.1%) had chemotherapy only, 6,964 (19.7%) had surgical resection with perioperative chemotherapy and 12,866 (36.5%) did not receive any treatment. We compared survival between different treatment modalities based on clinical stage. In stage I, we found patient who were treated with surgery only had better median OS (mOS) compared to adjuvant chemotherapy (65.7 vs 50.4 months, P<0.001) and no statistically significant difference between neoadjuvant chemotherapy and surgery only (mOS 79.8 vs 65.7 months, P=0.63). Whereas in stage II, patients who were treated with adjuvant and neoadjuvant chemotherapy had better mOS compared to those treated with surgery only (33.9 and 40.3 vs 29.9 months with P<0.001 and P=0.005, respectively). Same trend was seen in stage III, patients who were treated with adjuvant and neoadjuvant chemotherapy had better mOS compared to surgery only (22.6 and 41.5 vs 19.5 months, respectively with P<0.001 for all). In multivariate analysis, adjuvant and neoadjuvant chemotherapy did not affect the OS in all stages, except in stage III where neoadjuvant chemotherapy was associated with better OS (HR 0.646 95% CI 0.530-0.786; P<0.001). Conclusions: Adjuvant and neoadjuvant chemotherapy do not seem to have survival benefit in early stage (stage I and II) cholangiocarcinoma. Whereas neoadjuvant chemotherapy tends to improve OS in stage III.
Real-world data in 1000 patients with unresectable hepatocellular carcinoma (HCC) treated with systemic therapy: Patient background in PRISM study.
Authors: Ikeda Masafumi , Itoh Shinji , Tateishi Ryosuke , Yamashita Tatsuya , Okusaka Takuji , Kato Naoya , Furuse Junji , Kudo Masatoshi
Published: January 2023

566

Background: Systemic therapy is one of the most important treatment modalities for unresectable hepatocellular carcinoma (HCC). At present, six regimens, except durvalumab plus tremelimumab, are reimbursable for the treatment of HCC in Japan. In clinical practice, there are various patient backgrounds and patterns in the treatment sequence of systemic therapy. Therefore, a prospective, observational, large-scale multicenter study of systemic therapy for HCC (PRISM) was conducted to establish real-world evidence from real-world data in Japan. Methods: Patients with histologically or clinically diagnosed HCC, with no prior systemic therapy, with written informed consent were consecutively enrolled into the study. The primary endpoint is overall survival, and the secondary endpoints are the progression-free survival, time-to-treatment failure, grade 3-4 adverse events, and proportion of transition to subsequent treatment; all endpoints are calculated by each regimen/treatment line. The planned sample size is 1,000 patients with an enrollment and follow-up period of 2 years each. Clinical trial registration: UMIN000040488. Results: From August 2020 to July 2022, the enrollment of 1,000 patients was completed in 42 participant hospitals in Japan. As of Sep 2022, the 1000 patients’ background data have been collected. The median age with range was 73 years (30-93). ECOG performance status was 0 in 612 patients (77.9%), and Child-Pugh score was 5 points in 358 (50.2%) and 6 in 226 (31.7%). BCLC stage was B in 277 patients (36.9%) and C in 391 patients (52.1%). 210 patients (26.8 %) and 207 patients (26.4%) had portal vein tumor thrombosis and extrahepatic metastasis, respectively. The median AFP level was 33 ng/mL (range: 1.1- 524878.9). As first-line therapy, atezolizumab plus bevacizumab was selected in 650 (82.5%), lenvatinib in 116 (14.7%), and sorafenib in 15 (1.9%) patients. Conclusions: The analysis of these real-world data of systemic therapy for patients with unresectable HCC could help clarify the treatment outcomes in clinical practice, and is expected to be broadly applicable to real-world evidence in all Japan. Clinical trial information: UMIN000040488 .
Impact of complete pathological response outcome in Latin American patients with rectal cancer.
Authors: Calderillo Ruiz German , Diaz Dr. Consuelo , Herrera Marytere , Ruiz-Garcia Erika , Miyagui-Adame Sayako Mariana , Carbajal Berenice , Albarrán-García Alejandra , Murguía-Guzmán Zugeyth Emireth
Published: January 2023

58

Background: Rectal cancer is one of the leading cancer-related causes of death worldwide. Nevertheless, complete pathological response (pCR) to neoadjuvant treatment has been associated with a decrease in local recurrence and distant disease, and therefore an improvement in disease-free survival (DFS) and overall survival (OS). The aim of this study was to evaluate the impact of pCR in DFS and OS Mexican patients with rectal cancer. Methods: Retrospective, observational study. Included patients with rectal adenocarcinoma treated with neoadjuvant chemo-radiotherapy between 1998 and 2021. Statistical analysis: X2 and t-test, Kaplan Meier, Log Rank, and Cox Regression. Statistical significance p <0.05 bilaterally. Results: A total of 707 patients were included in the analysis. 52.3% were male with a median age of 57 (18 – 86) years. According to clinicopathological features, moderate-grade was the most prevalent at 66%, 38.5% were low-rectum and 32% of patients reported an ACE<10mg/dL. Patients were divided into 2 groups: pCR (n=155) and non-pCR (n=552) for the analysis. According to surgical margins, 89%(n=491) non-pCR-patients reported R0 (p=0.003). Recurrence rate was 12.9%(n=20) versus 35.7%(n=197) in pCR and non-pCR respectively (p<0.001). Regarding DFS analysis, pCR-patients median-DFS was Not Reached (NR), while non-pCR-patients median-DFS was 154 months (p<0.001; HR:0.32, 95%CI:0.20-0.51). At OS analysis, pCR-patients median-OS was NR, non-pCR-patients median-OS was 166 months (p<0.001; HR:0.41,95%CI 0.26-0.65). At DFS-multivariate analysis, location (p<0.001; HR:1.47, 95%CI:1.20-1.80) and rPC (p=0.013; HR:0.48,95%CI:0.27-0.85) remained predictive factors of DFS. At OS-multivariate analysis, ACE (p=0.047; HR:1.37, 95%CI:1.00-1.89) and pCR (p=0.009; HR:0.45, 95%CI:0.24-0.81) remained as predictive factors of OS. Conclusions: The pCR rate in our population is similar of what is reported in the literature. Our study demonstrates that pCR significantly impacts DFS and OS, rectal cancer patients. Total neoadjuvant chemo-radiotherapy, short-scheme-radiotherapy, and immunotherapy in selected populations can achieve doubling the percentage of pCR. [Table: see text]
Genomic profiling to provide new treatment opportunities in ampullary carcinoma.
Authors: Fabregat Franco Carles , Castet Florian , Saoudi Gonzalez Nadia , Castillo Gloria , Acosta Eyzaguirre Daniel , Salcedo Maria Teresa , Verdaguer Helena , Macarulla Teresa
Published: January 2023

582

Background: Ampullary carcinoma (AC) is a rare heterogeneous group of diseases with an abysmal prognosis. Treatment options are limited, and the molecular landscape of this disease and its therapeutic implications have been incompletely explored. Here, we aim to provide a clinical and genomic characterization of AC and explore opportunities for precision oncology. Methods: Patients diagnosed with AC and treated at a single tertiary institution between 2010 and 2022 were reviewed. Molecular profiles were analyzed by applying an in-house exome-targeted panel or the FoundationOne CDx panel. Gene mutations were categorized into molecular pathways and potentially targetable alterations were classified according to the ESCAT scale. Overall survival (OS) and disease-free survival (DFS) were estimated by using the Kaplan-Meier method. Results: We included 64 patients with a median age of 66 years, 51.6% were women, most were classified as pancreatobiliary tumours (PB, 58.3%), followed by intestinal (INT, 33.3%) and mixed histologies (8.3%). 18.8%, 23.4%, 32.8% and 25.0% of the patients were diagnosed at stage I, II, III and IV, respectively. 81.2% of the patients were treated with surgery. The INT subtype was enriched in WNT pathway alterations (28.6 vs 6.2%, p=0.02) and showed a non-significant enrichment in the apoptotic pathway (57.1 vs 34.4%, p=0.08). Conversely, BP showed a non-significant enrichment in HRR pathway alterations (16.7 vs 54.5%, p=0.3). The frequency of KRAS mutations were similar in both subtypes (38.1 vs 37.5%). Potentially actionable molecular alterations were found in 46.7% of the patients (9 ERBB2, 8 HRD, 8 PI3KCA, 2 MSI, 2 BRAF, 2 PTEN and 1 KRAS G12C). Importantly, KRASwt tumours were enriched in potentially targetable alterations (ESCAT I-IIIA), including 20% ERBB2 amplification/mutations, 6% MSI and 3% BRCA1. 6 patients received matched targeted therapies during their disease course, 66% of which responded and 100% stable disease, with a median TTD of 7 months. Conclusions: More than 45% of AC harbor potentially targetable genomic alterations that may provide novel therapeutic opportunities and enhance personalized medicine in this rare disease entity.
Genetic heterogeneity of intrahepatic cholangiocarcinoma: Implications for outcome.
Authors: Song Yi , Boerner Thomas , Drill Esther N. , Shin Paul , Cercek Andrea , Kemeny Nancy E. , Abou-Alfa Ghassan K. , Iacobuzio-Donahue Christine A , Schultz Nikolaus , Walch Henry S. , Sigel Carlie S. , Kingham T. Peter , Soares Kevin , Wei Alice Chia-chi , D'Angelica Michael Ian , Drebin Jeffrey A. , Chandwani Rohit , Harding James J. , Jarnagin William R.
Published: January 2023

595

Background: Intrahepatic cholangiocarcinoma (IHC) is characterized by marked clinical heterogeneity, likely the result of multiple cells of origin and variable driver gene alterations. The hidden-genome classifier is a statistical algorithm that classifies tumors by integrating multi-level genomic features. In this study, we trained the hidden-genome classifier with extrahepatic cholangiocarcinoma (EHC), gallbladder cancer (GBC) and hepatocellular carcinoma (HCC) as extremes of a spectrum to quantify the genetic heterogeneity of IHC with a view toward improved tumor classification. Methods: An IRB approved retrospective review of patients with biopsy confirmed IHC, EHC, GBC and HCC was conducted. All tumors were subjected to MSK-IMPACT to determine the mutational profile. A two-class model was built and internally validated with the genomic data of EHC/GBC as one class and HCC as the other class. IHC tumors were analyzed in the model and classified into three groups based on their proportional genetic resemblance to EHC/GBC (Biliary Class) or HCC (HCC Class), with the remainder as Intermediate Class. The classification thresholds were 90% resemblance to EHC/GBC or HCC and were determined by the inflection point of predicted survival. The survivals of the three groups were analyzed and compared. Results: A total of 1497 patients were included: IHC (733), EHC (208), GBC (258) and HCC (298). 527 IHC tumors with complete metagenetic information were analyzed in the model, showing a continuous spectrum of alterations, ranging from Biliary Class (122 tumors), Intermediate Class (375 tumors) to HCC Class (30 tumor). The biliary-class IHC was characterized by frequent alterations of IDH1 R132C, KRAS, SMAD4, ERBB2 gain, MDM2 gain, and CKDN2A loss, while the HCC-class IHC was primarily characterized by TERT alterations. In patients with unresected IHCs, the median survival ranged from 1 year (CI 0.77, 1.5) in Biliary Class, 1.8 years (CI 1.5, 2.0) in Intermediate Class, to 2 years (CI 0.93, NR) in HCC Class. In patients subjected to resection, the median survival of Biliary Class (2.4 years, CI 2.1, NR) was lower than both the Intermediate Class (5.1 years, CI 4.8, 6.9) and the HCC Class (3.4 years, CI 2.7, NR). Conclusions: By integrating multi-level genomic features, we leveraged the mutational heterogeneity to classify IHC based on its resemblance to EHC/GBC or HCC tumors. We found that the survival in IHC patients appeared to decline with increasing genomic similarity to Biliary Class. The results support a genomic basis for IHC’s variable clinical behavior and point to a role of mutational testing to guide clinical intervention. [Table: see text]
The efficacy of immune checkpoint inhibitors in biliary tract cancer with KRAS mutation.
Authors: Jeong Sun Young , Kim Seung Tae , Jang Jae Yeon
Published: January 2023

598

Background: Biliary tract cancer (BTC) is rare cancer but has a poor prognosis with only 10% of 5-year overall survival (OS). The treatment of advanced BTC remains challenging with limited standard options. With a 15% of incidence, KRAS is one of the most common mutations in BTC. The immune checkpoint inhibitor as salvage therapy has modest activity in BTC. Methods: We conducted molecular profiling including tumor mutational burden in BTC patients with immune checkpoint inhibitors (ICI) as salvage therapy. Programmed death ligand 1 (PD-L1) expression on tumor cells and on tumor-infiltrating lymphocytes (TIL) was also assessed. Results: Between 2020 to 2022, a total of 62 patients were analyzed. The median age was 68 (58.0-73.0). 47 patients (75.8%) received pembrolizumab and 15 (24.2%) received nivolumab as salvage therapy. All patients received gemcitabine plus cisplatin as the frontline therapy, and 53.2% had fluoropyrimidine plus oxaliplatin (FOLFOX) before ICIs. The median lines of prior chemotherapy were 2.5 (2.0-3.0). KRAS mutation was found in 14 patients (22.6%). 28 patients (45.2%) were positive for PD-L1. There was no statistical correlation between KRAS mutation and PD-L1 expression. The median OS and PFS of patients were 5.2 and 3.5 months respectively. There were no statistically significant differences in PFS according to the status of KRAS mutation (Mutant type vs. Wild type) and PD-L1 expression (Positive vs Negative). In subgroup analysis, patients with KRAS mutation and PD-L1 positivity had longer PFS as compared to patients with KRAS mutation and PD-L1 negative (6.5 vs 2.6 months, p=0.047). This finding was not shown in patients without KRAS mutation. Conclusions: The PD-L1 expression might be a novel biomarker for ICIs in BTC patients with KRAS mutation but not in those with the wild type of KRAS.
Do nonoperative modality (NOM) treatments of rectal cancer compromise the chance of cure? Final surgical salvage results from OPERA phase 3 randomised trial (NCT02505750).
Authors: Sun Myint Arthur
Published: January 2023

6

Background: Watch and wait strategy without surgery for rectal cancer is gaining popularity as it avoids a stoma. We set up an OPERA trial to evaluate the role of radiation dose escalation using Contact X-ray brachytherapy [CXB] (Papillon). We report on the final surgical salvage results for local failures of non-surgical approach. Methods: OPERA is a European phase 3 randomised trial between (Arm A-standard arm)EBCRT 45Gy/25/5weeks with oral capecitabine 825mg/m2 and EBRT boost of 9Gy/5/5 days randomised against experimental arm (Arm B) EBCRT followed by CXB boost (90 Gy/3/4 weeks). Patients were assessed at 14, 20 and 24 weeks. Watch & wait policy was adopted for patients with cCR and surgery (TME or local excision) offered for residual disease or recurrence after cCR. Results: From July 2015 –June 2020, 148 patients were randomised of which 141 were evaluable. Median age was 68 years and 88 (61%) patients were males. There were 69 patients in Arm A (standard of care with EBRT boost) and 72 patients in Arm B (experimental with CXB boost). All patients received the protocol stratified radiation dose. Median follow-up was 38.2 months (95% CI:34.2-42.5). Clinical complete response (cCR) was observed in 44/69 (64%) in Arm A and 66/72 (92%) in Arm B at 24 weeks (p< 0.001). Surgery was carried out in 66/141 (47%) with suspected residual tumour or local regrowth after achieving cCR. Total 39/66 (59%) patients had TME surgery. Local excision was carried out in 27 /49(41%). Our primary endpoint of organ preservation (OP) rate was 59% (95% CI: 48-72) in Arm A vs. 81% (95% CI: 72-91) in Arm B (HR 0.36, 95% CI: 0.19-0.70; P= 0.0026). When comparing A1(<3cm) vs. B1(<3cm), OP rate was 63% vs. 97% respectively (HR: 0.072, 95% CI 0.0093-0.57; P= 0.0123]). Overall TME free overall survival was 57% for Arm A and 79% for Arm B (HR 0.37,95% CI 0.2-0.71; P=0.0026). Conclusions: OPERA data at 38 months suggest that non-surgical treatment for cT2-cT3a-b rectal cancer is feasible and those who needed surgery for local failures can be salvaged without compromising their chance of cure. There is significant improvement in OP rate for rectal cancer <3cm to start with CXB followed by EBCRT. This option should be discussed with patients wishing to avoid surgery and a stoma as an initial treatment. Clinical trial information: NCT02505750 . [Table: see text]
Comprehensive molecular profiling in patients with advanced biliary tract cancers (BTC) in a Latinx-rich cohort.
Authors: Kapoor Vidit , Keiser Sylvia , Liu Qianqian , Michalek Joel , Arora Sukeshi Patel
Published: January 2023

605

Background: BTC are genetically diverse and heterogeneous. Despite knowledge of molecular subtypes of BTC, the distribution of molecular aberrations in the Latinx population has been understudied. These may have prognostic and/or predictive implications. Therefore, we analyzed our cohort of Latinx-rich patients with advanced BTC. Methods: We analyzed patients with advanced BTC, who were seen at the Mays Cancer Center from Jan 2018-Dec 2021. Tumor samples profiled by Next Generation Sequencing (NGS) were identified retrospectively. Associations between demographics, clinical characteristics, and genetic alterations were identified. Results: 88 patients with locally advanced/metastatic BTC were identified. 50 (56.2%) were Latinx. 42 (47.7%) had intrahepatic CA (IHCA), 14 (15.9%) had extrahepatic CA (EHCA), 16 (18.2%) had Gall Bladder Carcinoma (GBC) and 16 (18.2%) had Ampullary/Periampullary Carcinoma (APC). 49 (56%) had NGS on their tumors out of which 30 (61.2%) were Latinx and 19 (38.8%) were non-Latinx. The most commonly altered genes were TP53 (34.7%), KRAS (24.5%), ARID1A (16.3%), BRCA-2 (12.2%), PDL-1 (12.2%), FGFR (12.2%), MET (10.2%), PTEN (10.2%) and HER-2 (8.2%). 14.3% patients had no identifiable mutations. There was no significant difference observed in the rates of different molecular mutations between Latinx and non-Latinx (p=1) and among different histologies of IHCA, EHCA, GBC and APC (p=1). The Median Overall Survival (OS) for Latinx population was 16.1 months (95% CI 12.3-28.2) which was similar to the median OS for non-Latinx population of 15.5 months (95% CI 11.6-28.6) (p=0.69). The median OS was not different due to the presence or absence of any one mutation (p values ranged from 0.04 to 0.9). Conclusions: BTCs are genetically diverse. Somatic alterations were identified in 85% patients who were tested. Only 56 % had molecular testing, when it should be 100% in advanced BTC, per NCCN guidelines. This may be due to inadequate tissue, lack of funding, use of alternate ctDNA, or the patient may have died before getting to testing/repeat biopsy. The likelihood of having a genetic alteration was similar between Latinx and non-Latinx patients and among different sites of disease. Latinx and Non Latinx with advanced BTC had similar survival rates. Survival rate was not different due to the presence or absence of any one mutation. Future studies should prospectively investigate implementation programs for NGS in tumor and blood in all patients with BTCs.
A glimpse into the future of hepatocellular carcinoma (HCC): Predicting the future incidence based on the current epidemiological data.
Authors: Tella Sri Harsha , Wieczorek Mikolaj , Hodge David , Mahipal Amit
Published: January 2023

615

Background: Accounting for 90% of primary liver cancers, HCC is the fourth-most common cause of cancer-related deaths in the United States. While the vaccination against hepatitis B and awareness on hepatitis C transmission possibly decreased the incidence of HCC in Eastern World, there was an uptrend in the HCC incidence the Western World over the past few years possibly related to metabolic causes. With this changing paradigm of hepatocellular carcinoma, it is important to estimate its future burden stratified based on the age, sex, and race, that could possibly help plan prevention, control, and treatment strategies for this cancer. Methods: We obtained histologically confirmed cases of HCC (ICD-0-3 Site: C220 and 228; codes: 8170-8175) from National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) 18 registries between 2000 to 2017 and predicted the incidence between the years 2018-2029. We applied age-period-cohort models to estimate future HCC incidence rates (per 100, 000) and the estimated disease burden by multiplying incidence forecasts by corresponding US Census population projections. Results: A total of 76029 patients with HCC were included in the final analysis. The median age was 62 (range: 20-79) years with male predominance (70%). The overall observed age-adjusted incidence of HCC between 2000-2017 was 6.22, which is predicted to increase to 9.03 by 2029 with a predominant increase in incidence rate observed in the age groups 70-79 and White males. Interestingly, we noticed a progressive decrease in incidence rate in Asian cohort (both males and females) and Black males. Incidence rates by sub-groups based on the age, sex, and race are summarized in the Table. Conclusions: We predict an overall increased incidence of hepatocellular carcinoma over the next decade in the United States, predominantly in 70-79 years age group irrespective sex and race, with an exception to Asian cohort probably representing differential risk factors. Further epidemiological studies are needed to determine the etiological factors contributing to predicted increase in incidence rate.[Table: see text]
Molecular genetic sequencing of neuroendocrine tumors of the gastrointestinal tract.
Authors: Androsova Alexandra , Orlova Rashida , Gordiev Marat , Ivanova Anastasia , Belyak Natalia P. , Kutukova Svetlana
Published: January 2023

651

Background: The objective of this work was to evaluate the molecular and genetic features of the NET gastrointestinal tract. Genomic sequencing of 30 tumor samples of the latest generation was carried out and the data obtained were evaluated. Methods: In total, 30 tumor blocks of patients with gastrointestinal NET were tested by the new generation sequencing (NGS) method. The following genes were analyzed: ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDK12, CHEK1, CHEK2, EPCAM, FANCL, MLH1, MSH2, NBN, NF1, PALB2, PMS2, RAD51B, RAD51C, RAD51D, RAD54L, STK11, TP53, POLE, KRAS, NRAS, BRAF, EGFR, ERBB2, PIK3CA, MET ex14, BAT25, BAT26, NR21, NR24, MONO27, KIT, PDGFRA, Pi3Ca. Preparation of libraries for sequencing was carried out using NimblGen SepCapEZ Choice. Sequencing was performed on the Illumina MiSeq device. Results: In the study cohort of patients whose tumor blocks were sent for examination by the NGS method, there were more women – 19 (63.3%) than men – 11 (36.7%). When analyzing the age of patients, it should be noted that among all age groups, elderly patients predominated (60-74 years according to the WHO classification, 2016) – 12 (40%). In the majority of patients – 10 (33.3%) – the primary tumor focus was localized in the pancreas, in 6 (20%) patients it was primarily affected stomach, 7 (23.3%) – small intestine. Other parts of the gastrointestinal tract were affected much less frequently: the colon – in 1 (3.3%) patients. According to the division according to the degree of differentiation of gastrointestinal NET10 tumors had a degree of differentiation G1 (33.3%), 16 -G3 (54.3%), 4– G3 (13.3%). In the tumor sample of a patient with gastric NET G1 (Ki 67 = 2%), POLE mutations were found: c.2276G > A, p.R759H and CHEK2: c.470T > C, p.I157T. Also, mutations MLH1: c.199G > A, p.G67R BRCA1: c.1881 were found in the tumor sample of another patient with gastric NET G2 (Ki 67 = 7%). Conclusions: To improve the survival rates of patients, it is worth paying special attention to the molecular genetic study of the NET gastrointestinal tract. It is molecular genetic profiling that can become the basis for building more individualized algorithms for treating patients. The results of this study allow us to count on the fact that when conducting a study on a larger cohort of patients with gastrointestinal NET, it is possible to obtain results that will expand our knowledge of this nosology and allow us to supplement the already available information about prognosis factors and predictors of response to treatment.
Socioeconomic disparities causing delays in pancreatic cancer germline genetic testing.
Authors: Zou Xianghui , King Daniel , Sidiqi Baho , Patruni Sunita , Hollweg Christopher , Kauff Noah D.
Published: January 2023

665

Background: Germline genetic testing is recommended for patients with pancreatic ductal adenocarcinoma (PDAC) and pre-diagnostic testing is offered to patients with a significant family history. However, only 36% of patients in our institution obtained genetic testing. We identified associations between patient social profiles (income, race, ethnicity, social work needs) and delays in obtaining germline genetic testing from New York’s largest healthcare system. Methods: Patients with PDAC were identified using billing records across our institution with an IRB-approved protocol. Median income was extrapolated using patient zip code. Date of diagnosis (DOD) was recorded as the date of biopsy or, if no biopsy was performed, the date of earliest lesion found on CT scan. Delays of testing was calculated as the difference between DOD and the date of germline sample collection. Results: Between Mar 2016 and Feb 2022, 305 patients with PDAC were identified, with 103 (36.3%) having reports found (F), and 202 (63.7%) not having reports found (NF). Availability of germline testing did not vary by median income (F: $95954, NF: $94368, t=0.414, p=0.68). There was no significant difference in the geographic distribution either (gender p=0.92, race p=0.92, ethnicity p=0.16). Pearson analysis between income (x) and delays of testing (y) showed a negative correlation (y=-0.0028x+316, r2=0.058, p=0.014). African American and Hispanic patients, grouped for this analysis as underserved (U), had a significant delay in obtaining germline genetic testing compared to the remainder of patients (not underserved, NU) (U: 92d, NU: 21d, u=305.5, p=0.0016). In addition, African American (AA) patients had a significant delay of testing compared to White (W) patients (AA: 92d, W: 13d, u=161.5, p=0.0002). Furthermore, all 11 patients (1 Asian, 10 White) who obtained pre-diagnostic testing were NU patients (χ2=5.005, p=0.025). Upon further analysis, patients who have social work (SW) needs have a significant delay in testing compared to patients without SW needs (SW: 109d, no SW: 23d, u=263, p=0.025). Of the 12 patients who have SW needs, the primary needs were home care, transportation, or financial assistance. In addition, there was a trend toward difference between English (E) and non-English (NE) speaking patients when comparing their delays in testing (E=26.5, NE=108.5, u=257, p=0.12). Conclusions: Analysis of germline and clinical data from our 305-patient cohort identified a striking and concerning negative correlation between patient income and delays in germline testing. In addition, underserved patients had significant delays in germline testing and did not obtain any pre-diagnostic testing. Furthermore, social needs and primary language may be barriers for germline testing. Interprofessional collaborations may be required to prompt germline testing at our institution or nationwide.
Clinical implications of peritoneal cytology evaluated by staging laparoscopy for potentially resectable pancreatic cancer.
Authors: Tanaka Haruyoshi , Fukasawa Mina , Igarashi Takamichi , Watanabe Toru , Saeki Shiori , Itoh Ayaka , Shibuya Kazuto , Kimura Nana , Hirano Katsuhisa , Nagamori Masakazu , Mori Kosuke , Takeda Naoya , Miwa Takeshi , Hashimoto Isaya , Hojo Shozo , Matsui Koshi , Yoshioka Isaku , Okumura Tomoyuki , Fujii Tsutomu
Published: January 2023

674

Background: Positive peritoneal cytology has been reported to indicate a poor prognosis in patients with pancreatic cancer even if the primary tumor is surgically resected. This study investigated the clinical implications of peritoneal cytology by staging laparoscopy for patients with potentially resectable pancreatic cancer for whom initial treatment will be started. Methods: We retrospectively reviewed 113 consecutive patients with pancreatic cancer diagnosed as resectable by computed tomography in whom peritoneal cytology was evaluated by staging laparoscopy between December 2018 and August 2022. Patients with positive cytology received induction chemotherapy, and those in whom cytology converted to negative underwent surgical resection as needed when possible. We set best tumor marker cutoff values for predicting positive cytology by maximizing the Youden index. Results: Seventy-three patients were men and the mean age was 72 years. Thirty patients (26.5%) had positive cytology at initial staging laparoscopy. Minimal peritoneal metastases were detected in seven of these patients and liver metastases in two. Larger tumor diameter ( > 30 mm), location in the pancreatic body or tail, an elevated CA19-9 level ( > 138.5 U/ml), an elevated CA125 level ( > 13.5 U/ml), and an elevated CEA level ( > 5.1 ng/ml) were associated with a significantly increased risk of positive cytology (odds ratio 4.71 [confidence interval 1.87–12.2] P = 0.001, 2.49 [1.07–6.05] P = 0.038, 2.95 [1.26–7.12] P = 0.014, 3.89 [1.57-10.7] P = 0.005, and 3.52 [1.23–10.2] P = 0.018, respectively). Eighteen patients (60%) who received induction chemotherapy converted from positive to negative cytology; seven (38%) of these patients underwent surgery and all remain alive without recurrence. Interestingly, median overall survival in patients with negative cytology was not necessarily inferior to that in those with positive cytology (23.4 months vs. 24.2 months, P = 0.33). Conclusions: Over a quarter of patients with pancreatic cancer that is diagnosed as resectable by computed tomography may have positive peritoneal cytology at the initial assessment. These patients tend to have higher CA19-9, CA125, and CEA levels, larger tumors, and tumors located in the body or tail of the pancreas. A more favorable prognosis may be achieved by administering induction chemotherapy until cytology converts to negative than by upfront surgery.
Adult BMI change over time and risk of colorectal adenoma.
Authors: Holum Parker Jayce , Palmer Chelsea , Sun Xiangqing , Venkatesh Samyukta , Devall Matthew , Cooper Gregory , Powell Steven M. , Yoshida Cynthia , Li Li
Published: January 2023

68

Background: Obesity and adult weigh gain are established risk factors for colorectal cancer (CRC). Few studies have investigated the association between adult body weight change over time and risk of colorectal adenoma. We hypothesize adult BMI change over time is associated with risk in the development of colorectal adenomas. Methods: We tested this hypothesis in 2,993 patients undergoing screening colonoscopy from 2007–2017. Weight at age 20, 30, 40, and 50 were self-reported via computer assisted personal interviews. Height and weight at recruitment were measured at the time of colonoscopy exam. BMI (kg/m2) change was calculated as the difference of BMI at recruitment from the BMI estimate for each of the age periods. Results: Of the 2,993 patients, 984 had pathologically confirmed diagnosis of colon adenoma. Multivariate logistic regression adjusted for potential confounders and BMI at recruitment showed statistically significant increase of risk of adenoma with increase of BMI since age 30, age 40, and age 50. Compared to those with BMI change of less than 5, the ORs for those with BMI gain of 5-10 and ≥10 were: 1) 1.16 (0.92-1.46) and 1.48 (1.08-2.03) respectively for change from age 30 (ptrend = 0.05); 2) 1.11 (0.87-1.43) and 1.60 (1.09-2.35) respectively for change from age 40 (ptrend = 0.05); and 3) 1.36 (0.95-1.94) and 2.95 (1.33-6.90) respectively for change from age 50 (ptrend = 0.01). Stratified analysis did not reveal noticeable gender differences. Conclusions: Large adult weight gain over time is an independent risk factor for colorectal adenoma. Our results suggest maintaining healthy body weight throughout adulthood is an important preventive measure against the development of early colorectal neoplasia. [Table: see text]
Phase I study of proton therapy in adjuvant pancreatic cancer (PROTON-PANC).
Authors: Weinberg Benjamin Adam , Wang Hongkun , Noel Marcus Smith , He Aiwu Ruth , Marshall John , Weiner Louis M. , Fishbein Thomas M. , Winslow Emily R. , Jackson Patrick G. , Guerra Juan F. , Aguila Francisco , Unger Keith Robert
Published: January 2023

709

Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of 10%. The current standard of care for patients with resectable disease is surgical resection followed by 6 months of adjuvant mFOLFIRINOX (mFFX) chemotherapy. As survival outcomes and distant recurrence rates improve with the use of mFFX, locoregional recurrence remains a significant cause of morbidity and mortality. We sought to integrate short-course proton radiation therapy (PRT) to the operative bed between cycles of adjuvant chemotherapy in patients with resected PDAC of the pancreatic head. Methods: Between 2019 and 2022, patients with resected PDAC with an R0 or R1 resection on adjuvant mFFX were enrolled in a phase I trial using a 3+3 dose-escalation schema (NCT03885284). Patients received mFFX as used in the PRODIGE 24 study and also received short-course PRT delivered over 1 week in 5 fractions (5 GyE each) between cycles 6 and 7 of mFFX. In dose level 1 (DL1), patients received PRT on days 15-19 in a 28-day cycle before starting cycle 7, and in dose level 2 (DL2) patients received PRT on days 8-12 in a 21-day cycle before starting cycle 7. Results: Nine patients were enrolled on the trial, median age 66 (range 52-78). Five had R0 resections, 4 had R1 resections, and 5 had node-positive disease. No patients received preoperative therapy, and none underwent vein reconstruction. Three patients were enrolled on DL1 and 6 patients on DL2. One dose limiting toxicity (DLT) occurred at DL2 (prolonged grade 3 neutropenia resulting in discontinuation of mFFX after cycle 7). No other DLTs were observed. Four patients completed the planned 12 cycles of mFFX (range 7-12, median 11). None of the patients have had local recurrence. Five of 9 patients had recurrence: 3 in the liver, 1 in the peritoneum, and 1 in the bone. Six patients are still alive, 4 of whom are recurrence free. With a median follow up from date of chemotherapy start of 12.5 months, median time to disease recurrence was 12 months (95% confidence interval [CI] 4-not reached [NR]), and median overall survival has not been reached (95% CI 6-NR, 2-year survival rate 57%). Conclusions: PRT integrated within adjuvant mFFX was well-tolerated and no local recurrence was observed for patients with resected PDAC. These findings warrant being confirmed in a phase II trial. Clinical trial information: NCT03885284 .
Metronomic oral cyclophosphamide as maintenance therapy in metastatic pancreatic ductal adenocarcinoma.
Authors: Reni Michele , Orsi Giulia , Peretti Umberto , Macchini Marina , Militello Anna Maria , Falconi Massimo , Cascinu Stefano
Published: January 2023

716

Background: Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC) has a grim prognosis, with limited therapeutic options. In this context, treating patients (pts) with chemotherapy (CT) till progression is not supported by scientific evidence and must be weighed against quality of life impairment and cumulative toxicity. Therefore, we explored the role of metronomic oral cyclophosphamide (mCTX) as maintenance therapy (MT) in mPDAC pts. Methods: Any age mPDAC pts, with Karnofsky performance status >60 and wild-type germline BRCA1-2, who were progression-free after at least 6 months of any regimen and line CT and received mCTX (50 mg/die) MT between August 2020 and July 2022, were included in the analysis. An historical cohort (HC) of mPDAC pts, who were progression-free after 6 months of 1st-line platinum-based combination CT and did not receive MT between 2000 and 2016, was considered for exploratory comparison. Progression-free and Overall Survival (PFS and OS) were calculated from last CT administration for both cohorts. Results: 41 and 122 pts were included in mCTX and HC, respectively. Median PFS was 4.1 (range 1.5-18.4) and 3.1 (1-141) months for mCTX and HC, respectively (p= 0.003). PFS rates at 6 and 12 months were 34.7% and 11.1% in the mCTX cohort, 18.9% and 6.6% in the HC. Median OS was not reached (range 1.5-25) and 10.2 (1.3-142) months for mCTX and HC, respectively (p= 0.002). OS rates at 6 and 12 months were 96.9% and 74.6% in the mCTX cohort, 74.5% and 46.9% in the HC. Factors associated with longer PFS in the mCTX cohort were normal CA19.9 at CT start (p= 0.006), female gender (p= 0.036), no liver metastases (p= 0.01), normalized CA19.9 after CT (p= 0.01). Only 2 pts receiving mCTX had Grade 3 toxicity. Conclusions: mCTX MT extends PFS and OS of mPDAC pts not progressing after at least 6 months of CT with unremarkable toxicity in our exploratory non-randomized analysis.[Table: see text]
Multiagent neoadjuvant chemotherapy compared to upfront surgery in pancreatic cancer of the body and tail using the National Cancer Database.
Authors: Franklin Oskar , Sugawara Toshitaka , Rodriguez Franco Salvador , Schulick Richard D. , Del Chiaro Marco
Published: January 2023

722

Background: While neoadjuvant chemotherapy is increasingly being using in pancreatic cancer treatment, it is unclear whether it is beneficial in treatment of body and tail tumors. Randomized controlled trials are lacking and previous observational studies have not demonstrated any benefit. We aimed to assess survival associations, trends over time and patient selection associations for multiagent neoadjuvant chemotherapy treated pancreatic cancer of the body and tail using data from the National Cancer Database (NCDB). Methods: We queried the NCDB for pancreatic adenocarcinoma in the body or tail diagnosed between 2010 – 2018 that received multiagent neoadjuvant chemotherapy and/or a distal pancreatectomy. Patients with clinical M1, clinical T4 and surgery other than partial pancreatectomy were excluded. Survival was compared with Kaplan-Meier estimates and multivariable Cox Proportional Hazard Estimates. Results: Between 2010 – 2018, the use of multiagent neoadjuvant chemotherapy increased from 5.7% to 31.8%. In total, 1951 patients were included with n = 384 receiving multiagent neoadjuvant chemotherapy (cases) and n = 1567 undergoing upfront surgery (controls). Neoadjuvant chemotherapy was associated with younger age, tumor in the pancreatic body, clinical N1-2 and with Ca 19-9 ≥98 U/mL. Neoadjuvant chemotherapy was associated with a decreased mortality rate in multivariable Cox regression models adjusting for preoperatively assessed variables (HR 0.65, 95% CI 0.53 – 0.81, p < 0.001) and results were significant in both clinical T1-2 and T3 tumors. Patients treated with upfront surgery had higher rates of adjuvant chemotherapy receipt after resection (41.4% vs 70.6%) but there was no difference in R1 resection rates or 90-day postoperative mortality between the groups. The addition of neoadjuvant radiotherapy was not associated with improved survival in patients receiving neoadjuvant chemotherapy. Conclusions: Multiagent neoadjuvant chemotherapy is increasingly being used in the treatment of pancreatic cancer of the body and tail, especially in younger patients and patients with more aggressive tumor characteristics. Multiagent neoadjuvant chemotherapy is associated with improved survival but randomized trials are needed to establish causal relationships.
Cost effectiveness of liquid biopsy for colorectal cancer screening.
Authors: Aziz Zainab , Wagner Sophie , Agyekum Alice , Prest Matthew , Pumpalova Yoanna S , Hur Chin
Published: January 2023

73

Background: Despite established screening guidelines, adherence to colonoscopy is approximately 60%. Blood-based screening tests, or Liquid Biopsies (LB), have the potential to close this screening gap. Our aim was to determine the cost-effectiveness of LB tests for CRC screening in the US. Methods: We developed a Markov model to compare four CRC screening strategies: no screening, or natural history (NH), colonoscopy (Colo) only, LB only, and colonoscopy to LB hybrid (C-LB). US SEER CRC incidence and mortality data were used to develop and validate the model. Many LB tests are in development awaiting validation; we used the preliminary performance characteristics for CRC screening of 82% sensitivity and 99.5% specificity (base case) from the Galleri multi-cancer early detection test (GRAIL). Screening ran from age 45 to 75; polyp surveillance ended at 85. We assumed 60.6% of the US population would undergo a screening colonoscopy, and 100% adherence for LB. In Colo, nonadherent patients were not offered other screening; in C-LB those who refused colonoscopy underwent LB. Primary outcomes were overall survival, total cost, incremental cost-effectiveness ratio (ICER), number of CRCs, and CRC deaths. Results: In the NH strategy, 5.2% of the population developed CRC and 1.8% died from CRC, with a cost of $7,802.15/individual. Compared to NH, in Colo, 40% of CRCs and 44% of CRC deaths were prevented, at a cost of $10,610.43/individual. In C-LB, 42% of CRCs and 50% of CRC deaths were prevented compared to NH, costing $13,762.61/individual. LB only prevented 2.0% of CRCs and 11% of CRC deaths compared to NH, and cost $34,339.85/individual. While LB showed an incremental benefit of 0.01 life years gained compared to NH, the ICER compared to NH is $2,653,770. Colo was most cost-effective with an ICER of $30,191.04. Although C-LB prevented the greatest number of CRCs, this strategy had an ICER of $457,057.64, above the accepted US willingness to pay threshold of $100,000/life year. We performed sensitivity analysis around base case estimates for LB. At both 70% and 90% test sensitivity, all outcomes remained largely constant. Conclusions: CRC screening with LB alone or with LB in conjunction with colonoscopy among nonadherent patients is not cost-effective in the US context. At this time, LB is unable to detect pre-cancerous colon polyps, which may limit its effectiveness as a CRC screening strategy. [Table: see text]