bluuebunny/crossref_metadata_2025 huggingface dataset:
Relations between mutant KRAS and TP53 subtypes and other co-mutations in pancreatic cancer.
Authors: Abraham Soniya , Zhang Janie Yue , Walther Zenta , Parekh Jay , Lacy Jill , Cecchini Michael , Hu Yiduo
Published: June 2023

e16294

Background: The most common mutations in pancreatic cancer are found in the KRAS, TP53, CDKN2A, or SMAD4 genes. Mutations in genes involved in the DNA damage repair (DDR) pathway are also frequently seen. Despite extensive research on the patho-genomic features of pancreatic cancer, the clinical significance of these recurring mutations remains poorly understood. Methods: We identified patients with pancreatic cancer treated at Yale Cancer Center between 2016 and 2021 who underwent Oncomine tumor profiling. The incidence and subtypes of KRAS and TP53, and their association with other genomic alterations and clinicopathological variables were measured. We compared the overall survival (OS) after the diagnosis of recurrent or metastatic disease using the Kaplan-Meier method and long-rank tests. Results: One hundred fifty-nine patients were identified and KRAS mutations were seen in 144 (90.6%) patients, including 64 G12D (44.4%), 48 G12V (33.3%), 19 G12R (13.2%), 6 Q61H (4.2%), and 7 others (4.9%). TP53 mutations were identified in 117 (73.6%) patients, including 80 loss-of-function (LOF) (68.4%), 24 gain-of-function (GOF) (20.5%), and 13 variants of unclear significance (VUS) (11.1%). TP53 LOF mutations were more common in tumors with KRAS WT (40.0%), G12D (56.3%), and G12V (56.3%), than in G12R (31.6%) and others KRAS mutation (30.1%). Conversely, TP53 GOF mutations were more common in tumors with G12R (26.3%) and other KRAS mutations (23.1%), than in KRAS WT (6.7%), G12D (14.1%), and G12V (12.5%). There was no difference in OS between KRAS subtypes (p=0.48) or TP53 subtypes (p=0.52). Patients with TP53 WT had a numerically longer but not statistically significant survival (median 1.65 years versus 1.16 years in patients with TP53 mutations, p=0.20). When each KRAS subtype was examined, patients with tumors with G12V but no TP53 mutation had longer OS (median 2.42 years) than those with WT KRAS or non-G12V mutation (median 1.38 years, p=0.02). Mutations in DDR genes were more frequently seen in the KRAS WT (33.3%) and G12D groups (15.6%), compared to that in the G12V (10.4%), G12R (10.5%) groups. Unique co-mutations were observed in certain KRAS subtypes but not others. Conclusions: In this retrospective study of comprehensive genomic and clinical data of pancreatic cancers, we found that KRAS or TP53 mutation subtypes had no significant impact on OS. Different KRAS subtypes have unique co-occurring genomic alterations, which may be clinically relevant as novel KRAS inhibitors continue clinical development.[Table: see text]
Adverse events in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who received FOLFIRINOX in the first line.
Authors: Kim George P. , Silver Michelle , Sanders Chad , Cockrum Paul , MacEwan Joanna P.
Published: June 2023

e16295

Background: Quality of life is particularly important for patients (pts) with short life expectancy, such as those with metastatic pancreatic ductal adenocarcinoma (mPDAC). While first line (1L) FOLFIRINOX (FFX) is recommended by treatment guidelines for pts with mPDAC and good performance status, the regimen is known to be associated with significant toxicity that impacts quality of life. More than half of pts experience adverse (AEs)—such as nausea and vomiting, diarrhea, fatigue, neuropathy, anemia, thrombocytopenia, and neutropenia—during treatment with FFX. Efforts to reduce AEs have led to the use of modified FFX (mFFX) regimens that utilize lower doses of components of the regimen. Additional evidence on AEs associated with FFX and mFFX in the real world (RW) is needed. We assessed AEs in a RW cohort of mPDAC pts treated with FFX or mFFX in 1L. Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between January 2015 and November 2022 who initiated treatment with FFX or mFFX within 90 days of their diagnosis for metastatic disease (1L) were included in the study. Pts were required to have an available body surface area measurement within 7 days of the index date. mFFX was defined as administration of (i) < 150mg/m2 of irinotecan, or (ii) < 2,720mg/m2 5-FU total during cycle 1. Diarrhea, fatigue, nausea and vomiting, and neuropathy were available in the data as ungraded AEs abstracted from clinician notes. Assessment of hematologic and hepatic AEs were based on observed lab values and were graded according to the Common Terminology Criteria for Adverse Events version 5. Results: Of the 1,326 pts meeting study inclusion criteria and receiving 1L treatment with FFX or mFFX, 1,325 received mFFX and 1 received FFX. The median age at 1L initiation was 65yr (IQR: 58–70), 57% (754 pts) were male, 69% (916 pts) were white, 15% (197 pts) had an ECOG score of 0, 42% (550 pts) had an ECOG score of 1, and 78% (1028 pts) were stage IV at diagnosis. The median number of cycles was 5 (IQR: 3–10) and the median dose intensity per week was 940 mg/m2 for 5-FU, 179 mg/m2 for leucovorin, 38 mg/m2 for oxaliplatin, and 73 mg/m2 for irinotecan. Notable grade 3/4 AEs were: 16.4% neutropenia, 4.4% thrombocytopenia, 5.7% anemia, 4.7% elevated ALT, 4.9% elevated AST, and 10.6% elevated ALP. Of the ungraded AEs reported in clinician notes, 17.3% of pts experienced diarrhea, 10.9% fatigue, 10.9% nausea and vomiting, and 11.9% neuropathy. Conclusions: In a RW cohort of mPDAC pts treated with 1L FFX or mFFX, nearly all were treated with mFFX. The burden of serious AEs for mPDAC pts during 1L treatment with FFX or mFFX was high, with 30% (403 pts) experiencing at least one grade 3/4 AE.
Incidence of palliative care consultations in end-of-life care among patients with pancreatic cancer in the US.
Authors: Gokul Kaushik , Zhang Zidong , Subramaniam Divya S.
Published: June 2023

e16302

Background: Integration of palliative care in the treatment plan for a variety of diseases has been shown to improve quality of life, reduce aggressive interventions, and reduce cost burdens. This study aimed to explore the incidence of palliative care consultations in pancreatic cancer patients and determine its influence on the utilizations of aggressive interventions towards end of life. Methods: We conducted a retrospective study using a de-identified national Electronic Health Record (EHR) database, which captured deceased patients between January 1, 2000 to December 21, 2018, with a diagnosis of pancreatic cancer. Clinical history from 0-6 months prior to death was examined for the presence of a palliative care consultation (PCC) encounter. Aggressive interventions of interest, namely emergency department visits, chemotherapy, and ICU admissions, were identified and recorded in both the last six months and the last month of life. Demographic variables such as age, gender, race, and location were also considered during analysis. The PCC group and non-PCC group were compared using the Whitney U-test and Chi-squared test. Results: 2,883 deceased patients with PanCa were identified. However, 2,025 of these patients did not receive PCC in the last six months of life. The average age of death was greater at 70.5 years within the PCC group as compared to 68.9 years within the non-PCC group. This difference was statistically significant. In the last 6 months prior to death, 14.1% of patients overall had chemotherapy. The proportion of patients having chemotherapy was greater among the PCC patients compared to those not (22.4% vs 10.6%). Compared to those who did not receive PCC, patients who had PCC in the end of life were also more likely to be hospitalized (81.1% vs 38.2%), visit emergency departments (45.1% vs 23.7%) and stay in the ICU (14.1% vs 4.0%). In the last 30 days of life, trends were similar. Within PCC, 3.4% had chemotherapy while 1.3% had chemotherapy in the non-PCC group. As far as hospitalizations go, among patients with PCC, 51.3% were hospitalized compared to 15.5% hospitalizations in non-PCC. In patients who had PCC, 14.8% had at least one emergency department visit while 4.8% of patients in the non-PCC group had at least one emergency department visit. Lastly, ICU stays showed a similar trend to the previous interventions. In PCC patients, 7.9% had at least one ICU stay while only 1.5% of patients had one in the non-PCC group. Conclusions: Our study found that less than 30% of patients with PanCa received PCC at the end of life. Findings show an urgency to increase awareness and utilization of PCC for such patients. Interventions should be developed to address this urgency to help improve quality and efficiency of care. Future studies will also identify barriers and facilitators in implementing PC and consultation for patients with PanCa.
Differences in outcomes of patients with advanced neuroendocrine tumors treated with chemotherapy versus targeted agents.
Authors: Freeman Jesica , Stacey Jennifer
Published: June 2023

e16303

Background: Pancreas NETs are uncommon and very rare cancer accounting for around 7% of the pancreatic cancer sub patient population, 4,200 patients in the US diagnoses yearly of all cancers in the pancreas. There are very few treatment options available for Metastatic Pancreatic Neuroendocrine Tumor patients. The survival rate depends on a variety of factors, including whether the tumor can be removed using surgery and if the cancer has spread to other parts of the body. The 5-year survival rate non-metastatic pancreas NETs is 93% while metastatic pancreas NETs is 24%. Therefore, this study compares the 5-year overall survival rate of metastatic pancreatic NETs ineligible for surgery who have received chemotherapy alone versus who have received targeted therapy. Methods: Patient cohorts were generated in an electronic medical records (EMR) TriNetX Research Network of 89M patient lives. Patients were identified as either receiving a targeted therapy or patients who were targeted therapy naïve receiving chemotherapy. Both cohorts had a diagnosis of pancreatic NETs (ICD-10 C25.4), at least one documentation of a related metastasis, and no history of any pancreatic surgery. The 5 year overall survival (OS) from first exposure to either targeted therapy or chemotherapy was analyzed using measures of association and survival analysis conducted via Kaplan-Meier estimator. Cohort comparisons were with propensity score matching (PSM) to control for demographic, comorbidity, medication, and diagnostic procedure confounders. Results: After matching, each cohort accounted for 389 patients (43% female, mean age at index 62 +/- 13 SD). There was a significant 5-year mortality risk difference (11.054%, p = 0.0020) between the chemotherapy only cohort (215 patients, 55.27%) vs. the targeted therapy cohort (172 patients, 44.216%) after adjusting for potential confounding factors. Additionally, the 5-year OS rate was 24.951% in the chemotherapy only cohort and 37.222% in the targeted therapy cohort. The difference in survival between the groups was statistically significant (log-rank p = 0.0001). Conclusions: In these cohorts of patients with metastatic pancreas NETs without surgical treatment, we found that targeted therapy was associated with a significant improvement in 5-year overall survival compared to standard chemotherapy alone. Our results suggest that targeted therapy should be considered as a first line treatment option for this severe patient population.
Description of technique for endoscopic ultrasound-guided tissue acquisition in pancreatic cancer for comprehensive molecular profiling: Results of a randomized trial.
Authors: Bang Ji Young , Jhala Nirag , Seth Anjali , Krall Konrad , Navaneethan Udayakumar , Hawes Robert , Wilcox C. Mel , Varadarajulu Shyam
Published: June 2023

e16306

Background: As theoretically actionable genomic lesions are found in almost 50% of pancreatic cancers which can impact clinical management in up to 30% of patients, there is increased focus on molecular profiling. Although EUS-FNB is an established method for achieving pathological diagnosis in pancreatic cancers, the technique of tissue acquisition for comprehensive molecular profiling (CMP) has not been described. Methods: Patients proven to have pancreatic adenocarcinoma using rapid onsite evaluation (ROSE) at EUS were randomized to undergo two or three dedicated FNB passes for CMP. Tissue was procured using 22G Franseen needle adopting the fanning technique and stylet-retraction maneuver. Genomic DNA and total RNA were extracted from formalin-fixed paraffin-embedded (FFPE) cell blocks (Qiagen AllPrep). Next-generation sequencing (NGS) was performed (Archer Panels) for analyzing 69 gene DNA mutations (single nucleotide variants, insertions, and deletions) and 53 RNA somatic oncogenic gene fusions. Main outcome measure was the proportion of specimens in which adequate DNA and RNA were extracted for CMP. Results: 33 patients (mean age 77.0 years [SD 7.7], female = 20) with pancreatic cancer (location = head/uncinate 22; other 11) were randomized to two (n = 17) or three (n = 16) FNB passes. While sufficient DNA was extracted from all 33 FFPE cell blocks, adequate RNA was extracted from 15 of 16 in the three pass (93.8%) vs. 16 of 17 in the two pass cohort (94.1%) (p = 0.99). There was no significant difference in the mean concentration of DNA (two passes 10.7 ng/ul [SD 7.1] vs. three passes 7.9 ng/ul [SD 4.4]; p = 0.19) or RNA (two passes 37.1 ng/ul [SD 26.5] vs. three passes 28.9 ng/ul [SD 13.2]; p = 0.29) between the groups. While somatic oncogene RNA fusion (LDAH-ETV1) predictive of metastatic disease was identified in one specimen, DNA mutations were identified in all 33 specimens that included one BRCA1 mutation that warranted Oxaliplatin-based chemotherapy. Conclusions: Specimens of adequate quantity and of high quality for comprehensive molecular profiling in pancreatic cancer can be procured in nearly 95% of patients by performing two dedicated passes using the 22G Franseen needle, adopting the fanning maneuver and stylet-retraction technique. Clinical trial information: NCT05043532 .
Comprehensive genomic landscape in pancreatic cancer using whole-exome sequencing.
Authors: He Yonggang , Huang Xiaobing , Zheng Lu , Huang Wen , Tang Yichen , Peng Xuehui , Li Jing , Wu Jing , You Nan , Liu Chuang , Zhang Yaxuan , Li Ling
Published: June 2023

e16307

Background: Pancreatic ductal adenocarcinoma is one of the fatal malignancies in the world, mostly as a result of the absence of early detection and specific treatment solutions. Consequently, identifying mutational profiles and molecular biomarker are essential for increasing the viability of precision therapy for pancreatic cancer. Methods: We gathered blood and tumour tissue samples from 47 Chinese pancreatic cancer patients and used whole-exome sequencing (WES) to evaluate the genetic landscape. Results: Our results showed the most frequently somatic alteration genes were KRAS (74.5%), TP53 (51.1%), SMAD4 (17%), ARID1A (12.8%), CDKN2A (12.8%), TENM4 (10.6%), TTN (8.5%), RNF43 (8.5%), FLG (8.5%) and GAS6 (6.4%) in Chinese pancreatic ductal adenocarcinoma patients. We also found that three deleterious germline mutations ( ATM c.4852C > T/p. R1618*, WRN c.1105C > T/p. R369*, PALB2 c.2760dupA/p. Q921Tfs*7) and two novel fusions ( BRCA1-RPRML, MIR943 (intergenic)- FGFR3). When compared to the Cancer Genome Atlas (TCGA) database, there is a greater mutation frequency of TENM4 (10.6% vs. 1.6%, p= 0.01), GAS6 (6.4% vs. 0.5%, p= 0.035), MMP17 (6.4% vs. 0.5%, p= 0.035), ITM2B (6.4% vs. 0.5%, p= 0.035) and USP7 (6.4% vs. 0.5%, p= 0.035) as well as a reduced mutation frequency of SMAD4 (17.0% vs. 31.5%, p= 0.075) and CDKN2A (12.8% vs. 47.3%, p< 0.001) were observed in the Chinese cohort. Among the 41 individual examined for PD-L1 expression, 15 (36.6%) had positive PD-L1 expression. The median tumour mutational burden (TMB) was found to be 12 muts (range, 0-124). The TMB index was higher in patients with mutant-type KRAS MUT/ TP53 MUT ( p< 0.001), CDKN2A ( p= 0.547), or SMAD4 ( p= 0.064) compared to patients with wild-type KRAS/ TP53, CDKN2A, or SMAD4. Conclusions: We exhibited real-world genetic traits and new alterations in Chinese individuals with cancer of pancreas, which might have interesting implications for future individualized therapy and medication development.
Efficacy of adjuvant chemoradiotherapy in patients with pancreatic ductal adenocarcinoma after surgery: A real-world study in high-volume pancreatic cancer center.
Authors: Wu Lili , Guo Xi , Xu Yaolin , Wang Dansong , Wu Wenchuan , Kuang Tiantao , Xu Xuefeng , Liu Liang , Wang Wenquan , Du Shisuo , Zhou Yuhong , Lou Wenhui
Published: June 2023

e16308

Background: Whether adjuvant chemoradiotherapy provides survival benefit for pancreatic ductal adenocarcinoma (PDAC) patients remains unknown. Methods: This prospective real-world study recruited PDAC patients receiving surgical treatment in Zhongshan Hospital Fudan University, Shanghai, China from June 2020 to December 2021. Patients with carcinoma in situ, distant metastases, synchronous cancers within 5 years, and receiving neoadjuvant therapy were excluded. Patients were then categorized into three groups according to their adjuvant treatment: C- (without adjuvant chemotherapy), C+R- (with adjuvant chemotherapy only), and C+R+ (with adjuvant chemoradiotherapy). Overall survival (OS) and disease free survival (DFS) were compared between groups. Results: A total of 216 patients were included in the final analyses. Median follow time for three groups ranged from 18 to 21.9 months. OS and DFS were significantly different between groups (OS, p value = 0.0088; DFS, p value = 0.0037). Median OS (mOS) for C- and C+R- were 24.3 (95% confidence interval [CI], 18 - not available [NA]) and 29.5 (24.9 – NA). Patients in C+R+ groups did not reach mOS (27.2 - NA). Median DFS (mDFS) for C-, C+R-, and C+R+ were 8.42 (5.72 - NA), 16.9 (13.91 - NA) and 19.66 (16.83 - NA), respectively. Conclusions: Adjuvant treatment significantly increased survival outcomes of pancreatic cancer patients after surgical treatment. In order to find out whom might benefit from additional radiotherapy and which is the best therapy combination, more detail information, including chemotherapy regimen, staging, resection margin, etc., were needed to include in the survival analyses. Clinical trial information: NCT04737551 . [Table: see text]
Evaluating adherence to NCCN guideline-directed genetic screening for patients with pancreatic ductal cell adenocarcinoma in rural northeast Georgia.
Authors: Ghosh Aditya Kumar , Bhushan Sheena , Abidoye Oluseyi , Sampat Devi
Published: June 2023

e16311

Background: Patients with mutations in BRCA 1/2 genes are at increased risk for pancreatic ductal cell adenocarcinoma (PDAC) in addition to breast and ovarian cancer. In 2019, the NCCN updated its guidelines recommending gene testing for all patients with PDAC to include associated genes: ATM, BRCA1, BRCA2, CDKN2A, MSH2, MLH1, MSH6, EPCAM, PALB2, STK11, TP53. This retrospective, observational study reports on adherence to genetic screening recommendations among patients with newly diagnosed PDAC who received oncologic care in rural Northeast Georgia (NEGA). Methods: Chart abstraction was performed utilizing the EPIC database from hospital electronic medical records of patients who were diagnosed with PDAC between 1/1/20-12/31/21 and received oncologic care in rural NE GA. This abstraction was completed to include information on gene testing recommendations, testing completion, and time from diagnosis to testing. The deidentified dataset was then analyzed using appropriate descriptive and associative statistical testing. Results: Of the cohort of 109 patients diagnosed with PDAC over these two years, only 32 (29.4%) received recommendations and completed genetic screening. Among this segment of patients, 16 (14.7%) were screened within 10 days of diagnosis, 8 (7.3%) within 11-30 days, and 6 (5.5%) were screened over 30 days after being diagnosed with PDAC. Among the 77 (70.6%) patients who did not receive screening, 45 of them (41.3%) did not receive any discussion regarding screening despite planning for other standard of care treatment. The remaining 32 patients (29.4% of the no screening cohort) did not receive screening due to desire to pursue palliative care/hospice/or due to terminal illness that prevented further workup. Of the 45 patients who did not receive screening despite PDAC treatment intent, majority (43; 95.5%) did not receive recommendations regarding the importance of genetic screening. Gene testing of the 32 patients who had screening completed showed that 4 (12.5%) had a pathogenic mutation (3 with CFTR; 1 ATM) and 16 (50%) had variants of unknown significance (VUS). Conclusions: This study highlights a gap in adherence to guideline-directed genetic testing in PDAC patients. Notable findings include increased likelihood to complete the test when recommendations and discussions of genetic screening occurred early in the course after initial diagnosis of PDAC. Moreover, 12.5% of those screened were found to have pathogenic mutation and half were found to have at least one VUS suggesting that genetic screening may potentially identify causative mutations. The findings also highlight the consideration for gene testing recommendation for the large proportion of patients who are terminally ill at diagnosis, as genetic screening would potentially benefit the family members and inform that they receive genetic screening as well.
Risk stratification of pancreatic ductal adenocarcinoma patients undergoing curative-intent surgery after neoadjuvant therapy.
Authors: Yang Hyun Kyung , Park Mi-Suk , Han Kyunghwa , Eom Geonsik
Published: June 2023

e16312

Background: To identify preoperative factors associated with survival in pancreatic ductal adenocarcinoma (PDAC) patients who underwent curative-intent surgery after neoadjuvant therapy (NAT) and develop risk stratification criteria. Methods: Consecutive PDAC patients who underwent post-NAT curative-intent surgeries between 2007 and 2020 at a high-volume center were retrospectively analyzed. Demographic, laboratory, surgical, and histopathologic variables were collected. Baseline, preoperative, and interval changes of CT findings proposed by the Society of Abdominal Radiology and the American Pancreatic Association were analyzed. Cox proportional hazard analyses were used to identify preoperative variables associated with survival since the time of diagnosis. We developed risk stratification criteria using the variables independently associated with survival, i.e., "post-NAT response criteria." We compared the discrimination performance of "post-NAT response criteria" with that of post-NAT pathological (yp) AJCC TNM staging system. Results: A total 145 PDAC patients who completed chemo- (n=47) or chemoradiation therapy (n=98) were included. Stable or increased tumor size on CT (hazard ratio, 2.58 [1.58, 4.21]; P < 0.001) and elevated preop. CA 19-9 level (1.98 [1.11, 3.55]; P = 0.021) were independent poor prognostic factors. The survival of the patient groups stratified by "post-NAT response criteria" which combined changes in tumor size and CA 19-9 showed significant difference (P < 0.001). Such stratification was comparable to ypTNM staging in discrimination performance (difference of C-index, 0.068 [-0.012, 0.142]). Conclusions: Decrease in tumor size and CA 19-9 normalization or staying normal until the time of surgery were independent favorable factors of survival. The combination of the two factors discriminated survival comparably to ypTNM staging.[Table: see text]
Regional hyperthermia with cisplatin added to gemcitabine versus gemcitabine in patients with resected pancreatic ductal adenocarcinoma: The HEAT randomized clinical trial.
Authors: Issels Rolf D. ,   for the European Society of Hyperthermia Oncology (ESHO) and the German Arbeitsgemeinschaft Internistische Onkologie (AIO) Study Group for Pancreatic Cancer
Published: June 2023

e16316

Background: Regional hyperthermia (RHT) with cisplatin added to gemcitabine showed efficacy in gemcitabine-pre-treated patients with advanced pancreatic ductal adeno- carcinoma. We conducted a randomised clinical trial to investigate RHT with cisplatin added to gemcitabine (GPH) compared with gemcitabine (G) in the adjuvant setting of resected pancreatic ductal adenocarcinoma. Methods: This randomised, multicentre, open-label trial randomly assigned patients to either GPH (gemcitabine 1000 mg/m2 on day 1, 15 and cisplatin 25 mg/m2 with RHT on day 2, 3 and 15,16) or to G (gemcitabine 1000 mg/m2 on day 1,8,15), four-weekly over six cycles. Disease- free survival (DFS) was the primary end-point. Secondary end-points included overall survival (OS) and safety. Results: A total of 117 eligible patients (median age, 63 years) were randomly allocated to treatment (57 GPH; 60 G). With a follow-up time of 56.6 months, the median DFS was 12.7 compared to 11.2 months for GPH and G, respectively (p= 0.39). Median post- recurrence survival was significantly prolonged in the GPH-group (15.3 versus 9.8 months; p= 0.031). Median OS reached 33.2 versus 25.2 months (p= 0.099) with 5-year survival rates of 28.4% versus 18.7%. Excluding eight patients who received additional capecitabine in the G- arm (investigators choice), median OS favored GPH (p= 0.052). Adverse events CTCAE (Common Terminology Criteria for Adverse Events) grade >=3 occurred in 61.5% (GPH) versus 63.6% (G) of patients. Two patients in the G-group died because of treatment- related toxic effects. Conclusions: The randomised controlled Hyperthermia European Adjuvant Trial study failed to demonstrate a significant difference in DFS. However, it showed a difference in post- recurrence survival and a strong trend for improved OS. Regional hyperthermia (RHT) with cisplatin offers innovative treatment options in PDAC. Clinical trial information: NCT01077427 .
30-day readmissions for venous thromboembolism and pulmonary embolism in patients with pancreatic cancer: A national population-based study.
Authors: Akhiwu Ted , Kanemo Philip Onyekaoso , Olafimihan Ayobami Gbenga , Ibrahim Muhammad Bilal , Ijeli Anthonia , Edigin Ehizogie
Published: June 2023

e16318

Background: Pancreatic cancer patients have a strong risk of Deep Venous thrombosis (DVT). Pulmonary Embolism (PE) can be a fatal complication of DVT. Both DVT/PE increases the risk of hospitalization and subsequent readmission. National population-based studies are scarce on DVT/PE readmissions among pancreatic cancer patients in the United States (U.S). In this study, we aim to describe the rate, reasons for readmissions, and outcome of readmissions for pancreatic cancer patients hospitalized for DVT/PE in the U.S. Methods: We analyzed the 2018 Nationwide Readmissions Database (NRD). It includes nested and weighted discharge data for 60% of the total U.S population from 28 states. These data are stratified in clusters to produce national estimates. The NRD captures admissions on a calendar-year basis without links to the following or preceding year. We included index hospitalizations for all pancreatic cancer patients (aged ≥18 years) admitted principally for DVT/PE using the International Classification of Diseases (ICD)-10 codes. We excluded elective and traumatic readmissions. 30-day readmission was calculated as the percentage of patients readmitted within 30 days over index hospitalizations that were discharged alive. Using a "rank" command in STATA, the most common reasons for readmission were outlined. Logistic regression was used to compare inpatient mortality between readmissions and index hospitalizations. STATA, 16 was used for analysis. Since NRD contains de-identified patient data, Institutional Review Board (IRB) review was not sought. Results: A total of 2339 index hospitalizations for DVT/PE among pancreatic cancer patients were discharged alive. Among these, 510 (21.8%) were readmitted within 30 days. The top 5 reasons for 30-day readmissions were sepsis, pancreatic cancer, PE without cor pulmonale, metastatic cancer of the liver and intra-hepatic duct, and pneumonia. 30-day readmissions were responsible for an aggregate of 5.9 million U.S dollars in hospital costs and 2443 hospital days in 2018. Compared to index hospitalizations, 30-day readmissions had higher inpatient mortality (13.4% vs 5.9%, p < 0.0001). Conclusions: 30-day readmissions for DVT/PE in patients with pancreatic cancer have a significant healthcare economic burden. PE, Pancreatic cancer, and infections were common reasons for readmissions. Readmissions have significantly greater inpatient mortality compared to index admissions. Adequate management of DVT/PE and underlying malignancy during index admissions and ensuring timely outpatient follow-up are important in reducing 30-day readmissions of these patients.
Does non-alcoholic fatty liver disease (NAFLD) influence outcomes of pancreatic cancer (PANC)? A nationwide analysis.
Authors: Chowdary Sriram Basappa , Yadukumar Lekha , Asija Udit , Sharma Amit Munshi , Sharma Namita
Published: June 2023

e16319

Background: Incidence of pancreatic cancer is 13.3 per 100,000 in the US, with a five-year survival rate of 11%. Studies worldwide have shown inconsistent positive associations between NAFLD and PANC in the general population. We aimed to assess the impact of NAFLD on trends of hospitalizations and outcomes of patients presenting with PANC in the US. Methods: We conducted a retrospective study from 2016 to 2020 using the National Inpatient Sample to identify PANC-related hospitalizations using ICD 10 codes. Population was divided based on the presence and absence of NAFLD. Pearson chi-square test and t-test were utilized. Primary outcome was in-hospital mortality. Secondary outcomes of hospitalization characteristics and comorbidities were compared. Multivariate analysis was used to adjust for confounders. Results: Out of the 4,34,160 hospitalizations with primary diagnosis of PANC, 1.43% of patients were found to have NAFLD. PANC with NAFLD cohort were younger with mean age 64.34 +/- 10.78 (vs. 68 +/-11.39). Females were common in the NAFLD group (56% vs. 48%). Caucasians were predominantly affected in both study groups. Patients with NAFLD had higher comorbidities such as diabetes (45.6% vs. 40%) and dyslipidemia (41.5% vs. 37%). Charlson's comorbidity index was > 3 in the entire population with NAFLD compared to 85% in the group without NAFLD. Mortality was lower in patients with NAFLD (5.22 vs. 7.51). NAFLD did not lead to poor survival outcomes in pancreatic cancer patients with an Odds ratio of 0.31 (95% CI 0.24 - 0.41, p-value <0.01). NAFLD patients had higher mean length of stay of 6.42 days (6.09-6.75) and were likely to incur higher hospitalization charges of $21,924 ($20,594 - $23,253). Conclusions: Patients with NAFLD presenting with PANC were younger, predominantly females, and had a marginally longer length of stay and healthcare utilization. NAFLD did not impact the mortality in patients hospitalized for PANC. [Table: see text]
An estimate of the burden of pancreatic cancer globally and its comparison with different WHO regions using Global Burden of Disease Database: A retrospective population-based analysis.
Authors: Punjwani Shoheera , Jaroenlapnopparat Aunchalee , Jani Chinmay , Singh Harpreet , Marshall Dominic C , Salciccioli Justin D , Shalhoub Joseph
Published: June 2023

e16321

Background: Pancreatic cancer is a highly aggressive malignancy and is the fourth leading cause of cancer-related deaths in the United States and seventh globally. Most pancreatic cancers are adenocarcinomas that have poor prognoses. The highest incidence is reported between 65-69 in men and 75-79 in women. Worldwide, both incidence and mortality are increasing. We must evaluate the global and regional patterns to understand the impact of risk factors and develop early detection methods and treatments. Methods: We extracted pancreatic cancer mortality data from the Global Burden of Disease database based on the International Classification of Diseases versions 10 and 9. Age-standardized incidence rates (ASIR), age-standardized mortality rates (ASMR), the age-specific death rate(ASDR), mortality-incidence ratio (MIR) and disability-adjusted life years (DALYs) were extracted for global as well as six WHO regions (Africa, Region of the Americas, South-East Asia, Europe, Eastern Mediterranean, Western Pacific) for both for the years 1990 and 2019. Joinpoint regression analysis was used to describe trends. Results: Between 1990 and 2019, pancreatic cancer ASIRs, ASMRs, and DALYs increased among the six regions in both males and females. Globally, ASIR, ASMR and DALY increased in males (+25.02%, +23.40%, +19.97%) and females (+26.35%, +24.30%, +22.08%). However, MIR decreased globally (males: -1.29%, females: -1.62%). The Eastern Mediterranean region showed the highest percentage change in ASIR, ASMR, and DALY in both males (+110.45%, +106.53%, +103.24%, respectively) and females (+140.20, +135.48%, +127.20% respectively), followed by the South-East Asia region (males: +71.38%, +70.03%, +63.80% respectively; females: +114.20%, +111.78%, +106.91% respectively). MIRs showed decreased trends among all six regions in both sexes. Europe region showed the highest decrease in males (-1.91%) and females (-3.09%). Conclusions: Overall, we reported the increasing disease burden of pancreatic cancer globally between 1990 and 2019. ASIRs, ASMRs and DALYs all increased throughout the six regions in both sexes, with the Eastern Mediterranean region being the highest. MIRs showed a global decreasing trend in both sexes, which may indicate an overall improvement in pancreatic cancer clinical care.
Genomic biomarker for the top risk factor of gallbladder cancer, cholelithiasis, in a Latinx population.
Authors: Yang Ping
Published: June 2023

e16326

Background: Cholelithiasis or Gallstone disease (GSD), is one of the most common and costly digestive disorders in adults worldwide, presenting 10-20% of the general population but in greater than 30% of Latina and Hispanic American women aged 40 years or older. Moreover, GSD individuals contribute significantly to the incidence and mortality of gallbladder and other digestive system cancers; specifically, the excessive risk of gallbladder cancer is 3-10-fold. Parallel to gallbladder cancer, an appalling female preponderance of GSD has been documented for decades; thus, precisely defining high-risk populations and properly managing patients with GSD would lead to reduced disease burden from GSD and multiple cancers. Several genome-wide association studies (GWAS) in the past have identified genes associated with GSD but few were focused on Latinx population. Methods: To identify genetic risk factors for GSD in Latinx population, we used the Sangre Por Salud cohort (SPS) where participants are Latinx adult individuals aged 18-85 years who were current patients in the Mountain Park Health Center in Arizona. This sample represents historically underrepresented population with low socioeconomic status that are primarily Spanish-speaking, majority being born outside of the US, with low rates of health insurance coverage. A total of 172 GSD cases were identified, each matched with 6 controls (n = 1032) who were people from the same community but without history of GSD diagnosis; matching variables are age at enrollment to SPS, sex, height and weight, dyslipidemia, and HbA1C level indicative of type 2 diabetes. We characterized genome-wide interrogation for biomarkers predicting GSD and contributing to the observed gender disparity by performing a GWAS using a matched case-control design. Results: We identified several novel loci associated with GSD and validated few loci that were reported in previous GWAS. The top 3 loci (MATN2, GPRIN3, GPC6) were strongly associated with GSD in our overall analysis; follow-up pathway enrichment analysis suggests enrichment of GO terms that are associated with immunological pathways, enzymatic processes in gallbladder, liver and gastrointestinal tract and GSD pathology. In a sex-specific analysis, CDHR3 and RPL31P35-SEC61G were identified for females, which have been associated respectively with rhinovirus C infection and HbA1c level in previous studies. Conclusions: Our findings suggest directions towards better and deeper understanding of sex differences in GSD pathology, biological mechanisms, and disease progression among Latinx people. Knowing approximately 80% of gallbladder cancer patients harbored gallstones, our optimal goal is to provide evidence for an innovative strategy to early detect and effectively intervene the modifiable risk factors to reduce gallbladder cancer burden in high risk populations.
Predictors of re-admission after COVID-19 hospitalizations in patients with underlying gastrointestinal malignancy.
Authors: Shah Mihir , Gajjar Rohan , Deenadayalan Vaishali , Ishaya Michelle , Litvin Rafaella , Ibrahim Muhammad Bilal , Olafimihan Ayobami Gbenga , Batra Kunnal
Published: June 2023

e16327

Background: COVID-19 infections have been known to cause worse outcomes in patients with underlying co-morbid conditions. Currently, there is limited data regarding re-admissions in such patients after COVID-19 infection. So, we pursued to assess the rates, predictors, and causes of re-admission after COVID-19 infection in patients who had underlying gastrointestinal malignancy. Methods: The National Readmission Database for 2020 was analyzed to identify patients with COVID-19 hospitalizations who also had a co-diagnosis of GI malignancy. Data for re-admission was gathered, at 30 and 90 days after initial hospitalization. Multivariate logistic and linear regression analysis was used accordingly to adjust for possible confounders. Results: For 30 days: A total of 2,726 COVID-19 hospitalizations had a co-diagnosis of GI malignancy. The mean LOS (length of stay) for index admission was 8.7 days. The mean TOTCHG (total hospital charge) for index admission was $85,747. Within 30 days from discharge, 462 (21%) were re-admitted. The in-hospital mortality in re-admissions (18.4%) was quite similar to that for index hospitalization (18.5%). Positive predictors of re-admission include shorter length of stay during initial hospitalization (<3 days), anemia, renal insufficiency/chronic kidney disease, and atherosclerosis of the aorta. Females had a lower chance of re-admission compared to males. Among the top causes of re-admission were ongoing COVID-19 infection (27%), sepsis (16.3%), acute kidney injury (2.4%), and metabolic encephalopathy (1.2%). For 90 days: A total of 1,782 COVID-19 hospitalizations had a co-diagnosis of GI malignancy. The mean LOS (length of stay) for index admission was 9.2 days. The mean TOTCHG (total hospital charge) for index admission was $90,908. Within 90 days from discharge, 411 (29%) were re-admitted. The in-hospital mortality in readmissions (14%) was lower than that for index hospitalization (20.3%). Predictors of re-admissions include secured insurance, anemia, renal insufficiency/chronic kidney disease, and cerebrovascular accidents. Top causes of re-admission were ongoing COVID-19 infection (18.5%), aspiration pneumonitis (2.9%), pneumonia (2.3%), and acute kidney injury (1.4%). Conclusions: Infections were the leading cause of re-admission, which is an important factor to consider when managing patients with GI malignancies due to sub-optimal immunity. Among these patients, those with concomitant anemia and chronic kidney disease were more prone to being re-admitted. Patients with GI malignancies also tended to have a higher length of stay, leading to higher charges, more exposure to nosocomial infections, and delays in cancer treatment leading to worse cancer outcomes. Pre-mature discharges, without medical optimization, can also potentially predispose to higher rates of re-admissions.
A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART SWOG 1609) in patients with refractory gallbladder cancer (cohort 48).
Authors: Patel Sandip Pravin , Guadarrama Elizabeth , Chae Young Kwang , Liao Chih-Yi , Kasi Anup , Tarabay Grace R. , George Thomas J. , Chung Liam , Lopez Gabby , McLeod Christine , Othus Megan , Chen Helen X. , Sharon Elad , Streicher Howard , Ryan Christopher W. , Blanke Charles David , Kurzrock Razelle
Published: June 2023

e16330

Background: Immune checkpoint blockade has improved outcomes in multiple tumor types, however little is known about the efficacy of these agents in rare tumors. We report the results of the gallbladder cohort of SWOG S1609 Dual Anti–CTLA-4 and anti–PD-1 blockade in Rare Tumors (DART). Methods: We performed a prospective, open label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the gallbladder cohort reported here. Eligible patients had progressed following at least one line of standard systemic therapy, and did not have an approved or standard therapy available that had been shown to prolong survival. All participants received nivolumab 240 mg i.v. every 2 weeks and ipilimumab 1 mg/kg i.v. every 6 weeks on a continuous schedule. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity Results: Nineteen patients (79% female) with a median age of 60 years were enrolled and received treatment. The median prior lines of therapy was 2 (range 1-6). The confirmed overall response rate was 16% [complete response, n=1 (5%); partial response, n=2 (11%)] (duration = 35+, 16, 13 mo). The unconfirmed overall response rate and clinical benefit rate were both 32% [complete response, n=1 (5%); partial response, n=5 (26%); stable disease > 6 months, n=0 (0%)]. The 6-month progression-free survival was 26% (95% CI 12-55%); median overall survival was 7.0 months (95% CI, 3.9-19.1 months). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was one death from hepatic failure possibly related to treatment in the setting of progressive liver metastasis and biliary infection. Conclusions: Ipilimumab plus nivolumab demonstrated a 16% ORR in patients with gallbladder cancer including a complete response lasting 35+ months; The unconfirmed overall response rate was 32%. Clinical trial information: NCT02834013 . [Table: see text]
Utility of circulating tumor DNA for identifying genetic mutations in cholangiocarcinoma of East Asian patients.
Authors: Liu Cheng , Fu Yiming , Xiao Zebin , Chen Yaru , Dai Defeng , Cheng Shaochen , Li Xiang
Published: June 2023

e16332

Background: Cholangiocarcinoma, also referred to as bile duct cancer, is a major global health concern. The diagnosis of this cancer is often difficult due to its lack of distinctive symptoms and its tendency to present at advanced stages. However, the recent emergence of blood liquid biopsy as a diagnostic tool has shown great potential for detecting and managing cholangiocarcinoma. The use of blood liquid biopsy in East Asian populations, where the incidence of cholangiocarcinoma is particularly high, has the potential to improve the accuracy of diagnosis, prognosis, and targeted treatment planning. Methods: The study cohort contains 53 Chinese cholangiocarcinoma patients, the examination of DNA from tumor tissue (tDNA), blood (cfDNA), and blood leukocytes (gDNA) was performed using 680 gene targeted capture sequencing and analyzing for CNV, fusion, SNV, indel, MSI, and TMB. The sequencing depth was 2200X for tDNA, 20000X for bDNA, and 10000X for gDNA. In the tissue samples evidence of PD-L1 expression was examined. The TMB was classified as high (TMB-H) with a cutoff > 10 mutations/megabase and low (TMB-L) < 10. Microsatellite instability-high (MSI-H) was identified in cases where instability was observed > 20% of 117 loci, and the microsatellite stable (MSS) rate was determined to be < 20%. Results: In a cohort of 53 patients, a thorough analysis of tissue and blood samples was conducted to detect somatic mutations. 146 (38.1%) shared mutations were found in both tDNA and cfDNA, while 211 (55.09%) and 25 (6.53%) unique mutations were found in tDNA and cfDNA respectively. Of the 64 mutations found in CNV, 5 (7.81%) were shared in tDNA and cfDNA, 52 (81.25%) were unique in tissues, and 7 (10.93%) were unique in blood. High frequency mutated genes were also revealed as TP53, KRAS, SMAD4, LRP1B, and ARID1A, which were consistent with the results from the IntoGen database (4 cohorts, 393 samples). Notably, LRP1B (11.32%, 6/53) was not detected in the validation cohort. 96.23% of the samples showed consistent tTMB vs. bTMB outcomes, with only 1 sample exhibiting high PD-L1 expression and TMB-L, MSS, and 1 sample (out of 52 with MSS) having TMB-H and PD-L1 expression less than 1%. Conclusions: The results of the mutation analysis suggest that relying solely on cfDNA for molecular typing of cholangiocarcinoma is not sufficient. This highlights the importance of testing tissue samples in order to accurately detect tumor mutations in cholangiocarcinoma. Further research is needed to determine the significance of LRP1B, a gene that was frequently mutated in the study cohort but not found in the validation cohort, in the diagnosis and treatment of cholangiocarcinoma.
A retrospective study on the efficacy and safety of avatrombopag in the treatment of chemotherapy-induced thrombocytopenia in gastrointestinal cancer.
Authors: Chen Junliang , Liao Wangjun , Zhu Lingjun , He Yifu , Jin Gang , Pan Ying , Wang Fenghua
Published: June 2023

e16334

Background: Chemotherapy-induced thrombocytopenia (CIT) is defined as post-chemotherapy platelets count < 100×109/L. Avatrombopag is an oral thrombopoietin receptor to treat thrombocytopenia. Although many factors lead to an increased risk of CIT in gastrointestinal cancer, there is currently no targeted research. This study aimed to investigate the efficacy and safety of avatrombopag for CIT in gastrointestinal cancer. Methods: This multicenter, retrospective study included adult gastrointestinal cancer patients with CIT who received avatrombopag treatment (40mg/60mg, 5 days) between September 2020 and February 2022. The patient meets one of the following conditions were included in this study: a) Platelet count <100×109/L before receiving avatrombopag treatment in the current chemotherapy cycle, and platelet count <50×109/L in the last cycle; b) Platelet count <75×109/L before receiving avatrombopag treatment in the current chemotherapy cycle. The main endpoint was the proportion of patients with platelet count >100×109/L or platelet count increased by >50×109/L or platelet count increased by > 100% in the cycle after the start of avatrombopag therapy. Results: 58 patients were included in this study. 53.40%, 82.80%, and 96.6% of the patients reached the effective endpoint after 5±2, 11±3, and 18±3 days of avatrombopag treatment, respectively. No drug toxicity related to avatrombopag was found in this study. No significant influencing factors of effective rate were found. And there was no significant difference was found among the effective rate and platelet transfusion rate of avatrombopag (AVA), AVA+Recombinant Human Interleukin-11 (rhIL-11), and AVA+Recombinant Human Thrombopoietin (rhTPO). However, compared with AVA+IL-11, the AVA+rhTPO group had lower baseline platelet counts. And the mean of increasing platelet counts on the 5±2 (41.32×109/L vs. 37.00×109/L) and 11±3 day (110.94×109/L vs. 84.00×109/L) were better in the AVA+rhTPO group, though not significantly. Conclusions: Avatrombopag has high efficacy and safety in the treatment of CIT in gastrointestinal cancer. rhTPO rather than rhIL-11 combined with avatrombopag may be more suitable for patients with low baseline platelet counts. [Table: see text]