bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world impact of olaparib use in patients (pts) with advanced pancreatic cancer (PC) harboring germline BRCA1/2 (gBRCA) mutations.
Authors: Milella Michele , Orsi Giulia , Di Marco Mariacristina , Salvatore Lisa , Procaccio Letizia , Noventa Silvia , Bozzarelli Silvia , Garajova Ingrid , Vasile Enrico , Giordano Guido , Macchini Marina , Cavaliere Alessandro , Gaule Marina , Barsotti Giulia , Palloni Andrea , Tortora Giampaolo , Sperduti Isabella , Reni Michele
Published: June 2023

e16278

Background: g BRCA mutations are found in approximately 8% of Italian PC pts screened within 3 months from diagnosis. g BRCA PC pts display enhanced sensitivity to platinum-based chemotherapy (CHT) and PARP inhibitors, such as olaparib. In metastatic g BRCA PC pts, maintenance olaparib after platinum-based CHT doubled PFS and resulted in twice as many long-term (3-yr) survivors (34% versus 18%) in the randomized POLO trial. However, despite guideline recommendations, olaparib is currently not reimbursed in Italy in metastatic g BRCA PC pts, based on the absence of significant differences in median OS. Methods: We analyzed the impact of exposure to olaparib on OS from the start of I-line treatment in a cohort of 114 Italian g BRCA PC pts, whose clinical characteristics and outcomes in response to first () and subsequent chemotherapy lines have been previously reported ( 10.1016/j.esmoop.2021.100238 ; 10.1038/s41416-022-02086-w ). Results: Clinical characteristics of patients who did or did not receive olaparib were well balanced, except for baseline CA19.9 levels (significantly lower in patients who received olaparib, p=0.043) and exposure to platinum-containing chemotherapy (significantly less in patients who did not receive olaparib, p<0.0001). In the entire cohort of g BRCA PC pts, OS from the start of I-line treatment for metastatic disease was significantly (p=0.02) longer in pts who had been exposed to olaparib in any treatment line (n=53). Since previous surgery and response to I-line chemotherapy were strong independent predictors of OS at multivariate analysis, we analyzed pts who were diagnosed with stage IV (M+, n=87) disease and pts who did not experience PD as best response to I-line chemotherapy (no PD, n=94), separately. A statistically significant difference in OS favoring g BRCA PC pts who were exposed to olaparib in any line of treatment was observed in the M+ cohort (p=0.0025), in the no PD cohort (p=0.049), but not in the M+/no PD cohort (n=73, p=0.057) or in the POLO-like population (I-line maintenance; n=60, p=0.334). Conclusions: In g BRCA PC pts, exposure to olaparib in any line of treatment in a real-world setting significantly impacts on OS; timing and setting of administration remain to be determined in order to optimize survival advantage. [Table: see text]
Molecular profiling as a predictor of treatment response and survival in unresectable pancreatic ductal adenocarcinoma.
Authors: Paredes Rodrigo , Banegas Marcela , Sucre Santiago , Ponce Cristina , Rattani Ahmed Anwer Ali , Peters Mary Linton Bounetheau
Published: June 2023

e16279

Background: To date, few targetable mutations have been found to enhance PDAC treatment. Next-generation sequencing (NGS) of somatic mutation profiles may help tailor cytotoxic chemotherapy selection and guide translational research. Methods: We analyzed NGS data from a retrospective cohort of 142 patients with unresectable biopsy-proven PDAC from August 2009 to December 2022. Individual mutations were grouped into 14 distinct signaling pathways: cell cycle, DNA damage repair, KIT, ErbB2, TP53, MAPK-RAS, PIK3, TGF-beta, NOTCH, ALK, FLT3, FGFR, and WNT. Treatment selection, duration of response, and survival were recorded. We stratified patients based on their first-line therapy, either FOLFIRINOX (FFX) or gemcitabine/nab-paclitaxel (GA). We present median time-to-first progression (PFS1) and overall survival (OS) based on the presence or absence of mutations in these pathways. The time-to-event endpoint was estimated by the Kaplan-Meier method. Results: Of 142 samples, 131 were analyzed for PFS1; 57 received FFX, and 60 received GA. In the FFX group, no pathway predicted PFS1 with statistical significance. In the GA group, KIT pathway mutations (n = 10) showed improved PFS1 vs. non-KIT mutated tumors (10.3 mos vs. 6.2 mos, p = 0.02). Similar improvement in PFS1 was seen for mutations in the PIK3 pathway (n = 25, 6.6 vs. 5.7, p = 0.02) and FLT3 pathway (n = 4, 13.1 vs. 6.2, p = 0.02). 125 samples were analyzed for OS. KIT pathway mutations (n = 21) showed a better OS vs. non-KIT mutated samples (21.3 mos vs. 12.2 mos, p = 0.04), as did NOTCH mutated samples (n = 44, 15 vs. 12.3, p < 0.01). FLT3 pathway mutations showed a trend toward improved OS (23.6 vs. 13, p = 0.3). PIK3 mutated tumors had no difference in OS. 8 samples were KRAS WT; removing these from the analysis did not change the results. Conclusions: In this sample, KIT, FLT3, and PIK3 pathway mutated tumors had improved PFS1 with GA (but not FFX) treatment. Tumors with KIT and NOTCH pathway mutations had an improved OS. This and similar analyses could help identify potential drivers of treatment response for unresectable pancreatic tumors. [Table: see text]
Components of total cost of care in real-world patients with mPDAC who received first-line FOLFIRINOX or Gem/Abrax.
Authors: Hirsch Jared , Cockrum Paul , Tomicki Samantha , Dieguez Gabriela , Bhatt Prachi , Kim George P.
Published: June 2023

e16282

Background: FOLFIRINOX (FFX) and Gemcitabine/Abraxane (Gem/Abrax) are two recommended options for the treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC). There is limited research assessing differences in costs between real-world patients with mPDAC who received first-line (1L) FFX or Gem/Abrax. Methods: We used ICD-10 diagnosis codes to identify patients aged 65+ with mPDAC without end-stage renal disease in the 2018-2021 Medicare Parts A, B, and D 100% Research Identifiable Files (RIF) data. Total cost of care (TCOC) represents mean Medicare paid amounts and patient cost sharing. Lines of therapy (LOTs) were assigned based on therapies used. LOTs ended the day before a new chemotherapy began, 28 days after the last chemotherapy (if no new chemotherapy), or upon death. Study patients were treated with FFX or Gem/Abrax as a 1L therapy. Results: We identified 8,889 patients with mPDAC that received an 1L FFX regimen between 2018 and 2021 and 15,053 patients that received a Gem/Abrax regimen in the same period. Total cost of care was similar among the two cohorts ($7,187 per administration cycle among patients receiving FFX vs. $7,240 among those receiving Gem/Abrax in 1L). Patients receiving Gem/Abrax had higher chemotherapy costs ($2,980) than FFX ($406), however, patients receiving FFX had higher granulocyte colony-stimulating growth factor costs ($1,592 FFX vs. $293 Gem/Abrax) and higher Other Part B costs ($1,301 FFX vs. $876 Gem/Abrax). Inpatient costs were similar between FFX ($1,732) and Gem/Abrax ($1,615), while outpatient costs were higher for patients receiving FFX ($1,549) than patients receiving Gem/Abrax ($847). Conclusions: Among Medicare Fee-For-Service patients with mPDAC, patients receiving FOLFIRINOX (FFX) or Gemcitabine/Abraxane (Gem/Abrax) as a first-line therapy incurred similar costs of care overall, with different distributions across service categories. While therapy costs were lower among patients receiving generic FFX than those receiving branded Gem/Abrax, higher costs from supportive therapies offset those differences.
A phase Ib/II, open-label, multicenter study to evaluate the safety, efficacy, and pharmacokinetics/pharmacodynamics of αvβ3/5 integrin and neuropilin-1 targeting peptide LSTA1 in patients with metastatic pancreatic ductal adenocarcinoma.
Authors: Xu Jianming , Niu Zuoxing , Bai Yuxian , Qiu Wensheng , Cui Jiuwei , Qu Xiujuan , Wu Zheng , Zha Yong , Zhang Tao , Cheng Wei , Han Cuicui , Si Meimei , Li Lingyan , Kang Xiaoyan
Published: June 2023

e16290

Background: LSTA1, formerly known as CEND-1, is a novel cyclic peptide which selectively binds to αv/β3 and β5 integrins, which are upregulated in solid tumors, where it undergoes protease cleavage producing a C-end rule peptide fragment (CendR) that selectively binds to and activates neuropilin-1 (NRP1). Once CendR binds NRP1, the CendR pathway is activated, leading to increased vascular permeability of tumors resulting in increased drug delivery and tumor accumulation of co-administered chemotherapeutic agents. Here we report the safety and efficacy results from a Phase Ib/II, multicenter study of LSTA1 plus (SoC) gemcitabine and locally produced nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods: The study included a 7-day safety run-in and dose expansion/extension parts. Previously untreated patients with histologically confirmed mPDAC and ≥1 target lesion were treated with systemic chemotherapy and received LSTA1 (1.6 mg/kg or 3.2 mg/kg), gemcitabine (1000 mg/m²) and nab-paclitaxel (125 mg/m2) on days 1, 8, 15, of each 28-day treatment cycle. LSTA1 alone was given during run-in to observe PK/PD. Treatment continued until disease progression or other discontinuation events. The primary endpoints were safety and preliminary efficacy. Results: As of 30 Nov 2022, 38 patients were enrolled at 10 sites in China (12 at 1.6 mg/kg; 26 at 3.2mg/kg). The median follow-up time was 6.28 months. 37 (97.4%) patients experienced TEAEs and 31 (81.6%) patients experienced grade≥3 TEAEs. The most common TEAEs were hematologic toxicity related to chemotherapy. The ORR was 42.9% (15/35) and DCR was 82.9% (29/35). The ORR in 1.6 mg/kg and 3.2 mg/kg groups was 45.5% and 41.7%, respectively. The mPFS in 1.6 mg/kg and 3.2 mg/kg groups was 7.43 months (95% CI: 0.59-NE) and 5.75 months (95% CI: 3.25-7.46) respectively. mOS was not reached. NRP1 expression levels were tested at baseline; six of whom had expression ≥40%. Of those, 4 had PRs and 2 had SD (ORR=66.7%; DCR=100%). The mPFS was 7.5 months. Conclusions: LSTA1 combined with SoC showed an acceptable safety profile in patients with mPDAC. Compared with historical SoC data, LSTA1 plus SoC numerically improved ORR and PFS. Higher NRP1 expression is associated with better ORR and PFS, suggesting NRP1 may be a potential biomarker of LSTA1 plus chemotherapy for mPDAC treatment. Further study is ongoing. Clinical trial information: NCT05052567 .
Integrated clinico-genomic characterization of pancreatic ductal adenocarcinoma in an Asian population.
Authors: Jung Kwangrok , Jung Jae Hyup , Ahn Jinwoo , Kim Bomi , Lee Jong-Chan , Kim Jaihwan , Hwang Jin-Hyeok
Published: June 2023

e16291

Background: Pancreatic cancer is a devastating malignancy with an extremely poor prognosis. However, the clinico-genomic understanding of pancreatic cancer that could play an important role to improve prognosis is highly limited, especially in Asian population. Methods: Using blood sample and primary pancreas tissues by endoscopic ultrasound guided fine needle biopsy (EUS-FNB) from 237 patients diagnosed with pancreatic ductal adenocarcinoma (PDA) at Seoul National University Bundang Hospital, WES and WTS were performed. Integrated clinico-genomic analysis was conducted by combining genomic data with diverse clinical information. Results: WES and WTS data were obtained from 205 and 93 patients, respectively. In WES, recurrent somatic mutations were identified in KRAS (89.3%), TP53 (68.8%), SMAD4 (22.4%) and CDKN2A (20.5%), and the overall mutation profile was not significantly different from TCGA dataset. Germline mutations related with hereditary cancer syndrome were found in 19 (9.3%), and BRCA2 mutation was the most common as in the Western data. At least one actionable mutation was reported in 61 (29.8%), and KRAS p.G12C, the emerging actionable mutation, was found in five (2.4%). In mutational signature analysis with single-base substitution (SBS), SBS1, SBS3 and SBS13 were identified in this cohort, and SBS3, a potential biomarker for DDR pathway related therapy, was positive in 25 (12.2%). Since this cohort contained 112 stage I-III (47.3%) and 125 stage IV (52.7%), genetic features according to stage or metastatic patterns were analyzed. There was no difference of mutation frequency and burden according to stage. However, liver metastasis was associated with higher frequency of TP 53 mutation (OR = 3.40; P = 0.010) and mutation burden was significantly lower in the lung metastasis (35.4 vs 50.9; P = 0.023). In the gene-set enrichment analysis using WTS, distinct pathways were observed according to the potential mechanism related with each metastatic pattern. Conclusions: Integrative clinico-genomic analysis of Asian PDA cohort provided various clues to better understand the genomic landscape of PDA.
Efficacy and safety of Kras inhibitors in pancreatic cancer: A systematic review of clinical trials.
Authors: Veeraballi Sindhusha , Aiman Wajeeha , Ahmad Amaar , Grewal Navjot , Qirem Murad , Jumean Samer , Montazerin Sahar Memar , Ali Muhammad Ashar , Guron Gunwant K. , Shaaban Hamid Salim
Published: June 2023

e16297

Background: Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive tumor and is one of the leading causes of cancer related deaths worldwide. Kirsten Rat Sarcoma (KRAS)mutation resulting in tumor cell proliferation and cancer progression is a frequently mutated oncogene in various cancers and is approximately seen in 90% of pancreatic ductal adenocarcinoma. Efforts are being done to target Kras mutation in the last 3–4 decades. Here in, we report the results of the systemic review of clinical trials done on chemotherapeutic agents targeting Kras mutated pancreatic cancer. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Clinicaltrials.gov, and Embase with mesh terms, “pancreatic neoplasm’’ and “kras” from the inception of data till 01/05/2023. We screened 4191 articles and included 3 clinical trials with published study results and 3 ongoing clinical trials. Results: In this systematic review, data on 2 chemotherapeutic agents Sotorasib (AMG510) and Adagrasib (MRTX849) which are Kras G12C inhibitors, are obtained from Code Break-100 and preliminary results of KRYSTAL-1 clinical trials, respectively. In these 2 clinical trials (N-48), all the patients had advanced pancreatic cancer with Kras G12C mutation and were previously treated with chemotherapy. 10 patients in Krystal-1 trial, who received adagrasib showed progression-free survival (PFS) of 6.6 months, disease control rate (DCR) of 100 % and partial response (PR) of 50%. 38 patients in the Code Break-100 trial, who received Sotorasib showed PFS of 4 months, DCR of 84.2% and PR of 21.1%. However, 50% of patients in the KRYSTAL-1 trial are still receiving treatment. Grade 3 /4 adverse events were seen in 21% and 16% of patients in the KRYSTAL-1 and Code Break-100 trial, respectively. Other Kras G12C inhibitors like D-1553, Sotorasib in combination with 2nd line chemotherapy are under investigation. Results of a clinical trial on anti KrasG12D siRNA done on locally advanced pancreatic cancer patients showed a median overall survival of 15.12 months with no dose limiting adverse events. A multinational randomized phase 2b clinical trial is ongoing for the evaluation of efficacy of siRNA based drug in combination with chemotherapy. Conclusions: Both Adagrasib and Sotorasib showed promising results in the pretreated Kras G12C pancreatic cancer patients with acceptable safety profile. Further exploration of these drugs and their combination with other chemotherapeutic agents is necessary. [Table: see text]
LDE-paclitaxel in second or later lines in advanced pancreatic cancer: A phase I trial.
Authors: Bighetti Bruna , Maranhão Raul Cavalcante , Forones Nora Manoukian
Published: June 2023

e16298

Background: Nanoparticles have been studied in association with chemotherapy, with objective of increasing the concentration of the drug in neoplastic cells and, thus, increasing its antitumor action. Nab-paclitaxel is a well-known nanotechnology association between paclitaxel and albumin and can be used in the treatment of advanced pancreatic cancer. LDE-Paclitaxel is a combination of paclitaxel and a synthetic molecule of low-density lipoprotein (LDE). It was previously evaluated in patients with gynaecological malignancies undergoing third-line treatment and showed higher rates of disease control than conventional regimens described in the literature. Our objective was to evaluate the efficacy of LDE-paclitaxel in the treatment of advanced pancreatic cancer (stage III and IV) in second or third line of therapy. Methods: This was a prospective phase I/II, single-arm study, in which we delivered LDE-Paclitaxel at a weekly dose of 85mg/m² to patients with pancreatic adenocarcinoma in second or third-line. The patients must had been through treatment of at least one standard chemotherapy scheme. Results: From October 2020 to November 2021, nine patients with advanced pancreatic adenocarcinoma were enrolled in this prospective, single-arm, phase 1/2 study in which we offered LDE-Paclitaxel at a dose of 85mg/m² intravenously, after progression to gemcitabine. During this period, patients underwent a maximum of 5 cycles, with no need to reduce the medication dose in any of the cycles, for any of the patients. LDE-paclitaxel presented mostly grade 1 and 2 toxicities, mainly anaemia and neuropathy; Grade 3 toxicity was presented by only 1 patient, which was acute kidney injury. Median overall patient survival was 20.14 months, and patient survival after enrolment in the study and initiation of LDE-paclitaxel use was close to 5 months, with no decline in the assessed quality of life indices. Conclusions: LDE-paclitaxel appears to be more tolerable, viable and less toxic than other standard chemotherapy in this setting. Our results suggest that LDE-paclitaxel could be a therapeutic possibility for patients with metastatic pancreatic cancer. For a better evaluation, further studies would be necessary, to obtain more data on the use of this medication in clinical practice and for a better understanding of other important outcomes. Clinical trial information: 4237198 .
Proteomic quantification of HER-2 abundance and activation in pancreatic ductal adenocarcinoma tumor specimens using reverse phase protein array.
Authors: Randall Jamie , Cannon Timothy Lewis , Hunt Allison L , Nutcharoen Aratara , Johnston Laura , Wang Hongkun , Wadlow Raymond Couric , Winer Arthur , Huynh Jasmine , Bateman Nicholas W. , Davis Justin B , Corgiat Brian , Petricoin Emanuel , Conrads Thomas P.
Published: June 2023

e16299

Background: Pancreatic adenocarcinoma (PDAC) is associated with poor survival and low response rates to available therapies, warranting a critical need for new treatment paradigms. Enrichment of tumor epithelium via laser microdissection (LMD) prior to reverse phase protein array (RPPA) analysis allows for the quantitative measurement and functional assessment of the activation state of protein drug targets. As part of an IRB-approved Molecular Tumor Board study at Inova Schar Cancer Institute, we harvested enriched tumor epithelium using LMD to support CLIA-based RPPA analysis of patients with pancreatic, breast, and other solid tumor malignancies to examine quantitative expression and activation (phosphorylation) of HER-2/3 and other known cancer-related pathways. Methods: Formalin fixed paraffin embedded (FFPE) primary and/or metastatic tumor biopsy specimens were obtained from 14 patients with PDAC, 14 patients with breast cancer, and 40 patients with other solid tumor malignancies. Tumor epithelium (5-10 µm2) was enriched via LMD prior to RPPA analysis for quantification of HER-2Total and phosphorylated (p)HER-2Y1248 and (p)HER-3Y1289 abundances as part of a 32-marker, CLIA-based RPPA panel examining the total and phosphoprotein abundances of targets with known relevance in solid tumors. Next generation sequencing (NGS; DNA-seq and RNA-seq) was performed on remaining tissue from each specimen. Fisher’s Exact test was used to compare activated HER2Total, pHER2Y1248 and pHER3Y1289. Results: RPPA analysis of LMD enriched tumor samples revealed significant HER-2Total expression in patients with PDAC vs other solid tumors (p=0.0112), with HER-2Total levels comparable to those measured in patients with breast cancer (p=0.0962). The mean HER-2Total abundances in PDAC, breast, and all other solid tumor malignancies were 1.6, 1.3, and 0.9, respectively. Activated pHER-2Y1248 and pHER-3Y1289 abundances did not differ between patients with PDAC vs all other solid tumors or between patients with PDAC vs breast cancer (p>0.05). RNA-seq analysis revealed ERBB2 overexpression in four of the 14 PDAC patients, while ERBB2 amplification by DNA-seq was not observed in any of the PDAC cases. Conclusions: HER-2 expression is not routinely evaluated in clinical practice in PDAC, but our results show higher median expression in PDAC than our solid tumor cohort, with nearly 50% of PDAC cases having total HER2 expression of 2+ or above. Our results may have clinical implications, especially as new classes of HER2 antibody drug conjugates are considered for patients with HER2 non amplified tumors across organ sites, and justify further investigation in a larger cohort. Clinical trial information: U20-11-4308 . [Table: see text]
Effect of locoregional injection of RNA oligonucleotide targeting carbohydrate sulfotransferase 15 on both tumoral and lymph node MDSCs and T cell infiltration in pancreatic tumor in mice.
Authors: Ye Juanjuan , Suizu Futoshi , Yamakawa Keiko , Kato Motohiko , Tsuchiya Takayoshi , Yoneyama Hiroyuki , Yahagi Naohisa
Published: June 2023

e16310

Background: Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and is responsible for tumor matrix remodeling. Intratumoral injection of CHST15 siRNA was shown to increase tumor-infiltrating T cells in patients with pancreatic cancer in the phase I/IIa study. However, the mechanism underlying the enhanced T cell accumulation is not fully explored. Here we investigated the effect of locally injected CHST15 siRNA on modulating tumor immune microenvironment in mice. Methods: For in vivo pharmacokinetics after a single local injection of CHST15 siRNA to normal C57BL/6J mice, RNA oligonucleotides were isolated from tissues and detected by HPLC. Mouse pancreatic cancer KPC cells were implanted subcutaneously into the left hind footpad of syngeneic C57BL/6J mice and the tumor growth was monitored. From week 1, intratumoral injections with 1 mg/mL of CHST15 siRNA or vehicle were performed twice a week for 2 weeks and mice were sacrificed at week 3. In separate experiments, human BxPC-3 cells were implanted subcutaneously in T cell-deficient nude mice, and the effect of intratumoral injections of CHST15 siRNA or vehicle for 2 weeks was also investigated. Immunohistochemical staining was performed for the tumor and tumor-draining lymph node (TDLN). Results: CHST15 siRNA was detectable in not only the local sites but also the draining LNs of normal mice 1 and 4 hours after locoregional injection. In the KPC-implanted syngeneic mouse model, CHST15 siRNA showed significant tumor growth inhibition compared to the vehicle. In tumor, CHST15 was expressed by tumor cells, and to a lesser extent, Ly6C/G+ MDSCs. CHST15 siRNA altered tissue remodeling by repressing dense fibrotic architecture and NETosis. CHST15 siRNA significantly diminished Ly6C/G+ MDSCs while increasing CD4+ and CD8+ T cells. In TDLN, CHST15 was expressed by Ly6C/G+ MDSCs. Locally injected CHST15 siRNA markedly diminished Ly6C/G+ MDSCs, while increasing Ki-67+ proliferating CD4+ and CD8+ T cells. In the BxPC-3-implanted nude mouse model, locally injected CHST15 siRNA repressed excessive fibrosis and NETosis in tumor, diminishing both tumoral and TDLN MDSCs, but tumor growth inhibition was marginal. These results suggest that locally injected CHST15 siRNA could enter into TDLN, directly diminishing CHST15+ MDSCs, and expanded T cells. Tumor growth inhibition was largely T-cell medicated. Conclusions: The present study demonstrated that CHST15 siRNA locally and remotely diminished MDSCs, leading to the enhancement of anti-tumor T cell activity. A novel role of locally-delivered RNA oligonucleotide is suggested.
Circulating tumor DNA (ctDNA) and disease recurrence in early stage pancreatic cancer.
Authors: Gong Zimu , Esmail Abdullah , Abdelrahim Maen
Published: June 2023

e16313

Background: Surgical resection with neoadjuvant and/or adjuvant chemotherapy remains to be the cornerstone in treatment for early-stage pancreatic adenocarcinoma. Disease recurrence after curative intent treatment remains to be very common, and early detection of disease recurrence remains challenging. Recent studies explored the role of ctDNA in guiding adjuvant treatment in colon cancer, but its role in pancreatic cancer remains unknown. Methods: Through comprehensive chart review, we identified patients who: 1. Diagnosed with early-stage pancreatic adenocarcinoma; 2. Underwent curative intent surgery at our institution from 2019 to 2021; 3. Have postoperative tissue informed ctDNA results with commercially available assay (Signatera, by Natera Inc). Results: A total of 14 patients, including 7 males and 7 females, were included in the study. Depending on location of tumor, types of surgery included Whipple procedure (N = 13) and distal pancreatectomy (N = 1). The median age at time of surgery was 62 years (Range: 41-83 years). Two patients received neoadjuvant chemotherapy, and 13 patients received adjuvant chemotherapy. Two patients also received adjuvant radiation. A total of 41 ctDNA readings were obtained. The median time from surgery to first ctDNA assay was 2.4 months. First post-op ctDNA was positive in 6 patients, all of whom received adjuvant chemotherapy but still experienced clinical recurrence after a median of 3.7 months. The median overall survival of those ctDNA+ patients was 11.4 months. In the remaining 8 patients, the median progression free survival was 14 months, with clinical recurrence being observed in 4 patients. Median overall survival was not reached at median follow up of 30.5 months (one patient died at 6 months without disease recurrence, and another died at 14 months with progressive disease). In the 4 patients who had clinical recurrence despite initially negative ctDNA, ctDNA turned positive 1 month before clinical recurrence in 1 patient. However, in the other 3 patients, recurrence occurred 3.1, 1.9 and 3.5 months after the most recent negative ctDNA result. Conclusions: Our study demonstrated that positive ctDNA reliably predicts clinical recurrence in early-stage pancreatic cancer after surgery, with a positive predictive value of 100%. Negative result appears to be less reliable. This may be explained by different shedding pattern and test sensitivity. Larger scale study is underway to further evaluate its role in determining prognosis and guiding adjuvant treatment.
miRNAs targeting RAS and their clinical relevance in resected pancreatic adenocarcinoma (PC): Results from a prospective study.
Authors: Lavacchi Daniele , Caliman Enrico , Pillozzi Serena , Polvani Simone , Scolari Federico , Boddi Anna , Pasqui Adriano , Fancelli Sara , Giommoni Elisa , Pellegrini Elisa , Vannini Agnese , Brugia Marco , Pugliese Lavinia , Messerini Luca , Taddei Antonio , Moraldi Luca , Galli Andrea , Antonuzzo Lorenzo
Published: June 2023

e16314

Background: Pancreatic adenocarcinoma (PC) is one of the big killers with a 5-year disease-free survival (DFS) rate of 19-26% after resection despite adjuvant treatments. KRAS mutations have been reported in approximately 90% of PC cases and, beyond KRAS activation by gene mutations, several miRNAs directly targeting KRAS have been reported to be simultaneously downregulated, strengthening the already activated RAS signaling. In addition, the interplay between miRNAs and RAS includes downstream miRNA effectors whose role needs to be elucidated. The aim of this study was to evaluate the expression of candidate miRNAs strictly related to KRAS expression in order to elucidate the prognostic value. Methods: In this single-center observational prospective study we included patients with pathologically confirmed PC, who underwent radical surgery and were referred to the Clinical Oncology Unit, Careggi University Hospital, Florence (Italy), between 2015 and 2022. Total RNA was extracted from FFPE sections, retro-transcribed and the resulting cDNA was then used for qPCR analysis. Results: Among 44 patients included in the study, 34.1% were male and 65.9% female (median age 75 years). The majority of cases had the primary tumor located at the head of the pancreas (65.9%) and the pathological stage was pT1-2 in 45.5%, pT3 in 54.5%, pN0 in 22.7%, pN+ in 77.3%. Overall, 63.6% of patients received adjuvant chemotherapy and 69.0% experienced disease recurrence. Twenty-three specimens were adequate for miRNA analysis. A different expression of the three target miRNAs between PC and healthy tissue was observed: miR-155 was overexpressed and miR-206 downregulated in PC, while miR-143 had a similar expression in both tissues. miR-143 overexpression was associated with nodal involvement (pN+) at the pathological examination (p = 0.029). Among clinicopathological features, pN+ was associated with shorter DFS (p = 0.009) and overall survival (OS) (p = 0.021) compared to pN0. A trend toward inferior DFS was observed for higher expression of miR-206 (p = 0.095) and miR-143 (p = 0.092). Among patients receiving a first-line treatment for advanced disease, miR-155 was overexpressed in responders vs non-responders (p = 0.048). Conclusions: miRNA expression is involved in tumorigenesis and metastatic spread in PC. A comprehensive analysis of the miRNA-RAS interplay deserves to be further investigated as a predictor of clinical outcome, especially for miR-143 overexpression which was associated with lymphatic spread and, consequently, poor prognosis.
A single-institution analysis of a rare variant of pancreatic neoplasm-osteoclastic giant cell tumor.
Authors: Kesireddy Meghana , Asif Samia , High Robin , Yu Fang , Krishnan Mridula
Published: June 2023

e16315

Background: Pancreatic osteoclastic giant cell tumor (OGCT) is a rare variant (<1% cases) of pancreatic neoplasm. Due to its rarity, prospective studies on management are limited. The prognosis and molecular characteristics may differ from pancreatic adenocarcinoma. Methods: We analyzed demographics, clinical features, treatment modalities, and outcomes of overall survival (OS) and progression-free survival (PFS) in patients with pancreatic OGCT at our institution from 2005-2022. Results: We identified 8 OGCT patients with a median age of 67, of whom 7 had locoregional disease (resectable- 5, borderline resectable- 1, locally advanced-1), and 1 had denovo metastatic disease at diagnosis. The borderline resectable and locally advanced patients eventually developed metastatic disease. The majority of patients were male (n=5), Caucasian (n=7), former smokers (n=5), had no significant alcohol use (n=8) and had no pre-existing pancreatitis (n=8). 4 of the 5 resectable patients had surgery, and 2 received adjuvant chemotherapy. The median OS was 54 months for locoregional disease (n=5) vs.16 months for metastatic disease (denovo metastatic and progression to metastatic disease, n=3). The median OS was 54 months for surgical resection (n=4) vs. 25 months for those without surgical resection (n=4) based on quartile computations from the Kaplan-Meier survival curve. Conclusions: Our patients had a longer OS than the previously reported OS of less than 12 months for all stages of pancreatic OGCT. There was no progression in resectable patients, indicating an indolent disease with an overall good prognosis. Patients with locoregional disease or those who underwent surgical resection had longer OS, but due to the small sample size and censored patient survival times (i.e., patients still alive), the statistical significance of this trend could not be calculated. Studies are required to understand tumor biology and determine the optimal multidisciplinary treatment. [Table: see text]
In-hospital outcomes of patients with pancreatic cancer and venous thromboembolism.
Authors: Sanghvi Ankushi , Nanavaty Dhairya , Bansal Kannu , Yekula Anuroop , Narayan Gayatri , Janamejey Fnu , Shah Shailja
Published: June 2023

e16317

Background: Pancreatic cancer accounts for about 3.2% of all new cancers in the US. It has dismal 5-year relative survival of 11.5% and accounts for 8.2% of all cancer deaths. Studies have shown a strong association of pancreatic cancer with venous thromboembolism (VTE). However, data surrounding outcomes associated with VTE in this population is limited. We aim to estimate the effect of VTE on mortality and healthcare utilization in this population. Methods: We queried the National Inpatient Sample (NIS) 2017-2019 for all adult patients with a diagnosis of pancreatic cancer. The cohort was further classified by the presence of VTE (either acute deep vein thrombosis (DVT) or acute pulmonary embolism (PE)). The primary outcome of interest was in-hospital mortality, and secondary outcomes included hospitalization cost and length of stay, reflecting resource utilization. Multivariable regression analysis was performed to examine the association. Results: Over a period of 3 years, 392,744 admissions were identified with a diagnosis of pancreatic cancer. The mean age was 67 years, and 48% were females. The prevalence of acute DVT and acute PE was 5.0% and 5.8% respectively. In-hospital mortality was roughly 12% in the study cohort who had either DVT or PE. The odds of all-cause mortality were higher in pancreatic cancer admissions complicated by DVT (OR 1.59, 95% CI: 1.34-1.70, p<0.001) or PE (OR 1.39, 95 %CI: 1.23-1.58, p<0.001). The presence of VTE was also associated with higher hospital costs ($17,351 (14,256-20,446, p<0.001) for DVT, and $5,710 (2,679-8,740, p<0.001) for PE and longer hospital stay (7.2 vs 5.7, p<0.001) for DVT and (6.6 vs 5.7, p<0.001) for PE. Conclusions: Our study suggests that the presence of VTE portends poor outcomes in patients with pancreatic cancer. They also increase healthcare expenditure and lead to a longer hospital stay. Current guidelines (2020) recommend against offering thromboprophylaxis to patients with any cancer. Given the worse outcomes, this study reflects the need to formulate risk assessment models for the role of primary thromboprophylaxis in pancreatic cancer.
Predicting the risk of pancreatic cancer in patients with new-onset diabetes based on CT image.
Authors: Zhou Yu , Yang Jiabin , Zeng Liangtang , Wu Lei , Wu Zhuo , Liu Si-Yang , Zheng Shangyou , Chen Changhao , Chen Rufu
Published: June 2023

e16320

Background: While long-standing diabetes mellitus (LsDM) is an etiologic factor for PC, new-onset diabetes (NoDM) has been considered as a manifestation and harbinger of this cancer as well. Current evidence support that the PC-associated NoDM was mainly caused by disease of the exocrine pancreas, which was different from the typical type 2 DM. Therefore, we hypothesize that, in the NoDM patients, CT image features of “normal” pancreas from PC-associated NoDM patients might be different from that of the new-onset type 2 DM. We sought to develop and validate a risk prediction model to facilitate the distinction between NoDM vs potential early PC-associated NoDM on pancreatic CT imaging. Methods: We retrospectively collected CT imaging from three types of patients at Guangdong Provincial People's Hospital between January 2015 and December 2022: PC patients with pathological diagnosis of pancreatic ductal adenocarcinoma (n=249: 139 patients without DM, 63 patients with NoDM, 47 patients with LsDM), NoDM patients diagnosed with PC within 3 years (n=12), NoDM patients without development of cancer within the next 5 years (n=151). We used four different machine learning algorithms, including support vector machine (SVM), random forest (RF), eXtreme Gradient Boosting (XGB), and generalized linear model (GLM), and gradient boost methods, to build prediction models based on PC pateints and cancer-free NoDM patients. The algorithm with best ROC was used to build a final model, which was validated in the “normal” CT images of NoDM patients prior to their diagnosis of PC within 3 years. Results: In PC cases, the radiomics features exclusive to NoDM-PC cases were selected using a non-parametric test, and 134 radiomics features were retained (86 from arterial and 48 from venous phases, respectively). The RF algorithm showed best prediction skill (AUC of ROC: 0.952). Based on the variable importance measures in the RF algorithm, a risk-scoring model was generated for NoDM patients as a tool to differentiate between PC patients and cancer-free DM patients. As a result of validation, the scores calculated based on the “normal” CT images of NoDM patients prior to their diagnosis of PC within 3 years, were significantly higher than the scores from CT images of NoDM patients who were cancer-free within the next 5 years (P < 0.01). Conclusions: In NoDM patients, even the PC lesion was nonvisible on CT, the radiomics features of “normal” pancreas of PC patients were different from that of the real DM patients. Our model has the potential for identifying individuals with PC in the whole NoDM population.
Impact of cirrhosis on mortality in gastrointestinal malignancies: A retrospective study from nationwide database.
Authors: Pan Chun-Wei , Cuartas Mesa Maria Cristina
Published: June 2023

e16324

Background: Cirrhosis is a leading cause of death in the United States, and it represents a significant cause of deterioration in the quality of life of patients worldwide. Patients with cirrhosis can be affected by malignant and non-malignant co-morbid conditions, which can impact their prognosis. Among these, gastrointestinal (GI) malignancies like colorectal, pancreatic, and hepatic represent some of the most prevalent tumors affecting the GI tract. As both cirrhosis and cancer rates rise, our study aims to explore the impact of cirrhosis on hospitalization outcomes in gastrointestinal (GI) Cancer. Methods: We used the National Inpatient sample from 2016-2020 and identified admission with a diagnosis of GI cancer using International Classification of Disease-10 codes. The cohort was further stratified into patients with a secondary diagnosis of Cirrhosis compared to those without cirrhosis. All analysis was performed using STATA V17, considering P < 0.05 statistically significant. Multivariate regression analysis was used, and confounding variables adjusted were age, gender, race, insurance, and baseline hospital characteristics. Results: A total of 1,391,165 admissions with GI malignancies were identified from 2016 to 2020. Among these, 272,729 (19.6%) had a secondary diagnosis of cirrhosis, while 1,118,435 (80.4%) did not. The cirrhotic cohort was more likely to be male (71.4%) compared to the non-cirrhotic cohort (55.5%). Cirrhosis was most commonly associated with hepatocellular carcinoma (81.7%), pancreatic cancer (8.1%), and colorectal cancer (5.7%). Patients with cirrhosis have higher mortality rates in various GI cancers. This includes esophageal cancer (17.0%) compared to those without cirrhosis (10.7%), with an adjusted odds ratio of 1.55 (95% confidence interval: 1.02-2.34, P < 0.05). Similarly, higher mortality rates were observed in gastric cancer (15.8%), colorectal cancer (12.6%), hepatocellular carcinoma (11.1%), biliary tract cancer (13.9%), and pancreatic cancer (11.5%) compared to those without cirrhosis, with adjusted odds ratios of 1.63, 2.06, 1.41, 1.78, and 1.41 respectively. Conclusions: In this study of 1.4 million gastrointestinal malignancy-related admissions from 2016 to 2020, 19.6% had a secondary diagnosis of cirrhosis. This cohort of patients had a higher mortality rate in various gastrointestinal cancers than those without cirrhosis. Cirrhosis was more commonly associated with hepatocellular carcinoma, followed by gastric cancer. These findings suggest that cirrhosis is a significant risk factor linked with higher mortality in gastrointestinal malignancy-related admissions. Further research is necessary to characterize this association better in order to improve outcomes for patients with cirrhosis and GI malignancies.
Epidemiology of cholangiocarcinoma in Florida, and differences in risk factors between intra- and extra-hepatic cholangiocarcinoma.
Authors: Pinheiro Paulo S. , Cranford Hannah M. , Liu Qinran , Jones Patricia Denise
Published: June 2023

e16329

Background: Albeit rare, cholangiocarcinoma (CC) is a poorly understood, highly fatal cancer with an incidence rate of less than 2.5 per 100,000 people. For most cases of CC, causes are not known. Here, we use population-based data from the diverse state of Florida to study the most recent incidence rates and trends for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and measure the prevalence of potential risk factors and preexisting conditions associated with liver cancer including biliary conditions, diabetes, obesity and dyslipidemia, hypertension, smoking, chronic hepatitis C (HCV) and hepatitis B (HBV) infections, alcohol-related disease, and auto-immunes diseases. Methods: We used the Florida Cancer Registry Data on all cases of cholangiocarcinoma (N = 5,096) diagnosed during 2010–2018 (2,930 intra-hepatic, 2,166 extra-hepatic). Data were linked with two other data sources: the Agency for Healthcare Administration and the Department of Viral Hepatitis. Age-adjusted rates by sex were computed, incidence trends using Joinpoint regression and 5-year age-adjusted survival, using lifetable methods, were estimated. Differences in prevalence of risk factors were tested using chi-square tests. Results: Both ICC rates, 1.7 (per 100,000) for males and 1.3 for females, and ECC rates, 1.0 in males and 0.7 in females are relatively low. ICC is currently the fastest increasing cancer at a rate of +7.2% per year in males and +6.5% in females, while ECC trends remain stable. The 5-year survival was 11.0% for ICC (95%CI: 9.2-12.8) and 12.9% (95%CI: 10.5-15.3) for ECC. Overall, conditions such as diabetes type 2 (29%), obesity and dyslipidemia (41%), and hypertension (61%) were highly but equally prevalent in both ICC and ECC. The presence of non-alcohol related cirrhosis (6.0% vs 2.8% for ICC and ECC, respectively), chronic HCV infection (6.6%, 2.0%), and smoking (52.7%, 48.5%) were significantly more prevalent in ICC, while cholangitis of any type (13.5%,26.0%), chronic pancreatitis, auto-immune diseases (all. Conclusions: Currently, ICC is the most rapidly increasing cancer in the US; though, the extent to which better recognition of ICC plays a role in this trend is unknown. ICC and ECC show similarities, but also, differences in the prevalence of specific risk factors and preexisting conditions. The commonly held perception that the increase in metabolic causes (diabetes and obesity), similarly present in both ICC and ECC, are responsible for the current trends is partially challenged by the stable trends in ECC. Given its dismal prognosis, cholangiocarcinoma, especially ICC, requires further research. Funding: This work was supported by Bankhead Coley Grant #20B16 from the Biomedical Research Program of the Department of Health State of Florida.
Gastrointestinal cancer trends in the Hispanic population: A SEER database population study (2000-2019).
Authors: Hechter Sharon , Nikiforov Ivan , Greenberg David B.
Published: June 2023

e16331

Background: Cancer continues to be the leading cause of death in the Hispanic population. Gastrointestinal cancer surveillance data in Hispanic individuals has only recently become available in the last 3 decades. Differences in incidence rates among Hispanics and Non-Hispanic Whites (NHWs) need further elucidation. In this study, we analyzed trends in Hispanics and NHW populations across multiple gastrointestinal cancers. Methods: Gastrointestinal cancers (liver, colon and rectum, pancreas, esophagus, gallbladder, stomach, small intestine, anus, anal canal and anorectum) diagnosed between 2000-2019 were identified in the Surveillance, Epidemiology, and End Results Program (SEER) Database. We calculated incidence rates, confidence intervals and incidence rate ratios. Rates are per 100,000 and age adjusted to the 2000 US standard population. Rate ratios are the rounded rates in Hispanic individuals divided by the rounded rates in NHWs. Results: There was a higher incidence of liver, gallbladder, and stomach cancers among Hispanics when compared to NHWs between the years 2000-2019. Liver cancer incidence rate is (11.5 per 100,000) in Hispanics compared with (6.3 per 100, 000) in NHWs with an incidence rate ratio of 1.8. Gallbladder cancer incidence rate is (2.2 per 100,000) in Hispanics compared with (0.9 per 100,000) in NHWs with an incidence rate ratio of 2.4. Stomach cancer is (10.9 per 100,000) in Hispanics compared with (5.7 per 100,000) in NHWs with an incidence rate ratio of 1.9. The lowest incidence rate ratio was seen for anus, anal canal and anorectum cancers in Hispanics compared to NHWs. The incidence rate is (1.2 per 100,000) in Hispanics compared with (2.1 per 100,000) in NHWs with an incidence rate ratio of 0.6. Remaining cancers had incidence rate ratios less than 1.0 and were more likely to occur in NHWs. Conclusions: This study illustrates differing incidence rates of multiple gastrointestinal cancers among Hispanics compared to NHWs. Liver, gallbladder and stomach cancer incidence rates in Hispanics is double that of NHWs. Interestingly, the remaining gastrointestinal cancers had higher incidence rates among NHWs. Further research is warranted to understand the differences in cancer risk within the Hispanic population as well as healthcare access, language barriers and cultural differences that may play a role. [Table: see text]
The impact of ImmunoPrecision in small bowel adenocarcinoma.
Authors: Chiu Vi Kien , Belmonte Jessica , Osman Diaa , Gong Jun , Hendifar Andrew Eugene , Osipov Arsen , Lou Emil , Ziyeh Sharvina , Zaghiyan Karen , Nissen Nicholas
Published: June 2023

e16333

Background: Although approaches to treating adenoCA of the small bowel (SBA) are extrapolated from those of the colon, SBA has distinct pathogenesis, clinical presentation and poorer prognosis. We examine the impact of SBA treatment by ImmunoPrecision, which combines Immunotherapy and Precision genomic targeting. Methods: SBA pts were identified retrospectively from Cedars-Sinai electronic health record (2000 – 2022) on an IRB-approved protocol. Microsatellite status and genomic testing were done in CLIA-certified, CAP-accredited labs. Pt characteristics, pathology, in-depth clinical history and genomics were summarized with descriptive statistics. Endpoint of median OS was estimated by Kaplan-Meier and calculated from pre-treatment imaging to last event. Treatment groups were compared using log-rank test. Results: Between Jan 2003 – Dec 2022, 137 stage 1 – 4 SBA pts (93 duodenal; 44 jejunal/ileal) were identified. Median age was 67 (range 22 – 95). Microsatellite status and genomic testing data were done or known for 72 pts (53%). In 35 pts who had metastases at initial presentation, 15 pts had NGS genomics, which identified actionable targets: 20% Her2amp/mut, 13% FGFR1amp/mut, 7% ALKfusion, 7% KRAS G12C, and 7% ATM R35*. 40% of 10 metastatic pts tested for microsatellite status were MSI/TMB-High, and only 1 pt received immunotherapy. In pts with metastases, median OS was 9.5 mo in duodenal adenoCA (51 pts) vs 13.0 mo in jejunal/ileum adenoCA (23 pts) (p = 0.46). There was a non-significant improvement in median OS to 20.5 mo in metastatic duodenal adenoCA pts who received targeted inhibition of actionable genomics or had MSI/TMB-High status (p = .51). Conclusions: Our real-world cohort of metastatic duodenal adenoCA shows a trend toward improved median OS from ImmunoPrecision targeting of frequent MSI/TMB-High status and actionable genomics. ImmunoPrecision clinical trial investigation is warranted in this rare SBA population. [Table: see text]