bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of cancer testis antigen expression with high type-I interferon signal and prognosis in small bowel neuroendocrine tumors.
Authors: Ayabe Reed I. , Seo Yongwoo David , Melendez Brenda , Lazcano Segura Rossana , Fields Brittany C. , Wani Khalida M. , Johnson Sarah , Witt Russell , Chelvanambi Manoj , Hudgens Courtney , Hernandez Sharia D. , Ajami Nadim J. , Wargo Jennifer Ann , Lazar Alexander J. , Halperin Daniel M. , Estrella Jeannelyn , Maxwell Jess
Published: January 2024

596

Background: Patients with small bowel neuroendocrine tumors (SBNET) frequently present with metastatic disease, and efficacy of available therapies, including immune checkpoint inhibitors (ICI), is limited. Toward developing novel immunomodulatory strategies, we evaluated the tumor immune microenvironment of SBNETs using bulk transcriptional and digital spatial profiling (DSP). Methods: Patients with SBNET who underwent surgical resection at MD Anderson Cancer Center from 2003-2016 were retrospectively analyzed. Overall survival (OS) was assessed using the Kaplan-Meier method and Cox proportional hazards model was used for multivariate analysis (MVA). Bulk transcriptional profiling was performed using the Nanostring PanCancer-Immune Panel. DSP was performed with whole human transcriptome using PanCK to segment tumor and adjacent stroma; 88 distinct regions were analyzed using differential gene expression and Reactome pathway enrichment pipelines. Results: Resected SBNETs from 42 patients were selected for transcriptional analysis. Unsupervised clustering of gene expression demonstrated dichotomization into high and low cancer testis antigen (CTA) expression. CTA-high patients (n=12) demonstrated elevated expression of type-I interferons (IFN) and CTAs such as PRAME, GAGE1, and MAGEA3 and had significantly longer OS compared to CTA-low patients (n=30; median OS not reached vs 1975 days, p=0.008). MVA controlling for age, sex, metastatic disease, and Ki-67% confirmed CTA-high status as an independent predictor of longer OS (hazard ratio [HR] 0.2, 95% confidence interval [CI] 0.05-0.83). A pilot DSP experiment with 4 CTA-high and 4 CTA-low tumors revealed higher expression of epigenetic modification genes (e.g., H3C1, H2BC8, p<0.001) in CTA-high tumors with significant enrichment in epigenetic pathways (e.g., histone acetylation, DNA methylation). CTA-high tumors exhibited increased M2 macrophage presence (p=0.025) and increased stromal compartment NK cell activation (p=0.001). Conclusions: High expression of CTA and type-I IFN in resected SBNET is associated with longer survival, agnostic of stage or grade. While CTA expression has been implicated in tumor immunogenicity, this is the first work to identify a clinical signal in SBNET. Increased IFN in CTA-high tumors, corroborated by increased stromal NK cell activation, suggests an immune-mediated component of improved survival. Spatial transcriptomic analysis reveals epigenetic differences in CTA-high tumors and highlights the potential for combination epigenetic modifiers and immunotherapy in future trials.
Second-line chemotherapy in elderly patients with advanced pancreatic cancer: A mono-institutional retrospective experience.
Authors: Trovato Giovanni , Bensi Maria , Beccia Viria , Spring Alexia , Barone Diletta , Ceccarelli Anna , Perazzo Serena , Messina Gloria , Chiofalo Laura , Bagalà Cinzia , Quero Giuseppe , Alfieri Sergio , Tortora Giampaolo , Salvatore Lisa
Published: January 2024

606

Background: Only few randomized clinical trials have been conducted for second line therapy in advanced pancreatic cancer (APC). In these studies, elderly patients are poorly represented, even if the median age at diagnosis of APC is increasing; therefore, limited efficacy and safety data are available. Here, we present a retrospective monocentric analysis of second line chemotherapy in elderly patients treated at our Hospital. Methods: This study included patients with APC and aged>70 years old receiving a second-line chemotherapy for APC at our institution from March 2015 to August 2020. The primary endpoints were progression-free survival to second line (PFS2) and overall survival (OS); the secondary endpoint was safety. The Kaplan–Meier method was used to estimate efficacy outcome; log-rank test and Cox-regression model were used to compare the differences, considering a statistically significant p value < 0.05. Results: 169 pts affected with APC received first-line chemotherapy and 61 of them (36%) received second-line therapy. The median age at diagnosis was 74 Years (70-83), 31 (50%) were female; ECOG PS was 0-1 in 44 pts (59%), 41% had at least 2 comorbidities. The regimens of chemotherapy used were: mFOLFOX (28; 46%), Gemcitabine (11; 18%), Capecitabine (15; 24.6%), FOLFIRI (6; 9.8%), mFOLFIRINOX (1; 1.6%). 4 pts (6.6%) had a partial response and 22 (36.1%) had a stable disease, with a disease control rate of 42.7%. The median follow-up was 22.8 months; median PFS2 was 4.5 months (IC 95%: 2.5-6.5) and median OS was 15.4 months (IC 95%: 7.2-23.6). At the univariable analysis, there was a statistically significant difference in mPFS2 according to ECOG PS (0-1 vs 2: 5.3 [IC 95%: 3.5-7.0] vs 2.2 [IC 95%: 1.2-5.4] months; p 0.02) and number of metastatic sites at the beginning of second line therapy (1 vs 2 or more: 5.8 [IC 95%: 4.8-6.7] vs 3.4 [IC 95%: 3.1-3.8] months; p 0.006). At the multivariable analysis, both number of metastatic sites and ECOG PS were confirmed associated with mPFS2. Number of metastatic sites and ECOG PS were both also associated with mOS. No unexpected adverse events were reported, and no patients had to interrupt treatment due to toxicity. Conclusions: In our experience, only about a third of elderly pts with APC received second-line therapy; in these patients, ECOG PS, disease’s burden and the response to therapy are all positive prognostic factors. With regard to the safety profile, older age does not seem to negatively increase serious toxicities. In conclusion, elderly pts should not be precluded from an active treatment (also in later lines setting) and careful patients selection should guide treatment indication.
Pancreatic biopsy evaluation with nsCanary: A “smart ROSE” device for feedback on sample adequacy and cancer presence in endoscopic biopsies—Initial human clinical trial results.
Authors: Bogdanowicz Les , Fidaner Onur , Guidetti Martina , Dibennardo Federica , Gehrke Daniel , Ceres Donato , John Margaret , Bovalis Constantine , Raijman Isaac
Published: January 2024

618

Background: Pancreatic cancer (PC) accounts for 0.5 million new cases and 4.7% of the world's cancer-related deaths in 2020. Endoscopic ultrasound (EUS) guided fine needle biopsies (FNB) are the current standard of care for confirming suspicious lesions, however the diagnostic accuracy is reported below 70%. Rapid on-site evaluation (ROSE) improves the diagnostic performances of biopsies to reduce the number of needle passes, complication rates, and the need for additional procedures. However, availability of an on-site pathologist is often not feasible. NovaScan has pioneered the use of an impedance spectroscopy biomarker for cancer detection in different tissues based on the Cole Relaxation Frequency (CRF). NovaScan has developed the nsCanary, a ”smart ROSE” device that assesses PC presence in FNBs obtained during endoscopic procedures ex vivo, in real-time and on-site, without altering the tissue sample or affecting the workflow. Methods: Data were collected in a double-blind, IRB approved study from a cohort of 53 patients (28 males, 25 females) undergoing EUS procedures for suspected pancreatic lesions at the Texas International Endoscopy Center. FNBs were performed with a 22 gauge biopsy from a transduodenal approach. Each biopsy sample was transferred onto a disposable strainer allowing for any excess fluid to drain. An electrode for scanning was placed onto the core samples for data collection with the nsCanary a low cost, portable device used in the operating room. CRF is measured in the 1 kHz - 10 MHz frequency range via custom-designed hardware and assessment of the sample is completed in a few seconds. Subsequently, the sample is flushed into a pathology jar to undergo the standard workflow for cytology. The algorithm for extracting the CRF from the measurement was developed based on our previous preclinical study with transgenic KPC mice Samples with a CRF below 1 MHz were considered noncancerous, while CRF values above 1MHz or the absence of a CRF reading were considered cancerous. Results: PC assessment provided by nsCanary was validated against pathology outcomes for each biopsy sample. Findings showing a sensitivity of 86.7% and a specificity of 84.2% are reported in the table. Conclusions: We believe the nsCanary device will provide immediate feedback to the endoscopist on cancer presence and on the adequacy of the sample. This device is intended to support the decision-making process, by enabling clinicians to overcome the challenge of proving cancer presence during the first biopsy procedure, ultimately avoiding revisits and unnecessary trauma.[Table: see text]
Advanced pancreatic cancer outcomes and the impact of COVID-19 pandemic: The experience of an academic cancer center.
Authors: Adams-Carey Christian , Shepard Anna , Moreland Katie , Olowokure Olugbenga Olanrele , Latif Tahir , Rojan Adam , Pan Jianmin , Rai Shesh , Sohal Davendra
Published: January 2024

626

Background: The COVID-19 pandemic increased all-cause mortality and disrupted healthcare delivery in the United States. Interruptions in cancer screening and surveillance because of the pandemic resulted in delayed diagnosis, diagnosis at later stages, and worse cancer-related outcomes. However, the effect of COVID-19 on pancreatic cancer outcomes has not been reported. This study aimed to investigate this question. Methods: We studied consecutive patients with unresectable and metastatic pancreatic cancer treated at the University of Cincinnati Cancer Center. Patients were divided into 2 cohorts: from January 2018 to December 2019 (pre-COVID) and from January of 2020 to December of 2021 (during-COVID). Descriptive data on patient characteristics, ECOG performance status (PS), laboratory values, therapies, and mortality were obtained by pre- and during-COVID. The categorical variables were compared using the Pearson Chi-square test for contingency tables (or Fisher’s exact test when the expected frequency within any cell was less than 5 in the contingency table), and the t-test or ANOVA was used for continuous variables. For overall survival time, the Kaplan-Meier curves were compared between pre- and during-COVID using log rank test. We fitted univariable Cox proportional-hazards model for each interest variable, and the multivariable Cox models, which includes only significant variables. Results: There were 81 and 64 patients in the pre- and during-COVID cohorts, respectively. Patients diagnosed during COVID were more likely to be female, have better PS, have higher proportion of alcohol use, and were more likely to receive 5-FU-based (compared with gemcitabine-based) chemotherapy upfront. There was no overall survival difference between the two cohorts. A Cox proportional hazards model showed that PS at diagnosis, history of chronic pancreatitis, any chemotherapy compared to no chemotherapy, serum albumin prior to initial chemotherapy, and body mass index at time of diagnosis were associated with survival. Conclusions: We observed no difference in overall survival in patients diagnosed with advanced stage pancreatic cancer during the first two years of the COVID-19 pandemic compared with the two prior years. While some differences were observed between patient groups and treatment selection before and during the pandemic, a concerted effort to maintain cancer care appears to have minimized the impact of the pandemic. Further analyses on patients undergoing treatment are being conducted.
Comparison between different therapeutic sequences in patients affected by metastatic pancreatic ductal adenocarcinoma.
Authors: Pretta Andrea , Giampieri Riccardo , Nichetti Federico , Ziranu Pina , Lupi Alessio , Moledda Giusy , Andena Paola , Felicetti Cristiano , D'Agata Alessandra Pia , Pircher Chiara Carlotta , Codipietro Claudia , Rota Simone , Rizzo Daiana , Sanna Giorgia , Lai Eleonora , Puzzoni Marco , Pusceddu Valeria , Berardi Rossana , Niger Monica , Scartozzi Mario
Published: January 2024

674

Background: The first-line treatment of metastatic pancreatic cancer involves different therapeutic regimens, among them, mFOLFIRINOX and gemcitabine-nabpaclitaxel. However, it remains to be clarified which sequence might correlate with better outcomes. The aim of our work was to evaluate which sequence leads to better overall survival in this setting. Methods: We retrospectively collected data from 358 patients affected by stage IV pancreatic ductal adenocarcinoma from 3 different Italian Institutions. Patients received mFOLFIRINOX or gemcitabine plus nabpaclitaxel as first-line chemotherapy, followed by a second-line non-cross-resistant chemotherapy (gemcitabine or fluoropyrimidine-based combinations). Survival distribution was assessed by Kaplan-Meier curves. The primary endpoint was median overall survival. Statistical analysis was performed with MedCalc package. Results: The median age was 66 (± 9), 195 (54,4%) were male and 163 (45,6%) were female. 292 (81,5%) patients start gemcitabine plus nabpaclitaxel as first line treatment, while 66 (18,5%) patients start mFOLFIRINOX first-line therapy. No statistically significant differences in terms of mOS were observed between the two mFOLFIRINOX and gemcitabine-nabpaclitaxel groups: 16 versus 15 months, respectively, p = 0,2). No significant differences were found in terms of mPFS either: 7 versus 8 months, respectively, p = 0,3). Conclusions: The results of our retrospective study showed no statistically significant survival advantage between the sequences starting with mFOLFIRINOX or with gemcitabine-nabpaclitaxel. Further studies will be necessary to establish the effectiveness of new therapeutic schemes to be introduced into clinical practice in order to define a better therapeutic algorithm.
Early molecular assessment to predict prognosis in patients who respond to chemotherapy on initial imaging in pancreatic cancer.
Authors: Watanabe Fumiaki , Suzuki Koichi , Rikiyama Toshiki
Published: January 2024

683

Background: It is helpful to predict early the response to anticancer drugs in non-resectable solid tumors. The purpose of this study is to evaluate whether circulating tumor DNA (ctDNA) helps predict prognosis in patients with non-resectable pancreatic cancer who have received first-line FFX or GnP therapy and have responded to treatment (CR, PR, SD groups) on initial imaging. Methods: A total of 61 patients with non-resectable pancreatic cancer treated with FFX (N=22) and GnP (N=39) as first-line therapy were included in the study. Before and after chemotherapy treatment (median 42 days, after two courses), KRAS-mutated ctDNA was measured using droplet digital PCR with CA19-9. We defined the Responder group as those with CR, PR, or SD other than PD on initial imaging and the molecular assessment as the change in KRAS-mutated ctDNA before and after treatment. (1) No appearance of KRAS-mutated ctDNA before and after treatment was defined as molecular negative (mNT); (2) disappearance of KRAS-mutated ctDNA or decrease in copy number after treatment was defined as molecular response (mR); (3) new appearance of KRAS-mutated ctDNA or increase in copy number after treatment was defined as molecular progressive disease (mPD). We investigated whether the increase or decrease of CA19-9 before and after treatment (Increase group, decrease group) and the molecular assessment were useful as prognostic factors in the Responder group. Results: Male: female = twenty-nine: thirty-two. There were fourteen patients in the locally advanced group and forty-seven patients in the distant metastatic group, both of whom were considered non-resectable. Thirty-eight patients received any second-line treatment. The prognosis of fourteen patients with PD on initial imaging was significantly worse than that of the Responder group (N=47) (Responder: PD=18.4: 9.2 months, p=0.000108). The molecular assessment in the responder group showed 30 patients in mNT group, 10 patients in mR group, and 7 patients in mPD group. The MST was 21.7, 13.2, and 13.2 months. In univariate analysis, increased CA19-9 (Increase group) and mPD were associated with worse prognosis (Increase: Decrease=13.6: 18.4 months, p=0.0487), (mPD: mNT+mR=13.2: 21.7 months, p=0.0194) and the only independent prognostic factor in multivariate analysis was mPD (Hazard ratio=3.005, p=0.0361). Conclusions: The prognosis of patients with molecular negative or molecular response after chemotherapy is relatively good (MST; 21.7 months), and efforts should be made to continue GnP and FFX. In contrast, the prognosis of patients with molecular progressive disease in the responder group is worse. Therefore, strict follow-up and change of anticancer drugs, including palliation, should be considered.
CEACAM6 and IFITM3 as potential biomarkers for pelareorep in pancreatic adenocarcinoma (PDAC).
Authors: Noonan Anne M. , David Jason , Hays John L. , Chen James Lin
Published: January 2024

684

Background: Pelareorep (P) is a proprietary formulation of live, replication-competent, naturally occurring Reovirus Type 3 Dearing strain. We previously performed a phase II trial of P with carboplatin (C) and paclitaxel (Pxl) vs C and Pxl alone in metastatic PDAC (NCT01280058). Although P did not improve progression-free survival compared to C and Pxl alone, some exceptional durable responses were seen in the P arm. Low levels of carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) mRNA expression were associated with prolonged PFS in P-treated pts (p=0.05) and there was a 3.3 times higher fold change in Interferon-inducible transmembrane protein 3 (IFITM3) expression in the pts doing poorly versus responders (nominal p<0.05) in P arm. Here we investigate mechanisms of resistance to P infection mediated through CEACAM6 and IFITM3 in a panel of pancreatic ductal adenocarcinoma cell lines. Methods: Prior studies noted CEACAM6 and IFITM3 may restrict cell entry of certain enveloped viruses. CEACAM6 and IFITM3 protein levels were measured in PDAC cell lines using Western blot. Flow cytometry was used to assess P infectivity. We have generated multiple knockdowns of CEACAM6 and IFITM3 in PDAC cell lines to determine changes in P infectivity and other inflammatory signalling pathways. Live cell imaging was used to assess cell viability. Results: Basal expression of CEACAM6 was measured in a panel of 4 PDAC cells (PANC10.5, HPAFII, BxPC3, CFPAC1). Panc10.05 had low basal expression nor could expression be induced by 24hr P infection. All other cell lines showed moderate to high basal expression that was inducible. P infectivity at 24hrs was significantly higher in Panc10.05 cells compared to high CEACAM6 expressing cell lines. There was varying basal expression of IFITM3, however all cell lines showed IFITM3 induction when exposed to P. Of the 3 cell lines that also expressed high levels of CEACAM6 (HPAFII, CFPAC1, BxPC3), low basal expression of IFITM3 was strongly associated with increased sensitivity to P infection and decreased viability at 72hrs, which could be induced by knockdown of IFITM3 in high expressing cell lines. Neither C or Pxl altered levels of CEACAM6 or IFITM3 in any of the four cell lines. Conclusions: High CEACAM6 and IFITM3 play a role in P viral infectivity across multiple pancreatic cell lines, confirming results obtained in translational datasets. Further analysis is ongoing to elucidate mechanism and identify pathways to alter expression of CEACAM6 and IFITM3 and enhance P infectivity in future trials.
Molecular characterization of small extracellular vesicles in patients with pancreatic cancer treated with neoadjuvant chemotherapy followed by stereotactic body radiation (SBRT).
Authors: Paluri Ravi Kumar , Su Yixin , Sing Sangeetha , Williams Grant Richard , Gbolahan Olumide B. , Manne Upender , Deep Gagan
Published: January 2024

685

Background: Currently, pancreatic cancer (PanC) is one of the serious gastrointestinal diseases, and more than 90% of the patients die within five years of diagnosis. Therefore, to improve PanC-related mortality, new therapeutic and diagnostic/prognostic measures are urgently needed. In this substudy, we examined the usefulness of plasma small extracellular vesicles (sEV) to discover molecular biomarkers associated with treatment response and overall survival from the plasma samples collected on a prospective clinical trial assessing the efficacy of SBRT following chemotherapy in pancreatic cancers (NCT03600623). Methods: PanCpatients (n=22) with locally advanced and borderline inoperable disease were recruited at the University of Alabama Comprehensive Cancer Center. They were administered either FOLFIRINOX (5-FU, folinic acid, oxaliplatin, and irinotecan) or paclitaxel (gemcitabine-nab-paclitaxel) for 2 months followed by SBRT (33 Gray in 5 fractions). The primary objective of this single-center pilot study was to evaluate the safety and tolerability of this treatment regimen. Further, blood was collected at baseline and, at the end of chemotherapy and radiotherapy. sEV were isolated from archived plasma samples by an established ultracentrifugation method and characterized for size and concentration by nanoparticle tracking analyses (NTA), shape and size by transmission electron microscope (TEM), and surface expression of exosomal tetraspanin markers (CD63, CD9, and CD81) and a PanC marker (CA19-9) by nano-flow cytometry. Lastly, sEV in longitudinal plasma samples were characterized for the expression of specific PanC-related miRNAs (miR196a-5p, miR155-5, miR194-5p, miR301-3p, miR21-5p, miR1246, and miR34a-5p) by real time-PCR (RT-PCR). Results: Neoadjuvant FOLFIRINOX and gemcitabine-nab-paclitaxel followed by SBRT were safe and well tolerated by most patients. NTA data showed that the ultracentrifugation method yielded highly pure sEV (with average diameter of <200 nm) from archived baseline and longitudinal plasma samples. TEM analysis further confirmed the shape and size of the isolated sEV. Nano-flow cytometry showed the expression of exosomal markers, CD63, CD9, and CD81, as well as PanC marker CA19-9 on the surfaces of sEV. The expression of various PanC-related miRNAs in sEV was heterogenous and correlated with corresponding clinical parameters, including treatment response and overall survival. Conclusions: Neoadjuvant chemotherapy in combination with SBRT is safe and tolerable regimen to treat patients with locally advanced and borderline PanC. Further, sEV in the plasma of PanC patients could serve as useful prognostic and predictive markers.
New cutoff of CA19-9 values for predicting pancreatic cancer using liquid biopsy.
Authors: Hasebe Ryuji , Watanabe Fumiaki , Suzuki Koichi , Rikiyama Toshiki
Published: January 2024

692

Background: Carbohydrate antigen 19-9 (CA19-9) is the biomarker most commonly used as a diagnostic aid for treatment efficacy and survival prediction for pancreatic ductal adenocarcinoma (PDAC). However, the cutoff value of CA19-9 is still being discussed. Instead, circulating tumor DNA (ctDNA) has been reported as a new biomarker for PDAC. Our previous study showed a correlation between CA19-9 levels and KRAS mutated ctDNA in the blood of PDAC patients. Based on this correlation, we validated an appropriate cutoff value for CA19-9 before surgery. Methods: We monitored continuously CA19-9 values and KRAS-mutated ctDNAs in unresectable PDAC patients (N=22) who underwent chemotherapy in 2015 to 2017. KRAS mutation in tumor tissues and mutated circulating tumor DNA (MctDNA) in plasma was analyzed for mutations by digital polymerase chain reaction (ddPCR) in 22 patients with pancreatic cancer. KRAS point mutation in plasma was analyzed, according to KRAS point mutation in tissue (ex. 12D, 12V). Receiver operating characteristics (ROC) curve analysis was plotted to determine new cutoff of CA19-9 value that emerged KRAS-mutated ctDNA in the longitudinal monitoring. Recurrence-free survival (RFS) and overall survival (OS) of 60 patients who underwent surgery for resectable PDAC in 2005 to 2013 were analyzed according to many survival variables including new cutoff of CA19-9 value and median CA19-9 before operation. Results: Receiver operating characteristic curve analysis identified 949.7 U/mL of CA19-9 as the cutoff value corresponding to the presence of KRAS mutated ctDNA. The median value of CA19-9 was 221.1 U/mL. Subsequently, these values were verified for their prognostic values of RFS and OS in 60 patients who underwent surgery in 2005 to 2013. Multivariate analysis revealed that 949.7 U/mL of CA19-9 was an independent risk factor for RFS and OS in these patients (P = 0.010 and = P = 0.001, respectively), along with lymph node metastasis( P = 0.017 and P = 0.008), unlike the median CA19-9 level (P = 0.210 and P = 0.150). Conclusions: The results of this study demonstrate that preoperative 949.7 U/mL ≥ CA19-9 may be associate with poor prognosis in PDAC. In summary, our study demonstrated, for the first time, that the adjusted cutoff value of CA19-9 was an important biomarker for the prediction of recurrence and prognosis in patients with resected PDAC. Patients with high levels of CA19-9 before surgery had a higher risk of recurrence and poorer prognosis than those with low levels of CA19-9, therefore they may have benefitted more from drug treatment than surgical intervention. Nevertheless, appropriate clinical decision-making for patients with high CA19-9 levels should be confirmed in future clinical trials. Although our study results should be interpreted within the study limitations and further examinations are required to draw a definitive conclusion, we believe that it clarifies the selection of patients with PDAC.
Inter-reader variability of imaging biomarkers for therapeutic response in pancreatic ductal adenocarcinoma.
Authors: Heiselman Jon Stanley , Horvat Natally , Agridag-Upcinar Burcin , Yildirim Onur , Ecker Brett Logan , O'Reilly Eileen Mary , Drebin Jeffrey A. , Balachandran Vinod P. , Kingham T. Peter , D'Angelica Michael Ian , Soares Kevin , Do Richard K. G. , El Homsi Maria , Jarnagin William R. , Wei Alice Chia-Chi , Chakraborty Jayasree
Published: January 2024

700

Background: Indeterminate borders of pancreatic ductal adenocarcinoma (PDAC) can impair reliability of lesion annotation in imaging assessment of therapeutic response (TR) after neoadjuvant chemotherapy (NAT). Previous work showed that longitudinal image registration algorithms can track treatment-related changes and produce quantitative imaging biomarkers (QIB) for TR that predict overall (OS) and recurrence-free survival (RFS). We compare inter-reader agreements of these biomarkers against conventional RECIST and tumor volume QIB. Methods: N=30 patients enrolled in a Phase II clinical trial comparing outcomes of a NAT regimen were retrospectively analyzed. In baseline and restaging CT, whole pancreas and tumor segmentations and tumor diameters were annotated by 2 expert attending radiologists and 2 novice radiology fellows. For each reader, percent change in tumor diameter (RECIST score), percent change in tumor volume (ΔV), and difference in ratio of tumor burden to pancreas volume (ΔB) were computed as QIB for TR across the NAT interval via two approaches: image registration of the baseline tumor region of interest, and direct segmentation of the PDAC lesion in baseline and restaging images. Inter-reader agreements of RECIST, ΔV, and ΔB QIB from both approaches were compared via concordance correlation coefficient (CCC). Associations with OS and RFS were compared over 5-year follow-up via Harrell’s C-index. Results: Among expert radiologists, RECIST score CCC was 0.77 [95% CI: 0.59-0.88], whereas image registration QIB CCC values were significantly higher (ΔV: 0.95 [0.90-0.98], p=0.002; ΔB: 0.93 [0.86-0.97], p=0.014). ΔV and ΔB QIB measured by direct tumor segmentation had significantly lower CCC than by image registration (p<0.001). Among novice readers, image registration QIB (ΔV: 0.83 [0.67-0.91], ΔB: 0.70 [0.48-0.84]) produced higher agreement than RECIST (0.26 [-0.17-0.61]; p=0.002 and p=0.035), with CCC more similar to expert readers. While image registration QIB did not differ from RECIST in association with RFS, registration-based QIB predicted OS with significantly higher C-index (ΔV: 0.58 [0.56-0.60], p<0.001; ΔB: 0.64 [0.62-0.66], p<0.001) than RECIST (0.50 [0.45-0.55]) among experts. Conclusions: Longitudinal registration of the pancreas yields more consistent QIB for PDAC TR with stronger association to OS outcomes than RECIST. These registration-based QIB aim to advance PDAC management by improving patient-specific discrimination of TR after NAT. [Table: see text]
Tumor immune microenvironment of KRAS G12C mutated pancreatic cancer as compared to other mutations and non-cancer pancreata.
Authors: Sahai Vaibhav , Gunchick Valerie , Paul Simi , Enzler Thomas , Zalupski Mark , Frankel Timothy
Published: January 2024

704

Background: KRAS G12C mutation occurs in approximately 1% of pancreatic ductal adenocarcinoma (PDA). KRAS G12C inhibitors have a reported response rate of 21-33% in patients with previously treated advanced PDA. KRAS is a known modulator of the tumor immune microenvironment (TME) and a greater understanding of the TME in KRAS G12C as compared to other mutations is crucial for developing rational therapeutic combination strategies in PDA. Methods: We performed multiplex fluorescent immunohistochemistry (mfIHC) on tissue obtained from patients with histologically confirmed PDA (KRAS G12C n=8; other mutations n=108) and normal pancreas (n=38). Serial staining was performed using antibodies against CD3, CD8, CD163, FoxP3 and PanCK for simple and complex phenotyping as well as spatial analyses in the TME. After tyramide based signal amplification, the slides were imaged at 20x magnification using the Mantra Quantitative Pathology workstation. Images were analyzed using inForm Cell Analysis software (Akoya Biosciences). All statistical analyses were performed using JMP Pro 13.2.0. Differences in phenotype, distances, and engagement were evaluated by 2-tailed Student’s t test or ANOVA. Results: Patients with KRAS G12C mutation had a median age of 70 (45-73) years of which majority (n=5, 62.5%) were men with advanced stage at diagnosis (n=6; 75%). The median overall survival is not yet reached (n=5, alive) after a median follow-up time of 14.4 months through reverse censoring methodology. When examining cellular infiltration, CD8+ cytotoxic T lymphocyte cells were significantly more abundant in the G12C TME compared to the cancer and non-cancer controls (p <0.01). Additionally, the relative frequency of CD4+ and Tregs (CD3+/CD8-/FoxP3+) were also significantly higher in G12C (p<0.01). The percentage of CD163+ antigen presenting cells (APCs) out of all cells was significantly higher in G12C (p<0.01) while the percentage of non-functional APCs (PDL1+/CD163+) of all APCs was significantly higher in G12C than cancer and non-cancer controls (p=0.03). In comparison, the PDL1+ epithelial cells were much lower in G12C TME (p<0.01). The cellular engagement and interaction data from the spatial analysis in the TME will be presented at the meeting. Conclusions: We identified increased infiltration of cytotoxic T lymphocytes and APCs in PDA patients with KRAS G12C mutations relative to other mutations and non-cancerous pancreata. Furthermore, while all PDAs had elevated PD-L1 expression on APCs, KRAS G12C tumors had minimal expression on epithelial cells suggesting a mutation specific impact and a potential role of immune checkpoint inhibitors in combination with G12C inhibitors.
Colorectal Cancer Alliance: Promoting prevention and early detection with screening navigation and a personalized recommendation via a digital screening quiz tool for colorectal cancer.
Authors: Newcomer Kim , Guevara Alex , Pearson Marianne , Hall Lisa
Published: January 2024

71

Background: Evaluating the effectiveness of a Colorectal Cancer screening navigation model delivered in a digital platform offered by a patient advocacy organization. Designed as a digital screening quiz tool and live navigation to promote CRC screening, the Colorectal Cancer Alliance’s Screening Quiz is a risk stratification tool that connects respondents to live certified cancer care navigators delivering evidence-based interventions to increase CRC screening, education and patient and family support. The framework utilizes small and mass media, one-on-one education and patient navigation services to help address and reduce barriers to care. Critical interventions which research shows that on-time screening for CRC leads to better outcomes. Methods: The Screening Quiz has been promoted through social sharing, community outreach, media, including influencer campaigns to increase outreach to at-risk communities. Questions assess personal and family history, hereditary syndromes, and demographics to provide a CRC screening recommendation based on current USPSTF guidelines. Respondents overdue for screening who opt in, are triaged to the Alliance’s patient navigation team for follow-up. This interaction includes phone calls and emails for symptomatic individuals or at high risk for CRC, telephonic and email for average-risk uninsured, and emails for average-risk insured. At-risk individuals are connected to resources, such as financial assistance, free at-home screening tests, and colonoscopy scheduling services. Results: July 2022 to August 2023, the Screening Quiz provided over 30,000 screening recommendations. The median age of respondents was 48; 33% of the respondents were between the ages of 45 to 64. Of the respondents, 29% were male and 71% were female. Most were White (74.3%), but nearly half of those who opted into navigation identified as BIPOC, including 14.4% Black/AA, 17.8% Hispanic or Latino, 7.7% Asian, and 2.5% AI/AN. Most respondents were symptomatic (65.5%) but 7.3% were asymptomatic high-risk. These two groups represented 88% of 1,851 respondents triaged to patient navigation. Conclusions: This digital screening tool and live navigation framework may serve as a key solution in driving CRC screening compared to other interventions. Providing access to live navigation, educational resources, and support services for CRC screening and diagnosis.The Alliance is uniquely positioned with its national network of volunteers, partners, and community presence to effectively reach at-risk communities. Aligning with the science of evidence-based interventions, the Alliance will continue to leverage the Screening Quiz in partnership with healthcare and community stakeholders to close Colorectal Cancer screening gaps.
Multicenter clinical validation of GutSeer: A cost-effective, blood-based assay for early detection and localization of major gastrointestinal cancers.
Authors: Chen Wanqing , Xia Changfa , Ma Chengcheng , Liu Yiying , Xu Minjie , Li Wei , Sun Jin , Gong Chengxiang , He Qiye , Zhang Yunzhi , Su Zhixi , Liu Rui
Published: January 2024

739

Background: Gastrointestinal (GI) cancers account for over one-third of cancer-related deaths. We have previously developed GutSeer, a non-invasive assay utilizing cell-free DNA (cfDNA) methylation and fragmentation signatures, to cost-effectively detect and localize five major GI cancers, including colorectal (CC), gastric (GC), liver (LC), esophageal (EC), and pancreatic cancer (PC). Methods: GutSeer was initially developed and validated in a large retrospective cohort of 1844 plasma samples, demonstrating excellent performance with specificity, sensitivity, and tissue of origin (TOO) accuracy at 96.7%, 86.2%, and 82%, respectively. In this study, we conducted a blind, multi-center clinical test for further validation. Participants were recruited from two centers, Beijing (BJ) and Shanghai (SH). Cohort BJ included 42 participants (20 healthy, 22 cancer), and Cohort SH comprised 403 participants (105 healthy, 123 benign, 175 cancer). Over half of the cancer samples in Cohort SH were in early-stage disease (TNM stages I and II). Results: In Cohort BJ, GutSeer showed 100% specificity, 68.2% sensitivity, and 86.7% TOO accuracy. Individual cancer type sensitivities within Cohort BJ were 100% for CC, 57.1% for EC, 75% for GC, 40% for PC, and 100% for LC. In Cohort SH, GutSeer exhibited 94.6% specificity for healthy samples and 86.2% for benign conditions. For cancer samples in Cohort SH, the overall sensitivity achieved 78.9%, with specific sensitivities of 92.3% for CC, 81.0% for EC, 78.4% for GC, 52.9% for PC, and 86.4% for LC. Moreover, GutSeer also efficiently detected early-stage cancers, with stage-wise sensitivities ranging from 64.7% (stage I) to 96.3% (stage IV). TOO accuracy in Cohort SH was 79.0%, with individual cancer types achieving accuracies from 71.7% to 94.7% (72.2% for CC, 71.7% for EC/GC, 94.7% for LC, and 77.8% for PC). Conclusions: GutSeer demonstrates promising potential as a cost-effective, non-invasive test for early detection and localization of major GI cancers. Its consistently high performance in both retrospective and multi-center blind clinical tests implies its potential to revolutionize the screening and diagnosis paradigm for GI cancers.
A review of comprehensive genomic profiling testing in a Japanese single institution.
Authors: Funatsu Nozomi , Takao Misato , Kanemasa Yusuke , Horiguchi Shinichiro , Sadato Daichi , Harada Yuka , Kawai Kazushige , Yamaguchi Tatsuro
Published: January 2024

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Background: In Japan, comprehensive genomic profiling (CGP) testing, including OncoGuide and FoundationOne CDx (F-1), were approved in June 2019 for patients with advanced solid tumors. Here, we report the landscape of CGP testing in our hospital. Methods: This study was conducted with a retrospective design to evaluate the clinico-genomic characteristics of patients who underwent CGP testing. OncoGuide is a panel using matched tumor tissue and blood sample, containing 124 genes, developed by the National Cancer Center. F1 is a tumor-only panel, containing 324 genes, developed by Foundation Medicine Industry. Results: Of the 460 patients enrolled in this study, 376 and 84 underwent F-1 and OncoGuide, respectively. The most common primary tumor was colorectal cancer (93 pts), followed by malignant melanoma (33 pts) and pancreatic cancer (33 pts). Actionable gene alteration was detected in 304 patients (66.1%). The detected actionable genes were TP53 (55.9%), APC (27.8%), KRAS (22.6%), and BRAF (8.5%) in colorectal cancer, BRAF (10.1%), CDKN2A (30.2%), CDKN2B (9.4%), and TERT (33.3%) in malignant melanoma, and KRAS (18.8%), TP53 (54.3%), and CDKN2A (21.8%) in pancreatic cancer. The mean time from sample shipment to result receipt was 42.5 days. As a result of CGP testing, candidate anticancer drugs were found in 304 patients: however, 108 patients were not treated due to poor general condition, complications, or age, which limited access to clinical trials. In germline findings, a pathogenic germline variant of BRCA2 was detected in one patient in OncoGuide, and presumed germline pathogenic variants of MLH1, BRCA2, and PTEN were detected in 1, 13, 26 patients in F-1. Conclusions: In Japan, CGP testing found candidate anticancer drugs, however it requires a significant amount of time to receive treatment because of limiting access to ongoing clinical trials and being typically performed after standard chemotherapy. Therefore, improving access to clinical trials, including determining the timing of testing and selecting appropriate cases, was critical.
Immune-related adverse events in patients with gastrointestinal cancer undergoing pembrolizumab monotherapy: A systematic review of clinical trials.
Authors: Naleid Nikolas , Mears Veronica , Kakish Hanna , Mahipal Amit , Chakrabarti Sakti
Published: January 2024

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Background: Pembrolizumab, an immune checkpoint inhibitor targeting programmed death 1 (PD-1), is widely employed in the treatment of various gastrointestinal (GI) cancers. This systematic review aims to assess the spectrum and incidence of immune-related adverse events (irAEs) associated with pembrolizumab monotherapy in GI cancer patients. Methods: A comprehensive search of PubMed/MEDLINE was conducted to identify full-text articles of clinical trials investigating pembrolizumab monotherapy in GI cancer patients. Two independent authors reviewed the articles and extracted data, with discrepancies resolved by consensus. Primary endpoints included the incidence of grade 3 or higher irAEs and the treatment discontinuation rate due to irAEs. Secondary endpoints encompassed the incidence of any-grade irAEs and specific irAEs such as pneumonitis, colitis, hepatitis, myositis, myocarditis, nephritis, pancreatitis, peripheral neuropathy, skin toxicity, endocrine toxicity, infusion reactions, and deaths. Results: After excluding duplicates and articles not meeting inclusion criteria, data extraction and analysis were performed on 25 selected articles. Common reasons for exclusion included concomitant use of chemotherapy or targeted therapy and trials involving non-GI cancer patients. The analysis included 2866 patients with a median age of 62 years, of which 29% were female. Tumor types included colorectal (13%), esophagogastric (46%), hepatocellular carcinoma (25%), and others (16%). The aggregate incidence of grade 3 or higher irAEs was 8.7%, with reported rates ranging from 3% to 41% across different trials. The incidence of any grade irAEs varied from 39% to 98%. The treatment discontinuation rate due to irAEs was 6.8%. The most common grade 3 or higher irAEs were hepatitis (3.6%), pneumonitis (0.8%), and colitis (0.7%). irAE-related deaths were infrequent (0.9%). Detailed irAE data are summarized in the Table. Conclusions: In GI cancer patients receiving pembrolizumab monotherapy, severe irAEs are rare. Treatment discontinuation and deaths attributed to pembrolizumab-related irAEs are infrequent, underscoring the safety profile of this therapy in patients with GI cancer. [Table: see text]
Efficacy of biomarker-matched therapy in clinical trials for advanced gastrointestinal cancers: A pooled analysis of SCRUM-Japan studies.
Authors: Hashimoto Tadayoshi , Fujisawa Takao , Machida Nozomu , Makiyama Akitaka , Boku Shogen , Kadowaki Shigenori , Takahashi Naoki , Oki Eiji , Morizane Chigusa , Sunakawa Yu , Komatsu Yoshito , Okano Naohiro , Esaki Taito , Ohta Takashi , Kato Takeshi , Ozaki Hiroshi , Iida Naoko , Nakamura Yoshiaki , Bando Hideaki , Yoshino Takayuki
Published: January 2024

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Background: We conduct the SCRUM-Japan MONSTAR-SCREEN, a nationwide molecular profiling project to facilitate the enrollment of patients with advanced solid tumors into matched clinical trials based on identified biomarkers. Here, we investigated clinical outcomes of patients with gastrointestinal cancers in this project. Methods: The SCRUM-Japan GI-SCREEN was launched for gastrointestinal cancers in 2015, followed by GOZILA, MONSTAR-SCREEN-1, and MONSTAR-SCREEN-2 for advanced solid tumors. The used profiling assay for genomic alterations was Oncomine Comprehensive Assay for tumor tissue in GI-SCREEN, Guardant360 for plasma in GOZILA, FoundationOne CDx for tissue and FoundationOne Liquid CDx for plasma in MONSTAR-SCREEN-1, and CARIS MI Profile for tissue in MONSTAR-SCREEN-2. Patients were treated in clinical trials or practice based on identified biomarkers. We analyzed data from patients with gastrointestinal cancers in this project. Results: Of 11,408 patients enrolled in our project as of May 22, 2023, 555 (5.0%) were enrolled in matched clinical trials based on identified biomarkers. The major cancer types that had matched clinical trials included colorectal (63.2%), biliary tract (12.4%), gastric (n=9.2%), esophageal (n=6.5%), and pancreatic cancer (n=4.7%). The objective response rate (ORR), median progression-free survival, and median overall survival (OS) for patients in matched trials were 27.8% (95% CI, 24.0% to 31.9%), 3.0 months (95% CI, 2.8 to 3.7 months), and 14.4 months (95% CI, 13.0 to 16.1). The major treatment lines in which investigational drugs were administered were third (24.6%) and fourth (16.0%) line. Evaluating by each drug target given to at least 20 patients, therapies targeting HER2 had the highest ORR of 46%, followed by PD-1/PD-L1 (33%), BRAF (30%), and MEK (28%). Antibody-drug conjugates demonstrated the highest ORR with 48.8%, followed by monoclonal antibodies at 37.7% and small molecule inhibitors at 23.0%. Overall, patients who received matched therapy in clinical trials or practice had significantly longer OS than those who did not (hazard ratio, 0.76; 95% CI 0.69 to 0.84; P <0.01). Conclusions: Our nationwide molecular profiling project has facilitated the enrollment of patients with advanced gastrointestinal cancers in clinical trials. Furthermore, it demonstrated a survival benefit by providing patients matching targeted therapy.
Role of circulating tumor DNA in metastatic appendiceal neoplasms: A systematic review.
Authors: Shahzad Moazzam , Dineen Sean P. , Ahmed Mamoon , Basharat Ahmad , Khalid Muhammad Fareed , Noor Jawad , Amin Muhammad Kashif , Imanirad Iman
Published: January 2024

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Background: Circulating tumor DNA (ctDNA), tumor DNA fragments detected in blood sourced from primary malignancy, is an emerging non-invasive tool in oncology for screening, diagnosis, and surveillance. Here, we analyze its utility in patients with metastatic appendiceal neoplasms. Methods: Following PRISMA guidelines, PubMed, Cochrane, and Clinicaltrials.gov were searched for ‘Appendiceal Neoplasms’ AND ‘Circulating Tumor DNA’. Four original studies reporting the role of ctDNA in appendiceal cancer were included after screening 195 articles. Results: A total of 196 patients were included in the review. (Table) The total number of collected samples was 209 and 41% were tested positive for ctDNA. Singh et al. 2023 reported eight stage IV appendiceal cancer patients with the median age of 64.5 (45-75) years. 37.5% were tested positive for ctDNA while 37.5% had undetectable ctDNA despite having residual peritoneal disease and 25% had insufficient DNA from tumor specimen. López-Rojo et al. 2020 reported 50% ctDNA positive rate. All included patients had KRAS mutation and received hyperthermic intraperitoneal chemotherapy (HIPEC). On 36.5 months follow-up all the patients were alive but one out of two ctDNA positive patients had a relapse at 39 months follow-up. Kothary et al. 2022 reported 51% ctDNA positivity and 11% had longitudinal ctDNA measurements available which correlated well with their disease course. Zeineddine et al. 2023 collected 160 blood samples from 147 patients. Of 75% with radiographically metastatic disease, 38% had positive ctDNA while out of 25% with no radiographically metastatic disease, 38% had positive ctDNA. The overall survival and progression free survival for ctDNA positive patients was 46.2 months and 60 months, respectively, versus not reached for ctDNA negative patients. When stratified according to tumor grade, the ctDNA detection rate was 22% for well-differentiated, 39% for moderately differentiated, and 49% for poorly differentiated tumors. Conclusions: The use of ctDNA in metastatic appendiceal tumor is not widespread and detection rates are heterogenous. It was observed more in poorly differentiated appendiceal cancers but further studies are needed to evaluate its utility in clinical practice. [Table: see text]