bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic factors, and survival difference in gastrointestinal extrapulmonary small cell carcinoma using SEER database.
Authors: Ulanja Mark Bilinyi , Alese Olatunji B.
Published: June 2022

e16170

Background: Gastrointestinal extrapulmonary small cell carcinoma (GI EPSCCa) is a rare and aggressive tumor. Current treatment guidelines are extrapolated from small cell lung cancer. Factors affecting survival, and the role of primary tumor location are currently unknown. Methods: Using the SEER database to identify patients diagnosed from 2000 to 2018, we used Cox proportional hazard models to assess prognostic factors based on primary tumor location. Results: Of the 1,687 patients included in the analysis, 79.7% were White and 56.9% male. Distribution of the primary location were 31.5% colorectal (CRC), 22.1% Esophagus, 20.6% pancreas, 13.3% hepatobiliary (HB), 10.6% stomach, and 1.8% small intestine (SI). Patients ≥65 years were more likely to have esophago-gastric, SI, HB and pancreatic EPSCCa (P<0.001). Males were more likely to have esophago-gastric, CRC and pancreatic EPSCCa (P<0.001). While Blacks were more likely to have esophago-gastric and SI EPSCCa, Whites were more likely to have CRC, HB and pancreas EPSCCa (P=0.012). There were no racial differences in overall survival (OS) for GI EPSCCa. Male gender (adjusted Hazard Ratio(aHR)=1.12, 95%CI:1.00-1.24, P=0.042), and age ≥65 (aHR)=1.21, 95%CI:1.09-1.35, P=0.001) were associated with inferior OS. Advanced stage at presentation, or not receiving radiation therapy/ chemotherapy were also associated with worse OS. Surgical intervention, and treatment period after 2006 were associated with superior OS (Table) Regarding GI site, HB EPSCCa was associated with inferior OS compared with esophageal EPSCCa (aHR)=1.21, 95%CI:1.00-1.46, P=0.048). SI EPSCCa had a trend toward improved OS (compared to esophageal EPSCCa) (P= 0.237). Conclusions: Chemotherapy, surgery, radiation therapy, female gender, younger age were associated with superior OS for GI EPSCCa, while advanced stage, HB sites (compared to esophageal EPSCCa) were associated with poorer outcome. OS for GI EPSCCa has improved over time. Prospective studies are needed to guide therapy for this aggressive tumor. [Table: see text]
Efficacy and safety of transcatheter arterial chemoembolization in combination with camrelizumab and targeted agents in intermediate-stage unresectable hepatocellular carcinoma: A single-arm, prospective, real-world study.
Authors: Li Jinpeng , Shi Jutian , Song Jinlong
Published: June 2022

e16190

Background: The prognosis for advanced hepatocellular carcinoma (HCC) is still very poor. This study aimed to explore the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with camrelizumab plus targeted therapy for the treatment of patients with advanced HCC. Methods: In this single-arm, prospective, real-world study, patients with intermediate-stage unresectable HCC who had a Child-Pugh score ≤ 7 and had not received prior systemic anti-cancer treatment would receive comprehensive treatment with TACE followed by immunotherapy with camrelizumab 200 mg every 3 weeks plus a tyrosine kinase inhibitor (TKI) agent selected from lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight < 60 kg), sorafenib 400 mg twice-daily or donafenib 200 mg twice-daily until intolerable toxicity or disease progression. During the study treatment, patients assessed as eligible for resection would undergo surgery. The primary endpoint was objective response rate (ORR) assessed by an independent review committee per modified RECIST. Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: From September 2020 to November 2021, 49 patients were enrolled. Among them, 45 (91.8%) patients were male, 41 (83.7%) patients were aged ≤65 years, 30 (61.2%) patients had extrahepatic metastases, and 41 (83.7%) patients had HBV infection. The ORR and DCR were 69.4% (34/49) and 87.8% (43/49), respectively. Five (10.2%) patients were assessed as eligible for surgery, and one of them already received surgery successfully and achieved pathological complete response. The median OS was not reached, and the median PFS was 6.1 months (95%CI, 1.4 -10.8). After 3 months, the alpha-feto-protein decreased compared with before treatment (p < 0.05). All patients had adverse events (AEs) of any grade. The most common AEs were reactive cutaneous capillary endothelial proliferation (30, 61.2%), abdominal pain (25, 51.0%), thyroid dysfunction (20, 40.8%) and fever (18, 36.7%). The majority of treatment-related AEs (TRAEs) were mild or moderate. Grade 3 TRAEs occurred in 3 (6.1%) patients, grade 4 TRAEs occurred in 1 (2.0%) patient, and no deaths occurred. Conclusions: TACE combined with camrelizumab plus targeted therapy in the treatment of advanced HCC shows good efficacy in controlling tumor progression and may provide opportunity of resection. Clinical trial information: ChiCTR2000039508.
Response to systemic treatments in advanced fibrolamellar carcinoma: A French multicenter retrospective cohort of the AGEO.
Authors: Ye-Tran Xixi , Bouattour Mohamed , Perret Audrey , Turpin Anthony , Walter Thomas , Vitellius Carole , Coriat Romain , Lequoy Marie , Blanc Jean Frederic , Regnault Hélène , Pietrasz Daniel , Sefrioui David , Lecomte Thierry , Moati Emilie , Caliez Olivier , Nguyen-Khac Eric , Fresneau Brice , Hautefeuille Vincent
Published: June 2022

e16194

Background: Fibrolamellar carcinomas (FLC) are rare hepatic malignancies affecting young patients without chronic liver disease, often diagnosed at an advanced stage. Few data are available regarding efficacy of systemic anti-tumor treatments. Main objective was to explore response according to RECIST 1.1 criteria in the first line setting in advanced FLC patients. Methods: This retrospective multicentric French cohort included 44 patients with advanced FLC who received at least one systemic treatment and had one morphological evaluation, performed every 2-3 months. Results: Median age at diagnosis was 24 years (range 13-62), 59.1% were female, 38% were at stage IVa (lymph node involvement) and 42% at stage IVb (metastatic involvement). Responses were analyzed in 42 patients, 7 receiving neoadjuvant treatment and 35 patients receiving a first line palliative treatment. There was no complete response, 14.3% (n = 5) had a partial response (PR), 37.1% (n = 13) had stable disease (SD) and 48.6% (n = 17) had progressive disease. GEMOX was the most prescribed regimen (n = 8) with a disease control rate (PR+SD) at 25% (PR = 12.5% and SD = 12.5%). Doxorubicine-platine was the second most prescribed association (n = 5) with a disease control rate at 80% (PR = 40% and SD = 40%). Tyrosine kinase inhibitors, i.e. sorafenib (n = 10) and sunitinib (n = 3) showed no response and a rate of SD of 40% and 33% respectively. The association of doxorubicine-platine plus sorafenib was used in 4 patients, with one PR and three SD. Only one patient received immunotherapy (nivolumab and ipilimumab), but progressed at first evaluation at two months. Median overall survival was 3.3 years. Five years overall survival was 35% (95%CI = 0.23-0.54). Patients who underwent surgery had a better prognosis (55 months vs 15.5 months). Unfortunately, disease relapsed quickly after surgery, with a median relapse-free survival of 11 months. Conclusions: Advanced fibrolamellar carcinomas have a low chemosensitivity to either cytotoxic chemotherapy or tyrosine kinase inhibitors. Larger studies are warranted to define a standard of care for these rare tumors requiring treatment in an expert centre, either with a molecular screening.
Combination of donafenib and anti-PD-1 antibody plus trans-arterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (uHCC).
Authors: Gu Shanzhi , Tan Yulin , Zhou Huan , Hu Hongtao , Zheng Tongsen , Zheng Zhendong , Zhu Xu , Yuan Mu
Published: June 2022

e16197

Background: Donafenib (Dona), a multikinase inhibitor recently marketed in China for advanced HCC with its superiority in overall survival (OS) over Sorafenib from a large head-to-head Phase 3 study. The clinical experience of triple therapy (TKIs + ICIs + TACE) in the treatment of patients (pts) with uHCC is limited. We assessed the safety and efficacy of triple therapy [Dona +anti-PD-1+ TACE] in uHCC in this Phase 1 study. Methods: The objective of this Phase 1, open-label, multicenter, dose-escalation and expansion study was to assess the MTD/recommended dose for Dona in combination of a fixed-dose anti-PD-1 plus TACE in uHCC. The primary endpoint was DLT occurring in the first treatment cycle. Secondary endpoints included the overall safety and tolerability, ORR and PFS by mRECIST. Qualified pts (age 18-75) were enrolled if uHCC without macrovascular invasion (VP3/4) or extrahepatic spread; measurable disease by mRECIST; ECOG 0 to 1; Child-Pugh A; systemic therapy naive. Results: At the cut-off date (Dec 31 2021), data of 25 pts who underwent triple therapy from 6 cancer centers in China were analyzed (Table). The median duration of follow-up was 105 days (1-358 days). No DLTs were observed [Dona 50 mg Bid (n=3); 150 mg Qd (n=3); 100 mg Bid (n=6)]. Additional 13 pts were treated with the recommended dose of Dona 100 mg Bid. Treatment-related adverse events (TRAE) occurred in 24 pts (Grade 3, 36%; no Grade 4). 16 pts had at least one response assessment, the ORR was 62.5%; in 12 pts with BLCL B, the ORR was 83.3%. mPFS was not reached. Conclusions: Combination of Dona, anti-PD-1 and TACE showed a high rate of tumor response and good safety profile in uHCC. Clinical trial information: NCT04605185. [Table: see text]
Effectiveness and safety of retreatment with lutetium Lu 177 DOTATATE in patients with progressive neuroendocrine tumors in the United States: A retrospective real-world study.
Authors: Delpassand Ebrahim , Yazdi Soheil Mohammadi , Ghantoji Shashank , Nakasato Antonio Reis , Strickland Corinne Denise , Nunez Rodolfo , Shafie Afshin , Cork Susan , Byrne Clare , Tang Jackson , Runeckles Kyle , Patel Jeetvan
Published: June 2022

e16215

Background: Advanced neuroendocrine tumors (NETs) are associated with a very poor prognosis. A regimen of 4 doses of lutetium Lu 177 (177Lu)-DOTATATE has been shown to improve both progression-free survival (PFS) and overall survival (OS) in patients with advanced NETs. This is the first United States (US) study to evaluate the effectiveness and safety of additional doses in patients with progressive NETs. Methods: This was a retrospective chart review of 31 adults with advanced NETs who had undergone initial treatment with up to 4 doses of 177Lu-DOTATATE and who, following disease progression and a period of ≥6 months since the end of initial treatment, were re-treated with ≥1 additional dose at a single US center (2010–2020). Patient characteristics, treatment patterns, and clinical outcomes were evaluated descriptively. Response was evaluated according to RECIST 1.1; toxicity was defined using CTCAE 5.0 criteria. Kaplan–Meier plots were used to evaluate PFS and OS. Results: Of the 31 patients who received 177Lu-DOTATATE re-treatment, 19 (61%) were male and 29 (94%) were white. Overall, patients received a median of 6 doses (4 initial doses and 2 re-treatment doses) and the mean±sd administered activity was 41.9±4.4 GBq. Two patients also went on to receive additional re-treatment (1 and 2 doses, respectively) following a second period of ≥6 months and progression after re-treatment. Best responses of partial response and stable disease were observed in 11 patients (35%) and 20 patients (65%) after initial treatment, and 7 patients (23%) and 14 patients (45%) after re-treatment (Table). The median PFS after initial treatment was 20.2 months and after re-treatment was 9.6 months. The median OS after initial treatment was 42.6 months and after re-treatment was 12.6 months. Hematological parameters decreased significantly during both initial and re-treatment but recovered such that there was no significant difference between the values prior to initial treatment and prior to re-treatment. Clinically significant hematotoxicity occurred in 1 and 3 patients following initial and re-treatment, respectively. No grade 3/4 nephrotoxicity (based on creatinine levels) was observed. Conclusions: Re-treatment with 177Lu-DOTATATE after progression appeared to be well-tolerated and offered disease control in patients with progressive NETs following initial 177Lu-DOTATATE treatment.[Table: see text]
Does the primary tumor origin affect the prognosis of patients with gastrointestinal malignancies and peritoneal carcinomatosis?
Authors: Wong Krista Michelle , Patell Kanchi , Ramsawak Seshma , Abuamsha Hasan
Published: June 2022

e16223

Background: Multiple gastrointestinal malignancies have the potential to metastasize in the peritoneal cavity. Peritoneal carcinomatosis (PC) is often associated with disease progression and poor prognosis. However, there has been limited data on the impact of tumor origin on the survival outcomes in patients with PC. We sought to examine the differences in the cancer-specific survival of gastrointestinal malignancies with PC. Methods: We performed a retrospective study of patients ≥18 years of age diagnosed with gastrointestinal malignancies (stomach, colorectal, small intestine, appendix) with PC between 2010-2016 using data extracted from the United States Surveillance, Epidemiology, and End Results (SEER) database. The study endpoint was cancer-specific mortality (CSM). We used the Kaplan-Meier method to evaluate the cancer-specific survival for each primary tumor. Cox proportional hazard regression analysis was used to examine the association between CSM and other patient characteristics. The effects were expressed as hazard ratios (HR) and 95% confidence intervals (CI). Results: We identified 7374 patients who met the inclusion criteria; 2797 (37.9%) with stomach cancer, 3274 (44.4%) with colorectal cancer, 703 (9.5%) with small intestine cancer, and 600 (8.1%) with appendiceal cancer. The median age at diagnosis was 64 (Interquartile Range (IQR), 53-75). Median follow-up was 11 months (IQR 3-22). 3709 patients (50.3%) were female. The majority was White (76.2%). 3942 (53.5%) were married. 5679 (77.0%) were insured. 4343 (58.9%) received chemotherapy and 3682 (49.9%) received surgery. Compared to PC of appendiceal cancer primary, stomach cancer primary had an increased risk of CSM (HR = 4.89; 95% CI 4.23-5.65), followed by colorectal cancer (HR = 2.78, 95% CI 2.41-3.21), and small intestine (HR = 1.17; 95% CI 0.98-1.41). Across all patients, surgery and chemotherapy were associated with a lower risk of CSM. Conclusions: Primary tumor origin significantly affects outcomes of gastrointestinal malignancies with PC. Surgery and chemotherapy were associated with decreased CSM. [Table: see text]
Real-world evaluation of AG plus PD-1 antibody in old patients with advanced unresectable pancreatic cancer.
Authors: Wang Bin , He Zenglei , Xue Liang , Mei Shengmin , Xu Li , Ling Qi
Published: June 2022

e16226

Background: Unresectable pancreatic cancer (PC) is associated with fatal outcomes despite chemotherapy and radiation. PD-1 antibodies might provide favorable long-term survival in combination with chemotherapy according to previous clinical trials and pilot studies. In this study, we conducted a real-world evaluation of PD-1 antibody in old patients with unresectable PC. We also aimed to explore biomarkers for the early prediction of PD-1 antibodies response. Methods: This is a single-arm, single-center, real-world study. Primary Objectives: ORR. Secondary Objectives: DCR, OS, PFS, Safety(CTCAE). Exploratory Objectives: The alteration of molecular biomarkers to PD-1 antibodies treatment including IL-2, IL-4, IL-10, IL-16, TNF¦Á and IFN-¦Ã, ect. Key eligibility criteria: Histopathologically confirmed advanced unresectable PC; Without systematic treatment; ¡Ý60 years old; ECOG PS 0 or 1; Evaluated by mRECIST PD-1 plus AG, Q3W Surgery Until disease progression, unacceptable toxicity, or up to 2 years. Results: From Jan 2021 to Dec 2021, 10 unresectable PC patients were enrolled in Yuhang campus, the first affiliated hospital, Zhejiang university school of medicine, which their baseline characteristics were listed in Table. A total of 9 patients were finally included and analyzed. Clinical decisions were made by multi-disciplinary team. The treatment efficacy was evaluated by mRECIST. A total of 9 patients were assessable for response. ORR was 33.3%, with 3/9 partial response (PR). 5/9 patients were stable disease (SD), and DCR was 88.9%. Conversion therapy uses rational immunotherapy and chemotherapy and so on combined with MDT assessment to translate initial unresectable case to resectable one, which obviously prolongs survival time and improves quality of life. For patients with surgically unresectable PC 2 patients were successfully transformed. The rate of overall surgical conversions was 22.2%. The most common adverse events were anemia (6 [60%] patients). There were no treatment-related level 4 and 5 adverse events. There was no treatment-related cardiotoxicity. No patients were interrupted due to adverse events. Conclusions: PD-1 antibody plus Chemotherapy demonstrates significant clinical activity and favorable tolerability in old patients with advanced unresectable PC, and DCR was 88.9%.[Table: see text]
Adherence to genetic testing guidelines in pancreatic cancer and impact on treatment.
Authors: Crowley Fionnuala , Rudshteyn Michelle , Gandhi Sonal , Wotman Michael , Sehmbhi Mantej , Cohen Deirdre Jill
Published: June 2022

e16238

Background: NCCN June 2019 Guidelines recommend that clinicians consider germline (GL) testing for patients(pts) diagnosed with pancreatic cancer (PDAC) and consider molecular analysis of tumors in pts with metastatic disease. Up to 25% of advanced PDAC pts have GL or somatic mutations in the DNA damage repair (DDR) pathway which are predictive of response to platinum chemotherapy (plat) and maintenance therapy with olaparib. Referral for genetic testing (GT) at our institution is currently made at provider discretion. We aimed to determine rates of GT, factors associated with GT, and outcomes of those tested. Methods: Frequency of GT testing was examined in pts with non-endocrine PDAC and >2 visits between 6/2019 and 6/2021 at Mount Sinai Health System. Clinicopathological variables and treatment outcomes were also recorded. Results: 149 pts were included. 71 pts (48%) were male. 25 pts (17%) had a personal history of cancer and 8 (5.3%) with history of DDR related cancer (prostate, breast, ovarian). 66 pts (44%) had GL testing: 42 (28%) at diagnosis with the remainder later in treatment. The rate of GL testing increased every year: 33% (2019), 44% (2020), 61% (2021). There was no statistically significant association between decision to do GL testing and age, ECOG, race, personal or family history (FH) of cancer. A FH of DDR related cancer was positively associated with GL testing (47% vs 27% p=0.039). 8 pts (12% of pts tested) had pathological gMut: BRCA1 (1), BRCA2 (1), ATM (2), PALB2 (2) , NTHL1 (1), both CHEK2 and APC (1). 6 pts (75%) had GL testing at diagnosis. One g BRCA2 pt had a plat response. Neither g BRCA pt received a PARP inhibitor. 24 pts in total had a response to plat, 16 (67%) of whom had GL testing. 94 pts (63%) had molecular tumor testing (including 65% of pts with metastases). Pathogenic mut in DDR genes were identified in 9 pts: ARID1A (2), BRCA2 (3), ATM (2), PALB2 (2), CHEK2 (1). Four of these pts had corresponding gMuts. One pt with somatic ATM mut had g BRCA1 mut. Two pts with BRCA2 somatic mut did not have GL testing. Conclusions: GT based on provider discretion resulted in suboptimal rates of GL testing. However, since inception of national guidelines, testing rates nearly doubled. Rates of GL DDR mutations were lower than previously reported, with varying response to plat in this cohort. Future studies are needed to understand barriers to GT and improve implementation.[Table: see text]
A peptide fused to CLDN18.2 antibody targeting the tumor antigen associated CD8+T cells for the treatment of pancreatic cancers.
Authors: Liu Jiajian , Luan Y. , Deng H. , Wang F. , Wang C. , Zhang Z.
Published: June 2022

e16240

Background: PD-1/PD-L1-targeted immunotherapies have become critical roles in the treatment for many tumors. However, there is limited progress in gastrointestinal cancers, especially in pancreatic ductal adenocarcinoma (PDAC). PDAC is low immunogenicity. PDAC microenvironment is immunosuppressive. More than 70% PDACs have few or no CD8+ T cells around the tumor cell or in the tumor microenvironment. Therefore, immunotherapy like PD-1/PD-L1 antibody alone is rarely effective for PDACs. Methods: Some cytokine or analogs may activate CD8+ T cells. An analog specifically activating tumor antigen associated (TAA) CD8+ T cells was fused to anti-CLDN18.2 antibody. Results: The specific bi-functional molecule (Bis2) has high affinity to human anti-CLDN18.2 (14pM) and CD8+T cells. Bis2 shows significant in vivo efficacy at 0.1 mpk. The efficacy lasts for more than 24 days, only given two doses at day 1 and day 3, respectively. IHC shows that the tumor infiltrated CD8+T cells significantly increased and IFNγ secretion enhanced as well. The IHC results are consistent with the mechanism that Bis2 induces TAA CD8+ T cell proliferation and prevents CD8+T cells from IFNγ-mediated apoptosis. Moreover, Bis2 also shows 100% tumor inhibition in combination with either chem (L-OHP+5FU) or PD-1 antibody in vivo which is better than chem in combination with PD-1 antibody. Bis2 also shows 60% tumor inhibition at 1mpk in CLDN18.2 negative cell based in vivo model. Bis2 shows ADA in monkeys in two weeks by dosing weekly. The repeated doses toxicity study shows an increase of MONO and %MONO and decrease in RBC, HGB, HCT, and MCHC. The HNSTD was 3mpk. The T1/2 was 40h. Conclusions: The Phase I study in advanced solid tumors is ongoing. The study uses accelerated titration starting from 0.01mpk combined with a BOIN design, maximum patient size of 36. In the expansion part, two cohorts of 10 CLDN18.2+ pancreatic cancer patients are planned for the treatment of Bis2 alone or Bis2 in combination with chemotherapy, respectively.
Application of XCELSIOR, a nationwide real-world observational research protocol, to identify efficacious targeted therapy regimens in advanced pancreatic adenocarcinoma.
Authors: Stuhlmiller Timothy Joseph , Wasserman Asher , Cole Zachariah , Kesari Santosh , Shapiro Mark
Published: June 2022

e16245

Background: The proliferation of multi-omic diagnostics, highly selective targeted therapies, multi-modal immunotherapies, and personalized vaccines has yielded many promising novel combination regimens. Still, many patients with advanced cancer are left without clear options because the clinical efficacy of these regimens is based on anecdotal evidence as collective learning from real world practice is uncoordinated across the US. XCLESIOR ( NCT03793088 ) is a nationwide observational research protocol designed to efficiently gather, centralize, and standardize electronic medical records from any institution in the country, permitting complete longitudinal histories to be compiled for individual patients and analyzed on aggregate. Methods: Patients with pancreatic carcinoma were e-consented to XCELSIOR and real world data was entered into a 21 CF Part 11-compliant database and source-verified from raw electronic medical records generated in the standard practice of medicine including physician clinic notes, radiology reports, lab testing values, and genomics reports. Time-on-treatment and overall survival (OS) were calculated for cohorts based on treatment regimens containing chemotherapy, immunotherapy, or molecularly-targeted therapy. Results: As of February 1st, 2022, a total of 330 patients (pts) with pancreatic carcinoma had consented to XCELSIOR representing 199 institutions or oncology practices. 195 pts with metastatic pancreatic adenocarcinoma had longitudinal data structured and suitable for analysis at time of writing. Median follow-up from diagnosis was 1.3 years. The most prevalent treatment regimens were FOLFIRINOX (154 pts) and gemcitabine/nab-paclitaxel (139 pts). 28 pts were treated with targeted therapies and had significantly longer OS than pts that were never treated with targeted therapies (2.6 vs. 1.1 years median OS). Targeted therapies were most commonly employed at 3rd line (15/28) and 4th line (7/28), suggesting they benefitted pts following SOC chemotherapeutic regimens. Molecular targeted therapies utilized included primarily PARP inhibitors, MAPK pathway inhibitors, and HER2-targeted therapies. Time-on-treatment for FOLFIRINOX was median 105 days (generally 1st line), for gemcitabine/nab-paclitaxel was median 143 days (generally 2nd line), and for all targeted therapies was median 106 days. Conclusions: XCELSIOR is an efficient nationwide observational research protocol designed to aggregate, structure, and analyze longitudinal clinical data. Application of this virtual platform to an emerging metastatic pancreatic adenocarcinoma dataset suggested biomarker-based molecular targeted therapies utilized at 3rd and 4th line have the potential to be efficacious. Further stratification and analyses will be performed as the data matures. Clinical trial information: NCT03793088.
Survival outcomes amongst patients with new onset diabetes preceding the diagnosis of pancreatic adenocarcinoma: Multicenter retrospective study.
Authors: Mohindroo Chirayu , Dy Paul Stendahl , Hande Suraj , Mavanur Arun A. , De Jesus-Acosta Ana , McAllister Florencia , Thomas Asha
Published: June 2022

e16251

Background: In patients (pts) with new-onset diabetes (NOD) above the age of 50 years, 1% are diagnosed with pancreatic adenocarcinoma (PDAC) within three years. Based on this, NOD has been proposed as an important factor for early diagnosis of PDAC. Research has been directed towards investigating NOD vs Type 2 diabetes and association with PDAC. Limited data exists on its impact on the survival outcomes amongst PDAC pts. Methods: We retrospectively analyzed clinical data of 150 pts diagnosed with a pancreatic mass at three hospitals from 2014 to 2021. NOD group consisted of pts diagnosed with Diabetes or Pre-Diabetes defined as HBA1c > 6.5% and 5.7-6.4%, respectively, within the three years prior to PDAC diagnosis. Primary aim of the study was the characterization of the impact of NOD on clinical outcomes. Results: 83 pts [mean age 68.32 yrs, 58% males, 61% white] were identified with biopsy proven PDAC, out of which, 9 (11%) pts had pre-existing Diabetes, 21 (25%) pts met the criteria for NOD group. In the NOD group whose weight was available (n = 15), 11 pts (79%) had experienced weight loss within one year of the NOD diagnosis with a median age of 68.46 yrs. No significant differences were noted between race (P = 0.36), age (P = 0.9), sex (P = 0.9), tumor location (P = 0.17), and chemotherapy received (P = 0.9) between the two groups. When comparing survival outcomes, no significant differences were noted in the metastatic cohort (n = 42, PFS HR 0.77, P = 0.4, OS HR 0.9 P = 0.7) including in the subgroup analysis for pts receiving FOLFIRINOX n = 20, PFS HR 0.59, P = 0.28, OS HR 0.66 P = 0.4) or Gemcitabine based treatment (n = 9, PFS HR 1.31, P = 0.7, OS HR 0.46 P = 0.3). In the resected cohort (n = 20), pts in the NOD group did worse than pts who did not meet the criteria with PFS 10 months vs. 18.3 months (P = 0.0058, HR 7.78), a similar trend was noticed in the OS 15.2 months vs. 28.2 months (P = 0.08 HR 2.98), but it did not reach statistical significance. Conclusions: Consistent with current literature, NOD preceding PDAC is distinct from Type 2 diabetes associated NOD, characterized by weight loss and occurring at a later age. Pts with NOD preceding PDAC were shown to have worse survival outcomes in the resected cohort. Larger studies need to be conducted in this context as this could have significant implications for PDAC screening and treatment.
Neoadjuvant modified FOLFIRINOX or gemcitabine-nab paclitaxel followed by stereotactic body radiotherapy (SBRT) for patients with locally advanced pancreatic cancer and borderline pancreatic inoperable cancers.
Authors: Paluri Ravi Kumar , Manne Upender , Reddy Sushanth , Posey James , Williams Grant Richard , Gbolahan Olumide B. , Bae Sejong , Jacob Rojymon
Published: June 2022

e16253

Background: We conducted a single center safety and feasibility trial to investigate feasibility and antitumor activity of sequential FOLFIRINOX or Gemcitabine-nab Paclitaxel (GnP)and Stereotactic Body Radiotherapy (SBRT) in patients with locally advanced pancreatic cancers (LAPC). Methods: Patients with biopsy proven LAPC treated between June 2017 and August 2020 were included. Patients received two months of neo-adjuvant chemotherapy with 4 cycles of FOLFIRINOX or two cycles of GnP followed by SBRT (5 fractions/6.6Gy), total 33gy over 5 days, if no tumor progression after the initial chemotherapy was observed. Patients were reassessed for resectability after SBRT. If unresectable, they were continued on systemic therapy. Primary outcome was safety measured by proportion of grade 3/4 adverse effects. The study is registered with, and is completed. Results: Twenty-five patients enrolled were treated with FOLFIRINOX (n = 16) and GnP (n = 9). Seven (28%) patients did not receive SBRT, due to disease progression (n = 6) after initial systemic therapy, and patients’ preference (n = 1). Eighteen (72%) patients received the SBRT. Thirty-five grade 3 or 4 adverse events were observed with FOLFIRINOX and twenty-five with GnP. No grade 3 or 4 adverse events after SBRT. SBRT was administered within two weeks (median 9 days) after completion of neoadjuvant therapy. Five (27%) patients underwent a resection, all resulting in a complete (R0) resection. The patients who underwent SBRT, the Median overall survival (OS) was 28.39 95%CI (26.45 46.75) and progression free survival was 26.45 95%CI 17.25 46.7. The one-year OS and PFS were 78% (95% CI: 52%-93%) and 67% (95% CI: 41%-87%), respectively. Conclusions: Neoadjuvant FOLFIRINOX or GnP followed by SBRT in patients with LAPC is feasible and shows antitumor activity. There were no safety concerns or treatment delays with incorporation of SBRT. Clinical trial information: NCT03600623.
Association of pathologic response and survival after peri-operative therapy in resected pancreatic adenocarcinoma: KU cancer center experience.
Authors: Rozeboom Brett , Martinez Maximillian , Mehta Kathan , Hamza Ameer , Chidharla Anusha , Saeed Anwaar , Al-Rajabi Raed Moh'd Taiseer , Baranda Joaquina Celebre , Kumer Sean , Schmitt Timothy , Lominska Christopher Erik , Hoover Andrew , Akhavan David , Dandawate Prasad , Anant Shrikant , Saha Subhrajit , Tiwari Ankita , Bossmann Stefan H. , Sun Weijing , Kasi Anup
Published: June 2022

e16254

Background: Neo-adjuvant therapy (NAT) and associated pathologic complete response (pCR) rates have correlated with improved survival in resected pancreatic ductal adenocarcinoma (PDAC). In this study, we explored the relationship between pathologic response, peri-operative therapy, and survival, especially the impact of change in adjuvant therapy in patients with no/poor path response to NAT. Methods: Retrospectively reviewed 66 PDAC patients who received NAT ± radiation and underwent resection at KU Cancer Center between 2011-2022. We compared DFS and OS between Path Responders vs Non-Responders based on standard Tumor Regression Scores from pathology reports. A subanalysis was performed in path non-responders based on switch in adjuvant therapy (AT) versus not. Results: Patient characteristics are summarized in the table. Among 66 PDAC patients, 50 (75.8%) achieved a path response (G0-G2), 16 (24.2%) experienced no/poor path response (G3). Of the 50 pts who achieved a path response, 4 (8.0%) had a complete path response (pCR; G0), 5 (10%) marked response (G1), 41 (82%) moderate response (G2). Median DFS (mDFS) was 17.3 months (95% CI: 12.7-22.4) in Path Responders vs 15.9m (95% CI: 9.6-35.8) in Non-Responders [p=0.59]. Median OS (mOS) was 32.9m (95% CI: 23.4-41.5) vs 27.7m (95% CI: 15.2-38.2), respectively [p=0.39). A sub-analysis in the Non-Responders (n=16) based on switch in AT (n=8) vs not (n=3), revealed mDFS 16.4m (95% CI: 9.6-41.8) when AT was switched vs mDFS 11.3m (95% CI: 5.9-16.6) when AT was not switched [p=0.24]; and mOS 30.6m (95% CI: 15.7-60.3) vs 17.2 months (95% CI: 6.7-27.7), respectively [p=0.18]. Conclusions: Our study found no statistical difference in DFS and OS between Pathologic Responders and Non-Responders to neo-adjuvant therapy. However, a sub-analysis within Pathologic Non-Responders revealed a longer DFS and OS after switching adjuvant therapy without reaching statistical significance, likely due to small sample size. Our findings warrant validation in a larger cohort as switch in adjuvant therapy could potentially change the treatment landscape for Pathologic Non-Responders.[Table: see text]
Homologous recombination deficiency (HRD) alterations as a predictor of responsiveness to combination pancreatic cancer in advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Randall Jamie , Cannon Timothy Lewis , Wadlow Raymond Couric , Wang Hongkun , Winer Arthur
Published: June 2022

e16259

Background: Advanced PDAC is associated with a poor prognosis and median survivals of less than one year. FOLFIRINOX and Gemcitabine/Nab-Paclitaxel are both considered standard of care in the first line setting, though there is considerable variability among oncologists regarding sequencing of these regimens. Pre-clinical and clinical data support the use of platinum therapy in HRD+ PDAC, but little is known about how this translates into best practices regarding sequencing of treatment or clinical benefit relevant to Gemcitabine based therapies in this population. Methods: Using the cancer registry and Inova molecular tumor board database, we retrospectively reviewed all patients from January 2015 until November 2021 with unresectable PDAC who had NGS performed and stratified by the presence or absence of HRD mutation. HRD mutations included by BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, ARID1A, FANCA, FANCL. We analyzed for RR to Folfirinox/Folfox and Gemcitabine based therapies, adjusted time to progression on Folfirinox/Folfox (time from first dose of oxaliplatin based combination to first dose of gemcitabine to account for those who stopped oxaliplatin early for neuropathy or received maintenance therapy), and time on gemcitabine based therapy. Results: 142 consecutive patients with advanced PDAC were examined, including 20 with HRD variants. When excluding those who eventually received surgery and those who never received platinum therapy, we were left with 87 (74 in Control and 13 in HRD) for analysis. RR to Folfirinox/Folfox was 60% in HRD+ and 31.25% in control (p = 0.71) (Table). Mean adjusted time to progression on Folfirinox/Folfox was 320.0 days in HRD+ group and 252.9 in the control group (p = 0.57) (Table 2). The time on treatment for gemcitabine based combination therapy was 260.7 in HRD+ and 165.1 in control group. Conclusions: HRD+ patients had longer durations of treatment on both 5-FU based therapy and Gemcitabine based combinations. These data challenges the importance of first line platinum therapy in HRD+ patients, and further exploration should be considered.[Table: see text]
A novel RAS inhibitor for pancreatic ductal adenocarcinoma.
Authors: Arshad Tariq
Published: June 2022

e16263

Background: Pancreatic cancer has a dismal survival rate and no good therapeutic options. Of all types of cancer, it is Pancreatic cancer that is most closely associated with activating mutations in the RAS oncoprotein. Approximately 90% of pancreatic adenocarcinomas carry point mutations activating RAS. Ras directed targeted therapy is the obvious approach to enhancing treatment options for the disease. There is now an FDA approved targeted RAS therapeutic specific to the RAS12C mutant form. However, this particular mutation is uncommon in Pancreatic cancer. Therefore, drugs which act more broadly on RAS are required. There are currently no approved pan-RAS inhibitors. We have developed a small molecule pan-RAS inhibitor which binds directly to all forms of RAS. It acts to block the ability of RAS and to bind and signal through its effectors. It is active in vitro and in vivo against multiple models of pancreatic cancer. Methods: In silico screening of a virtual compound library was performed to identify an initial candidate inhibitor. Iterative rounds of Medicinal Chemistry informed by structural modeling and bioassay in 3D vs 2D growth assays were performed to identify an enhanced activity derivative. Target binding was confirmed by Microscale Thermophoresis and NMR. RAS/RAF complex status was measured by co-immunoprecipitation of the endogenous proteins. Ras signaling was assayed by Western analysis of Phospho-ERK and RAL-GTP pull down assays. In vitro activity was measured using 3D soft agar assays. In vivo activity was measured by ip or po administration against pancreatic tumor cell line xenografts and pdx systems. Results: The current lead, designated RAS-F binds all three main isoforms of RAS at low uM kd and modulates the RAS effector domain in NMR studies. It suppresses RAS signaling pathways in transient assays and suppresses pancreatic tumor cell growth in soft agar with IC50s below 500nM. It suppresses xenograft development of human and mouse RAS driven pancreatic tumor cell lines and reduces the growth of a pancreatic cancer pdx. Conclusions: We have developed a pre-clinical pan-RAS inhibitor that is active in vitro and in vivo against pancreatic cancer models. Funding: NIH 5U01HL127518-03, Kentucky Lung Cancer Research Program (GJC), Qualigen Therapeutics LLC.
Deep learning on time series laboratory test results from electronic health records for early detection of pancreatic cancer.
Authors: Park Jiheum , Artin Michael , Lee Kate E , Pumpalova Yoanna S , Ingram Myles , May Benjamin , Park Michael , Hur Chin , Tatonetti Nicholas
Published: June 2022

e16268

Background: Pancreatic cancer (PC) has a uniquely poor survival rate due to the absence of proven and effective methods for early detection. We thus aimed to leverage recent advances in deep learning towards the task of inferring early risk of PC from longitudinal laboratory test data contained within Electronic Health Records (EHR) data. Methods: In this study, we develop a novel deep learning framework for incorporating longitudinal clinical data from EHR to infer risk for PC. This framework includes a novel training protocol, which enforces an emphasis on early detection by applying an independent Poisson-random mask on proximal-time measurements for each variable. Data fusion for irregular multivariate time-series features is enabled by a “grouped” neural network (GrpNN) architecture, which uses representation learning to generate a dimensionally reduced vector for each measurement set before generating a final prediction. These models were evaluated using EHR data from Tripartite Request Assessment Committee (TRAC). Results: Our framework demonstrated better performance on early detection (AUROC 0.671, CI 95% 0.667–0.675, p < 0.001) at 12 months prior to diagnosis compared to a logistic regression and a feedforward neural network baseline (black-box model). We demonstrate that our masking strategy results greater improvements at distal times prior to diagnosis, and that our GrpNN model improves generalizability by reducing overfitting relative to the feedforward baseline (Table). The results were consistent across reported race. Conclusions: Our study presents new approaches for integrating multimodal longitudinal clinical data with bias reduction strategies which results in improved early detection of PC. This study demonstrates for the first time the utility of multivariate time series laboratory test results for early detection of PC. Our proposed algorithm is potentially generalizable to improve risk predictions for other types of cancer and other diseases where early detection can improve survival. We split data into train set (80%) and hold-out set (20%) and presented mean AUROC and AUPRC with 95% confidence intervals.[Table: see text]
Metabolomics in advanced pancreatic cancer (PC) patients (pts) achieving weight stability on enteral feeding for cachexia.
Authors: Akinsola Rasaq , Muranaka Hayato , Hendifar Andrew Eugene , Osipov Arsen , Moshayedi Natalie , Thomassian Shant , Stotland Aleksandr , Parker Sarah , Van Eyk Jennifer , Devkota Suzanne , Bhowmick Neil , Gong Jun
Published: June 2022

e16291

Background: We previously showed that enteral feeding was associated with weight stability and compositional changes in the gut microbiome with increased abundance of the gram-negative genera Veillonella over time. Here, we evaluated the potential of plasma metabolites as predictors of weight stability and high Veillonella abundance in enteral fed pts. Methods: The PANCAX-1 (NCT02400398) prospective trial enrolled 31 cachectic advanced PC pts to receive jejunal tube peptide-based diet for 12 weeks (wks) who were planned for standard chemotherapy. In preplanned exploratory analyses, serial blood samples were collected over 12 wks of enteral feeding. Up to 219 plasma metabolites were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by two-sample t-tests. Pts were stratified by weight stable (WS, defined as weight change < 0.1 kg/baseline BMI-unit over 12 wks of enteral feeding) vs. weight unstable (WU) and high (HV) vs. low Veillonella (LV) abundance (defined by dichotomizing at the mean relative abundance in WS pts). Results: Of 31 cachectic pts enrolled into PANCAX-1, a total of 55 blood samples were collected from 28 pts for plasma metabolomics. Out of 16 evaluable pts, 62.5% receiving enteral feeding met the primary endpoint of weight stability at 12 wks. Plasma metabolomics in 10 pts showed that WU pts (n = 4) had significantly decreased levels of essential amino acids (AAs, L-histidine, L-phenylalanine) and non-essential AAs (L-citrulline, L-tyrosine, all p < 0.05) than WS pts (n = 6) at the end of 12 wks of enteral feeding. In 7 WS pts with complete serial sets of blood samples available, enteral feeding over 12 wks was associated with increases in markers of muscle mass (creatinine) but decreases in nucleotide precursors (all p < 0.05) compared to baseline. Comparison of baseline metabolites between 6 WS pts with HV and 4 WU pts with LV showed that HV was associated with increases in the nucleotide dCDP and essential AA L-isoleucine but decreased TCA cycle metabolite alpha-ketoglutarate (all p < 0.05). Decreases in lactic acid was observed at 12 wks of enteral feeding in HV pts when compared to baseline (p < 0.05). Conclusions: Our findings are hypothesis-generating in that metabolites unique to weight stability and Veillonella abundance may inform future studies of anti-cachexia therapies involving enteral feeding or microbial modulation.
The mutational pattern of DNA damage repair pathway in pancreatic cancer patients.
Authors: Song Yanfang , Wang Huina , Liu Huanhuan , Zhang Yanrui , Li Mingwei , Lou Feng , Cao Shanbo
Published: June 2022

e16293

Background: Besides BRCA1/2, there are various genes involved in DNA damage repair that could predict patients’ response to treatments such as platin-based therapy, PARP inhibitors, and immunotherapy. While the mutational pattern of DNA damage repair (DDR) gene alterations in pancreatic patients remains unknown. Methods: Tumors and blood samples from 490 pancreatic patients were analyzed with next-generation sequencing (NGS) that covered 808 genes. Patients were classified based on the presence or absence of deleterious mutations across a panel of 98 DDR genes. Results: 70.4% (345/490) pancreatic cancer patients harbored DDR gene pathogenic mutations (mut). Among DDR-mut patients, 84.6% (292/345) had only somatic DDR gene alterations, 6.4% (22/345) had only germline DDR gene alterations, and 9.0% (31/345) had both. The most frequently mutated somatic DDR genes were TP53 (73.9%), CDKN2A (17.1%), ARID1A (10.1%), ATM (4.1%), and BRCA2 (4.1%). The most commonly mutated germline DDR genes were BRCA2 (4.1%), RAD51B (2.0%), ATM (2.0%), FANCE (0.9%), PALB2 (0.9%). Among the functional pathways of DDR genes, the most commonly mutated pathways were others (77.2%), FA (10.1%), CCC (7.7%), HR (1.5%), NHEJ (1.4%), MMR (1.4%), and BER (0.8%). No patients were found to harbor mutations in NER, TLS, and DR pathways. In addition, the mean TMB was significantly higher in the DDR-mut group compared with the wild-type DDR (wt) group (6.2 vs. 5.0 muts/Mb; p < 0.05). No significant difference in microsatellite instability was observed between DDR-mut and DDR-wt patients (p = 0.67). In terms of HRD status, 87.5% (28/32) HRD-positive patients and 73.1% (19/26) HRD-negative patients had DDR gene mutations. No significant difference in DDR variants was found between HRD-positive and HRD-negative patients, suggesting that HRD detection is necessary for DDR-mut patients. Within individual DDR genes, CDKN2A mutation was significantly associated with HRD-positivity (p < 0.05) whereas BRCA1, BRCA2, ATM, and PALB2 were not. Conclusions: An expanding set of DDR genes profiling provides more therapeutic opportunities for pancreatic patients who might benefit from PARP inhibitor owing to pathogenic mutations in DDR genes. This retrospective study may serve as a benchmark for the future design of an expanded association study between DDR mutations and the therapeutic outcome of pancreatic cancer.