bluuebunny/crossref_metadata_2025 huggingface dataset:
Early experience of combining immune checkpoint inhibitor and radiotherapy in heavily pretreated hepatobiliary cancer.
Authors: Kim Yong Tae , Lee Byung Min , Seong Jinsil
Published: January 2022

457

Background: Promising therapeutic results of immune checkpoint inhibitor (ICI) have been reported in various solid tumors. Radiotherapy (RT) is known to enhance the immunogenic effect. The immunogenic effect of RT is expected to improve the therapeutic effect of ICI. In this study, we aimed to investigate the efficacy and toxicity of combining ICI and RT in hepatobiliary cancer. Methods: Patients who received RT and ICI combination therapy for hepatobiliary cancer from January 2020 to April 2021 were retrospectively reviewed. Baseline patient characteristics such as age at diagnosis, stage, previous treatment, radiation dose, tumor volume, and lymphocyte count were recorded. The primary endpoints were in-field and out-field control rate. The secondary endpoint was treatment-related toxicities. Overall survival and progression-free survival were also evaluated. The disease control rate and survival were assessed using the Kaplan-Meier method. Results: In total, 17 patients and 35 treated lesions were included for analysis. The median follow up period was 5.5 months (range 2.4 – 19.8 months). Of the 17 patients, 14 were diagnosed hepatocellular carcinoma (82.4%). Twelve patients had distant metastasis (70.6%). Various treatments were administered to the patients prior to ICI and RT combination treatment. The 6-month overall survival and progression-free survival was 62.7% and 26.5%, respectively. The 6-month in-field control rate was 67.4% and 6-month out-field control rate was 26.6%. Higher BED (≥ 90 Gy) was a significant prognostic factor for both in-field and out-field control, and lymphopenia (≤ 800 /μL) at the time of RT start was a poor prognostic factor for outfield control. Fractional dose of less than 5 Gy showed improved in-field and out-field control. Treatment related toxicity occurred in 10 patients (58.8%). The most frequent adverse event was GI disorders such as esophagitis (n = 3) and epigastric pain (n = 3). Patients who experienced treatment-related toxicity were well recovered after conservative care. There was no grade 3 or 4 toxicity. Conclusions: The combination of ICI and RT showed substantial efficacy with acceptable toxicity in heavily pretreated advanced hepatobiliary cancer patients. Dose per fraction of less than 5 Gy may be appropriate for better efficacy in future study of combining ICI and RT. The results of this study provides a basis for future prospective study in hepatobiliary cancer.
Safety and dose-escalation study of a targeted oncolytic adenovirus, suratadenoturev (OBP-301), in patients with refractory advanced liver cancer: Phase I clinical trial.
Authors: Heo Jeong , Liang Ja-Der , Kim Chang Won , Woo Hyun Young , Shih I-Lun , Su Tung-Hung , Lin Zhong-Zhe , Chang Stanley , Urata Yasuo , Chen Pei-Jer
Published: January 2022

459

Background: Suratadenoturev (OBP-301) is an oncolytic adenovirus that harbors a promoter of human telomerase reverse transcriptase ( hTERT) and is genetically modified to selectively replicate within and then lyse cancer cells. The aim of this study was to assess the safety and optimal dosage for intratumoral (IT) injection of OBP-301 in patients with advanced hepatocellular carcinoma (HCC). Methods: An open-label, non-comparative, phase I dose-escalation trial was performed in 20 patients who had refractory advanced HCC. OBP-301 was administered to the primary tumor using ultrasound guidance. A single IT injection of 1010 virus particles (VP) was administered to patients in the initial cohort (Cohort-1), and the subsequent single-dose cohorts received 1011 VP (Cohort-2), 1012 VP (Cohort-3), and 3×1012 VP (Cohort-4). A multiple dose cohort (Cohort-5) received 2×1012 VP × 3 times every 2 weeks. Each of the single-dose cohorts had 3 patients and there was a single escalating dose of OBP-301 from 1010 to 3×1012 VP. The multiple-dose cohort had 8 patients, and 6 of them received multiple escalating doses of 2×1012 VP ×3 times every 2 weeks. Results: There were 18 males and 2 females, and the median age was 59.39 years (range: 48.4–65.9). Patients had good tolerance of the single dose and multiple-dose regimens, and the maximum tolerated dose (MTD) was more than 6×1012 VP/patient. There was no evidence of toxicity with increasing dose, but there was a greater frequency of treatment-emergent adverse events (TEAEs) in Cohorts 4–5 than in Cohorts 1–3. The most common TEAEs related to OBP-301 were influenza-like illness (30%), pyrexia (15%), and fatigue, decreased platelet count, abdominal distension, and anemia (10% each). The overall intrahepatic mRECIST response occurred in 7 patients (39%) with confirmed stable disease (SD) and 11 (61%) with progressive disease (PD). The best target response occurred in 14 patients (78%) and 4 (22%) of them had PD. There was evidence of OBP-301 replication-dependent dissemination in the blood. Cohorts 4–5 had about 50% greater levels of CD8+ T cells in peripheral blood after OBP-301 injection. Conclusions: Multiple IT injections of OBP-301 are well-tolerated in advanced HCC. Although antitumor activity of the study medication alone would not be demonstrated obviously, SD observed as best local response was higher than as overall response. Improved anti-tumor efficacy can be achieved with adjusting viral injection volume to the target sites as well as with adopting the combination therapy with another immunothrapeutics in further study (JRCT ID: jRCT2033200223). Clinical trial information: NCT02293850.
Transition of the tumor microenvironment with clonal evolution of hepatocellular carcinoma.
Authors: Kanzaki Hiroaki , Ogasawara Sadahisa , Sakuma Takafumi , Fujita Naoto , Kojima Ryuta , Koroki Keisuke , Kobayashi Kazufumi , Nakamura Masato , Kanogawa Naoya , Kiyono Soichiro , Kondo Takayuki , Saito Tomoko , Nakagawa Ryo , Nakamoto Shingo , Muroyama Ryosuke , Chiba Tetsuhiro , Ikeda Junichiro , Ohtsuka Masayuki , Kato Naoya
Published: January 2022

467

Background: The combination of atezolizumab and bevacizumab has become a standard treatment for advanced hepatocellular carcinoma (HCC). The indications for combination immunotherapy, including adjuvant therapy and combination with local therapy, are expected to expand in the future. Although exploring the tumor microenvironment has essential clinical implications in the era of combination immunotherapy, most studies on the tumor microenvironment in HCC are based on the analysis of archival samples at the time of HCC diagnosis. Considering the lengthy clinical course and characteristics of multicentric carcinogenesis, the tumor microenvironment may not be constant, but may differ from that at the time of advanced HCC. The present study aimed to assess the changes in the tumor microenvironment during the evolution to advanced HCC using archival samples and samples obtained prior to systemic therapy from the same patients. Methods: The tumor microenvironment was compared in 20 cases by immunohistochemical analyses of CD8, PD-L1, and VEGF expression. Levels of CD8-positive lymphocytes were defined as the mean number of CD8-positive lymphocytes in the tumor per 1 mm2 and classified as low or high infiltration using the median value. PD-L1 expression was classified as negative (< 1%) or positive (≥1%). VEGF expression was classified as low (< 50%) or high (≥50%). Of the 20 cases, gene expression analysis was performed by the PanCancer IO360 Panel in 14 cases. Results: Approximately 40% of the archived samples were obtained at the early stage. Comparison of the tumor microenvironment between the two time points showed that 35% of the patients changed to CD8-positive lymphocyte high infiltration, 20% to positive PD-L1 expression, and 29% to high VEGF expression. The result of comparing gene profile was different between the archival samples and those prior to systemic therapy in 64% of the patients on the expression heat map. Gene set enrichment analysis showed significant changes in T cell cytotoxicity between the two time points. Conclusions: The tumor microenvironment might not be constant, but may change during the evolution to advanced HCC. In the present study, based on the results of the gene mutation analysis using whole-exome sequencing, we also reported the analyses by carcinogenic patterns such as multicentric occurrence and intrahepatic metastasis.
IMbrave150: Exploratory efficacy and safety in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab beyond radiological progression until loss of clinical benefit in a global phase III study.
Authors: Toh Han Chong , Galle Peter R. , Zhu Andrew X. , Nicholas Alan , Gaillard Vincent , Ducreux Michel , Cheng Ann-Lii , Finn Richard S.
Published: January 2022

470

Background: First-line atezolizumab (atezo) + bevacizumab (bev) has been approved in > 80 countries based on significantly longer survival vs sorafenib (sor) in systemic treatment (tx)–naive patients (pts) with unresectable HCC in IMbrave150 (NCT03434379; Finn NEJM 2020). This clinically meaningful tx benefit was maintained with an additional 12 months of follow-up (Finn ASCO GI 2021). We report the efficacy and safety in pts who received atezo beyond radiological progression until loss of clinical benefit. Methods: Pts were randomized 2:1 to receive atezo 1,200 mg IV + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator (INV). In the presence of clinical benefit, pts with progressive disease (PD) per INV RECIST 1.1 (not at a critical anatomical site) could continue study tx. Pts from the atezo + bev arm who had PD and continued atezo were included. Results: Of the 336 pts who received atezo + bev, 236 had PD, of whom 130 continued atezo (± bev), 60 had other tx, and 46 received no tx on or after first PD. Of the pts who continued atezo, 78% were Barcelona Clinic Liver Cancer (BCLC) stage C and 80% Child-Pugh A5 vs pts receiving other tx (85% BCLC stage C, 72% Child-Pugh A5). Sor (13% and 53%) and lenvatinib (14% and 35%) were the most common other txs received post PD among pts who continued atezo or received other tx, respectively. At clinical cutoff (August 31, 2020), the median number of cycles of atezo received post PD was 5 (range, 1-33) and 41 (32%) pts received ≥ 10 cycles. 60 of 130 (46%) pts who continued atezo died vs 180 of 336 (54%) receiving atezo + bev in the ITT population. See Table for efficacy data from baseline (BL) and PD. Grade (Gr) 3/4 and tx-related Gr 3/4 AEs occurred in 30 (23%) and 21 (16%) pts who continued atezo, respectively. There were 6 (5%) Gr 5 AEs, none tx-related. Conclusions: Atezo + bev is the standard of care for pts with unresectable HCC. In IMbrave150, pts with maintained clinical benefit continuing atezo after PD may have further benefited from staying on tx, although interpretation is limited by selection bias (prespecified criteria excluding pts with loss of clinical benefit). These data suggest that tx with atezo until loss of clinical benefit may contribute to post-PD outcomes. Beyond this exploratory analysis in select pts, the value of tx with atezo beyond formal progression will be assessed prospectively in IMbrave251 (NCT04770896). Clinical trial information: NCT03434379. [Table: see text]
Influence of cirrhosis on outcomes of patients with advanced intrahepatic cholangiocarcinoma receiving chemotherapy.
Authors: D'abrigeon Constance , McNamara Mairead Geraldine , Le Sourd Samuel , Lamarca Angela , Lièvre Astrid , Hubner Richard A , Valle Juan W. , Edeline Julien
Published: January 2022

475

Background: Cirrhosis is a risk factor for intrahepatic cholangiocarcinoma (iCC). However, its impact on the management of advanced disease is not established. Methods: Retrospective analysis of patients (pts) treated with systemic chemotherapy for advanced iCC in the first-line setting at 2 tertiary cancer referral centers, the second center used to validate findings from the first. Cirrhosis was diagnosed based on at least one element among pathological diagnosis, baseline platelet < 150 G/L, portal hypertension and/or dysmorphic liver at imaging. Results: In the first center (n=185), 55 pts (29.7%) had cirrhosis (74.5 % based on pathological diagnosis). Main aetiology of cirrhosis was alcohol for 17 pts (31%), non-alcoolic steato-hepatitis (NASH) for 10 pts (18.2%), and mixed alcohol and NASH for 9 pts (16.4%). 102 (57.0%) pts received gemcitabine-cisplatin, 55 (30.7%) pts received gemcitabine-oxaliplatin, and 11 (6%) pts received gemcitabine, with no difference between cirrhotic and non-cirrhotic pts (p=0.38). Second-line treatment was less frequent in cirrhotic pts (21.8% vs. 50.0%, p=0.001). Cirrhotic pts experienced more grade 3/4 hematologic toxicity than non-cirrhotic pts (38% vs. 20%, respectively, p=0,014), and more grade 3/4 non-hematologic toxicity (28% vs. 15%, respectively, p=0.048). The overall survival (OS) was significantly shorter in cirrhotic pts; median: 9.0 vs. 13.8 months for non-cirrhotic pts (HR = 1.54 [95%CI: 1.09-2.16]; p = 0.014); confirmed on multivariable analysis, adjusted on ALBI-score, ECOG PS, extension of the disease (liver only disease and bilobar) (HR = 1.53 [95% CI: 1.01-2.33]; p=0.046). However, PFS was not significantly shorter in cirrhotic pts: median 9,9 months vs. 11.7 for non-cirrhotics (p = 0.35). In the second center (n=102), similar results were seen: 27 (26.5%) pts had cirrhosis. The cirrhotic pts experienced more grade 3/4 hematologic toxicities than non-cirrhotic pts (55.6% vs. 25.4%, respectively, p=0.005), and more grade 3/4 non-hematologic toxicity (44.4% vs. 12.7%, respectively, p = 0.001). OS was shorter in cirrhotic pts; median 9.1 months vs. 11.7 months for non-cirrhotic pts (HR = 1.81 [95%CI: 1.14-2.87]; p = 0.011). PFS was not significantly shorter in cirrhotic pts: 7.5 months for patients without cirrhosis, and 4.2 months for pts with cirrhosis (p=0.221). Conclusions: Cirrhosis was frequent in pts with advanced iCC, and had a negative impact on patients’ outcomes, with increased chemotherapy-induced toxicity and shorter OS. Formal assessment and consideration of cirrhosis in the therapeutic management should be recommended and could lead to a dose adjustment.
Prevalence of germline mutations and homologous recombination deficiency (HRD) in a real-world biliary tract cancer (BTC) cohort.
Authors: Kelley Robin Kate , Ashok Arya , Mauer Elizabeth , Abdel-Wahab Reham , Azad Nilofer Saba
Published: January 2022

476

Background: Biliary tract cancers (BTC) are a heterogeneous family of cancers including intrahepatic and extrahepatic cholangiocarcinomas (ICC, ECC) and gallbladder carcinomas (GBC). Treatment options remain limited and prognosis is poor for advanced BTC, underscoring the need for early detection and new therapeutic targets. Next-generation sequencing (NGS) studies have identified mutations associated with homologous recombination deficiency (HRD) in up to 25% of BTC patients, but the proportion with germline (GMut) versus somatic (SMut) mutations has not been established. This retrospective study was designed to determine the prevalence of GMut and HRD-associated SMut in a large BTC convenience sample and their association with key clinical parameters. Methods: We retrospectively analyzed de-identified records from 804 BTC patients who received tumor/normal (T/N) matched NGS between 2017-2021 via the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage; full transcriptome RNA-seq). This targeted panel detects single nucleotide variants (SNVs), indels, copy number variants (CNVs), and a selection of rearrangements. Analyses focused on pathogenic/likely pathogenic SMut and CNVs, as well as incidental GMut limited to SNVs and small indels in 50 hereditary cancer genes. HRD-associated GMut and SMut were analyzed across 9 and 18 HRR pathway genes, respectively. Results: We identified a cohort of 804 patients with BTC, composed of ICC (n=499), ECC (n=83), and GBC (n=222). The median age was 66 years; 55% were female; and race was White/Black/Asian in 78%/12%/6%. The prevalence of GMut was 4.6% overall. Subgroup analyses showed GMut in 5% of ICC, 4.8% of ECC, and 3.6% of GBC. For patients <50 years of age at diagnosis, pooled prevalence was 6.1% (n=82) vs. 4.5% (n=641) for age ≥50 years (p=0.6). HRD-associated GMut were present in 3.2%. HRD-associated SMut or CNVs were present in 13%, and showed significant variation across subsite (p=0.002) with highest prevalence in GBC (19%, Table). HRD-associated GMut were identified in ATM (n=8), BRCA2 (n=6), and BRCA1 (n=5). Microsatellite instability was present in 1.4% of samples. Conclusions: A significant proportion of BTC patients harbors potentially clinically-relevant GMut and SMut associated with HRD. Future studies are warranted to define the role of germline testing and to examine the activity of HRD-targeted therapies in BTC patients.[Table: see text]
Perioperative optimization with nutritional supplements in patients undergoing gastrointestinal surgery for cancer: A randomized, placebo controlled feasibility clinical trial.
Authors: Serrano Aybar Pablo Emilio , Parpia Sameer , Simunovic Marko , Duceppe Emmanuelle , Pinto-Sanchez Maria Ines , Bhandari Mohit , Levine Mark Norman
Published: January 2022

482

Background: Nutritional status is a major determinant of outcomes following surgery. Perioperative nutritional supplementation may improve postoperative outcomes, however, studies on the topic have led to controversial results. Methods: Single-centre, feasibility randomized trial among gastrointestinal cancer patients undergoing surgery, comparing perioperative nutritional supplements versus placebo. The supplements included: protein supplementation (preoperative day 30-6), “immunonutrition” (preoperative day 5-1 and postoperative day 1-5), and carbohydrate loading (surgery day). Primary outcome was enrollment fraction (i.e., enrolled/eligible patients). Secondary outcomes were patient compliance with study packages (target > 70% of total packages provided) and 90-day postoperative complication rate, including postoperative infectious complications. A priori, we considered protocol modifications to improve enrollment fraction and compliance. Results: From October 2018 to March 2020, 495 patients were screened, of which, 144 were eligible and 71 were enrolled (enrollment fraction: 49%, 95%CI, 41-57%). Patients did not enroll for various reasons including refusal without reason (n = 33) and too much burden (n = 25). Protocol modifications did not impact enrollment fraction or compliance. Modifications included decreasing the interval from enrollment to surgery from 4 weeks to 2 weeks, and decreasing the complexity and length of the baseline assessment. Median overall compliance was 80%, lower for intervention versus control arm (67% and 87%, respectively). Postoperative complication rates were similar between control (18/31 (58%, 95% CI: 41-74)) and intervention (22/34 (65%, 95%CI 48-79)) arms. There was a trend for lower postoperative infectious rates in the intervention arm (12/34 (35%, 95%CI 22-52)) compared to control (16/31 (52%, 95%CI 35-68)). Conclusions: A trial like this is feasible, with an enrollment fraction of 49% and an overall patient compliance with study packages of 80%. Pilot trial protocol modifications did not increase these proportions. Clinical trial information: NCT03445260.
Early-onset well differentiated pancreatic neuroendocrine tumors: Clinical presentation, pathologic features, and oncological outcomes.
Authors: Pulvirenti Alessandra , Hauser Haley , Le Tiffany , McIntyre Caitlin A. , Reidy Diane Lauren , Wei Alice Chia-chi , Raj Nitya Prabhakar
Published: January 2022

507

Background: Young onset of several gastrointestinal cancers is associated with more advanced disease and poor oncological outcomes, however, this association has not been fully investigated for well differentiated pancreatic neuroendocrine tumors (PanNET). Our study aimed to evaluate clinical and pathological differences as well as disease outcomes between young-onset PanNET (YO-PanNET) and late-onset PanNET (LO-PanNET). Methods: Patients with localized PanNET who underwent surgery at Memorial Sloan Kettering Cancer Center between 2000 to 2017 were identified. Those with hereditary syndromes, metastatic disease, and postoperative mortality were excluded. YO-PanNET was defined as <50 and LO-PanNET >50 years of age at time of diagnosis. Family history, clinical and pathology characteristics, were recorded. Fisher’s exact test was used to detect difference between the age groups. Kaplan-Meier method was used to investigate age prognostic significance. Results: A total of 366 patients were identified, 84 (23%) with YO-PanNET. Compared with LO-PanNET, YO-PanNET were less likely to have a personal history of another cancer (p<0.001) and a first-line relative with cancer (p<0.015). We did not observe any significant differences between YO-PanNET and LO-PanNET with regards to pathology features such as tumor grade (p=0.7), size (p=0.5), nodal metastases (p=0.8), and stage of disease (p=0.7). With a median follow-up of 68 months (range 0-238), 5-year recurrence-free survival was 76% and 83%, and 10-year RFS was 69% and 78%, respectively, in YO-PanNET and LO-PanNET (p=0.12; see Table) with similar 5- and 10-year overall survival (p=0.31). Conclusions: In this large retrospective surgical series, we found that YO-PanNET is not associated with an increased rate of personal or familial history of cancer. Pathological characteristics and long-term oncological outcomes do not significantly differ between YO-PanNET and LO-PanNET. Current efforts include next-generation sequencing analysis in the resected surgical specimens to evaluate for genomic biomarkers of recurrence.[Table: see text]
Temozolomide treatment duration and secondary hematological neoplasms: A review of the literature and implications for patients with neuroendocrine tumors.
Authors: Park Robin , Amin Manik A. , Trikalinos Nikolaos A.
Published: January 2022

510

Background: Evidence-based recommendations for the optimal duration of temozolomide-based treatment in advanced neuroendocrine neoplasms are lacking. Because of the relatively long median survival of NEN and the potential long-term myelotoxicities of temozolomide, suggestions have been made to optimize the duration of temozolomide-based therapy. Here, we have conducted a systematic review of the literature for a descriptive analysis of temozolomide-associated myelodysplasias and leukemias to guide treatment planning. Methods: A database search of PubMed and Embase was conducted to identify case reports and/or case series reporting secondary myelodysplasias or leukemias in the setting of temozolomide therapy. Key data items extracted from the studies were the temozolomide dose and duration, latency to hematologic disorder, type of secondary malignancy and cytogenetics. Reported cases were summarized graphically and descriptively analyzed. Results: A total of 14 studies with 25 patient cases of therapy-related hematologic neoplasms were identified, all of which were case reports or case series. The median treatment duration and cumulative dose were 15 months and 18000 mg/m 2 respectively. Most patients (20/25) were diagnosed on or after 12 months while only one patient was diagnosed before 6 months of treatment. Majority of the patients were diagnosed while still on treatment with temozolomide. Graphically, cases clustered around a cumulative dose of 10,000 to 30,000 mg/m 2 and a latency period of 10 to 40 months which translates to an approximate treatment duration of 12.5 – 37.5 months. Conclusions: Taken together, treatment-related hematologic neoplasms appear to develop beyond the 12-month mark while still on treatment with temozolomide. We suggest an approach to optimizing treatment duration by establishing disease response at 6 months before continuing further treatment and restricting treatment to 12 months or establishing closer vigilance beyond 12 months.
Association between Environmental Quality Index and metastatic pancreatic cancer.
Authors: Ozer Muhammet , Goksu Suleyman Yasin , Khatib Jude , Al Mutar Salwan , Aguilera Todd Anthony , Zeh Herbert , Beg Muhammad Shaalan , Kazmi Syed Mohammad Ali
Published: January 2022

521

Background: Pancreatic cancer ranks as the 3rd leading cause of cancer mortality. Overall more than 50% of patients have metastatic disease at diagnosis. In this study, we evaluated the association between the national level Environmental Quality Index (EQI) and metastatic pancreatic cancer in the US. Methods: Adult patients with pancreatic cancer in the SEER database from 2010-2016 were included in this study. The unknown stage was excluded. Patients were categorized into two groups: metastatic vs. non-metastatic disease. EQI provides county-level environmental quality data from 2005-2010 and presents five domains (built, sociodemographic, air, water, land). EQI was categorized into quintiles, with the 5th quantile representing a poorer environmental quality. We used the multivariable logistic regression analysis to assess the association between EQI quintiles and metastatic pancreatic cancer adjusting by age, gender, and race (White, Black, and Others). In addition, the SEER*Stat was used to evaluate the age-adjusted incidence rate, and the correlation coefficient between EQI domains and incidence rate was calculated. Results: A total of 75,461 pancreatic cancer patients were included; 55% had metastatic disease. In the adjusted multivariable analysis, metastatic pancreatic cancer was associated with poor built EQI (OR 1.06 [1.01-1.11]). Among metastatic pancreatic cancer patients, poor overall EQI was strongly associated with age > 50 years (OR 1.06 [1.01-1.11]) and Black race (OR 1.29 [1.10-1.51]). Lower built EQI domain was associated with > 50 (OR 1.07 [1.02-1.12]) and White race (OR 1.07 [1.02-1.12]). The incidence rate of metastatic pancreatic cancer was positively correlated with total EQI (rho=0.02, p<0.001), sociodemographic EQI (rho=0.23, p<0.001), land EQI (rho=0.14, p<0.001), and air EQI (rho=0.34, p<0.001). Conclusions: Using population-based environmental data, we found built EQI to be associated with metastatic pancreatic cancer. Among metastatic pancreatic cancer patients, total environmental quality was associated with older age at diagnosis and the Black race, while built EQI domain was associated with older age at diagnosis and the White race. Environmental quality was positively correlated with the incidence rate of metastatic pancreatic cancer.[Table: see text]
Large scale proteomics of circulating extracellular vesicles to reveal novel biomarkers for pancreatic cancer.
Authors: Bockorny Bruno , Muthuswamy Lakshmi , Huang Ling , Hadisurya Marco , Tsai Leo , Gill Ritu R. , Wei Jesse , Bullock Andrea J. , Grossman Joseph Elan , Besaw Robert J. , Lim Christine Maria , Narasimhan Supraja , Perea Sofia , Sawhney Mandeep , Tao W. Andy , Freedman Steven , Hidalgo Manuel , Iliuk Anton , Muthuswamy Senthil
Published: January 2022

523

Background: Robust biomarkers are urgently needed to assist in diagnosing pancreatic cancer. Earlier cancer diagnosis could increase survival rates by an estimated 5-fold and more reliable and real-time assessment of treatment effects in patients with cancer could improve quality of life and reduce healthcare costs. Isolation of circulating extracellular vesicles (cEVs) as ‘liquid biopsies’ offers an advantageous approach to diagnose and monitor disease status. Methods: We conducted a comprehensive proteomics study of cEVs from plasma samples to identify EV proteins that may be used as biomarkers for the diagnosis and prognosis of pancreatic cancer. Patients with pancreatic ductal adenocarcinoma (PDAC) of various tumor stages, chronic pancreatitis, intraductal papillary mucinous neoplasm (IPMN), and age-matched controls were enrolled. EVs were isolated directly from plasma samples using the affinity-based EVTrap method then subject to quantitation by liquid chromatography-tandem mass spectrometry. Results: A total of 124 patients (93 with PDAC, 12 with chronic pancreatitis, 8 with IPMN and 11 controls) were included in the discovery cohort. The isolation of EVs with EVtrap allowed the identification on average of 912 EV proteins per 100µL of sample. Principal component analysis of the cEV proteome showed clear separation between PDAC and benign pancreatic diseases. Individuals with IPMN were more closely related to controls, whereas chronic pancreatitis cases were more related to PDAC. At the functional level, we noted that cytokeratin, protein folding chaperons, and actin dynamics regulators were among protein clusters more highly altered in the cEV of patients with PDAC. We further identified new cEV markers associated with metastatic disease, such as PSMB4, RUVBL2, and ANKAR, as well as other EV proteins with strong correlation to prognosis, such as CRP, RALB, and CD55. Finally, we validated a 7-protein PDACEV signature in a validation cohort of 36 separate patients (24 with PDAC, 6 with chronic pancreatitis and 6 with IPMN) which yielded an 89% prediction accuracy for the diagnosis of PDAC. Conclusions: This study provides a valuable resource to the scientific community with a comprehensive catalog of novel proteins on circulating EVs that may assist in the development of novel biomarkers and improve the outcomes of patients with pancreatic cancer.
Pathogenic germline mutations prevalence in Saudi patients with pancreatic ductal adenocarcinoma.
Authors: Algarni Mohammed Ahmed , Alshammari Kanan , Al Olayan Ashwaq , Sabatin Fouad , Mabsout Nadine , Zaher Horya , Shehata Husam , Al Turki Saeed
Published: January 2022

538

Background: While the majority of pancreatic ductal adenocarcinoma(PDAC) cases are sporadic, about 10% related to familial and hereditary component. Multiple studies have shown that germline genetic testing regardless of family history for patients with PDCA is feasible and more likely to identify the carrier of pathogenic mutations. There is no data about the prevalence of pathogenic germline mutations in Saudi population. We aimed to study the prevalence of these mutations in Saudi patient patients with PDAC regardless of the family history of cancer. Methods: By using our cancer genetics database, we analyzed all the confirmed cases of PDAC who were referred to the cancer genetic clinic at King Abdulaziz medical city in Riyadh, Kingdom of Saudi Arabia. Since November 2018, a comprehensive hereditary cancer gene panel (including 70 genes) is offered to all referred PDAC cases regardless of their family history of cancer after obtaining a genetic counselling assessment and an informed consent. Results: Between November 2018 and August 2021, a total of 88 patients with PDAC cases have been tested. The median age was 60 and the majority of patients were males (n=56, 64%). Most of the patients had stage IV disease (n=75, 85.23%). The genetic result was available for 86 patients. Pathogenic variant(PVs) was reported in 8.1% (n=7), variant of uncertain significance (VUSs) was reported in 15% (n=13) while no mutation reported in the rest of the patients. The PVs reported were BRCA2 (n=4), BRIP1 (n=1), PMS1(n=1) and MRE11 (n=1). All the carriers of the PVs had no documented family history of breast, ovarian or pancreatic cancers at the time of genetic counselling. Conclusions: This study confirms the importance of genetic testing in all patients with PDAC regardless of the family history. This is in line with previous studies from other populations. This is the first study from Saudi patients with PDAC and to the best of our knowledge, the first study in Arab population.
Initial observation of contrast profiles for 3D and 2D MRI sequences in MR-guided radiation therapy for locally advanced pancreatic cancer.
Authors: Gill Gobind S. , Hunt Brady , Zhang Rongxiao , Williams Benjamin B. , Thomas Charles R. , Zaki Bassem I.
Published: January 2022

541

Background: MR-guided stereotactic body radiation therapy (MR-SBRT) is a novel method of treating mobile tumors with soft-tissue gating and on-table adaptive planning. In our experience using the ViewRay MRIdian system (VR) for treating locally advanced pancreatic cancer (PA) with MR-SBRT, the true-fast imaging with steady-state free precession (TRUFI) sequences on the VR impart differing intensities for relevant structures seen on the pre-treatment high resolution 3D MRI (3D MRI) versus the real-time 2D cine MRI (2D cine) used for target tracking. Since these variations can confound target tracking selection, we propose that an understanding of the differing contrast profiles could improve selection of tracking structures and optimize treatment delivery. Methods: We retrospectively reviewed both 3D MRI and 2D cine images for patients (pts) with PA (n =20) treated on the VR. At simulation, an appropriate tracking target was identified and contoured on a single 3mm sagittal slice of the 3D MRI. This sagittal slice was directly compared to the registered 7mm 2D cine to identify structures with notable discrepancies in signal intensity. The 3D MRI was then explored in additional planes to confirm structure identities. For quantitative verification of the clinically observed differences, the pixel intensity distributions of 3D MRI and 2D cine DICOM image datasets were statistically compared. Results: In all pts reviewed, arteries (aorta, celiac, SMA) appeared with similar contrast profiles on both images. However, veins (portal vein, SMV) appeared hypointense on 3D MRI but hyperintense on 2D cine. Biliary structures appeared hyperintense on 3D MRI but only mildly hyperintense on 2D cine. The pixel intensity distributions extracted from 3D MRI and 2D cine images were confirmed to differ significantly (two sample Kolmogorov-Smirnov test; test statistic =0.40; p < 0.001). Conclusions: There are significant variations in image intensity between the initial treatment planning 3D MRI and the immediate pre-treatment 2D cine obtained with the VR. Understanding these discrepancies can guide radiation oncologists in choosing optimal tracking targets. Future work will focus on identifying the particular causes and frequencies of target tracking failures and exploring alternative tracking algorithms using artificial intelligence which could ultimately allow for VMAT on the ViewRay system.
Randomized phase II trial of neoadjuvant chemotherapy with modified FOLFIRINOX versus modified FOLFIRINOX and PD-1 antibody for borderline resectable and locally advanced pancreatic cancer (the CISPD-4 study).
Authors: Chen Yiwen , Guo Chengxiang , Bai Xueli , Gao Shunliang , Shen Yan , Zhang Min , Wu Jian , Que Risheng , Li Xiang , Liang Tingbo , Wu Jian
Published: January 2022

562

Background: Neoadjuvant chemotherapy is recommended for BRPC and LAPC planned resection. PD-1 antibody alone was failed in advanced pancreatic cancer, but chemotherapy combined with PD-1 antibody are promising. Methods: This is a randomized, controlled, open-label phase II study including patients with BRPC or LAPC. Modified FOLFIRINOX (mFFX) is used as neoadjuvant chemotherapy. Patients will be randomly allocated into two groups: mFFX group and mFFX plus PD-1 antibody group (PD-1 group). Imaging evaluation will be discussed by the MDT. Surgical resection will be performed if the MDT confirms the resectability. (NCT03983057). Results: From March 4, 2019 to August 1, 2021, 146 patients (62 BRPCs and 84 LAPCs) were enrolled. 115 patients received at least four cycles of therapy. In PD-1 group, irAEs happened in seven patients (9.7%), including rash (3 patients, Grade 1), hepatic AE (2 patients Grade 3, 1 patient Grade 2), renal AE (2 patients, Grade 2), and hyperglycemia (2 patients). Radiological PR were noted in 13.3% patients in mFFX group, and 26.9% in PD-1 group. For BRPC patients, the radiological PR was 13.0% and 36.3%, respectively. The resection rate was similar in two groups (47.4% and 51.7%). R0 resections were performed in 70.3% and 86.6% patients, respectively. For LAPC patients, PD-1 group has a higher resection rate (37.1% vs. 48.0%). The survival data are not mature at present. Conclusions: Modified FOLFIRINOX plus PD-1 antibody is feasible and well-tolerated for BRPC and LAPC patients. The study will be continued and the detailed data will be reported. Clinical trial information: NCT03983057.
A single-center analysis of 30- and 90-day post-pancreatectomy complications in patients undergoing neoadjuvant radiation with EBRT versus MRI-guided SBRT.
Authors: Saad Mariam , Clark Julie , Shah Rupen A. , Siddiqui Farzan , Parikh Parag , Gartrelle Kendyll , Natour Abdul Kader , Khan Gazala , Kwon David S.
Published: January 2022

572

Background: Stereotactic MRI -guided adaptive radiation therapy (SMART) is being investigated for enhanced efficacy in locally advanced, borderline resectable and medically inoperable pancreatic cancer. Traditionally, conventionally fractioned chemoradiation (EBRT) has been used for operable patients. We sought to evaluate whether there would be differences in surgical complications and outcomes in the 30- and 90- day postoperative period in patients who received either neoadjuvant EBRT or SMART followed by definitive surgery. Methods: A retrospective single-center analysis of patients with either resectable, borderline resectable or locally advanced tumors of the pancreas or duodenum, treated with neoadjuvant radiation and surgical management between 2014 and 2021 was performed. Patient demographics and post-surgical complications were collected and stratified according to both treatment arms. The International Study Group of Pancreatic Surgery (ISGPS) classifications were used to define and grade postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE) and postpancreatectomy hemorrhage (PPH). A univariate analysis was done followed by a multivariate analysis. Results: Among the 65 patients (mean age 62.6 years, 46% female) who underwent definitive surgical intervention, 44 (67.7%) received EBRT, and 21 (32.3%) received SMART. Baseline characteristics including age, sex, race, ASA, and Charlson comorbidity index (CCI) scores were found to be similar. On univariate analysis, PPH was significantly higher in SMART (OR, 6.6; 95% CI, 1.2 to 37.3; p = 0.034). After adjusting for confounders on multivariate analysis, it appears there is a trend towards higher PPH in the SMART cohort ( p = 0.052). Conclusions: Neoadjuvant SMART followed by definitive surgery is not associated with worse outcomes in the 30- and 90- day postoperative period vs. neoadjuvant EBRT. Although there was a trend towards PPH on multivariate analysis, further discussion is warranted involving vascular resection, vascular stents and anticoagulation.[Table: see text]
Phase II study of PEGPH20 plus pembrolizumab for patients (pts) with hyaluronan (HA)-high refractory metastatic pancreatic adenocarcinoma (mPC): PCRT16-001.
Authors: Zhen David Bing , Whittle Martin , Ritch Paul S. , Hochster Howard S. , Coveler Andrew L. , George Ben , Hendifar Andrew Eugene , Dragovich Tomislav , Green Steven , Dion Barbara , Stoll-D'Astice Amy C. , Lee Arthur , Thorsen Shelley M. , Rosenthal Adam , Hingorani Sunil R. , Chiorean E. Gabriela
Published: January 2022

576

Background: Stromal HA poses a physical barrier and protects tumor cells from immune surveillance. PEGPH20 is a pegylated, human recombinant PH20 hyaluronidase that remodels tumor stroma. Preclinical studies of PEGPH20 showed improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies. This study aimed to evaluate the efficacy, safety, and translational biomarkers of PEGPH20 plus pembrolizumab in pts with HA-high refractory mPC. Methods: mPC pts with HA-high expression, ECOG PS 0-1, ≤ 2 prior therapies for metastatic disease, life expectancy ≥ 12 weeks were treated with PEGPH20 3 µg/kg iv on D1, D8, D15 and pembrolizumab 200 mg iv on D1 in 21-day cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, overall survival (OS), and objective response rate (ORR). Blood and tumor biopsies were collected at baseline and on-study. Translational endpoints included flow cytometry and IHC for immune subsets, T-cell receptor sequencing, immune transcriptome, circulating cytokines, and plasma and tumor HA levels. Assuming a one-sided α-level of 0.05 and power of 80%, 31 evaluable pts were needed to detect an improvement of median PFS from 3 to 6 months. Results: Between May 2019 to Nov 2019, 38 pts were screened for HA expression, and 8 pts were enrolled, with median age 68 years (range 60-73), 7 males, and median 2 prior therapies (range 1-4). The accrual was stopped early by Halozyme Pharmaceuticals due to lack of benefit from PEGPH20 added to chemotherapy in the HALO-301 study. Treatment exposure median was 2 cycles (range 1-6). Reasons for study discontinuation were disease progression (n = 4), termination by sponsor (n = 3), patient withdrawal to enroll in hospice (n = 1). Treatment related toxicities were musculoskeletal (n = 6, grade 1/2), edema (n = 2, grade 1), fatigue (n = 1, grade 3), dyspnea (n = 1, grade 2), hypothyroidism (n = 1, grade 2). Median OS was 7.2 months (95% CI 1.2-11.8), and median PFS was 1.5 months (95% CI 0.9-4.4). Best response was stable disease (n = 2, 25%) lasting 2.2 and 9 months, respectively, and no responses were noted. Patients with available molecular sequencing data had MSS tumors. Translational biomarkers will be presented. Conclusions: Pembrolizumab and PEGPH20 did not increase PFS compared to historical data among heavily pretreated mPC pts, but the median OS of 7.2 months is encouraging. Translational analyses will provide insights into immune modulatory effects from PEGPH20 that could inform future studies with stroma targeted therapies and immune checkpoint blockade in mPC. Clinical trial information: NCT03634332.
Impact of nuclear factor of activated T cells (NFAT) families as a poor prognostic factor in pancreatic cancer patients.
Authors: Kamioka Yuto , Hiroshima Yukihiko , Kawahara Shinnosuke , Murakawa Masaaki , Yamamoto Naoto , Tamagawa Hiroshi , Oshima Takashi , Miyagi Yohei , Rino Yasushi , Morinaga Soichiro ,   Department of Gastrointestinal Surgery, Kanagawa Cancer Center
Published: January 2022

584

Background: Pancreatic cancer microenvironment is crucial in cancer development, and cancer-stromal interactions have been recognized as important targets for cancer therapy. Nuclear factor of activated T-cells (NFAT) has been found in T cells as a transcriptional activator of IL-2, and known to be involved in various processes including the immune system. In cancer tissues, NFAT has been reported to be involved in metastasis. In breast and colorectal cancers, NFATc2 and NFAT5 have been reported to interact with integrins to promote cancer cell migration. On the other hand, in pancreatic cancer, NFAT5 has been reported to be a poor prognostic factor via regulation of PGK1 transcription. In the present study, we evaluated the expression of NFATc2 and NFAT5 in pancreatic cancer and examined their relationship with prognosis. Methods: One hundred and sixty five pancreatic cancer patients who underwent curative-intrent resection at our hospital between 2010 and 2020 were included in this study. We performed immunostaining for NFATc2 and NFAT5 using the tissue micro array. We evaluated the expression of NFATc2 and NFAT5 protein and examined their correlation with clinicopathological factors. Results: Of the 165 pancreatic cancer cases, we detected increased NFATc2 protein expression in cytoplasm of cancer cells in 53 cases (32.1%) and NFAT5 in 104 cases (63.0%), and NFATc2/NFAT5 co-expression in 43 cases (26.1%). NFATc2 expression was not correlated with any clinicopathological factors, NFAT5 expression was correlated with venous invasion (p = 0.047), and NFATc2/NFAT5 co-expression was slightly correlated with Stage (p = 0.054). Relapse free survival (RFS) was estimated in all 165 patients. There was no significant difference for RFS in either NFATc2-high group or NFAT5-high group (p = 0.314 or p = 0.574), however, NFATc2/NFAT5 co-expression group showed significantly poor RFS (p = 0.023). Overall survival (OS) was also estimated in all 165 patients. There was no significant difference for OS in either NFATc2-high group or NFAT5-high group (p = 0.146 or p = 0.529), however, NFATc2/NFAT5 co-expression group showed significantly poor survival (p = 0.006). In multivariate analysis, lymphatic invasion, curability and NFATc2/NFAT5 co-expression were independent prognostic factors for RFS, and lymphatic invasion, curability, presence of adjuvant therapy and NFATc2/NFAT5 co-expression were independent prognostic factors for OS. Conclusions: In pancreatic cancer, NFATc2/NFAT5 co-expression was suggested to be involved in the critical process of pancreatic cancer progression, and may be a novel therapeutic target.
Prognostic impact of common pathologic alterations in pancreatic ductal adenocarcinoma from the veterans health administration.
Authors: Mehlhaff Eric Glenn , Zafar Syed Nabeel , Lesnik Dyan M. , LoConte Noelle K. , Lubner Sam Joseph , Kratz Jeremy D.
Published: January 2022

603

Background: The Veteran Health Administration’s (VHA) National Precision Oncology Program was established to provide comprehensive molecular profiling for US military veterans with advanced cancers. There is an urgent need for precision strategies in pancreatic ductal adenocarcinoma (PDAC), as it is a leading cause of cancer-related mortality. We hypothesized that contributions of molecular alterations in PDAC would fail to stratify overall survival (OS), as current strategies are largely dependent on the activity of cytotoxic chemotherapy. Methods: A retrospective, multicenter cohort of 342 veterans with PDAC were identified from January 2016 to March 2021 who underwent comprehensive next-generation sequencing of tumor using FoundationOne CDx (UW IRB#2020-0696). Subjects were stratified by localized (L) or metastatic (M) disease at the time of diagnosis. Molecular alterations were compared by disease presentation using chi-squared analysis, and the clinical outcomes of overall survival (OS) were evaluated using Student’s t-test. Results: Baseline characteristics were representative of the VA population across 80 independent sites. The cohort was male-dominant (97%) with a median age of 69 years at diagnosis. Of this sample, 55% had M disease (n=189) compared to 45% with L disease (n=153). Median OS for M PDAC was 8.9±10.2 months (mo) v. L PDAC with median OS 22.5±18.0 mo (p<0.00005). Primary driver alterations were representative of PDAC and comparable between L and M on presentation, respectively; these included KRAS (92% v. 91%), TP53 (73% v. 80%), CDKN2A (29% v. 32%), SMAD4 (18% v. 23%), ARID1A (15% v. 16%) and BRCA2 (9% v. 12%). Primary driver alterations did not confer differences in OS across the population when comparing mutant (mt) to wildtype (wt) for KRAS (10.7 v. 11.8 mo, n=312), TP53 (10.3 v. 11.8 mo, n=263), CDKN2A (10.2 v. 10.9 mo, n=105), ARID1A (10.8 v. 10.9 mo, n=53), SMAD4 (11.3 vs 10.7 mo, n=72), and BRCA2 (13.8 v. 10.7 mo, n=37). Conclusions: Using the largest report of molecular profiles in veterans with PDAC to date, current therapeutic strategies fail to differentiate clinical outcomes by common molecular alterations with cytotoxic chemotherapy. The molecular profiles of veterans are representative of PDAC and do not vary significantly between localized and metastatic disease. There remains a persistent unmet need for therapeutic strategies including ongoing investigations of novel metabolic and immune-based therapies.