bluuebunny/crossref_metadata_2025 huggingface dataset:
Introducing yttrium-90 radioembolization to atezolizumab and bevacizumab regimen for intermediate and advanced stage hepatocellular carcinoma: A preliminary report of safety and effectiveness.
Authors: Yu Qian , Wang Yating , Ungchusri Ethan , Patel Mikin , Pillai Anjana , Van Ha Thuong , Liao Chih-Yi , Ahmed Osman
Published: June 2023

e16231

Background: The IMbrave150 Phase III trial demonstrated superiority of atezolizumab and bevacizumab (Atezo/Bev) over sorafenib in unresectable hepatocellular carcinoma (HCC). Combined radiotherapy and immune checkpoint inhibitors have been shown to induce synergistic effects in treatment of HCC and other solid tumors. Barcelona Clinic Liver Cancer 2022 updated guidelines recommend consideration of transarterial radioembolization (TARE) for early stage and very early stage HCC. The present study sims to evaluate the safety and effectiveness of combining TARE and the Atezo/Bev regimen for intermediate and advanced stage HCC. Methods: Retrospective review at a single institution was performed between May 2021 and December 2022. Patients who received TARE using yttrium-90 (Y90) with concomitant or sequential Atezo/Bev systemic treatment were included. The following outcomes were retrieved: overall survival (OS), radiologic tumor response, progression-free survival, technical adverse events related to TARE, and toxicity based on the National Cancer Institute–Common Terminology Criteria for Adverse Events version 5.0. Results: Ten consecutive patients (9 male, 1 female) with unresectable HCC received TARE and Atezo/Bev were included. A total 21 of doses of Y90 were administered with a median target dose of 156 Gy. Tumor control was achieved in all target lesions (100%) based on modified Response Evaluation Criteria in Solid Tumors criteria. Overall disease progression occurred in 4 patients after TARE with a 6- month PFS of 80% (95%CI: 40.9-95.6%) and 12-month PFS of 53.3% (17.3%-79.8%). Two patients died during follow-up, with 6-month and 12-month OS rates of 88.9% (95%CI: 43.3-98.4%) and 76.2% (95%CI: 33.2-93.5%), respectively. One patient developed grade 3 transaminitis and hypoglobulinemia. Atezo/Bev was switched to Lenvatinib in one patient due to myositis. Bevacizumab was held in one patient due to suspected transient ischemic attack. Conclusions: This small patient cohort demonstrated preliminary safety and effectiveness of TARE in combination with Atezo/Bev in treating intermediate and advanced stage HCC. Further prospective and comparative studies with large sample sizes are warranted.
Neoadjuvant immunotherapy in hepatocellular carcinoma: A systematic review and meta-analysis.
Authors: Parekh Jay , Abraham Soniya , Andanamala Haripriya , Rehman Asad , Xie Yiyu , Adjepong Yaw , Stein Stacey
Published: June 2023

e16232

Background: The addition of immunotherapy in neoadjuvant hepatocellular carcinoma (HCC) has been studied recently in early phase clinical trials due to high rate of recurrence after surgery. We aim to systematically review the evidence of efficacy and safety of neoadjuvant immunotherapy treatment. Methods: We carried out a systematic search on MEDLINE, Cochrane, and ASCO meetings library. Screening was done to include clinical trials with HCC patients who underwent any combination of neoadjuvant immune checkpoint inhibitors (ICIs). Quality assessment was performed using methodological index for non-randomized studies (MINORS) tool. The primary efficacy outcomes evaluated included complete pathological response (pCR), major pathological response (MPR), 1 year recurrence free survival (RFS) and overall response rate (ORR). Treatment related adverse events (TRAE) were assessed as a safety outcome. Predefined subgroup analysis was performed based on studies including of tyrosine kinase inhibitors (TKIs) in regimen. Data was analyzed using R version 4.2.1. Results: 5 phase I/II clinical trials were included consisting of 96 patients. Trials administered neoadjuvant immunotherapy agents nivolumab (with TKI cabozantinib) (N = 1), camrelizumab (with TKI apatinib) (N = 1), cemiplimab (N = 1) and nivolumab plus ipilimumab (N = 2). 78(81.2%) of patients were males. 56(59.3%) of patients had viral etiology. 14(14.5%) patients had surgeries delayed or cancelled due to any cause per trial protocols. Meta-analysis of 96 patients from 5 trials showed a pooled pCR rate of 14.49% (95% CI: 6.82 to 23.93%) with low heterogeneity (I2 = 0%, p value 0.55). Pooling the MPR resulted in an estimate of 35.30% (95% CI: 18.80% to 53.57%) with significant heterogeneity (I2 = 58.8%, p value 0.04). Three trials with total 45 patients reported a 12-month RFS rate of 51.08% (95% CI: 40.59 to 70.67%) with significant heterogeneity (I2 = 84.2%, p value 0.002). The overall response rate was 13.7% (95% CI: 6.9 to 22.1%) (I2 =0%, p =0.8). Overall rate of TRAE of any grade was 73.8% (95% CI: 63.1 to 82.5%) (I2 = 83.4%, p <0.001) among all trials and grade 3 adverse events was 21.21% (95% CI: 11.4 to 32.7%) (I2 = 33.8%, p = 0.159). 17(17.8%) patients had elevation in liver enzymes. On subgroup analyses, no difference in pathological outcomes, ORR and grade 3 adverse events was observed with addition of TKIs. Exploratory analysis showed no difference in pCR rates with single ICI vs combination with ipilimumab. Conclusions: The addition of ICIs in neoadjuvant settings appears to be a safe and feasible option. The addition of TKIs to neoadjuvant ICIs does not appear to affect pathological and safety outcomes. Further studies are needed to identify ICI based regimens to improve pCR rates and validate pathological outcomes in HCC after correlating with recurrence and survival.
Incidence of hepatocellular cancer in India: Analysis of population based cancer registry data.
Authors: Gopalakrishna Harish , Huang Bin , Mathew Aju
Published: June 2023

e16233

Background: Hepatocellular cancer (HCC) is the most common primary liver cancer and the third most common cause of cancer death globally. HCC incidence rate is declining in certain highly prevalent regions, however, continues to rise in many countries where the prevalence is currently low. To understand the trend of HCC incidence in India, we analyzed HCC incidence from various regions in India from 2004 to 2014. Methods: We obtained data on HCC incidence from the Population Based Cancer Registries (PBCR) of the National Cancer Registry Program. This registry includes data from different regions spread across India. We calculated age-standardized incidence rates (to WHO World standard population 2000) for periods of diagnosis (2004-05, 2006-08, 2009-11, and 2012-14). Results: From 2004 to 2014, HCC incidence rates increased relatively by 11%. When compared to data from 2004-2005, HCC incidence rate increased absolutely from 3 per 100,000 persons to 3.3 per 100,000 persons in 2012-2014. From 2004 to 2014, the relative increase in incidence rate was 13.3% in males and 7.4% in females. Conclusions: Rising HCC incidence rate is a cause for concern in India. Globally Nonalcoholic fatty liver disease (NAFLD) is swiftly becoming the most important cause of HCC. The rise in HCC incidence in India could be likely due to the increasing prevalence of NAFLD. Effective strategies are needed to improve surveillance and early diagnosis in patients with high risk of developing hepatocellular cancer. NAFLD preventive strategies must be an urgent public health measure in India.[Table: see text]
Real world sequence of peptide receptor radionucleotide therapy (PRRT) and chemotherapy in patients with metastatic pancreatic neuroendocrine tumors (pNETs).
Authors: Phillips William James , Tsvetkova Elena , Leung Macyn , Nair Gautham , Welch Stephen , Laidley David , Asmis Tim , Vickers Michael M. , Black Morgan , Sachdeva Robin , Marginean Horia , Goodwin Rachel Anne
Published: June 2023

e16237

Background: Peptide Receptor Radionuclide Therapy (PRRT) is an effective therapy for advanced pNETs but carries long-term risks of myeloid neoplasia. Early data from United States centres may suggest a higher risk of myelodysplasia and leukemia in patients treated with temozolomide prior to PRRT. The objective of this study is to characterize the sequence of PRRT and chemotherapy at two Canadian pNET treatment centres, distinguished by the availability of PRRT. Methods: This is a multicentre retrospective cohort study involving The Ottawa Hospital Cancer Centre (TOHCC; PRRT non-treatment centre (PRRT-NTC)) and London Regional Cancer Centre (LRCC; PRRT treatment centre (PRRT-TC). Patients with histologically confirmed pNETs between January 2010 – June 2021 over the age 18 (n=226), with metastatic disease (n=177) were included. Demographic, clinical and cancer treatments were collected. Descriptive statistics were used to evaluate the sequence of systemic therapy. Results: 177 patients with metastatic pNET were identified. Systemic therapies included octreotide (n=59, 40%), lanreotide (n=47, 32%), targeted agents (n=40, 27%), chemotherapy (n=48, 33%) and PRRT (n=47, 32%). Of patients receiving chemotherapy, 22 (46%) received temozolomide-containing regimens. The most frequent first line therapies were somatostatin analogues (SSAs, n=76, 43%), chemotherapy (n=23, 13%) and observation (n=18, 10%), second-line were PRRT (n=24, 14%), targeted therapy (n=26, 15%) and SSA (n=13, 7%), and third-line were PRRT (n=15, 9%), chemotherapy (n=11, 6%) and targeted therapy (n=8, 5%). There were 83 (47%) patients treated at the PRRT-TC, of which 33 (40%) received PRRT prior to chemotherapy and 7 (8%) received temozolomide-containing therapy prior to PRRT. In comparison, 94 (53%) patients were treated at the PRRT-NTC, of which 1 (1%) received PRRT prior to chemotherapy and 0 (0%) received PRRT prior to temozolomide-containing therapy. Conclusions: In this large cohort of metastatic pNET patients, the sequence of chemotherapy and PRRT showed centre-to-centre variability with patients treated at a PRRT-TC being more likely to receive chemotherapy, including temozolomide, prior to PRRT. This may be explained in-part by referral/practice patterns, and PRRT availability. These findings suggest an opportunity to evaluate and optimize the sequence of systemic therapy with the increasing availability of PRRT.
Pathologic exploration of neuroendocrine differentiation in carcinomas.
Authors: Wen Yaru , Shi Susheng
Published: June 2023

e16238

Background: Tumor with neuroendocrine differentiation (NED) has been verified in non-neuroendocrine organ adenocarcinomas. However, the incidence of NED in various studies varies greatly due to the different selection and criteria of NED markers. Further analysis of large clinical samples is still needed to reveal its biological characteristics and clarify the diagnosis and treatment of NED. Methods: From January 2017 to June 2018，a total of 450 histopathological samples were collected and analyzed retrospectively from patients with multiple malignant cancers, including gastric cancer (GC), colorectal cancer (CRC), lung cancer, breast cancer and prostate cancer treated in Cancer Hospital, Chinese Academy of Medical Sciences. Immunohistochemical staining for NED markers such as synaptophysin (Syn), chromogranin A (ChrA), and neural cell adhesion molecule (CD56) were performed to explore the incidence of different cancer types. Furthermore, NED or non-NED patients were evaluated comparatively in terms of pathological characteristics and prognosis. Results: Up to February 6, 2023, 129 CRC and GC samples were measured. 9 (15.3%) of 59 CRC patients were positive for NED markers, including 7 cases of Syn (+), 6 cases of ChrA (+) and 2 cases of CD56 (+). Moreover, 4 (6.8%) of 59 patients were positive for at least 2 NED markers in CRC. 18 (52.9%) of 34 gastric signer ring cell carcinoma patients were positive for NED markers, including 15 cases of Syn (+) and 14 cases of ChrA (+). Meanwhile, 10 (27.8%) of 36 gastric tubular adenocarcinoma patients were positive for NED markers, including 6 cases of Syn (+) and 10 cases of ChrA (+). Particularly, 17 (24.3%) (11/6, signer ring cell carcinoma/ tubular adenocarcinoma) of 70 GC patients were positive for at least two NED markers. Conclusions: NED is widely present in colorectal cancer and gastric cancer, especially in gastric signer ring cell carcinoma. The encouraging outcomes of the NED prevalence rate may shed light on the individualized treatments for patients with carcinomas. Further explorations are needed in the following research. [Table: see text]
Chromogranin A as surveillance biomarker in patients with carcinoids: CASPAR.
Authors: Meng Qing , Halfdanarson Thorvardur Ragnar , Bornhorst Joshua , Jann Henning , Shaheen Shagufta , Shi Run Zhang , Halperin Daniel M.
Published: June 2023

e16242

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare cancers with highly heterogeneous growth rates, yielding very broad ranges of radiographic imaging intervals in standard guidelines, with a multitude of risk for patients. Better tools are needed to reduce risks for these patients. Chromogranin A (CgA) is released by GEP-NET cells and has been associated with increased tumor burden. The European Neuroendocrine Tumor Society (ENETS) considers CgA to be the most practical and useful general serum tumor marker in patients with NETs. However, clinical utility has been limited by the lack of prospective validation studies and by different sensitivity of CgA according to NET tumor type and volume. Accordingly, expert consensus guidelines have offered varying advice regarding the use of CgA to practicing clinicians. The aim was to evaluate the performance of the B·R·A·H·M·S CgA II KRYPTOR immunoassay to monitor the course of disease in patients with well-differentiated GEP-NETs (grade 1 and grade 2). This is the first prospective validation of a clinical algorithm for the interpretation of CgA values in patients with advanced GEP-NETs. Methods: This prospective, multi-center, observational study was designed to validate the performance of the B·R·A·H·M·S CgA II KRYPTOR assay in monitoring disease progression in a defined population of GEP-NET patients with minimal confounding from end organ dysfunction or concomitant medications (e.g. PPIs). Patients were followed for up to 36 months including the evaluation of tumor burden with RECIST 1.1 categorization by imaging (CT/MRI scans). A clinical cut-off for changes in CgA levels over time to indicate the risk that a tumor progression occurred was derived from a retrospective, bicentric observational pilot study. A change in CgA levels between visits was considered positive, if the CgA concentration increased by more than 50% to an absolute value of >100 ng/ml. Results: A total of 175 adult patients were enrolled, and 153 patients had measurable disease at baseline and ≥1 follow-up visit. Using the cut-off for CgA increase defined above resulted in a sensitivity of 34.4% (95%-CI: 25.6% - 44.3%, p < 0.001) and a specificity of 93.4% (95%-CI: 90.4% – 95.5%, p < 0.001). Positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-) to diagnose whether a tumor progression occurred according RECIST 1.1 criteria were 57.9% (95% CI: 45.0-69.8), 84.3% (95% CI: 80.5-87.6), 5.20 (95% CI: 3.23-8.36), and 0.70 (95% CI: 0.61-0.81), respectively. The AUC was estimated at 0.731 (95% CI: 0.670-0.793). Conclusions: B·R·A·H·M·S CgA II KRYPTOR can be used in conjunction with other clinical methods as an aid in monitoring of disease progression during the course of disease and treatment in patients with gastroentero-pancreatic neuroendocrine tumors (GEP-NETs, grade 1 and grade 2).
Clinical and radiological criteria for candidate patients with small bowel neuroendocrine neoplasms (SB-NEN) for minimally invasive surgery: A single-centre experience.
Authors: Guidi Lorenzo , Conti Guglielmo , Bonomi Alessandro Michele , Spada Francesca , Gervaso Lorenzo , Cella Chiara Alessandra , Bertani Emilio , Zugni Fabio , Benini Lavinia , Borghesani Michele , Algeri Laura , Curigliano Giuseppe , Funicelli Luigi , Fumagalli Romario Uberto , Fazio Nicola
Published: June 2023

e16246

Background: Although open resection represents the standard of care of localized small bowel neuroendocrine neoplasms (SB-NEN), minimally invasive surgery (MIS) has proven to be a viable alternative in patients with low disease burden. This study aims to assess the reliability of preoperative clinical and radiological criteria used at European Institute of Oncology (IEO) to candidate patients with SI-NEN to MIS. Methods: Patients diagnosed with SB-NEN and eligible for MIS at IEO were retrospectively evaluated between 2013 and 2022. Preoperative physical examination, CT enterography (CTE) and Ga68-DOTATOC-PET-CT were used for clinical staging. At IEO NEN multidisciplinary tumor board, the following eligibility criteria were adopted to candidate patients to MIS (curative or palliative): number and localization of primary tumor, grade of superior mesentery artery and vein encasement by lymph-node metastases of 0-2 according IEO criteria (based on Lardiere-Degalte classification). Information on morphology and carcinoid syndrome were collected. The primary endpoint was laparotomy conversion rate. Results: Twelve patients were selected. Patients’ characteristics are available. Median age at surgery was 55 years (range: 33–73). Among these patients, based on pathological findings, 8 (67%) had confirmed nodal involvement, 3 (25%) metastatic disease and 4 (33%) multifocal primary tumor. Vascular involvement (based on IEO criteria) was found in 9 patients (75%). Of note, only 3 (25%) patients had a functioning tumor as a preoperative finding and all tumors resulted well-differentiated. Among 12 patients which underwent laparoscopic surgery, none has been converted to laparotomy surgery. After a median follow-up of 25.3 months (range: 2.5-71.3), the 1-year disease free survival for non-metastatic patients was of 100%. Conclusions: the assessment of tumor burden with 68Ga-PET-CT and CTE according to IEO criteria could be a reliable method to candidate patients affected by SB-NEN to MIS, according to a multidisciplinary approach.[Table: see text]
Prognostic value of total tumor volume with 68Ga DOTATOC PET/CT in predicting response to 177-Lu-DOTATOC treatment in metastatic well-differentiated neuroendocrine tumors (NETs).
Authors: Vega-Zolano Elizabeth , Ruiz Erika , Caderillo-Ruiz German , Diaz Consuelo , Herrera Marytere , Torres Agredo Liliana Patricia , Soldevilla-Gallardo Irma , Michel-Sanchez Emiliano , Garcia-Perez Francisco Osvaldo
Published: June 2023

e16248

Background: PET/CT with somatostatin analogues (68 Ga DOTATOC) is essential for decision-making prior to treatment with [177Lu–Dota0–Tyr3]–Octreotate (177Lu-DOTATOC), there are biological characteristics in this type of neoplasms that allow predicting the response to therapy, the tumor burden is one of the most important variables, however its estimation with conventional imaging tools is limited, currently there are reconstruction algorithms based on artificial intelligence that allow estimating the tumor burden using molecular imaging studies with 68 Ga DOTATOC, aim of this work is to determine the value of the total tumor load with this radiotracer as a predictor of overall survival in patients treated with 177Lu DOTATOC. Methods: 45 patients (11 men and 34 women) with an average age of 57.2 (range 47.2 to 66.5) with histopathological and immunohistochemical diagnosis of well-differentiated neuroendocrine tumors (NETs) in the period from 2015 to 2021 who received therapy with (177Lu-DOTATOC) and who had a baseline 68Ga DOTATOC PET to calculate total tumor volume (TVV) and semiquantitative uptake values were retrospectively included. Results: The mean follow-up was 29.3 +/- 6 months. Using ROC curves, a cut-off point of 100 cm3 was determined to differentiate responding and non-responding patients. The difference in the overall survival curves between both groups was statistically significant (470 days vs. 180 days) with p=0.07. The main sites of origin of the primary tumor were pancreas (n=24), lung (n=11), small intestine (n=7) and liver (n=3). The mean tumor volume was 305.8 cm3 (+/- 272). The organs with the highest uptake values were pancreas with SUVmax of 27.9 (range 10.1-42.4), rectum with SUVmax 26.5 (10.7-42.3) and liver with SUVmax of 22.1 (14.4-31.7), these uptake values did not have any type of relation to patient survival. Regarding therapy with 177 Lu DOTATOC, 8 received 14.8 Gbq (400mCi), 12; 22.2 GBq (600mCi) and 25; 29.6 GBq (800 mCi), no serious adverse effect or kidney function impairment was demonstrated after 177Lu DOTATOC therapy. No grade 3 or 4 haematological toxicity was identified. Conclusions: PET/CT with 68 Ga-DOTATOC is routinely used in the management of patients with neuroendocrine tumors and also allows categorizing patients according to their tumor volume to predict overall survival in patients treated with 177 Lu-DOTATOC, thus in such a way that it could be considered as an easily accessible and widely available prognostic imaging biomarker.
Treatment and outcomes of pancreatic cancer in Armenia: Hospital-based study.
Authors: Bardakhchyan Samvel , Mkhitaryan Sergo , Zohrabyan Davit , Safaryan Liana , Avagyan Armen , Harutyunyan Lilit , Arakelyan Jemma , Gharadaghyan Hovsep , Azizyan Sahak , Mailyan Mariam , Sargsyan Amalya , Harutyunyan Martin , Karapetyan Nune
Published: June 2023

e16251

Background: Pancreatic cancer is one of the deadliest cancers in the world. In Armenia, pancreatic cancer is on the 12th place by incidence. The aim of this study is to evaluate treatment and outcomes of pancreatic cancer in Armenia during the last 12 years. Methods: For this retrospective hospital-based study we have collected data from three oncology centers in Armenia: “Muratsan” Hospital of Yerevan State Medical University, “Miqaelyan institute of surgery” and “Hematology center after prof. Yeolyan”. The information about patients with pancreatic cancer who were treated at these centers during 01/01/2010 - 01/01/2022 period was collected from the medical records. Log- rank test and Kaplan-Meier curves were used for survival analysis. Cox regression analysis was done for identification of main prognostic factors. Results: 70 patients with pancreatic cancer were involved in the final analysis. From them 44.3% were female. Median age at diagnosis was 63 years. Median follow up time was 10,5 months (range 2-146). 11,4% of patients had stage I-II, 27,1% stage III, 58,6% stage IV cancer. The main independent prognostic factor for overall survival (OS) was tumor grade, while TNM stage was not significant. 23% of patients were alive before study end date. Median OS was 12 months (range 2-146 months). Median overall survival was 35 months in stage I-II, 11 months in stage III and 11 months in stage IV. In stage I-III pancreatic cancer patients, those who had undergone surgery (44.4%) lived significantly longer (35 vs 11 months, p=0.011). 38.6% of patients received chemotherapy with Gemcitabine plus Capecitabine regimen, while 41.4% with FOLFIRINOX regimen. No significant difference in survival was found between these groups (11 vs 13 months, p=0.35). Conclusions: As our results has shown survival of pancreatic cancer patients in Armenia is dismal, not exceeding 1 year. Hopefully further research in the field and new treatment modalities will improve the situation.
Homologous recombination-related (HRR) gene mutation profiling and the association with TMB in Chinese patients with pancreatic cancer.
Authors: Wu Yin Bing , Yi Huan , Yu Yangyang , Xiao Mingzhe , Qi Chuang
Published: June 2023

e16252

Background: Homologous recombination deficiency (HRD) is associated with tumorigenesis and could predict the response of PARP inhibitor (PARPi) therapy and immunotherapy. Loss of function or deleterious mutations in homologous recombination-related (HRR) genes contribute to HRD phenotype. Methods: Tumor tissue samples from 669 Chinese patients with pancreatic cancer were sequenced with 551 cancer-related genes. Based on the clinical evidence, 15 HRR genes ( ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L, PPP2R2A) were selected. 495 patients with WES data from the TCGA datasets were included for analysis. Results: In the Chinese cohort, 10.46% (70/669) patients exhibited somatic HRR (sHRR) gene mutations. ATM (4%) was the most common mutant gene, followed by BRCA2 (3%), BARD1 (1%), BRCA1 (1%), BRIP1 (1%), RAD51D (1%), CHEK2(1%). The germline HRR (gHRR) gene mutations were identified in 55.67% (118/245) patients. BRCA2 (23%) was the most common mutant gene, followed by ATM (10%), BRCA1 (9%), BRIP1 (9%), PALB2 (8%), BARD1 (7%), FANCL (3%). 1.49% (10/669) patients carried both germline and somatic HRR gene mutations. The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (3.97 vs 2.13, p<0.001). However, the median TMB was similar between the gHRR-Mut and the gHRR-WT patients (2.13 vs 2.13, p=0.49). In the TCGA cohort, 9.09% (45/495) patients exhibited sHRR gene mutations. The most common mutant gene was ATM (4%), followed by CDK12 (2%) BRCA2 (2%), BARD1 (1%). The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (1.03 vs 0.71, p<0.001). Totally, the somatic mutant frequency of HRR genes was similar between Chinese cohort and TCGA cohort (10.46% vs 9.09%, p = 0.113). For the TCGA cohort, the patients with sHRR-Mut had a similar median progression free survival compared to the ones with sHRR-WT (74.4 months vs not reached, p = 0.299). Conclusions: Our data reported the genetic landscape of HRR gene in Chinese pancreatic cancer patients. Patients with somatic HRR gene mutations had a significantly elevated TMB level. Our data suggest that patients with altered HRR genes may be rational candidates for precision oncology treatment and provide new opportunities to predict the tumor response to multiple treatments.
The efficacy of cationic amphiphilic antihistamines on outcomes of patients with pancreatic ductal adenocarcinoma.
Authors: Chiang Cho Han , Chiang Cho Hung , See Xin Ya , Hsia Yuanping , Chang Yu-Cheng , Wang Shih-Syuan , Chen Yuan-Jen , Chiang Cho Hsien , Peng Cheng-Ming , Shiah Her-Shyong
Published: June 2023

e16253

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. H1 antihistamines with cationic amphiphilic properties have been shown to possess antitumor effects and were associated with reduced mortality in several cancer types. We aimed to investigate the effects of cationic amphiphilic antihistamines on the outcomes of patients with PDAC. Methods: We conducted a retrospective cohort study at two tertiary centers in Taiwan between 2010 and 2021. We included all adult patients with histologically confirmed PDAC. Cationic amphiphilic antihistamines included desloratadine, cyproheptadine, and ebastine. The rest of the antihistamines were classified as non-cationic amphiphilic. Patients treated with cationic amphiphilic antihistamines were matched in a 1:2 ratio to patients treated with non-cationic amphiphilic antihistamines based on age, sex, and cancer stage. The primary outcome was overall survival (OS) and the secondary outcomes were progression-free survival (PFS) and objective response rates (ORR). Results: Among 407 patients included in the study, 28 cationic amphiphilic antihistamine users were matched to 56 non-cationic amphiphilic antihistamine users. Over a median follow-up of 6.3 [IQR, 2.0-13.8] months, 67 patients died. Compared with non-users, patients who received cationic amphiphilic antihistamines had a longer OS (median 16.4 [IQR, 2.8 – 89.0] vs. 5.8 [IQR, 2.0 – 9.8] months; p < 0.001) and PFS (median 12.2 [IQR, 2.2 – 83.3] vs. 5.2 [IQR, 1.7 – 8.4] months; p = 0.002). In Cox proportional hazard models, the use of cationic amphiphilic antihistamines was associated with an approximately 60% lower risk of all-cause mortality and disease progression. Cationic amphiphilic antihistamine users also had greater ORR than non-users (complete or partial response, 39% vs. 7%, p = 0.004). Conclusions: The use of cationic amphiphilic antihistamines was associated with improved survival among patients with pancreatic cancer. [Table: see text]
Phase 1b study of batiraxcept (AVB-S6-500, BT) plus gemcitabine (G) and nab-paclitaxel (NP) as first-line treatment (1L) for advanced pancreatic adenocarcinoma (PDAC).
Authors: Sahai Vaibhav , Oberstein Paul Eliezer , Krishnamurthi Smitha S. , Gabrail Nashat Y. , Fountzilas Christos , Brenner Warren S. , Wainberg Zev A. , Yan Hongxia , McIntyre Gail , Lopez Charles D. , Mettu Niharika B. , Geller Robert B.
Published: June 2023

e16258

Background: PDAC is a deadly aggressive cancer characterized by up to 80% tumor stroma enriched by macrophages, fibroblasts, and collagen deposition that influences resistance to therapy. Tyrosine kinase receptor AXL and ligand expression of growth arrest specific protein 6 (GAS6) produce tumor associated macrophages and fibroblasts and correlate with poor prognosis. GAS6 blockade partially reverses epithelial-to-mesenchymal transition of tumor and supports NK cell activation, inhibiting metastasis. As a novel decoy FC fusion protein, batiraxcept (BT) binds to GAS6 and demonstrates highly potent and specific AXL inhibition. Preclinical studies showed a relationship between AXL signaling and response to DNA damage in PDAC models. Methods: This dose escalation study tested BT 15 mg/kg on day 1 and 15 in combination with G 1000 mg/m2 and NP 125 mg/m2 days 1, 8, 15 of a 28-day cycle. Primary endpoints are safety and objective response rate (ORR) using RECIST v1.1; key secondary endpoints are progression free survival (PFS) and overall survival (OS); pharmacokinetic data were collected to determine exposure-PFS response (E-R) relationship. Results: As of January 17, 2023, 21 patients (pts) received BT/G/NP of which 10 (48%) were male and 3 (14%) received prior neoadjuvant/adjuvant therapy. BT-related AEs > 10% pts included fatigue (n=7, 33%), diarrhea (n=4, 19%), infusion related reaction and neutropenia (n=3, 14% each). Grade ≥ 3 BT-related AE occurred in 6 pts (29%). BT administration reduced GAS6 to non-quantifiable levels until treatment ended. 18 pts (86%) discontinued treatment, primarily due to toxicity (n=2) and progressive disease (n=13). Median (m) BT/G/NP treatment duration was 13.1 weeks (range 0.1─74.7). ORR is 29%; mPFS and mOS were 5.4 mo (2.1, 5.6) and 12.3 mo (4.11─NE) respectively. BT efficacy results are described by a minimally efficacious concentration (MEC) of 14.5 mg/L identified by E-R modeling. Conclusions: BT/G/NP combination was well tolerated, and the BT safety profile is consistent with prior trials. Patients with BT trough > MEC had longer PFS and OS. In addition, in these patients OS appears longer than historical data of 8.5 months. Due to increased stroma seen in PDAC, a higher BT MEC may be required to maximize efficacy. Higher BT dose levels in combination with G/NP are under study. Clinical trial information: NCT04983407 . [Table: see text]
Molecular and clinical characteristics of patients with KRAS mutated pancreatic ductal adenocarcinoma.
Authors: Xiao Alexander Hua , Desai Aakash , Halfdanarson Thorvardur Ragnar , Alberts Steven R , McWilliams Robert R. , Mahipal Amit , Bekaii-Saab Tanios S. , Shi Qian , Carr Ryan Michael , Ma Wen Wee
Published: June 2023

e16259

Background: Patients with KRAS mutant (mt) pancreatic ductal adenocarcinoma (PADC) have worse survival outcomes compared to KRAS wild-type (wt) PDAC patients. However, the prognostic implication of the KRAS mutation subtype (e.g. G12D, G12R, G12V and Q61) remains unclear. Furthermore, the clinical and molecular characteristics associated with these mutation subtypes remain not well defined. Methods: A retrospective review was conducted on patients with KRAS PDAC who underwent Next Generation Sequencing at Mayo Clinic between December 1, 2018 and December 1, 2021. Their somatic mutations, RNA expression, demographics, disease characteristics, therapies offered, and clinical outcomes were collected via chart review. Results on KRAS wt were reported previously; KRAS mt are reported here. Results: A total of 158 KRAS mt patients (at diagnosis: average age 63.8 years, 57% male, 88 (56%) Stage IV) were included. 10% of patients had KRAS Q61 mutation, 14% G12R, 30% G12V and 46% G12D. G12R had a longer overall survival (OS) compared to the others (median 24.8 vs 17.5 months, unadjusted hazard ratio (HR) 0.68, p=0.05), particularly in patients with localized disease at diagnosis (median 35.4 vs 28.3 months, p=0.08). Among patients with metastatic disease at diagnosis, G12V had the lowest OS (median 9.8 vs 12.4 months, unadjusted HR 1.8, p=0.02). 137 (87%) patients had at least one pathogenic somatic variant, with statistically significant differences in SMAD4, TP53, MYC, RB1, KMT2D, RBM10, RNF43, KDM6A, KMT2C, RBM10, LRP1B, PIK3CA, and SMARC among the KRAS mt subtypes. 82 (52%) patients had at least one RNA expression variant, with statistically significant differences in CCND1, CCNE1, HRAS, MET, EGFR, and ERB3 among KRAS mt subtypes. Between these subtypes, there were no statistically significant differences in TMB value, location of PDAC or subsequent metastasis, lines of treatment (average 2.3), age at diagnosis, or gender. Conclusions: KRAS mt subtypes may confer different PDAC phenotypes. In our cohort, G12R is associated with improved OS while G12V correlates with worse prognosis in de novo metastatic disease. Additionally, there are differences in genomic variations and RNA expression between the KRAS mt subtypes. To further examine this, transcriptomic analysis is underway. [Table: see text]
Survival outcomes of liposomal irinotecan in patients with advanced pancreatic adenocarcinoma previously treated with conventional irinotecan-based chemotherapy: A single-institution experience.
Authors: Gupta Amol , Kamel Ihab R. , Laheru Dan
Published: June 2023

e16260

Background: Gemcitabine-based and FOLFIRINOX (Oxaliplatin, irinotecan [IRI], 5-fluorouracil [5-FU], and leucovorin [LV]) regimens are common front-line therapies for patients with advanced pancreatic cancer (APC). Later-line options for these patients remain limited. Liposomal irinotecan (nal-IRI) plus 5-FU-LV has demonstrated a survival benefit in APC patients previously treated with gemcitabine-based treatment. However, the efficacy of nal-IRI plus 5-FU-LV in patients previously treated with conventional IRI containing regimens is controversial. Methods: A retrospective chart review was conducted on consecutive APC patients treated at our institution between November 2016 to January 2023 who completed at least one cycle of nal-IRI plus 5-FU-LV and were previously treated with conventional IRI. Data regarding survival outcomes were retrieved. The association between the survival outcomes and the interval between conventional IRI and nal-IRI was analyzed. Results: Forty-one patients met the inclusion criteria. One patient (2.4%) had a partial response (PR), and 12 patients (29.3%) had stable disease (SD) as their best response. The median overall duration of nal-IRI treatment was 2.2 (IQR: 1.4 – 5.2) months. The median progression-free survival (mPFS) was 1.9 (95% confidence interval [CI] 1.7 – 2.0) months, while the 6-month PFS rate was 24.4%. The median overall survival (mOS) was 5.9 (95% CI 3.5 – 8.2) months, and the 6-month OS rate was 48.7%. The median interval between the discontinuation of conventional IRI and starting nal-IRI was 6.5 (3.4 – 13.2) months. An interval between conventional IRI and nal-IRI ≥6.5 months was significantly associated with prolonged OS (8.5 [95% CI 5.9 - 11.1] versus 4.3 [95% CI 2.7 – 5.9] months; p = 0.017), but comparable PFS (2.0 [95% CI 1.0 – 2.8] versus 1.7 [95% CI 1.5 – 1.9] months; p = 0.052). Conclusions: Patients previously treated with conventional IRI containing regimens appear to still benefit from nal-IRI plus 5-FU-LV. A longer interval between conventional IRI and nal-IRI was associated with better OS. A sequence strategy introducing a nal-IRI-based regimen at later lines may be feasible in selected APC patients previously treated with conventional IRI, given the limited therapeutic options. Further prospective studies are warranted. [Table: see text]
Single-cell RNA sequencing and influences of necroptosis-associated myeloid lineages in immune microenvironment of PDAC.
Authors: Dong Weiwei , Zhao Huixia , Zhang He , Zeng Zhiyan , Hu Yanyan , Fan Tongqiang , Zheng Liuqing , Wang Qian , Xiao Shanshan , Wang Tao , Xiao Wenhua
Published: June 2023

e16261

Background: Tumor-infiltrating myeloid cells (TIMs) are abundant in tumor stroma and emerging evidence indicate that the presence of these cells influences clinical outcomes in many cancer types. TIMs play important roles in tumor progression and specific subsets may exhibit divergent anti-tumor or tumor-promoting functions. Currently, the molecular characteristics of TIMs in pancreatic ductal adenocarcinoma (PDAC) largely remain unknown. Like other programmed cell death procedures such as ferroptosis and pyroptosis, necroptosis has recently emerged as an important cellular event that modulates tumorigenesis and tumor progression. Combination of necroptosis and TIMs is of great interest to study the molecular mechanism of clinical outcomes for PDAC patients. Methods: This study enrolled 16 PDAC patients. The scRNA-seq data were obtained from a published dataset and each patient included primary tumor, metastatic tumor, primary tumor-adjacent and PBMC samples. All myeloid cells comprising granulocytes, monocytes, macrophages, and dendritic cells from enrolled patients were extracted for further analysis. We performed comprehensive analysis about the characteristics of myeloid lineages, differentially expressed genes, pathway enrichment analysis and novel cell subtype identification. The necroptosis-associated novel TIMs cell sub-clusters were elucidated in detail. Results: To comprehensively analyze the heterogeneous TIMs microenvironment in PDAC patients using scRNA-seq dataset, we firstly obtained consistently upregulated genes among granulocytes, monocytes, macrophages, and dendritic cell types between tumor samples and non-tumor samples. Those uniquely expressed genes represent different functions in necroptosis-associated TIMs cells. In total, we identified 10 necroptosis-associated upregulated genes in PDAC tumors and 5 upregulated genes in tumor-adjacent and peripheral blood samples, respectively. Based on the cells expressed those necroptosis-related genes, we identified three novel cell populations, including GLUL-SQSTM1- RTM, HSP90AA1+HSP90AB1+ mast cells, and JAK3+TLR4+ CD16 monocytes, which were regulators of immunity either tumor-promoters or tumor-suppressors. Clinical outcomes further supported their function roles in the PDAC tumor microenvironment. Conclusions: This study comprehensively studied the heterogeneity of myeloid microenvironment in PDAC by scRNA-Seq. Several necroptosis-associated genes and myeloid cell sub-clusters were identified and they have prognostic clinical values in PDAC. These preliminary results were helpful for further understanding the molecular mechanism of PDAC treatment strategies.
NALIRIFOX vs FOLFIRINOX vs gemcitabine plus nab-paclitaxel as first-line treatment of advanced pancreatic cancer: An individual patient data pooled analysis of phase 3 registration trials.
Authors: Nichetti Federico , Rota Simone , Gusmaroli Eleonora , Pircher Chiara Carlotta , Franza Andrea , De Braud Filippo G. , Di Bartolomeo Maria , Niger Monica
Published: June 2023

e16262

Background: The NAPOLI-3 trial showed the superiority of the NALIRIFOX regimen over the combination of gemcitabine and nab-Paclitaxel (GemNabP) as first-line treatment (1LTx) of advanced pancreatic cancer (PDAC), thus being candidate as a reference regimen in this setting. However, a comparison with the FOLFIRINOX regimen has not yet been performed. Methods: We performed a pooled analysis of phase III trials that defined FOLFIRINOX, NALIRIFOX and GemNabP as optimal 1LTx options in advanced PDAC. Individual patient outcomes were retrieved from Kaplan Meier plots of each trial, and analysed after assessment of data reconstruction accuracy. Progression free survival (PFS) and overall survival (OS) were compared between the three different arms, using Cox proportional hazard models including each trial as a random effect variable to account for inter-trial variability. Overall response rates (ORR) and Grade 3 or 4 (G3/4) toxicity rates were also compared. Results: A total of 1372 patients treated with FOLFIRINOX (n=171, 12), NALIRIFOX (n=383, 28) and GemNabP (n=818, 60) were included. Median PFS was significantly longer in patients treated with NALIRIFOX (7.4 months) as compared to FOLFIRINOX [6.4 months, HR 1.48 (95% CI 1.21 - 1.82), p<.001] and GemNabP [5.6 months, HR 1.45 (95% CI 1.24 - 1.70), p = p<.001]. NALIRIFOX also provided significantly higher ORR [42% vs 32% (FOLFIRINOX) vs 29% (GemNabP), p<.001]. GemNabP was associated with poorer OS [9.2 months, HR 1.25 (95% CI 1.07 - 1.46), p=0.005], while no significant difference was observed between FOLFIRINOX [11.1 months, HR 1.12, (95% CI 0.88 - 1.43), p=0.344] and NALIRIFOX (11.1 months). Among G3/4 events, NALIRIFOX was associated with higher rates of diarrhea [p<.001] and lower rates of peripheral neuropathy, thrombocytopenia and neutropenia [p<.001], though with no difference in febrile neutropenia occurrence [p=0.158]. Conclusions: NALIRIFOX may provide superior ORR and PFS as compared to FOLFIRINOX and GemNabP as 1LTx of advanced PDAC, though with higher gastrointestinal toxicities and no difference in OS compared to FOLFIRINOX. Careful patient selection, drug costs consideration and direct comparison between FOLFIRINOX and NALIRIFOX is warranted. [Table: see text]
Total pancreatectomy: Experience within an integrated health care system.
Authors: Chang Amber , Kwak Hyunjee V. , Peng Peter D , Kazantsev George , Spitzer Austin L , Chang CK
Published: June 2023

e16269

Background: Total pancreatectomy (TP) is most used for pancreatic adenocarcinoma (PC) but also for main duct intra-ductal papillary mucinous neoplasm. The authors report on a retrospective study of 61 patients who underwent TP in an integrated healthcare system. Methods: A retrospective review was performed of all patients treated with TP between January 2012 and December 2022. Patient demographics, tumor characteristics, treatment modalities, and mean overall survival (OS) were evaluated. Results: An intra-operative positive pancreatic neck margin for cancer or high-grade dysplasia was the most common indication for TP in 77% (47/61) of patients. The mean OS for patients with pancreatic cancer was 18 months, however, patients with a pre-op diagnosis of IPMN had a mean OS of 50 months. Multivariate analysis of PC without IPMN showed that neoadjuvant and NPH insulin were associated with a decrease in overall survival ( p< .05). Overall HbA1c were higher in patients after one year after surgery for patients taking NPH (8.6) as opposed to an insulin pump (7.6) or Lantus (7.6) but not significant ( p= .346). Mean OS for patients with PC and type of insulin used was statistically significant at 24.4 months vs 13.1 months respectively for Lantus vs NPH ( p= .033). Conclusions: Conversion to TP for positive neck margins did not improve survival in patients who receive neoadjuvant chemotherapy but may be helpful in patients with IPMN. Blood sugar control after one year was similar among the various indication groups as well the type of insulin use. Although Lantus insulin was associated with improved overall survival for patients with pancreatic cancer, the exact reason is unclear and requires further studies.
A retrospective real-world study of nimotuzumab combined with chemotherapy for advanced pancreatic cancer.
Authors: Wu Yinying , Dong Xuyuan , Li EnXiao , Fan Yangwei , Dong Danfeng , Shi Yu , Wang Meichen , Yang Nan , Ou Fengyun , Wang Jia , Yang Yuqian
Published: June 2023

e16271

Background: Existing treatment options including gemcitabine-based therapy and 5FU-based chemotherapy have limited prognostic impact in advanced pancreatic cancer (APC): the median overall survival (mOS) was 6-11 months for 1st line therapy and 4-9 months for 2nd line therapy. Nimotuzumab (nimo), anti-EGFR monoclonal antibody, had been shown to be more effective against APC in two previous studies, PCS07 (a phase II study in Germany) and NOTABLE study (a phase III study in China). Although the NOTABLE study obtained an encouraging result in China, it focused on a narrow population, KRAS wild-type patients. This study aimed to explore the efficacy and safety of nimo in the real-world population with APC. Methods: In this retrospective observational study, patients with APC were treated with nimo and followed up in a real-world clinical setting. Demographic and clinical data of these patients were collected from electronic medical records of First Affiliated Hospital of Xi’an Jiaotong University from April 2018 to June 2022. The primary efficacy endpoint was overall survival. Results: A total of 104 patients (median age was 60.5 years, range 34-84) treated with nimo and chemotherapy were analyzed. Among them, 11 (10.6%) were in stage II (AJCC 8th edition), 23 (22.1%) were in stage III, and 70(67.3%) were in stage IV. The treatment regimen included gemcitabine plus nab-paclitaxel (AG, 80.77%), gemcitabine plus S-1 (GS, 10.58%) and others. The dosage of nimo was 200-400mg weekly, of which above 50% of patients received nimo 400 mg weekly. About 66 (63.5%) patients received nimo as 1st line therapy and 38 (36.5%) patients as 2nd line therapy. Up to July 5, 2022, the median follow-up time was 8.12 months and the mOS was not reached. The 1-year and 2-year OS rate were 80.2% and 74.4%, respectively. Further subgroup analysis showed that the mOS was also not reached in 1st line treatment of nimo (median follow-up time 8.77 months) as well as the 2nd line treatment of nimo (median follow-up time 7.62 months), showing a potential survival benefit. No grade 3 or above toxicities were observed. Conclusions: AG regimen was the most common therapy in clinical practice in China. The real world study displayed the addition of nimo would prolong the survival for APC, with a good safety profile.