Biliary Tract Tumors Research Articles

CASE OF SYNCHRONOUS HEPATOBILIARY TUMOUR; DIAGNOSTIC DILEMMA

Synchronous biliary tract tumours are very rare. Synchronous double cancers of the extrahepatic bile duct with-out abnormal pancreatobiliary junction are extremely rare, and to date only 4 cases have been reported in the English literature [1-3]. Until now less than 10 cases have been reported all over the world. Usually, the coexistence is attributed to abnormal pancreatobiliary junction [4-6], local spread or metastasis or de novo. In cases apart from anomalous pancreatobiliary junction, p53 mutations have been associated with simultaneous cancers. Contrast enhanced tomography is done as the initial investigation and FDG-PET is increasingly being used in the staging work up. When there is a suspicion of periampullary growth on cross sectional imaging, side viewing scopy is done to evaluate the lesion and take biopsies. The case presented here is interesting as PET showed metabolically active lesions in the the gall bladder and periampullary region, the latter being subtle on endoscopy.

Durable Responses in Patients With Advanced Cholangiocarcinoma on Sequential Dual-agent Immunotherapy After Progressing on Single-agent Immunotherapy.

Objectives:Biliary tract tumors have a poor prognosis despite advancements in targeted therapies. More recent studies have started to investigate the use of combination immunotherapy in advanced biliary cancers. However, currently, there are no clinical trials investigating the use of dual-agent immunotherapy with ipilimumab and nivolumab as a sequential treatment after patients have progressed on single-agent immunotherapy. In this case series, we discussed 3 patients with advanced cholangiocarcinoma who have an objective response to dual-agent immunotherapy with ipilimumab and nivolumab after having disease progression on pembrolizumab and multiple other failed lines of treatment.Materials and Methods:A case series, including 3 patients treated at the University of California, Irvine Chao Family Comprehensive Cancer Center, was completed.Results:Although none of the 3 patients had microsatellite instability or high tumor-mutation burden and were not necessarily predicted to have a response to dual-agent immunotherapy, all 3 patients had an objective radiographic and/or tumor-marker response to a combination of ipilimumab and nivolumab.Conclusions:This case series serves as proof of the concept that sequential immunotherapy can be beneficial after progression on single-agent immunotherapy for patients with advanced cholangiocarcinoma. This study can also serve as the foundation to build further tests on the true effectiveness and ideal duration of sequential therapy with dual immunotherapy agents.

1707P The landscape of PALB2 alteration in Chinese solid tumor patients

Partner and localizer of BRCA2 (PALB2) is a nuclear protein that localizes to sites of DNA double-strand breaks and interacts with BRCA1 and BRCA2 to promote DNA repair. The differences in mutation profiles of PALB2 gene in pan-cancer can help understand pathogenesis, prognosis, and identify targets for therapy. Using commercial NGS assays, we retrospectively analyzed genomic DNA alterations in normal-paired samples from 3880 patients with malignancies between 2019 to 2021, and alterations including single base substitution, short and long insertion/deletions, copy number variations, gene fusions and rearrangements. PALB2 gene was altered in 2.0% (78 of 3880) of all solid tumors, comparable to 1.5% (158 of 10336) of PALB2 alterations in the MSK-IMPACT Clinical Sequencing Cohort (MSKCC, Nat Med 2017). The frequency of PALB2 variations was assessed in multiple cancer types, including bladder cancer 6.1% (2/33), thyroid cancer 4.9% (2/41), colorectal cancer 4.0% (19/478), prostatic cancer 3.8% (1/26), small cell lung cancer 3.4% (1/29), pancreatic cancer 2.5% (4/160), gastrointestinal stromal tumor 2.3% (1/44), liver cancer 2.2% (5/230), biliary tract tumor 2.1% (3/141) and non-small cell lung cancer 2.0% (28/1402). A total 93 genetic alterations were identified in 78 patients, including 58 missense mutations (63%), 18 nonsense (12%), 12 frameshift (10%), 3 splicing (8%), 5 copy number loss (5%), 1 in-frame insertion (2%), 1 in-frame deletion (2%). Among these patients, 14 had pathogenic or likely pathogenic germline PALB2 heterozygous mutations, including prostatic cancer 3.8% (1/26), biliary tract tumor 2.1% (3/141), pancreas tic cancer 1.3% (2/160), colorectal cancer 0.8% (4/478), liver cancer 0.4% (1/230) and non-small cell lung cancer 0.2% (3/1821). Furthermore, in our cohort, PALB2 mutation carriers also owned other actionable, the most frequent one was TP53 (65%), followed by LRP1B (28%), KRAS (27%) and PIK3CA (24%). PALB2 deleterious mutations are highly diverse and present at low to moderate frequencies across many cancers. PALB2 alterations warrant further investigation as predictive biomarkers of response to PARP inhibitors or platinum-based therapy.

A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of select human epidermal growth factor receptor 2 (HER2)-expressing solid tumors (DESTINY-PanTumor02) (296)

<b>Objectives:</b> Human epidermal growth factor receptor 2 (HER2) is an established therapeutic target in both breast and gastric cancer. However, HER2-targeting therapies are not approved beyond these malignancies despite a high prevalence of HER2 expression across cancers of epithelial origin. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In a cohort of pretreated patients with multiple HER2-expressing tumors, T-DXd demonstrated promising antitumor activity, with an investigator-assessed confirmed objective response rate of 40.9% (9 of 22 patients) and median progression-free survival of 11.1 months (95% CI: 5.4-20.5 months; Tsurutani J, et al. <i>Cancer Discov</i>. 2020;10:688-701). Here we describe the phase II DESTINY-PanTumor02 trial evaluating T-DXd in patients with select HER2-expressing solid tumors. <b>Methods:</b> DESTINY-PanTumor02 (NCT04482309) is an open-label, multi-center, multi-cohort, phase II study evaluating T-DXd for the treatment of patients with select HER2-expressing locally advanced, unresectable, or metastatic tumors. The study will consist of seven cohorts of patients (<i>n</i>≈40 each) with urothelial bladder, biliary tract, cervical, endometrial, ovarian, pancreatic, or rare tumors (tumors excluding those in the other cohorts and breast, gastric, colorectal, and non-small cell lung cancer). Patients are required to have disease progression following ≥1 prior systemic treatment for advanced or metastatic disease or have no satisfactory alternative treatment options. Prior HER2-targeting therapy is allowed. The primary endpoint is investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include duration of response, disease control rate, progression-free survival (all per investigator assessment according to RECIST 1.1), overall survival, safety, pharmacokinetics, and immunogenicity. Previously presented at the ESMO Congress 2021, FPN:1869 TiP, Meric-Bernstam, et al. - Reused with permission.

A Tertiary Care Center's Experience with Clinicopathological Characteristics of Gallbladder Carcinoma in Our Population.

IntroductionGallbladder cancer (GBC) is the most common malignant biliary tract tumor with the shortest survival from the time of diagnosis. This poor prognosis is due to the destructive biologic behavior of GBC, lack of sensitive screening tests for early detection, and vague nature of first presentation. Here in this study, we will evaluate the baseline characteristics of the patients presenting with gallbladder carcinoma in our population.Materials and methodsThis retrospective study was conducted in the Department of Gastroenterology at Sindh Institute of Urology and Transplantation (SIUT), Karachi. Patient data were compiled and composed from the in-patient health records, radiology, and operational records. Those patients with suspicion of GBC, but negative at histology, or patients having inconclusive radiologic findings, were excluded. Baseline characteristics were recorded. Results were presented as means ± SD for quantitative data or as numbers with percentages for qualitative data. Continuous variables were analyzed using the Student's t-test, while categorical variables were analyzed using the Chi-square test. A p-value of <0.05 was considered statistically significant.ResultsA total of 162 patients were included in our study. Among them, 101 (62.3%) were females. Hypertension was the most common comorbid illness noted in 29 (17.9%) patients while 91 (56.2%) patients had no concurrent comorbidities. Most common risk factor for carcinoma of gallbladder was gallstones seen in 106 (65.1%) patients. The most common presenting complaint was combination of obstructive jaundice, weight loss with right hypochondrial pain seen in 66 (40.7%) patients. On CT abdomen, direct liver infiltration without lymphovascular invasion was noted in 77 (47.5%) patients followed by liver infiltration along with lymphovascular invasion in 26 (16%) patients and distant metastasis in 24 (14.8%) patients. On gallbladder (GB) mass biopsy, 58 (35.8%) patients had well-differentiated, 46 (28.4%) had moderately differentiated, while 33 (20.4%) had poorly differentiated adenocarcinoma. Of 162 patients, 103 (63.6%) patients underwent endoscopic retrograde cholangiopancreatography (ERCP). The most common finding on ERCP was proximal common bile duct (CBD) stricture with intrahepatic biliary system dilatation which was noted in 95 (58.6%) patients. Percutaneous transhepatic cholangiography (PTC) was performed only in 9 (5.6%) patients. Seventeen (10.5%) patients were managed by simple cholecystectomy, 39 (24.1%) patients underwent extended cholecystectomy, 14 (8.6%) patients underwent chemotherapy, while 102 (56.8%) patients were given palliative management. When followed for 1 year, 101 (62.3%) patients died within 6 months.ConclusionThe baseline characteristics, biopsy findings, modes of treatment, and rates of 1 year mortality were studied in patients with gallbladder carcinoma in our population. Advanced age, high white blood cell counts, and serum bilirubin at presentation with low lymphocyte count and presence of comorbid illnesses were the factors independently associated with increased mortality in patients with gallbladder carcinoma. However, further studies with large sample size and stratification with respect to age, gender, and different variables can be done in terms of mortality in patients with gallbladder carcinoma.How to cite this articleAkbar N, Yaseen T, Muhammad A, et al. A Tertiary Care Center's Experience with Clinicopathological Characteristics of Gallbladder Carcinoma in Our Population. Euroasian J Hepato-Gastroenterol 2022;12(1):35–39.

Clinical and genomic characterization of ERBB2-altered gallbladder cancer.

4114 Background: Gallbladder cancer (GBC) is a molecularly distinct entity among biliary tract tumors. ERBB2 amplification and mutation have been described in GBC, however, clinical and genomic characterization of the ERBB2-altered subgroup has been limited. Methods: Patients with GBC treated at Memorial Sloan Kettering and Pontificia Universidad Católica de Chile with genomic tumor profiling between 2014 and 2021 were included. Clinical information was retrieved from electronic medical records. Categorical data were analyzed by Fisher exact test and time-to-event data were analyzed by Cox proportional hazards models. Results: During the study period 260 GBC patients underwent genomic profiling. The prevalence of ERBB2 alterations was 14% including 8% with ERBB2 gene amplification, 4.2% with ERBB2 mutation, 1.5% with concurrent amplification and mutation and 0.4% with ERBB2 fusion. There was no age difference between GBC patients with and without ERBB2 alterations (63.6 vs. 65.4; p = 0.36) and in both subgroups there was a majority of female patients (75% vs. 84%; p = 0.44). Patients with ERBB2-altered tumors had a different genomic profile with lower concurrent KRAS alterations (2% vs. 12%; p = 0.14) and higher prevalence of TP53 alterations (81% vs. 59%; p = 0.01). There was no difference in the prevalence of PIK3CA mutations (13% vs. 9%; p = 0.38). GBC patients with ERBB2 alterations had a longer overall survival (22.3 vs. 12.1 months; HR 0.54 95% CI 0.3 to 0.98). Conclusions: ERBB2 amplification and mutation are the most frequent potentially targetable alterations in GBC (14%). ERBB2-driven GBC has higher concurrent alterations of TP53, while KRAS alterations appear to be less frequent. While no particular clinical feature was associated with this subgroup, overall survival was longer.

A prospective, multicenter, phase II trial of albumin-paclitaxel plus cisplatin versus gemcitabine plus cisplatin in first-line treatment of advanced biliary tract tumors.

4099 Background: The prognosis of biliary system tumors is poor, Gemcitabine combined with cisplatin has been the standard first-line treatment for advanced biliary system tumors, but its efficacy and adverse effects are unsatisfactory. Albumin-paclitaxel is a novel paclitaxel with a broad-spectrum anti-tumor effect, which has been widely used in the treatment of digestive system malignant tumors. Therefore, we designed this study to investigate the efficacy and safety of the combination of albumin-paclitaxel and cisplatin compared with gemcitabine combined with cisplatin in patients with previously untreated advanced biliary tract tumors. Methods: This is a multicenter, randomized, controlled, investigator-initiated Phase II trial designed to enroll patients with unresectable, recurrent, or metastatic cholangiocarcinoma (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder carcinoma). After enrollment, patients were randomly assigned to the experimental TP group (albumin paclitaxel 125mg/m2 iv, D1, 8 cisplatin 75mg/m2 IV, D1 Q21 ) or the control GP group (gemcitabine 1000mg/m2 IV, D1, 8 cisplatin 75mg/m2 iv, D1 Q21) and received six cycles of chemotherapy. The primary endpoint was PFS, and the secondary endpoint was OS, ORR, and safety. Results: Up to January 2022, 67 patients were enrolled, the 41male and 26 female patients had a median age of 55(range 32-74) years. Of the 67 enrolled patients, 33 were randomly assigned to the TP group and 34 to the GP group. Among the these patients, 47 were diagnosed with intrahepatic cholangiocarcinoma, 7 with extrahepatic cholangiocarcinoma, and 13 with gallbladder cancer. 48 patients had completed at least 2 cycles of chemotherapy and were available for evaluation, mPFS in the TP and the GP groups was 7.7 and 7.5 months, respectively (HR 1.33, CI 0.61 - 2.91,P = 0.469), mOS in TP and GP groups was 12.1 months and 12.9 months, respectively (HR 1.62, 95% CI 0.67-4.17,P = 0.271). After the first assessment, the ORR was 39.4% and 35.3% in the TP group and the GP group, respectively. In terms of side effects, bone marrow suppression (61% vs 76%) was the most predominant adverse events in both groups, abnormal liver and kidney function (56% vs 67%), gastrointestinal reactions (including nausea, vomiting, diarrhea, constipation, etc.) (46% vs 43%), rash or allergy (44% vs 37%), and other side effects such as fever and influenza symptoms (21% vs 24%) were also observed in the TP group and the GP group. Conclusions: The result of this study showed that the regimen of albumin paclitaxel combined with cisplatin was non-inferior to gemcitabine combined with cisplatin in terms of PFS, OS and ORR, and the safety advantages of the combination of albumin paclitaxel and cisplatin make it a potential regiment for first-line treatment of advanced biliary tract tumors. Clinical trial information: ChiECRCT-20180167.

Lymphadenectomy and margin-negative resection for biliary tract cancer surgery in the United States-Differential technical performance by approach.

As minimally invasive surgery (MIS) approaches to biliary tract cancers become more commonplace, understanding the adequacy of their oncologic performance is key. The National Cancer Database 2010-2016 was queried for patients who underwent hepatectomy for intrahepatic cholangiocarcinoma (IHC) and T1b or more advanced gallbladder cancer (GBC). Patients were grouped by approach: open (OA), laparoscopic (LA), and robotic (RA). Margin status, rate of lymph node (LN) dissection, and yield of LN dissection were evaluated. This cohort of 8612 patients, including 4034 patients with IHC (OA: 3281, LA: 675, RA: 78) and 4578 patients with GBC (OA: 1893, LA: 2588, RA: 97), MIS was used 40% of the time. R0 resection was achieved in 82% OA, 84% LA, and 91% RA, p = 0.004. Rate of LN dissection was 53% (OA: 60%, LA: 42%, RA: 51%, p < 0.001). Among patients who underwent lymphadenectomy, 6 + LN were retrieved less commonly with a LA (OA: 27%, LA: 20%, and RA: 30%, p < 0.001). High-volume MIS hepatectomy centers were more likely to perform a lymphadenectomy (odds ratio [OR]: 1.41) and a sampling of 6 + LN (OR: 1.18). Regardless of approach, lymphadenectomy is underperformed nationwide for biliary tract tumors, particularly with LA. As the use of MIS grows for the treatment of biliary tract cancers, scrutiny of oncologic outcomes is required.

TO ESTIMATE THE LEVELS OF CA19-9 AND ITS SIGNIFICANCE IN DIAGNOSIS AND TREATMENT OF PANCREATICOBILIARY AND GASTROINTESTINAL MALIGNANCIES

Objective: This study was designed and conducted to establish the relationship of biomarker CA19-9 levels in pancreaticobiliary and gastrointestinal malignancies. Methods: 50 patients with confirmed diagnosis of pancreaticobiliary and gastrointestinal malignancies and 30 age and gender matched controls were included in the study. Serum values of CA19-9 were determined in patients before surgery and chemotherapy. Results: In our present study, maximum number of patients were in the age group of 51–60 years. Mean levels of serum CA19-9 in patients (n=50) are 146.28±156.87 U/mL. Total patients (n=50), in 19 patients CA19-9 levels were ≤37 U/mL and in 31 patients CA19-9 levels were &gt;37 U/mL. CA19-9 levels were highest in pancreatic and cholangiocarcinoma. Conclusion: High sensitivity and specificity of CA19-9 in pancreatic and biliary tract tumors identified CA19-9 as a best validated biomarker.

Therapeutic Effect and Prognosis of Biliary Tract Tumor Transformation.

Biliary tract tumor is a common malignant disease in clinical practice. Its incidence rate and mortality rate are high, which seriously endangers the health of the people. At present, gastrointestinal surgery is mainly used to treat patients at home and abroad. This paper discusses the main risk factors of biliary tract cancer transformation, analyzes its prognostic characteristics and clinical efficacy, and compares them by comprehensive evaluation methods such as observation group control method, blood routine examination and treatment. The results are as follows: the postoperative adverse reactions in the control group are more obvious than those in the experimental group. There were no obvious clinical manifestations or adverse reactions in the experimental group. The therapeutic effect of biliary tumor transformation can effectively help patients improve their quality of life. Through the prognosis recovery of biliary tract tumor transformation treatment, the health level of patients in the experimental group was higher than that in the control group.

Diagnostic Utility of the PD-L1 Immunostaining in Biopsy Specimens of Patients with Biliary Tract Neoplasms

BackgroundAnti-programmed death 1/programmed death ligand 1 (PD1/PD-L1) antibodies have been successfully used as treatment agents for several solid tumors; however, it is difficult to predict their effectiveness. We evaluated whether biopsy specimens could predict the positive status of PD-L1 in surgically resected tissue. MethodsAmong 91 patients who underwent tissue sampling with endoscopic or liver biopsy before surgery for biliary tract neoplasms in an academic center, 45 (49%) patients were selected for retrospective analysis because the quality and quantity of their biopsy specimens were adequate for histologic evaluation. We performed immunohistochemical staining to investigate the PD-L1 expression in both resected and biopsy specimens. The percentage of the positively stained cells was calculated for subsequent use in the correlation investigation. ResultsThe biopsy methods were endoscopic retrograde cholangiopancreatography (ERCP) in 28 cases, percutaneous liver biopsy in 10 cases, and endoscopic ultrasound fine-needle aspiration in 7 cases. Among the 45 patients, when patients with > 10% positive tumor cells in surgically resected tissues were regarded as truly positive PD-L1, the positive and negative concordance rates between surgically resected tissues and biopsy samples were 56% (5/9) and 100% (36/36), respectively. With regard to the use of preoperative biopsy as a diagnostic tool, all (5/5) PD-L1-positive patients had a positive resected specimen. The accuracy of each biopsy method was as follows: ERCP, 89% (25/28); fine-needle aspiration, 86% (6/7); and liver biopsy, 100% (10/10). ConclusionsBiopsy samples could be a surrogate material for the assessment of the PD-L1 expression with substantial positive and high negative concordance rates.

A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of select human epidermal growth factor receptor 2 (HER2)-expressing solid tumors (DESTINY-PanTumor02).

TPS623 Background: Human epidermal growth factor receptor 2 (HER2) is an established therapeutic target in both breast and gastric cancer. However, HER2-targeting therapies are not approved beyond these malignancies despite a high prevalence of HER2 expression across cancers of epithelial origin. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In a cohort of pretreated patients with multiple HER2-expressing tumors, T-DXd demonstrated promising antitumor activity, with an investigator-assessed confirmed objective response rate of 40.9% (9 of 22 patients) and median progression-free survival of 11.1 months (95% CI, 5.4-20.5 months; Tsurutani J, et al. Cancer Discov. 2020;10:688-701). Here we describe the phase 2 DESTINY-PanTumor02 trial evaluating T-DXd in patients with select HER2-expressing solid tumors. Methods: DESTINY-PanTumor02 (NCT04482309) is an open-label, multicenter, multicohort, phase 2 study evaluating T-DXd for the treatment of patients with select HER2-expressing locally advanced, unresectable, or metastatic tumors. The study will consist of 7 cohorts of patients (n≈40 each) with urothelial bladder, biliary tract, cervical, endometrial, ovarian, pancreatic, or rare tumors (tumors excluding those in the other cohorts and breast, gastric, colorectal, and non-small cell lung cancer). Patients are required to have disease progression following ≥1 prior systemic treatment for advanced or metastatic disease or have no satisfactory alternative treatment options. Prior HER2-targeting therapy is allowed. The primary endpoint is investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include duration of response, disease control rate, progression-free survival (all per investigator assessment according to RECIST 1.1), overall survival, safety, pharmacokinetics, and immunogenicity. Previously presented at the ESMO Congress 2021, FPN: 1869 TiP, Meric-Bernstam et al. Reused with permission. Clinical trial information: NCT04482309.

Bortezomib-Encapsulated Dual Responsive Copolymeric Nanoparticles for Gallbladder Cancer Targeted Therapy.

Gallbladder cancer (GBC) is a rare but the most malignant type of biliary tract tumor. It is usually diagnosed at an advanced stage and conventional treatments are unsatisfactory. As a proteasome inhibitor, bortezomib (BTZ) exhibits excellent antitumor ability in GBC. However, the long‐term treatment efficacy is limited by its resistance, poor stability, and high toxicity. Herein, BTZ‐encapsulated pH‐responsive copolymeric nanoparticles with estrone (ES‐NP(BTZ; Ce6)) for GBC‐specific targeted therapy is reported. Due to the high estrogen receptor expression in GBC, ES‐NP(BTZ; Ce6) can rapidly enter the cells and accumulate near the nucleus via ES‐mediated endocytosis. Under acidic tumor microenvironment (TME) and 808 nm laser irradiation, BTZ is released and ROS is generated by Ce6 to destroy the “bounce‐back” response pathway proteins, such as DDI2 and p97, which can effectively inhibit proteasomes and increase apoptosis. Compared to the traditional treatment using BTZ monotherapy, ES‐NP(BTZ; Ce6) can significantly impede disease progression at lower BTZ concentrations and improve its resistance. Moreover, ES‐NP(BTZ; Ce6) demonstrates similar antitumor abilities in patient‐derived xenograft animal models and five other types of solid tumor cells, revealing its potential as a broad‐spectrum antitumor formulation.

Yolk sac tumor of biliary tract: A rare biliary space-occupying entity in children

Yolk sac tumor(YST) is one of the malignant germ cell tumors that usually involves the gonads (ovaries and testes). Only one case of biliary YST was reported according to PubMed. Here we reported a case of a 2-year-old boy who presented with obstructive jaundice and was finally diagnosed as biliary YST. Basing on this case report, we review the literature about biliary space-occupying lesions and suggest a more comprehensive differentiation among children with obstructive jaundice resulting from biliary mass.

Living Donor Liver Transplantation for Samll Ducts Intrahepatic Cholangiocarcinoma with Neoadjuvant Chemotherapy: A Pioneer Experience in South America

Introduction: Cholangiocarcinomas are heterogeneous biliary tract tumors with dismal prognosis. Curative treatment options are limited to early stage disease, and include surgical resection and liver transplantation after neoadjuvant therapy. Brazilian legislation does not allow the allocation of organs from deceased donors to patients with cholangiocarcinoma, leaving the option the transplant with a living donor.

Abstract P110: Neandertal introgressions contribute to upper aero-digestive tract tumor patient survival and identify patients who may benefit from STING agonist treatment

Abstract Background: Admixture of archaic (Neandertal and Denisova) and ancestral genes enhanced natural immunity during out of Africa migrations and modulates modern susceptibility to autoimmunity and cancer. We investigated a series of functional interactions between archaic and ancestral STING1 and TLR genes to identify vulnerabilities that could be addressed by STING agonist therapy. Methods: Gene variants from 10,389 cancer patients (pts) were obtained from TCGA. Archaic sequences were accessed using UCSD genome browser 410. Linkage disequilibrium was investigated using LDlink v5.0. Patient 1 was treated within NCT04144140. Results: STING1 variants were overrepresented in gastroesophageal cancer pts. V48V (rs7447927-C&amp;gt;G) with GWAS of lower rate of Asian esophageal cancer was in linkage disequilibrium with the reference alleles of the partially active HAQ and REF variants, and with rs13153461, present in Neandertal sequences. STING1 rs7447927-G was also associated with HLA A*24:02 (p&amp;lt;0.001), A*02:06 (p=0.01), and A*31:01 (p=0.02), of Neandertal origin. We then investigated a potential epistasis between STING1 rs7447927-G and TLR variants associated with decreased H. pylori prevalence: Neandertal-like TLR10 I775V (rs4129009) and ancestral TLR6 S249P (rs5743810). No independent prognosis was identified in 32 TCGA legacy studies; however, in upper aerodigestive (oral cavity, oropharynx, esophageal, gastric, biliary tract) tumor pts who carried reference/heterozygous TLR6 S249P and/or reference TLR10 I775, Neandertal-associated STING1 rs7447927-G zygosity was a strong predictor of survival. Hazards ratio for rs7447927-GG vs GC (4.8 vs 2.7 yrs. median survival), and GG vs CC (4.8 vs 1.8 yrs.) were respectively 0.71 and 0.53, N=713, p=0.0003. Patient 1 was a 75 yr.-old male esophageal cancer pt with GERD, Barrett’s esophagus and TLR6 S249/STING1 rs7447927-GC, who was progressing from anti-PD1 and chemotherapy and received 75 microg intra-tumoral injections of the STING agonist E7766. Non treatment-related grade 2 events of anemia and hyponatremia, serum IFNbeta and IP10 levels induction, 20% tumor size reduction including abscopal effects, and 6.3 months PFS benefit were observed. Conclusion: Genotyping of STING1, TLR6-10 variants could contribute to identify pts who may benefit from E7766 treatment. Citation Format: Antonio Gualberto, Tenghui Chen, Catherine Scholz, Jason Luke. Neandertal introgressions contribute to upper aero-digestive tract tumor patient survival and identify patients who may benefit from STING agonist treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P110.

“Diagnostic-Therapeutic Management in Patients with Extrahepatic Bile Duct Cancer”

Introduction: Biliary tract tumors, or cholangiocarcinomas (CCAs), comprise a heterogeneous group of malignant tumors that can affect any part of the biliary tree, from the interlobular canals of Hering to the primary biliary duct. In the last 20-30 years, the incidence of these tumours has increased especially after the introduction of the new imaging techniques endoscopic retrograde cholangiopancreatography (ERCP, percutaneous transhepatic cholangiography) and the increased interest for this pathology. Objective: To evaluate the diagnostic methods and therapeutical results in patients with extrahepatic bile duct cancer. Material and Method: This cross-sectional study was conducted in the Department of Surgery, Department of Surgery, Mymensingh Medical College Hospital, Mymensingh, Bangladesh from Jun-2018 to July-2021. We included 124 consecutive patients with suspected bile duct cancer who underwent endoscopic retrograde cholangiopancreatography (ERCP). Every patient underwent an ultrasound (US) examination before ERCP. ERCP was considered as the “gold standard” for diagnosis. The therapy applied consisted of endoscopic stenting, US guided biliary drainage or surgery. The sensitivity, specificity and accuracy were calculated for every tumour localisation and also globally for all tumours. Results. The sensitivity, specificity and accuracy of US were 85.9%, 76.9% and 84.4% for hilar localization, 59.1%, 50% and 57.1% for the mid common bile duct (CBD) and 33.3%, 42.8% and 36.8% for the distal CBD tumours. The global performances for US in diagnosing extrahepatic chlonagiocarcinoma were 73.5%, 61.5% and 70.9%. In 73 cases (74.5%) an endoscopic stent was placed. In 11 cases (11.2%) we performed an US guided biliary drainage and in 14 cases (14.2%) surgery was recommended. Conclusion: Ultrasonography proved to be a reliable method for the diagnosis of bile duct cancer in spite of its low accuracy for distal localization. The combination of the two investigations (US and ERCP) was very efficient in the management of these patients. Endoscopic stenting for hilar localization is a good therapeutical option.

Perineural Invasion and Associated Pain Transmission in Pancreatic Cancer.

Simple SummaryPerineural invasion is a complicated process involving a series of cells and extracellular matrix components in the tumor microenvironment, particularly the crosstalk between cancer cells and neurons. Perineural invasion occurs in many malignant tumors, including gastric carcinoma, biliary tract tumor and pancreatic cancer. It is identified in approximately 80–100% of pancreatic cancer patients and is correlated with poor survival and decreased quality of life. Extensive studies have revealed the subtle molecule regulatory mechanisms during perineural invasion, as well as the potential causal link with pancreatic cancer-associated pain. Here, we introduce the underlying mechanism of perineural invasion and its possible relationship with the intractable pain in pancreatic cancer patients.Pancreatic ductal adenocarcinoma (PDAC) is one of the cancers with the highest incidence of perineural invasion (PNI), which often indicates a poor prognosis. Aggressive tumor cells invade nerves, causing neurogenic inflammation; the tumor microenvironment also induces nerves to undergo a series of structural and functional reprogramming. In turn, neurons and the surrounding glial cells promote the development of pancreatic cancer through autocrine and/or paracrine signaling. In addition, hyperalgesia in PDAC patients implies alterations of pain transmission in the peripheral and central nervous systems. Currently, the studies on this topic are relatively limited. This review will elaborate on the mechanisms of tumor–neural interactions and its possible relationship with pain from several aspects that have been focused on in recent years.

Expert opinion on nutritional treatment for patients with biliary tract tumors

Expert opinion on nutritional treatment for patients with biliary tract tumors

Pharmacogenetic markers of chemotherapy toxicity in gastrointestinal tumors: a preliminary analysis

Aim. To assess the association between the carriage of minor allelic variants of 8 genes that encode key enzymes involved in the metabolism of anticancer drugs (DPYD, GSTP1, MTHFR, UGT1A1) and cell repair (XPC, ERCC1, TYMP, NQO1) and the severity of adverse drug events in patients with common gastrointestinal tumors. Tasks. To study the frequency of minor allelic variants of the DPYD, GSTP1, MTHFR, UGT1A1, XPC, ERCC1, TYMP, NQO1 genes; to assess the frequency and severity of adverse drug events of chemotherapy treatment in the study population. Materials and methods. For the period from October 2020 to April 2021, 56 patients (women 29, men 27) with verified malignant tumors of the gastrointestinal tract were included in a prospective clinical study as a part of the RSF grant No. 20-75-10158. The mean age was 62.311.4 years. Colon cancer was detected in 24 patients, tumors of the esophagus and stomach in 19 patients, tumors of pancreas and biliary tract in 13 patients. First-line palliative chemotherapy was given to 27 patients, adjuvant 19 patients, neoadjuvant 10 patients. All patients had not previously received cytotoxic or radiation treatment. Point nucleotide variants of genes DPYD, XPC, GSTP1, MTHFR, ERCC1, UGT1A1, TYMPS, NQO1 were determined by hybridization analysis on biological microchips. Differences in the tolerance of cytotoxic therapy (5-fluorouracil, platinum preparations, irinotecan) depending on the genotype were assessed using Fishers exact test. Results. The average number of chemotherapy courses received was 4.22.6 (112). There was a statistically significant difference in the tolerability of chemotherapy in patients with minor allelic variants of the GSTP1 rs1695 (p=0.03), ERCC1 rs11615 (p=0.01), and UGT1A1 rs8175347 (p=0.003) genes. Conclusion. The use of hybridization analysis on biological microchips to assess allelic variants responsible for the tolerability of cytotoxic therapy is reasonable and requires further prospective assessment.