Tract Adenocarcinoma Research Articles

Aberrant Expression of Pneumocytic Markers (TTF-1 and Napsin-A) in Biliary Duct and Gallbladder Adenocarcinomas; A Potential Diagnostic Pitfall.

Cholangiocarcinomas and gallbladder carcinomas are epithelial tumours with biliary differentiation. On histology and immunohistochemistry, they resemble adenocarcinomas and possess overlapping immunohistochemical profiles. Diagnosing these tumours is best done using appropriate imaging and clinical features with compatible immunohistochemistry. Immuno-staining for thyroid transcription factor-1 (TTF-1) and novel aspartic proteinase of pepsin A (Napsin-A) is believed to be specific for primary pulmonary adenocarcinomas. We herein report uncommon instances of strong and diffuse expression of these markers in two examples of adenocarcinomas arising from the bile duct and gallbladder. A review of the literature and a summary of similar studies relating to aberrant TTF-1 and Napsin-A expression in biliary tract adenocarcinomas are presented.

7 Oral: SHR-1701 combined with famitinib for patients with previously treated advanced biliary tract or pancreatic ductal adenocarcinoma: A phase II open-label, single-arm study

7 Oral: SHR-1701 combined with famitinib for patients with previously treated advanced biliary tract or pancreatic ductal adenocarcinoma: A phase II open-label, single-arm study

GASTROINTESTINAL TRACT ADENOCARCINOMA IDENTIFIED IN CAPTIVE GILA MONSTERS (HELODERMA SUSPECTUM) IN A NORTH AMERICAN ZOO, 1997-2023.

Neoplasia in the Gila monster (Heloderma suspectum) is not commonly investigated, and literature regarding the prevalence and type of neoplasms that affect this species is sparse. Gastrointestinal tract adenocarcinoma (GTA) in particular has only been reported twice in Gila monsters, once in the small intestine and once in the colon. In this case series, 50% (7/14) of the Gila monsters presented to the pathology service at Smithsonian's National Zoo and Conservation Biology Institute (SNZCBI) over the span of 26 yr (1997-2023) were found to have intestinal and/or colonic adenocarcinoma. The frequency of GTA reported in this collection likely represents a multifactorial etiology including geriatric age of specimens, chronic inflammation, gastrointestinal tract infection, and/or increased cognizance of the disease because of previous reports within the collection. An increased awareness of GTA in this species may lead to improved recognition of the disease.

Bevacizumab Erlotinib Switch Maintenance in Chemo-Responsive Advanced Gallbladder and Cholangiocarcinoma (BEER BTC): A Multicenter, Open-Label, Randomized, Phase II Trial.

Patients with chemotherapy-responsive advanced biliary tract cancers (BTCs) are usually observed after 6 months of gemcitabine-based therapy. There is limited prospective evidence for maintenance strategies after chemotherapy. This investigator-initiated, open-label, randomized, integrated phase II-III study enrolled adult patients with advanced BTC from two cancer centers in India. Patients with histologically confirmed advanced biliary tract adenocarcinoma who had at least disease stabilization after 6 months of gemcitabine-based chemotherapy were randomly assigned (1:1) to either active surveillance or switch maintenance, which was a combination of bevacizumab 5 mg/kg intravenous once every 21 days plus erlotinib 100 mg once daily. Both arms were continued until disease progression, unacceptable toxicity, or patient decision to withdraw. The primary end point of the phase II component of the trial was investigator-evaluated progression-free survival. This trial is registered with Clinical Trials Registry of India (CTRI/2019/05/019323I). From May 2021 to November 2022, 98 patients were randomly assigned to active surveillance (n = 49) or bevacizumab-erlotinib (n = 49). A majority of patients had gallbladder cancer (80%). The median follow-up was 13.4 months. The median progression-free survival was 3.1 months (95% CI, 2.47 to 3.64) in the active surveillance group versus 5.3 months (95% CI, 3.53 to 7.04) in the bevacizumab-erlotinib group (hazard ratio, 0.51 [95% CI, 0.33 to 0·74]; P = .0013). The most common grade 3 class-specific adverse events associated with bevacizumab-erlotinib were acneiform rash 1 (2%) and oral stomatitis 1 (2%) with erlotinib and bleeding 1 (2%) with bevacizumab. The combination of bevacizumab and erlotinib as switch maintenance improves progression-free survival with an acceptable safety profile compared with active surveillance in patients with advanced BTCs in this phase II study. The trial moves on to the phase III component to evaluate improvement in overall survival.

A phase II multicenter study of enfortumab vedotin with or without pembrolizumab in rare genitourinary tumors (E-VIRTUE).

TPS4628 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting nectin-4 with a monomethyl auristatin E (MMAE) payload, a potent microtubule inhibitor. It is standard of care (SOC) in metastatic urothelial carcinoma in combination with pembrolizumab in untreated patients and as monotherapy in post-chemotherapy, post-immune checkpoint blockade (ICB) patients. Nectin-4 expression has been retrospectively observed in 66.7-100% of urinary tract adenocarcinoma, 70-100% of urinary tract squamous cell carcinoma (SCC) (Case et al., 2022; Hoffman-Censits et al., 2021) and 36% of testicular germ cell tumors (GCTs) (The Human Protein Atlas). Metastatic urinary tract adenocarcinoma and SCC, and treatment refractory GCTs do not have an established SOC. Given the known nectin-4 expression, we hypothesize that EV with or without pembrolizumab will be active in these rare GU tumors. Methods: E-VIRTUE is an open-label, non-randomized, Phase 2 multicenter study. Eligible patients must have locally advanced or metastatic urinary tract pure adenocarcinoma, urinary tract pure SCC or refractory GCTs and have measurable disease by RECIST 1.1. Patients may have received any number of lines of prior systemic therapy except EV or other MMAE-based ADCs, and GCT patients must be refractory to all curative SOC treatments. Each histology will have an ICB-naïve and post anti-PD-1/PD-L1 ICB cohort: ICB-naïve patients will be given EV 1.25 mg/kg (maximum 125 mg) on Days 1 and 8 and pembrolizumab 200 mg on Day 1 of 21-day cycles, and post ICB patients will be given EV 1.25 mg/kg (maximum 125 mg) on Days 1, 8 and 15 of 28-day cycles. EV will be given for up to 5 years and pembrolizumab will be given for up to 2 years, or until progressive disease (PD) or unacceptable toxicity. Patients who stop pembrolizumab after achieving a complete response may resume it for 1 year after developing PD. The primary objective is to evaluate the objective response rate (ORR) in all cohorts. Secondary objectives include safety, progression-free survival (PFS) and overall survival (OS). The initial 6 cohorts will each be evaluated with exploratory intent. With 10 patients in each cohort, an exact binomial test with a 10% one-sided significance level will have 85.3% power to detect the difference between a very low (5%) ORR and a higher (30%) ORR. If there are ≥2/10 objective responses in any cohort, activity will be demonstrated. Additional histologies may be added after nectin-4 data emerges to justify their inclusion. Exploratory objectives include estimating the level of nectin-4 expression for each histology, performing DNA and RNA sequencing of tumor and blood samples, and observing changes in levels of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) with treatment and disease status. Clinical trial registration NCT06041503. Clinical trial information: NCT06041503 .

312P Trastuzumab plus lapatinib for second-line treatment of human epidermal growth factor receptor 2-positive advanced biliary tract adenocarcinoma: A retrospective single-centre study

312P Trastuzumab plus lapatinib for second-line treatment of human epidermal growth factor receptor 2-positive advanced biliary tract adenocarcinoma: A retrospective single-centre study

Clinical and socioeconomic determinants of survival in biliary tract adenocarcinomas.

Despite advances in detection and treatments, biliary tract cancers continue to have poor survival outcomes. Currently, there is limited data investigating the significance of socioeconomic status, race/ethnicity, and environmental factors in biliary tract cancer survival. To investigate how socioeconomic status and race/ethnicity are associated with survival. Data from the Surveillance, Epidemiology, and End Results database for biliary and gallbladder adenocarcinomas were extracted from 1975 to 2016. Socioeconomic data included smoking, poverty level, education, adjusted household income, and percentage of foreign-born persons and urban population. Survival was calculated with Cox proportional hazards models for death in the 5-year period following diagnosis. Our study included 15883 gallbladder, 11466 intrahepatic biliary, 12869 extrahepatic biliary and 7268 ampulla of Vater adenocarcinoma cases. When analyzing county-specific demographics, patients from counties with higher incomes were associated with higher survival rates [hazard ratio (HR) = 0.97, P <0.05]. Similarly, counties with a higher percentage of patients with a college level education and counties with a higher urban population had higher 5-year survival rates (HR = 0.96, P = 0.002 and HR = 0.97, P = 0.004, respectively). Worse survival outcomes were observed in lower income counties while higher income and education level were associated with higher 5-year overall survival among gallbladder and biliary malignancies.

Abstract 3987: PD-L1 antigen stability using PD-L1 IHC pharmDx on human cancer tissues

Abstract Diagnostic evaluation and selection of potential pembrolizumab-responsive patients is achieved by determining the programmed cell death ligand-1 (PD-L1) expression using the companion diagnostic PD-L1 IHC 22C3 pharmDx assay, for several indications. PD-L1 expression is evaluated by immunohistochemistry (IHC) and is currently the most widely used selective biomarker for response to pembrolizumab anti-PD-1 therapy. Antigen stability on cut tissue sections, also referred to as cut section stability (CSS), and its impact on IHC results is of interest when determining PD-L1 positive or negative status for clinical trials and diagnostic purposes. Since the stability of cut sections from formalin-fixed paraffin-embedded (FFPE) tissue relies on retention of PD-L1 antigenicity following tissue sectioning, the aim of these studies was to measure CSS across multiple tumor indications using combined positive score (CPS). The impact of aged cut sections was evaluated for PD-L1 expression based on pathologist CPS scores of blinded and randomized stained sections. To assess CSS, fresh unstained 4µm cut tissue sections were stored in the dark at 2-8 °C. Staining was performed according to the instructions for use at predefined timepoints. Studies included neoplastic specimens from biliary tract adenocarcinoma (BTAC), cervical cancer (CC), colorectal (CRC) and gastric (GC) carcinoma, esophageal cancer (EC), head and neck squamous cell carcinoma (HNSCC), nasopharyngeal (NPC), ovarian (OC), renal cell (RCC), and triple negative breast (TNBC) carcinoma. Data for each indication and timepoint were used to evaluate average drift in CPS scores over time, starting with scores from a set of respective slides stained at timepoint zero, prior to aging of unstained cut slides. CSS for each specimen within each indication was based on the intersection point of the two-sided 95% confidence interval for the regression line on CPS drift with allowable drift limits. Overall CSS for each indication was defined based on the specimen that exhibited the shortest shelf-life. Linear regression analysis was performed to evaluate average CPS drift over time and define the CSS per indication. This analysis identified the following CSS (in days) for each tumor type when stored at 2-8 °C: 105 (CC), 113 (OC), 115 (BTAC), 135 (EC), 163 (GC), 180 (RCC), 197 (HNSCC), 231 (TNBC), 240 (NPC), and 300 (CRC). The minimal shelf life for unstained cut sections stored at 2-8 °C across the 10 indications in these studies was 105 days, indicating a possible minimum threshold for indications tested when sectioned specimens are stored at 2-8 °C. These data provide high confidence in determining PD-L1 expression on properly stored aged cut sections. Commercial claims may be shorter based on region, as specified in the local instructions for use. Citation Format: Megan Kalpakoff, Emily Olander, Kelci Jones, Stephanie Hund, Tiffany Evans, Joseph Barreto, Deanna Moquin, Grant Toland, Siena Tabuena-Frolli, Kristopher Kersch, Karina Kulangara, Jeanette Musser. PD-L1 antigen stability using PD-L1 IHC pharmDx on human cancer tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3987.

Prognostic significance of tumour budding in noncolorectal gastrointestinal tract and pancreatobiliary tract: a systematic review and meta-analysis.

Tumour budding shows promise as a prognostic factor in various cancers, but its widespread application is hindered by the lack of large, validated studies and standardized criteria. This meta-analysis aims to review and examine the prognostic role of tumour budding specifically in noncolorectal gastrointestinal and pancreatobiliary tract cancers, broadening our perspective on its clinical relevance. The literature review was conducted through PubMed, Embase, and Web of Science from inception till 20 February 2023. Pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) were calculated to assess the relation between tumour budding and clinicopathologic features, as well as overall survival. Each study was evaluated using the Newcastle-Ottawa Scale and both heterogeneity and publication bias were analysed. In this meta-analysis of 57 studies across various cancer types, multivariate HR revealed worse overall survival in oesophageal squamous cell carcinoma (HR 3.34 [95% CI 2.21-5.04]), gastric adenocarcinoma (2.03 [1.38-2.99]), pancreatic ductal adenocarcinoma (2.56 [2.02-3.25]), and biliary tract adenocarcinoma (3.11 [2.46-3.93]) with high-grade tumour budding. Additionally, high-grade tumour budding consistently correlated with adverse clinicopathological features, including lymph node metastasis, lymphovascular invasion, and distant metastasis without any observed inverse association. High heterogeneity was noted. Our study suggests that tumour budding is a valuable prognostic marker in various cancers. Nonetheless, standardized criteria tailored to specific organ types are necessary to enhance its clinical utility.

Prevalence and Pattern of GATA3 Immunohistochemical Expression in Female Genital Tract Adenocarcinomas.

GATA3 immunohistochemistry has been described as a highly sensitive marker in determining carcinomas of breast and urothelial origin. In the gynecologic system, it can be used as a marker to diagnose mesonephric or mesonephric-like carcinomas and trophoblastic tumors. The present study was performed to determine the diagnostic value of GATA3 in gynecological adenocarcinomas. A total of 187 samples from different types of endometrial, endocervical, and ovarian carcinomas were analyzed for intensity and percentage of GATA3 expression in tumor cells. The relationship between GATA3 expression and clinicopathological parameters was investigated. A total of 187 patients including 101 ovarian, 77 endometrial, and 9 endocervical adenocarcinomas were investigated. Weak and focal expression of this marker was observed in 5. 1% (4/77) endometrial, 12.9% (13/101) ovarian, and 11.1% (1/9) endocervical adenocarcinomas. The mean H score in all subtypes was less than 10.6 (2-35). There was no statistically significant correlation between GATA3 expression in tumor cells with clinical stage, and tumor recurrence or metastasis. GATA3 is infrequently, weak, or focally expressed in most of the common gynecological adenocarcinomas.

Same-session endoscopic diagnosis and symptom palliation in pancreato-biliary malignancies: Clinical impact of rapid on-site evaluation (ROSE).

Background and study aims Besides increasing adequacy, rapid on-site evaluation (ROSE) during endoscopic ultrasound (EUS) or endoscopic retrograde cholangiopancreatography (ERCP) may impact choices and timing of subsequent therapeutic procedures, yet has been unexplored. Patients and methods This was a retrospective evaluation of a prospectively maintained database of a tertiary, academic centre with availability of ROSE and hybrid EUS-ERCP suites. All consecutive patients referred for pathological confirmation of suspected malignancy and jaundice or gastric outlet obstruction (GOO) between Jan-2020 and Sep-2022 were included. Results Of 541 patients with underlying malignancy, 323 (59.7%) required same-session pathological diagnosis (male: 54.8%; age 70 [interquartile range 63-78]; pancreatic cancer: 76.8%, biliary tract adenocarcinoma 16.1%). ROSE adequacy was 96.6%, higher for EUS versus ERCP. Among 302 patients with jaundice, ERCP-guided stenting was successful in 83.1%, but final drainage was completed in 97.4% thanks to 43 EUS-guided biliary drainage procedures. Twenty-one patients with GOO were treated with 15 EUS-gastroenterostomies and six duodenal stents. All 58 therapeutic EUS procedures occurred after adequate ROSE. With ERCP-guided placement of stents, the use of plastic stents was significantly higher among patients with inadequate ROSE (10/11; 90.9%) versus adequate sampling (14/240; 5.8%) P <0.0001; OR 161; 95%CI 19-1352). Median hospital stay for diagnosis and palliation was 3 days (range, 2-7) and median time to chemotherapy was 33 days (range, 24-47). Conclusions Nearly two-thirds of oncological candidates for endoscopic palliation require contemporary pathological diagnosis. ROSE adequacy allows, since the index procedure, state-of-the-art therapeutics standardly restricted to pathologically confirmed malignancies (e.g. uncovered SEMS or therapeutic EUS), potentially reducing hospitalization and time to oncological treatments.

Exploring virulence factors of Helicobacter pylori isolated from gastric biopsy.

Helicobacter pylori (H. pylori) colonizes human gastric mucosa and is classified as class one carcinogenic bacteria. In this regard, this study aimed to detect major virulence factors in H. pylori strains recovered from gastric biopsy in patients referred to Aras Clinique in Ardabil, northwest of Iran (2019-2021). In this descriptive-cross sectional study, 287 dyspeptic patients were included. For bacterial isolation, gastric biopsy specimens (n=287) were taken from gastric antrum, then aseptically were cultured on the selective medium and incubated at 37C in microaerophilic conditions for 3-5 days. 25.18% of all (n = 70) patients were found to be infected withH. pylori uponendoscopy. Of them, 9 patients (12.857%) and 2 patients (2.875%) had peptic ulcer disease and gastric cancer respectively. According to the different patterns of virulence factors, 57 virutypes were identified in which oipA-vacAs1-vacAm2 (3, 4.28% n =) and oipA-vacAs1-vacAs2-vacAm2 (3, 4.28% n =) were the most common patterns. The simultaneous presence of vacAS2, vacAm2 and hopQ2 genes was observed in both patients with gastric cancer. OipA (n = 562.5%), VacAs1 (n = 6.75%), VacAs2 (n = 6.75%), and VacAm2 (n = 787.5%) were found to be the most prevalent virulence factor. According previous studies, it is confirmed that the cagPAI gene cluster and vacA gene alleles are strongly correlated with gastritis and gastrointestinal tract adenocarcinomas. Our study indicated that 50% of the indigenous strains of H. pylori harbor these oncogenic genes and they are hypervirulent.

Unusual pattern of microsatellite instability in gastric neuroendocrine tumor

Abstract Introduction/Objective Evaluation of microsatellite instability (MSI) is routinely performed in gastrointestinal tract adenocarcinomas including gastric adenocarcinoma. It confers a good prognosis and is predictive of response to immunotherapy. However, the role of MSI in prognosis and treatment of well differentiated neuroendocrine tumors is controversial. Accordingly, MSI status is not extensively evaluated in neuroendocrine tumors. Limited available literature reports the usual paired losses and loss of MSH6 only in gastric well differentiated neuroendocrine tumor is unheard of. The purpose of this case is to report loss of MSH6 only in a patient with gastric well differentiated neuroendocrine tumor, grade 2. Methods/Case Report A 64-year-old female presented with abdominal pain and nausea. Endoscopy revealed erythematous nodules in the stomach which were removed by endoscopic mucosal resection. Microscopically, the tumor had vague nested appearance with areas more infiltrative appearance. However, cytologically tumor cells were bland and monotonous. Immunohistochemical stains showed the tumor cells to be positive for synaptophysin, chromogranin, pancytokeratin, and Cam 5.2, and negative for CK 7, CK 20 and CDX2. Ki-67 proliferation index was 3.7%. Therefore, diagnosis of well differentiated neuroendocrine tumor, grade 2 was rendered. Additionally, MSI by immunohistochemistry was ordered which showed intact nuclear expression of MSH2, MLH1 and PMS2 but loss of nuclear expression for MSH6. Results (if a Case Study enter NA) NA Conclusion This case highlights the fact that MSI in gastric neuroendocrine tumors can manifest as only MSH6 loss. Whether or not, it is of clinical and prognostic utility, is still up for debate.

Trastuzumab (T) plus gemcitabine-cisplatin (GC) for treatment naïve HER2 positive biliary tract adenocarcinomas (BTC): A multicentre open-label, phase II study (TAB).

4089 Background: HER2 over-expression or amplification is seen in 4%-16% of BTCs and is a therapeutic target of interest. Gemcitabine-cisplatin (GC) is one of the standard regimens of choice in advanced BTCs. We aimed to evaluate the clinical activity of GC plus anti-HER2 antibody trastuzumab as initial treatment in HER2-positive BTC. Methods: This study was an investigator-initiated, open-label, single-arm, multi institutional, phase II trial in patients (pts) aged 18 years or older with HER2-positive (defined as IHC 3+ or IHC 2+ and FISH positive), treatment naïve BTCs. Patients received GC (Gem 1000 mg/m2 IV and Cisplatin 25mg/m2 IV on day 1 and 8, q 3 weeks) combined with Trastuzumab at 8mg/kg as initial dose followed by 6mg/kg q 3 -weekly till disease progression (PD) or unacceptable toxicities. The primary end-point of the study was an improvement in 6-month progression free survival (PFS) from 40% (historical cohort) to 60% in the study arm. Next generation sequencing to evaluate HER2 and other mutations was conducted on the tissue samples of the patients screened for this study. Results: From March 2020 to August 2022, of the 876 patients were screened for HER2 status, 118 (13.4%) were found to have HER2 positive status and 90 of them were enrolled into the study. A majority of patients had GBC (95.6%) and at-least 2 sites of metastatic disease beyond primary (77.8%). With a median follow up of 8.5 months, 72 patients had PD and the median PFS was 7.95 months (95% CI: 6.84 -9.06; median overall survival (OS) was 9.95 months (95% CI: 9.25 – 10.66). Partial responses (PR) were seen in 8 patients (8.9%) and 61 had stable disease (67.7%) for a disease control rate of 76.6%. Common chemotherapy-related grade 3 or 4 adverse events were anemia [26 (28.9%)], neutropenia [18(20%)] and thrombocytopenia [8(8.9%)] while one patient has Trastuzumab related asymptomatic fall in cardiac ejection fraction (&gt;=10%). The presence of isolated TP53 mutations predicted for inferior PFS compared to patients with other mutations (TERT promoter, HER2, PIK3CA etc) or no detected mutations (6.51 months vs. 12.02 months vs. 10.58 months; p&lt;0.001). Conclusions: The combination of GC and trastuzumab shows near doubling of survival in treatment naive HER2 positive BTC in a prospective manner for the first time and sets the stage for a larger phase III trial with the combination. Evaluating mutations like TP53, HER2, TERT promoter and PIK3CA along with HER2 testing could be considered as a preferred modality to select these patients for anti HER2 therapy. Clinical trial information: CTRI/2019/11/021955 . [Table: see text]

Preoperative EUS vs. PET-CT Evaluation of Response to Neoadjuvant Therapy for Esophagogastric Cancer and Its Correlation with Survival.

The objective of our study was to investigate whether Endoscopic Ultrasonography (EUS) and Positron Emission Tomography-Computed Tomography (PET-CT) restaging can predict survival in upper gastrointestinal tract adenocarcinomas and to assess their accuracy when compared to pathology. We conducted a retrospective study on all patients who underwent EUS for staging of gastric or esophago-gastric junction adenocarcinoma between 2010 and 2021. EUS and PET-CT were performed, and preoperative TNM restaging was conducted using both procedures within 21 days prior to surgery. Disease-free survival (DFS) and overall survival (OS) were evaluated. A total of 185 patients (74.7% male) were included in the study. The accuracy of EUS for distinguishing between T1-T2 and T3-T4 tumors after neoadjuvant therapy was 66.7% (95% CI: 50.3-77.8%), and for N staging, the accuracy was 70.8% (95% CI: 51.8-81.8%). Regarding PET-CT, the accuracy for N positivity was 60.4% (95% CI: 46.3-73%). Kaplan-Meier analysis revealed a significant correlation between positive lymph nodes on restaging EUS and PET-CT with DFS. Multivariate COX regression analysis identified N restaging with EUS and PET-CT, as well as the Charlson comorbidity index, as correlated factors with DFS. Positive lymph nodes on EUS and PET-CT were predictors of OS. In multivariate Cox regression analysis, the independent risk factors for OS were found to be the Charlson comorbidity index, T response by EUS, and male sex. Both EUS and PET-CT are valuable tools for determining the preoperative stage of esophago-gastric cancer. Both techniques can predict survival, with preoperative N staging and response to neoadjuvant therapy assessed by EUS being the main predictors.

A Two-Step Diagnostic Approach for NTRK Gene Fusion Detection in Biliary Tract and Pancreatic Adenocarcinomas.

It is of interest to determine the incidence and molecular characteristics of NTRK gene fusions in patients with bilio-pancreatic cancers, because of possible treatment with TRK inhibitors for advanced tumors. The aim of the present study was to apply the guidelines for NTRK testing algorithm to a series of patients with bilio-pancreatic cancers. Immunohistochemistry screening was applied on formalin-fixed paraffin-embedded archival blocks from surgical resections, biopsies, or cytological samples of biliary tract and pancreatic adenocarcinomas. The presence of at least a weak staining in rare tumor cells led to testing by 2 RNA-based NGS panels. For biliary tract tumors, 153 samples have been selected. A total of 140 samples were suitable to perform IHC, and 17 samples were IHC positive. RNA NGS testing of the 17 IHC-positive samples revealed a single NTRK3 gene fusion (ETV6(4)-NTRK3(14)) that was detected by both NGS panels. In this perihilar cholangiocarcinoma, IHC performed on a biopsy showed a weak focal cytoplasmic and nuclear staining. No other NTRK fusion was detected on the 16 other samples with both panels. Overall in the patients screened by IHC and confirmed by NGS, the percentage of NTRK fusions was 0.7%. For pancreatic cancers, 319 samples have been selected and 297 were suitable to perform IHC. Nineteen samples were IHC positive. No fusion was detected by NGS. NTRK gene fusions are rare in bilio-pancreatic cancers but testing is of high interest due to possible treatment with specific TRK inhibitors.

Efficacy and safety of the MDM2–p53 antagonist BI 907828 in patients with advanced biliary tract cancer: Data from two phase Ia/Ib dose-escalation/expansion trials.

543 Background: Standard-of-care treatment for advanced biliary tract cancer (BTC) is chemotherapy and outcomes remain poor; hence, there is a clinical need for effective targeted treatments. As MDM2 is a negative regulator of the tumor suppressor p53, blocking the MDM2–p53 interaction is a potential antitumor strategy. Further, preliminary data indicate that MDM2 amplification is a negative prognostic marker in BTC. The MDM2–p53 antagonist BI 907828 has shown preclinical antitumor activity in a range of malignancies and is currently being assessed in two phase Ia/Ib dose-escalation/expansion trials in patients with advanced solid tumors: as monotherapy (NCT03449381) and in combination with an anti-PD-1 antibody, ezabenlimab (NCT03964233). Here, we present data for patients with advanced BTCs in these trials. Methods: Patients in the monotherapy trial received escalating doses of BI 907828 on day 1 of 21-day cycles (q3w). Patients in the combination trial received escalating doses of BI 907828 and 240 mg ezabenlimab q3w (doublet); one patient also received the anti-LAG-3 antibody BI 754111 (a drug that has since been discontinued; triplet). Results: A total of 8 patients with BTC were enrolled in the 2 trials, 4 in the monotherapy trial and 4 in the combination trial. In the monotherapy trial, 2 patients had ampullary carcinoma (both received BI 907828 45 mg q3w), and 2 had cholangiocarcinoma (CC; 1 received BI 907828 45 mg q3w and 1 with intrahepatic CC [iCC] received 80 mg q3w). In the combination trial, 3 patients with iCC received 30 mg/45 mg BI 907828 doublet or 45 mg triplet, and 1 with gallbladder carcinoma (GBC) received BI 907828 45 mg doublet. Across both trials, 5 patients achieved PR, 2/4 in the monotherapy trial and 3/4 in the combination trial. In the monotherapy trial, the responding patients had iCC (80 mg q3w; MDM2-amplified; 73% tumor shrinkage; PFS event at 404 days) and ampullary adenocarcinoma (45 mg q3w; MDM2-amplified; 51% tumor shrinkage; ongoing, PFS censored at 255 days). In the combination trial, all 3 responding patients had MDM2-amplified biliary tract adenocarcinoma (2 iCC, 1 GBC); tumor shrinkage was 49–54%; PFS was 162–241 days. A further 2 patients (1 in each trial) achieved stable disease (SD). In the monotherapy trial, most common grade ≥3 treatment-related AEs (TRAEs) were thrombocytopenia, decreased white blood cell (WBC) count and neutropenia (2 patients each). In the combination trial, most common grade ≥3 TRAEs were anemia and decreased WBC count (3 patients each), neutropenia and thrombocytopenia (2 patients each). Conclusions: The MDM2–p53 antagonist BI 907828 has shown a manageable safety profile and encouraging preliminary efficacy in patients with BTC, with 5 PRs and 2 SD in 8 patients. A phase IIa/IIb trial of BI 907828 (45 mg q3w) in patients with BTC is planned to start recruitment at the end of 2022 (NCT05512377). Clinical trial information: NCT03449381 and NCT03964233 .

Nab-paclitaxel plus tegafur gimeracil oteracil potassium capsule (S-1) as first-line treatment for advanced biliary tract adenocarcinoma: a phase 2 clinical trial.

This study aimed to evaluate the efficacy and safety of a new combination of nab-paclitaxel plus tegafur gimeracil oteracil potassium capsule (S-1) for patients with advanced biliary tract carcinoma (BTC). Patients were treated with nab-paclitaxel at a dose of 125 mg/m2 on day 1 and 8, and S-1, 80 to 120 mg/day on days 1-14 of a 21-day cycle. Treatments were repeated until disease progression or unacceptable toxicity occurred. The primary endpoint was objective response rate (ORR). The secondary endpoints were median progression-free survival (PFS), overall survival (OS), and adverse events (AEs). The number of patients enrolled were 54, and 51 patients were evaluated for efficacy. A total of 14 patients achieved partial response (PR) with an ORR of 27.5%. The ORR varied by sites, with 53.8% (7/13) for gallbladder carcinoma, 18.4% (7/38) for cholangiocarcinoma. The most common grade 3 or 4 toxicities were neutropenia and stomatitis. The median PFS and OS were 6.0 and 13.2 months, respectively. The combination of nab-paclitaxel with S-1 showed explicit antitumor activities and favorable safety profile in advanced BTC and could serve as a potential non-platinum and -gemcitabine-based regimen.

Automated analysis of computerized morphological features of cell clusters associated with malignancy on bile duct brushing whole slide images.

Bile duct brush specimens are difficult to interpret as they often present inflammatory and reactive backgrounds due to the local effects of stricture, atypical reactive changes, or previously installed stents, and often have low to intermediate cellularity. As a result, diagnosis of biliary adenocarcinomas is challenging and often results in large interobserver variability and low sensitivity OBJECTIVE: In this work, we used computational image analysis to evaluate the role of nuclear morphological and texture features of epithelial cell clusters to predict the presence of pancreatic and biliary tract adenocarcinoma on digitized brush cytology specimens. Whole slide images from 124 patients, either diagnosed as benign or malignant based on clinicopathological correlation, were collected and randomly split into training (ST , N= 58) and testing (Sv , N= 66) sets, with the exception of cases diagnosed as atypical on cytology were included in Sv . Nuclear boundaries on cell clusters extracted from each image were segmented via a watershed algorithm. A total of 536 quantitative morphometric features pertaining to nuclear shape, size, and aggregate cluster texture were extracted from within the cell clusters. The most predictive features from patients in ST were selected via rank-sum, t-test, and minimum redundancy maximum relevance (mRMR) schemes. The selected features were then used to train three machine-learning classifiers. Malignant clusters tended to exhibit lower textural homogeneity within the nucleus, greater textural entropy around the nuclear membrane, and longer minor axis lengths. The sensitivity of cytology alone was 74% (without atypicals) and 46% (with atypicals). With machine diagnosis, the sensitivity improved to 68% from 46% when atypicals were included and treated as nonmalignant false negatives. The specificity of our model was 100% within the atypical category. We achieved an area under the receiver operating characteristic curve (AUC) of 0.79 on Sv , which included atypical cytological diagnosis.

Development and task of gynecologic pathology

Gynecological pathology, formed in the late 19th century, has greatly prompted the development of gynecology with its continuous exploration since the early time. In the progress of over 130 years, gynecological pathology has formed a completed set of scientific system by absorbing the contemporary advanced technologies and cooperating with gynecologists. In China, the late-started gynecological pathology has been faced with the dilemma of imbalanced regional development and endowed with the dual tasks of dissemination and self-improvement. In future, gynecological pathology in China needs to solve the following problems: (1) improving diagnostic accuracy of squamous intraepithelial lesions of the female genital tract and cervical adenocarcinoma in situ; (2) giving special attention to the correct diagnosis of hormone-related diseases especially tumor-like lesions; (3) focusing our efforts on the difficulties in clinical practice as well as the growing demands of clinical treatments; (4) actively utilizing molecular biological techniques and exploring options in accord with domestic conditions; (5) standardizing diagnostic terminology and providing the essential prognostic parameters for clinical application.