Lower CA125 Research Articles

Abstract B027: A blood-based, multiplex protein biomarker signature shows superior performance in detection of early-stage pancreatic ductal adenocarcinoma (PDAC)

Abstract BACKGROUND: A sensitive and specific blood biomarker test is needed to improve survival in PDAC through early detection. An initial discovery study analyzing more than 3000 proteins using both pre-selected immunoassays and the Olink proteomics platform identified 15 promising protein candidates, of which ten were successfully pre-verified for ELISA immunoassay analysis. This model-development study was conducted to develop and pre- validate a specific and sensitive biomarker signature for the early detection of PDAC. METHODS: This multicenter case-control study was performed using existing bio-banked pretreatment samples from patients with newly diagnosed PDAC (Stages I-II) and participants in PDAC high-risk surveillance programs as controls. Blinded quantitative measurement of protein biomarkers was performed using ELISA-based immunoassays. CA19-9 was measured on a Roche COBAS instrument. An AI-derived predictive mathematical biomarker signature incorporating multiple protein biomarkers was developed and assessed using standard cross- validation techniques. RESULTS: 128 Stage 1 and 2 PDACs and 495 high-risk control serum samples were analyzed with 10 predetermined biomarkers to develop a four-protein biomarker signature. The model predicted PDAC versus non-PDAC with 84% sensitivity at 98% specificity. Model performance was significantly better when compared to CA19-9 alone (sensitivity 65% at 98% specificity, p<0.001). In those patients with low CA19-9 (<37 U/ml), the model predicted PDAC with 62% sensitivity at 98% specificity, performing significantly better than CA19-9 alone (9% sensitivity at similar 98% specificity (p<0.001). Additionally, in patients >65 years old, the signature predicted PDAC with 90% sensitivity at 98% specificity, which was significantly more sensitive than CA19-9 alone (75% sensitivity at 98% specificity, p<0.001). Test accuracy was not affected by diabetes status. CONCLUSIONS: This blood-based, multiplexed biomarker signature showed high sensitivity and specificity and significantly outperformed CA19-9 for early-stage PDAC. This biomarker model has the potential to improve outcomes in PDAC patients through early detection. Analytical and clinical validation studies are planned. Citation Format: Norma Palma, Ralph Schiess, Thomas King, Alcibiade Athanasiou, Natasha Kureshi, Lisa Ford, Aimee Lucas, Bryson Katona, Randall Brand, Diane Simeone. A blood-based, multiplex protein biomarker signature shows superior performance in detection of early-stage pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B027.

Enhancing endometrioma management: Diagnostic biomarkers and predictive outcomes in Ruptured vs. Non-Ruptured cases

ObjectiveTo compare the outcomes between patients undergoing surgery for ruptured endometrioma versus non-ruptured endometrioma. Study DesignThe study was conducted at Health Sciences University, Etlik Zübeyde Hanım Training and Research Hospital Infertility Clinic. All patients who had a histopathology report of endometrioma between January 2014 and December 2020 were recruited. Patient files, surgery notes and laboratory values were extracted from the electronic recording system and patients with ruptured endometriomas (RE) or non-ruptured endometriomas (NRE) were compared. ResultsOverall, 181 patients were recruited to the study. No rupture was detected in 146 (80.7 %) patients while 35 patients (19.3 %) underwent surgery for RE. Pre-operative CRP, CA 125, CA 19–9, CA 15–3, CEA and mean platelet volume (MPV) values and postoperative MPV and neutrophil/lymphocyte ratio (NLR) values were statistically significantly higher (p < 0.01) in the RE group compared to the NRE group. Post-operative lymphocyte (p = 0.029) and eosinophyl (p = 0.015) values were significantly lower in the RE group compared to the NRE group. Among the preoperative biomarkers that are evaluated for prediction of rupture; MPV, CA 19–9 and CA-15.3 had a high specifity (>75 %) but a rather low sensitivity (<60 %), meanwhile CRP, CA-125 and CEA had high sensitivity but a low specifity. ConclusionRE patients had significantly higher preoperative CRP, CA 125, CA 19–9, CA 15–3, CEA, and MPV values and postoperative MPV and NLR values while postoperative, lymphocyte and eosinophyl values were significantly lower compared with the NRE patients. Prospective studies with larger sample sizes are needed to determine biomarkers and parameters that can be used for non-invasive diagnosis of endometriosis and predict the possibility of endometrioma rupture.

Sialyl-Tn serves as a potential therapeutic target for ovarian cancer

BackgroundOvarian cancer remains the deadliest of the gynecologic cancers in the United States. There have been limited advances in treatment strategies that have seen marked increases in overall survival. Thus, it is essential to continue developing and validating new treatment strategies and markers to identify patients who would benefit from the new strategy. In this report, we sought to further validate applications for a novel humanized anti-Sialyl Tn antibody-drug conjugate (anti-STn-ADC) in ovarian cancer.MethodsWe aimed to further test a humanized anti-STn-ADC in sialyl-Tn (STn) positive and negative ovarian cancer cell line, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. Furthermore, we sought to determine whether serum STn levels would reflect STn positivity in the tumor samples enabling us to identify patients that an anti-STn-ADC strategy would best serve. We developed a custom ELISA with high specificity and sensitivity, that was used to assess whether circulating STn levels would correlate with stage, progression-free survival, overall survival, and its value in augmenting CA-125 as a diagnostic. Lastly, we assessed whether the serum levels reflected what was observed via immunohistochemical analysis in a subset of tumor samples.ResultsOur in vitro experiments further define the specificity of the anti-STn-ADC. The ovarian cancer PDO, and PDX models provide additional support for an anti-STn-ADC-based strategy for targeting ovarian cancer. The custom serum ELISA was informative in potential triaging of patients with elevated levels of STn. However, it was not sensitive enough to add value to existing CA-125 levels for a diagnostic. While the ELISA identified non-serous ovarian tumors with low CA-125 levels, the sample numbers were too small to provide any confidence the STn ELISA would meaningfully add to CA-125 for diagnosis.ConclusionsOur preclinical data support the concept that an anti-STn-ADC may be a viable option for treating patients with elevated STn levels. Moreover, our STn-based ELISA could complement IHC in identifying patients with whom an anti-STn-based strategy might be more effective.

ReClassification of Patients with Ambiguous CA125 for Optimised Pre-Surgical Triage.

Pre-surgical clinical assessment of an adnexal mass is a complex process, and ideally requires accurate and rapid identification of disease status. Gold standard biomarker CA125 is extensively used off-label for this purpose; however its performance is typically inadequate, particularly for the detection of early stage disease and discrimination between benign versus malignant status. We recently described a multi-marker panel (MMP) and associated risk index for the differentiation of benign from malignant ovarian disease. In this study we applied a net reclassification approach to assess the use of MMP index to rescue those cases where low CA125 incorrectly excludes cancer diagnoses, or where benign disease is incorrectly assessed as "high risk" due to elevated CA125. Reclassification of such patients is of significant value to assist in the timely and accurate referral for patients where CA125 titer is uninformative.

Outcomes of the IMMray PanCan-d Test in High-Risk Individuals Undergoing Pancreatic Surveillance: Pragmatic Data and Lessons Learned.

An effective blood-based test for pancreatic cancer (PC) screening has remained elusive. The IMMray PanCan-d is the first commercially available blood-based test specifically designed for early detection of PC; however, outcomes from its use in clinical practice have not been reported. We performed a blinded spike-in study of 100 individuals who had an IMMray PanCan-d test, including 94 high-risk individuals (HRIs) undergoing PC surveillance and six individuals with known PC. Specimens were processed blindly following the commercial laboratory's standardized operating procedure. Positive predictive value (PPV) and negative predictive value (NPV) were calculated. Cohort characteristics included a median age of 63 (IQR, 55-70) years, 57% female, 96% non-Hispanic White, 57% with a pathogenic variant in a PC risk gene (BRCA2 most commonly-18%), and 83% with a family history of PC. Among IMMray PanCan-d results from 94 HRIs undergoing PC surveillance, there was one positive (1%), seven borderlines (7%), 73 negatives (78%), and 13 tests not performed because of low CA19-9 expression (14%). No PC was diagnosed among these HRIs; however, there were two sub-cm pancreatic neuroendocrine tumors, seven clinically diagnosed side branch intraductal papillary mucinous neoplasms ≥1 cm, and a sub-cm solid mass with indeterminate cytology requiring close follow-up; all these individuals had negative IMMray PanCan-d tests. Of the six spiked-in PCs, four (67%) yielded a positive and two (33%) yielded a negative. With an estimated disease prevalence of 2%, the PPV and NPV are 52% and 99%, respectively, if borderline results are considered negative and 12% and 99%, respectively, if borderline tests are considered positive. In clinical practice, IMMray PanCan-d has a robust NPV; however, PPV is dramatically influenced by whether borderline results are characterized as a positive or negative result.

Predictive value of baseline serum carbohydrate antigen 19-9 level on treatment effect of neoadjuvant chemoradiotherapy in patients with resectable and borderline resectable pancreatic cancer in two randomized trials.

Guidelines suggest that the serum carbohydrate antigen (CA19-9) level should be used when deciding on neoadjuvant treatment in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer). In patients with resectable pancreatic cancer, neoadjuvant therapy is advised when the CA19-9 level is 'markedly elevated'. This study investigated the impact of baseline CA19-9 concentration on the treatment effect of neoadjuvant chemoradiotherapy (CRT) in patients with resectable and borderline resectable pancreatic cancers. In this post hoc analysis, data were obtained from two RCTs that compared neoadjuvant CRT with upfront surgery in patients with resectable and borderline resectable pancreatic cancers. The effect of neoadjuvant treatment on overall survival was compared between patients with a serum CA19-9 level above or below 500 units/ml using the interaction test. Of 296 patients, 179 were eligible for analysis, 90 in the neoadjuvant CRT group and 89 in the upfront surgery group. Neoadjuvant CRT was associated with superior overall survival (HR 0.67, 95 per cent c.i. 0.48 to 0.94; P = 0.019). Among 127 patients (70, 9 per cent) with a low CA19-9 level, median overall survival was 23.5 months with neoadjuvant CRT and 16.3 months with upfront surgery (HR 0.63, 0.42 to 0.93). For 52 patients (29 per cent) with a high CA19-9 level, median overall survival was 15.5 months with neoadjuvant CRT and 12.9 months with upfront surgery (HR 0.82, 0.45 to 1.49). The interaction test for CA19-9 level exceeding 500 units/ml on the treatment effect of neoadjuvant CRT was not significant (P = 0.501). Baseline serum CA19-9 level defined as either high or low has prognostic value, but was not associated with the treatment effect of neoadjuvant CRT in patients with resectable and borderline resectable pancreatic cancers, in contrast with current guideline advice.

DEB-TACE with irinotecan versus C-TACE for unresectable intrahepatic cholangiocarcinoma: a prospective clinical study.

Objectives: DEB-TACE with irinotecan and C-TACE were compared with regards to safety and efficacy for the therapy of intrahepatic cholangiocarcinoma (ICC). Methods: Institutional Review Board approved our trial and we registered it in the Chinese Clinical Trial Registry (ChiCTR1900022856). Forty patients with biopsy-confirmed ICC were randomised to either receive DEB-TACE or C-TACE treatment with 20 patients in each treatment arm. The primary endpoints objective response rate (ORR) and progression free survival (PFS) using the mRECIST to evaluate the tumours. The secondary endpoints were overall survival (OS) and safety. The chi-square was used to analyse the data. The Kaplan-Meier method and Cox analysis were used to evaluate the survival data. Results: ORR (70% in DEB-TACE group vs. 20% in C-TACE, p = .001) at 1month after therapy, ORR (50% vs. 15%, p = .018) at 3months and DCR (70% vs. 30%, p = .011) at 6months, while no difference was found in other groups. (all p > .05) The median PFS with DEB-TACE was longer than that with C-TACE (8.0months vs. 3.0months) (p = .042). Although the median OS was longer with DEB-TACE than with C-TACE (11.5months vs. 9.0months), the difference was not statistically significant (p = .280). The Cox regression analysis demonstrated that TACE sessions (p = .017) and low CA125 levels (p = .001) were independent favourable prognostic factors. The most frequent adverse event was elevated transaminase levels (20/20 in DEB-TACE group vs. 15/20 in C-TACE group) (p = .047). Conclusion: Our prospective study suggested better ORR and PFS with DEB-TACE with irinotecan as compared to C-TACE with irinotecan in the treatment of unresectable ICC.

Nectin-4 as Blood-Based Biomarker Enables Detection of Early Ovarian Cancer Stages.

Ovarian cancer is the third most common gynecological malignancy and has the highest mortality rate. Owing to unspecific symptoms, ovarian cancer is not detected until an advanced stage in about two-thirds of cases. Therefore, it is crucial to establish reliable biomarkers for the early stages to improve the patients’ prognosis. The aim of this study is to investigate whether the ADAM17 substrates Nectin-4, Heparin-binding EGF-like growth factor (HB-EGF) and Amphiregulin (AREG) could function as potential tumor markers for ovarian cancer. In this study a set of 231 sera consisting of 131 ovarian cancer patients and 100 healthy age-matched controls were assembled. Nectin-4, HB-EGF and AREG levels of preoperatively collected sera were determined by enzyme-linked immunosorbent assay (ELISA). Our analysis revealed that Nectin-4 and HB-EGF were significantly increased compared to the age-matched control group (p < 0.0001, p = 0.016). Strikingly, significantly higher Nectin-4 and HB-EGF levels were detected in early-stage FIGO I/II (p <0.001; p = 0.025) compared to healthy controls. Eighty-four percent (16/19) of patients with low Ca-125 levels showed increased Nectin-4 levels. Our study proposes Nectin-4 and HB-EGF as promising blood-based biomarkers for the detection of early stages of ovarian cancer patients that would not have been detected by Ca-125.

Serum α2,6-sialylated glycoform of serotransferrin as a glycobiomarker for diagnosis and prediction of clinical severity in cholangiocarcinoma

BackgroundGlycoprotein sialylation changes are associated with severe development of various cancers. We previously discovered the sialylation of serotransferrin (TF) in cholangiocarcinoma (CCA) using glycoproteomics approach. However, a simple and reliable method for validating sialylation of a specific glycobiomarker is urgently needed. MethodsWe identified the altered glycosylation in CCA tissues by glycoproteomics approach using mass spectrometry. An enzyme-linked lectin assay (ELLA) was developed for determining the serum levels of sialylated TF in CCA, hepatocellular carcinoma (HCC) and healthy controls in training and validation cohorts. ResultsThe nine highly sialylated glycoforms of TF were markedly abundant in CCA tumor tissues than in control. Serum SNA-TF and MAL1-TF were significantly higher in CCA patients. Under receiver operating characteristic curve, serum SNA-TF concentrations significantly differentiated CCA from healthy control. Higher SNA-TF were significantly correlated with severe tumor stages and lymph node metastasis. The combined SNA-TF, MAL1-TF, and CA19-9 as a novel glycobiomarkers panel demonstrated the highest specificity (96.2%) for distinguishing CCA from HCC patients. In CCA patients with low CA19-9 levels, SNA-TF in combination with CA19-9 achieved in 97% diagnostic accuracy. ConclusionsSialylated serotransferrin glycoforms could be used as a novel glycobiomarker for diagnosis and prediction of clinical severity in CCA patients.

The Impact of Carbohydrate Antigen 19-9 on Survival in Patients with Clinical Stage I and II Pancreatic Cancer.

Carbohydrate antigen (CA)19-9 is a biomarker to monitor treatment effect. A threshold to predict prognostic significance remains undefined. We evaluated the impact of CA19-9 on overall survival (OS) in patients with early-stage pancreatic cancer (PC) utilizing the National Cancer Database (NCDB). The NCDB was queried from 2010 to 2014 to identify patients with clinical stage I-II PC. Patients who had undocumented pretreatment CA19-9 were excluded. Patients were stratified into two cohorts: CA19-9 < 98U/mL and CA19-9 ≥ 98U/mL, and further categorized into surgery versus no surgery. Twelve- and 24-month OS rates are reported. Overall, 32,382 patients (stage I: 12,173; stage II: 20,209) were included. The majority of stage I (52.1%) and II (60%) patients had CA19-9 ≥ 98U/mL. Stage I-II patients with CA19-9 < 98U/mL had improved OS rates (stage I: 67.5%, 42.6%; stage II: 59.8%, 32.8%) compared with stage I and II patients with CA19-9 ≥ 98U/mL (stage I: 50.7%, 26.9%; stage II: 48.1%, 22%). Among resected stage I patients, CA19-9 <98U/mL was associated with improved OS (< 98: 80.5%, 56%; ≥ 98: 70.2%, 42.8%), and a similar trend was seen in resected stage II patients (< 98: 77.6%, 49.9%; ≥ 98: 71%, 39.2%). Unresected stage I patients with lower CA19-9 had improved OS (< 98: 42.1%, 17.5; ≥ 98: 29.9%, 10%), with similar findings in unresected stage II patients (< 98: 41.1%, 15.3%; ≥ 98: 33.4%, 10.6%). Our study demonstrated the prognostic value of CA19-9 in patients with clinical stage I-II PC, with a value < 98 U/mL demonstrating improved survival. Surgery significantly improved survival at 12 and 24 months irrespective of CA19-9.

Validation of a genotype-based algorithm that identifies individuals with low, intermediate, and high serum CA19-9 levels in cancer-free individuals and in patients with colorectal cancer

BackgroundSerum levels of Carbohydrate antigen CA19-9 are determined by the genotype of fucosyltransferases 2 and 3. To validate, possibly modify, and improve a grouping algorithm based on these genotypes.MethodsCA19-9 levels genotypes and of fucosyltransferase 2 and 3 were analyzed in cancer-free and colorectal cancer patients. Patients were assigned to groups with low (group A), intermediate (B), or high (C) CA19-9 biosynthetic activity based on a previously developed grouping algorithm based on genotype of fucosyltransferases 2 and 3.ResultsThree hundred thirty-eight patients were included (n=177 cancer-free). Of cancer-free patients 7.9%, 75.7%, and 16.4% were assigned to groups A, B, and C, respectively. In colorectal cancer patients it 7.5%, 77.0%, and 15.5%, respectively. There were significant differences between median CA19-9 levels in the three groups (P<0.001) in both cohorts. The T59G single-nucleotid polymorphism in fucosyltransferase 3 had a significant influence on CA19-9 levels in cancer-free group B patients, which led to establishment of subgroups B1 and B2. However, no difference in CA19-9 levels between these subgroups was found in colorectal cancer patients. A receiver-operating characteristic showed similar areas under the curve for original group B as well as for subgroups B1 and B2.ConclusionsThe grouping algorithm based on genotype of fucosyltransferases 2 and 3, which defines groups with distinct CA19-9 serum levels, was validated in cancer-free patients and in colorectal cancer patients. No clinically relevant improvement to the grouping algorithm was identified.

Systemic therapy and perioperative management improve the prognosis of pancreatic ductal adenocarcinoma: A retrospective cohort study of 2000 consecutive cases

ObjectiveThis study aimed to explore patterns of the treatment strategies of pancreatic ductal adenocarcinoma based on 2000 consecutive cases of a prospective database since 2012 to obtain new insights for future directions. MethodsAmong 2000 patients enrolled in this study, 210 patients were excluded, and 710, 521, and 559 patients were treated between 2012 and 2015 (group 1), between 2016 and 2017 (group 2), and between 2018 and 2019 (group 3), respectively. Patient clinicopathologic and biological factors, and perioperative outcomes were used to assess the prognostic factors. ResultsThe median survival for all patients with pancreatic ductal adenocarcinoma was 21.7 months (1-year survival, 75.0%; 2-year survival, 43.7%; 5-year survival, 19.7%). Group 3 had a better survival outcome than groups 1 and 2 (median survival time: 23 versus 20.5 and 21.1 months). The proportion of patients younger than 65 gradually increased over time, as did the use of systemic chemotherapy and postoperative adjuvant radiotherapy. The tendency for early diagnosis (lower CA19-9 and CEA levels, smaller size, and earlier N stage), use of chemotherapy and radiotherapy, early recovery (lesser hospital stay and Clavien-Dindo grade <3), absence of abdominal pain, younger age, length of operation ≤3 h, and pathological factors (absence of lymphovascular invasion, peripancreatic fat infiltration and neural invasion, higher differentiation) were related to patients' survival. Multivariable analysis for prognosis revealed that tumor biological factors (increased preoperative serum CA19-9 level, tumor size, tumor differentiation, N stage, and presence of lymphovascular invasion and neural invasion), chemotherapy, radiotherapy, abdomen pain, operation period, length of stay, and length of operation correlated with patients’ survival. ConclusionsSystemic therapy, including chemotherapy and radiotherapy, has gradually improved the prognosis after operative resection for pancreatic ductal adenocarcinoma. Neoadjuvant therapy is also beneficial to improve the prognosis to a certain extent. The enhanced recovery after surgery (ERAS) policies and the specific assessment of postoperative pancreatic fistula (POPF) risk may be related to reduced hospital stays and the reduction of serious complications. These advancements show that the concept of systemic therapy has been accepted and actively applied by Chinese medical institutions.

Treatment of unresectable intrahepatic cholangiocarcinoma using transarterial chemoembolisation with irinotecan-eluting beads: analysis of efficacy and safety.

This retrospective study evaluated the efficacy, safety, and factors affecting the prognosis of transarterial chemoembolisation with irinotecan-eluting beads with CalliSpheres (DEB-TACE) for intrahepatic cholangiocarcinoma (ICC). We retrospectively collected data on 39 patients with unresectable ICC who received DEB-TACE therapy. We assessed the indicators of tumour response, progression-free survival (PFS), overall survival (OS), and the incidence of adverse events. PFS and OS were analysed using Kaplan-Meier curves, while Cox analysis was used to identify factors affecting the prognosis. The 3-month objective response rate (ORR) and disease control rate (DCR) of the 39 patients with unresectable ICC were 35.9% and 56.4%, respectively, while the 6-month ORR and DCR were 23.0% and 40.9%, respectively. The median OS and PFS were 11.0months and 8.0months, respectively. Cox analysis demonstrated that combined therapy (adjuvant sorafenib after DEB-TACE) and a low cancer antigen (CA) 125 level (≤ 35 U/ml) were independent favourable prognostic factors. Transient elevation of the aminotransferase level, nausea, vomiting, abdominal pain, fever, and hyper-bilirubinaemia were common adverse events in patients with unresectable ICC treated with DEB-TACE with CalliSphere beads (CBs). Hepatic abscess was the most serious complication, observed in one patient. DEB-TACE with CBs is a safe and well-tolerated therapy in patients with unresectable ICC with a low incidence of adverse events and relatively prolonged survival. Combined therapy and low CA125 are prognostic factors associated with longer survival.

Metastatic tumors to the pancreas: Balancing clinical impression with cytology findings.

Backgrounds/AimsMetastatic lesions of the pancreas (PMET) account for 1%–5% of all malignant solid pancreatic lesions (SPL). In this study we evaluated the utility of endoscopic ultrasonography with fine needle aspiration (EUS-FNA) in diagnosing PMET.MethodsPatients who underwent EUS-FNA at a community referral center between 2011–2017 for SPL were identified. Clinical, radiologic, and EUS-FNA features of those with PMET were compared to those with primary solid tumors of the pancreas: pancreatic adenocarcinoma (PDAC) and neuroendocrine tumors (PNET).ResultsA total of 191 patients were diagnosed with solid pancreatic malignancy using EUS-FNA: 156 PDAC, 27 PNET, and eight (4.2%) had PMET. Patients with PMET were less likely to have abdominal pain (25.0% vs. 76.3% vs. 48.2%; p < 0.01) or obstructive jaundice (37.5% vs. 58.3% vs. 0%; p < 0.01) compared to PDAC and PNET. Those with PMET were more likely to have mass lesions with/without biliary or pancreatic ductal dilatations (100% vs. 86.5% vs. 85.2%; p < 0.01) and lower CA19-9 (82.5 ± 43.21 U/mL vs. 4,639.30 ± 11,489.68 U/mL vs. 10.50 ± 10.89 U/mL; p < 0.01) compared to PDAC and PNET. Endosonographic features were similar among all groups. Seven (87.5%) patients with PMET had a personal history of malignancy prior to PMET diagnosis. The primary malignancy was renal cell carcinoma in five PMET.ConclusionsPMET are exceedingly rare, comprising less than 5% of SLP. Patients with PMET are less likely to present with symptoms and mostly identified by surveillance imaging for the primary malignancy.

Driver mutations of intrahepatic cholangiocarcinoma shape clinically relevant genomic clusters with distinct molecular features and therapeutic vulnerabilities.

Purpose: To establish a clinically applicable genomic clustering system, we investigated the interactive landscape of driver mutations in intrahepatic cholangiocarcinoma (ICC).Methods: The genomic data of 1481 ICCs from diverse populations was analyzed to investigate the pair-wise co-occurrences or mutual exclusivities among recurrent driver mutations. Clinicopathological features and outcomes were compared among different clusters. Gene expression and DNA methylation profiling datasets were analyzed to investigate the molecular distinctions among mutational clusters. ICC cell lines with different gene mutation backgrounds were used to evaluate the cluster specific biological behaviors and drug sensitivities.Results: Statistically significant mutation-pairs were identified across 21 combinations of genes. Seven most recurrent driver mutations (TP53, KRAS, SMAD4, IDH1/2, FGFR2-fus and BAP1) showed pair-wise co-occurrences or mutual exclusivities and could aggregate into three genetic clusters: Cluster1: represented by tripartite interaction of KRAS, TP53 and SMAD4 mutations, exhibited large bile duct histological phenotype with high CA19-9 level and dismal prognosis; Cluster2: co-association of IDH/BAP1 or FGFR2-fus/BAP1 mutation, was characterized by small bile duct phenotype, low CA19-9 level and optimal prognosis; Cluster3: mutation-free ICC cases with intermediate clinicopathological features. These clusters showed distinct molecular traits, biological behaviors and responses to therapeutic drugs. Finally, we identified S100P and KRT17 as “cluster-specific”, “lineage-dictating” and “prognosis-related” biomarkers, which in combination with CA19-9 could well stratify Cluster3 ICCs into two biologically and clinically distinct subtypes.Conclusions: This clinically applicable clustering system can be instructive to ICC prognostic stratification, molecular classification, and therapeutic optimization.

The prognostic factor for recurrence in advanced-stage high-grade serous ovarian cancer after complete clinical remission: a nested case-control study

BackgroundWomen with advanced-stage high-grade serous ovarian cancer (HGSOC) are likely to have a bad prognosis. Relapses are common in patients even with no evidence of disease after primary treatment. We aimed to identify the prognostic factors for disease recurrence in these patients.MethodsA nested case-control study was conducted in a large medical center in Southwest China. The primary outcome was recurrence of disease within 3 years after clinical remission (CR). Cox regression was used to calculate the time to event analysis in different groups.ResultsNinety-seven patients were finally included. Fifty-seven patients (58.8%) relapsed within 3 years after CR. Among all the variables, the difference in posttreatment CA-125 level was statistically significant (P <0.05) between the recurrent group and the progression-free group in both univariate and multivariable analysis. A cutoff value was set at the median level in the recurrent group (10 U/ml) to categorize patients into two arms. In Cox regression, the posttreatment CA-125 level was identified as a prognostic factor for recurrence with an OR of 1.05 (95% CI: 1.02–1.10, P = 0.033). The median time (from initiation of treatment) until relapse was 25 months for patients whose posttreatment CA-125 levels were higher than 10 U/ml, while it was undefined for patients whose posttreatment CA-125 level were ≤ 10 U/ml. Patients with a higher posttreatment CA-125 level showed an increased risk for OC relapse compared to those with a lower posttreatment CA-125 level. Furthermore, as shown in line graphs recording serum CA-125 levels during follow-up in each recurrent case, the increments of serum CA-125 levels were delayed in recurrent OC patients who had a posttreatment CA125 level ≤ 10 U/ml compared with those with a higher CA-125 level.ConclusionA low serum CA-125 level after primary treatment was a potential prognostic factor in women with advanced HGSOC.

Lymphocyte-to-monocyte ratio combined with CA19-9 for predicting postoperative recurrence of colorectal cancer in patients with diabetes.

ObjectiveTo investigate the significance of lymphocyte‐to‐monocyte ratio (LMR) combined with carbohydrate antigen (CA) 19‐9 for predicting postoperative recurrence of colorectal cancer (CRC) in patients with type II diabetes.MethodsWe conducted a retrospective analysis of 106 postoperative patients with stage II–III CRC and with type II diabetes. Their clinical indexes such as LMR and CA19‐9 were collected, and the patients were followed up for 5 years.ResultsThe CA19‐9 level was 119.7 U/ml at baseline in the relapsed group, while this was 24.81 U/ml in non‐relapsed group (p = 0.001). On the contrary, the LMR level was 5.10 and 2.57 for non‐relapsed and relapsed group (p < 0.001), respectively. Kaplan‐Meier survival curves stratified by CA19‐9 and LMR suggested that patients with lower CA19‐9 had higher survival probability (p < 0.001), while patients with high LMR level had higher survival probability (p < 0.001). The multivariable Cox proportional hazard regression analysis with CA19‐9 and LMR indicated that although the baseline CA19‐9 is significantly associated with increasing risk of disease recurrence, the HR (HR = 1.0, 95% CI 1.00–1.01) was small and close to 1, whereas the high baseline LMR (HR = 0.44, 95% CI 0.32–0.61) was associated with decrease in disease recurrence. Model with continuous CA19‐9 and LMR was able to better predict (AUC 73.17%) the disease recurrence.ConclusionLMR combined with CA19‐9 may become a new index for predicting postoperative recurrence of CRC in patients with diabetes.

CA19-9 Level to Serum γ-Glutamyltransferase as a Potential Prognostic Biomarker in Patients with Pancreatic Head Carcinoma

BackgroundThe aim of this study was to reduce the influence of biliary obstruction on carbohydrate antigen 19-9 level (CA19-9) by introducing the CA19-9 level to serum γ-glutamyltransferase (GGT) ratio as an indicator, and ultimately to reveal the correlation between CA19-9/GGT and the prognosis of patients with pancreatic head carcinoma (PHC).MethodsA total of 339 enrolled patients who underwent pancreatoduodenectomy for PHC in Beijing ChaoYang Hospital from January 2010 to December 2019 were analyzed retrospectively. The optimal cut-off value, according to which patients were divided into a low-ratio group (Group 1, n=179) and a high-ratio group (Group 2, n=160), was determined by the ROC curve obtained from preoperative CA19-9/GGT and 1-year survival. Through univariate and multivariate analyses, risk factors for postoperative tumor recurrence and long-term survival were screened out among PHC patients.ResultsThe best cut-off value of CA19-9/GGT was 2.07 (area under the curve=0.567, 95% CI 0.498–0.636). Compared with Group 2, Group 1 had lower CA19-9, and higher GGT, total bilirubin (TB) and lymph-node metastasis rate (P<0.05). The 1-, 2- and 3-year disease-free survival rates of patients in Groups 1 and 2 were 68.2%, 42.5% and 28.2%, and 42.2%, 19.3% and 18.3%, respectively (P=0.000), and the 1-, 2- and 3-year overall survival rates were 79.1%, 50.7% and 29.1%, and 56.7%, 22.2% and 17.2%, respectively (P=0.000). Multivariate analysis showed that CA19-9/GGT, portal system invasion and lymph-node metastasis were independent risk factors for postoperative tumor recurrence and long-term survival among patients with PHC.ConclusionCompared with CA19-9 level alone, CA19-9/GGT plays a more precise role in the evaluation of postoperative tumor recurrence and the long-term prognosis of PHC patients. The lower the ratio, the better the long-term prognosis. The CA19-9/GGT ratio may prove to be a useful biomarker for identifying PHC patients at high risk of early recurrence and unfavorable prognosis.

CA125: A superior prognostic biomarker for colorectal cancer compared to CEA, CA19-9 or CA242.

The tumor stage represents the single most important prognostic factor for colorectal cancer (CRC), although more accurate prognostics remain much needed. Previously, we identified CA125 as an independent significant prognostic factor, which we have further validated along with CEA, CA19-9, and CA242 in a large cohort of CRC patients. Using enzyme-linked immunosorbent assays, we analyzed preoperative serum samples in 322 CRC patients operated on between 1998 and 2003. Using the Spearman's rho model, we calculated the correlation between our previous findings on MUC16 and CA125, for which the correlation coefficient was 0.808 (p < 0.001). The Cox regression analysis of the linear and logarithmic values of CEA, CA125, CA242, and CA19-9 identified only CA125 (hazard ratio [HR] 1.03; 95% confidence interval [95% CI] 1.02-1.04; p < 0.001) as significant when using the linear values. Survival among CRC patients with a high CA125 level was poor compared with CRC patients with a low CA125 level (HR 2.48; 95% CI 1.68-3.65; p < 0.001). In subgroup analyses, patients with high CA125 levels and aged ≤67 or >67, with stage I-II or III-IV, and both colon and rectal cancer exhibited poor prognoses. In the multivariate analysis, we used clinical pathological variables in the model, where age, gender, and stage served as the background characteristics. We dichotomized CA125 using the Youden maximal cutoff point, and the median values for CEA, CA19-9, and CA242. CA125 emerged as the only marker remaining significant and independent together with stage, location, and age (HR 1.91; 95% CI 1.24-2.95; p 0.003). CA125 represents a significant and independent prognostic factor in CRC patients, superior to CEA. Furthermore, CA242 served as a better prognostic marker than both CEA and CA19-9. We recommend including both CA125 and CA242 in prognostic clinical trials among CRC patients.

Predictive effects of preoperative serum CA125 and AFP levels on post-hepatectomy survival in patients with hepatitis B-related hepatocellular carcinoma.

The association between the serum levels of cancer antigen 125 (CA125; also termed MUC16) and the prognosis of patients with hepatocellular carcinoma (HCC) has not been widely reported to date. The aim of the present study was to determine the association between preoperative serum CA125 levels and prognosis of patients with hepatitis B virus (HBV)-related HCC after hepatectomy. The study included 306 patients with HBV-related HCC who underwent liver resection and were classified into four subgroups based on their baseline CA125 and α-fetoprotein (AFP) levels. The perioperative clinical data were compared and analyzed. Kaplan-Meier and Cox regression analyses were performed to determine the associations between patient clinicopathological characteristics and survival. The results revealed that the median follow-up time was 35 months. Patients with low preoperative serum CA125 levels presented with improved 3-year disease-free survival (DFS) (79.3 vs. 75.7%; P=0.278) and overall survival (OS) (84.4 vs. 77.1%; P=0.001) rates compared with those among patients with high preoperative serum CA125 levels. High preoperative serum CA125 levels were a risk factor associated with short DFS and OS rates in all patients. In patients with baseline AFP levels >100 ng/ml, low preoperative serum CA125 levels were significantly associated with prolonged DFS and OS rates (log-rank test P=0.002 and P=0.005, respectively). In patients with AFP levels ≤100 ng/ml, no significant differences were observed in DFS or OS rates between the high and low preoperative serum CA125 groups. Patients with high preoperative serum CA125 and AFP levels exhibited the worst prognosis (low DFS and OS rates). In conclusion, high baseline CA125 levels may be associated with a poor prognosis in patients with HBV-related HCC.