Normal CA-125 Research Articles

Systemic Treatment Followed by Radical Resection Combined with Intestinal Autotransplantation (RRCIA) for Locally Advanced Pancreatic Cancer: A Retrospectively Observational and Prospectively Validated Study.

The present study aimed to assess the efficacy of this approach and establish the criteria that identify LAPC patients who may achieve survival benefits from RRCIA. Surgical resection for locally advanced pancreatic cancer (LAPC) remains challenging and associated with high morbidity and mortality, especially for surgery with major arterial reconstruction. We previously showed the feasibility and safety of Radical Resection Combined with Intestinal Autotransplantation (RRCIA) after systemic treatment. A retrospectively observational and prospectively validated study with three cohorts was conducted using multiple treatments. Overall survival (OS) and progression-free survival (PFS) were compared for both analyses. Propensity-score matching (PSM) and stabilized inverse probability of treatment weighting (IPTW) were performed to adjust for potential confounders. Among 208 patients with LAPC we identified 48 who underwent systemic treatment followed by RRCIA. Using Propensity-score matching (PSM) and stabilized inverse probability of treatment weighting (IPTW) analyses, we observed that patients who underwent RRCIA had better overall and progression free survival compared with patients who did not have surgery (PSM cohort: median OS: 25.8mo vs. 14.2mo, P=0.0031, and IPTW cohort: median OS: 23.2mo vs. 15.4mo, P=0.0069) and PFS (PSM cohort: median PFS: 13.3mo vs. 7.0mo, P=0.0246, and IPTW cohort: median OS: 13.3mo vs. 8.8mo, P=0.002). Further prospective analysis showed that patients who received systemic treatment followed by RRCIA were associated with improved OS and PFS compared with patients who were eligible but did not receive RRCIA (median OS: 22.6mo vs. 18.2mo, P=0.035; median PFS: 13.2mo vs. 10.3mo, P=0.0412). Moreover, stratified and multivariable analysis demonstrated that preoperative CA19-9 normalization and duration of initial treatment over 8 cycles were predictors for precise selection of patients who would benefit from RRCIA. Meanwhile, adjuvant therapy after RRCIA was a significant factor for improving survival. This study suggests that RRCIA appears to be effective and associated with improved outcomes for LAPC patients with favorable response to systemic treatment. LAPC patients Should have at least 8 cycles of systemic treatment and CA19-9 normalization to be considered for RRCIA.

Prognostic factors in localized pancreatic ductal adenocarcinoma after neoadjuvant therapy and resection: a systematic review and Meta-Analysis.

Prognostic markers for overall survival (OS) in resected pancreatic ductal adenocarcinoma (PDAC) are well-established but remain unclear following neoadjuvant therapy (NAT). This systematic review and meta-analysis aimed to determine factors associated with OS following NAT in resected PDAC. The PubMed, Embase, Scopus, Web of Science, and Cochrane CENTRAL databases were systematically searched from inception till May 2024. Studies that reported univariable and multivariable hazard ratios (HRs) were included if patients underwent NAT and resection for localized PDAC. Study quality assessment was performed using the Newcastle-Ottawa scale. Meta-analysis was performed using generic inverse-variance random-effects models. Among 2,208 unique articles identified by the search, 92 were included in the meta-analysis. Eighty-five of these were of 'good' and 7 of 'poor' quality. The NAT regimen was described in 84 studies, of which 62 included patients treated with FOLFIRINOX (FFX). Margin status, nodal disease, AJCC T-stage, and normalization of CA19-9 after NAT were prognostic for OS, while age, sex, perineural invasion, baseline tumor size, and baseline CA19-9 were not. The test for subgroup differences between ypN-substages was not significant in the multivariable model. Neoadjuvant FFX was associated with better survival than other regimens. This meta-analysis identified margin status, nodal disease, AJCC T-stage, and normalization of CA19-9 after NAT as prognostic factors for OS in patients with resected localized PDAC following NAT.

12556 Medullary Thyroid Cancer With Persistent Elevation Of Carcinoembryonic Antigen: Case Report

Abstract Disclosure: M.S. Campana: None. Introduction: Medullary thyroid Cancer (MTC) is a rare neuroendocrine tumor that originates from thyroid parafollicular C-cells and represents 5 % of all thyroid cancers. MTC can be sporadic (75%) or hereditary (25%) associated with multiple endocrine neoplasia type 2 syndrome (MEN2). Serum calcitonin (Ctn) and carcinoembryonic antigen (CEA) are its tumor markers. We report a case of persistently elevated CEA levels despite an undetectable Ctn in a patient with MTC after initial thyroid lobectomy. Description of the case: A 42-year-old woman self-identified a neck lump after intentional weight loss. A neck US showed a right lobe thyroid nodule which resulted as suspicious for malignancy (Bethesda V) with subsequent right lobectomy. Pathology reported a 2.6 cm unexpected MTC with negative surgical margins, extrathyroidal extension, angioinvasion, and lymphatic invasion. No cervical lymph nodes (LNs) were removed. Immunohistochemistry was positive for CEA, chromogranin A, synaptophysin, and Ctn. T2 Nx. One month after lobectomy, the Ctn was 10.5 (0-3.0 pg/mL) and CEA 205.2 (0-3.0 ng/mL Non-smoker; 0-5.0 ng/mL smoker). The patient was then referred to our clinic for further management. Laboratories showed normal serum calcium, PTH, and fractionated plasma metanephrine/normetanephrine. A 2-month post-operative Ctn was undetectable, but CEA was elevated at 24.5. Subsequently, we broaden imaging studies to include neck US, CT neck /chest with contrast, and MRI abdomen pelvis with contrast. The only remarkable finding was a 6.7 cm pelvic mass with normal Ca-125. Genetic testing was negative for germline RET, ruling out MEN2. Patient underwent completion left lobectomy with prophylactic bilateral central neck dissection. Pathology showed benign thyroid parenchyma with multinodular hyperplasia and 0/12 LNs. Because of concerning pelvic mass, the patient was referred to OB/GYN. She underwent a laparoscopic bilateral salpingo-oophorectomy. Pathology showed a follicular ovarian cyst, negative for malignancy. A year post-completion total thyroidectomy Ctn remains undetectable, and a CEA is normal at 1.3. Discussion: Because Ctn was already undetectable 1 month after lobectomy with persistent elevated CEA a complete total thyroidectomy with prophylactic bilateral central neck dissection was indicated to achieve operative cure. Ctn is specific to MTC but variable. CEA is more reproducible with less variability; however, it is not specific to MTC and can also be elevated in smokers, benign breast and genitourinary disease, emphysema, cirrhosis, and cancer of colon, rectum, liver, genitourinary, and lung. If residual disease is present, Ctn tends to be proportionally more elevated than CEA. When the opposite occurs, poorly differentiated MTC with possibility of distant metastases vs. a second primary malignancy vs. a distant benign neoplasm known to elevate CEA need to be ruled out. Presentation: 6/2/2024

6712 Intractable Hypoglycemia: A Clue to Tumor Diagnosis

Abstract Disclosure: N. Kharkongor Chengappa: None. E.I. Krug: None. Background: Non-Islet Cell Tumor Hypoglycemia (NICTH) known as Doege-Potter syndrome, is a rare paraneoplastic syndrome of hypo-insulinemic hypoglycemia caused by excessive production of partially processed IGF-II from a solitary fibrous tumor (SFT).We present a case of a patient admitted with intractable hypoglycemia leading to the diagnosis and treatment of a large pelvic SFT. Clinical Case: A 59-year-old male with type 2 Diabetes Mellitus on metformin mono therapy, was admitted after he collapsed at work and was found to have blood glucose (BG) of 22 mg/dl. He was previously in his usual state of health except for an increase in his shoe size over the past year. Physical examination revealed coarse thick skin, large coarse bullous nose, enlarged fingers and a non-tender, firm abdomen with no obvious organomegaly. Laboratory results including CBC, CMP and thyroid function were normal. ACTH stimulation test revealed normal adrenal function. Hypoglycemic drug screen and insulin antibodies were negative. During a hypoglycemic event (BG of 45mg/dl) he had C-peptide level < 0.1ng/ml, beta-hydroxybutyrate levels of <0.05 and insulin level <0.4uIU/ml, indicating non-insulin mediated hypoglycemia. IGF-I and IGF-II levels were ordered. Due to a concern for paraneoplastic etiology of hypoglycemia. CT scan revealed a 20 cm solid mass, filling most of the pelvis and extending into the lower abdomen. Further investigations revealed normal PSA, CEA, CA19-9 and undetectable hCG and AFP levels. MRI confirmed a presence of 23 cm pelvic mass with few areas of central necrosis, extending into the lower abdomen. CT-guided biopsy revealed spindle cell neoplasm consistent with SFT. The patient underwent pelvic mass resection. Postoperatively, hypoglycemia resolved with BG readings of 138mg/dl to 178mg/dl. Surgical pathology results confirmed malignant SFT with positive STAT 6 and CD34 markers. IGF-II level obtained prior to surgery was markedly elevated at 2029 ng/ml (38-267 ng/mL). Conclusion: NICTH was described in 1930 by KW Doege and RP Potter. Less than 5% of patients with SFTs develop NICTH. Diagnosis requires manifestation of Whipple's triad, low insulin, pro-insulin and C-peptide levels, elevated IGF-II levels, or an IGF-I/IGF-II ratio>2, and the identification of the tumor. Positive immunohistochemical stain of the tumor for STAT6 confirms the diagnosis. Management involves resection of the tumor when feasible or debulking. For higher-risk tumors, radiation therapy may be considered. In inoperable cases, glucocorticoids, recombinant hGH and glucagon are recommended for palliation of hypoglycemia. Octreotide and Diazoxide are ineffective in NICTH.

Effectiveness, safety, and biomarker analysis of lenvatinib plus toripalimab as chemo-free therapy in advanced intrahepatic cholangiocarcinoma: a real-world study

BackgroundTreatment options for advanced intrahepatic cholangiocarcinoma (ICC) are currently limited. Chemo-containing regimens are the mainstay treatments but associated with notable toxicity, poor tolerance, and reduced compliance, necessitating exploration of alternative therapies. Lenvatinib plus PD-1 inhibitors has shown substantial clinical activity in preliminary studies. This study aimed to assess the effectiveness and safety of lenvatinib plus toripalimab (a novel PD-1 antibody) as chemo-free therapy in advanced ICC.MethodsThis retrospective study included consecutive advanced ICC patients receiving lenvatinib plus toripalimab between February 2019 and December 2023. The main outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Prognostic factors and exploratory analyses for genetic alternations were also conducted.ResultsA total of 78 patients were included, with a median follow-up of 25.9 months. Median OS and PFS were 11.3 (95% CI: 9.5–13.1) and 5.4 (95% CI: 3.8–7.0) months, respectively. ORR was 19.2% and DCR was 75.6%. The incidence of grade 3 or 4 adverse events (AEs) was 50.0%, with no grade 5 AEs reported. Patients with normal baseline CA19-9 levels exhibited a higher ORR (p = 0.011), longer PFS (11.5 versus 4.6 months; HR 0.47; p=0.005), and OS (21.0 versus 9.7 months; HR 0.43; p=0.003). The presence of IDH1 mutations correlated with increased ORR (60.0% versus 8.9%, p=0.016).ConclusionLenvatinib plus toripalimab represents an effective and well-tolerated chemo-free therapeutic option for advanced ICC. Baseline CA19-9 levels and IDH1 mutations may serve as predictive treatment-related biomarkers.

Liver transplantation for unresectable Klatskin tumor: experience of two centers, first distant results

Aim. Evaluation of the first distant results of the combined experience of liver transplantation for unresectable portal cholangiocarcinoma from two large specialized clinical centers.Materials and methods. In total, 23 attempts at liver transplantation for unresectable Klatskin tumor were undertaken. Out of them, 10 were conducted at the A.M. Granov Russian Research Center for Radiology and Surgical Technologies (Granov Center), and 13 were conducted at the Minsk Scientific and Practical Center for Surgery, Transplantology, and Hematology (Minsk Center). The maximum tumor size was 5 and 3 cm in patients operated at the Granov and Minsk Centers, respectively. In the Granov Center, neoadjuvant therapy included a combination of endobiliary photodynamic therapy, regional and systemic chemotherapy. Patients were included in the waiting list only in cases of decreased tumor marker levels and in the absence of disease progression and acute cholangitis. In the Minsk Center, stereotactic radiotherapy was used for neoadjuvant treatment in the absence of active cholangitis; the first 3 patients underwent liver transplantation without prior neoadjuvant treatment.Results. Due to disease progression, six patients were excluded. In three patients at the Mink Center, the diagnosis was not morphologically confirmed after liver transplantation. A total of 14 liver transplantations were performed for unresectable hilar cholangiocarcinoma. After neoadjuvant treatment at the Granov Center, normalization of the CA19-9 marker was observed in four patients, its decrease by 3–4 times was observed in two patients. Liver transplantation was performed in six patients. The average time from the onset of treatment to transplantation was 9.1 months (6–14). Out of the six patients, one was alive for 34 months, with the median overall survival being 22.2 months. Progression was the cause of death in only one patient. Out of the three patients without neoadjuvant treatment at the Minsk Center, two were alive at 16 and 134 months without progression. One patient died after transplantation from disease progression at 24 months. Stereotactic radiotherapy achieved normalization of CA19-9 in four patients; its twofold reduction was observed in one patient. The average time from the onset of treatment to transplantation was six months (3–12). The average CA19-9 tumor marker level by the time of transplantation was 11.3 IU/mL. At 20–26 months, three patients were alive without evidence of disease progression; two patients died of progression after 9 and 59 months.Conclusion. Liver transplantation for unresectable portal cholangiocarcinoma after neoadjuvant treatment regardless of the methods used is highly promising in carefully selected recipients.

Risk-prediction models in postmenopausal patients with symptoms of suspected ovarian cancer in the UK (ROCkeTS): a multicentre, prospective diagnostic accuracy study

Multiple risk-prediction models are used in clinical practice to triage patients as being at low risk or high risk of ovarian cancer. In the ROCkeTS study, we aimed to identify the best diagnostic test for ovarian cancer in symptomatic patients, through head-to-head comparisons of risk-prediction models, in a real-world setting. Here, we report the results for the postmenopausal cohort. In this multicentre, prospective diagnostic accuracy study, we recruited newly presenting female patients aged 16-90 years with non-specific symptoms and raised CA125 or abnormal ultrasound results (or both) who had been referred via rapid access, elective clinics, or emergency presentations from 23 hospitals in the UK. Patients with normal CA125 and simple ovarian cysts of smaller than 5 cm in diameter, active non-ovarian malignancy, or previous ovarian malignancy, or those who were pregnant or declined a transvaginal scan, were ineligible. In this analysis, only postmenopausal participants were included. Participants completed a symptom questionnaire, gave a blood sample, and had transabdominal and transvaginal ultrasounds performed by International Ovarian Tumour Analysis consortium (IOTA)-certified sonographers. Index tests were Risk of Malignancy 1 (RMI1) at a threshold of 200, Risk of Malignancy Algorithm (ROMA) at multiple thresholds, IOTA Assessment of Different Neoplasias in the Adnexa (ADNEX) at thresholds of 3% and 10%, IOTA SRRisk model at thresholds of 3% and 10%, IOTA Simple Rules (malignant vs benign, or inconclusive), and CA125 at 35 IU/mL. In a post-hoc analysis, the Ovarian Adnexal and Reporting Data System (ORADS) at 10% was derived from IOTA ultrasound variables using established methods since ORADS was described after completion of recruitment. Index tests were conducted by study staff masked to the results of the reference standard. The comparator was RMI1 at the 250 threshold (the current UK National Health Service standard of care). The reference standard was surgical or biopsy tissue histology or cytology within 3 months, or a self-reported diagnosis of ovarian cancer at 12 month follow-up. The primary outcome was diagnostic accuracy at predicting primary invasive ovarian cancer versus benign or normal histology, assessed by analysing the sensitivity, specificity, C-index, area under receiver operating characteristic curve, positive and negative predictive values, and calibration plots in participants with conclusive reference standard results and available index test data. This study is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN17160843). Between July 13, 2015, and Nov 30, 2018, 1242 postmenopausal patients were recruited, of whom 215 (17%) had primary ovarian cancer. 166 participants had missing, inconclusive, or other reference standard results; therefore, data from a maximum of 1076 participants were used to assess the index tests for the primary outcome. Compared with RMI1 at 250 (sensitivity 82·9% [95% CI 76·7 to 88·0], specificity 87·4% [84·9 to 89·6]), IOTA ADNEX at 10% was more sensitive (difference of -13·9% [-20·2 to -7·6], p<0·0001) but less specific (difference of 28·5% [24·7 to 32·3], p<0·0001). ROMA at 29·9 had similar sensitivity (difference of -3·6% [-9·1 to 1·9], p=0·24) but lower specificity (difference of 5·2% [2·5 to 8·0], p=0·0001). RMI1 at 200 had similar sensitivity (difference of -2·1% [-4·7 to 0·5], p=0·13) but lower specificity (difference of 3·0% [1·7 to 4·3], p<0·0001). IOTA SRRisk model at 10% had similar sensitivity (difference of -4·3% [-11·0 to -2·3], p=0·23) but lower specificity (difference of 16·2% [12·6 to 19·8], p<0·0001). IOTA Simple Rules had similar sensitivity (difference of -1·6% [-9·3 to 6·2], p=0·82) and specificity (difference of -2·2% [-5·1 to 0·6], p=0·14). CA125 at 35 IU/mL had similar sensitivity (difference of -2·1% [-6·6 to 2·3], p=0·42) but higher specificity (difference of 6·7% [4·3 to 9·1], p<0·0001). In a post-hoc analysis, when compared with RMI1 at 250, ORADS achieved similar sensitivity (difference of -2·1%, 95% CI -8·6 to 4·3, p=0·60) and lower specificity (difference of 10·2%, 95% CI 6·8 to 13·6, p<0·0001). In view of its higher sensitivity than RMI1 at 250, despite some loss in specificity, we recommend that IOTA ADNEX at 10% should be considered as the new standard-of-care diagnostic in ovarian cancer for postmenopausal patients. UK National Institute of Heath Research.

Abstract A048: Paricalcitol improves survival in tumor-permissive cancer-associated fibroblast subtype of pancreatic cancers

Abstract INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with poor survival and limited therapy options. While traditional cytotoxic agents target cancer cells, there has been growing interest in tumor microenvironment (TME) modulation given that desmoplastic stroma and immune suppression are hallmarks of PDAC. Recently, vitamin D agonism has been identified as a potential treatment to normalize the PDAC TME. We have previously described tumor-intrinsic and cancer-associated fibroblast (CAF) subtypes of PDAC that independently predict survival, but whether these subtypes are associated with outcomes after TME modulation has not been studied. METHODS: We evaluated the association of treatment outcomes in a Phase 2 trial of neoadjuvant nab-paclitaxel (A), gemcitabine (G), cisplatin (C), and paricalcitol (P) (NCT03138720) and a Phase 2 trial of A+G+C+hydroxychloroquine (HCQ) (NCT04669197) in patients with non-metastatic PDAC. RNA-sequencing was performed on 28 pretreatment biopsy samples. PurIST and DeCAF were used to determine tumor-intrinsic and CAF subtypes, respectively. Clinical variables such as CA19-9 levels, resectability, and overall survival (OS) were examined. RESULTS: For tumor-intrinsic subtypes, 5 tumors (18%) were basal-like and 23 (82%) were classical. For CAF subtypes, 11 (39%) were tumor-permissive (perm)CAF and 17 (61%) were tumor-restraining (rest)CAF. Neither tumor-intrinsic or CAF subtypes were associated with CA19-9 normalization or resectability at time of diagnosis in either trial. OS was available for NCT03138720; patients with basal-like tumors receiving A+G+C+P had worse median survival of 12.3 months compared to 20.9 months for those with classical tumors, although this difference did not reach statistical significance (log-rank P = 0.065). In two independent cohorts of 925 and 129 patients, those with permCAF tumors had an increased hazard ratio of at least 1.5 (P &amp;lt; 0.001) compared to patients with restCAF tumors for OS. Compared to this historical data, we did not find a difference in OS between patients with permCAF tumors (19.5 months) compared to restCAF tumors (19.7 months, log-rank P = 0.56). CONCLUSION: In the study of A+G+C+P, there was a disparity in OS between patients with basal-like vs. classical tumors, in contrast to the interim results of the COMPASS and PASS-01 trials, where patients with basal-like tumors receiving A+G had similar OS compared to patients with classical tumors. Compared to prior analysis, there was no difference in OS for patients with permCAF tumors vs. those with restCAF tumors, which may suggest that either paricalcitol (or the cytotoxic combination) may be of benefit for patients with permCAF tumors and normalize the CAF landscape. Single-agent studies with paired pre- and post-treatment samples are needed to better understand how to best tailor therapy regiments for patients based on tumor subtypes. Citation Format: Jaewon J Lee, Priscilla S Chan, Changfei Luan, Elena V Kharitonova, Naim U Rashid, Xianlu L Peng, Erkut H Borazanci, Jen Jen Yeh. Paricalcitol improves survival in tumor-permissive cancer-associated fibroblast subtype of pancreatic cancers [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 A048.

A dual-center study: can ultrasound radiomics differentiate type I and type II epithelial ovarian cancer patients with normal CA125 levels?

CA125 is recommended by many countries as the primary screening test for ovarian cancer. But there are patients with ovarian cancer having normal CA125. We hope to identify the types of EOC with normal CA125 levels better by building a refined model based on the ultrasound radiomics, thus providing precise medical treatment for patients. We included 58 patients with EOC with normal CA125 from 2 centres, who were confirmed by preoperative ultrasound and pathology. We extracted 1130 radiomics features based on the tumour's region of interest from the most typical ultrasound image of each patient. We selected radiomics and clinical features by LASSO and logistic regression to construct Rad-score and clinical models, respectively. Receiver operating characteristic curves judged their test efficacy. On the basis of the combined model, we developed a nomogram. Area under the curves (AUCs) of 0.93 and 0.83 were achieved in both the training and test groups for the combined model. There were similar AUCs between the Rad-score and clinical models of 0.82 and 0.80, respectively. By analysing the calibration curves, it was determined that the nomogram matched actual observations in the training cohort. Ultrasound radiomics can differentiate type I and type II EOC with normal CA125 levels. This study is the first to focus on EOC cases with normal level of CA125. The subset of patients constituting 20% of the disease population may require more refined radiomics models.

Exploring metastasis and recurrence patterns in low-risk grade 3 endometrial cancer: A multicenter retrospective cohort study

ObjectiveFemales with low-risk endometrial cancer typically have low lymph node metastasis risk and promising prognosis without lymphadenectomy. However, the impact of grade 3 endometrial cancer on nodal involvement, recurrence, and prognosis within this specific subgroup remains unclear. Therefore, in this study, we aimed to investigate the prognosis, patterns of metastasis, and recurrence in a subgroup of females with grade 3 early-stage low-risk endometrioid endometrial cancer. MethodsWe identified patients from the endometrial cancer cohorts of seven institutional hospitals. The study included patients who underwent hysterectomy between January 2013 and December 2021 with preoperative endometrioid histological type, less than half myometrial invasion, no tumor spread outside the corpus on imaging, normal CA-125 level, and histological grade 3. The clinicopathological characteristics and survival outcomes of the patients were collected. Recurrence-free survival was estimated using the Kaplan–Meier method and compared using the log rank test. ResultsOverall, 36 patients were included in this analysis. Of the 33 patients who underwent lymphadenectomy, 1 (1/33, 3.0 %) had lymph node metastasis and 27 (75.0 %) received adjuvant therapy. At a median follow-up of 58 months, three females (8 %) had recurrence and all cases involved lymph nodes. The 5-year recurrence-free survival was 88.7 %. No significant difference was observed in the recurrence-free survival between females who did and did not undergo lymphadenectomy (p = 0.554). ConclusionFemales diagnosed with low-risk grade 3 endometrial cancer typically have favorable prognosis. However, lymph node metastasis and recurrence risks still exist, with all recorded instances of recurrence involving lymph nodes.

Prognosis and predictive factors of conversion surgery for initially unresectable advanced colorectal cancer

PurposeThe aim of this study was to report the outcomes of conversion surgery for initially unresectable advanced colorectal cancer and to identify factors that enable successful conversion surgery.MethodsWe compared the outcomes of patients with colorectal cancer with distant metastases, including extrahepatic metastases, who underwent upfront surgery, neoadjuvant chemotherapy, conversion surgery, and chemotherapy only at our department from 2007 to 2020. In addition, factors influencing the achievement of conversion surgery in patients who were initially unresectable were examined in univariate and multivariate analyses.ResultsOf 342 colorectal cancer patients with distant metastases treated during the study period, 239 were judged to be initially unresectable, and 17 (conversion rate: 7.1%) underwent conversion surgery. The prognosis for the conversion surgery group was better than that of the chemotherapy only group but worse than that of the upfront surgery group. In the conversion surgery group, the recurrence-free survival after resection was significantly shorter than that upfront surgery group and neoadjuvant chemotherapy group, and no patients have been cured. Among patients who were initially unresectable, left-sided primary cancer and normal CA19-9 level were identified as independent factors contributing to the achievement of conversion surgery in a multivariate analysis.ConclusionsAlthough relapse after conversion surgery is common, and no patients have been cured thus far, overall survival was better in comparison to patients who received chemotherapy only. Among unresectable cases, patients with left-sided primary cancer and normal CA19-9 levels are likely to be candidates for conversion surgery.

Circulating tumor DNA for recurrence monitoring following resection for pancreas adenocarcinoma.

e16365 Background: Detecting early recurrence among patients with resected pancreatic cancer may facilitate earlier treatment and better outcomes for patients with resected pancreatic ductal adenocarcinoma (PDAC). Circulating tumor DNA (ctDNA) has shown promise as a tumor-specific biomarker for PDAC but has not yet entered routine clinical use. This study aims to conduct analytical and clinical validation of Signatera ctDNA profiling to predict recurrence in patients with PDAC. Methods: A retrospective IRB-approved protocol evaluating the use of Signatera ctDNA testing among patients who underwent resection at Northwell Health during 2019-2023. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed using cox regression. Results: There were 91 ctDNA tests among 24 patients. With a median follow-up of 15 months, recurrence was observed in 38% (9/24) of patients and 8 patients died. Among patients with recurrence, most of them had positive ctDNA before showing signs of recurrence on the imaging (6/9, 66.7%) with mean lead time of 116 days, while 2 of them had positive ctDNA after recurrence and one patient never had positive ctDNA. At the time of recurrence, eight patients had elevated CA19-9, while two patients with normal CA19-9 had positive ctDNA. The median recurrence-free survival (RFS) was 23 months (95% CI, 11-not reached). Patients with detectable preoperative ctDNA had significantly decreased median RFS (14 months; 7 of 10 (70%) recurred) when compared with patients negative for ctDNA [not reached; 2/14 (14.3%) recurred; P= 0.005). In multivariable Cox model after adjusting for potential risk factors, detection of ctDNA was associated with RFS. (table). Conclusions: Signatera ctDNA profiling identified relapse earlier than imaging for most patients. These results suggest the potential for a prospective trial evaluating early treatment interventions in this deadly disease to improve survival rates. [Table: see text]

Abstract PO3-20-09: METACHRONOUS METAPLASTIC BREAST CARCINOMA IN A 55-YEAR-OLD PATIENT WITH SEROUS OVARIAN CARCINOMA

Abstract Metaplastic breast carcinoma is a rare histologic subtype of breast carcinoma, accounting for only 0.2 to 2% of all breast cancers. It is comprised of a heterogeneous histology involving mesenchymal and epithelial components. Metaplastic breast carcinoma usually harbors a triple-negative phenotype, but carries a worse prognosis compared to other breast cancer subtypes. Due to its unique histopathological and molecular characteristics, there has been limited data on the optimal management of metaplastic breast carcinoma. Moreover, the presence of a secondary breast neoplasm in the background of a prior ovarian carcinoma represents a diagnostic and therapeutic challenge. We report a case of a 55-year-old female with a previous history of serous ovarian carcinoma six years ago, who presented with an enlarging right breast mass. Digital mammography showed a right retro-areolar mass, 5.7 x 4.8 x 5.4 cm, BIRADS 4C. Initial biopsy done showed presence of atypical cells in a background of cystic change. The patient underwent modified radical mastectomy with incision biopsy and frozen section. Final histopathologic diagnosis was consistent with metaplastic breast carcinoma, mixed epithelial and mesenchymal type, Nottingham grade 2, with no lymphovascular invasion identified, pT2N0. Tumor was ER negative, PR negative, Her 2 neu negative, with Ki-67 of 10% on immunohistochemistry. She then underwent adjuvant treatment with 6 cycles of paclitaxel and carboplatin. Six years prior, the patient was likewise diagnosed with high-grade serous ovarian carcinoma. She had total abdominal hysterectomy with bilateral salpingo-oophorectomy and adjuvant chemotherapy with 6 cycles of Paclitaxel and Carboplatin was given. She had recurrence in the paraaortic lymph node after 3 years and underwent cytoreductive surgery with excision of nodule and hyperthermic intraperitoneal chemotherapy with cisplatin. Currently, the patient has no evidence of disease in the recent positron emission tomography scan, with normal serum CA-125 level. The current standard of care for metaplastic breast carcinoma follows that of triple-negative breast cancer. However, previous literature has shown that metaplastic breast carcinoma is more chemo-refractory compared to triple-negative breast cancer, with more response seen with taxane-based chemotherapy. Due to poor response rates to neoadjuvant chemotherapy, surgical management for early-stage disease is warranted. Targeting molecular alterations is necessary to improve the prognosis of this subtype. Genomic features of homologous recombination deficiency were also found to be more prevalent in metaplastic breast cancer, thus genomic testing is warranted, especially in the setting of a prior history of ovarian carcinoma. Citation Format: Raye Angeli Abella, Carlos Dy. METACHRONOUS METAPLASTIC BREAST CARCINOMA IN A 55-YEAR-OLD PATIENT WITH SEROUS OVARIAN CARCINOMA [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-20-09.

Effect of glycotoxicity and lipotoxicity on carbohydrate antigen 19 − 9 in the patients with diabetes

ObjectivesIn comparison to the subjects without diabetes, a greater concentration of serum carbohydrate antigen 19 − 9 (CA 19 − 9) was observed in the subjects with diabetes. Nevertheless, since the occurrence of abnormal CA 19 − 9 is not widespread among the whole diabetic population, this phenomenon has not attracted enough attention. The prevalence of abnormal CA 19 − 9 in hospitalized patients with diabetes was the focus of our research.MethodA total of 385 subjects with diabetes and 200 controls were enrolled and all had been tested the CA19-9 levels. Cases of cancers were excluded through examination and followup for 1 year.ResultsWe found that the rate of patients with abnormal CA19-9 level was 8.3%. The rate of patients with abnormal CA19-9 level was 14.0% in the HbA1c ≥ 9% group, and 3.0% in the HbA1c < 9% group, 2.5% in the control group. There was no significant difference in the HbA1c < 9% group and the control group. A significant correlation between serum CA19-9 and both HbA1c and total cholesterol was observed, yet no difference in CRP level was observed between subjects with normal CA19-9 level and subjects with abnormal CA19-9 level. However, a significant difference in fasting C-peptide levels was observed between the two groups, p = 0.039.ConclusionThe percentage of patients with diabetes exhibiting elevated CA19-9 level is 14% in the HbA1c ≥ 9% diabetic patients, much higher than expected. The underlying mechanism may be related to islet injury caused by glycotoxicity and lipotoxicity. Strengths and limitations of the studyWe studied the rate of hospitalized diabetic patients with elevated CA 19 − 9 which were characterized with poorly controlled blood glucose. We found that the elevation of CA 19 − 9 was unexpectedly high in diabetic inpatients without development to cancer. The limitation of this study is that the underlying mechanism is not sufficiently studied.

Clinical Utility of the Combined Use of CA19-9 and DUPAN-2 in Pancreatic Adenocarcinoma

PurposePancreatic ductal adenocarcinoma (PDAC) patients with normal carbohydrate antigen (CA) 19-9 levels can have early-stage cancer or advanced cancer without elevation of CA19-9 level; estimating their malignant potential is difficult. This study investigated the clinical utility of the combined use of preoperative CA 19-9 and Duke pancreatic monoclonal antigen type 2 (DUPAN-2) levels in patients with PDAC.MethodsPatients who underwent curative-intent surgery for PDAC between November 2005 and December 2021 were investigated. Eligible patients were classified into four groups based on these two markers. Among patients with normal CA19-9 levels, those with normal and high DUPAN-2 levels were classified into normal/normal (N/N) and normal/high (N/H) groups, respectively. Among patients with high CA19-9 levels, those with normal and high DUPAN-2 levels were classified into high/normal (H/N) and high/high (H/H) groups, respectively. Survival rates were compared between the groups.ResultsAmong 521 patients, the N/N, N/H, H/N, and H/H groups accounted for 25.0%, 10.6%, 35.1%, and 29.4% of patients, respectively. The proportions of resectable PDAC in the N/N and H/N groups (71.5% and 66.7%) were significantly higher than those in the N/H and H/H groups (49.1% and 54.9%) (P < 0.01). The 5-year survival rates in the N/N, N/H, H/N, and H/H groups were 66.0%, 31.1%, 34.9%, and 29.7%, respectively; the rate in the N/N group was significantly better than those in the other three groups (P < 0.0001, P < 0.0001, and P < 0.0001, respectively).ConclusionsOnly patients with normal CA19-9 and DUPNA-2 values should be diagnosed with early-stage PDAC.

Large Ovarian Cyst - Laparoscopic Entry: A Case Report

This report is aimed at introducing a simple technique to improve safety in drainage of large ovarian cyst managed with laparoscopic techniques. A 31-year-old, nulliparous woman, presented with a massive unilocular ovarian cyst measuring 22.48 cm in height, 18.92 cm in transverse axis, and 8.03 cm antero posteriorly. She had a normal CA125 level. Entry was done with the open technique (Hasson's) at the midpoint between umbilicus and the xiphisternum (Lee Huang). Through this opening the cyst wall was separated by blind dissection to avoid damage to cyst wall. Then the cyst contents were drained with a Veress needle. Troche was inserted through the same incision and pneumoperitoneum was created allowing a routine cystectomy. The critical step in managing large cysts is safe entry and inducing pneumoperitoneum. Using a simple technique, could improve safety resulting in successful a successful outcome of laparoscopic techniques for large ovarian cysts.

The relationship between clinical and pathological findings and FDG - PET uptake in metastatic colorectal cancers.

In metastatic colorectal cancer (mCRC), the genetic structure and cell metabolism of the primary tumor lesion might be different from metastatic lesions. It is thought that cell-level glucose metabolism may differ due to the difference in RAS wild and mutant mCRC patients' prognosis. In this study, we aimed to compare 2-deoxy-2-[fluorine-18]-fluoro-D-glucose Positron Emission Tomography (18F-FDG PET/CT) uptake levels for KRAS mutation status and primary-metastatic tumor localization. Our study is a retrospective cohort analysis that included RAS mutation status study and staging-oriented 18F-FDG PET/CT conducted on mCRC patients. There was no significant relationship between metastasis and primary tumor maximum Standardized uptake value (SUVmax) values according to the KRAS mutational status (P > 0.05). Patients with liver metastasis along with mutant BRAF mutation status had significantly higher SUVmax values in PET-CT scans (P = 0.04). There was a negative correlation between SUVmax values of lung metastases and overall survival (r = -0.35, P = 0.04). Patients with high carcinoembryonic antigen (CEA) levels had significantly higher SUVmax values of lung metastasis than patients with normal CEA levels (P = 0.009). Patients with high CA19-9 levels had significantly higher SUVmax values of liver, peritoneal, and bone metastasis than patients with normal CA19-9 levels (P = 0.002, P = 0.001, P = 0.004, respectively). There was no significant correlation between SUVmax values of metastasis and Lactate dehydrogenase (LDH) values. Liver metastasis of right-sided mCRCs had significantly higher SUVmax values (P = 0.03). We could not demonstrate a significant association between KRAS mutation and SUVmax values of PET scan in primary or metastatic tumor sites in advanced CRC.

A phase II trial of induction systemic mFOLFIRINOX followed by hepatic arterial infusion of floxuridine and dexamethasone given concurrently with systemic mFOLFIRI as a first-line therapy in patients with unresectable liver-dominant intrahepatic cholangiocarcinoma (HELIX-1).

511 Background: Most patients with intrahepatic cholangiocarcinoma (ICC) have unresectable or multifocal liver-dominant disease. Survival after first-line systemic therapy remains poor, with median progression-free (mPFS) and overall survival of 7.2 and 12.8 months, respectively. Hepatic arterial infusion (HAI) therapy with floxuridine maximizes liver-specific treatment with minimal systemic toxicity and potentially offers improved disease control when combined with systemic therapy. Methods: HELIX-1 (NCT04251715) is an investigator-initiated, first-line, single-center, single-arm phase II clinical trial for patients with liver-dominant unresectable or multifocal ICC. The trial was designed with a patient safety run-in evaluating toxicity from the combined therapy. Pre-trial screening included laparoscopy, biopsies, and PET/CT. Eligible patients were treated with systemic mFOLFIRINOX for 4 cycles in order to select those likely to benefit from HAI. Patients with disease control on restaging proceeded to HAI pump placement and treatment with HAI floxuridine for 14 days followed by systemic mFOLFIRI on a 28-day cycle. The co-primary objectives were to assess safety of the combined therapeutic strategy and the disease control rate (DCR) at 6 months (RECIST v1.1) at end of trial (EOT). Results: A total of n=5 patients with liver-only ICC enrolled in the trial and completed the entire study protocol. The median age was 60 years (range 42-69) with a dominant lesion size of 9.8cm (range 8.4-14.5). All patients had both right and left hemiliver involvement with a median of 9 intrahepatic tumors (range 1-15). No patients experienced grade 3 or 4 adverse events, or hepatic dysfunction leading to cessation of HAI therapy. The DCR at 6 months was 100%, with a mPFS of 18.2 months. All five patients achieved partial radiographic response (PR) while receiving HAI therapy, and remain alive with liver-only disease at a median of 18.4 months (range 12.7-20) after study enrollment. After continuing treatment with HAI and systemic mFOLFIRI beyond the EOT, two patients transitioned to HAI treatment only and then to biochemical and radiographic surveillance without therapy after demonstrating PR and CA19-9 normalization. Conclusions: Integration of HAI floxuridine with mFOLFIRI following mFOLFIRINOX induction for patients with liver-only advanced ICC is well-tolerated and demonstrates longer DCR in comparison to historical controls. The combined regimen minimized systemic toxicity and allowed a large proportion of patients to transition to liver-only HAI treatment with maintained disease control. Future directions include combining HAI with new first-line systemic regimens for patients with advanced ICC. Clinical trial information: NCT04251715 .

BNT321, a novel monoclonal antibody targeting sialyl Lewis A: Phase 1 monotherapy and combination with mFOLFIRINOX in patients with advanced CA19-9 expressing cancers.

654 Background: BNT321 is a high affinity human monoclonal antibody targeting the sialyl Lewis A epitope of CA19-9. This Phase 1/1b dose escalation/expansion study investigated BNT321 as monotherapy and in combination with mFOLFIRINOX (mFFX) in patients (pts) with advanced CA19-9 expressing cancers. Methods: Eligible pts: progressive CA19-9 expressing solid tumors, liver transaminases ≤ 2 x ULN, bilirubin WNL, ECOG PS 0-1. BNT321 given on Qwk, Q2wk, and Q4wk schedules. Lead in dose (1 mg/kg given 1 wk prior to assigned dose) evaluated on Q2wk + Q4wk schedules. BNT321 + mFFX given Q2wk as 1L or 2L metastatic therapy (1L+2L met). Dexamethasone given as premedication. Endpoints: safety, MTD, RP2D, efficacy, PK, changes in serum CA19-9. Results: 82 pts received BNT321 monotherapy and 15 received BNT321 + mFFX. BNT321 monotherapy MTD was 2 mg/kg Q2wk and MTD with mFFX was 1 mg/kg. Schedule and lead in dose did not significantly alter MTD. Dose limiting toxicities (DLTs) for BNT321 monotherapy and with mFFX were elevations in hepatic AST and ALT with or without bilirubin elevations. These events generally occurred early (cycle 1), resolved with drug hold, and did not preclude subsequent reduced dose BNT321. Frequent related AEs (total %/ &gt; grade 3 %) for BNT321 include increased ALT (39%/19%), AST (35%/12%), T bilirubin (27%/9%), fatigue (21%/0%), infusion related reaction (IRR) (17%/1%) and for BNT321 + mFFX fatigue (67%/0%), increased AST (40%/27%), ALT (33%/20%), diarrhea (33%/0%), nausea (20%/0%). At combination MTD (n=7): fatigue (71%/0%), diarrhea (29%/0%), IRR (29%/0%), nausea (28%/0%), increased AST (14%/14%), ALT (14%/14%). BNT321 demonstrated a T1/2 of 11.75 days + dose proportional Cmax and AUC with intra-patient variability. Enhanced clearance observed among pts with higher baseline (BL) serum CA19-9. For BNT321 monotherapy stable disease (RECIST 1.1) was best response, with time on study &gt; 90 days and &gt; 180 days in &gt; 20% and 10% of pts, respectively. Correlation between time on study and post BL normalization of CA19-9 was observed. For BNT321 + mFFX (1L+2L met), PRs were observed in 3/11 (27%) response evaluable pts who had time on study 10.0-15.8 months. Conclusions: BNT321 and BNT321 + mFFX MTDs were 2 mg/kg and 1 kg/kg, respectively. DLTs were hepatic AST, ALT and T bilirubin elevations which were generally cycle 1 and did not preclude subsequent BNT321 at reduced dose. BNT321 monotherapy resulted in disease stabilization and prolonged time on study (&gt; 90 days for &gt; 20%) in pts with advanced line, metastatic PDAC and other CA19-9+ cancers. BNT321 significantly decreased CA19-9 in the majority of pts and PK was similar to other human monoclonal antibodies. BNT321 + mFFX (1L+2L met) demonstrated multicycle tolerability and a 27% PR rate with 10+ months duration on study. BNT321 + mFFX is being evaluated in resected PDAC in the adjuvant setting. Clinical trial information: NCT02672917 .

Abstract B002: Phase I study of endoscopic ultrasound (EUS)-guided NBTXR3 delivery activated by radiotherapy (RT) for locally advanced or borderline resectable pancreatic cancer (LAPC or BRPC)

Abstract Patients with LAPC or BRPC often receive radiation therapy (RT) after chemotherapy (chemo) if no metastatic progression has occurred. Historically, CA19-9 normalizes in ~20 to 30% of patients after all therapy. While escalated dose radiotherapy (EDR) has shown promising survival in selected patients, extending use of EDR to all patients is challenging due to RT dose limitations of the bowel. To overcome this limitation, we are investigating NBTXR3, composed of functionalized hafnium oxide nanoparticles administered by a single intratumoral injection, locally amplifying the RT dose. In this phase 1 trial, the primary objective is to determine the NBTXR3 recommended phase 2 dose (RP2D). Secondary objectives are to measure anti-tumor effects. The study uses a Bayesian optimal interval design (BOIN) and has two parts: dose-finding (NBTXR3 at [level 1] 33% of gross tumor volume [GTV] or [level 2] at 42% of GTV) and cohort expansion at RP2D. In part 1, eligibility criteria included only LAPC patients with no evidence of metastatic disease after 2-6 months of chemo, part 2 allows BRPC. NBTXR3 was administered once prior to RT via an EUS-guided intratumoral injection. All patients received 45 Gy in 15 fractions with intensity modulated radiation therapy (IMRT). Patients were followed up to 1 year. Dose-limiting toxicities (DLTs) were defined as any grade ≥ 3 adverse events definitely or possibly related to NBTXR3 and/or RT. Target tumor response was per RECIST v1.1 criteria. CA19-9 was measured serially. We defined CA19-9 normalization as a value of 37 U/ml after finishing NBTXR3/RT. We compared rates of CA19-9 normalization in this phase 1 trial to a historical cohort of patients who received modern chemo/RT without NBTXR3. As of July 12, 2023, 15 LAPC patients have been treated with NBTXR3/RT. The median age was 63 years [range 43-81], 8 males, 7 females. The first patient (level 1) and subsequent 14 patients (level 2) had no injection complications. Level 2 had 1 non-serious DLT related to RT. At 4 weeks post RT, 13 had stable disease (SD) locally (2 had progressive disease [PD] overall), 1 had PD locally, and 1 had radiographic complete response (CR). At 3 months post RT, 11 had SD locally (1 PD overall), 1 PD locally, and 1 had surgery with negative margins and no residual viable tumor. 9 patients had elevated CA19-9 before NBTXR3/RT, 7 of these 9 (78%) had a decrease in CA19-9 subsequently, and 2 of these 9 (22%) had CA19-9 normalization eventually. 12 patients had elevated CA19-9 at diagnosis, and 5 out of 12 patients (42%) had normalization of CA19-9 after all therapy. We reviewed 455 patients with LAPC/BRPC between 2015-2019 who were treated at our institution as a comparison cohort for CA19-9 normalization rates. Out of 307 patients with elevated CA19-9 at diagnosis and normal bilirubin, 95 normalized (31%) and 212 did not normalize (69%) within 6 months of receiving cytotoxic therapy. The RP2D of NBTXR3 is 42% of GTV. The responses and CA19-9 results in comparison to historical data suggest promising anti-tumor efficacy of NBTXR3/RT. Citation Format: Gabriela Fuentes, Maria J. Rodriguez, Matthew H.G. Katz, Naruhiko Ikoma, Ching-Wei D. Tzeng, Michael Overman, Shubham Pant, Michael S. Lee, Robert A. Wolff, Milind Javle, Cullen M. Taniguchi, Emma B. Holliday, Ethan B. Ludmir, Prajnan Das, Albert C. Koong, Omar I. Vivar, Suyu Liu, Eric P. Tamm, Leonard A. Farber, Manoop S. Bhutani, Eugene J. Koay. Phase I study of endoscopic ultrasound (EUS)-guided NBTXR3 delivery activated by radiotherapy (RT) for locally advanced or borderline resectable pancreatic cancer (LAPC or BRPC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B002.