Gemcitabine Chemotherapy Research Articles

Anlotinib plus chemotherapy as first-line therapy for patients with gastrointestinal tumor with unresectable liver metastasis: Updated results from a multi-cohort, multi-center phase II trial ALTER-G-001-cohort C.

653 Background: Advanced gastrointestinal (GI) tumors, such as colorectal, gastric and pancreatic cancers (CRC, GC, and PC), and esophageal squamous cell carcinoma (ESCC), 20%-50% with liver metastases (LMs) have a poor prognosis. Previous trials showed that anlotinib plus chemotherapy has promising clinical activity and a tolerable safety profile for advanced CRC and ESCC, especially with LMs. In this phase II trial, we assessed the efficacy and safety of anlotinib plus chemotherapy as first-line treatment for LMs GI tumors. Methods: Patients with unresectable LMs GI tumors and without previous systemic treatment would be divided into cohort A (CRC), cohort B (ESCC), and cohort C (other GI tumors, such as PC, GC, biliary tract cancer (BTC), etc.). In cohort C, patients received induction therapy: anlotinib plus standard chemotherapy. Patients without PD and radical resection received anlotinib and metronomic capecitabine (500 mg, PO, BID, days 1-21, q3w) maintenance until PD or unacceptable toxicity. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints were DoR, PFS, OS, DCR, radical resection rate for LMs, and safety. Results: As of September 14, 2023, 41 patients were enrolled in cohort C (29 PC, 6 GC, 5 BTC, and others), the median age was 64 years (34-74), 63.4% male, 92.7% ECOG-PS 1 and 56.1% had LMs only. The majority of the pancreatic cancer patients (26/29) received gemcitabine plus nab-paclitaxel chemotherapy combination with anlotinib as induction therapy. After induction therapy, 4 patients (1 PC, 2 GC, 1 BTC) received surgical resection. Of 37 evaluable patients in cohort C, ORR and DCR were 45.9% and 86.5% (PR, n=17; SD, n=15, 12 SD had reduced tumor size). Of 25 evaluable pancreatic cancer patients, 12 had PR, 10 had SD, ORR and DCR were 48% and 88%. According to the Kaplan-Meier method, the median DoR was 4.2 months (95%CI, 1.7-6.6) and the median PFS was 5.5 months (95%CI, 4.7-6.3). 37 patients in cohort C had TEAEs and ≥ grade 3 TEAEs (51.2%) mainly included neutropenia (19.5%), white blood cell decreased (12.2%), and blood platelet decreased (9.8%). Conclusions: Anlotinib plus chemotherapy as first-line treatment has shown promising efficacy and acceptable safety and maybe a favorable option for advanced LMs GI tumors, especially for pancreatic cancer. Clinical trial information: NCT05262335 .

A phase 2, open-label, safety and efficacy study of telotristat ethyl plus first-line chemotherapy in patients with advanced biliary tract cancer.

472 Background: Patients (pts) with unresectable biliary tract cancer (BTC) have a poor prognosis. In preclinical models of cholangiocarcinoma (CCA) telotristat ethyl (TE), a tryptophan hydroxylase inhibitor that reduces production of serotonin, enhanced the antiproliferative effects of gemcitabine and cisplatin (GC) chemotherapy. This trial assessed the safety and efficacy of adding TE to GC chemotherapy in pts with advanced BTC. Methods: This was a Phase 2 open-label study. Eligible pts had unresectable, locally advanced, or metastatic BTC, were treatment naïve and had plans to initiate GC chemotherapy. On Day 1, pts received Gem 1000mg/m2 and Cis 25mg/m2 with TE 250 mg orally three times daily (TID) for 7 days. Thereafter, pts received TE 500 mg TID continuously plus GC therapy on days 1 and 8 of each 21-day cycle. The study comprised of 2 stages: stage 1 would enroll 20 patients with a safety run-in cohort in the first 6 pts to monitor safety and tolerability of TE + GC treatment for 21 days. Stage 2 would enroll 33 patients if no significant/unresolved grade 3 or higher toxicities related to study drug occurred in stage 1. The primary endpoint was 6-month (mo) progression free survival (PFS) rate according to RECIST 1.1. If 60% of pts (≥34) in the safety population were alive and progression free at 6-mos, the study was considered successful. Secondary endpoints included overall response rate (ORR) and disease control rate (DCR). Restaging occurred every 9 weeks using RECIST 1.1 and toxicities were graded using CTCAE v 5.0. Results: Between 2019 and 2021, fifty-three pts were enrolled across 12 study sites and comprised the safety population. The majority of pts were female (62.3%) and median age was 66 yrs (range 33 to 79). Baseline mean plasma 5-HIAA was 11.1 µg/L (ULN defined as >10.8 µg/L). Thirty-one pts (58.5%) had plasma 5-HIAA levels ≤ULN and 22/53 (41.5%) had 5-HIAA levels >ULN. Majority of pts had metastatic BTC (85%) and liver was the most common primary tumor site (66%). The 6-month PFS rate was 22.6% (12/53). Based on blinded independent central review, the ORR was 13.2% and DCR was 62.3%. Mean reduction in plasma 5-HIAA at 6 mos was -1.735 µg/L (SD 8.69) in 24 patients with available data. There was no difference in 6-mo PFS rate based on pts baseline 5-HIAA status; 58% (14/24) pts had ≥30% decrease from baseline in 5-HIAA, however there was no correlation with 6-month PFS. The most common TE related TEAEs were constipation (43.4%), nausea (28.3%) and fatigue (28.3%). Conclusions: The study did not achieve its primary endpoint of 60% of patients on TE plus GC chemotherapy being alive and progression free at 6 months. TE did reduce 5-HIAA levels in a subset of pts; however, this did not correlate to improved clinical outcomes. No significant safety issues noted with TE in combination with GC chemotherapy. Clinical trial information: NCT03790111 .

Abstract A040: Assessing the ability of Fc3TSR to remodel the tumor microenvironment and enhance efficacy of immunotherapies and chemotherapy in a murine model of pancreatic ductal adenocarcinoma

Abstract Introduction: Pancreatic Ductal Adenocarcinoma (PDAC) has a poor survival rate due to late diagnosis where metastasis has often occurred. Angiogenesis, the process by which new vessels form from pre-existing vasculature, is crucial for tumor growth and metastasis. Tumors aggressively upregulate expression of pro-angiogenic factors, stimulating rapid vessel formation. These vessels often lack pericyte coverage and have dysfunctional morphology, leading to high interstitial fluid pressure (IFP). Impaired perfusion and high IFP impede therapy uptake. Fc3TSR is a novel fusion protein derived from the potent angiogenic inhibitor thrombospondin 1, which we have shown to normalize vasculature in ovarian cancer, significantly decreasing tumor size and improving uptake of many therapies. In this study, we evaluated Fc3TSR’s ability to remodel the tumor microenvironment to induce tumor regression and to enhance efficacy of other therapies. Methods: We developed an orthotopic syngeneic murine model of PDAC, whereby we surgically injected 2.5 × 104 murine PDAC cells (KPC) into the tail of the pancreas of C57BL/6 mice. Tumors were allowed to progress for 14 days before intraperitoneal (IP) administration of Fc3TSR (0.158mg/kg) or PBS (control) on day 14 and 21. Gemcitabine (GEM) chemotherapy treated mice received either daily, metronomic dosages of GEM, or weekly, maximum tolerated dosages GEM starting on day 23. Checkpoint inhibitor mice received either PD-L1 (25ug) or CTLA4 (25ug) checkpoint inhibitors on day 23 and 26. Mice were euthanized on day 30 and tumors and the draining lymph nodes were collected and weighed. 1 hour before euthanasia, Fc3TSR and PBS mice were IP injected with Hypoxyprobe (Pimonidazole Hydrochloride) and tumors were immunostained for markers of blood vessels and tumor hypoxia. Results: Fc3TSR induced tumor regression when compared to PBS, but GEM at either dosage did not further enhance this effect. Following Fc3TSR, PD-L1, but not CTLA-4 checkpoint inhibitors significantly reduced tumor size when compared to mice pre-treated with PBS. Fc3TSR treatment also reduced the area of tumor hypoxia. Tumor vasculature is currently being imaged and analyzed for Fc3TSR’s effect on vessel morphology. Conclusion: Our data suggests that normalizing the tumor microenvironment can enhance the uptake and efficacy of combination therapies. Enhanced perfusion could facilitate the migration of activated immune cells and may enhance immune responses in PDAC patients. Here we demonstrate a novel approach to optimize therapeutic efficacy in advanced stage PDAC. Citation Format: Bianca Garlisi, Caroline Aitken, Sylvia Lauks, Julia Stewart, Duncan Petrik, Jack Lawler, Jim Petrik. Assessing the ability of Fc3TSR to remodel the tumor microenvironment and enhance efficacy of immunotherapies and chemotherapy in a murine model of pancreatic ductal adenocarcinoma [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 A040.

Transcriptomic insights into UTUC: role of inflammatory fibrosis and potential for personalized treatment

BackgroundUpper tract urothelial carcinoma (UTUC) is a rare disease, belonging to the same category of urothelial cancers as bladder cancer (BC). Despite sharing similar non-surgical treatment modalities, UTUC demonstrates a higher metastasis propensity than BC. Furthermore, although both cancers exhibit similar molecular disease emergence mechanisms, sequencing data reveals some differences. Our study investigates the transcriptomic distinctions between UTUC and BC, explores the causes behind UTUC's heightened metastatic tendency, constructs a model for UTUC metastasis and prognosis, and propose personalized treatment strategies for UTUC.MethodsIn our research, we utilized differential gene expression analysis, interaction networks, and Cox regression to explore the enhanced metastatic propensity of UTUC. We formulated and validated a prognostic risk model using diverse techniques, including cell co-culture, reverse transcription quantitative polymerase chain reaction (rt-qPCR), western blotting, and transwell experiments. Our methodological approach also involved survival analysis, risk model construction, and drug screening leveraging the databases of CTRPv2, PRISM and CMap. We used the Masson staining technique for histological assessments. All statistical evaluations were conducted using R software and GraphPad Prism 9, reinforcing the rigorous and comprehensive nature of our research approach.ResultsScreening through inflammatory fibrosis revealed a reduction of extracellular matrix and cell adhesion molecules regulated by proteoglycans in UTUC compared with BC, making UTUC more metastasis-prone. We demonstrated that SDC1, LUM, VEGFA, WNT7B, and TIMP3, are critical in promoting UTUC metastasis. A risk model based on these five molecules can effectively predict the risk of UTUC metastasis and disease-free survival time. Given UTUC's unique molecular mechanisms distinct from BC, we discovered that UTUC patients could better mitigate the issue of poor prognosis associated with UTUC's easy metastasis through tyrosine kinase inhibitors (TKIs) alongside the conventional gemcitabine and cisplatin chemotherapy regimen.ConclusionsThe poor prognosis of UTUC because of its high metastatic propensity is intimately tied to inflammatory fibrosis induced by the accumulation of reactive oxygen species. The biological model constructed using the five molecules SDC1, LUM, VEGFA, WNT7B, and TIMP3 can effectively predict patient prognosis. UTUC patients require specialized treatments in addition to conventional regimens, with TKIs exhibiting significant potential.

Efficacy and Safety Assessment of Intrathoracic Perfusion Chemotherapy Combined with immunological factor Interleukin-2 in the Treatment of Advanced Non-Small Cell Lung Cancer: A Retrospective Cohort Study.

Objective: This study evaluated the efficacy and safety of the gemcitabine and oxaliplatin intrathoracic perfusion chemotherapy (IPCGOR) regimen combined with interleukin-2 (IL-2) for advanced non-small cell lung cancer (NSCLC). Methods: We conducted a retrospective analysis of 460 advanced NSCLC patients from the Yunnan Province Early Cancer Diagnosis and Treatment Project (June 2020-October 2022), assessing the IPCGOR and IL-2 combination. Outcomes were measured based on RECIST 1.1 criteria, focusing on objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (MOS), and treatment safety. Results: The treatment demonstrated an ORR of 67.4%, a DCR of 97.4%, an mPFS of 8.5 months, and an MOS of 12.5 months. 14 patients underwent successful surgery post-treatment. Common adverse reactions were manageable, with no treatment-related deaths reported. Conclusion: The IPCGOR combined with IL-2 regimen shows promising efficacy and a tolerable safety profile for advanced NSCLC. These findings suggest its potential as a reference for treating advanced NSCLC. However, the study's retrospective nature and single-center design pose limitations. Future research should focus on prospective studies, randomized controlled trials, and long-term outcome assessments, particularly in diverse patient subgroups, to further validate and refine the clinical application of this regimen.

Evaluation of response to gemcitabine plus cisplatin-based chemotherapy using positron emission computed tomography for metastatic bladder cancer.

The purpose of the present study was to examine retrospectively the contribution of 18Fluorodeoxyglucose positron emission tomography computed tomography (18FDG-PET/CT) to the evaluation of response to first-line gemcitabine plus cisplatin-based chemotherapy in patients with metastatic bladder cancer. To evaluate the response to Gemcitabine plus Cisplatin -based chemotherapy using 18FDG-PET/CT imaging in patients with metastatic bladder cancer. Between July 2007 and April 2019, 79 patients underwent 18FDG-PET/CT imaging with the diagnosis of Metastatic Bladder Carcinoma (M-BCa). A total of 42 patients (38 male, 4 female) were included in the study, and all had been administered Gemcitabine plus Cisplatin-based chemotherapy. After completion of the therapy, the patients underwent a repeat 18FDG-PET/CT scan and the results were compared with the PET/CT findings before chemotherapy according to European Organisation for the Research and treatment of cancer criteria. Mean age was 66.1 years and standard deviation was 10.7 years (range: 41-84 years). Of the patients, seven (16.6%) were in complete remission, 17 (40.5%) were in partial remission, six (14.3%) had a stable disease, and 12 (28.6%) had a progressive disease. The overall response rate was 57.1 percent. 18FDG-PET/CT can be considered as a successful imaging tool in evaluating response to first-line chemotherapy for metastatic bladder cancer. Anatomical and functional data obtained from PET/CT scans may be useful in the planning of secondline and thirdline chemotherapy.

Immunologic Signatures of Peripheral Blood T Cells Reveal the Outcome of p53MVA Vaccine and Pembrolizumab Treatment in Patients with Advanced Ovarian Cancer.

Our previous studies indicated that p53-reactive T cells were associated with clinical benefit in patients with advanced ovarian cancer who were treated with p53-expressing modified vaccinia Ankara (p53MVA) vaccine and gemcitabine chemotherapy. To replace chemotherapy with an approach that will enhance vaccine efficacy and antitumor immunity, we treated patients with p53MVA in combination with PD-1 checkpoint blocker, pembrolizumab. We also attempted to further characterize the activation status of T cells prior to vaccination and during treatment. Patients received up to three triweekly vaccinations concurrent with pembrolizumab, followed by pembrolizumab monotherapy at 3-week intervals. Correlative studies analyzed peripheral blood T-cell phenotypes and profiles of immune function gene expression. We observed 6/28 (21%) patients with a clinical benefit to therapy, including 3 partial responses (PR) and 3 patients with stable disease (SD) for 6+ months. The median progression-free survival was 1.8 months (95% confidence interval: 1.7-3.8) and median overall survival was 15.1 months (9.4-30.4). Two patients remain progression-free at 28 and 33 months. Of the 18 patients evaluable in correlative studies, 6 were immunologic responders of whom 5 had clinical benefit (3 PR, 2 SD). Immunologic non-responders expressed in pretreatment peripheral blood mononuclear cell samples high levels of mRNA for multiple molecules associated with terminally differentiated T cells. p53MVA/pembrolizumab immunotherapy showed promising antitumor activity in patients who demonstrated functionally competent peripheral blood T cells. Detection of markers of terminally differentiated T cells before treatment may identify patients unlikely to respond to p53MVA/pembrolizumab. The activity of a combination immunotherapy of p53 vaccine and PD-1 checkpoint blockade in patients with platinum-resistant ovarian cancer was evaluated in a phase II trial. Clinical benefit was correlated with the responsive immune status of patients before and during the treatment, defining potential predictive markers for immune therapy.

Translational PK-PD/TD modeling of antitumor effects and peripheral neuropathy in gemcitabine and nab-paclitaxel chemotherapy from xenograft mice to patients for optimal dose and schedule.

Gemcitabine and nab-paclitaxel (GnP) treatment, the standard first-line chemotherapy for unresectable pancreatic cancer, often causes peripheral neuropathy (PN). To develop alternative dosing strategies to avoid severe PN, understanding the relationship between pharmacokinetics (PK) and pharmacodynamics/toxicodynamics (PD/TD) is necessary. We established a PK-PD/TD model of GnP treatment to develop an optimal dose schedule. A mouse xenograft model of human pancreatic cancer was generated to measure drug concentrations in the plasma and tumor, antitumor effects, and PN after GnP treatment. The Simeoni tumor growth inhibition model with tumor concentrations and empirical indirect response models were used for the PD and TD models, respectively. Clinical outcomes were predicted with reported population estimates of PK parameters in cancer patients. The PK-PD/TD model simultaneously described the observed tumor volume and paw withdrawal frequency in the von Frey test. For the standard GnP regimen, the model predicted clinical overall response (75.1%), which was overestimated compared to that in a recent phase II study (42.1%) but lower than the observed disease control rate (96.5%). Model simulation showed that dose reduction to less than 40% GnP dose was not effective; a change of dose schedule from every week for 3weeks to every 2weeks was a more favorable approach than dose reduction to 60% every week. The PK-PD/TD model-based translational approach provides a guide for optimal dose determination to avoid severe PN while maintaining antitumor effects during GnP chemotherapy. Further research is needed to enhance its applicability and potential for combination chemotherapy regimens.

The addition of tislelizumab to gemcitabine and cisplatin chemotherapy increases thrombocytopenia in patients with urothelial carcinoma: A single-center study based on propensity score matching.

Whether the addition of tislelizumab to gemcitabine and cisplatin (GC) chemotherapy increases the incidence of myelosuppression has not been well established. This study identified the risk factors for the development of myelosuppression in patients with urothelial carcinoma (UC) after receiving GC chemotherapy with or without tislelizumab. We enrolled 192 UC patients who received GC with or without tislelizumab at the Affiliated Hospital of Xuzhou Medical University between July 2014 and November 2022. Patient baseline characteristics were included in the statistical analyses after adjusting for previously reported risk factors affecting survival using propensity score matching (1:1). Binary logistic regression analysis was used to identify the risk factors associated with posttreatment myelosuppression. A total of 192 patients were enrolled, of whom 96 were treated with tislelizumab plus gemcitabine and cisplatin (T + GC) and 96 with GC alone. The incidence of leukopenia, anemia, and thrombocytopenia of any grade was 50.0%, 70.8%, and 42.7%, respectively, in the T + GC group and 41.7%, 72.9%, and 20.8%, respectively, in the GC group. In multivariate analysis, patients aged over 70 years (OR = 2.486, 95% CI: 1.067-5.792, p = 0.035) and those who received T + GC (OR = 3.119, 95% CI: 1.576-6.173, p = 0.001) were more likely to develop thrombocytopenia. Patients aged over 70 years (OR = 3.213, 95% CI: 1.254-8.237, p = 0.015) were more likely to develop anemia, and patients with renal insufficiency (OR = 2.105, 95% CI: 1.035-4.280, p = 0.040) were more likely to develop leukopenia. Eventually, 99 (51.6%) patients with UC successfully completed all the treatment cycles. This study demonstrates that the addition of tislelizumab to GC chemotherapy led to a considerable increase in the occurrence of thrombocytopenia, whereas no significant changes were observed regarding anemia or leukopenia. It is crucial to fully inform patients at increased risk for myelosuppression of potential risks and closely monitor changes in their blood routines.

Addition of Chidamide to a Sandwich Protocol, Pegaspargase, Gemcitabine and Oxaliplatin Chemotherapy Combined with Radiotherapy, As First-Line Treatment in Early Stage NK/T-Cell Lymphoma: Real World Outcomes in a Retrospective Study

Background: Extranodal NK/T-cell lymphoma, nasal type (ENKTL-NT) is a highly invasive tumor with a short doubling time and poor prognosis. Clinically, it usually involves the upper aerodigestive tract and mainly presents with early-stage. Initially, intensity modulated radiation therapy (IMRT) has been considered the preferred first-line therapy for early-stage ENKTL due to its high response rate. In recent years, more and more studies show that adding chemotherapy, especially asparaginase (ASP)-based regimens, provide survival benefit in early-stage patients. However, the optimal chemotherapy regimen has not been fully defined. Epigenetic regulatory mechanisms related to histone deacetylase (HDAC) have been found to play a role in the evolution and progression of ENKTL. Chidamide, a new HDAC inhibitor, has been confirmed to be effective and tolerable to treat lymphoma. Recently, Xue et al showed that chidamide in combination with cisplatin, etoposide or gemcitabine showed synergistic effect and reversed the chemotherapy resistance in the relapsed/refractory B-cell lymphoma. Here, we investigate the safety and efficacy of adding chidamide to a sandwich protocol, P-GEMOX (pegaspargase/gemcitabine/oxaliplatin) regimen (CP-GEMOX) combined with IMRT as first-line treatment in early-stage ENKTL-NT patients. Methods: We retrospectively reviewed data of early-stage ENKTL-NT patients in the first affiliated hospital of Soochow University from March 2020 to April 2023. A total of 21 patients diagnosed with early-stage (stage Ⅰ or Ⅱ) ENKTL-NT were enrolled and treated with 2 cycles of CP-GEMOX followed by IMRT and 1 or 2 cycles of CP-GEMOX sequentially as consolidation. After consolidation, chidamide was administrated as a maintenance therapy for 1 year. In the induction therapy phase, chidamide was administered orally at a dose of 20 mg twice a week for two weeks, with a one-week discontinuation period; During the maintenance treatment phase, the original dose of chidamide was still maintained and used without pause. The baseline clinical features for the 21 patients were summarized in Table 1. Results: Among 21 patients, 14 were males and 7 were females, and their median age was 57 (range, 41-75) years. Elevated lactate dehydrogenase, elevated β2-microglobulin, stage II disease and primary tumor invasion were present in 4.8% (1/21), 19.0% (4/21), 61.9% (13/21) and 61.9% (13/21) patients. According to the early stage-adjusted nomogram-revised risk index, the majority of patients (76.2%, 16/21) were classified into intermediate- (1-2) and high (≥3) risk groups. The baseline clinical features for the 21 patients were summarized in Table 1. During treatment, all patients were well-tolerated and the most common adverse events were hematological toxicities with neutropenia, thrombocytopenia and anemia. Among non-hematological adverse events, nausea, vomiting and reduced appetite were most common. Other side effects included coagulation dysfunction, skin reaction, diarrhea, serum amylase and alanine aminotransferas /aspartate aminotransferase /bilirubin elevation. No anaphylactic reaction to pegaspargase, hemophagocytic syndrome, pancreatitis or sepsis were observed during chemotherapy. Some patients had mucositis and xerostomia when receiving local radiotherapy. All side effects could be reversed with proper treatment, and there were no therapy related mortality. All patients completed 2 cycles of CP-GEMOX, 19 patients achieved complete remission (CR) and 2 patients achieved partial remission (PR) with a CR rate of 90.5% (19/21) and overall response rate (ORR) of 100.0% (21/21) after 2 cycles of CP-GEMOX. Among the 21 patients, 18 patients completed treatment and CR rate was improved to 100.0% (18/18), giving an ORR of 100% (18/18). After a median follow-up of 25.6(range, 2.6-39) months , all patients were alive except one patient relapsed 20 months after treatment and died of COVID-19 related pneumonia 1 month later. The 2-year progression-free survival and overall survival were all 91.5% (Figure 1). Conclusions: This study demonstrates that sandwich CP-GEMOX chemoradiotherapy is a safe and promising approach to managing patients with early-stage ENKTL-NT. Keywords: Extranodal NK/T-cell lymphoma; chidamide; pegaspargase; gemcitabine; radiation therapy.

Comparison of adjuvant nab-paclitaxel plus gemcitabine, S-1 and gemcitabine chemotherapy for resectable pancreatic cancer: a real-world study.

A survival benefit has been seen for both adjuvant nab-paclitaxel plus gemcitabine (AG) and S-1 chemotherapy compared to gemcitabine (GEM) for resectable pancreatic cancer in the APACT (2019) and JASPAC01 trials (2016), respectively. However, supporting evidence regarding the effectiveness of AG or S-1 compared to gemcitabine in real-world clinical practice remains lacking. Our study included all 246 pancreatic cancer patients who underwent surgical treatment and received postoperative adjuvant chemotherapy with AG, S-1, or GEM except for those meeting exclusion criteria (R2 resection, neoadjuvant therapy, or synchronous malignancy) at Tianjin Medical University Cancer Institute and Hospital from June 2015 to July 2021. The primary outcome was overall survival (OS) and recurrence-free survival (RFS). In total, 246 patients were included, of whom 54(22%) received adjuvant AG, 103(41%) received adjuvant S-1, and 89(37%) received adjuvant GEM. Adjuvant S-1 was associated with a prolonged OS compared to GEM (median OS S-1 vs GEM: 27.0 vs 20.0 months; HR: 0.65, P = .016) and a significantly prolonged RFS compared to GEM (median RFS S-1 vs GEM: 20.0 vs 8.2 months; HR: 0.58, P = .002). After adjusting for known prognostic factors in multivariate Cox regression analysis, this survival benefit persists and is consistent in most subgroups in our subgroup analysis. However, no statistically significant differences in OS or RFS were seen between patients treated with AG and patients treated with GEM. In this retrospective real-world study, adjuvant S-1 chemotherapy was associated with improved survival compared to GEM while no differences in OS or RFS were observed for AG compared to GEM.

DERL2 (derlin 2) stabilizes BAG6 (BAG cochaperone 6) in chemotherapy resistance of cholangiocarcinoma.

DERL2 (derlin 2) is a critical component of the endoplasmic reticulum quality control pathway system whose mutations play an important role in carcinogenesis, including cholangiocarcinoma (CHOL). However, its role and its underlying mechanism have yet to be elucidated. Herein, we revealed that DERL2 was highly expressed in CHOL and considered as an independent prognostic indicator for inferior survival in CHOL. DERL2 ectopically expressed in CHOL cells promoted cell proliferation and colony formation rates, and depleting DERL2 in CHOL cells curbed tumor growth in vitro and in vivo. More interestingly, the knockout of DERL2 augmented the growth-inhibitory effect of gemcitabine chemotherapy on CHOL cells by inducing cell apoptosis. Mechanistically, we discovered that DERL2 interacted with BAG6 (BAG cochaperone 6), thereby extending its half-life and reinforcing the oncogenic role of BAG6 in CHOL progression.

Camrelizumab with Chemoradiotherapy for Locally Advanced Biliary Tract Cancer: Preliminary Results from A Phase II Study

For locally advanced biliary tract cancer (BTC), capecitabine-based chemoradiotherapy (CRT) is commonly used but has limited benefits. Immunotherapy is potentially effective for BTC and may be synergized with CRT. Followed by gemcitabine and cisplatin (GP) consolidation chemotherapy (CT), we evaluated the safety and efficacy of combined camrelizumab and capecitabine-based CRT for locally advanced BTC. Patients had stage II-III (T4N0M0, T1-4N+M0) BTC (per the 7th [2010] edition of the American Joint Committee on Cancer staging system) were eligible for CRT (capecitabine plus [50-60 Gy] radiotherapy), to be followed by GP CT. Camrelizumab was given concurrently with CRT. Safety was defined as the incidence and severity of adverse events (AEs), while efficacy was defined as overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). Ten patients completed the planned treatment. None experienced grade ≥3 treatment-related AEs during CRT. Grade ≥3 immune-related AEs occurred in 2 of 10 patients (20%) only during GP CT. The mean OS time was 18.2 months (95% confidence interval [CI] 12.9m-23.5m) while the median OS time was 14.1 months (95% CI 10.1m-18.1m). OS rates were 100%, 59%, 44% at 6 months, 1 year and 2 years, respectively. The ORR was 30% while the DCR was 90%. Two patients (20%) obtained OS over 2 years with partial response (25.9m, 29.1m). Median PFS time was 14.1 months (95% CI 9.3m-18.9m). Camrelizumab in combination with concurrent CRT was well tolerated and did not impair delivery of CRT in patients with locally advanced BTC.

Stereotactic Ablative Radiotherapy Boost to Bladder Tumor for Bladder Preservation in Patients with Muscle-Invasive Bladder Cancer

Previous studies showed that selective bladder-sparing approach using TMT is an established therapy of MIBC with outcomes that are comparable to those of radical cystectomy. However, it has been shown that the 5-year local recurrence in the bladder is greater than 40% after TMT. One of the possible reasons was that the RT dose to the bladder tumor or tumor bed was insufficient. Thus, we assessed the effectiveness and safety of Stereotactic Ablative Radiotherapy (SABR) boost to bladder tumor or tumor bed for patients with muscle invasive bladder cancer (MIBC). A total of 59 consecutive patients with cT2-4 bladder cancer underwent transurethral resection of bladder tumor (TURBT). TURBT was visibly complete in 25 cases. Patients received SABR to the tumor or tumor bed in the bladder followed by conventionally fractionated RT (CFRT) to pelvis and total bladder with concomitant weekly radio-sensitizing chemotherapy. During SABR intravesical installation of isovolumetric saline through urinary catheter ensured adequate bladder filling. Response rate was assessed by cystoscopic evaluation and pelvic MRI or CT. Toxicities were reported per the RTOG acute and late Radiation Morbidity Scoring Schema. The median age of all patients was 76 years (35-90 years). All patients completed SBRT boost and 61% patients received concurrent Gemcitabine chemotherapy. After a median follow-up time of 28 months, the rate of local control (LC) at 3 years was 90.0%. The overall survival (OS) and cancer-specific survival (CSS) rates at 3 years were 61.6% and 77.5%, respectively. Of the surviving patients, 84.4% have a disease-free and functioning bladder. Acute grade 3 gastrointestinal (GI) or genitourinary (GU) toxicities occurred in only 1.7% of the patients. Late grade 3 GU toxicity occurred in 5.1% of the patients. No patients experienced grade 4 GI or GU toxicities. SABR boost followed by chemoradiation to the pelvis was found to be a well-tolerated and effective treatment for MIBC patients who are either not candidates for cystectomy or who desire bladder preservation. Randomized study is required to further evaluate this novel tri-modality treatment paradigm.

The Efficacy of Neoadjuvant Gemcitabine and Cisplatin Chemotherapy for cT3N0M0 Upper Tract Urothelial Carcinoma: The Impact of Tumor Location.

Upper tract urothelial carcinoma (UTUC) can be divided into renal pelvis tumor (RPT) and ureteral tumor (UT) based on the tumor origin. This study aimed to evaluate the efficacy of neoadjuvant chemotherapy with gemcitabine and cisplatin (NAC-GC) in terms of the pathological outcomes and oncological prognoses in patients with UTUC. We also compared its efficacy between RPT and UT. Patients who underwent radical nephroureterectomy for clinical T (cT)3N0M0 UTUC between 1999 and 2021 were included. Patients who underwent NAC-GC and those who did not were included in the NAC-GC and non-NAC-GC groups, respectively. Based on the tumor origin, we divided patients with UTUC into RPT and UT groups. Oncological prognosis was assessed using progression-free survival (PFS) and overall survival. Of 44 patients, 20 (45.5%) and 24 (54.5%) patients were in the NAC-GC and non-NAC-GC groups, respectively. The NAC-GC group had significantly lower pathological T stage and negative lymphovascular invasion (LVI), and a better PFS (p < .05) compared to those in the non-NAC-GC group. Among patients with RPT, the NAC-GC group had significantly negative LVI and better PFS than the non-NAC-GC group (p < .05). In contrast, in patients with UT, the NAC-GC group had no significant difference in pathological outcomes, and no significant difference in oncological prognosis was observed between the NAC-GC and non-NAC-GC groups. NAC-GC improves both pathological outcomes and oncological prognosis in patients with cT3N0M0 UTUC. With regard to tumor location, RPT has better pathological outcomes and oncological prognoses than UT.

Effects of intravenous chemotherapy after TURBT for high-risk nonmuscle invasive bladder cancer: results of a retrospective study.

This study compared the efficacy and safety of intravenous chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for high-risk nonmuscle invasive bladder cancer (HRNMIBC) patients after transurethral resection of the bladder tumor (TURBT) surgery. A retrospective analysis was performed on 349 HRNMIBC cases admitted to TangDu hospital between January 2014 and June 2019. After TURBT, 262 patients received intravesical chemotherapy alone, whereas 87 patients underwent intravesical chemotherapy in combination with intravenous chemotherapy. The recurrence rate and progression rate were assessed by Chi-square test, the prognostic factors for tumor recurrence were predicted by univariable and multivariable Cox hazards analyses, recurrence-free survival (RFS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. In this study, the recurrence rate was 24.7% (19/77) in the intravenous chemotherapy combined group and 41.6% (102/245) in the intravesical chemotherapy group, while the progression rate was 6.5% (5/77) and 14.3% (35/245) in the two groups respectively. The two groups differed significantly in recurrence rate (p = 0.007) while the progression rate did not show a significant difference (p = 0.071). Multivariable analyses revealed that additional intravenous chemotherapy treatment was an independent prognostic factor for tumor recurrence in the cohort (hazard ratio [HR], 0.495, 95% confidence interval [CI], 0.275-0.892, p = 0.019). Kaplan-Meier curves showed significant differences in RFS and PFS between the two groups, with a log-rank P value of p < 0.005 and p = 0.045, respectively. Grade 3/4 toxicity was reported in 2 of 77 patients in the intravenous chemotherapy combined group, including nausea/vomiting 1.3% (1/77) and hypoleukemia 1.3% (1/77). Intravenous chemotherapy of gemcitabine and cisplatin combined with intravesical chemotherapy after TURBT can effectively reduce the postoperative recurrence rate, most toxicities were minor and reversible, and it may be considered as a new choice for HRNMIBC patients.

Predicting response of gemcitabine plus cisplatin chemotherapy using RNA sequencing in patients with advanced urothelial carcinoma.

66 Background: Despite of advancement using new agents including ICIs in treatment of urothelial carcinoma (UC), cisplatin-based chemotherapy is still standard of care in both 1st line palliative setting and perioperative setting. Previous studies regarding response prediction of cisplatin-based chemotherapy are limited in selecting target molecule or gene, there have been no comprehensive study for whole genome information. This study aimed to identify key genes to predict response of gemcitabine plus cisplatin (GC) in advanced UC by mRNA sequencing (RNA-seq). Methods: Between JAN 2016 and DEC 2019, advanced UC patients treated with GC and underwent response evaluation were enrolled. Patients were divided into the responder group (CR or PR) and non-responder group (SD or PD). RNA was extracted from the formalin fixed embedded tissue (FFED) and RNA-seq was performed on the Illumina RNA-seq platform. Differentially expressed genes (DEGs) were identified between responder group and non-responder group. Marker selection was performed as following steps: (1) DESeq2 (Adjusted P-value &lt; 0.1) and Mann-Whitney U test (P-value &lt; 0.05), (2) random forest (RF) and logistic regression, and (3) assessments for relevant markers by analyzing RNA/Protein expression level, survival information, and antibody staining results using ProteinAtlas. Results: Twenty-nine patients received GC chemotherapy during study period. Among them, 10 patients who had available FFED specimens and clear response evaluation were enrolled and performed RNA-seq. Median age was 65.5 years (range, 62-76), and all were male. They were grouped of 7 patients in responder and 3 patients in non-responder. Among 13,773 genes based on RNAseq, we identified 37 DEGs candidate (Step 1), followed by 22 DEGs selected (Step 2), and finally 9 DEGs were identified (Step 3). Among the 9 DEGs, 3 genes (UPK2, PCGF3, and POFUT1) were consistently expressed with survival data of TCGA, the expression of 3 (ITGA3, HSPA1B, GSTM3) was the opposite of that of TCGA, and the remaining 3 genes (S100A2, TDRP, and RPS6KA2) were not relevant. Conclusions: We found 3 key genes (UPK2, PCGF3, and POFUT1) that related with favorable response of GC in our advanced UC cohort which were confirmed in TCGA data. Our study results should be further investigated in an expansion cohort using immunohistochemistry staining matched with key genes for convenient practical application.

Comparison of gemcitabine plus oxaliplatin versus gemcitabine plus nab-paclitaxel as first-line chemotherapy for advanced pancreatic adenocarcinoma: A single-center retrospective analysis.

Pancreatic cancer is mostly diagnosed in an advanced stage and treated with systemic therapy with palliative intent. Nowadays, the doublet chemotherapy of Gemcitabine and nab-paclitaxel (Gem-Nab) is one of the most frequently used regimens worldwide, but is not ubiquitarily available or reimbursed. Therefore, we compared the clinical efficacy of Gem-Nab to a historical control of patients treated with gemcitabine and oxaliplatin (Gem-Ox) at our tertiary cancer center, which was the standard treatment prior to the introduction of FOLFIRINOX. This single-center retrospective real world study includes 121 patients diagnosed with locally advanced or primary metastatic pancreatic adenocarcinoma who were treated with chemotherapy doublet, with either Gem-Nab or Gem-Ox in palliative first-line. Survival rates were analyzed using the Kaplan-Meier method, and comparisons were made with log-rank tests. Gem-Ox was considered as standard first line therapy at our institution for patients who were deemed fit for doublet chemotherapy between the years 2006 to 2012. These patients were compared to a cohort of patients treated with the new standard first-line therapy of Gem-Nab between 2013 and 2020. A total of 554 patients with pancreatic cancer of all stages were screened, and 73 patients treated with Gem-Nab and 48 patients treated with Gem-Ox in the palliative first-line setting were identified and included in this analysis. Patients receiving Gem-Ox had a statistically significantly better performance score (ECOG PS) when compared to the Gem-Nab group (Odds ratio (OR) 0.28, 95% CI 0.12-0.65, p = 0.005), more often suffered from locally advanced than metastatic disease (OR 3.10, 95% CI 1.27-7.91, p = 0.019) and were younger in age (OR 0.95, 95% CI 0.91-0.99, p = 0.013). Median overall survival (OS) of the whole study cohort was 10.3 months (95% CI 8.5-11.6). No statistically significant difference in OS could be observed between the Gem-Nab and the Gem-Ox cohort (median OS: 8.9 months (95% CI 6.4-13.5) versus 10.9 months (95% CI 9.5-13.87, p = 0.794, HR 1.27, 95% CI 0.85-1.91)). Median progression-free survival (PFS) was 6.8 months in the entire cohort (95% CI 4.9-8.4). No statistically significant difference in PFS could be observed between the Gem-Nab and the Gem-Ox cohort (median PFS: 5.8 months (95% CI 4.3-8.2) versus 7.9 months (95% CI 5.4-9.5) p = 0.536, HR 1.11, 95% CI 0.74-1.67). Zero-truncated negative binomial regressions on OS and PFS adjusting for gender, age, performance status (ECOG PS), and CA19-9 levels yielded no significant difference between Gem-Nab or Gem-Ox. From our analysis, we could evidence no difference in outcome parameters in this retrospective analysis despite the worse prognostic pattern for GemOX. Therefore, we suggest Gem-Ox as potential first line treatment option for inoperable locally advanced or metastatic pancreatic cancer, especially if Gem-Nab is not available.

Immunomodulatory Effects of Endoscopic Ultrasound-Guided Thermal Ablation in Patients with Pancreatic Ductal Adenocarcinoma.

Immunological consequences of endoscopic ultrasound (EUS)-local thermal ablation (LTA) for pancreatic ductal adenocarcinoma (PDAC) have not been extensively assessed. We aimed to explore EUS-LTA effects on the systemic immune response in PDAC. Peripheral blood was collected from 10 treatment-naïve patients with borderline resectable and locally advanced PDAC, randomly allocated to Nab-paclitaxel plus Gemcitabine chemotherapy (CT-arm, n = 5) or EUS-LTA with HybridTherm Probe plus CT (HTP + CT-arm, n = 5). Twenty healthy donors were included as controls. Flow-cytometry and multiplex assays were used to profile immune cell subsets and measure serum cytokines/chemokines, respectively. At baseline, PDAC patients showed increased circulating monocytes and lower circulating lymphocytes and CD19+ B cells counts compared to healthy controls. After 4 months, CT induced decrease of B regulatory cells, CD4+ cytotoxic T cells and IL-1β. The addition of EUS-HTP to CT selectively decreased the serum levels of APRIL/TNFSF13 as well as T regulatory cells, total, classic and inflammatory monocytes. Serum levels of APRIL/TNFSF13 and total, classic and inflammatory monocytes counts at baseline were associated with worse overall survival. EUS-HTP has the potential to selectively impact on immune cells and cytokines associated with poor outcomes in PDAC.

Impact of conversion surgery after chemotherapy in patients with initially unresectable and recurrent biliary tract cancer.

Gemcitabine, cisplatin, and S-1 chemotherapy was superior to gemcitabine and cisplatin chemotherapy for progression-free survival and overall survival for unresectable and recurrent biliary tract cancer in a randomized phase III trial (KHBO1401). This study aimed to evaluate the outcome of conversion surgery after chemotherapy in biliary tract cancer patients (ancillary study, KHBO1401-3C). A total of 246 patients were enrolled in KHBO1401. We compared progression-free and overall survivals between the conversion surgery and non-conversion surgery groups. Eight patients (3.3%) underwent conversion surgery with chemotherapy, seven of whom were diagnosed with unresectable disease and one with recurrence. Six and two patients received gemcitabine, cisplatin, and S-1 chemotherapy as well as gemcitabine and cisplatin chemotherapy, respectively. Three patients in the conversion surgery group who received gemcitabine, cisplatin, and S-1 chemotherapy showed no disease progression and survived without postoperative chemotherapy. Preoperative carbohydrate antigen 19-9 (CA19-9) level was a prognostic factor for conversion surgery. After correcting for immortal time bias, 1-year progression-free survival rates in the conversion surgery and non-conversion surgery groups were 50.0% and 19.0%, respectively (hazard ratio 0.343, 95% confidence interval 0.286-0.843, p = 0.0092). One-year overall survival rates in the conversion surgery and non-conversion surgery groups were 87.5% and 56.0%, respectively (hazard ratio 0.222, 95% confidence interval 0.226-0.877, p = 0.0197). Conversion surgery might be an option for the treatment of unresectable and recurrent biliary tract cancer in patients with normal preoperative CA19-9 level.