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Introduction: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with treatment outcomes closely tied to liver function. This study evaluates the prognostic utility of the albumin-bilirubin (ALBI) score compared to the traditional Child-Pugh (CP) grading, leveraging real-world evidence from a large-scale, multi-center database. Methods: The Liver Cancer IN Korea (LINK) research network, a multi-center initiative, retrospectively collected electronic health records from three academic hospitals in South Korea, encompassing HCC patients diagnosed between 2015 and 2020. Inclusion criteria mandated at least one HCC treatment and excluded patients with other primary cancer diagnoses. The study followed patients until death, the last visit, or June 2021, employing standardized data processing and rule-based algorithms for data consistency. The prognostic efficacy of ALBI scores and CP scores was compared through time-dependent receiver operating characteristic (ROC) curves and the inverse probability censoring weighting method. Results: From 25,248 newly diagnosed patients, 10,297 were included, with 65.82% having hepatitis B etiology and a mean follow-up of 27.49 months. Patients’ classification by modified ALBI (mALBI) grade at diagnosis revealed: grade 1 (48.87%), 2a (20.50%), 2b (24.54%), and 3 (5.17%), with a minimal percentage missing (0.92%). Transarterial therapy (54.07%) and tyrosine kinase inhibitors (84.14% as the first-line systemic therapy) were predominant treatments. The ALBI score demonstrated greater prognostic efficacy than the CP score in long-term outcomes, with time-dependent area under the ROC curve analysis showing a score of 0.71 for ALBI versus 0.67 for CP at 60 months. Furthermore, higher mALBI grades were significantly associated with poorer survival outcomes, as indicated by both univariate and multivariate Cox proportional regression model analyses (p < 0.001). Conclusions: The study confirmed the ALBI score’s superior prognostic ability over the CP score, especially evident in long-term outcomes, suggesting a shift toward more nuanced liver function assessment tools in real-world clinical practice.

Abstract Research on the treatment outcomes and mortality of patients with cancer and hip fractures remains limited. We aimed to assess the treatment outcomes and mortality in older patients with cancer and hip fractures. We retrospectively reviewed the data of 1264 patients aged ≥ 60 years treated for hip fractures between January 2005 and April 2022. The operation time, blood transfusion-related indicators, postoperative complications, reoperation rate, length of hospital stay, admission to the intensive care unit, mortality rate, and clinical scores were compared. We also performed survival analysis. Subsequently, 1:1 propensity-score matching was performed. In the unmatched cohort, we compared 273 patients with cancer and 991 controls. The cancer group exhibited a higher incidence of pneumonia (P = 0.025) and higher in-hospital and 1-year follow-up mortality rates (P = 0.044 and P

Exosomes are nanosized extracellular vesicles secreted by various cell types, including those of the immune system, such as natural killer (NK) cells. They play a role in intercellular communication by transporting signal molecules between the cells. Recent studies have reported that NK cell-derived exosomes (NK-exo) contain cytotoxic proteins-induced cell death. However, the characteristics and potential functions of NK-exo, especially for the liver cancer are poorly understood. In this study, we investigated the anti-tumor effects of NK-exo in the primary liver cancer, hepatocellular carcinoma (HCC), using the orthotopic and subcutaneous tumor model. We found that NK-exo expressed both typical exosomal markers (e.g. CD63, CD81, and Alix) and cytotoxic proteins (e.g. perforin, granzyme B, FasL, and TRAIL). NK-exo were selectively taken up by HCC cells (e.g. Hep3B, HepG2, and Huh 7). Interestingly, Hep3B cells induced the highest cytotoxicity compared with HepG2 and Huh7 cells, and substantially enhanced the apoptosis by NK-exo. Furthermore, we demonstrated that NK-exo inhibited the phosphorylation of serine/threonine protein kinases (e.g. AKT and ERK1/2), and enhanced the activation of specific apoptosis markers (e.g. caspase-3, -7, -8, -9, and PARP) in Hep3B cells. NK-exo also exhibit the active targeting ability and potent therapeutic effects in both orthotopic and subcutaneous HCC mouse models. Overall, these results suggest that NK-exo indicate strong anti-tumor effects in HCC, which are mediated by novel regulatory mechanisms involved in serine/threonine kinase pathway-associated cell proliferation and caspase activation pathway-associated apoptosis.

Abstract Cancer of unknown primary (CUP) is a heterogeneous malignancy in which the primary site of the tumor cannot be identified through standard work-up. The survival outcome of CUP is generally poor, and there is no consensus for treatment. Here, we comprehensively analyzed the real-world data of 218 patients with CUP (median age, 62 years [range, 19–91]; male, 62.3%). Next-generation sequencing was conducted in 22 (10%) patients, one of whom showed level 1 genetic alteration. Most (60.3%) patients were treated with empirical cytotoxic chemotherapy, and two patients received targeted therapy based on the NGS results. The median OS was 8.3 months (95% confidence interval [CI] 6.2–11.4), and the median progression-free survival of patients treated with chemotherapy was 4.4 months (95% CI 3.4–5.3). In multivariate Cox regression analysis, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 and localized disease were significantly associated with favorable survival outcomes. Collectively, we found that CUP patients had a poor prognosis after standard treatment, and those with localized disease who received local treatment and those with better PS treated with multiple lines of chemotherapy had better survival outcomes. Targeted therapies based on NGS results are expected to improve survival outcomes.

Abstract Background Programmed death‐ligand 1 (PD‐L1) has functional roles in cancer stem‐like cell (CSC) phenotypes and chemoresistance besides immune evasion. Chemotherapy is a common treatment choice for colorectal cancer (CRC) patients; however, chemoresistance limits its effectiveness of treatment. Methods We examined the role of S100A14 (SA14) in CRC by adopting PD‐L1high subpopulations within CRC cell lines and patient tumours, by establishing PD‐L1high chemoresistant CRC sublines through prolonged exposure to 5‐fluorouracil/oxaliplatin‐based chemotherapy in vitro and in vivo, and by analysing a public database. Results We identified a novel function of SA14 as a regulator of immune surveillance, major CSC phenotypes, and survival capacity under hostile microenvironments, including those harbouring chemotherapeutics, and as a prognostic biomarker in CRC. Mechanistically, SA14 inhibits PD‐L1 expression by directly interacting with signal transducer and activator of transcription 3 (STAT3) and inducing its proteasome‐mediated degradation. While gain‐of‐SA14 causes loss of PD‐L1 expression and tumourigenic potential and sensitisation to chemotherapy‐induced apoptosis in chemoresistant CRC cells, loss‐of‐SA14 causes increases in PD‐L1 expression, tumourigenic potential, and chemoresistance in vitro and in vivo. We further show that a combinatorial treatment with chemotherapy and recombinant SA14 protein effectively induces apoptosis in PD‐L1high chemoresistant CRC cells. Conclusions Our results suggest that SA14‐based therapy is an effective strategy to prevent tumour progression and that SA14 is a predictive biomarker for anti‐PD‐L1 immunotherapy and chemotherapy in combination.

Background: Adjuvant chemotherapy is the standard treatment after curative-intent surgery for pancreatic ductal adenocarcinoma (PDAC). The phase-3 ESPAC-4 trial demonstrated significantly improved overall survival (OS) with Gemcitabine plus capecitabine (GemCap) over Gemcitabine (Gem) in Europe. We conducted a retrospective efficacy and safety evaluation of GemCap versus Gem in an Asian population. Methods: This retrospective analysis included 292 patients with PDAC who received adjuvant Gem or GemCap after curative resection between January 2017 and December 2020 at Asan Medical Center, Seoul, Korea. Results: Adjuvant Gem and GemCap were administered to 161 (55.1%) and 131 (44.8%) patients, respectively. The Gem group had significantly older patients (median 66 versus 63 years, p = 0.001); otherwise, the groups had similar baseline characteristics. With median follow-up durations of 39.4 [95% confidence interval (CI), 36.9–45.0] and 39.4 (95% CI, 34.7–41.6) months in the Gem and GemCap groups, the median OS was 36.8 (95% CI, 29.7–43.5) and 46.1 (95% CI, 31.5–not reached) months in the Gem and GemCap groups, respectively [unadjusted hazard ratio (HR) = 0.7; 95% CI, 0.5–1.0; p = 0.07). The median recurrence-free survival was 14.3 (95% CI, 12.9–17.7) and 17.0 (95% CI, 13.3–28.2) months, respectively ( p = 0.5). Hand-foot skin reactions (any grade, 15.3% versus 0.6%; p median) were significantly associated with worse OS. Conclusions: Adjuvant GemCap showed the consistent clinical outcomes with the ESPAC-4 trial. As mFOLFIRINOX is the new standard treatment for medically fit patients with resected PDAC, further evaluation of optimal adjuvant chemotherapy in daily practice is warranted.

Abstract There is an unmet medical need for later-line treatment options for patients with metastatic colorectal cancer (mCRC). Considering that, beyond progression, co-treatment with bevacizumab and cytotoxic chemotherapy showed less toxicity and a significant disease control rate, we aimed to evaluate the efficacy of capecitabine and bevacizumab. This single-center retrospective study included 157 patients between May 2011 and February 2018, who received bevacizumab plus capecitabine as later-line chemotherapy after progressing with irinotecan, oxaliplatin, and fluoropyrimidines. The study treatment consisted of bevacizumab 7.5 mg/kg on day 1 and capecitabine 1,250 mg/m2 orally (PO) twice daily on day 1 to 14, repeated every 3 weeks. The primary endpoint was progression-free survival (PFS). The median PFS was 4.6 months (95% confidence interval [CI] 3.9–5.3). The median overall survival (OS) was 9.7 months (95% CI 8.3–11.1). The overall response rate was 14% (22/157). Patients who had not received prior targeted agents showed better survival outcomes in the multivariable analysis of OS (hazard ratio [HR] = 0.59, 95% CI 0.43–0.82, P = 0.002) and PFS (HR = 0.61, 95% CI 0.43–0.85, P = 0.004). Bevacizumab plus capecitabine could be a considerably efficacious option for patients with mCRC refractory to prior standard treatments.

BackgroundGallbladder cancer (GBC) has a poor prognosis. Although complete surgical resection is the only successful approach for improving survival, additional therapeutic modalities are required for recurrent or surgically unresectable GBCs.Materials and MethodsTo determine the expression status of HER2 and the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, immunohistochemical staining of MMR proteins and HER2 was carried out in 216 surgically resected GBCs. HER2 labeling was scored by adopting a scoring system for gastric carcinomas. Tissues scoring 0 to 2+ were defined as HER2 negative, whereas those scoring 3+ were regarded as HER2-positive. In addition, silver in situ hybridization and microsatellite instability (MSI) analysis were conducted to confirm HER2 amplification and MSI, respectively.ResultsThree of 216 GBCs (1.3%) showed MMR protein deficiency. All three observed MSI cases exhibited dual loss of MSH2 and MSH6 protein expression. However, no cases showed loss of either MLH1 or PMS2 expression. No association was observed between MMR protein deficiency and other clinicopathological factors. HER2 amplification was noted in 30 (13.9%) GBCs and associated with Crohn-like lymphoid reaction (P = 0.023). No survival difference was observed based on HER2 overexpression or HER2 amplification status.ConclusionMMR protein deficiency and HER2 overexpression were observed in a small subset (1.3% and 13.9%, respectively) of GBCs without simultaneous occurrence of deficient MMR protein expression and HER2 overexpression. The presence of Crohn-like lymphoid reaction may help identify cases with HER2 amplification, by using hematoxylin-stained slides. Although the proportion of MMR protein-deficient- and HER2-overexpressing GBCs was small, applying immunotherapy to MMR protein-deficient GBCs and herceptin to HER2-overexpressing GBCs may provide alternative treatment options for patients with GBC.

Abstract Background Utility weight, a measure of health-related quality of life, is used in disease burden measurements and economic evaluations. In this study, we used the visual analogue scale (VAS) and standard gamble (SG) method to determine the utility weights of lung cancer health states in South Korea from a societal perspective. Methods Six hypothetical health states for lung cancer or a related health state reflective of disease severity were developed: 1) Stage I, 2) Stage II, 3) Stage IIIa, 4) Stage IIIB, 5) Stage IV, and 6) Pulmonary nodule. The description of each health state description was divided into four parts: diagnosis, symptoms, treatment, and progression and prognosis. A total of 515 representative adult Korean participants used a VAS and SG to evaluate these six health states via face-to-face computer-assisted interviews. The means, standard deviations, and median utility weights of the six health states were estimated by valuation method. Results The two valuation methods of the scenarios yielded the same mean utility rankings. Pulmonary nodule received the highest rank (VAS, 0.66 and SG, 0.83), whereas Stage 4 was assigned the lowest rank (VAS, 0.09 and SG, 0.31). For all health states, the mean utility weights calculated using the SG were greater than those calculated using the VAS. The differences between the utility weights obtained using the two valuation methods ranged from 0.14 (Stage I) to 0.22 (Stage IV). The two approaches tended to yield larger differences for more severe stages. Conclusions This study determined utilities for squamous cell lung cancer that will be useful for estimating the burden of lung cancer and for conducting economic evaluations of lung cancer interventions.

Introduction: Liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has shown clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on gemcitabine-based chemotherapy. However, its role in patients with mPAC previously treated with conventional irinotecan-containing chemotherapy has not been appropriately investigated. Methods: In this retrospective analysis, patients with mPAC who received nal-IRI plus 5-FU/LV after conventional irinotecan-containing regimen between January 2017 and March 2020, were identified from two referral cancer centers in South Korea. The ratio of time to progression (TTP) with nal-IRI plus 5-FU/LV to TTP with conventional irinotecan (TTPr) was analyzed with respect to the duration and cumulative dose of conventional irinotecan treatment. Results: In total, 35 patients treated with nal-IRI plus 5-FU/LV after the irinotecan-containing regimen were analyzed. The median age was 58 years and 16 (46%) patients were male. The median duration of conventional irinotecan therapy was 4.6 months at a median cumulative dose of 1230 mg. The objective response rate of nal-IRI plus 5-FU/LV was 2.9%, and stable disease was achieved in 11 (31.4%) patients. During the median follow-up of 9.2 [95% confidence interval (CI): 7.8–10.5] months, the median progression-free survival (PFS) and overall survival (OS) were 2.0 (95% CI: 1.4–2.6) months and 4.4 (95% CI: 3.6–5.7) months, respectively. The 6-month PFS and OS rates were 16.3% and 37.5%, respectively. The median TTPr was 0.41 (range, 0.07–2.07), showing a negative correlation with the cumulative dose of prior irinotecan therapy (R = −0.37, p = 0.041). A tentative negative correlation between TTPr and duration of prior irinotecan therapy was observed ( R = −0.35, p = 0.062). The most common grade 3–4 toxicities were neutropenia (20%) and fatigue (8.6%). Conclusion: Nal-IRI plus 5-FU/LV showed modest effectiveness and manageable toxicities for patients with mPAC previously treated with conventional irinotecan-containing chemotherapy. The cumulative dose of prior conventional irinotecan therapy may be inversely correlated with the effectiveness of nal-IRI plus 5-FU/LV.

PurposeMore than half of patients with bile duct cancer (BDC) develop recurrence even after curative resection. Recurrent BDC has a poor prognosis, and no optimal treatment modality has been established. We therefore analyzed our experience on the survival outcomes of radiation therapy (RT) for recurrent extrahepatic bile duct cancer (EHBDC).Patients and methodsWe retrospectively analyzed the records of patients with recurrent EHBDC who underwent concurrent chemoradiation therapy (CCRT) or RT alone at our institution between January 2001 and June 2015. Freedom from locoregional progression (FFLP), progression-free survival (PFS), and overall survival (OS) were assessed, and univariate and multivariate analyses were performed to identify the prognostic factors.ResultsA total of 76 patients were included in the analysis. The median OS was 16 months and the rates of 2-year FFLP, PFS, and OS were 61%, 25%, and 33%, respectively. Among the evaluable patients, the first site of failure was the locoregional area in 16 patients, distant metastasis in 27, and both sites in 8. On univariate analysis, disease-free interval (p = 0.012) and concurrent chemotherapy (p = 0.040) were found as significant prognostic factors for OS. One patient with CCRT developed a grade 3 hematologic toxicity, and two patients experienced late grade 3 toxicities including duodenal ulcer bleeding and obstruction.ConclusionsRT for recurrent EHBDC showed favorable survival and local control with limited treatment-related toxicities. Considering that the most common pattern of failure was distant metastasis, further studies on the optimal scheme of chemotherapy and RT are warranted.

In locally advanced pancreatic cancer (LAPC), stereotactic body radiation therapy (SBRT) has been applied as an alternative to concurrent chemoradiotherapy (CCRT); however, direct comparative evidence between these two modalities is scarce. The aim of this study was to compare the clinical outcomes of SBRT with CCRT for LAPC. We retrospectively reviewed the medical records of patients with LAPC who received SBRT (n = 95) or CCRT (n = 66) with a concurrent 5-FU-based regimen between January 2008 and July 2016. The clinical outcomes of freedom from local progression (FFLP), progression-free survival (PFS), overall survival (OS), and toxicities were analyzed before and after propensity score (PS) matching. After a median follow-up duration of 15.5 months (range, 2.3–64.5), the median OS, PFS, and FFLP of the unmatched patients were 17.3 months, 11 months, and 19.6 months, respectively. After PS matching, there were no significant differences between the SBRT and CCRT groups in terms of the 1-year rates of OS (66.7% vs. 80%, p = 0.455), PFS (40.0% vs. 54.2%, p = 0.123), and FFLP (77.2% and 87.1%, p = 0.691). Our results suggest SBRT could be a feasible alternative to CCRT in treating patients with LAPC.

Background: We evaluated the safety and efficacy of direct oral anticoagulants (DOACs) versus subcutaneous dalteparin for cancer-associated venous thromboembolism (CA-VTE) in patients with advanced upper gastrointestinal (GI) tract, hepatobiliary, or pancreatic cancer. Methods: This was a multicenter, randomized, open-label, phase II trial in five centers. Patients randomly received rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily)/apixaban (10 mg twice daily for the first 7 days, then 5 mg twice daily) or dalteparin (200 IU/kg once daily for the first month, then 150 IU/kg once daily). Randomization was stratified by the Eastern Cooperative Oncology Group Performance Status, primary cancer type, active chemotherapy, and participating centers. The primary endpoint was the rates of clinically relevant bleeding (CRB) in the full analysis set (FAS). Results: A total of 90 patients were randomly assigned to the DOAC (n = 44) and dalteparin groups (n = 46) in FAS. CRB and major bleeding (MB) rates were 34.1% and 13.0% (p = 0.018) and 18.2% and 4.3% (p = 0.047) for the DOAC and dalteparin groups, respectively. Time to CRB and MB was higher in the DOAC group than in the dalteparin group (hazard ratio [HR] 2.83; p = 0.031 and HR 4.32; p = 0.064). Cancer involvement at the GI mucosa was also a significant risk factor for CRB. Recurrent CA-VTE occurred in 2.3% and 2.2% of patients given DOAC and dalteparin, respectively (p = 1.000). Conclusion: DOAC therapy further increased the risk of bleeding compared with dalteparin in patients with active advanced upper GI tract, hepatobiliary, or pancreatic cancer, suggesting that extra caution should be taken when selecting anticoagulants for CA-VTE.

Background: Despite the scarcity of data based on randomized trials, FOLFIRINOX is widely used in the management of borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). We investigated the clinical outcomes of neoadjuvant FOLFIRINOX in patients with BRPC and LAPC. Methods: This single-center retrospective analysis included a total of 199 consecutive patients with BRPC or LAPC who received conventional or modified FOLFIRINOX between February 2013 and January 2017. An independent radiologist reviewed all baseline computed tomography or magnetic resonance imaging scans were reviewed for vascular invasion status. Results: With median follow-up duration of 40.3 months [95% confidence interval (CI), 36.7–43.8] in surviving patients, median progression-free survival (PFS) and overall survival (OS) were 10.6 (95% CI, 9.5–11.7) and 18.1 (95% CI, 16.0–20.3) months, respectively. The 1-year PFS rate was 66.0% (95% CI, 65.3–66.7%), and the 2-year OS rate was 37.2% (95% CI, 36.5–37.9%). PFS and OS did not differ between BRPC and LAPC groups [median PFS, 11.1 months (95% CI, 8.8–13.5) versus 10.1 months (95% CI, 8.4–11.8), p = 0.47; median OS, 18.4 months (95% CI, 16.1–20.8) versus 17.1 months (95% CI, 13.2–20.9), p = 0.50]. Curative-intent conversion surgery (R0/R1) was performed in 63 patients (31.7%). C•A 19-9 response, objective tumor response to FOLFIRINOX, and conversion surgery were independent prognostic factors for OS. Conclusion: FOLFIRINOX was effective for management of BRPC and LAPC. Given the potential for cure, a significant proportion of patients can undergo conversion curative-intent surgery following FOLFIRINOX.

Background: FOLFIRINOX (fluorouracil, folinic acid, irinotecan plus oxaliplatin) is an effective standard first-line treatment option for advanced pancreatic ductal adenocarcinoma (PDAC). There is no clear consensus on the second-line treatment following progression on FOLFIRINOX. In this multicenter retrospective analysis, we evaluated the efficacy and tolerability of second-line nab-P/Gem (nab-paclitaxel and gemcitabine) after progression on FOLFIRNOX in PDAC. Methods: Patients with unresectable or metastatic PDAC who received nab-P/Gem after progression on FOLFIRINOX between February 2016 and February 2019 were identified from five referral cancer centers in South Korea. Baseline characteristics, treatment history, survival outcomes, and toxicity profile were obtained retrospectively from medical records. Results: A total of 102 patients treated with second-line nab-P/Gem for advanced PDAC after progression on FOLFIRINOX were included. At the time of nab-P/Gem, the median age was 60 years, with males comprising 49.0%, and most (75.5%) had metastatic disease. Patients received a median of three cycles (range 1–12) of nab-P/Gem. The median overall survival (OS) and progression-free survival (PFS) from the start of second-line nab-P/Gem therapy were 9.8 (95% CI, 8.9–10.6) and 4.6 months (3.7–5.5), respectively. A partial response was achieved in 8.5%, and the disease control rate was 73.6%. From the start of first-line FOLFIRIOX, the OS 1+2 and PFS 1+2 were 20.9 (15.7–26.1) and 13.9 (10.8–17.0) months, respectively, with a 2-year survival rate of 45.1%. There was no treatment-related mortality and grade ⩾3 toxicity was observed in 60.2%. Conclusion: Our results showed that nab-P/Gem was an effective and tolerable second-line treatment option in medically fit patients with advanced PDAC who progressed on first-line FOLFIRNOX. ClinicalTrials.gov identifier: NCT04133155

Pemetrexed and platinum (PP) combination chemotherapy is the current standard first-line therapy for treatment of malignant mesothelioma (MM). However, a useful predictive biomarker for PP therapy is yet to be found. Here, we performed targeted exome sequencing to profile somatic mutations and copy number variations in 12 MM patients treated with PP therapy. We identified 187 somatic mutations in 12 patients (65 synonymous, 102 missense, 2 nonsense, 5 splice site, and 13 small coding insertions/deletions). We identified somatic mutations in 23 genes including BAP1, TP53, NRAS, and EGFR. Interestingly, rare NRAS p.Q61K and EGFR exon 19 deletions were observed in 2 patients. We also found somatic chromosomal copy number deletions in CDKN2A and CDKN2B genes. Genetic alteration related to response after PP therapy was not found. Somatic mutation profiling in MM patients receiving PP therapy revealed genetic alterations in potential therapeutic targets such as NRAS and EGFR. No alterations in genes with potential predictive role for PP therapy were found.

Pancreatic cancer is characterized by late detection, frequent drug resistance, and a highly metastatic nature, leading to poor prognosis. Antibody-based immunotherapy showed limited success for pancreatic cancer, partly owing to the low delivery rate of the drug into the tumor. Herein, we describe a poly(lactic-co-glycolic acid;PLGA)-based siRNA nanoparticle targeting PD-L1 (siPD-L1@PLGA). The siPD-L1@PLGA exhibited efficient knockdown of PD-L1 in cancer cells, without affecting the cell viability up to 6 mg/mL. Further, 99.2% of PDAC cells uptake the nanoparticle and successfully blocked the IFN-gamma-mediated PD-L1 induction. Consistently, the siPD-L1@PLGA sensitized cancer cells to antigen-specific immune cells, as exemplified by Ovalbumin-targeting T cells. To evaluate its efficacy in vivo, we adopted a pancreatic PDX model in humanized mice, generated by grafting CD34+ hematopoeitic stem cells onto NSG mice. The siPD-L1@PLGA significantly suppressed pancreatic tumor growth in this model with upregulated IFN-gamma positive CD8 T cells, leading to more apoptotic tumor cells. Multiplex immunofluorescence analysis exhibited comparable immune cell compositions in control and siPD-L1@PLGA-treated tumors. However, we found higher Granzyme B expression in the siPD-L1@PLGA-treated tumors, suggesting higher activity of NK or cytotoxic T cells. Based on these results, we propose the application of siPD-L1@PLGA as an immunotherapeutic agent for pancreatic cancer.

Abstract Background In metastatic colorectal cancer, the location of the primary tumor has been suggested to have biological significance. In this study, we investigated whether primary tumor location affects cetuximab efficacy in patients with RAS wild-type metastatic colorectal cancer. Methods Genotyping by the SequenomMassARRAY technology platform (OncoMap) targeting KRAS, NRAS, PIK3CA, and BRAF was performed in tumors from 307 patients who had been given cetuximab as salvage treatment. Tumors with mutated RAS (KRAS or NRAS; n = 127) and those with multiple primary location (n = 10) were excluded. Right colon cancer was defined as a tumor located in the proximal part to splenic flexure. Results A total of 170 patients were included in the study (right versus left, 23 and 147, respectively). Patients with right colon cancer showed more mutated BRAF (39.1% vs. 5.4%), mutated PIK3CA (13% vs. 1.4%), poorly differentiated tumor (17.4% vs. 3.4%), and peritoneal involvement (26.1% vs. 8.8%) than those with left colon and rectal cancer. Right colon cancer showed poorer progression-free survival (2.0 vs.5.0 months, P = 0.002) and overall survival (4.1 months and 13.0 months, P

Biliary tract cancers (BTCs) are a group of aggressive malignancies that arise from the bile duct and gallbladder. BTCs include intrahepatic cholangiocarcinoma (IH-CCA), extrahepatic cholangiocarcinoma (EH-CCA), and gallbladder cancer (GBCA). BTCs are highly heterogeneous cancers in terms of anatomical, clinical, and pathological characteristics. Until recently, the treatment of resectable BTC, including surgery, adjuvant chemotherapy, and radiation therapy, has largely been based on institutional practice guidelines and evidence from small retrospective studies. Recently, several large randomized prospective trials have been published, and there are ongoing randomized trials for resectable BTC. In this article, we review prior and recently updated evidence regarding surgery, adjuvant and neoadjuvant chemotherapy, and adjuvant radiation therapy for patients with resectable BTC.

Abstract Background Pancreatic ductal adenocarcinomas are among the most malignant neoplasms and have very poor prognosis. Our understanding of various cancers has recently improved the survival of patients with cancer, except for pancreatic cancers. Establishment of primary cancer cell lines of pancreatic ductal adenocarcinomas will be useful for understanding the molecular mechanisms of this disease. Methods Eighty-one surgically resected pancreatic ductal adenocarcinomas were collected. Six novel pancreatic cancer cell lines, AMCPAC01–06, were established and histogenetic characteristics were compared with their matched tissues. The clinicopathologic and molecular characteristics of the cell lines were investigated by KRAS and TP53 sequencing or SMAD4 and p53 immunohistochemistry. Xenografts using AMCPAC cell lines were established. Results From the 81 pancreatic ductal adenocarcinomas, six (7.4% success rate) patient-derived primary cell lines were established. The six AMCPAC cell lines showed various morphologies and exhibited a wide range of doubling times. AMCPAC cell lines contained mutant KRAS in codons 12, 13, or 61 and TP53 in exon 5 as well as showed aberrant p53 (5 overexpression and 1 total loss) or DPC4 (all 6 intact) expression. AMCPAC cell lines demonstrated homology for the KRAS mutation and p53 expression compared with matched primary cancer tissues, but showed heterogeneous DPC4 expression patterns. Conclusions The novel AMCPAC01–06 cell lines established in this study may contribute to the understanding of pancreatic ductal adenocarcinomas. Trial registration Retrospectively registered

Background: Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) was effective and well-tolerated in patients with metastatic pancreatic adenocarcinoma (mPAC) that progressed on gemcitabine-based therapy in the global NAPOLI-1 trial. Real-world data may further clarify the outcomes and safety profile of nal-IRI + 5-FU/LV in clinical practice. Methods: This retrospective analysis included patients with mPAC who received nal-IRI + 5-FU/LV following gemcitabine-based therapy under a Managed Access Program in Korea. Results: From January 2017 to April 2018, 86 patients across 10 institutions received nal-IRI + 5-FU/LV (median age, 61 years; 60% male; ECOG performance status, 0–1). A total of 35 (41%) and 51 (59%) patients had received less than two and two or more lines of chemotherapy before inclusion, respectively. At a median follow up of 6.4 months, median overall survival (OS) was 9.4 months (95% confidence interval [CI] 7.4–11.4) and median progression-free survival (PFS) was 3.5 months (95% CI 1.3–5.7). Six-month OS and PFS rates were 65.1% and 37.5%, respectively. Objective response and disease control rates were 10% and 55%, respectively. Most common grade 3–4 toxicities were neutropenia (37.2%), nausea (10.5%), vomiting (9.3%), anorexia (8.1%) and diarrhoea (4.7%). Conclusion: Real-life data for Korean patients indicate that, consistent with NAPOLI-1, nal-IRI + 5-FU/LV is effective and well-tolerated in patients with mPAC that progressed on gemcitabine-based therapy.

PurposeStereotactic body radiation therapy (SBRT) is a promising treatment modality for locally advanced pancreatic cancer (LAPC). We evaluated the clinical outcomes of SBRT in patients with LAPC.Patients and methodsWe retrospectively analyzed the medical records of patients with LAPC who underwent SBRT at our institution between April 2011 and July 2016. Fiducial markers were implanted using endoscopic ultrasound guidance one week prior to 4-dimensional computed tomography (CT) simulation and daily cone beam CT was used for image guidance. Patients received volumetric modulated arc therapy or intensity modulated radiotherapy using respiratory gating technique. A median dose of 28 Gy (range, 24-36 Gy) was given over four consecutive fractions delivered within one week. Survival outcomes including freedom from local disease progression (FFLP), progression-free survival (PFS), and overall survival (OS) were analyzed. Acute and late toxicities related to SBRT were assessed.ResultsA total of 95 patients with LAPC were analyzed, 52 of which (54.7%) had pancreatic head cancers. Most (94.7%) had received gemcitabine-based chemotherapy. The 1-year FFLP rate was 80.1%. Median OS and PFS were 16.7 months and 10.2 months, respectively; the 1-year OS and PFS rates were 67.4% and 42.9%, respectively. Among 79 patients who experienced failure, the sites of first failures were isolated local progressions in 12 patients (15.2%), distant metastasis in 55 patients (69.6%), and both in 12 patients (15.2%). Seven patients (7.4%) were able to undergo surgical resection after SBRT and four had margin-negative resections. Three patients (3.2%) had grade 3 nausea/vomiting during SBRT, and late grade 3 toxicity was observed in another three patients.ConclusionsLAPC patients who received chemotherapy and SBRT had favorable FFLP and OS with minimal treatment-related toxicity. The most common pattern of failure was distant metastasis, which warrants further studies on the optimal scheme of chemotherapy and SBRT.

The prognosis of advanced biliary tract cancer (BTC) is poor with the standard gemcitabine and cisplatin (GemCis) regimen. Given that the rates of human epidermal growth factor receptor 2 (HER2) positivity in BTC reaches around 15%, HER2-targeted therapy needs further investigation. This study aims to evaluate the preliminary efficacy/safety of first-line trastuzumab-pkrb plus GemCis in patients with advanced BTC. Patients with unresectable/metastatic HER2-positive BTC received trastuzumab-pkrb (on day 1 of each cycle, 8 mg/kg for the first cycle and 6 mg/kg for subsequent cycles), gemcitabine (1000 mg/m2 on day 1 and 8) and cisplatin (25 mg/m2 on day 1 and 8) every 3 weeks. Of the 41 patients screened, 7 had HER2-positive tumours and 4 were enrolled. The median age was 72.5 years (one male). Primary tumour locations included extrahepatic (N = 2) and intrahepatic (N = 1) bile ducts, and gallbladder (N = 1). Best overall response was a partial response in two patients and stable disease in two patients. Median progression-free survival (PFS) was 6.1 months and median overall survival (OS) was not reached. The most common grade 3 adverse event was neutropenia (75%), but febrile neutropenia did not occur. No patient discontinued treatment due to adverse events. Trastuzumab-pkrb with GemCis showed promising preliminary feasibility in patients with HER2-positive advanced BTC.

Background: The association between optimal carbohydrate antigen (CA) 19-9 concentration after neoadjuvant chemotherapy (NACT) and prognosis has not been confirmed in patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). Methods: This retrospective study included 122 patients with BRPC and 103 with LAPC who underwent surgery after NACT between 2012 and 2019 in a tertiary referral center. Prognostic models were established based on relative difference of the CA 19-9 (RDC), with their prognostic performance compared using C-index and Akaike information criterion (AIC). Results: CA 19-9 concentrations of 37–1000 U/mL before NACT showed prognostic significance in patients with BRPC and LAPC (hazard ratio [HR]: 0.262; 95% confidence interval [CI]: 0.092–0.748; p = 0.012). Prognostic models in this subgroup showed that RDC was independently prognostic of better overall survival (HR: 0.262; 95% CI: 0.093–0.739; p = 0.011) and recurrence free survival (HR: 0.299; 95% CI: 0.140–0.642; p = 0.002). The prognostic performances of RDC (C-index: 0.653; AIC: 227.243), normalization of CA 19-9 after NACT (C-index: 0.625; AIC: 230.897) and surgery (C-index: 0.613; AIC: 233.114) showed no significant differences. Conclusion: RDC was independently associated with better prognosis after NACT in patients with BRPC or LAPC. Decreased CA19-9 after NACT was a prognostic indicator of better survival and recurrence, as was normalization of CA 19-9 after both NACT and surgery.

The clinical benefit and potential risks of conversion surgery after neoadjuvant chemotherapy (NACT) have not been fully investigated in patients with borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). Therefore, this has been evaluated in a retrospective, prospective cohort-based analysis. Between October 2005 and April 2017, 135 patients (65 with BRPC and 70 with LAPC) received conversion surgery after NACT. Exploratory analysis to assess clinical outcomes in comparison with patients who underwent upfront surgery in the same time period (n = 359) was also conducted. NACT with gemcitabine-based regimens (including gemcitabine monotherapy, gemcitabine-capecitabine combination, and gemcitabine-erlotinib combination) was used in 69 patients (51%) and FOLFIRINOX in 66 patients (49%). The median overall survival (OS) and disease-free survival (DFS) from the time of surgery was 25.4 months (95% CI, 18.6⁻32.2 months) and 9.0 months (95% CI, 6.8⁻11.2 months), respectively. The median OS and progression-free survival from the initiation of NACT was 29.7 months (95% CI, 22.5⁻36.8 months) and 13.4 months (95% CI, 12.5⁻14.4 months), respectively. In the exploratory analysis, conversion surgery after NACT was associated with a better median OS and DFS than upfront surgery (vs. 17.1 months; 95% CI, 15.5⁻18.7 months; p = 0.001 and vs. 7.1 months; 95% CI, 6.4⁻7.8 months; p = 0.005, respectively). There was no difference in length of hospital stay between the two groups, and conversion surgery after NACT showed a significantly lower incidence of postoperative complications than upfront surgery (38% vs. 27%, p = 0.03). Conversion surgery after NACT is a feasible and effective therapeutic strategy for the treatment of patients with BRPC and LAPC. Further clinical trials investigating optimal therapeutic strategies for BRPC and LAPC are warranted.

Purpose There are no reliable biomarkers to guide treatment for patients with borderline resectable pancreatic cancer (BRPC) in the neoadjuvant setting. We used plasma circulating tumor DNA (ctDNA) sequencing to search biomarkers for patients with BRPC receiving neoadjuvant mFOLFIRINOX in our phase 2 clinical trial (NCT02749136). Materials and Methods Among the 44 patients enrolled in the trial, patients with plasma ctDNA sequencing at baseline or postoperation were included in this analysis. Plasma cell-free DNA isolation and sequencing were performed using the Guardant 360 assay. Detection of genomic alterations, including DNA damage repair (DDR) genes, were examined for correlations with survival. Results Among the 44 patients, 28 patients had ctDNA sequencing data qualified for the analysis and were included in this study. Among the 25 patients with baseline plasma ctDNA data, 10 patients (40%) had alterations of DDR genes detected at baseline, including ATM, BRCA1, BRCA2 and MLH1, and showed significantly better progression-free survival than those without such DDR gene alterations detected (median, 26.6 vs. 13.5 months; log-rank p=0.004). Patients with somatic KRAS mutations detected at baseline (n=6) had significantly worse overall survival (median, 8.5 months vs. not applicable; log-rank p=0.003) than those without. Among 13 patients with post-operative plasma ctDNA data, eight patients (61.5%) had detectable somatic alterations. Conclusion Detection of DDR gene mutations from plasma ctDNA at baseline was associated with better survival outcomes of patients with borderline resectable pancreatic ductal adenocarcinoma treated with neoadjuvant mFOLFIRINOX and may be a prognostic biomarker. [ABSTRACT FROM AUTHOR]

Purpose The benefit of adjuvant chemotherapy following curative-intent surgery in pancreatic ductal adenocarcinoma (PDAC) patients who had received neoadjuvant FOLFIRINOX is unclear. This study aimed to assess the survival benefit of adjuvant chemotherapy in this patient population. Materials and Methods This retrospective study included 218 patients with localized non-metastatic PDAC who received neoadjuvant FOLFIRINOX and underwent curative-intent surgery (R0 or R1) between January 2017 and December 2020. The association of adjuvant chemotherapy with disease-free survival (DFS) and overall survival (OS) was evaluated in overall patients and in the propensity score matched (PSM) cohort. Subgroup analysis was conducted according to the pathology-proven lymph node status. Results Adjuvant chemotherapy was administered to 149 patients (68.3%). In the overall cohort, the adjuvant chemotherapy group had significantly improved DFS and OS compared to the observation group (DFS: median, 13.8 months [95% confidence interval (CI), 11.0 to 19.1] vs. 8.2 months [95% CI, 6.5 to 12.0]; p < 0.001; and OS: median, 38.0 months [95% CI, 32.2 to not assessable] vs. 25.7 months [95% CI, 18.3 to not assessable]; p=0.005). In the PSM cohort of 57 matched pairs of patients, DFS and OS were better in the adjuvant chemotherapy group than in the observation group (p < 0.001 and p=0.038, respectively). In the multivariate analysis, adjuvant chemotherapy was a significant favorable prognostic factor (vs. observation; DFS: hazard ratio [HR], 0.51 [95% CI, 0.36 to 0.71; p < 0.001]; OS: HR, 0.45 [95% CI, 0.29 to 0.71; p < 0.001]). Conclusion Among PDAC patients who underwent surgery following neoadjuvant FOLFIRINOX, adjuvant chemotherapy may be associated with improved survival. Randomized studies should be conducted to validate this finding. [ABSTRACT FROM AUTHOR]