Efficacy of second-line chemotherapy after treatment with gemcitabine plus nab-paclitaxel or FOLFIRINOX in patients with metastatic pancreatic cancer.

First-line chemotherapy for patients with metastatic pancreatic cancer (MPC) includes gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX). However, the efficacy of second-line chemotherapy and the role of combination chemotherapy in clinical practice is still unknown. Data was gathered from 14 hospitals in the Kyushu area of Japan from December 2013 to March 2017. The median overall survival (mOS) from second-line treatment was contrasted between patients who received second-line chemotherapy (CT group) and those who received the best supportive care (BSC group). Furthermore, the mOS of combination chemotherapy was compared to mono chemotherapy in the CT group. To control possible bias in the selection of treatment, we performed a propensity score-adjusted analysis. A total of 255 patients received GnP or FFX as first-line chemotherapy. There were 156 in the CT group and 77 in the BSC group of these. The CT group had a significantly longer mOS than the BSC group (5.2 vs. 2.6 months; adjusted hazard ratio (HR) 0.38; 95% CI 0.27-0.54). In the CT group, 89 patients received combination chemotherapy while 67 received mono chemotherapy. The mOS did not differ significantly between the combination and mono chemotherapy groups (5.5 vs. 4.8 months; adjusted HR 0.88; 95% CI 0.58-1.33). Among patients with MPC receiving second-line treatment, the CT group had a significantly longer mOS than the BSC group, but combination chemotherapy conferred no improvement in survival compared to mono chemotherapy.

C-reactive protein/albumin ratio is the most significant inflammatory marker in unresectable pancreatic cancer treated with FOLFIRINOX or gemcitabine plus nab-paclitaxel.

There are limited absolute biomarkers for determining the prognosis before first- and second-line palliative chemotherapy in unresectable pancreatic cancer (urPC) patients. To find the best prognostic inflammatory marker, we investigated relationships between overall survival (OS) and six inflammatory markers; C-reactive protein/albumin ratio (CAR), neutrophil-lymphocyte ratio (NLR), prognostic nutrition index (PNI), platelet-lymphocyte ratio (PLR), Glasgow prognostic score (GPS), and prognostic index (PI). We examined 255 patients who received gemcitabine + nab-paclitaxel or FOLFIRINOX as first-line chemotherapy and 159 patients who subsequently underwent second-line chemotherapy. First-line patients with lower CAR had better OS compared to those with a higher CAR (hazard ratio 0.57; 95% confidential index 0.42-77; P < 0.01). Similarly, lower NLR (P = 0.01), higher PNI (P = 0.04), lower PLR (P = 0.03), GPS score of 0 (P < 0.01) and PI score of 0 (P < 0.01) were all associated with better OS. CAR demonstrated the best superiority for determining survival prognosis through the use of area under the curve of time-dependent receiver-operating characteristic curves. Furthermore, a lower CAR before second-line therapy exhibited better OS versus higher CAR (P < 0.01). Therefore, CAR might be a useful biomarker for predicting urPC patient prognosis in both first- and second-line chemotherapy.

Scoring model with serum albumin and CA19-9 for metastatic pancreatic cancer in second-line treatment: results from the NAPOLEON study.

BACKGROUND: Patients with metastatic pancreatic cancer refractory to first-line chemotherapy (CTx) have few treatment options. It is unclear what kind of patients could be brought about survival benefit by 2nd-line CTx after refractory to gemcitabine + nab-PTX (GnP) or FOLFIRINOX. METHODS: This analysis was conducted as part of a multicenter retrospective study of GnP or FOLFIRINOX in patients with metastatic pancreatic cancer. Excluding censored cases, 156 and 77 patients, respectively, received second-line chemotherapy (CTx) and best supportive care (BSC). Using prognostic factors for post-discontinuation survivals (PDSs) at the first-line determination in multivariate analysis, we developed a scoring system to demonstrate the benefit of second-line CTx. RESULTS: The second-line CTx group had a median PDS of 5.2 months, whereas the BSC group had a median PDS of 2.7 months (hazard ratio 0.42; 95% confidence interval [CI] 0.31-0.57; p < 0.01). According to the Cox regression model, serum albumin levels below 3.5 g/dL, and CA19-9 levels above 1000 U/mL were independent prognostic factors (p < 0.01). Serum albumin (≥ and < 3.5 g/dL allotted to scores 0 and 1) and CA19-9 (< and ≥ 1000 U/mL allotted to scores 0 and 1) at first-line determination were used to develop the scoring system. The PDSs of patients with scores of 0 and 1 were significantly better than those of the BSC group; however, there was no significant difference between the PDSs of patients with score 2 and the BSC group. CONCLUSION: The survival advantage of second-line CTx, was observed in patients with scores of 0 and 1 but not in those with score 2.

Conversion Surgery for Unresectable Pancreatic Cancer Treated With FOLFIRINOX or Gemcitabine Plus Nab-paclitaxel.

BACKGROUND/AIM: Recent advances in chemotherapy have made significant progress in conversion surgery (CS) for unresectable pancreatic cancer (uPC). However, the success rate and efficacy of CS have not been fully demonstrated in patients with uPC treated with FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GnP). PATIENTS AND METHODS: We retrospectively reviewed the records of 318 patients with uPC who received FFX or GnP as first-line chemotherapy. The efficacy in the CS group, defined as undergoing complete resection after chemotherapy, was analyzed, and compared with the non-CS group; then, contributing factors to achieving CS were extracted. We also analyzed differences in the efficacy of CS between locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC). RESULTS: Overall, CS was achieved in 4.3% of cases, eight patients (13.3%) with LAPC and five (2.1%) with MPC. Contributing factors to CS were LAPC, no liver metastasis, CA19-9 ≤37, and chemotherapy response. After adjusting for these, overall survival was significantly better in the CS group than in the non-CS group [median of 32.9 vs. 11.3 months; adjusted hazard ratio (HR)=0.32; 95% confidence interval (CI)=0.14-0.70; p<0.01]. Median relapse-free survival duration after CS was 19.1 and 18.1 months in the LAPC-CS and MPC-CS group, respectively (p=0.84). The median post-conversion survival was 27.6 months in the entire CS group, 43.8 months in the LAPC-CS group and 21.3 months in the MPC-CS group. CONCLUSION: CS was achieved in 13.3% of LAPC and 2.1% of MPC cases. If possible, CS can markedly improve prognosis, even in MPC.

Multicenter Retrospective Analysis of Original versus Modified FOLFIRINOX in Metastatic Pancreatic Cancer: Results of the NAPOLEON Study.

INTRODUCTION: Original FOLFIRINOX (oFFX) is more toxic than other regimens for patients with metastatic pancreatic cancer (mPC); therefore, a modified FFX (mFFX) regimen with a reduced dosage has been used in Japanese clinical practice. However, very few studies have compared these two regimens. METHODS: This study was conducted as part of a multicenter retrospective study of 318 patients with mPC across 14 centers in Japan (NAPOLEON study). To control for potential bias and confounders, we conducted a propensity score-adjusted analysis of patient characteristics and clinical outcomes. RESULTS: oFFX and mFFX were administered to 48 and 54 patients. More patients with younger age and poorer performance status were included in the oFFX group. The overall survival (OS; median, 11.6 vs. 11.3 months; hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.60-1.40; p = 0.67), progression-free survival (PFS) (median, 6.3 vs. 5.7 months; HR, 0.85; 95% CI, 0.56-1.28; p = 0.44), and overall response rate (29 vs. 26%, p = 0.71) were not significantly different for the oFFX and mFFX groups. Thrombopenia and liver dysfunction were significantly more frequent with oFFX than with mFFX. The median received dose intensity of CPT-11 was higher with oFFX than with mFFX (299 vs. 270 mg/m2/week, p < 0.01). The propensity score-adjusted analysis revealed no statistically significant differences in OS and PFS between the two groups. CONCLUSION: In our data, there was no significant difference in efficacy between mFFX and oFFX, and mFFX has fewer adverse events.

First-line pembrolizumab ± chemotherapy for recurrent/metastatic head and neck cancer: Japanese subgroup of KEYNOTE-048.

BACKGROUND: Here, we report the results of the Japanese subgroup of the phase 3 KEYNOTE-048 study of pembrolizumab alone, pembrolizumab plus platinum and 5-fluorouracil (pembrolizumab-chemotherapy), or cetuximab plus platinum and 5-fluorouracil (EXTREME) in previously untreated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). METHODS: Primary end points were overall survival (OS) and progression-free survival (PFS). Efficacy was evaluated in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1 and the total Japanese subgroup (n = 67). RESULTS: At data cutoff (25 February 2019), pembrolizumab led to longer OS versus EXTREME in the PD-L1 CPS ≥ 20 subgroup (median, 28.2 vs. 13.3 months; HR, 0.29 [95% CI 0.09-0.89]) and to similar OS in the total Japanese (23.4 vs. 13.6 months; HR, 0.51 [95% CI 0.25-1.05]) and CPS ≥ 1 subgroups (22.6 vs. 15.8 months; HR, 0.66 [95% CI 0.31-1.41]). Pembrolizumab-chemotherapy led to similar OS versus EXTREME in the PD-L1 CPS ≥ 20 (median, 18.1 vs. 15.8 months; HR, 0.72 [95% CI 0.23-2.19]), CPS ≥ 1 (12.6 vs. 15.8 months; HR, 1.19 [95% CI 0.55-2.58]), and total Japanese subgroups (12.6 vs. 13.3 months; unadjusted HR, 1.10 [95% CI 0.55-2.22]). Median PFS was similar for pembrolizumab and pembrolizumab-chemotherapy versus EXTREME in all subgroups. Grades 3-5 treatment-related adverse events occurred in 5 (22%), 19 (76%), and 17 (89%) patients receiving pembrolizumab, pembrolizumab-chemotherapy, and EXTREME, respectively. One patient receiving pembrolizumab-chemotherapy died because of treatment-related pneumonitis. CONCLUSION: These results support the use of first-line pembrolizumab and pembrolizumab-chemotherapy for Japanese patients with R/M HNSCC. Clinical trial registry ClinicalTrials.gov, NCT02358031.

A multicentre retrospective study comparing site-specific treatment with empiric treatment for unfavourable subset of cancer of unknown primary site.

BACKGROUND: Patients with cancer of unknown primary site are divided into two distinct groups, favourable and unfavourable subsets. For the unfavourable subset, empiric treatment or site-specific treatment is recommended, but limited knowledge exists about the efficacy of site-specific treatment compared with empiric treatment in clinical practice. METHODS: In this multicentre retrospective study, we reviewed the medical records of patients with cancer of unknown primary site treated with chemotherapy (or chemoradiotherapy) as first-line treatment from eight institutions during 2006-18. We investigated the workup modality and categorized the patients into favourable and unfavourable subsets, which were further divided into site-specific and empiric treatment groups. Site-specific treatment is defined as a standard chemotherapy for an estimated primary site. We examined the efficacy in the favourable and unfavourable subsets and performed multivariable analysis for estimating the overall survival in the unfavourable subset. RESULTS: Of 177 patients with cancer of unknown primary site, 33 and 144 were categorized into favourable and unfavourable subsets, respectively. In the unfavourable subset, 84 patients (58.3%) received empiric therapy, and 60 patients (41.7%) received site-specific treatment. Median overall survival was 10.0 and 10.1 months in site-specific and empiric treatment groups, respectively, with no significant difference (hazard ratio 1.01, 95% confidence interval 0.70-1.45, P = 0.95). Multivariable analysis revealed performance status, number of metastatic sites and hypoalbuminaemia as independent prognostic factors for overall survival in the unfavourable subset. CONCLUSIONS: Overall survival in site-specific and empiric treatment groups was similar in the unfavourable cancer of unknown primary site subset in this study. Further research is needed to prolong overall survival in patients in the unfavourable cancer of unknown primary site subset.

Prognostic nomogram for patients with unresectable pancreatic cancer treated with gemcitabine plus nab-paclitaxel or FOLFIRINOX: A post-hoc analysis of a multicenter retrospective study in Japan (NAPOLEON study).

BACKGROUND: No reliable nomogram has been developed until date for predicting the survival in patients with unresectable pancreatic cancer undergoing treatment with gemcitabine plus nab-paclitaxel (GnP) or FOLFIRINOX. METHODS: This analysis was conducted using clinical data of Japanese patients with unresectable pancreatic cancer undergoing GnP or FOLFIRINOX treatment obtained from a multicenter study (NAPOLEON study). A Cox proportional hazards model was used to identify the independent prognostic factors. A nomogram to predict 6-, 12-, and 18-month survival probabilities was generated, validated by using the concordance index (C-index), and calibrated by the bootstrapping method. And then, we attempted risk stratification for survival by classifying the patients according to the sum of the scores on the nomogram (total nomogram points). RESULTS: A total of 318 patients were enrolled. A prognostic nomogram was generated using data on the Eastern Cooperative Oncology Group performance status, liver metastasis, serum LDH, serum CRP, and serum CA19-9. The C-indexes of the nomogram were 0.77, 0.72 and 0.70 for 6-, 12-, and 18-month survival, respectively. The calibration plot showed optimal agreement at all points. Risk stratification based on tertiles of the total nomogram points yielded clear separations of the survival curves. The median survival times in the low-, moderate-, and high-risk groups were 15.8, 12.8 and 7.8 months (P<0.05), respectively. CONCLUSIONS: Our nomogram might be a convenient and inexpensive tool to accurately predict survival in Japanese patients with unresectable pancreatic cancer undergoing treatment with GnP or FOLFIRINOX, and will help clinicians in selecting appropriate therapeutic strategies for individualized management.

Gemcitabine plus nab-paclitaxel in older patients with metastatic pancreatic cancer: A post-hoc analysis of the real-world data of a multicenter study (the NAPOLEON study).

OBJECTIVES: This study aimed to examine the efficacy and safety of gemcitabine plus nab-paclitaxel (GnP) in older patients with metastatic pancreatic cancer (MPC), especially those ≥75 years old. MATERIALS AND METHODS: This study retrospectively enrolled 153 patients with MPC who received GnP as first-line chemotherapy. Patients ≥75 years old were allocated to the older group, and those <75 years old were assigned to the non-older group. We compared safety, antitumor efficacy, and survival between the two groups. In the older group, prognostic indicators of survival were also assessed. RESULTS: The pretreatment characteristics of the two groups were not significantly different excluding age, history of malignancy, and C-reactive protein levels. The initial dose and relative dose intensities of GnP were significantly lower in the older group. There were no significant differences in the adverse event and antitumor response rates between the two groups. Median progression-free survival and overall survival were 5.5 and 12.0 months, respectively, in the older group, versus 6.0 and 11.1 months, respectively, in the non-older group. In the older group, a Geriatric Nutrition Risk Index (GNRI) of less than 86 was associated with poor prognosis. CONCLUSION: GnP exhibited acceptable efficacy and safety in patients ≥75 years old with MPC. GNRI might be helpful for identifying older individuals at higher risk of unfavorable outcomes.

Gemcitabine Plus Nab-Paclitaxel Versus FOLFIRINOX in Locally Advanced, Unresectable Pancreatic Cancer: A Multicenter Observational Study (NAPOLEON Study).

OBJECTIVES: FOLFIRINOX (FFX, a combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin) and gemcitabine plus nab-paclitaxel (GnP) have been used as standard, first-line treatments for advanced pancreatic cancer. However, no study has compared the efficacy of the 2 regimens. This study retrospectively compared the efficacy and safety of the 2 regimens in patients with locally advanced pancreatic cancer. METHODS: We reviewed the records of patients with locally advanced pancreatic cancer who started FFX or GnP as first-line chemotherapy as part of a multicenter retrospective study in patients with unresectable pancreatic cancer treated with FFX or GnP (NAPOLEON study). RESULTS: Sixteen of the 63 patients were treated with FFX, and the other 47 patients were treated with GnP between December 2013 and March 2017. There were no significant differences in median overall survival rate between the GnP (15.5 months) and FFX (14.3 months, P = 0.60) groups or median progression-free survival rate between the GnP (8.8 months) and FFX (8.1 months, P = 0.51) groups. Both treatments were generally well tolerated, although anorexia was more severe in the FFX group than in the GnP group. CONCLUSIONS: The effects of FFX and GnP were similar but resulted in different toxicities, which could guide agent choice.

Gemcitabine Plus Nanoparticle Albumin-bound Paclitaxel Versus FOLFIRINOX for Recurrent Pancreatic Cancer After Resection.

BACKGROUND/AIM: The aim of the study was to evaluate gemcitabine plus nanoparticle albumin-bound paclitaxel (GnP) and FOLFIRINOX for recurrent pancreatic cancer (rPC) after resection. PATIENTS AND METHODS: Forty-four patients with rPC and 211 with de novo metastatic pancreatic cancer (mPC) who received GnP or FOLFIRINOX as first-line chemotherapy were retrospectively analyzed. RESULTS: On crude analysis, the median overall survival (OS) was significantly longer in the rPC group than in the mPC group (14.0 vs. 10.6 months, respectively; p=0.02). However, the difference was not significant on adjusted analysis using the Cox proportional hazards model (adjusted p=0.90). Patients receiving FOLFIRINOX (n=10) and GnP (n=34) in the rPC group had comparable OS (medians, 12.2 vs. 14.4 months, respectively; p=0.82) even after adjusting for covariates using the Cox model (adjusted p=0.18). CONCLUSION: The outcomes of patients in the rPC and mPC groups were comparable following chemotherapy. Both FOLFIRINOX and GnP may be reasonable options for treating rPC.

Predictive impact of C-reactive protein to albumin ratio for recurrent or metastatic head and neck squamous cell carcinoma receiving nivolumab.

Although the neutrophil to lymphocyte ratio (NLR) was reported to be a predictive biomarker for clinical outcomes in various types of cancer, including recurrent or metastatic head and neck cancer (R/M HNSCC) treated with nivolumab, the usefulness of the pretreatment C-reactive protein/albumin ratio (CAR) as a prognostic marker remains to be clarified. This study aimed to analyze the clinical usability of the CAR in comparison with that of the NLR. 46 R/M HNSCC patients treated with nivolumab were retrospectively analyzed. The optimal cutoff value for the CAR was calculated using receiver operating characteristic curve analysis. The optimal cutoff value for the CAR was set to 0.30. On multivariate analyses, a high CAR was significantly associated with poor overall survival (adjusted HR, 2.19; 95% CI, 1.42-3.47; p < 0.01) and progression-free survival (adjusted HR, 1.98; 95% CI, 1.38-2.80; p < 0.01). The overall response rate and disease control rate for the high CAR patients were lower than for the low CAR patients. The CAR had significantly higher area under the curve values than the NLR at 2 and 4 months. The pretreatment CAR might be an independent marker for prognosis and efficacy in R/M HNSCC patients treated with nivolumab.

A multicenter propensity score analysis of FOLFIRINOX vs gemcitabine plus nab-paclitaxel administered to patients with metastatic pancreatic cancer: results from the NAPOLEON study.

PURPOSE: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX, FFX) and gemcitabine plus nab-paclitaxel (GnP) are considered standard treatments for patients with metastatic pancreatic cancer. Direct comparisons are not available that establish which is optimal. METHODS: We conducted a propensity score-adjusted analysis of patients with metastatic pancreatic cancer to identify the therapeutic advantages of these standard therapies. We used clinical data as part of a multicenter retrospective study of patients with unresectable or recurrent pancreatic cancer treated with FFX or GnP (NAPOLEON study). RESULTS: FFX and GnP were initially administered to 102 and 153 patients, respectively. The GnP group comprised more patients of advanced age, worse performance status, lower body mass index, recurrence, and lower albumin concentrations. Median overall survival (OS) and progression-free survival (PFS) were 11.5 months and 5.8 months in the FFX group and 11.1 months and 5.9 months in the GnP group, respectively. Propensity score-adjusted analysis indicated that the administration of FFX or GnP was not independently associated with OS (adjusted hazard ratio [HR] 1.06; 95% confidence interval [CI] 0.76-1.47; P = 0.73). Similarly, the difference in PFS was not significant between groups (adjusted HR 0.93; 95% CI 0.68-1.26; P = 0.62). Gastrointestinal disorders were more common in the FFX group, whereas the frequencies of hematological, nervous system, and skin disorders were higher in the GnP group. CONCLUSION: The efficacies of FFX and GnP were comparable, although safety profiles differed and should be considered in selecting treatment.

OX40 and LAG3 are associated with better prognosis in advanced gastric cancer patients treated with anti-programmed death-1 antibody.

BACKGROUND: Anti-PD-1 monoclonal antibody, nivolumab, has shown efficacy for advanced gastric cancer (AGC). However, the specific immune cell subsets predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. METHODS: Peripheral blood of 30 AGC patients treated with nivolumab was prospectively obtained before the initial and second administrations and at the time of progressive disease (PD). The proportions of immune cell subsets and the serum concentrations of cytokines were systematically analysed by flow cytometry. Associations of subsets and serum cytokines with therapeutic effects were evaluated. RESULTS: After the initial administration, significant increases in activated central/effector memory, activated effector T cells, and activated T-helper 1 subsets were observed. At the time of PD, activated regulatory T cells, LAG3-positive CD4+/CD8+ T cells, and TIM3-positive CD4+/CD8+ T cells increased significantly. Significant positive correlations were shown between progression-free survival and proportions of LAG3-positive CD4+/CD8+ T cells and of OX40-positive CD4+/CD8+ T cells (log-rank p = 0.0008, 0.0003, 0.0035 and 0.0040). CONCLUSIONS: Nivolumab therapy enhances activation of central/effector memory and effector subsets of CD4+/CD8+ T cells. The expression levels of LAG-3 and OX40 on T cells correlated with the efficacy of nivolumab therapy and could be reasonable biomarkers for anti-PD-1 therapy.

Efficacy and safety of ramucirumab plus modified FOLFIRI for metastatic colorectal cancer.

BACKGROUND: Dose modification of chemotherapy for metastatic colorectal cancer (MCRC) is often needed, especially in second-line and later-line treatments due to adverse events of previous treatment and poor patient condition. No study has focused on ramucirumab plus modified dose of FOLFIRI for MCRC, and whether low relative dose intensity (RDI) affects treatment efficacy has not been clarified. METHODS: MCRC patients who received ramucirumab plus FOLFIRI, which consisted of 150 mg/m2 of irinotecan, at six institutions were retrospectively analyzed. RESULTS: A total of 43 patients were assessed. Median age was 63 years, and 22 patients (51%) were women. Twenty-six patients (60%) were given ramucirumab plus FOLFIRI as second-line therapy, and 17 (40%) as third or later-line. The median relative dose intensity (RDI) of irinotecan was 60.6%, which is lower than that in the pivotal phase 3 study (RAISE), and other agents showed the same trend. Median progression-free survival was 4.8 [95% confidence interval (CI) 3.2-5.7] months for all patients, 5.4 (95% CI 3.5-7.2) months for second-line patients, and 2.8 (95% CI 1.6-5.8) months for third or later-line patients. Median overall survival was 17.3 (95% CI 11.5-22.4) months for all patients. Patients with irinotecan RDI less than 60% showed similar treatment efficacy. Hematological toxicities of grade 3 or worse were observed in 21 patients, but all were manageable. CONCLUSION: Low RDI did not compromise the treatment efficacy of ramucirumab plus modified FOLFIRI for MCRC patients.

The Effectiveness of Hepatic Arterial Infusion Chemotherapy with 5-Fluorouracil/Cisplatin and Systemic Chemotherapy with Ramucirumab in Alpha-Fetoprotein-Producing Gastric Cancer with Multiple Liver Metastases.

Alpha-fetoprotein- (AFP-) producing gastric cancer (AFPGC) is characterized by a high incidence of liver and lymph node metastases and poor prognosis. Although several case reports have described successful multidisciplinary treatment, there are currently no standard therapies for AFPGC. A 57-year-old man presented with upper abdominal pain. His serum AFP level was extremely high (588.9 ng/mL). Computed tomography (CT) revealed multiple liver metastases with several lesions at an imminent risk of rupture. Five days after admission to our hospital, one lesion ruptured. Transarterial chemoembolization (TACE) of the ruptured tumor was performed, and hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil (5-FU)/cisplatin (CDDP) to the other liver metastases was administered. The patient's AFP levels decreased to 297.1 ng/mL. Gastrointestinal endoscopy revealed Borrmann type 2 lesion in the pyloric portion. Pathological examination indicated hepatoid adenocarcinoma of the stomach and metastatic liver. The final diagnosis was AFPGC and multiple liver metastases. The patient underwent systemic chemotherapy with capecitabine/CDDP (cape/CDDP) for three months. His AFP level increased extremely, and CT revealed progression of the liver metastases. TACE was performed, and HAIC (5FU/CDDP) was administered to the progressive lesion of the liver. Originating from the gastric lesion, a distal gastrectomy and D2 + α lymph node resection were performed. One month after the operation, the patient underwent systemic chemotherapy with paclitaxel/ramucirumab (PTX/RAM). After eight cycles of chemotherapy, his AFP level had declined, and CT showed a complete response. After three months of drug withdrawal, the patient has undergone maintenance treatment with RAM. It has been two years since the recurrence. Our experience suggests that HAIC with 5-FU/CDDP and systemic chemotherapy with a regimen including RAM may be an effective treatment for AFPGC.

PD-1+ TIM-3+ T cells in malignant ascites predict prognosis of gastrointestinal cancer.

The liquid biopsy of ascites fluid could be an excellent source of tumor and microenvironment for the study of prognostic biomarkers because of its accessibility. Tumor-infiltrating lymphocytes (TILs) can predict prognosis in multiple malignancies, including the response to immune checkpoint inhibitors, a breakthrough cancer therapy. However, TILs' profiles from malignant ascites have not been extensively studied. Using flow cytometric analysis, we quantified the proportion of exhausted T cells and memory/naive/effector T-cell subsets, among the CD4+ and CD8+ T-cell populations of paired TILs and peripheral blood T cell samples (n = 22). The correlation between CD4+ and CD8+ subset profiles suggested that the combined analysis of CD4+ and CD8+ cells in malignant ascites was clinically significant. We found that cells positive for the exhaustion markers programmed cell death-1 (PD-1), and T-cell immunoglobulin and mucin domain 3 (TIM-3), and cells coexpressing PD-1 and TIM-3 abundantly exist among malignant ascites TILs. Furthermore, patients with high frequency of PD-1+ TIM-3+ cells among the CD4+ and CD8+ T-cell population showed worse clinical outcome in multivariate analysis (n = 27). We propose that exhausted ascites TILs represent a clinically significant prognostic biomarker in advanced gastrointestinal cancer and represent an important target for immune checkpoint inhibitors.

Epithelial-mesenchymal transition is activated in CD44-positive malignant ascites tumor cells of gastrointestinal cancer.

Disseminated cancer cells in malignant ascites possess unique properties that differ from primary tumors. However, the biological features of ascites tumor cells (ATC) have not been fully investigated. By analyzing ascites fluid from 65 gastrointestinal cancer patients, the distinguishing characteristics of ATC were identified. High frequency of CD44+ cells was observed in ATC using flow cytometry (n = 48). Multiplex quantitative PCR (n = 15) showed higher gene expression of epithelial-mesenchymal transition (EMT)-related genes and transforming growth factor beta (TGF-beta)-related genes in ATC than in the primary tissues. Immunohistochemistry (n = 10) showed that ATC also had much higher expression of phosphorylated SMAD2 than that in the corresponding primary tissues. TGF-beta 1 was detected in all cases of malignant ascites by enzyme-linked immunoassay (n = 38), suggesting the possible interaction of ATC and the ascites microenvironment. In vitro experiments revealed that these ATC properties were maintained by TGF-beta 1 in cultured ATC(n = 3). Here, we showed that ATCrevealed high frequencies of CD44 and possessed distinct EMT features from primary tissues that were mainly maintained by TGF-beta 1 in the ascites.