A multi-institutional randomized phase III study comparing minimally invasive distal pancreatectomy versus open distal pancreatectomy for pancreatic cancer; Japan Clinical Oncology Group study JCOG2202 (LAPAN study).

BACKGROUND: Minimally invasive distal pancreatectomy (MIDP), including laparoscopic and robotic distal pancreatectomy, has gained widespread acceptance over the last decade owing to its favorable short-term outcomes. However, evidence regarding its oncologic safety is insufficient. In March 2023, a randomized phase III study was launched in Japan to confirm the non-inferiority of overall survival in patients with resectable pancreatic cancer undergoing MIDP compared with that of patients undergoing open distal pancreatectomy (ODP). METHODS: This is a multi-institutional, randomized, phase III study. A total of 370 patients will be enrolled from 40 institutions within 4 years. The primary endpoint of this study is overall survival, and the secondary endpoints include relapse-free survival, proportion of patients undergoing radical resection, proportion of patients undergoing complete laparoscopic surgery, incidence of adverse surgical events, and length of postoperative hospital stay. Only a credentialed surgeon is eligible to perform both ODP and MIDP. All ODP and MIDP procedures will undergo centralized review using intraoperative photographs. The non-inferiority of MIDP to ODP in terms of overall survival will be statistically analyzed. Only if non-inferiority is confirmed will the analysis assess the superiority of MIDP over ODP. DISCUSSION: If our study demonstrates the non-inferiority of MIDP in terms of overall survival, it would validate its short-term advantages and establish its long-term clinical efficacy. TRIAL REGISTRATION: This trial is registered with the Japan Registry of Clinical Trials as jRCT 1,031,220,705 [ https://jrct.niph.go.jp/en-latest-detail/jRCT1031220705 ].

Development of a nomogram to predict survival in advanced biliary tract cancer.

The prognosis of advanced biliary tract cancer (BTC) patients remains poor due to limited efficacy of chemotherapy and difficulties in management. Thus, prediction of survival is crucial for the clinical management of advanced BTC. The aim was to develop and validate a nomogram to predict 6-month and 12-month survival in advanced BTC patients treated with chemotherapy. A multivariable Cox regression model was used to construct a nomogram in a training set (JCOG1113, a phase III trial comparing gemcitabine plus S-1 [GS] and gemcitabine plus cisplatin, n = 351). External validity of the nomogram was assessed using a test set (JCOG0805, a randomized, phase II trial comparing GS and S-1 alone, n = 100). Predictive performance was assessed in terms of discrimination and calibration. The constructed nomogram included lymph node metastasis, liver metastasis, carbohydrate antigen 19-9, carcinoembryonic antigen, albumin, and C-reactive protein. Uno's concordance index was 0.661 (95% confidence interval [CI] 0.629-0.696) in the training set and 0.640 (95% CI 0.566-0.715) in the test set. The calibration plots for 6-month and 12-month survival showed good agreement in the two analysis sets. The present nomogram can facilitate prediction of the prognosis of advanced BTC patients treated with chemotherapy and help clinicians' prognosis-based decision-making.

Effect of systemic inflammatory response on induction chemotherapy followed by chemoradiotherapy for locally advanced pancreatic cancer: an exploratory subgroup analysis on systemic inflammatory response in JCOG1106.

OBJECTIVE: JCOG1106, a randomized phase II trial conducted to compare chemoradiotherapy (S-1 concurrent radiotherapy) with (Arm B) or without (Arm A) induction chemotherapy using gemcitabine in patients with locally advanced pancreatic cancer, showed a more favorable long-term survival in Arm A. This study was aimed at exploring whether some subgroups classified by the systemic inflammatory response might derive greater benefit from either treatment. METHODS: All subjects eligible for JCOG1106 were included in this analysis (n = 51/49 in Arm A/B). This exploratory subgroup analysis was performed by Cox regression analysis to investigate the impact of the systemic inflammatory response, as assessed based on the serum C-reactive protein, serum albumin (albumin), Glasgow Prognostic Score and derived neutrophil-lymphocyte ratio, at the baseline on overall survival. P values <0.1 for the interaction were regarded as denoting significant association. RESULTS: Glasgow prognostic score showed significant treatment interactions for overall survival. Hazard ratios of Arm B to Arm A were 1.35 (95% confidence interval, 0.82-2.23) in the Glasgow Prognostic Score 0 (C-reactive protein ≤10 mg/L and albumin ≥35 g/L) (n = 44/34 in Arm A/B) and 0.59 (95% confidence interval, 0.24-1.50) in the Glasgow Prognostic Score 1/2 (C-reactive protein >10 mg/L and/or albumin <35 g/L) (n = 7/15) (P-interaction = 0.06). C-reactive protein alone and albumin alone also showed significant treatment interactions for overall survival. CONCLUSIONS: Survival benefits of induction chemotherapy in chemoradiotherapy for locally advanced pancreatic cancer were observed in patients with elevated Glasgow Prognostic Score, high C-reactive protein and low albumin. These results suggest that systemic inflammatory response might be considered to apply induction chemotherapy preceding chemoradiotherapy.

Potential efficacy of hepatic arterial infusion chemotherapy using gemcitabine, cisplatin, and 5-fluorouracil for intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis, as the resectability rate is low due to its diagnosis at a late/advanced stage. Moreover, most patients with resected ICC eventually relapse. Hepatic arterial infusion chemotherapy (HAIC) has been indicated only by a few reports to be effective in patients with advanced ICC; thus, its efficacy for these patients remains unclear. This study aimed to evaluate the efficacy of HAIC using gemcitabine, cisplatin, and 5-fluorouracil in patients with advanced ICC. A total of 18 patients who underwent HAIC were retrospectively investigated. The patients received gemcitabine, cisplatin, and 5-fluorouracil through one artery. In patients who received gemcitabine plus cisplatin (n = 10), the response and disease control rates were 0% and 80.0%, respectively; the median overall survival (OS) and progression-free survival (PFS) after treatment initiation were 6.3 and 3.7 months, respectively. In patients who never received chemotherapy (n = 8), the response and disease control rates were 37.5% and 75%, respectively; the median OS and PFS were 20.6 and 8.1 months, respectively. Moreover, we compared the patients who received HAIC using gemcitabine, cisplatin, and 5-fluorouracil to patients whose tumors were refractory to systemic gemcitabine and cisplatin therapy. The OS of the patients who received HAIC was better than that of the patients who received standard chemotherapy cohort since the gemcitabine plus cisplatin combination therapy-refractory response and disease onset (P = 0.045, 0.006). HAIC using gemcitabine, cisplatin, and 5-fluorouracil may be effective as a therapeutic option for patients with advanced ICC.

The clinical outcomes of combination chemotherapy in elderly patients with advanced biliary tract cancer: an exploratory analysis of JCOG1113.

In the FUGA-BT trial (JCOG1113), gemcitabine plus S-1 (GS) showed non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) with good tolerance for patients with advanced biliary tract cancer (BTC). We performed a subgroup analysis focused on the elderly cohort of this trial. All 354 enrolled patients in JCOG1113 were classify into two groups; < 75 (non-elderly) and ≥ 75 years (elderly) group. We investigated the influence of age on the safety analysis, including the incidence of chemotherapeutic adverse events and the efficacy analysis, including OS. There were no remarkable differences in OS between the elderly (n = 60) and the non-elderly groups (n = 294). In the elderly group, median OS was 12.7 and 17.7 months for those who received GC (n = 20) and GS (n = 40), respectively. The prevalence of all-grade adverse events was similar between the elderly and the non-elderly groups. However, among the elderly group, Grade ≥ 3 hematological adverse events were more frequently observed in the GC arm than in the GS arm. The clinical outcomes of combination chemotherapy in elderly patients with advanced BTC were comparable to non-elderly patients. GS may be the more favorable treatment for elderly patients with advanced BTC.

Postoperative Treatment of Resectable Pancreatic Cancer With Positive Peritoneal Lavage Cytology: A Multicentre Retrospective Study.

BACKGROUND/AIM: We aimed to evaluate pancreatic cancer (PC) with positive peritoneal lavage cytology (CY1) outcomes following a change in adjuvant therapy. PATIENTS AND METHODS: The clinicopathological data of patients with pancreatic adenocarcinoma with CY1 at 14 institutions, between 2007 and 2015, were collected and analyzed. RESULTS: Of the 124 eligible patients, 114 underwent macroscopically curative resection. Of the 114 patients, 80 (70%) did not have early recurrence and received postoperative chemotherapy that was S-1 in 43 (54%), gemcitabine in 31 (39%), and others in six (7%). The median overall survival was 21.0 months in S-1 and 19.2 in gemcitabine therapy (p=0.23), whereas the median relapse-free survival was 10.2 and 7.1 months (p=0.03), respectively. CONCLUSION: Following the change in adjuvant therapy, most PC patients with CY1 who underwent macroscopically curative resection received S-1; however, it was insufficient. Further development of postoperative chemotherapy is required.

Comparison of gemcitabine-based chemotherapies for advanced biliary tract cancers by renal function: an exploratory analysis of JCOG1113.

JCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504-0.937) in the low CCr group. Although the total number of incidences of all Grade 3-4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function.

Risk stratification and prognostic factors in patients with unresectable undifferentiated carcinoma of the pancreas.

BACKGROUND: Undifferentiated carcinoma (UC) of the pancreas has been considered a highly aggressive malignancy. However, only a few studies have systematically described the clinical course of UC patients. The aim of this study was to clarify the prognosis and construct a prognostic model for patients with unresectable UC. METHODS: This study was conducted at 17 institutions in Japan, and a total of 55 patients were analyzed. RESULTS: The median overall survival (OS) of patients with unresectable UC was 3.95 months. In the multivariate Cox proportional hazards (CPH) model, age ≥65 years, Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, and C-reactive protein (CRP) >10 mg/L were independent prognostic factors for OS (age ≥65 years: hazard ratio [HR], 2.732; 95% confidence interval [CI], 1.353-5.515; ECOG PS ≥ 2: HR, 7.866; 95% CI, 1.981-31.241; CRP >10 mg/L: HR, 1.956; 95% CI, 1.013-3.775). Based on the ß coefficients from the CPH model, the prognostic scores were defined as follows: age ≥65 years (3 points), ECOG PS ≥ 2 (6 points), and CRP >10 ml/L (2 points). The final prognostic model was the sum of the points. The derived prognostic model stratified patients into high-risk (score ≥4) and low-risk (score 0-3) groups, with significant differences in OS (1.45 vs. 8.19 months, respectively; p < 0.001). CONCLUSIONS: The prognostic model stratified patients into high-risk and low-risk groups. These findings suggest that this model can serve as a tool for patient information and decision-making with regard to the therapeutic strategy for UC.

Clinical outcomes of chemotherapy in patients with undifferentiated carcinoma of the pancreas: a retrospective multicenter cohort study.

BACKGROUND: Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer. Although UC has been considered a highly aggressive malignancy, no clinical studies have addressed the efficacy of chemotherapy for unresectable UC. Therefore, we conducted multicenter retrospective study to investigate the efficacy of chemotherapy in patients with UC of the pancreas. METHODS: This multicenter retrospective cohort study was conducted at 17 institutions in Japan between January 2007 and December 2017. A total of 50 patients treated with chemotherapy were analyzed. RESULTS: The median overall survival (OS) in UC patients treated with chemotherapy was 4.08 months. The details of first-line chemotherapy were as follows: gemcitabine (n = 24), S-1 (n = 12), gemcitabine plus nab-paclitaxel (n = 6), and other treatment (n = 8). The median progression-free survival (PFS) was 1.61 months in the gemcitabine group, 2.96 months in the S-1 group, and 4.60 months in the gemcitabine plus nab-paclitaxel group. Gemcitabine plus nab-paclitaxel significantly improved PFS compared with gemcitabine (p = 0.014). The objective response rate (ORR) was 4.2% in the gemcitabine group, 0.0% in the S-1 group, and 33.3% in the gemcitabine plus nab-paclitaxel group. Gemcitabine plus nab-paclitaxel also showed a significantly higher ORR compared with both gemcitabine and S-1 (gemcitabine plus nab-paclitaxel vs. gemcitabine: p = 0.033; gemcitabine plus nab-paclitaxel vs. S-1: p = 0.034). A paclitaxel-containing first-line regimen significantly improved OS compared with a non-paclitaxel-containing regimen (6.94 months vs. 3.75 months, respectively; p = 0.041). After adjustment, use of a paclitaxel-containing regimen in any line was still an independent predictor of OS (hazard ratio for OS, 0.221; 95% confidence interval, 0.076-0.647; p = 0.006) in multiple imputation by chained equation. CONCLUSIONS: The results of the present study indicate that a paclitaxel-containing regimen would offer relatively longer survival, and it is considered a reasonable option for treating patients with unresectable UC.

Epidermoid cyst within an intrapancreatic accessory spleen exhibiting abrupt changes in serum carbohydrate antigen 19-9 level: a case report.

BACKGROUND: Epidermoid cyst within an intrapancreatic accessory spleen (ECIAS) is a rare disease. While the detection of solid components relevant to an accessory spleen is a key diagnostic finding, the differential diagnosis between ECIAS and malignant tumors is difficult without resection in patients with no other findings of an accessory spleen. CASE PRESENTATION: A 73-year-old male was found to have an elevated carbohydrate antigen (CA) 19-9 level (95 U/mL) at an annual checkup, and a cystic lesion in the pancreatic tail was located by abdominal ultrasound. Abdominal magnetic resonance imaging (MRI) revealed a multicystic mass, 24 mm in diameter, which exhibited varying intensities on T2-weighted images. There were no findings suggesting solid components on contrast-enhanced computed tomography and magnetic resonance imaging. Re-evaluation of serum CA 19-9 level revealed a rapid increase to 901 U/mL, which declined to 213 U/mL 3 weeks later. Ruling out the lesion's malignant potential was difficult, and the patient underwent distal pancreatectomy with splenectomy. Histological findings revealed an ECIAS including multiple cysts, with the mucinous component of each cyst exhibiting different stages of biological reaction; one ruptured cyst exhibited inflammatory changes. CONCLUSIONS: Careful observation for changes in serum CA 19-9 level and MRI findings might facilitate the diagnosis of ECIAS without a solid component by imaging studies.

Validation and clinical usefulness of pre- and postoperative systemic inflammatory parameters as prognostic markers in patients with potentially resectable pancreatic cancer.

BACKGROUND: Several preoperative systemic inflammatory parameters, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index (PNI), and Glasgow prognostic score, have been reported to be associated with the prognosis of solid tumors. In this study, we compared pre- and postoperative hematological inflammatory parameters and validated their prognostic significance in pancreatic cancer patients who underwent surgical resection. METHODS: Clinical records from 211 consecutive pancreatic cancer patients who underwent surgical resection at our institution were retrospectively analyzed. The optimal cutoff values of hematological inflammatory parameters, including lymphocyte count, NLR, PLR, LMR, and PNI, were determined by time-dependent receiver-operating characteristic analysis. RESULTS: The postoperative neutrophil count and serum albumin level were significantly decreased in patients who underwent pancreatoduodenectomy (PD group) and in those who underwent distal pancreatectomy (DP group) compared to the levels at baseline. The postoperative lymphocyte count, monocyte count, and platelet count were significantly increased in the DP group compared to those at baseline. As a result, the postoperative NLR and PNI significantly decreased in both groups. The multivariate analysis identified intraoperative peritoneal washing cytology, administration of adjuvant therapy, tumor size, extrapancreatic nerve plexus invasion, and preoperative PLR as independent prognostic factors for overall survival. CONCLUSIONS: Systemic inflammatory responses were altered after pancreatic resection in pancreatic cancer patients. Preoperative PLR may be a useful prognostic marker in pancreatic cancer patients undergoing surgical resection.

Outcomes in patients with pancreatic cancer as a secondary malignancy: a retrospective single-institution study.

PURPOSE: This study aimed to evaluate the clinicopathological features and oncological outcomes of pancreatic cancer (PC) patients with prior malignancies (2nd primary PC) compared with those of patients without any prior malignancies in their history (1st primary PC). METHODS: We retrospectively reviewed clinical data from 185 PC patients undergoing surgical resection. Patients were divided into the 1st and 2nd primary PC groups. RESULTS: Forty-three patients (23.2%) had a history of prior malignancy. The 2nd primary PC group was significantly older than the 1st primary PC group (mean, 72.1 vs. 65.9 years, respectively, P < 0.001) and was more frequently asymptomatic compared to the 1st primary PC group (67.4 vs. 31.0%, respectively, P < 0.001). The tumor size was larger, and extrapancreatic nerve plexus invasion, venous invasion, and lymph node metastasis were more frequently observed in the 1st primary PC group. The rate of adjuvant therapy administration was lower in 2nd primary PC patients (72.5 vs. 51.2%, P = 0.009). In the survival analysis, no significant difference in overall or disease-free survival was found between the two groups (16.8 vs. 16.4 months, P = 0.725, and 8.7 vs. 9.3 months, P = 0.284, respectively). CONCLUSION: Despite significant surveillance bias, such as earlier detection in 2nd primary PC, the outcomes of patients with 2nd primary PC were comparable to those of patients with 1st primary PC. Further investigation with a larger sample size and matching for patient age and tumor stage in both groups is needed to elucidate the biological features of 2nd primary PC.

Predictive Factors for Elevated Postoperative Carbohydrate Antigen 19-9 Levels in Patients With Resected Pancreatic Cancer.

AIM: In this study, we investigated the clinical significance of postoperative serum carbohydrate antigen (CA) 19-9 in patients with pancreatic ductal carcinoma (PDAC). PATIENTS AND METHODS: A series of 116 patients with macroscopically curative PDAC resection was retrospectively evaluated. The cut-off level for elevated postoperative CA 19-9 was 37 U/ml. RESULTS: Patients with high postoperative CA19-9 levels had a significantly poorer prognosis than patients with normal postoperative CA19-9 levels, as revealed by the log-rank test. Multivariate analysis identified R1 resection and preoperative serum CA19-9 level ≥400 U/ml independently predicted elevated postoperative CA 19-9 levels. R1 resection and preoperative serum CA19-9 ≥400 U/ml were significantly associated with the recurrence of peritoneal dissemination and hepatic metastasis, respectively, within one year of operation. CONCLUSION: Elevated postoperative serum CA 19-9 level was associated with a poor prognosis and reflected positive resection margins and high preoperative CA 19-9 levels, which indicated presence of occult distant metastasis in patients with PDAC.

Association of Preoperative Platelet-to-Lymphocyte Ratio with Poor Outcome in Patients with Distal Cholangiocarcinoma.

BACKGROUND: Several preoperative systemic inflammatory parameters, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and Glasgow Prognostic Score, have been reported to be associated with the prognosis of solid tumors. However, there are conflicting survival data regarding these parameters in cholangiocarcinoma. OBJECTIVES: In this study, we performed a retrospective cohort analysis of patients with distal cholangiocarcinoma (DCC) who underwent surgical resection to evaluate the prognostic value of a cluster of preoperative hematological inflammatory parameters for survival. METHOD: Fifty-three patients with DCC who underwent pancreaticoduodenectomy with curative intent were enrolled. The optimal cutoff values of hematological inflammatory parameters, including the absolute lym-phocyte count, NLR, PLR, and LMR, were determined by time-dependent receiver operating characteristic analysis. -Results: The univariate analysis for overall survival (OS) of conventional factors and hematological inflammatory parameters identified that portal vein invasion and PLR had p values of ≤0.1. The univariate analysis for disease-free survival (DFS) identified that lymph node metastasis, PLR, lymphocyte count, and number of positive lymph nodes (≥3) had p values of ≤0.1. These factors were incorporated into the full model and variables were selected using the backward stepwise method. The multivariate analysis identified portal vein invasion and high PLR as independent prognostic factors for OS (p = 0.033 and 0.039, respectively) and high PLR and number of positive lymph nodes (≥3) as independent prognostic factors for DFS (p = 0.016 and 0.004, respectively). CONCLUSIONS: Preoperative PLR assessment may be useful for detecting high-risk DCC patients undergoing surgical resection for aggressive adjuvant therapy.

Rapid progression of a granulocyte colony-stimulating factor-producing liver tumor metastasized from esophagogastric junction cancer: A case report and literature review.

The current study presents the case of a 72-year-old woman with a rapidly enlarged liver metastasis from esophagogastric junction (EGJ) cancer, accompanied by progressive leukocytosis (47,680/µl) and elevated serum granulocyte colony-stimulating factor (G-CSF; 779 pg/ml). The patient underwent right hemihepatectomy 26 months after a total gastrectomy. On the seventh post-operative day the patient's leukocyte count and serum G-CSF level decreased to 4,280/µl and ≤19.5 pg/ml, respectively. Histologically, the lesion was a well to moderately differentiated adenocarcinoma similar to the primary lesion. Therefore, this tumor was clinically diagnosed as a G-CSF-producing liver metastasis from EGJ cancer, although immunohistochemical staining for G-CSF was negative. A right pulmonary nodule detected simultaneously with the hepatic mass was resected four months following the hepatectomy and was diagnosed as a pulmonary metastasis. The patient's leukocyte count was normal at the time of her initial surgery for EGJ cancer, and her clinical course varied for different metastatic sites. The liver metastasis was accompanied by progressive leukocytosis and elevated serum G-CSF and demonstrated rapid tumor growth during a six-month period, whereas the non-G-CSF-producing pulmonary metastasis grew slowly during the same period. In addition 21 reported cases of G-CSF-producing upper gastrointestinal tract cancer were reviewed to elucidate the clinicopathological features of this disease.

Clinical implications of the proliferative ability of the squamous component regarding tumor progression of adenosquamous carcinoma of the pancreas: A preliminary report.

OBJECTIVES: The objectives of this study were to examine the clinicopathological characteristics of patients with adenosquamous carcinoma of the pancreas (ASCP) and assess whether the proliferative ability of the squamous cell carcinoma (SCC) component contributes to either its proportion within the tumor or tumor progression. METHODS: We retrospectively reviewed 12 patients with resected ASCP and compared their clinicopathological characteristics with those of 161 patients with adenocarcinoma of the pancreas (ACP). The Ki-67 indexes of the separate ASCP components were assessed. RESULTS: All the clinicopathological characteristics and outcomes were similar between the ASCP patients and ACP patients. Among the 12 ASCP cases, nine exhibited higher Ki-67 levels in the SCC component than in the corresponding adenocarcinoma (AC) component at primary sites (P = 0.022). The component with a higher Ki-67 level coincided with the predominant component at the primary site in nine of 11 patients. In all 10 patients who presented lymph node metastasis, the metastases almost entirely consisted of either the SCC or AC component. The SCC component was absent from metastatic lymph nodes in five of 10 patients even though the Ki-67 levels at the primary site in four of these patients were higher in the SCC component than in the AC component. CONCLUSIONS: The enhanced proliferative ability of the SCC component of ASCP is reflected by its proportion within the tumor. However, other biological factors might contribute to metastasis in ASCP.

Perioperative plasma glypican-3 level may enable prediction of the risk of recurrence after surgery in patients with stage I hepatocellular carcinoma.

Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored cell surface protein overexpressed in hepatocellular carcinoma(HCC), and its overexpression is associated with poor prognosis. The diagnostic potential of GPC3 as a serum marker has been reported. In the present study, we evaluated the usefulness of plasma GPC3 as a predictor for recurrence after surgical resection in stage I HCC patients by newly developed an enzyme-linked immunosorbent assay (ELISA) system. Current study demonstrated that high levels of preoperative plasma GPC3 patients tended to experience postoperative recurrence. On the other hand, pre- and postoperative plasma GPC3 positivity of non-recurrence patients was very low. Moreover, even after surgery, approximately half of patients who experienced recurrence were positive for plasma GPC3. Postoperative plasma GPC3 positivity was significantly correlated with worse recurrence-free survival. Immuohistochemical analysis also showed positive rate of GPC3-expression in HCC was higher in recurrence patients than in non-recurrence patients. These results suggested that both pre- and postoperative plasma GPC3 levels may be accurate predictors for recurrence after curative resection of early-stage HCC. It should be noted that the current study only examined a small number of cases; thus, a larger sample size is necessary to validate GPC3 as a predictor for HCC recurrence.

Prognostic significance of intraoperative peritoneal washing cytology for patients with potentially resectable pancreatic ductal adenocarcinoma.

BACKGROUND: The prognostic significance of intraoperative peritoneal washing cytology (IPWC) in pancreatic ductal adenocarcinoma (PDAC) remains controversial, and the treatment strategy for PDAC patients with positive cytology has not been established. OBJECTIVES: The objective of this study was to evaluate the clinical significance of IPWC in PDAC patients. METHODS: This study included a retrospective cohort of 166 patients with curatively resected PDAC who underwent IPWC. RESULTS: Overall, 17 patients (10%) had positive cytology (CY+), and 149 (90%) patients were negative (CY-). Tumor location in the pancreatic body and/or tail and pancreatic anterior capsular invasion were independent predictors of a CY+ status (P = 0.012 and 0.041, respectively). The initial recurrence occurred at the peritoneum with a significantly higher frequency in CY+ patients (50%) than in CY- patients (12%) (P = 0.003). The median overall survival (OS) for CY+ patients was 12 months. The OS rates at 1 and 3 years were significantly higher for CY- patients (75.1% and 35.3%, respectively) versus CY+ patients (47.1% and 17.6%, respectively; P = 0.012). However, one CY+ patient survived for 66 months, and another two CY+ patients have survived for more than three years after surgery without evidence of peritoneal recurrence. In the multivariate analysis, the independent predictors of OS were a CY+ status, lymph node metastasis, and adjuvant chemotherapy. CONCLUSIONS: This study demonstrates that positive IPWC predicts early peritoneal recurrence and a poor prognosis for PDAC patients. However, a small but not insignificant subset of CY+ patients with PDAC may avoid peritoneal carcinomatosis.

Adenosquamous carcinoma in the biliary tract: association of the proliferative ability of the squamous component with its proportion and tumor progression.

OBJECTIVES: The purpose of this study was to evaluate the association of the proliferative ability of squamous cell carcinoma (SCC) component with its proportion and tumor progression in adenosquamous carcinoma (ASC) in the biliary tract. METHODS: Nine patients with ASC in the biliary tract (four each in the gallbladder and the extrahepatic bile duct and one in the ampulla of Vater) who underwent surgical resection were retrospectively reviewed. RESULTS: The proportion of the SCC component in the primary sites ranged from 30% to 95%. The Ki-67 index of the SCC component was higher than that of the adenocarcinoma component in all cases, regardless of the component ratio in the patients' primary lesions. Predominance of the SCC component in the advancing region of the tumor, in angiolymphatic invasion and in perineural invasion was observed in most of the cases. The component ratio in metastatic lymph nodes differed from that in the corresponding primary lesions in all six cases with lymph node metastasis. Among these cases, the proportion of the SCC component was increased in the metastatic lymph nodes compared with that in the corresponding primary lesion in two cases, whereas the proportion was decreased in four cases. CONCLUSIONS: The SCC component of ASC in the biliary tract displayed a relatively higher proliferative ability, which might be associated with local invasiveness. However, not only the high proliferative ability of the SCC component but also other biological factors might contribute to tumor progression and metastasis in ASC of the biliary tract.

Analysis of cytotoxic T lymphocytes from a patient with hepatocellular carcinoma who showed a clinical response to vaccination with a glypican­3­derived peptide.

Glypican-3 (GPC3), which is a carcinoembryonic antigen, is overexpressed in human hepatocellular carcinoma (HCC). Previously, we performed a phase I clinical trial of GPC3­derived peptide vaccination in patients with advanced HCC, and reported that GPC3 peptide vaccination is safe and has clinical efficacy. Moreover, we proposed that a peptide­specific CTL response is a predictive marker of overall survival in patients with HCC who receive peptide vaccination. In this study, we established GPC3­derived peptide-specific CTL clones from the PBMCs of an HLA-A*02:07-positive patient with HCC who was vaccinated with an HLA-A2-restricted GPC3 peptide vaccine and showed a clinical response in the phase I clinical trial. Established CTL clones were analyzed using the IFN-γ ELISPOT assay and a cytotoxicity assay. GPC3 peptide-specific CTL clones were established successfully from the PBMCs of the patient. One CTL clone showed cytotoxicity against cancer cell lines that expressed endogenously the GPC3 peptide. The results suggest that CTLs have high avidity, and that natural antigen-specific killing activity against tumor cells can be induced in a patient with HCC who shows a clinical response to vaccination with the GPC3144-152 peptide.