Safety and Feasibility of Neoadjuvant-Modified FOLFIRINOX in Elderly Patients with Pancreatic Cancer.

The optimal treatment strategy for neoadjuvant chemotherapy in elderly patients with pancreatic cancer (PC) remains unclear. Hence, this study was aimed at evaluating the safety and feasibility of neoadjuvant-modified FOLFIRINOX (mFOLFIRINOX) in elderly patients with PC. We retrospectively collected data from 62 patients who received neoadjuvant mFOLFIRINOX between May 2015 and October 2023 and comparatively analyzed the clinicopathological data and outcomes between the non-elderly group (age: <75 years) and elderly group (age: >75 years). The non-elderly and elderly groups comprised 39 and 23 patients, respectively. Although elevated levels of aspartate aminotransferase (p = 0.0173) and alanine aminotransferase (p = 0.0378) and nausea (p = 0.0177) were more frequent in the elderly group, the incidence of severe adverse events was similar between the groups. Intergroup differences in resection rate (p = 0.3381), postoperative severe complication rates (p = 0.2450), and postoperative hospital stay (p = 0.3496) were not significant. Furthermore, no significant intergroup differences were found in survival in either the whole or the resection cohorts. The perioperative and postoperative outcomes of elderly patients treated with neoadjuvant mFOLFIRINOX were comparable with those of non-elderly patients. Neoadjuvant mFOLFIRINOX should be considered a feasible option for elderly patients with PC.

Preventing Pneumonia in High-risk Patients After Esophageal Cancer Surgery: Mini-tracheostomy and Tazobactam/Piperacillin.

BACKGROUND/AIM: We evaluated the usefulness of prophylactic mini-tracheostomy (PMT) and perioperative administration of tazobactam/piperacillin (TAZ/PIPC) in high-risk patients after esophagectomy. PATIENTS AND METHODS: We retrospectively studied 89 consecutive high-risk patients who underwent esophagectomy for esophageal cancer between January 2013 and December 2021. We defined patients with two or more of the following factors as high risk: age ≥70 years, performance status ≥1, respiratory dysfunction, liver dysfunction, cardiac dysfunction, renal dysfunction, diabetes mellitus, albumin <3.5 g/dl, and Brinkman index >600. Standard management was administered to the first 50 patients (standard group). PMT and TAZ/PIPC were administered to the next 39 patients (combination group). Patient characteristics and short-term outcomes were compared before and after propensity-score matching. RESULTS: Before propensity-score matching, 24-hour urine creatinine clearance, retrosternal route, 3-field lymph node dissection, and open abdominal approach were more common, postoperative pneumonia (13% vs. 36%, p=0.045) and complications of grade ≥3b (2.6% vs. 22%, p=0.01) were less frequent, and the postoperative hospital stay was shorter (median: 23 vs. 28 days, p=0.022) in the combination group than in the standard group. In propensity-score matching, patient characteristics, except for 24-h creatinine clearance and reconstructive route, were matched for 23 paired patients. Postoperative pneumonia (8.7% vs. 39%, p=0.035) and complications of grade ≥3b (0% vs. 26%, p=0.022) were less frequent and postoperative hospital stay was shorter (median: 22 vs. 25 days, p=0.021) in the combination group than in the standard group. CONCLUSION: PMT with TAZ/PIPC can potentially prevent postoperative pneumonia in high-risk patients after esophagectomy.

Exosomal miR-141-3p Induces Gemcitabine Resistance in Biliary Tract Cancer Cells.

BACKGROUND/AIM: Gemcitabine (GEM)-based chemotherapy has been established as the core multimodal therapy for biliary tract cancer (BTC). However, the prognosis of BTC is unfavorable because of its resistance to GEM. Exosomes play important roles in the regulation of tumor progression and metastasis, immune dysregulation, and chemoresistance. This study investigated the effects of exosomes on GEM resistance in BTC. MATERIALS AND METHODS: The human intrahepatic cholangiocarcinoma cell line CC-LP-1, its GEM-resistant (GR) derivative cell line CC-LP-1-GR, and the human intrahepatic cholangiocarcinoma cell lines HuCCA-1 and HuCCT1, were used. GEM resistance was examined by measuring cell viability in the presence of GEM using an MTS assay. Exosomes were isolated using ultracentrifugation and quantified using ELISA. Comprehensive expression analysis was performed using RNA sequencing. The effects of microRNAs were examined by miRNA mimic transfection. RESULTS: The conditioned medium and exosomes derived from CC-LP-1-GR cells enhanced the GEM resistance of parental CC-LP-1 cells. In the presence of GEM, the p53 pathway was negatively enriched in CC-LP-1-GR and CC-LP-1 cells treated with exosomes from CC-LP-1-GR (rExo) compared to CC-LP-1 cells. The expression of miR-141-3p was higher in rExos than in CC-LP-1 cells. CC-LP-1 cells transfected with miR-141-3p mimic showed significantly (p<0.05) increased viability in the presence of GEM. CONCLUSION: A GEM-resistant human BTC cell line, CC-LP-1-GR, may acquire resistance to GEM by exosomes containing miR-141-3p.

Multicenter Prospective Cohort Study of Neoadjuvant Chemotherapy for Borderline Resectable Pancreatic Cancer (YPB-001).

OBJECTIVES: The present multicenter prospective observational study investigated the effectiveness and safety of neoadjuvant chemotherapy (NAC) for patients with borderline resectable pancreatic cancer (BRPC) and those with RPC contacting major vessels, with respect to a historical control of upfront surgery. MATERIALS AND METHODS: Patients with BRPC and RPC contacting major vessels were prospectively registered and administered NAC with durations and regimens determined by the corresponding treating physician. Our primary aim was to assess the R0 resection rate, and secondary aim was to evaluate safety, resection rate, time to treatment failure, overall survival, and response rate. RESULTS: Fifty of 52 enrolled patients were analyzed; 2 with serious comorbidities died during treatment. Thirty-one patients underwent resection, with R0 resection being achieved in 26 (52% of total and 84% of all resected cases). Univariate and multivariate analyses indicated age (≥75 years) as the only independent predictor of nonresection. Median progression-free survival and median survival time were longer in the prospective cohort than in the historical cohort. CONCLUSIONS: Overall, NAC for BRPC in real-world setting might yield R0 resection rates similar to those reported in previous clinical studies. Development of safe regimens and management strategies that can maintain treatment intensity in geriatric patients is warranted.

Effect of Paxillin Expression and Phosphorylation on Colorectal Cancer Prognosis and Metastasis.

BACKGROUND/AIM: Colorectal cancer (CRC) is the third most common cancer worldwide, and metastasis is strongly associated with poor prognosis in patients with CRC. We have previously found that the expression and phosphorylation of paxillin (PXN) play an important role in the metastatic potential of breast cancer. This study examined the potential role of PXN in CRC metastasis. MATERIALS AND METHODS: Resected tumor specimens from 92 patients with CRC were subjected to immunohistochemical analysis of PXN levels. Three human CRC cell lines, HCT116, LoVo, and SW480 were used for scratch and transwell invasion assays to examine the effects of PXN over-expression. RNA sequencing was performed to obtain the expression profiles under PXN over-expression. RESULTS: High levels of PXN were significantly correlated with advanced stage, higher carcinoembryonic antigen and carbohydrate antigen 19-9 levels, and poorer overall survival. The migration ability of CRC cells was enhanced by exogenous PXN over-expression, but this enhancement was not observed in cells harboring exogenously mutated PXN at Tyr31 or Tyr88 phosphorylation sites. In PXN-over-expressing cells, TNF-α signaling via NF-[Formula: see text]B was positively enriched. CONCLUSION: PXN expression and phosphorylation at Tyr31 or Tyr88 may influence the migration and invasion of CRC cells. PXN expression and phosphorylation at Tyr31 or Tyr88 are promising targets for evaluating prognosis and treating CRC.

High serum proteinase-3 levels predict poor progression-free survival and lower efficacy of bevacizumab in metastatic colorectal cancer.

BACKGROUND: To improve the prognosis of patients with metastatic colorectal cancer (mCRC), investigating predictive biomarkers of their prognosis and chemotherapeutic responsiveness is necessary. This study aimed to analyze the clinical significance of serum proteinase-3 (PRTN3) as a predictor for prognosis and chemosensitivity, especially to bevacizumab therapy, in mCRC. METHODS: This single-center retrospective observational study enrolled 79 patients with mCRC in our hospital and 353 patients with colorectal cancer in the TCGA database. Preoperative serum PRTN3 levels were measured using an enzyme-linked immunosorbent assay. The clinicopathological characteristics and prognosis according to serum PRTN3 levels were then evaluated. PRTN3 expression in tumor and stromal cells was evaluated immunohistochemically. The impact of PRTN3 levels on angiogenesis and bevacizumab sensitivity was evaluated using the tube formation assay. RESULTS: Serum PRTN3 levels were an independent poor prognostic factor for progression-free survival (PFS) (hazard ratio, 2.082; 95% confidence interval, 1.118-3.647; P=0.010) in patients with mCRC. Similarly, prognostic analysis with TCGA data sets showed poorer overall survival in patients with PRTN3 expression than that in patients without PRTN3 expression, especially in patients with stage IV. Immunohistochemical analysis of resected specimens revealed that stromal neutrophils expressed PRTN3, and their expression level was significantly correlated with serum PRTN3 levels. Interestingly, the effectiveness of first-line chemotherapy was significantly poorer in the high serum PRTN3 level group. High serum PRTN3 was significantly associated with poor PFS (hazard ratio, 3.027; 95% confidence interval, 1.175-7.793; P=0.0161) in patients treated with bevacizumab, an anti-angiogenic inhibitor. The tube formation assay revealed that PRTN3 administration notably augmented angiogenesis while simultaneously attenuating the anti-angiogenic influence exerted by bevacizumab therapy. CONCLUSIONS: Serum PRTN3 levels could be a novel predictive biomarker of PFS of first-line chemotherapy, especially for bevacizumab therapy, in patients with mCRC.

Third Report of the Japan Diabetes Society (JDS)/Japanese Cancer Association (JCA) Joint Committee on diabetes and cancer: summary of the results of a questionnaire survey of oncologists and diabetologists-secondary publication.

The Japan Diabetes Society (JDS) and the Japan Cancer Association (JCA) launched a joint committee and published their "First Joint Committee Report on Diabetes and Cancer" in 2013, compiling recommendations for physicians and healthcare providers as well as for the general population. In 2016, the "Second Joint Committee Report on Diabetes and Cancer" summarized the current evidence on glycemic control and cancer risk in patients with diabetes. The current "Third Joint Committee Report on Diabetes and Cancer", for which the joint committee also enlisted the assistance of the Japanese Society of Clinical Oncology (JSCO) and the Japanese Society of Medical Oncology (JSMO), reports on the results from the questionnaire survey, "Diabetes Management in Patients Receiving Cancer Therapy," which targeted oncologists responsible for cancer management and diabetologists in charge of glycemic control in cancer patients. The results of the current survey demonstrated that there is a general consensus among oncologists and diabetologists with regard to the need for guidelines on glycemic control goals, the relevance of glycemic control, and glycemic control during cancer therapy in cancer patients.

Third Report of the Japan Diabetes Society/Japanese Cancer Association Joint Committee on Diabetes and Cancer: Summary of the results of a questionnaire survey of oncologists and diabetologists-Secondary publication.

The Japan Diabetes Society and the Japan Cancer Association launched a joint committee and published their "First Joint Committee Report on Diabetes and Cancer" in 2013, compiling recommendations for physicians and health-care providers as well as for the general population. In 2016, the "Second Joint Committee Report on Diabetes and Cancer" summarized the current evidence on glycemic control and cancer risk in patients with diabetes. The current "Third Joint Committee Report on Diabetes and Cancer", for which the joint committee also enlisted the assistance of the Japanese Society of Clinical Oncology and the Japanese Society of Medical Oncology, reports on the results from the questionnaire survey, "Diabetes Management in Patients Receiving Cancer Therapy," which targeted oncologists responsible for cancer management and diabetologists in charge of glycemic control in cancer patients. The results of the current survey indicated that there is a general consensus among oncologists and diabetologists with regard to the need for guidelines on glycemic control goals, the relevance of glycemic control, and glycemic control during cancer therapy in cancer patients.

Laparoscopic spleen-preserving distal pancreatectomy: A novel technique with splenic artery resection and splenic vein preservation.

INTRODUCTION: Laparoscopic spleen-preserving distal pancreatectomy (LSDP) is widely performed to treat benign and low-grade malignant diseases. Although preservation of splenic vessels may be desirable considering the risk of postoperative complications, it is sometimes difficult due to tumor size, inflammation, and proximity of the tumor and splenic vessels. Herein, we present the first case of LSDP with splenic artery resection and splenic vein preservation. MATERIALS AND SURGICAL TECHNIQUE: A 40-year-old woman with a pancreatic tumor was referred to our hospital. Contrast-enhanced computed tomography (CT) revealed a tumor in the pancreatic tail that was in contact with the splenic artery and distant from the splenic vein. The splenic artery and vein were separated from the pancreas near the dissection line. The splenic artery was resected after pancreatic dissection using a linear stapler. After the pancreatic tail was separated from the splenic hilum while preserving the splenic vein, the distal side of the splenic artery was resected, and the specimen was removed. The postoperative course was uneventful and the patient was discharged on postoperative Day 9. Four months after surgery, postoperative follow-up CT findings showed neither splenic infarction nor gastric varices. DISCUSSION: This technique is an alternative method of splenic preservation when there is no attachment of the tumor to the splenic vein or uncontrolled expected bleeding of the splenic artery using the Kimura technique.

Impact of tumor shrinkage pattern with biweekly triplet gemcitabine+cisplatin+S-1 regimen for biliary tract cancers: Implications for neoadjuvant therapy from the data of KHBO1401 (KHBO1401-1A study).

BACKGROUND: The multicenter randomized phase III KHBO1401 study (gemcitabine+cisplatin+S-1 [GCS] versus GC in biliary tract cancers [BTC]) demonstrated that GCS not only prolonged patient survival but also achieved a high response rate and that it should be good for neoadjuvant therapy. Therefore, to explore the possibilities of neoadjuvant therapy, we investigated the tumor shrinkage pattern. METHODS: Among the total of 246 patients enrolled in the KHBO1401, the tumor shrinkage pattern and survival were investigated in patients with measurable BTC (n=183, 74%; GCS, n=91; GC, n=92). RESULTS: The tumor shrinkage pattern could be divided to 4 categories based on the response at 100 days after enrollment: category A (<-30% in size), B (-30% to 0%), C (0% to +20%), and D (>+20%). The GCS arm included more category A and B cases (61 [67%] vs. 33 [36%], P<0.0001). Each category predicted best response and overall survival (P<0.0001). Category A showed sustained tumor response compared with category B; in GCS, the time to maximum tumor response was 165 ± 76 days in category A and 139 ± 78 in category B. Categories C and D did not achieve tumor shrinkage. The maximum tumor shrinkage size in category A was -53% in the GCS arm and -65% in the GC arm (P=0.0892). Twenty percent of patients in the GCS showed tumor regrowth 154 ± 143 days later. CONCLUSION: GCS provided faster and greater tumor shrinkage with better survival in comparison to GC, although 20% of patients showed re-growth after 6 cycles.

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

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

Efficacy of Staging Laparoscopy in Patients With Pancreatic Cancer: A Single Center Prospective Cohort Study.

BACKGROUND/AIM: Staging laparoscopy (SL) for pancreatic cancer (PC) is considered useful to improve accuracy of staging and resectability. However, given the current accuracy of preoperative imaging, the routine application of SL remains unclear. Therefore, we aimed to investigate the importance of SL in patients with PC without radiological distant metastasis. PATIENTS AND METHODS: This was a prospective, cohort, observational study. SL was performed in all patients with PC without radiological distant metastasis before pancreatectomy or chemotherapy at the Yamaguchi University Hospital. RESULTS: Between July 2020 and March 2023, 55 patients underwent SL with peritoneal cytology. The median age was 71, with 53% male patients. SL revealed occult metastasis in six (11%) patients including positive peritoneal cytology (n=6), and peritoneal dissemination (n=1). The resectability of unresectable locally advanced (UR-LA) was associated with a significantly increased risk of occult metastasis (p=0.0211). The median operative time was 40 min, and the median volume of blood loss was 3 ml. There were no severe complications (Clavien-Dindo III or higher). CONCLUSION: SL with peritoneal cytology regardless of previous abdominal surgery is safe and effective to determine accurate staging. Therefore, SL with peritoneal cytology should be considered for patients with PC without radiological distant metastasis, especially in those with UR-LA.

A novel prediction model of pancreatic fistula after pancreaticoduodenectomy using only preoperative markers.

BACKGROUND: Since clinically relevant postoperative pancreatic fistula (CR-POPF) can cause intra-abdominal hemorrhage and abscesses, leading to surgery-related deaths after pancreaticoduodenectomy (PD), its preoperative prediction is important to develop strategies for surgical procedures and perioperative management. This study aimed to establish a novel prediction model for CR-POPF using preoperative markers. METHODS: On a training set of 180 patients who underwent PD at the Yamaguchi University Hospital, a combination of CR-POPF predictors were explored using the leave-one-out method with a unique discrete Bayes classifier. This predictive model was confirmed using a validation set of 366 patients who underwent PD at the Osaka University Hospital. RESULTS: In the training set, CR-POPF occurred in 60 (33%)　of 180 patients and 130 (36%)　of 366 patients in the validation set using selected markers. In patients with pancreatic ductal adenocarcinoma (PDAC), the main pancreatic duct (MPD) index showed the highest prognostic performance and could differentiate CR-POPF with 87% sensitivity and 81% specificity among 84 patients in the training set. In the validation set, the sensitivity and specificity of the MPD index-based model for 130 PDAC samples were 93% and 87%, respectively. In patients with non-PDAC, the MPD index/body mass index (BMI) combination showed the highest prognostic performance and could differentiate CR-POPF with 84% sensitivity and 57% specificity among 96 patients in the training set. In the validation set, the sensitivity and specificity of the MPD index/BMI-based model for 236 non-PDAC samples were 85% and 53%, respectively. CONCLUSION: We developed a novel prediction model for pancreatic fistulas after PD using only preoperative markers. The MPD index and MPD index/BMI combination will be useful for CR-POPF assessment in PDAC and non-PDAC samples, respectively.

Incidence and risk factors for venous thromboembolism in the Cancer-VTE Registry pancreatic cancer subcohort.

BACKGROUND: This substudy of the Cancer-VTE Registry estimated venous thromboembolism (VTE) incidence and risk factors in pancreatic cancer patients. METHODS: The Cancer-VTE Registry was an observational study that collected VTE data from patients with solid tumors across Japan. We measured baseline VTE prevalence, and at 1-year follow-up, the cumulative incidence of symptomatic and composite VTE (symptomatic VTE and incidental VTE requiring treatment), bleeding, cerebral infarction/transient ischemic attack (TIA)/systemic embolic event (SEE), and all-cause death. RESULTS: Of 1006 pancreatic cancer patients, 86 (8.5%) had VTE at baseline, and seven (0.7%) had symptomatic VTE. Significant risk factors of baseline VTE were Eastern Cooperative Oncology Group performance status (ECOG PS) of 1, body mass index (BMI) ≥ 25 kg/m2, history of VTE, D-dimer > 1.2 µg/mL, and hemoglobin < 10 g/dL. At 1-year follow-up, the cumulative incidence of events was higher for pancreatic cancer vs other cancers. Pancreatic cancer patients with VTE vs those without VTE had significantly higher incidences of bleeding, cerebral infarction/TIA/SEE, and all-cause death. No significant risk factors for composite VTE were identified. CONCLUSIONS: The cumulative incidence of composite VTE during cancer treatment was higher in pancreatic cancer than in other cancer types. Some risk factors for VTE prevalence at cancer diagnosis were identified. Although VTE prevalence at cancer diagnosis did not predict the subsequent 1-year incidence of composite VTE, it was a significant predictor of other events such as all-cause death in pancreatic cancer patients. TRIAL REGISTRATION: UMIN Clinical Trials Registry; UMIN000024942.

Current progress in perioperative chemotherapy for biliary tract cancer.

Biliary tract cancer (BTCs) is a heterogeneous malignancy divided into cholangiocarcinoma, gallbladder cancer, and ampullary cancer. Due to little or no symptoms, most patients with BTCs are diagnosed with unresectable or metastatic disease. Only 20%-30% of all BTCs are suitable for potentially resectable diseases. Although radical resection with a negative surgical margin is the only potentially curative method for BTCs, most patients develop postoperative recurrence, which is associated with poor prognosis. Therefore, perioperative treatment is necessary to improve survival. There are very few randomized phase III clinical trials of perioperative chemotherapy due to the relative rarity of BTCs. Adjuvant chemotherapy with S-1 for patients with resected BTC significantly increased overall survival compared with upfront surgery in a recent ASCOT trial. In East Asia, S-1 is currently considered the standard adjuvant chemotherapy, while capecitabine may still be used in other areas. Since then, our phase III trial (KHBO1401), gemcitabine and cisplatin plus S-1 (GCS) has become the standard chemotherapy for advanced BTCs. GCS not only improved overall survival but demonstrated a high response rate. The efficacy of GCS as a preoperative neoadjuvant chemotherapy for resectable BTCs has been investigated in a randomized phase III trial (JCOG1920) in Japan. In this review, we summarize the current and ongoing clinical trials focusing on adjuvant and neoadjuvant chemotherapy for BTCs.

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.

IL-6 Levels Correlate with Prognosis and Immunosuppressive Stromal Cells in Patients with Colorectal Cancer.

BACKGROUND: The prognosis for patients with colorectal cancer (CRC) is determined by tumor characteristics as well as the host immune response. This study investigated the relationship between an immunosuppressive state and patient prognosis by evaluating the systemic and tumor microenvironment (TME) interleukin (IL)-6 levels. METHODS: Preoperative serum IL-6 levels were measured using an electrochemiluminescence assay. Expression of IL-6 in tumor and stromal cells was evaluated immunohistochemically in 209 patients with resected CRC. Single-cell analysis of tumor-infiltrating immune cells was performed using mass cytometry in 10 additional cases. RESULTS: Elevated serum IL-6 levels were associated with elevated stromal IL-6 levels and a poor prognosis for patients with CRC. High IL-6 expression in stromal cells was associated with low-density subsets of CD3+ and CD4+ T cells as well as FOXP3+ cells. Mass cytometry analysis showed that IL-6+ cells among tumor-infiltrating immune cells were composed primarily of myeloid cells and rarely of lymphoid cells. In the high-IL-6-expression group, the percentages of myeloid-derived suppressor cells (MDSCs) and CD4+FOXP3highCD45RA- effector regulatory T cells (eTreg) were significantly higher than in the low-IL-6-expression group. Furthermore, the proportion of IL-10+ cells in MDSCs and that of IL-10+ or CTLA-4+ cells in eTregs correlated with IL-6 levels. CONCLUSION: Elevated serum IL-6 levels were associated with stromal IL-6 levels in CRC. High IL-6 expression in tumor-infiltrating immune cells also was associated with accumulation of immunosuppressive cells in the TME.

Phase I study of a novel therapeutic vaccine as perioperative treatment for patients with surgically resectable hepatocellular carcinoma: The YCP02 trial.

AIM: Developing effective adjuvant therapies is essential for improving the surgical outcomes in patients with hepatocellular carcinoma (HCC). Immunotherapy against HCC has become a promising strategy; however, only approximately 30% of all HCC patients respond to immunotherapy. Previously, we generated the novel therapeutic vaccine comprising multi-human leukocyte antigen-binding heat shock protein 70/glypican-3 peptides with a novel adjuvant combination of hLAG-3Ig and poly-ICLC. We also confirmed the safety of this vaccination therapy, as well as its capacity for the effective induction of immune responses in a previous clinical trial. METHODS: In this phase I study, we administered this vaccine intradermally six times before surgery, and 10 times after surgery to patients with untreated, surgically resectable HCC (stage II to IVa). The primary end-points of this study were the safety and feasibility of this treatment. We also analyzed the resected tumor specimens pathologically using hematoxylin-eosin staining and immunohistochemistry for heat shock protein 70, glypican 3, CD8 and programmed death-1. RESULTS: A total of 20 human leukocyte antigen-matched patients received this vaccination therapy with an acceptable side-effect profile. All patients underwent planned surgery without vaccination-related delay. Immunohistochemical analyses revealed that potent infiltration of CD8+ T cells into tumors with target antigen expression was observed in 12 of 20 (60%) patients. CONCLUSIONS: This novel therapeutic vaccine was safe as perioperative immunotherapy for patients with HCC, and has the potential to strongly induce CD8+ T cells infiltration into tumors.