Dorsal approach for advanced gastric cancer invading the transverse mesocolon.

Minimally invasive gastrectomy is increasingly performed for advanced gastric cancer, but the indication for this procedure for a tumor invading adjacent structures is still limited. In cases with tumors invading the transverse mesocolon, a large tumor together with the involved mesocolon blocks the surgical view, which prevents evaluation of the extent of invasion and makes it difficult to ensure oncologically adequate resection. To solve these technical issues, we established a novel method that uses a dorsal approach. By approaching the transverse mesocolon from the dorsal side, tumor penetration and involvement of the colic vessels or pancreas can be evaluated, and margin-free resection of the tumor becomes easier. In a series of 13 patients with mesocolon invasion, a dorsal approach enabled minimally invasive margin-free resection in 11 cases by resection of the anterior layer of the mesocolon (n = 6); enucleation of the mesocolon (n = 4); or enucleation plus distal pancreato-splenectomy (n = 1). Two patients with broad invasion that obstructed the view underwent combined colectomy by open conversion. A major postoperative complication of pancreatic fistula following distal pancreatectomy occurred in one case. These results suggest that a dorsal approach may be useful for minimally invasive combined resection of gastric cancer invading the transverse mesocolon.

Prosaposin, tumor-secreted protein, promotes pancreatic cancer progression by decreasing tumor-infiltrating lymphocytes.

Glycoproteins produced by tumor cells are involved in cancer progression, metastasis, and the immune response, and serve as possible therapeutic targets. Considering the dismal outcomes of pancreatic ductal adenocarcinoma (PDAC) due to its unique tumor microenvironment, which is characterized by low antitumor T-cell infiltration, we hypothesized that tumor-derived glycoproteins may serve as regulating the tumor microenvironment. We used glycoproteomics with tandem mass tag labeling to investigate the culture media of three human PDAC cell lines, and attempted to identify the key secreted proteins from PDAC cells. Among the identified glycoproteins, prosaposin (PSAP) was investigated for its functional contribution to PDAC progression. PSAP is highly expressed in various PDAC cell lines; however, knockdown of intrinsic PSAP expression did not affect the proliferation and migration capacities. Based on the immunohistochemistry of resected human PDAC tissues, high PSAP expression was associated with poor prognosis in patients with PDAC. Notably, tumors with high PSAP expression showed significantly lower CD8+ T-cell infiltration than those with low PSAP expression. Furthermore, PSAP stimulation decreased the proportion of CD8+ T cells in peripheral blood monocytes. Finally, in an orthotopic transplantation model, the number of CD8+ T cells in the PSAP shRNA groups was significantly increased, resulting in a decreased tumor volume compared with that in the control shRNA group. PSAP suppresses CD8+ T-cell infiltration, leading to the promotion of PDAC progression. However, further studies are warranted to determine whether this study contributes to the development of a novel immunomodulating therapy for PDAC.

Complement factor B regulates cellular senescence and is associated with poor prognosis in pancreatic cancer.

BACKGROUND: The interplay between cancer cells and stromal components, including soluble mediators released from cancer cells, contributes to the progression of pancreatic ductal adenocarcinoma (PDAC). Here, we set out to identify key secreted proteins involved in PDAC progression. METHODS: We performed secretome analyses of culture media of mouse pancreatic intraepithelial neoplasia (PanIN) and PDAC cells using Stable Isotope Labeling by Amino acid in Cell culture (SILAC) with click chemistry and liquid chromatography-mass spectrometry (LC-MS/MS). The results obtained were verified in primary PDAC tissue samples and cell line models. RESULTS: Complement factor B (CFB) was identified as one of the robustly upregulated proteins, and found to exhibit elevated expression in PDAC cells compared to PanIN cells. Endogenous CFB knockdown by a specific siRNA dramatically decreased the proliferation of PDAC cells, PANC-1 and MIA PaCa-II. CFB knockdown induced increases in the number of senescence-associated-ß-galactosidase (SA-ß-gal) positive cells exhibiting p21 expression upregulation, which promotes cellular senescence with cyclinD1 accumulation. Furthermore, CFB knockdown facilitated downregulation of proliferating cell nuclear antigen and led to cell cycle arrest in the G1 phase in PDAC cells. Using immunohistochemistry, we found that high stromal CFB expression was associated with unfavorable clinical outcomes with hematogenous dissemination after surgery in human PDAC patients. Despite the presence of enriched CD8+ tumor infiltrating lymphocytes in the PDAC tumor microenvironments, patients with a high stromal CFB expression exhibited a significantly poorer prognosis compared to those with a low stromal CFB expression. Immunofluorescence staining revealed a correlation between stromal CFB expression in the tumor microenvironment and an enrichment of immunosuppressive regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). We also found that high stromal CFB expression showed a positive correlation with high CD8+/Foxp3+ Tregs populations in PDAC tissues. CONCLUSIONS: Our data indicate that CFB, a key secreted protein, promotes proliferation by preventing cellular senescence and is associated with immunological tumor promotion in PDAC. These findings suggest that CFB may be a potential target for the treatment of PDAC.

C4b-binding protein α-chain enhances antitumor immunity by facilitating the accumulation of tumor-infiltrating lymphocytes in the tumor microenvironment in pancreatic cancer.

BACKGROUND: Recent studies indicate that complement plays pivotal roles in promoting or suppressing cancer progression. We have previously identified C4b-binding protein α-chain (C4BPA) as a serum biomarker for the early detection of pancreatic ductal adenocarcinoma (PDAC). However, its mechanism of action remains unclear. Here, we elucidated the functional roles of C4BPA in PDAC cells and the tumor microenvironment. METHODS: We assessed stromal C4BPA, the C4BPA binding partner CD40, and the number of CD8+ tumor-infiltrating lymphocytes in resected human PDAC tissues via immunohistochemical staining. The biological functions of C4BPA were investigated in peripheral blood mononuclear cells (PBMCs) and human PDAC cell lines. Mouse C4BPA (mC4BPA) peptide, which is composed of 30 amino acids from the C-terminus and binds to CD40, was designed for further in vitro and in vivo experiments. In a preclinical experiment, we assessed the efficacy of gemcitabine plus nab-paclitaxel (GnP), dual immune checkpoint blockades (ICBs), and mC4BPA peptide in a mouse orthotopic transplantation model. RESULTS: Immunohistochemical analysis revealed that high stromal C4BPA and CD40 was associated with favorable PDAC prognosis (P=0.0005). Stromal C4BPA strongly correlated with the number of CD8+ tumor-infiltrating lymphocytes (P=0.001). In in vitro experiments, flow cytometry revealed that recombinant human C4BPA (rhC4BPA) stimulation increased CD4+ and CD8+ T cell numbers in PBMCs. rhC4BPA also promoted the proliferation of CD40-expressing PDAC cells. By contrast, combined treatment with gemcitabine and rhC4BPA increased PDAC cell apoptosis rate. mC4BPA peptide increased the number of murine T lymphocytes in vitro and the number of CD8+ tumor-infiltrating lymphocytes surrounding PDAC tumors in vivo. In a preclinical study, GnP/ICBs/mC4BPA peptide treatment, but not GnP treatment, led to the accumulation of a greater number of CD8+ T cells in the periphery of PDAC tumors and to greater tumor regression than did control treatment. CONCLUSIONS: These findings demonstrate that the combination of GnP therapy with C4BPA inhibits PDAC progression by promoting antitumor T cell accumulation in the tumor microenvironment.

Fucosylated C4b-binding protein α-chain, a novel serum biomarker that predicts lymph node metastasis in pancreatic ductal adenocarcinoma.

C4b-binding protein α-chain (C4BPA) was previously identified as a novel serum biomarker for pancreatic ductal adenocarcinoma (PDAC). To apply this biomarker for clinical diagnosis, a lectin ELISA was established to measure serum fucosylated (Fuc)-C4BPA levels in 45 patients with PDAC, 20 patients with chronic pancreatitis (CP) and 50 healthy volunteers (HVs) in one training and three validation sets. The lecithin ELISA developed in the current study exhibited satisfactory within-run (2.6-6.7%) and between-day (1.8-3.6%) coefficient of variations. Serum Fuc-C4BPA levels in patients with PDAC (0.54±0.27 AU/ml) was significantly higher than that in HVs (0.21±0.06 AU/ml; P<0.0001) and patients with CP (0.25±0.03 AU/ml; P<0.0001). Additionally, serum Fuc-C4BPA levels in preoperative patients were significantly decreased compared with postoperative patient sera (P<0.0003). The receiver operating characteristic (ROC) curve analyses revealed that the area under the curve (AUC) of Fuc-C4BPA (0.985) was higher than that of carbohydrate antigen (CA)19-9 (0.843), carcinoembryonic antigen (0.548) and total C4BPA (0.875) (P<0.001). To analyze the clinical significance of Fuc-C4BPA, the ability of Fuc-C4BPA to predict lymph node metastasis was compared with that of CA19-9. The AUC of serum Fuc-C4BPA levels (0.703) was significantly higher than that of serum CA19-9 levels (0.500) in patients with PDAC (P<0.001). The current study established a novel lectin ELISA for measuring serum Fuc-C4BPA levels. Thus, Fuc-C4BPA has potential clinical applications owing to its high diagnostic value in PDAC.

PTHrP Drives Pancreatic Cancer Growth and Metastasis and Reveals a New Therapeutic Vulnerability.

Pancreatic cancer metastasis is a leading cause of cancer-related deaths, yet very little is understood regarding the underlying biology. As a result, targeted therapies to inhibit metastasis are lacking. Here, we report that the parathyroid hormone-related protein (PTHrP encoded by PTHLH) is frequently amplified as part of the KRAS amplicon in patients with pancreatic cancer. PTHrP upregulation drives the growth of both primary and metastatic tumors in mice and is highly enriched in pancreatic ductal adenocarcinoma metastases. Loss of PTHrP-either genetically or pharmacologically-dramatically reduces tumor burden, eliminates metastasis, and enhances overall survival. These effects are mediated in part through a reduction in epithelial-to-mesenchymal transition, which reduces the ability of tumor cells to initiate metastatic cascade. Spp1, which encodes osteopontin, is revealed to be a downstream effector of PTHrP. Our results establish a new paradigm in pancreatic cancer whereby PTHrP is a driver of disease progression and emerges as a novel therapeutic vulnerability. SIGNIFICANCE: Pancreatic cancer often presents with metastases, yet no strategies exist to pharmacologically inhibit this process. Herein, we establish the oncogenic and prometastatic roles of PTHLH, a novel amplified gene in pancreatic ductal adenocarcinoma. We demonstrate that blocking PTHrP activity reduces primary tumor growth, prevents metastasis, and prolongs survival in mice.This article is highlighted in the In This Issue feature, p. 1601.

The prognostic impact of neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) in patients with distal bile duct cancer.

BACKGROUND: A growing body of evidence suggests that inflammatory response markers such as the neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) are associated with outcomes of various malignancies. However, no study has reported the prognostic value of NLR and LMR in patients with distal bile duct cancer (DBDC) to date. We investigated the prognostic significance of these inflammatory markers in patients with DBDC who underwent radical resection. METHODS: The study included 40 patients diagnosed with DBDC who underwent pancreaticoduodenectomy at Narita Red Cross Hospital between January 2000 and December 2017. The cutoff values for these markers were determined by receiver operating characteristic curve analysis. Survival curves are estimated for each group in the study considered separately using the Kaplan-Meier method. The association between overall survival (OS) and the NLR, LMR, and other prognostic factors was investigated using log-rank test and multivariate Cox proportional hazards regression analysis. RESULTS: Corresponding to the point with the maximum combined sensitivity and specificity on the ROC curve, the best cutoff value for NLR and LMR was determined to be 3.14 and 4.55, respectively. Most clinicopathological factors were not associated with the NLR and LMR based on these cutoff values. However, serum albumin levels were associated with both the NLR and LMR (P = 0.011 and P = 0.023, respectively), and serum carbohydrate antigen 19-9 (CA 19-9) levels were also associated with the LMR (P = 0.030). Univariate analysis showed that a high NLR (P < 0.001), low LMR (P = 0.002), hypoalbuminemia (P = 0.004), high serum CA 19-9 levels (P = 0.008), and lymph node metastasis (P = 0.033) were significantly associated with poor survival rates. Multivariate analysis showed that a high NLR (hazard ratio 5.799, 95% confidence interval 1.188-28.32, P = 0.030) and a low LMR (hazard ratio 4.837, 95% confidence interval 1.826-2.331, P = 0.025) were independent prognostic factors for OS. CONCLUSION: Both NLR and LMR may serve as significant independent preoperative prognostic indicators of disease in patients with DBDC who undergo radical resection.

[A Case of Advanced Gastric Cancer Responding to Neoadjuvant Chemotherapy with Docetaxel, Cisplatin, and 5-Fluorouracil, Leading to a Pathological Complete Response].

We report a 72-year-old woman who was initially diagnosed with locally advanced gastric cancer with involvement of the esophagus and pancreas. She received 3 courses of neoadjuvant chemotherapy(NAC)with docetaxel, cisplatin, and 5- fluorouracil(the DCF regimen)and achieved an excellent response. She underwent total gastrectomy with distal pancreatectomy, splenectomy, and D2 lymphadenectomy. Histological examination confirmed a pathological complete response. NAC chemotherapy can down stage/down size the disease and allow some patients to undergo curative radical surgery.

[Successful Surgical Treatment for Hepatocellular Carcinoma with Portal Vein Tumor Thrombus after Favorable Response to Irradiation and Transcatheter Arterial Chemoembolization].

Here, we describe the surgical treatment of a patient with hepatocellular carcinoma(HCC)with portal vein tumor thrombus (PVTT) after irradiation and transcatheter arterial chemoembolization (TACE). A 51-year-old man was being followed-up for HBV-related liver cirrhosis and HCC that was previously treated by radio-frequency ablation (RFA) and TACE. A follow up CT study revealed recurrence of HCC in segment 6 of the liver with PVTT extending to the right branch. As early recurrence was likely after resection and due to insufficient hepatic functional reserve, primary radiotherapy for PVTT was performed followed by TACE. After non-surgical treatment, a favorable tumor response was observed with no evidence of intrahepatic disease within the left lobe of the liver, and the volume of the future liver remnant increased, allowing us to perform splenectomy and right hemihepatectomy combined with portal vein resection/reconstruction.

[Simultaneous Resection of Sigmoid Colon Cancer and Synchronous Liver Metastasis by Laparoscopic Surgery].

We report the case of a patient with sigmoid colon cancer with synchronous liver metastasis who underwent simultaneous sigmoid colectomy and partial hepatectomy by laparoscopic surgery. A 70-year-old man with positive fecal occult blood was diagnosed with sigmoid colon cancer and referred to our hospital. Staging computed tomography (CT) revealed a solitary liver metastasis in segment 6, confirmed by magnetic resonance imaging (MRI). He underwent simultaneous laparoscopic sigmoid colectomy and partial hepatectomy. The patient's postoperative recovery was uneventful and he was discharged 12 days later. The patient was alive without recurrence 4 months after surgery. Laparoscopic surgery is an accepted mode of treatment for colorectal cancer. However, the use of laparoscopy in liver surgery is still limited. There have only been few case reports of combined laparoscopic colorectal and liver resection. Simultaneous laparoscopic colectomy and hepatectomy is feasible for selected colorectal cancer patients with liver metastases. It may provide significant decrease in morbidity, length of hospitalization time, and intraoperative blood loss, without compromising curability or increasing mortality. Further studies are needed to confirm the feasibility of this approach.

[A Case of R0 Resection of Locally Advanced Pancreatic Cancer Following Chemoradiation Therapy].

Patients with borderline resectable pancreatic cancer have a poorer prognosis than patients with resectable pancreatic cancer, but some cases treated with neoadjuvant chemoradiation therapy and radical surgery (R0 surgery) show long-term survival. A 72-year-old woman presented with a history of back pain and weight loss. Computed tomography revealed a cancer of the pancreatic body encasing the celiac trunk, common hepatic artery, and portal vein. After neoadjuvant chemotherapy ( S-1) and carbon-ion radiotherapy, the tumor was considered to be resectable. Distal pancreatectomy with en bloc celiac trunk resection (DP-CAR), portal vein resection, and reconstruction was performed. The histopathologic findings showed that the effect of NACRT was gradeⅡa (Evens' classification), and the surgical margins were histologically clear. S-1 was administered again for half a year as postoperative chemotherapy. With post-operative follow-up of 1 year and 1 month after surgery, the patient shows no signs of recurrent disease.