Vascular endothelial growth factor inhibitors promote antitumor responses via tumor microenvironment immunosuppression in advanced colorectal cancer.

PURPOSE: This study aims to investigate changes in the tumor immune environment of patients who underwent therapy with a vascular endothelial growth factor (VEGF) inhibitor for advanced colorectal cancer. METHODS: Patients (n = 135) with T3 or T4 colorectal cancer were included in this retrospective study. They were classified as follows: patients who had not received preoperative treatment (UPFRONT group, n = 54), who had received FOLFOX as preoperative chemotherapy (FOLFOX group, n = 55), and who had undergone resection after combination FOLFOX and bevacizumab as unresectable colorectal cancer (B-MAB group, n = 26). The number of cytotoxic T lymphocytes (CTLs), FOXP3+ lymphocytes (including regulatory T cells (Tregs)), CD163+ monocytes (including M2-type tumor-associated macrophages (TAM-M2 type)), and programmed cell death 1 (PD-1)+ lymphocytes was evaluated immunohistochemically in the cancer cell area (CC) and stromal cell area (ST) of surgical specimens, and compared among the three groups. RESULTS: The CTL population did not differ among the three groups in both areas. In the B-MAB group, the numbers of PD-1+ cells in the ST, FOXP3+ lymphocytes in both areas, and CD163+monocytes in the ST was lower than that in the other two groups, and a correlation with the histological therapeutic effect was observed. CONCLUSIONS: In advanced colorectal cancer, VEGF inhibitors may decrease the number of PD-1+ cells and inhibit the infiltration of FOXP3+ lymphocytes and CD163+monocytes into the tumor environment.

[Stenotic ischemic enteritis secondary to intraperitoneal band infiltration: a case report].

A 55-year-old man presented with vomiting and upper abdominal pain. Two months later, computed tomography revealed jejunal wall thickening and contrast enhancement. Double-balloon endoscopy revealed severe jejunal stenosis and mucosal prolapse. The patient was diagnosed with stenotic ischemic small bowel inflammation and underwent partial small bowel resection. Clinicians should consider intraperitoneal band formation in the differential diagnosis of patients without a history of abdominal surgery or trauma. Surgical resection should be considered to prevent strangulation ileus.

The 1-year outcomes after pancreaticogastrostomy using vertical versus horizontal mattress suturing for gastric wrapping.

PURPOSE: To investigate the differences in nutritional status 1 year after pancreaticogastrostomy (PG) using vertical suturing (VS) vs. twin square horizontal mattress (HMS) suturing in patients undergoing pancreaticoduodenectomy (PD). METHODS: The subjects of this study were 134 patients who underwent PD, followed by PG, which was closed by VS in 52 and by HMS in 82. We evaluated the peri- and postoperative factors, nutritional parameters, diameter of the remnant main pancreatic duct, and glucose intolerance 1 year postoperatively. RESULTS: Forty-five (87%) patients from the VS group and 75 (91%) patients from the HMS group survived for more than 1 year. The incidences of intraabdominal abscess and pancreatic fistula were significantly lower in the HMS group than in the VS group (19.2% vs. 6.6% and19.2% vs. 2.6%, respectively). There were no significant changes in the total protein, serum albumin, and HbA1c levels 1 year postoperatively. The postoperative expansion ratio of the main pancreatic duct diameter was significantly smaller in the HMS group than in the VS group. The strongest risk factor for body weight loss 1 year postoperatively was a non-soft pancreas texture. CONCLUSION: HMS was superior to VS for preventing early postoperative complications and did not affect pancreatic function.

Lung recurrence and its therapeutic strategy in patients with pancreatic cancer.

BACKGROUND: /Objectives: The lung is a major metastatic site of pancreatic cancer (PC). We aimed to assess the features and prognosis of patients with PC according to the recurrence pattern and the effect of resection of recurrent lung lesion. METHODS: We enrolled 168 PC patients who had undergone macroscopically curative resection. All resected lung tumors were evaluated immunohistochemically for expressions of thyroid transcription factor-1 (TTF-1) and napsin A. RESULTS: The most common site of first recurrence was the liver and local site, followed by the lung, peritoneum, and lymph node. Lung recurrence was observed significantly later than was liver recurrence. The median survival time (MST) after recurrence in patients with first recurrence in the lung was significantly longer than MST in patients with first recurrence in the liver (15.2 months vs 5.2 months, p = 0.039). Seven patients with lung recurrence underwent resection of the recurrent lesion. Surgical resection of single metastasis limited to the lung showed favorable overall survival after recurrence (MST = 36.5 months). Patients with single metastasis limited to the lung showed significantly lower value of FDG-PET SUVmax of the primary pancreatic tumor. CONCLUSIONS: Patients with first recurrence in the lung showed better prognosis than did patients with first recurrence in the liver. Single metastasis limited to the lung could benefit from surgical resection and was significantly associated with lower FDG-PET SUVmax of the primary pancreatic tumor.

[Single Liver Metastasis of Breast Cancer Mimicking Intrahepatic Cholangiocarcinoma 13 Years after the Primary Surgery-A Case Report].

A 78-year-old woman underwent left total mastectomy for breast cancer at 65 years of age.Thirteen years after the primary surgery, CT showed a single 46mm tumor located in liver segment 4.The tumor was difficult to distinguish between cholangiocellular carcinoma and liver metastasis of the breast cancer.We did not perform biopsy, considering dissemination, and performed left hemihepatectomy and left caudate lobectomy.Pathological findings revealed liver metastasis of breast cancer.Hepatic resection is a useful option in cases of single liver metastasis from breast cancer that are difficult to distinguish from cholangiocellular carcinoma.

Gene regulation by antitumor miR-130b-5p in pancreatic ductal adenocarcinoma: the clinical significance of oncogenic EPS8.

Our ongoing analyses identifying dysregulated microRNAs (miRNAs) and their controlled target RNAs have shed light on novel oncogenic pathways in pancreatic ductal adenocarcinoma (PDAC). The PDAC miRNA signature obtained by RNA sequencing showed that both strands of pre-miR-130b (miR-130b-5p, the passenger strand and miR-130b-3p, the guide strand) were significantly downregulated in cancer tissues. Our functional assays revealed that miR-130b-5p significantly blocked the malignant abilities of PDAC cell lines (PANC-1 and SW1990), e.g., cancer cell proliferation, migration, and invasion. A total of 103 genes were identified as possible oncogenic targets by miR-130b-5p regulation in PDAC cells based on genome-wide gene expression analysis and in silico database search. Among the possible targets, high expression of 9 genes (EPS8, ZWINT, SMC4, LDHA, GJB2, ZCCHC24, TOP2A, ANLN, and ADCY3) predicted a significantly poorer prognosis of PDAC patients (5-year overall survival, p < 0.001). Furthermore, we focused on EPS8 because its expression had the greatest impact on patient prognosis (overall survival, p < 0.0001). Overexpression of EPS8 was detected in PDAC clinical specimens. Knockdown assays with siEPS8 showed that its overexpression enhanced cancer cell proliferation, migration, and invasion. Analysis of downstream RNA networks regulated by EPS8 indicated that MET, HMGA2, FERMT1, RARRES3, PTK2, MAD2L1, and FLI1 were closely involved in PDAC pathogenesis. Genes regulated by antitumor miR-130b-5p were closely involved in PDAC molecular pathogenesis. Our approach, discovery of antitumor miRNAs and their target RNAs, will contribute to exploring the causes of this malignant disease.

Adenovirotherapy Delivering Cytokine and Checkpoint Inhibitor Augments CAR T Cells against Metastatic Head and Neck Cancer.

In solid tumors, chimeric antigen receptor (CAR)-modified T cells must overcome the challenges of the immunosuppressive tumor microenvironment. We hypothesized that pre-treating tumors with our binary oncolytic adenovirus (CAd), which produces local oncolysis and expresses immunostimulatory molecules, would enhance the antitumor activity of HER2-specific CAR T cells, which alone are insufficient to cure solid tumors. We tested multiple cytokines in conjunction with PD-L1-blocking antibody and found that Ad-derived IL-12p70 prevents the loss of HER2.CAR-expressing T cells at the tumor site. Accordingly, we created a construct encoding the PD-L1-blocking antibody and IL-12p70 (CAd12_PDL1). In head and neck squamous cell carcinoma (HNSCC) xenograft models, combining local treatment with CAd12_PDL1 and systemic HER2.CAR T cell infusion improved survival to >100 days compared with approximately 25 days with either approach alone. This combination also controlled both primary and metastasized tumors in an orthotopic model of HNSCC. Overall, our data show that CAd12_PDL1 augments the anti-tumor effects of HER2.CAR T cells, thus controlling the growth of both primary and metastasized tumors.

Intraoperative Identification of the Parathyroid Gland with a Fluorescence Detection System.

BACKGROUND: Intraoperative identification of the difficult-to-spot parathyroid gland is critical during surgery for thyroid and parathyroid disease. Recently, intrinsic fluorescence of the parathyroid gland was identified, and a new method was developed for intraoperative detection of the parathyroid with an original fluorescent detection apparatus. Here, we describe a method for intraoperative detection of the parathyroid using a ready-made photodynamic eye (PDE) system without any fluorescent dye or contrast agents. METHODS: Seventeen patients who underwent surgical treatment for thyroid or parathyroid disease at Kagoshima University Hospital were enrolled in this study. Intrinsic fluorescence of various tissues was detected with the PDE system. Intraoperative in vivo and ex vivo intrinsic fluorescence of the parathyroid, thyroid, lymph nodes and fat tissues was measured and analyzed. RESULTS: The parathyroid gland had a significantly higher fluorescence intensity than the other tissues, including the thyroid glands, lymph nodes and fat tissues, and we could identify them during surgery using the fluorescence-guided method. Our method could be applicable for two intraoperative clinical procedures: ex vivo tissue identification of parathyroid tissue and in vivo identification of the location of the parathyroid gland, including ectopic glands. CONCLUSION: The PDE system may be an easy and highly feasible method to identify the parathyroid gland during surgery.

Survivin-responsive conditionally replicating adenovirus kills rhabdomyosarcoma stem cells more efficiently than their progeny.

BACKGROUND: Effective methods for eradicating cancer stem cells (CSCs), which are highly tumorigenic and resistant to conventional therapies, are urgently needed. Our previous studies demonstrated that survivin-responsive conditionally replicating adenoviruses regulated with multiple factors (Surv.m-CRAs), which selectively replicate in and kill a broad range of cancer-cell types, are promising anticancer agents. Here we examined the therapeutic potentials of a Surv.m-CRA against rhabdomyosarcoma stem cells (RSCs), in order to assess its clinical effectiveness and usefulness. METHODS: Our previous study demonstrated that fibroblast growth factor receptor 3 (FGFR3) is a marker of RSCs. We examined survivin mRNA levels, survivin promoter activities, relative cytotoxicities of Surv.m-CRA in RSC-enriched (serum-minus) vs. RSC-exiguous (serum-plus) and FGFR3-positive vs. FGFR3-negative sorted rhabdomyosarcoma cells, and the in vivo therapeutic effects of Surv.m-CRAs on subcutaneous tumors in mice. RESULTS: Both survivin mRNA levels and survivin promoter activities were significantly elevated under RSC-enriched relative to RSC-exiguous culture conditions, and the elevation was more prominent in FGFR3-positive vs. FGFR3-negative sorted cells than in RSC-enriched vs. RSC-exiguous conditions. Although Surv.m-CRA efficiently replicated and potently induced cell death in all populations of rhabdomyosarcoma cells, the cytotoxic effects were more pronounced in RSC-enriched or RSC-purified cells than in RSC-exiguous or progeny-purified cells. Injections of Surv.m-CRAs into tumor nodules generated by transplanting RSC-enriched cells induced significant death of rhabdomyosarcoma cells and regression of tumor nodules. CONCLUSIONS: The unique therapeutic features of Surv.m-CRA, i.e., not only its therapeutic effectiveness against all cell populations but also its increased effectiveness against CSCs, suggest that Surv.m-CRA is promising anticancer agent.

Genetic assessment of IPMN for predicting concomitant pancreatic ductal adenocarcinoma.

OBJECTIVE: Krüppel-like transcription factor 4(KLF4) mutations are more frequently observed in low-grade lesions than in high-grade lesions of intraductal papillary mucinous neoplasms (IPMN) of the pancreas. However, the role of KLF4 mutations in IPMNs with concomitant pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study clarified the rate and effect of KLF4 mutations in IPMN with concomitant PDAC. METHODS: DNA was extracted from 65 formalin-fixed and paraffin-embedded samples from 52 patients including 13 IPMN with concomitant PDAC and 39 IPMN alone. A comprehensive screening was performed using next-generation sequencing (NGS) for the 5 IPMNs with concomitant PDAC and 5 IPMNs alone, followed by targeted sequencing for KLF4, GNAS, and KRAS mutations. RESULTS: In NGS screening, KRAS mutations were observed in all samples except for one, GNAS mutation in two IPMNs with concomitant PDAC, and a KLF4 mutation in one IPMN with concomitant PDAC. Targeted sequence detected KLF4 mutations in 11 of the 52 IPMNs. Concomitant PDAC developed only in the non-intestinal, non-invasive, and branch duct IPMN cases, and KLF4 mutations were more frequent in this IPMN type than in the other type (36% vs. 10%, p = 0.04). For this IPMN type with KLF4 mutation, PDAC-prediction sensitivity, specificity, and accuracy were 63%, 82%, and 79%, respectively. CONCLUSION: For selected IPMNs with non-intestinal, non-invasive, and branch duct, genetic assessment might be a helpful tool for predicting the possible development of concomitant PDAC, although a prospective validation study using a larger study population is needed.

Clinical significance of ¹8F-fluorodeoxyglucose positron emission tomography in superficial esophageal squamous cell carcinoma.

PURPOSE: To assess the clinical usefulness and significance of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in superficial esophageal squamous cell carcinoma (ESCC). METHODS: We examined FDG-PET for 80 consecutive patients with superficial ESCC without neoadjuvant treatment. Fifty-seven patients underwent radical esophagectomy, and 23 patients received endoscopic resection. The FDG uptake index was evaluated with clinicopathological findings, and glucose transporter 1 (Glut-1) expression in primary tumors was examined immunohistochemically. RESULTS: The FDG uptake in primary tumors correlated with histology, depth of tumor invasion, lymph node metastasis, lymphatic invasion, vascular invasion, and Glut-1 expression. All patients with more than 4.4 maximum standardized uptake value (SUVmax) had deeper invasion of submucosa. Among 16 patients with lymph node metastasis, only two were found to have lymph node metastasis. FDG uptake, depth of tumor invasion, lymph node metastasis, and histology were found to be prognostic factors, and histology was an independent prognostic factor. In FDG uptake-positive patients, depth of tumor invasion and histology were prognostic factors. CONCLUSIONS: FDG-PET is useful for diagnosing tumors with deeper invasion of submucosa and is helpful in making decisions regarding endoscopic treatment for superficial ESCC. Patients with FDG uptake-positive disease, deeper invasion of submucosa, poorly differentiated tumor, and poor prognosis should receive multimodal treatment.

Are intratumoral microbiota involved in the progression of intraductal papillary mucinous neoplasms of the pancreas?

BACKGROUND: Microbiota have been reported to influence the development of various gastrointestinal neoplasms through the mechanism of sustained inflammation; however, few data are available regarding their influence on intraductal papillary mucinous neoplasms. The aim of this study was to assess the association between specific microbiota and the clinicopathologic characteristics of intraductal papillary mucinous neoplasms of the pancreas. METHODS: DNA was extracted from formalin-fixed, paraffin-embedded samples of 30 patients who underwent pancreatectomy for intraductal papillary mucinous neoplasm, and polymerase chain reaction was used to create sequence libraries using the primer set for the V3 and V4 region of 16S recombinant DNA. Filtered sequence reads were then processed into operational taxonomic units with a 97% identity threshold and the relative abundance of bacteria compared between the 2 groups using operational taxonomic units. RESULTS: There was a trend toward fewer Firmicutes and more Proteobacteria and Fusobacteria in the relative abundance of main duct operational taxonomic units than in branch duct operational taxonomic units. The relative abundances of Bacteroidetes (P < .01) and Fusobacteria (P = .04) were significantly higher in invasive intraductal papillary mucinous neoplasms than in noninvasive intraductal papillary mucinous neoplasms. The relative abundance of the intestinal type was significantly lower in Firmicutes than the relative abundance of the nonintestinal type (P = .04). Notably, main duct operational taxonomic units with the intestinal subtype were affected by increased proportions of Proteobacteria and Fusobacteria, and Fusobacteria were abundant in the intestinal type of invasive main duct operational taxonomic units. CONCLUSION: Intratumoral microbiota may be involved in the progression of operational taxonomic units.

VEGF-A165 is the predominant VEGF-A isoform in platelets, while VEGF-A121 is abundant in serum and plasma from healthy individuals.

Vascular endothelial growth factor A (VEGF-A) plays pivotal roles in regulating tumor angiogenesis as well as physiological vascular function. The major VEGF-A isoforms, VEGF-A121 and VEGF-A165, in serum, plasma, and platelets have not been exactly evaluated due to the lack of the appropriate assay system. Antibodies against human VEGF-A121 and VEGF-A165 (hVEGF-A121 and hVEGF-A165) were successfully produced and Enzyme-Linked ImmunoSorbent Assay (ELISA) for hVEGF-A121 and hVEGF-A165 were separately created by these monoclonal antibodies. The measurement of recombinant hVEGF-A121 and hVEGF-A165 by the created ELISA showed no cross-reaction between hVEGF-A121 and hVEGF-A165 in conditioned media from HEK293 cells transfected with either hVEGF-A121 or hVEGF-A165 expression vector. The levels of VEGF-A121 and VEGF-A165 in serum, plasma, and platelets from 59 healthy volunteers proved that VEGF-A121 level was higher than VEGF-A165 in both plasma and serum in all the cases. VEGF-A121 or VEGF-A165 in serum represented higher level than that in plasma. In contrast, the level of VEGF-A165 was higher than VEGF-A121 in platelets. The newly developed ELISAs for hVEGF-A121 and hVEGF-A165 revealed different ratios of VEGF isoforms in serum, plasma, and platelets. Measuring these isoforms in combination provides useful information as biomarkers for diseases involving VEGF-A121 and VEGF-A165.

Curative resection after chemotherapy and chemoradiotherapy for postoperative recurrence of pancreatic tail cancer in the abdominal wall: a case report.

BACKGROUND: Locoregional recurrence and metastasis to the liver, peritoneum, and lung are the most common recurrent patterns of pancreatic ductal adenocarcinoma (PDAC) after radical resection. Recurrence in the abdominal wall is extremely rare. Herein, we report our experience with a patient who had recurrent PDAC in the abdominal wall with long-term survival by means of multidisciplinary therapy. CASE PRESENTATION: A 76-year-old Japanese woman was diagnosed with resectable pancreatic tail cancer. She underwent distal pancreatectomy with regional lymphadenectomy after two cycles of gemcitabine plus S-1 as neoadjuvant therapy. She also received eight cycles of S-1 as adjuvant chemotherapy. Approximately 14 months after the initial surgery, imaging examinations identified a mass suggesting recurrence in the abdominal wall at the middle wound that involved the transverse colon. After two cycles of gemcitabine plus nab-paclitaxel, chemoradiotherapy (S-1 plus 45 Gy) and seven cycles of modified FOLFIRINOX (5-fluorouracil/leucovorin, irinotecan, and oxaliplatin) were administered. The patient did not develop any new recurrent lesions during chemotherapy and chemoradiotherapy. Therefore, the recurrent lesion in the abdominal wall and the involved transverse colon were resected. We confirmed the lack of peritoneal dissemination during surgery. Pathological examination revealed that the resected lesion was metastasis of primary PDAC, and the surgical margin was 1 mm. However, re-recurrence localized in the abdominal wall was detected 9 months later. The re-recurrent lesion was diagnosed as local recurrence of the first recurrent lesion. We performed a second resection of the abdominal wall using a femoral myocutaneous flap to achieve sufficient surgical margin. The pathological findings of the resected specimen were the same as those of the previous specimens, and the resection margin was negative. The patient's postoperative course was uneventful. Seven years after the initial surgery and 3 years and 7 months after the third surgery, the patient is alive with no signs of recurrence. CONCLUSIONS: Long-term survival could be achieved by radical resection with sufficient surgical margins for recurrence of PDAC in the abdominal wall if new other recurrent lesions, including peritoneal dissemination, are prevented through chemotherapy.

Implications of PD-1, Tim-3, and TIGIT Expression for Cancer Immunity and Pancreatic Cancer Prognosis.

BACKGROUND/AIM: The development and application of cancer immunotherapy to pancreatic cancer has not progressed because its efficacy has not been proven in clinical trials. In this study, we aimed to explore potential targets of immune checkpoint inhibitor therapy for pancreatic cancer treatment. MATERIALS AND METHODS: We collected resected specimens from 40 patients with pancreatic cancer who underwent resection at our Institution without any preoperative treatment. We evaluated the expression of molecules in the programmed death receptor-1 (PD-1), T cell immunoglobulin mucin-3 (Tim-3)/Galectin-9, and CD155/T cell immunoreceptor with Ig and ITIM domains (TIGIT) pathways using immunohistochemical staining. The correlation between the expression pattern of these molecules and patient prognosis were assessed using Kaplan-Meier analysis. RESULTS: An increased number of CD8+ T cells in pancreatic cancer tissue was significantly associated with a better patient prognosis. Additionally, patients with a higher ratio of PD-1 expression to CD8+ T cells had a worse prognosis. We observed no correlation between the Tim-3/Galectin-9 and CD155/TIGIT pathways and patient prognosis. CONCLUSION: Modifications in the immune environment to increase T cell infiltration into tumors could result in the PD-1 pathway becoming a potential target to treat pancreatic cancer using immune checkpoint inhibition.

Multidisciplinary treatment of advanced or recurrent solid pseudopapillary neoplasm of the pancreas: three case reports.

BACKGROUND: Solid pseudopapillary neoplasm (SPN) is a rare pancreatic tumor that predominantly affects young females. Prognosis is excellent; however, 10-15% of patients show metastasis at the time of surgery or develop tumor recurrence after pancreatectomy. CASE PRESENTATION: We reviewed the clinical course of three patients with advanced or recurrent SPN and subsequently underwent multidisciplinary treatment at our institution between 2002 and 2019. The primary tumor was resected in all three patients, and metastases were also resected if indicated. Intensive combined therapy, including re-resection, chemotherapy, ablation, arterial chemoembolization, and radiation therapy, allowed all patients to survive for a long time. The literature review showed that resection seems to be more effective than other treatments for metastatic SPN. CONCLUSIONS: Multidisciplinary treatment, including resection, may improve the prognosis of patients with SPN with recurrence or metastasis.

Clinical Benefits of Conversion Surgery for Unresectable Pancreatic Ductal Adenocarcinoma: A Single-Institution, Retrospective Analysis.

BACKGROUND: Unresectable pancreatic ductal adenocarcinoma (UR-PDAC) has a poor prognosis. Conversion surgery is considered a promising strategy for improving the prognosis of UR-PDAC. This study aimed to investigate the clinical benefits of conversion surgery in patients with UR-PDAC. METHODS: We retrospectively evaluated patients with PDAC who were referred to our department for possible surgical resection between January 2006 and December 2019. Conversion surgery was performed only in patients with UR-PDAC who could expect R0 resection. We analyzed the prognostic factors for overall survival among patients who underwent conversion surgery. RESULTS: Overall, 638 patients with advanced pancreatic cancer were enrolled in this study. According to resectability, resectable cancer (R) was present in 180 patients, borderline resectable cancer (BR) was present in 60 patients, unresectable locally advanced cancer (UR-LA) was present in 252 patients, and unresectable cancer with distant metastasis (UR-M) was present in 146 patients. Conversion surgery was performed in 20 of the 398 UR cases (5.1%). The median period between the initial therapy and conversion surgery was 15.5 months. According to the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation, the treatment response was CR in one patient, PR in 13, SD in five, and PD in one. Downstaging was pathologically determined in all cases. According to the Evans grading system, grade I was observed in four patients (20%), grade IIb was observed in seven (35%), III was observed in seven (35%), and IV was observed in two (10%). We compared the overall survival period from initial treatment among patients undergoing conversion surgery; the median overall survival durations in the conversion surgery, R, BR, UR-LA, and UR-M groups were 73.7, 32.7, 22.7, 15.7, and 8.8 months, respectively. Multivariate analysis revealed that the presence or absence of chemoradiotherapy (CRT) and the RECIST partial response (PR)/complete response (CR) for the main tumor were statistically significant prognostic factors for overall survival among patients undergoing conversion surgery (p = 0.004 and 0.03, respectively). CONCLUSION: In UR-PDAC, it is important to perform multidisciplinary treatment, including CRT with conversion surgery.

Locally advanced cholangiolocellular carcinoma successfully treated with curative resection after downsizing chemotherapy: a case report.

BACKGROUND: Cholangiolocellular carcinoma (CoCC) is an extremely rare disease comprising less than 1% of all primary malignant liver tumors. No effective treatment other than resection has been established. Herein, we report a case of locally advanced CoCC diagnosed as unresectable, which was successfully treated with curative resection after downsizing chemotherapy. CASE PRESENTATION: A 59-year-old Japanese woman with chronic hepatitis B was diagnosed with locally advanced intrahepatic cholangiocellular carcinoma. As it was difficult to perform R0 resection in the local hospital, chemotherapy combined with gemcitabine plus cisplatin was administered every 3 weeks. After a total of 10 courses of chemotherapy over 10 months the tumor was shown to be reduced in size by computed tomography imaging, and she was referred to our department for surgical resection. The effect of chemotherapy was classified as a "partial response" in the response evaluation criteria of solid tumors. After adding one course of chemotherapy, an extended left hepatectomy with resection of the caudate lobe was performed. R0 resection was achieved. Based on the pathological findings, the final diagnosis of CoCC was determined and eight courses of S-1 adjuvant chemotherapy were administered. At 14 months after the operation, the patient was alive without tumor recurrence. CONCLUSIONS: Downsizing chemotherapy with gemcitabine and cisplatin may be an effective treatment strategy in locally advanced CoCC. Further evidence is required to establish an optimal strategy for the treatment of locally advanced CoCC.

Postoperative recurrence with right cervical lymph node metastasis in hepatocellular carcinoma: a case report.

BACKGROUND: Hepatocellular carcinoma (HCC) patients with metastases to the cervical lymph nodes are extremely rare, and its clinical course is characterized by rapidly progressive disease. Hence, there have been no reports of metastatic cervical lymph node recurrence indicated after a long postoperative surveillance period. CASE PRESENTATION: The patient was a 63-year-old male who underwent right hepatectomy for HCC of the right upper lobe. Three years after resection, metastatic lymph node recurrence was detected in the subdiaphragm, superior mediastinum, and right cervical lymph nodes. The patient underwent excisional biopsy of the cervical lymph node, followed by molecular-targeted therapy and radiation therapy. Lenvatinib reduced the size of all metastatic lymph nodes and the patient survived for a relatively long period of 43 months after the recurrence was detected. CONCLUSIONS: After resection of HCC in the right upper lobe, there is the possibility of metastatic lymph node recurrence in unusual sites, including the cervical region, and lenvatinib may be effective in those recurrences.

Molecular Pathogenesis and Regulation of the miR-29-3p-Family: Involvement of ITGA6 and ITGB1 in Intra-Hepatic Cholangiocarcinoma.

The aggressive nature of intrahepatic cholangiocarcinoma (ICC) renders it a particularly lethal solid tumor. Searching for therapeutic targets for ICC is an essential challenge in the development of an effective treatment strategy. Our previous studies showed that the miR-29-3p-family members (miR-29a-3p, miR-29b-3p and miR-29c-3p) are key tumor-suppressive microRNAs that control many oncogenic genes/pathways in several cancers. In this study, we searched for therapeutic targets for ICC using the miR-29-3p-family as a starting point. Our functional studies of cell proliferation, migration and invasion confirmed that the miR-29-3p-family act as tumor-suppressors in ICC cells. Moreover, in silico analysis revealed that "focal adhesion", "ECM-receptor", "endocytosis", "PI3K-Akt signaling" and "Hippo signaling" were involved in oncogenic pathways in ICC cells. Our analysis focused on the genes for integrin-α6 (ITGA6) and integrin-ß1 (ITGB1), which are involved in multiple pathways. Overexpression of ITGA6 and ITGB1 enhanced malignant transformation of ICC cells. Both ITGA6 and ITGB1 were directly regulated by the miR-29-3p-family in ICC cells. Interestingly, expression of ITGA6/ITGB1 was positively controlled by the transcription factor SP1, and SP1 was negatively controlled by the miR-29-3p-family. Downregulation of the miR-29-3p-family enhanced SP1-mediated ITGA6/ITGB1 expression in ICC cells. MicroRNA-based exploration is an attractive strategy for identifying therapeutic targets for ICC.