[A Case of Pancreatic Cancer That Developed Peritoneal Recurrence after Radical Surgery following Neoadjuvant Chemoradiation Therapy(NACRT)with Pathological Complete Response(pCR)].

A 71-year-old woman was diagnosed with a tumor in the pancreatic head on CT imaging, which was performed as a close examination of an exacerbation of diabetes mellitus. The pancreatic tumor was diagnosed as resectable pancreatic cancer, and after preoperative adjuvant chemoradiotherapy, pancreatoduodenectomy was performed as a radical surgery. There were no residual tumor cells in the resected specimen histopathologically, and the patient was judged to have a pathological complete response(pCR). Six months of postoperative adjuvant chemotherapy was administered, but peritoneal recurrence was observed at 20 months postoperatively, and the patient is currently undergoing treatment for recurrence. There have been other reports of recurrence even after pCR was achieved with preoperative treatment, so it is important to follow up carefully, keeping in mind that pancreatic cancer is a latent systemic disease.

Predicting Post-Hepatectomy Liver Failure Using Intra-Operative Measurement of Indocyanine Green Clearance in Anatomical Hepatectomy.

BACKGROUND: Prediction of post-hepatectomy liver failure (PHLF) based on remnant liver function reserve is important for successful hepatectomy. The aim of this study was to investigate whether intraoperative indocyanine green (ICG) clearance in a future remnant liver was a predictor of PHLF. METHODS: This prospective study enrolled 31 consecutive patients who underwent anatomical hepatectomy between June 2016 and August 2019. Intraoperative ICG plasma disappearance rate (ICG-PDR) and ICG retention rate at 15 min (ICG-R15) were measured after clamping the selective hepatic inflow to the liver to be resected. The discriminative performance of the ICG-associated variables for the prediction of PHLF grade B/C was evaluated by receiver operator curve (ROC) analysis. RESULTS: Of the operations performed, 87.1% were major hepatectomy. PHLF Grade B/C was observed in eight patients (25.8%) with no mortality. The concordance indices of intraoperative ICG-PDR and ICG-PDR for predicting PHLF were 0.834 (95% CI, 0.69-0.98) and 0.834 (95% CI, 0.69-0.98), respectively. A subgroup analysis of patients with preoperative biliary drainage (BD) (n = 17) showed that the concordance indices of intraoperative ICG-PDR increased to 0.923 (95% CI, 0.79-1.00). CONCLUSIONS: Intraoperative ICG clearance in the remnant liver was a promising predictor for PHLF in patients undergoing anatomical hepatectomy, especially in patients with BD.

Accuracy comparison of MR elastography and biological markers in detecting liver fibrosis and predicting postoperative ascites.

BACKGROUND: This retrospective study aimed to compare the discriminative performance between magnetic resonance elastography (MRE) and biological markers in detecting liver fibrosis and in predicting postoperative ascites (PA). METHODS: We enrolled 77 patients consecutively who underwent hepatectomy between March 2017 and June 2019. Liver fibrosis was histopathologically graded using the METAVIR scoring system as reference. Discriminative performance of non-invasive assessments in detecting different stages of liver fibrosis and predicting PA was evaluated by receiver-operator curve analysis. RESULTS: The concordance indices (C-indices) for MRE and biological markers for detecting significant fibrosis (≥F2) and cirrhosis (F4) were: MRE, 0.84 and 0.86; Wisteria floribunda agglutinin + Mac-2 binding protein (WM2BP), 0.63 and 0.71; Hyaluronic acid (HA), 0.72 and 0.75; 7 S-type 4 collagen (T4C), 0.61 and 0.66; APRI, 0.76 and 0.83; and Fib-4, 0.75 and 0.76. Univariable logistic analysis for predicting PA showed that C-indices were 0.751 (p = 0.007), 0.798 (p = 0.106), 0.771 (p = 0.050), 0.674 (p = 0.855), 0.655 (p = 0.263), and 0.560 (p = 0.640) for MRE, WM2BP, Fib-4, HA, APRI, and T4C, respectively. CONCLUSION: MRE has a higher diagnostic performance than biological markers in detecting the stages of liver fibrosis and is a predictor for PA after hepatectomy.

[FOLFIRINOX for Locally Advanced and Recurrent Pancreatic Cancer with UGT1A1 *6 and or UGT1A1*28 Polymorphisms-A Report of Two Cases].

Treatment containing FOLFIRINOX was planned to be administered to a 51-year-old man with locally advanced pancreatic cancer as second-line chemotherapy and to a 66-year-old woman with recurrent pancreatic cancer as third-line chemotherapy in their treatments. Since both patients were revealed to harbor UGT1A1 polymorphisms, which were highly associated with irinotecan-induced toxicity(the former: UGT1A1 *6/*28, the latter: UGT1A1*6/*6), there was no alternative hopeful treatment other than FOLFIRINOX for them. Therefore, FOLFIRINOX was administered very carefully. Although both patients showed Grade 4 neutropenia during the initial course, it was controllable with G-CSF administration and following stepwise reduction of the irinotecan dose. Severe diarrhea and other adverse events were not observed in both cases. Since the determined regimen of FOLFIRINOX for patients with high-risk UGT1A1 polymorphisms has not been developed yet, it would be critical to accumulate and review an experience of FOLFIRINOX administration for these patients.

[A Case of Long-Term Survival of Metastatic and Recurrent Duodenal Gastrointestinal Stromal Tumor Treated with Multimodality Managements].

We hereby report a case of long-term survival of metastatic and recurrent duodenal gastrointestinal stromal tumor(GIST) treated with multimodality managements. A 59-year-old man was diagnosed with duodenal GIST and underwent surgical resection of a primary lesion of the duodenum. Since the pathological findings on mitotic rate indicated its high risk of recurrence, the systemic treatment by imatinib mesylate was given shortly after the surgery. Six months later, metastatic lesions being considered to be imatinib-resistant were observed in the remnant liver. Since there were no other drugs available for GISTs in clinic at that time, surgery of central bisegmentectomy with partial resection of the liver was performed to eliminate all metastatic lesions. However, recurrences had been repeatedly diagnosed afterward. In response to them, four more surgery for recurrent liver or peritoneal tumors, two transcatheter arterial chemoembolizations(TACE)and one radiofrequency ablation(RFA)were performed on the basis of its resectability. Sunitinib malate had been given since it was approved for imatinib-resistant GISTs in clinic. Eventually, as long as 99 months had passed since we observed the first evidence of the resistance to imatinib mesylate when he died from the GIST.

[A Case of Long-Term Survival of the Pancreatic Tail Cancer with the Concomitant Small Liver Metastasis].

We hereby report a case of long-term survival of the pancreatic tail cancer with a synchronous small liver metastasis. A 62- year-old male with pancreatic tail cancer was incidentally diagnosed with single tiny metastasis in the left medial section of the liver duringthe distal pancreatectomy. The lesion was also resected together with primary lesion. Since then, systemic chemotherapies such as gemcitabine(GEM)plus S-1 combination therapy, GEM alone therapy and S-1 alone therapy had been given to escape from recurrence. However, the recurrences were found in the liver at 21 months after surgery. Left hepatectomy was performed for metastatic lesions. Afterwards, proton radiation therapy was twice performed for the metastatic lesions in the liver which were unable to be removed by surgery alone. Partial resection of transverse colon was also needed to be performed for the bowel obstruction caused by recurrence on the surgical margin of the liver. Systemic chemotherapies includingS -1 therapy, FOLFIRINOX therapy and GEM plus nab-paclitaxel therapy have been continued throughout his entire treatment history after recurrence. He has been keepingin good physical condition with these multidisciplinary therapies, even though 51 months have passed since the first evidence of liver metastasis was diagnosed.

[Regulation of PD-L1 by MicroRNA in Mismatch Repair Deficient-Colorectal Cancer].

Programmed cell death 1(PD-1)/PD-ligand 1(PD-L1)immune checkpoint blockade has emerged as a promising therapeutic strategy in various types of cancer. In a recent phase II clinical trial, treatment with the anti-PD-1 agent, pembrolizumab, resulted in considerable clinical benefit in patients with mismatch repair(MMR)-deficient colorectal cancer(CRC). Upregulation of PD-1on T-cells and PD-L1 on tumor cells induces inhibitory signals to suppress T-cell activation, leading to an immune-suppressive microenvironment particularly in MMR-deficient tumors. However, the regulation of PD-L1 expression on CRC cells is poorly understood. We hypothesized that certain microRNAs(miRNAs)are involved in the immunosuppressive microenvironment by directly targeting PD-L1. We identified candidate miRNAs by RNA-sequence analyses for mRNA and miRNA expression obtained from the TCGA colon adenocarcinoma database combined with miRNA target prediction programs. We found that forced miRNA expression could decrease PD-L1 expression on cancer cell lines. Our findings may facilitate an understanding of the role of miRNAs in PD-L1 regulation and also suggest potential miRNAs to serve as biomarkers and therapeutic targets for cancer immunotherapy.

A mouse model of KIF5B-RET fusion-dependent lung tumorigenesis.

Oncogenic fusion of the RET (rearranged during transfection) gene was recently identified as a novel driver gene aberration not only for the development of thyroid carcinoma but also of lung adenocarcinoma, the most frequent histological type of lung cancer. This study constructed and analyzed transgenic mice expressing KIF5B-RET, the predominant form of RET fusion gene specific for lung adenocarcinoma, under the control of the SPC (surfactant protein C) gene promoter. The mice expressed the KIF5B-RET fusion gene specifically in lung alveolar epithelial cells, and developed multiple tumors in the lungs. Treatment of the transgenic mice with vandetanib, which is a RET tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration for the treatment of thyroid carcinoma, for 8 or 20 weeks led to a marked reduction in the number of lung tumors (3.3 versus 0 and 6.5 versus 0.2 per tissue section, respectively; P < 0.01, t-test). The results suggest that the RET fusion functions as a driver for the development of lung tumors, whose growth is inhibited by RET tyrosine kinase inhibitors.

Coil embolization of a celiac artery pseudoaneurysm under balloon-assisted flow control: A case report.

Coil migration can occur when coil embolization is used for treating pseudoaneurysms associated with large arteries. The double microcatheter technique is useful for preventing coil migration; the balloon catheter can reduce blood flow and active bleeding upon balloon inflation, and can also compress the bleeding point and arrest bleeding temporarily. We report a case describing the management of a pseudoaneurysm with coil embolization using double microcatheters and a balloon catheter to control blood flow and prevent coil migration. A 73-year-old male patient presented with a pseudoaneurysm of the celiac artery arising from the splenic artery stump following surgery. Coil embolization of the pseudoaneurysm using a double microcatheter embolization technique with a balloon catheter was considered. A balloon catheter was inserted into the celiac artery and active bleeding was temporarily arrested with the inflated balloon. First, a microcatheter was inserted into the balloon catheter, and another microcatheter was placed in the celiac artery. An electrical detachable coil was inserted into the proximal common hepatic artery just distal to the pseudoaneurysm. The second electrically detachable coil was inserted while the first coil remained attached. After detachment of the second coil, additional electrically detachable coils were inserted for similar embolization. The balloon was gradually deflated. Finally, the first coil was detached and we confirmed absence of the bleeding. Our case report demonstrated that a balloon catheter can control the flow vessels, and the double microcatheter embolization technique with a balloon catheter is useful for coil embolization in high-flow or large vessels.

The ratio of intratumoral CD15+ neutrophils to CD8+ lymphocytes predicts recurrence in patients with gastric cancer after curative resection.

BACKGROUND: An elevated neutrophil-to-lymphocyte ratio (NLR) in peripheral blood is an independent prognostic indicator of various cancers. AIMS: In this study, we aimed to investigate the prognostic relevance of the intratumoral immune cell balance in gastric cancer. METHODS AND RESULTS: The study included 82 patients who underwent curative resection for gastric cancer. The intratumoral cluster of differentiation (CD) 15- and CD8-positive cells were evaluated using immunohistochemical staining. Additionally, clinicopathological factors and prognoses were analyzed. Patients with high intratumoral CD15/CD8 ratios had significantly lower overall survival (OS) and relapse-free survival (RFS) compared to those with low CD15/CD8 ratios (p = .0026 and p < .0001, respectively). Additionally, a high CD15/CD8 ratio was associated with lymph node metastasis (p = .019). Patients with high NLR had a significantly lower RFS than those with low NLR (p = .0050). Multivariate analysis revealed that the intratumoral CD15/CD8 ratio, NLR, and venous invasion were independent prognostic indicators of RFS (CD15/CD8 ratio: p < .001, hazard ratio (HR) = 14.7, 95% confidence interval (CI) = 3.8-56.8; NLR: p = .010, HR = 5.4, 95% CI = 1.5-19.6; venous invasion: p = .005, HR = 7.4, 95% CI = 1.8-29.7). CONCLUSION: In summary, we found that the intratumoral CD15/CD8 ratio is an independent prognostic factor following gastric cancer resection and its increase is associated with lymph node metastasis and microscopic lymph vessel invasion. Immunological evaluation with additional aspects of innate immunity may be useful in predicting cancer prognosis.

IgG4-related intrahepatic sclerosing cholangitis resulting in sepsis caused by secondary suppurative inflammation: report of a case.

We report a case of pre-disseminated intravascular coagulation caused by secondary suppurative inflammation in a patient with immunoglobulin (Ig) G4-related sclerosing cholangitis. The patient was a 78-year-old man in whom a localized stenosis of the intrahepatic bile duct was found without any other bile duct stricture or symptoms. He underwent surgical resection 6 months later for acute severe cholangitis and sepsis caused by bile duct obstruction. The resected specimen contained an abscess and nodulary mass in the liver. Immunohistochemical analysis revealed IgG4-positive plasma cell infiltration, whereby we diagnosed IgG4-related sclerosing cholangitis. As IgG4-related sclerosing cholangitis limited to within the intrahepatic portion is extremely rare, we present this case with a review of the literature.

Case report: Unusual development of hepatocellular carcinoma during immunosuppressive treatments against rheumatoid arthritis overlapping Sjögren's syndrome; cirrhotic steatohepatitis with liver inflammation and fibrosis lurks in autoimmune disorders.

The sequential progression from chronic liver disease to cirrhosis may be a risk factor for hepatocellular carcinoma (HCC) development. Although HCC originates from hepatitis B virus- or hepatitis C virus-associated liver cirrhosis, it has recently been reported in patients with non-alcoholic steatohepatitis (NASH) with advanced fibrosis. However, little is known about the pathophysiological mechanisms linking HCC to rheumatic disorders, including rheumatoid arthritis (RA). Herein, we describe the case of HCC with NASH complicated by RA and Sjögren's syndrome (SS). A fifty-two-year-old patient with RA and diabetes was referred to our hospital for further examination of a liver tumor. She received methotrexate (4 mg/week) for 3 years and adalimumab (40 mg/biweekly) for 2 years. On admission, laboratory data showed mild thrombocytopenia and hypoalbuminemia, with normal hepatitis virus markers or liver enzymes. Anti-nuclear antibodies were positive with high titers (x640), and anti-SS-A/Ro (187.0 U/ml; normal range [NR]: ≤6.9 U/mL) and anti-SS-B/La (320 U/ml; NR: ≤6.9 U/mL) antibodies were also high. Abdominal ultrasonography and computed tomography revealed liver cirrhosis and a tumor in the left lobe (S4) of the liver. She was diagnosed with HCC based on imaging findings, and elevated levels of protein induced by vitamin K absence- II (PIVKA-II) were detected. She underwent laparoscopic partial hepatectomy, and histopathological examination revealed steatohepatitis HCC with background liver cirrhosis. The patient was discharged on the 8th day post-operation without any complications. At the 30 months follow-up, no significant evidence of recurrence was observed. Our case suggests that clinical screening for HCC is needed in patients with RA who are at a high risk of NASH, as they may progress to HCC even without elevated liver enzymes.

Tissue-Engineered Hepatocyte Sheets Supplemented with Adipose-Derived Stem Cells.

The ability to engineer biologically viable hepatocytes and tissue matrices with long-term functional maintenance has attracted considerable interest in the fields of hepatocyte transplantation and liver tissue engineering. Here, newly developed hepatocyte sheets supplemented with adipose-derived stem cells (ADSCs) were evaluated to assess the effects of ADSCs on hepatocyte function and engraftment into the subcutaneous space. Eight-week-old male C57BL/6J mice were used as donors, and 6-week-old male C.B-17/Icr-scid/scid mice were used as recipients. Hepatocyte-ADSC composite sheets were developed using temperature-responsive culture dishes. Hepatocyte viability in the hepatocyte-ADSC composite sheets was evaluated in an in vitro assay, and the outcome of subcutaneous transplantation of the sheet was evaluated. Hepatocyte viability was sustained in the hepatocyte-ADSC composite sheets in vitro. Albumin secretion was significantly higher (p = 0.015) in the hepatocytes of the hepatocyte-ADSC composite sheets (70.5 µg/mL) than in hepatocyte-only sheets (24.0 µg/mL). Cytokine assays showed that hepatocyte growth factor and interleukin-6 were contributed by ADSCs and not hepatocytes, which were not capable of constitutively secreting them. Immunohistochemically, phosphorylated STAT3 and c-MET expression in hepatocytes in the hepatocyte-ADSC composite sheets was significantly higher than that in the hepatocyte-only sheets. Engraftment of the transplanted hepatocyte-ADSC composite sheets was significantly enhanced without pretreatment of the subcutaneous tissue to induce a vascular network. In the hepatocyte-ADSC composite sheets, the viability of the hepatocytes was significantly maintained as the co-cultured ADSCs provided cytokines, enhancing pivotal cell signaling necessary for hepatocyte activity. Impact statement Hepatocyte transplantation is a safe, less invasive bridge treatment for liver transplantation, but its effectiveness is low and transitory. Herein, we introduce newly developed hepatocyte-adipose-derived stem cell composite sheets with improved strength, easier transplantation, and increased hepatocyte viability in the subcutaneous transplantation compared with hepatocyte-only sheets.

Aberrant phosphorylation of human LRH1 at serine 510 is predictable of hepatocellular carcinoma recurrence.

We previously identified the AKT-phosphorylation sites in nuclear receptors and showed that phosphorylation of S379 in mouse retinoic acid γ and S518 in human estrogen receptor α regulate their activity independently of the ligands. Since this site is conserved at S510 in human liver receptor homolog 1 (hLRH1), we developed a monoclonal antibody (mAb) that recognized the phosphorylation form of hLRH1S510 (hLRH1pS510) and verified its clinicopathological significance in hepatocellular carcinoma (HCC). We generated the anti-hLRH1pS510 mAb and assessed its selectivity. We then evaluated the hLRH1pS510 signals in 157 cases of HCC tissues by immunohistochemistry because LRH1 contributes to the pathogenesis of diverse cancers. The developed mAb specifically recognized hLRH1pS510 and worked for immunohistochemistry of formalin-fixed paraffin-embedded tissues. hLRH1pS510 was exclusively localized in the nucleus of HCC cells, but the signal intensity and positive rates varied among the subjects. According to the semi-quantification, 45 cases (34.9%) showed hLRH1pS510-high, and the remaining 112 cases (65.1%) exhibited hLRH1pS510-low. There were significant differences in the recurrence-free survival (RFS) between the two groups, and the 5-year RFS rates in the hLRH1pS510-high and hLRH1pS510-low groups were 26.5% and 46.1%, respectively. In addition, high hLRH1pS510 was significantly correlated with portal vein invasion, hepatic vein invasion, and high levels of serum alpha-fetoprotein (AFP). Furthermore, multivariable analysis revealed that hLRH1pS510-high was an independent biomarker for HCC recurrence. We conclude that aberrant phosphorylation of hLRH1S510 is a predictor of poor prognosis for HCC. The anti-hLRH1pS510 mAb could provide a powerful tool to validate the relevance of hLRH1pS510 in pathological processes such as tumor development and progression.

[A case of carcinoma associated with anal fistula in which reconstruction using a gracilis musculocutaneous flap was performed after preoperative chemoradiotherapy].

The patient was a 47-year-old man with a 24-year history of anal fistula. A carcinoma associated with anal fistula was diagnosed after a biopsy was performed because the anal fistula was not improving. Computed tomography and magnetic resonance imaging showed that the tumor had invaded the spongy urethra. Therefore, preoperative chemotherapy(S-1 plus radiation at a dose of 60 Gy/body) was performed. Because the size of tumor decreased, we performed abdominoperineal resection with reconstruction using a gracilis musculocutaneous flap, which enabled the spongy urethra to be fully preserved. Histopathologically, no cancer cells were found to exist on the surgical margin. This case suggested that surgical treatment combined with preoperative chemoradiotherapy may be effective for locally advanced carcinoma associated with anal fistula. Furthermore, improvement of the reconstruction technique for both pelvic and perianal skin defects due to extended resection is an important element of curative surgery.

Laparoscopic Surgery for Acute Diffuse Peritonitis Due to Gastrointestinal Perforation: A Nationwide Epidemiologic Study Using the National Clinical Database.

Background: Elective laparoscopic surgery is now widely accepted in the treatment of abdominal diseases because of its minimal invasiveness and rapid postoperative recovery. It is also used in the emergency setting for the diagnosis and treatment of acute diffuse peritonitis regardless of the causative disease. However, the value of laparoscopy in acute diffuse peritonitis remains unclear. In this study we aimed to show trends in the use of laparoscopy over time and compare the real-world performance of laparoscopic surgery with that of open surgery for acute diffuse peritonitis due to gastrointestinal perforation. Methods: We extracted data from the National Clinical Database, a nationwide surgery registration system in Japan, for patients with a diagnosis of acute diffuse peritonitis due to gastroduodenal or colorectal perforation between 2016 and 2019. Trends in the use of laparoscopy over time were identified. Patient characteristics, laboratory findings, surgical findings, and postoperative complications were compared between laparoscopic surgery and open surgery. Results: Patients in poor condition and those with abnormal laboratory findings tended to undergo open surgery. Anesthesia time and operating time were longer for laparoscopic surgery in patients with gastroduodenal perforation but shorter in those with colorectal perforation. Fewer complications occurred in patients who underwent laparoscopic surgery. The number of institutions where laparoscopic surgery was performed and the proportion of the use of laparoscopy at each institution increased over time. Conclusion: The use of laparoscopy is becoming common in surgery for acute diffuse peritonitis due to gastrointestinal perforation. This approach may be a useful option for acute diffuse peritonitis.

Intratumor Abscess in a Posttraumatic Hepatic Inflammatory Pseudotumor Spreading Out of the Liver.

A 45-year-old woman with abdominal pain after minor trauma was referred to our hospital. Computed tomography (CT) showed a hypovascular tumor in the left liver lobe. A tumor biopsy revealed granuloma, although no findings indicated malignancy or infection. A follow-up imaging study showed spread of the hepatic tumor. Her abdominal pain worsened after a second minor trauma. CT revealed an intratumor abscess, and pus overflowed from the patient's umbilicus. The abscess was improved by antibiotics and drainage therapy. In this case, unusual imaging findings and an atypical disease course of a hepatic inflammatory pseudotumor were observed.

Early intra-abdominal infection following pancreaticoduodenectomy:associated factors and clinical impact on surgical outcome.

Early intra-abdominal infection (IAI) following pancreaticoduodenectomy (PD) is an initial event relating to morbidities caused by postoperative pancreatic fistula (POPF). The aims of this study were to determine factors associated with IAI, and to investigate its impact on postoperative outcome.Consecutive patients, 113 in total, who underwent PD at Fukushima Medical University Hospital between January 2012 and September 2017 were included in this retrospective study. IAI was defined by positive bacterial culture from intra-abdominal drainage fluid any time through postoperative day 3 (POD3). Logistic regression analysis was used to identify the relevant factors associated with IAI. The clinical impact of the POD3 infection indicators related to POPF were assessed by multivariate analysis.The incidence of IAI, POPF, and mortality were 36.1%, 36.1%, and 0%, respectively. Independent factors associated with IAI were preoperative biliary drainage (PBD) (OR = 2.91, CI = 1.16-7.33, p = 0.023) and soft pancreas (OR = 8.67, CI = 2.37-31.77, p = 0.001). Among infection markers on POD3, the significant factors for POPF were CRP (OR = 1.18, CI = 1.08-1.30, p < 0.001), IAI (OR = 7,37, CI = 2.53-21.5, p < 0.001), and drain amylase (OR = 1.00, CI = 1.00-1.01, p = 0.001).In conclusion, PBD, soft pancreas, and higher age were associated with IAI. IAI has a significantly negative impact on postoperative outcome.

[Efficacy and safety of high-dose toremifene for hormone-responsive advanced or metastatic breast cancer patients with failed prior treatment by aromatase inhibitors].

BACKGROUND: Recently, aromatase inhibitors (AI) are widely used in postoperative adjuvant therapy for breast cancer. Nevertheless, studies of postoperative therapeutic strategies for recurrent breast cancer are insufficient. SUBJECTS AND METHOD: Data on 12 post-menopausal advanced/recurrent breast cancer patients in our department during June 2003- April 2007 were used for this study. No patient had responded to high-dose toremifene (TOR), a third-generation AI. Their therapeutic outcomes were analyzed retrospectively. The median observation period of the subjects was 16.1 months (4.0-40.9 months). Subjects were all hormone-sensitive. Overexpression of HER2 protein was found in only one case. During AI therapy immediately prior, exemestane (EXE) and anastrozole (ANA) had been given in nine and three cases, respectively. RESULTS: The complete response rate of AI therapy was 16.7% (2/12). The clinical benefit rate was 58.3% (7/12). The median of time to progression (TTP) was 33.8 weeks. Neither the presence nor absence of past history of treatment with tamoxifen (TAM) or other chemotherapies affected the anti-tumor effect. Analysis by the site of metastasis or recurrence revealed that the therapeutic effects were better for non-life-threatening cases in the lung, pleura, soft tissue, etc. The severities of adverse effects were all less than grade 2; the major ones were flushing and sweating. CONCLUSION: Results show that high-dose TOR given at an early stage can provide clinical benefits for post-menopausal advanced/recurrent breast cancer not responding to AI.

miRNA-148a-3p Regulates Immunosuppression in DNA Mismatch Repair-Deficient Colorectal Cancer by Targeting PD-L1.

Immunotherapy against the interaction between programmed cell death 1/programmed cell death ligand 1 (PD-L1) has emerged as a promising strategy for colorectal cancer with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). The study aimed to identify miRNAs that posttranscriptionally control PD-L1 expression on tumor cells and also regulate immune evasion. A comprehensive miRNA screening using The Cancer Genome Atlas (TCGA) dataset (n = 260) combined with eight different miRNA target prediction programs resulted in the identification of a tumor suppressive miRNA, miR-148a-3p, as a potential negative regulator of PD-L1 expression, particularly in dMMR/MSI-H colorectal cancer. Using multiple cohorts of colorectal cancer, including TCGA data, a microarray dataset (n = 148), and formalin-fixed, paraffin-embedded samples (n = 395), we found that the expression of miR-148a-3p was decreased in dMMR/MSI-H tumors, correlating inversely with PD-L1 levels. We demonstrate that miR-148a-3p directly binds to the 3'-untranslated region of PD-L1, thereby reducing whole-cell and cell surface PD-L1 levels in HCT116 and SW837 cell lines. Overexpression of miR-148a-3p repressed IFNγ-induced PD-L1 expression on tumor cells and consequently diminished T-cell apoptosis in a coculture model of IL2-activated T cells and IFNγ-treated tumor cells. In conclusion, our data support a regulatory mechanism of PD-L1 expression on tumor cells and immune suppression via miR-148a-3p downregulation in colorectal cancer. IMPLICATIONS: This study provides novel evidence that miR-148a-3p negatively regulates tumor cell PD-L1 expression and decreased levels of miR-148a-3p contributes to the immunosuppressive tumor microenvironment.