Preoperative diagnosis of tumor depth in gastric cancer using transabdominal ultrasonography compared to using endoscopy and computed tomography.

BACKGROUND: An accurate evaluation method for preoperative diagnosis has not yet been established in patients with gastric cancer (GC), though it is essential for optimal treatment. Current standard modalities are endoscopy and contrast computed tomography (CT). In this study, we investigated the efficacy and limitations of transabdominal ultrasonography (TUS) for the assessment of tumor invasion. METHODS: We enrolled 178 consecutive patients with GC evaluated by TUS, endoscopy, and contrast CT before gastrectomy. For the TUS examination, patients ingested water to fill their stomachs. The clinical staging determined using these modalities was compared to the pathological staging. RESULTS: The overall accuracy of clinical T staging using TUS was 47.8% (pT1a: 5.8% (2/35); pT1b: 58.8% (20/35); pT2: 69.6% (16/23); pT3: 66.7% (22/33); pT4a: 46% (23/50); pT4b: 100% (2/2)). Using endoscopy, contrast CT, and TUS, the overall accuracy was 60.7%. The accuracy of TUS was associated with the tumor region (U region: 50% (14/28); M: 31.8% (14/44); L: 53.7% (57/106); P = 0.048), but not with the cross-sectional parts (P = 0.49). Multivariate analysis identified inaccurate TUS as independently correlating with tumor region (M vs. U/L, odds ratio (OR) = 3.11, 95% confidence interval (CI) 1.41-6.87; P = 0.005) and pT (pT1 vs. pT2-4, OR = 3.00, 95%CI 1.31-6.87; P = 0.009). CONCLUSIONS: The present study demonstrated the importance of TUS in evaluating GC. Thus, TUS may be useful for clinical T staging in certain circumstances, leading to treatment optimization.

[A Case of Peritoneal Lymphomatosis Diagnosed by Single-Port Laparoscopic Biopsy].

Peritoneal lymphomatosis is an extremely rare presentation of non-Hodgkin lymphoma. We report a case of peritoneal lymphomatosis diagnosed by single-port laparoscopic biopsy. A 70-year-old woman presented to our hospital with a 2-day history of increasing abdominal distension. Abdominal CT and positron emission tomography/CT(PET-CT)demonstrated extensive disseminated disease with marked thickening of the peritoneal surfaces, and a large omental cake with large volume ascites. Under the diagnosis of peritoneal carcinoma, single-port laparoscopic biopsy was performed. Pathological and immunohistochemical examination revealed diffuse large B-cell lymphoma presenting as peritoneal lymphomatosis. She was treated with a combination chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, and prednisolone(R- CHOP), and no recurrence was reported for 1 year and 6 months. Single-port laparoscopic biopsy was minimally invasive, and helpful for an urgent and accurate diagnosis and treatment of the disseminated peritoneal disease.

Endogenous CXCL9 affects prognosis by regulating tumor-infiltrating natural killer cells in intrahepatic cholangiocarcinoma.

CXCL9, an IFN-γ inducible chemokine, has been reported to play versatile roles in tumor-host interrelationships. However, little is known about its role in intrahepatic cholangiocarcinoma (iCCA). Here, we aimed to elucidate the prognostic and biological implications of CXCL9 in iCCA. Endogenous CXCL9 expression and the number of tumor-infiltrating lymphocytes were immunohistochemically assessed in resection specimens. These data were validated in mice treated by silencing CXCL9 with short hairpin RNA. In addition, the induction of endogenous CXCL9 and the effects of CXCL9 on tumor biological behaviors were evaluated in human cholangiocarcinoma cell lines. Immunohistochemical analyses revealed that high CXCL9 expression was closely correlated with prolonged postoperative survival and a large number of tumor-infiltrating natural killer (NK) cells. In fact, due to the trafficking of total and tumor necrosis factor-related apoptosis-inducing ligand-expressing NK cells into tumors, CXCL9-sufficient cells were less tumorigenic in the liver than CXCL9-deficient cells in mice. Although CXCL9 involvement in tumor growth and invasion abilities differed across cell lines, it did not exacerbate these abilities in CXCL9-expressing cell lines. We showed that CXCL9 was useful as a prognostic marker. Our findings also suggested that CXCL9 upregulation might offer a therapeutic strategy for treating CXCL9-expressing iCCA by augmenting anti-tumor immune surveillance.

Plasma ghrelin suppression as an early predictor for postoperative complications after pancreatoduodenectomy.

BACKGROUND/OBJECTIVES: The gut peptide hormone ghrelin induces appetite and exhibits an anti-inflammatory effect. Serial perioperative changes in ghrelin have been examined in several surgical procedures, but few in pancreatectomy. The present study analyzed perioperative changes in plasma ghrelin levels after pancreaduodenectomy (PD). METHODS: The study included 24 patients undergoing PD between May 2015 and January 2016 at Osaka University Hospital. Plasma ghrelin and interleukin-6 (IL-6) levels, as well as white blood cells (WBCs) and C-reactive protein (CRP), were measured preoperatively and on postoperative day (POD) 1, 3, 7, and 14 by enzyme-linked immunosorbent assay. The relationship between the individual ghrelin ratio relative to preoperative value (IGR) and the development of grade IIIa-V Clavien-Dindo (CD) complications was examined. RESULTS: Twelve patients (50%) developed grade IIIa CD complications (n = 6 [25%] pancreatic fistula, n = 7 [29%] intraabdominal abscess, n = 3 [13%] post-pancreatectomy hemorrhage, n = 5 [21%] wound infection, and n = 1 [4%] lymphorrhea). The IGR on POD 1 was significantly lower (p = 0.014) in patients who developed the complications compared to those who did not, but no significant differences were found in terms of WBC, CRP, or IL-6 on POD 1. When the IGR cut-off was set to 82% by receiver operative curve analysis, the sensitivity was 83%, specificity 75% and area under the curve 0.80. The lower IGR group (≤82%) had more postoperative complications and longer hospital stay. CONCLUSIONS: The IGR on POD 1 after PD is a useful marker for predicting postoperative complications.

Clinical Impact of Preoperative Sarcopenia on the Postoperative Outcomes After Pancreas Transplantation.

BACKGROUND: The importance of evaluating sarcopenia is increasingly being recognized in the field of transplantation because sarcopenia can have an adverse effect on the treatment outcomes. However, the clinical significance of preoperative sarcopenia on the postoperative outcomes following pancreas transplantation (PTx) has been largely unknown. The objective of this study was to investigate the role of preoperative sarcopenia in predicting the postoperative outcomes following PTx in recipients with type 1 diabetes mellitus (T1D). METHODS: Forty-one recipients with severe T1D who underwent PTx were retrospectively reviewed. The psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC), as determined by preoperative computed tomography, were substituted for the quantity and quality of skeletal muscle for the definition of sarcopenia, respectively. Gender-specific quartiles were generated, and PMI lower than the first quantile or IMAC higher than the third quantile was considered to represent sarcopenia. The postoperative outcomes included postoperative surgical complications and pancreas graft survival. RESULTS: Sarcopenia was identified in 11 recipients according to both the PMI and IMAC stratifications. The multivariate analyses revealed that high IMAC was independently associated with the development of postoperative surgical complications (odds ratio, 9.35; p = 0.016). In addition, the recipients with high IMAC showed unfavorable graft survival compared to those with normal IMAC (log-rank test; p = 0.038). In contrast, low PMI was not significantly associated with the postoperative outcomes. CONCLUSIONS: Our data suggested that preoperative sarcopenia, especially a decline in the quality of skeletal muscle, predicted poorer postoperative outcomes in T1D recipients undergoing PTx.

[A Case of Repeated Surgical Resections for Tumor Seeding of Hepatocellular Carcinoma after Radiofrequency Ablation].

We report a case of repeated surgical resections for the tumor seeding of hepatocellular carcinoma(HCC)after radiofrequency ablation(RFA). A 79-year-old man, who had an intrahepatic recurrence of HCC(segment 2)5 months after RFA, was referred to our hospital for surgery, and underwent a laparoscopic lateral segmentectomy. Histological examination showed a poorly differentiated HCC(pStage II). Eight months after RFA, subcutaneous nodules along the RFA needle tract were pointed out by abdominal CT, and a tumorectomy was performed. Nineteen months after RFA, abdominal CT showed a 33mm tumor on the side of the spleen, leading to the diagnosis of the peritoneal dissemination following RFA. The tumor has been growing up to 49mm in size in spite of a radiation therapy. Accordingly, a laparoscopic tumorectomy was performed 26 months after RFA. His resected tumors were morphologically identical to the intrahepatic recurrence of HCC. The patient had remained recurrence-free for 4 months after the second tumorectomy. Our case demonstrated the utility of surgical resection for the tumor seeding of HCC following RFA.

CT Density in the Pancreas is a Promising Imaging Predictor for Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Fatty pancreas (FP) was recently recognized as a risk factor for pancreatic ductal adenocarcinoma (PDAC). It is unclear whether computed tomography (CT) can be used to make a FP diagnosis. This study investigated whether CT could provide a predictive value for PDAC by diagnosing FP. METHODS: The study included 183 consecutive patients who underwent distal pancreatectomy from February 2007 to January 2017, including 75 cases of PDAC and 108 cases of other pancreatic disease. Pancreatic CT density (pancreatic index; PI) at the initial diagnosis was calculated by dividing the CT number in the pancreas by the number in the spleen. To assess whether CT could be used to detect FP, 43 cases were evaluated pathologically for FP. We investigated the correlation between FP and PI, and determined the optimal PI cutoff value for detecting FP using receiver operating characteristics analysis. We then investigated whether the PI value could be used as a predictor for PDAC. RESULTS: Fourteen cases (32.6%) were pathologically diagnosed with FP. PI was significantly lower in the FP group versus the non-FP group (0.51 vs. 0.83; p = 0.0049). ROC analysis indicated that the PI had good diagnostic accuracy for FP diagnosis (cutoff value 0.70; sensitivity 0.79, specificity 0.79). Low PI (≤0.70) was identified in the multivariate analysis as an independent risk factor for PDAC (odds ratio 2.31; p = 0.023). CONCLUSIONS: PI was strongly associated with pathological FP, which was independently associated with PDAC. PI shows promise as an imaging predictor for PDAC.

Prognostic impact of nodal statuses in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The present study aimed to clarify the prognostic impact of nodal statuses in pancreatic ductal adenocarcinoma (PDAC) after potentially curative pancreatectomy. METHODS: In 110 patients with >10 examined lymph nodes (ELNs), we investigated how nodal statuses were associated with postoperative survival. Nodal statuses included the number of positive LNs (PLNs); the ratio of PLNs to ELNs (lymph node ratio; LNR); and the location of regional LN metastases, classified as group one (peripancreatic area) and group 2 (outside the peripancreatic area). The maximum χ2 value, provided by a Cox proportional hazards model, was used to determine the optimal cutoff value for the number of PLNs and the LNR. RESULTS: The median numbers of ELNs and metastatic LNs were 33 and 2, respectively. Median survival was longer in patients with ≤3 PLNs (37.5 months), LNR <0.11 (36.1 months), and group 1 LN metastases (37.5 months) compared to in patients with ≥4 PLNs (23.7 months), LNR ≥0.11 (23.9 months), and group 2 LN metastases (22.8 months), respectively. Multivariate analyses revealed that all three investigated nodal statuses were independent factors associated with survival: HR of 2.38 and p = 0.0006 for the location of LN metastases, HR of 1.92 and p = 0.0071 for the number of PLNs, and HR of 1.89 and p = 0.010 for the LNR. CONCLUSIONS: Three nodal statuses-the number of PLNs, the LNR, and the location of LN metastases-could stratify postoperative survival among PDAC patients with an adequate number of examined LNs after pancreatectomy.

Effectiveness of a preoperative exercise and nutritional support program for elderly sarcopenic patients with gastric cancer.

We established a preoperative exercise and nutritional support program for elderly sarcopenic patients with gastric cancer. Twenty-two gastric cancer patients aged 65 years or older with a diagnosis of sarcopenia according to the algorithm proposed by the European Working Group on Sarcopenia in Older People received our preoperative program. The median duration of the program participation was 16 days. Total calorie and protein intakes were significantly higher after the program than before [29.4 ± 6.9 kcal/kg ideal body weight (IBW) vs 27.3 ± 5.6 kcal/kg IBW, p = 0.049, and 1.3 ± 0.4 g/kg IBW vs 1.1 ± 0.3 g/kg IBW, p = 0.0019, respectively]. Handgrip strength significantly increased after the program (21.2 ± 5.2 kg vs 20.0 ± 5.3 kg, p = 0.022). Likewise, gait speed and skeletal muscle mass index increased, although the differences did not reach statistical significance. Four patients became nonsarcopenic after the program. Postoperative complications were observed in three patients (13.6%); however, none of these complications were severe (Clavien-Dindo grade III or lower). A preoperative exercise and nutritional support program has the potential to reduce sarcopenia and improve postoperative outcome in elderly sarcopenic patients with gastric cancer.

A novel preoperative predictor of pancreatic fistula using computed tomography after distal pancreatectomy with staple closure.

PURPOSE: A thick pancreas has proven to be a conspicuous predictor of pancreatic fistula (PF) following distal pancreatectomy (DP) using staples. Other predictors for this serious surgical complication currently remain obscure. This study sought to identify novel predictors of PF following DP. METHODS: One hundred and twenty-two patients were retrospectively assessed to determine the correlation between PF occurrence and the clinicopathological findings and radiologic data from preoperative computed tomography (CT). CT assessments included the thickness of the pancreas (TP) and pancreatic CT number (pancreatic index; PI), calculated by dividing the pancreatic CT by the splenic CT density. RESULTS: Twenty-four patients (19.7%) developed a clinically relevant PF. TP was identified as an independent risk factor for PF in multivariate analyses (odds ratio 1.17; P = 0.0095). In subgroup analyses, a lower PI in a thick pancreas was a significant predictor of PF (P = 0.032). The combination of these two prediction parameters, known as the TP-to-PI ratio (TPIR), showed a significantly better prediction ability than TP alone (area under the receiver operating characteristic curve for the incidence of PF, TPIR 0.80 vs. TP 0.69; P = 0.037). CONCLUSION: Combining the CT number with TP substantially improves the prediction ability for the incidence of PF following DP with staple use.

Sarcopenia is associated with severe postoperative complications in elderly gastric cancer patients undergoing gastrectomy.

BACKGROUND: Malignancy is a secondary cause of sarcopenia, which is associated with impaired cancer treatment outcomes. The aim of this study was to investigate the prevalence of preoperative sarcopenia among elderly gastric cancer patients undergoing gastrectomy and the differences in preoperative dietary intake and postoperative complications between sarcopenic and non-sarcopenic patients. METHODS: Ninety-nine patients over 65 years of age who underwent gastrectomy for gastric cancer were analyzed. All patients underwent gait and handgrip strength testing, and whole-body skeletal muscle mass was measured using a bioimpedance analysis technique based on the European Working Group on Sarcopenia in Older People (EWGSOP) algorithm for the evaluation of sarcopenia before surgery. Preoperative dietary intake was assessed using a food frequency questionnaire. RESULTS: Of these patients, 21 (21.2 %) were diagnosed with sarcopenia. Sarcopenic patients consumed fewer calories and less protein preoperatively (23.9 vs. 27.8 kcal/kg ideal weight/day and 0.86 vs. 1.04 g/kg ideal weight/day; P = 0.001 and 0.0005, respectively). Although the overall incidence of postoperative complications was similar in the two groups (57.1 % vs. 35.9 %; P = 0.08), the incidence of severe (Clavien-Dindo grade ≥ IIIa) complications was significantly higher in the sarcopenic group than in the non-sarcopenic group (28.6 % vs. 9.0 %; P = 0.029). In the multivariate analysis, sarcopenia alone was identified as a risk factor for severe postoperative complications (odds ratio, 4.76; 95 % confidence interval, 1.03-24.30; P = 0.046). CONCLUSIONS: Preoperative sarcopenia as defined by the EWGSOP algorithm is a risk factor for severe postoperative complications in elderly gastric cancer patients undergoing gastrectomy.

Prevalence of Malnutrition Among Gastric Cancer Patients Undergoing Gastrectomy and Optimal Preoperative Nutritional Support for Preventing Surgical Site Infections.

BACKGROUND: Malnutrition is an independent risk factor for postoperative mortality and morbidity in major gastrointestinal surgery. The aim of this study was to investigate the prevalence of malnutrition and identify the optimal preoperative nutritional support for preventing postoperative surgical site infections (SSIs) in malnourished gastric cancer patients undergoing gastrectomy. METHODS: We analyzed 800 patients with gastric cancer who underwent gastrectomy. Nutritional risk factors included weight loss >10 % within 6 months, body mass index <18.5 kg/m(2), Subjective Global Assessment Grade C, and serum albumin <3.0 g/dl. Adequate energy intake was defined as receiving ≥25 kcal/kg ideal body weight per day. Optimal nutritional support was examined in terms of both duration and calorie intake. RESULTS: Overall, 152 patients (19.0 %) were classified as malnourished. The incidence of SSIs was significantly higher in malnourished patients than in well-nourished patients (35.5 vs. 14.0 %; p < 0.0001). The incidence of SSIs in malnourished patients was significantly lower in the well-supported group receiving adequate energy support for at least 10 days than in the poorly-supported group, which received inadequate or no energy support or adequate energy support for <10 days (17.0 vs. 45.4 %; p = 0.0006). In multivariate analysis, well-managed nutritional support was identified as an independent factor associated with fewer SSIs (odds ratio 0.14; 95 % confidence interval 0.05-0.37; p = 0.0002). CONCLUSIONS: Malnutrition, a risk factor for SSI, was prevalent in gastric cancer patients preoperatively. Well-managed preoperative nutritional support decreased the incidence of postoperative SSIs in malnourished patients.

[A case of HER2-positive advanced gastric cancer with extensive lymph node metastasis treated via chemotherapy with a trastuzumab-containing regimen followed by conversion surgery].

A 62-year-old man presented with type 3 gastric cancer (tub1, HER2 positive) in the cardia, with 10-cm direct invasion into the lower esophagus, and extensive lymph node metastasis (Virchow and paraaortic nodes). Trastuzumab (Her), in the XP regimen (capecitabine and cisplatin [CDDP] plus Her; Xeloda®: 2,000 mg/m² on day 1-14, CDDP: 80 mg/m² on day 1, Her: 8(6) mg/kg on day 1), was administered every 3 weeks and repeated for 6 courses. After administering 6 courses of the XP plus Her regimen, without severe adverse events in the patient, computed tomography (CT) revealed shrinkage of both the main tumor and the metastatic sites, by 51%. Esophagectomy and proximal gastrectomy with 3-field lymphadenectomy and gastric tube reconstruction was performed via right thoracotomy and laparotomy (R0). However, Grade 3 pneumonia occurred postoperatively, and the patient was discharged on day 67 after surgery. After treatment, the tumor was histologically evaluated as Grade 1b gastric cancer, and remnant cancer cells also expressed HER2. The patient was too frail to receive adjuvant chemotherapy, and he died of pneumonia 11 months after surgery, without obvious relapse. Perioperative chemotherapy with a regimen containing Her has a possible role in treating advanced HER2-positive gastric cancer. Multiple invasive conversion surgeries might decrease the feasibility of adjuvant chemotherapy and worsen the prognosis.

[A case of resection margin involvement gastric carcinoma that relapsed late after additional gastrectomy].

We report a case of a patient with resection margin involvement gastric carcinoma that recurred 5.5 years after additional resection. A 64-year-old man underwent distal gastrectomy for advanced gastric carcinoma (sig+por2, pSE, pN0, pStage IIB) in January 2008. A total gastrectomy was performed 2 months after the initial gastrectomy because of proximal resection line involvement, and curative resection was obtained. Adjuvant chemotherapy with S-1 was completed, and follow-up surveillance was finished 5 years after the additional surgery. In November 2013, the patient experienced bouts of vomiting, and a computed tomography (CT) scan showed an abdominal abscess that had spread to the liver and communicated with the intestine. Despite abscess drainage and antibiotic therapy, infection control was difficult and the patient died 20 days after hospitalization. An autopsy showed the recurrence lesions had diffusely spread to the peritoneum and was also disseminated around the Roux-Y jejunum. These findings suggest that peritoneal recurrence might lead to penetration of the intestine and abscess formation.

[A case of metachronous triple cancer treated with a multimodal approach including surgical resection].

We report a patient with metachronous triple cancer of the hypopharynx, esophagus, and tongue. A 37-year-old man with hypopharyngeal cancer underwent hypopharyngolaryngectomy and cervical lymphadenectomy in 1999. Submental lymphadenectomy following adjuvant radiotherapy was performed for lymph node recurrence in 2000. The patient then underwent esophagectomy for esophageal cancer in 2004. Subsequently, the patient underwent 2 partial resections and 1 subtotal resection of the tongue for tongue cancer in 2005, 2007, and 2008, respectively. The pathological findings for each cancer were squamous cell carcinoma. Two rounds of radiotherapy were performed for bone metastasis of the esophageal cancer and for the local recurrence of the tongue cancer. A total of 7 lines of chemotherapy, including superselective arterial infusion chemotherapy, were administered to treat the recurrences. The patient died in 2013, but he showed long-term survival of 13 years from the first operation owing to the multimodality treatment.

[A case of advanced gastric cancer successfully treated with second-line chemotherapy followed by curative conversion gastrectomy].

We report a case of advanced gastric cancer that was successfully treated with second-line chemotherapy followed by curative conversion gastrectomy. The patient was a 71-year-old man. Endoscopic examination revealed a type 3 gastric cancer in the lower third of the stomach. Abdominal computed tomography (CT) revealed multiple lymph node metastases and metastasis to the peritoneal cavity. The clinical diagnosis was cT4N3aP1H0M1(LYM), cStage IV. The patient was treated with S-1 (80 mg/m² on days 1-28, every 6 weeks [q6w]) in November 2009. Temporarily, both the size of the primary lesion and the swelling of the lymph nodes were markedly reduced. However, after 10 courses of chemotherapy, the primary lesion was found to be enlarged again. The patient was then treated with S-1(80 mg/m², on days 1-14, every 6 weeks [q3w]) plus CPT- 11 (150 mg/m² on day 1, q3w) as the second-line chemotherapy. After 8 courses, an abdominal CT showed no peritoneal or lymph node metastases, but gastric endoscopy revealed the presence of a residual primary lesion. After staging laparoscopy, distal gastrectomy with D2 lymphadenectomy was performed. The histological diagnosis was ypT3 (SS) N1M0, Stage IIB. Analysis of the histological features of the primary tumor and peritoneal metastases resulted in their classifications as Grade 1a and Grade 3, respectively. After surgery, there were no serious adverse events. The patient has been in good health without recurrence for over 3 years after surgery.

Endometrioid adenocarcinoma arising from inguinal endometriosis during follow-up for gastric cancer surgery: a case report and literature review.

Malignant transformation of inguinal endometriosis is rare. A 56-year-old woman underwent surgery for advanced gastric cancer 5 years ago and received postoperative adjuvant chemotherapy. She had no recurrence since then. However, 5 years after surgery, contrast-enhanced computed tomography (CT) showed a mass in the right inguinal region suspected to be a hydrocele of the canal of Nuck, with a blood test showing a slightly elevated CA19-9 level (63.0 U/mL). Six months later, CT showed an enlarged mass in the right inguinal region and inflammation in the surrounding area. In addition, both inguinal lymph nodes and those in the right iliac artery area were enlarged, suggesting the possibility of malignancy. For diagnostic purposes, a right inguinal mass was excised. Histopathological examination revealed that it was endometrioid adenocarcinoma with ectopic endometriois as the origin. The differential diagnoses for inguinal masses in women include an inguinal hernia, hydrocele of the canal of Nuck, ectopic endometriosis, lymphoma, and metastatic malignancy. The presence of a primary malignancy in the inguinal region is sporadic but must be differentiated. This is the first case of malignant transformation of inguinal endometriosis developed during postoperative follow-up of another cancer.

Inhibition of Microsomal Prostaglandin E2 Synthase Reduces Collagen Deposition in Melanoma Tumors and May Improve Immunotherapy Efficacy by Reducing T-cell Exhaustion.

The arachidonic acid pathway participates in immunosuppression in various types of cancer. Our previous observation detailed that microsomal prostaglandin E2 synthase 1 (mPGES-1), an enzyme downstream of cyclooxygenase 2 (COX-2), limited antitumor immunity in melanoma; in addition, genetic depletion of mPGES-1 specifically enhanced immune checkpoint blockade therapy. The current study set out to distinguish the roles of mPGES-1 from those of COX-2 in tumor immunity and determine the potential of mPGES-1 inhibitors for reinforcing immunotherapy in melanoma. Genetic deletion of mPGES-1 showed different profiles of prostaglandin metabolites from that of COX-2 deletion. In our syngeneic mouse model, mPGES-1-deficient cells exhibited similar tumorigenicity to that of COX-2-deficient cells, despite a lower ability to suppress PGE2 synthesis by mPGES-1 depletion, indicating the presence of factors other than PGE2 that are likely to regulate tumor immunity. RNA-sequencing analysis revealed that mPGES-1 depletion reduced the expressions of collagen-related genes, which have been found to be associated with immunosuppressive signatures. In our mouse model, collagen was reduced in mPGES-1-deficient tumors, and phenotypic analysis of tumor-infiltrating lymphocytes indicated that mPGES-1-deficient tumors had fewer TIM3+ exhausted CD8+ T cells compared with COX-2-deficient tumors. CAY10678, an mPGES-1 inhibitor, was equivalent to celecoxib, a selective COX-2 inhibitor, in reinforcing anti-PD-1 treatment. Our study indicates that mPGES-1 inhibitors represent a promising adjuvant for immunotherapies in melanoma by reducing collagen deposition and T-cell exhaustion. Significance: Collagen is a predominant component of the extracellular matrix that may influence the tumor immune microenvironment for cancer progression. We present here that mPGES-1 has specific roles in regulating tumor immunity, associated with several collagen-related genes and propose that pharmacologic inhibition of mPGES-1 may hold therapeutic promise for improving immune checkpoint-based therapies.

Indirect cholecystoduodenal fistula via hepatoduodenal ligament secondary to gangrenous cholecystitis: a case report.

BACKGROUND: Cholecystoduodenal fistula is an infrequent complication of gallbladder diseases. In the majority of cases, the fistula is formed by direct communication between the gallbladder and duodenum due to gallstone impaction in the gallbladder neck. We herein report a rare case of indirect cholecystoduodenal fistula via the hepatoduodenal ligament secondary to gangrenous cholecystitis. CASE PRESENTATION: An 80-year-old woman suspected of having emphysematous cholecystitis by a previous doctor was referred to our hospital for urgent surgery. The initial diagnosis based on additional examinations was gangrenous cholecystitis penetrating the hepatoduodenal ligament. Since she did not complain of signs of peritonitis and was taking an anticoagulant medicine, we avoided surgery and selected percutaneous gallbladder drainage (PTGBD) instead. Contrast imaging of the PTGBD tube and upper endoscopy identified the indirect cholecystoduodenal fistula via the hepatoduodenal ligament. Despite repeated attempts at endoscopic fistula closure using clips, the fistula did not close successfully. We therefore performed laparoscopic cholecystectomy and fistula closure. The postoperative clinical course was uneventful, and she left the hospital on postoperative day 15. The resected gallbladder contained small black stones, and a histological examination revealed gangrenous cholecystitis with no malignant signatures. CONCLUSION: We encountered a rare case of indirect cholecystoduodenal fistula via the hepatoduodenal ligament secondary to gangrenous cholecystitis that was successfully treated by laparoscopic cholecystectomy and fistula closure. It is important to recognize the possible formation of indirect cholecystoduodenal fistula in cases of gangrenous cholecystitis penetrating the hepatoduodenal ligament.

Three-dimensional Vascularized ß-cell Spheroid Tissue Derived From Human Induced Pluripotent Stem Cells for Subcutaneous Islet Transplantation in a Mouse Model of Type 1 Diabetes.

BACKGROUND: Islet transplantation is an effective replacement therapy for type 1 diabetes (T1D) patients. However, shortage of donor organ for allograft is obstacle for further development of the treatment. Subcutaneous transplantation with stem cell-derived ß-cells might overcome this, but poor vascularity in the site is burden for success in the transplantation. We investigated the effect of subcutaneous transplantation of vascularized ß-cell spheroid tissue constructed 3-dimensionally using a layer-by-layer (LbL) cell-coating technique in a T1D model mouse. METHODS: We used MIN6 cells to determine optimal conditions for the coculture of ß-cell spheroids, normal human dermal fibroblasts, and human umbilical vein endothelial cells, and then, under those conditions, we constructed vascularized spheroid tissue using human induced pluripotent stem cell-derived ß-cells (hiPS ß cells). The function of insulin secretion of the vascularized hiPS ß-cell spheroid tissue was evaluated in vitro. Furthermore, the function was investigated in T1D model NOD/SCID mice subcutaneously transplanted with the tissue. RESULTS: In vitro, the vascularized hiPS ß-cell spheroid tissue exhibited enhanced insulin secretion. The vascularized hiPS ß-cell spheroid tissue also significantly decreased blood glucose levels in diabetic immunodeficient mice when transplanted subcutaneously. Furthermore, host mouse vessels were observed in the explanted vascularized hiPS ß-cell spheroid tissue. CONCLUSIONS: Vascularized hiPS ß-cell spheroid tissue decreased blood glucose levels in the diabetic mice. This therapeutic effect was suggested due to host angiogenesis in the graft. This method could lead to a promising regenerative treatment for T1D patients.