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Immunotherapy has become the standard-of-care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy-susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC.We performed RNA-seq of tumor tissues in 113 patients with nonviral HCC and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into three molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with cadherin-associated protein beta 1 (CTNNB1) mutations. Thirty-eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune-enriched but immune-exhausted TIME characterized by T cell exhaustion, M2 macrophage and cancer-associated fibroblast (CAF) infiltration, high PD-L1 expression, and TGF-β signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Patients with steatotic HCC, confirmed by chemical-shift MR imaging, had significantly longer PFS with combined immunotherapy using anti-PD-L1 and anti-VEGF antibodies.Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune-exhausted immunotherapy-susceptible TIME.

Background Creating a good surgical visual field is one of the most important factors for performing a successful surgery. Here, we introduce a useful technique for creating a good liver parenchymal visual transection plane during laparoscopic partial hepatectomy and compare the perioperative outcomes of our current technique with those of conventional techniques. Methods We reviewed the data of patients who underwent laparoscopic partial hepatectomy between July 2016 and December 2020. The current technique for creating transection planes was first applied in our department in April 2019. The patients were divided into conventional (forceps) and current (silicone ring) technique groups, depending on the surgical technique. Results Twenty-eight and 12 patients underwent laparoscopic partial hepatectomy using the conventional and current techniques, respectively, when the difficulty level-as determined by IWATE criteria-was low. Although the tumor size was significantly larger (median: 22.5 vs. 15 mm, P=0.04) in the current technique group, the estimated intraoperative blood loss was significantly lower (median: 50 vs. 100 mL, P=0.01), and the median surgical margin was significantly longer (median: 7 vs. 3 mm, P=0.02). There were no significant between-group differences in surgical time (median: 344 vs. 240 min, P=0.14), postoperative hospital stay duration (median: 11 vs. 9.5 d, P=0.051), and the incidence of complications (P=0.63). Conclusion We believe that the technique involving the use of a silicone ring can result in better surgical outcomes as it provides a good visual hepatic transection plane during laparoscopic partial hepatectomy.

Neoadjuvant therapy (NAT) is used to treat not only advanced pancreatic cancer but also resectable lesions. The present study investigated the effectiveness of postoperative adjuvant chemotherapy for patients with pancreatic cancer who underwent surgical resection after NAT. Patients who underwent macroscopically curative resection after NAT for pancreatic cancer were enrolled. Adjuvant chemotherapy was defined as at least 1 cycle of planned chemotherapy within 3 months after the date of surgery and included S-1, gemcitabine, or both. We retrospectively examined the effect of adjuvant chemotherapy on overall survival (OS) and recurrence-free survival (RFS) as a function of patients’ clinicopathological factors. Ninety-seven patients were included in the study, of which 68 (70.1%) underwent adjuvant chemotherapy. Administration of adjuvant chemotherapy was significantly associated with prolonged OS and RFS in patients whose elevated levels of carbohydrate antigen 19-9 or duke pancreatic monoclonal antigen type-2 did not normalize after NAT. In patients with pathological lymph node metastasis, the administration of adjuvant chemotherapy was significantly associated with longer OS but did not improve PFS. Postoperative adjuvant chemotherapy was associated with prolonged postoperative survival in patients with pancreatic cancer who did not sufficiently respond to NAT as judged by tumor marker expression.

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.

In the gastrointestinal tract musculatures, c-Kit receptor tyrosine kinase is specifically expressed in interstitial cells of Cajal (ICC). ICC are distributed among the smooth muscle cells and are either bipolar or multipolar in shape. Our previous and current study shows that c-Kit-immunopositive smooth muscle cells are present in the murine cecum. Here, we found that c-Kit-expressing smooth muscle cells (named Kit-SM cells) are situated at the submucosal surface of the circular muscle layer. These cells showed smooth muscle actin and myosin immunoreactivities and ultrastructural features such as thick and thin filaments and caveolae. Kit-SM cells also expressed TMEM16A and LRIG1, which are known to be expressed in ICC. Although the functional significance of Kit-SM cells has yet to be revealed, these cells can be considered to have proliferation or differentiation potential in the cecal musculature.

BACKGROUND Removing the jugular tubercle (JT) is regarded as an important step in the far-lateral approach; however, few cadaveric studies have objectively evaluated it. OBJECTIVE To quantitatively analyze the effect of JT removal in the far-lateral approach, using cadaveric computed tomography (CT) and magnetic resonance (MR) imaging. METHODS The far-lateral, supra-articular transcondylar transtubercular approach was employed on 23 sides of 13 formalin-fixed cadaveric heads. CT bone images were obtained before and after JT removal, and MR images were obtained before dissection and were merged with the CT bone images. The angles of attack used to approach the ventral region of the medulla, the distances between the medulla and the bony structure, and the volume of the paramedullary space were measured at the level of the JT on axial CT-MR fusion images. The values obtained after JT removal were compared with those obtained before JT removal. RESULTS All evaluated values were significantly increased after JT removal, including the angle of attack at the level of the JT (29.8 ± 7.4° vs 58.2 ± 15.5°, P

The c-Kit receptor tyrosine kinase regulates the development and differentiation of several progenitor cells. In the gastrointestinal (GI) tract, the c-Kit regulates the development of the interstitial cells of Cajal (ICC) that are responsible for motility regulation of the GI musculature. W-sash (Wsh) is an inversion mutation upstream of the c-kit promoter region that affects a key regulatory element, resulting in cell-type-specific altered gene expression, leading to a decrease in the number of mast cells, melanocytes, and ICC. We extensively examined the GI tract of Wsh/Wsh mice using immunohistochemistry and electron microscopy. Although the musculature of the Wsh/Wsh mice did not show any c-Kit immunoreactivity, we detected intensive immunoreactivity for transmembrane member 16A (TMEM16A, anoctamin-1), another ICC marker. TMEM16A immunopositive cells were observed as ICC-MY in the gastric corpus-antrum and the large intestine, ICC-DMP in the small intestine, and ICC-SM in the colon. Electron microscopic analysis revealed these cells as ICC from their ultrastructural features, such as numerous mitochondria and caveolae, and their close contact with nerve terminals. In the developmental period, we examined 14.5 and 18.5 day embryos but did not observe c-Kit immunoreactivity in the Wsh/Wsh small intestine. From this study, ICC subtypes developed and maturated structurally without c-Kit expression. Wsh/Wsh mice are a new model to investigate the effects of c-Kit and unknown signaling on ICC development and function.

Objective: Chemotherapy is generally recommended as the first-line standard treatment in patients with liver metastasis from gastric cancer. However, the clinical impact of surgical treatment remains unclear in responders after chemotherapy. The present study aimed to investigate the tumor response and prognosis after chemotherapy and to assess the clinical indication of conversion surgery in responders. Methods: The study retrospectively reviewed the clinical data of 44 patients with liver metastasis from gastric cancer who were treated with chemotherapy between February 2002 and January 2019. These patients were classified into progressive disease (PD) and non-PD groups according to tumor response. Results: Among the 44 patients, 7 and 26 had peritoneal dissemination and ≥5 had metastatic liver nodules. Additionally, 15 and 29 patients had PD and non-PD, respectively. Surgical treatment was significantly correlated with tumor response (p < 0.0321). Prognostic differences between the PD and non-PD groups were significant (p < 0.0001). Moreover, gastrectomy and hepatectomy were significantly correlated with the number of liver metastases (≥5 vs. p = 0.0025 and p = 0.0169, respectively). The 3-year survival rates among patients with non-PD undergoing both gastrectomy and hepatectomy (n = 6), gastrectomy alone (n = 7), and nonsurgical treatments (n = 16) were 100, 66.7, and 0%, respectively (p = 0.0026). Multivariate analysis identified peritoneal dissemination as an independent prognostic factor (p = 0.0225). Conclusion: Our preliminary results suggest that conversion surgery for gastric cancer with liver metastasis might be clinically indicated in chemotherapy responders with

Highlights • Retroperitoneal schwannomas in the abdominal cavity are rare and pose difficulty in preoperative diagnosis and management. • Imaging modalities are usually not sufficient to conclude a diagnosis. • EUS-FNA is useful to confirm preoperative diagnosis. • In EUS-FNA, diagnosis can be accurate if the tumor size is small and tumor is devoid of intratumoral degenerations., Introduction Schwannomas are tumors that originate from the Schwann cells present in the nerve sheath of peripheral nerves. They are commonly seen in cephalocervical areas. Schwannomas in the abdominal cavity are rare. Here, we discuss a case of retroperitoneal schwannoma lying dorsal to pancreas with critical relations to surrounding vessels. Presentation of case A 74 years old asymptomatic male was found with elevated amylase level on his routine blood examination. MR imaging revealed retroperitoneal mass of size 21*18*24 mm. EUS-FNA confirmed retroperitoneal schwannoma. The patient had co-morbid renal disease and was on hemodialysis. During the latest follow up, the tumor was 41*37*41 mm in size located dorsal to the confluence of right renal vein and inferior vena cava. The tumor was in contact with inferior vena cava, horizontal part of duodenum, right renal artery, right kidney, and adrenal gland. The patient underwent laparotomy and the tumor was extract with intact capsule. There were no post-operative complications. Discussion Pre-operative diagnosis in retroperitoneal schwannomas is challenging because imaging features are usually non-specific, and biopsy is the only diagnostic technique. EUS-FNA, which has low diagnostic accuracy, is useful in pre-operative diagnosis of small tumors devoid of intra-tumoral degeneration. Conclusion Retroperitoneal schwannoma is a rare entity. Preoperative diagnosis and curative resection are technically difficult. Care should be given during preoperative investigations and surgical resection of the tumor. EUS-FNA can be a useful diagnostic tool.

Highlights • Detection of colorectal cancer liver metastasis (CRCLM) with the infiltration of lymph nodes (LNs) in the hepatic pedicle is not so simple. • When detecting tumor progression from CRCLM along with Glisson branch, the possibility of hepatic hilar LNs involvement should be considered. • Surgical approach against CRCLM with hepatic hilar LNs involvement is controversial, but could be acceptable., Background Colorectal cancer liver metastasis (CRCLM) concomitant with infiltration of lymph nodes (LNs) in the hepatic pedicle is difficult to manage, and is regarded as an extrahepatic metastasis; undertaking hepatectomy is controversial in such a scenario. Case presentation Case 1, A 55-year-old woman was diagnosed with multiple liver metastases arising from rectal cancer along with enlargement of a retropancreatic LN. A characteristic image prior to hepatectomy demonstrated evident tumor progression from a metastatic lesion in segment 5 of the liver (S5) to the hepatic hilum along with Glisson 5. Post-operative histopathological examination revealed viable adenocarcinoma cancer cells originating from rectal cancer in all the liver metastatic lesions and retropancreatic LN. Case 2, A 89-year-old woman was diagnosed with transverse colon cancer with multiple liver metastases. Radiological examination before hepatectomy revealed tumor progression from a metastatic lesion in the segment 6 of the liver (S6) to the hepatic hilum along with Glisson 6 and LN involvement in the hepatoduodenal ligament. Post-operative histopathological examination demonstrated adenocarcinoma cancer cells in the liver metastatic lesions and in a hepatoduodenal LN. Conclusion When encountering tumor progression from liver metastatic lesions to hepatic hilum along with its Glisson branch, the possibility of hepatic hilar LN involvement should be considered. Indeed, the surgical management of CRCLM with hepatic hilar LN involvement is controversial, but could be acceptable if the positive LNs are limited to the hepatic pedicle and retropancreatic area.

Imprint lithography is an effective and well-known technique for replication of nano-scale features. Nanoimprint lithography (NIL) manufacturing equipment utilizes a patterning technology that involves the field/shot-by-field/shot deposition and exposure of a low viscosity resist deposited by jetting technology onto the substrate. The patterned mask is lowered into the fluid which then quickly flows into the relief patterns in the mask by capillary action. Following this filling step, the resist is crosslinked under UV radiation, and then the mask is removed, leaving a patterned resist on the substrate. The technology faithfully reproduces patterns with a higher resolution and greater uniformity compared to those produced by photolithography equipment. Additionally, as this technology does not require an array of wide-diameter lenses and the expensive light sources necessary for advanced photolithography equipment, NIL equipment achieves a simpler, more compact design, allowing for multiple units to be clustered together for increased productivity. Previous studies have demonstrated NIL resolution better than 10nm, making the technology suitable for the printing of several generations of critical memory levels with a single mask. In addition, resist is applied only where necessary, thereby eliminating material waste. Given that there are no complicated optics in the imprint system, the reduction in the cost of the tool, when combined with simple single level processing and zero waste leads to a cost model that is very compelling for semiconductor memory applications. Any new lithographic technology to be introduced into manufacturing must deliver either a performance advantage or a cost advantage. Key technical attributes include alignment, overlay, defectivity and throughput. Advanced memories, such as DRAM and phase change memory are challenging, because the roadmap for these devices calls for continued scaling, eventually reaching half pitches of 14nm and beyond. Scaling also impacts the overlay budget. For DRAM, as an example, overlay on some critical layers is much tighter than NAND Flash, with an error budget of 15-20% of the minimum half pitch. For 14nm, this means 2.1nm - 2.8nm. DRAM device design is also challenging, and layouts are not always conducive to pitch dividing methods such as self-aligned double patterning (SADP) and self-aligned quadruple patterning (SAQP). This makes a direct printing process, such as NIL an attractive solution. In previous papers, overlay has been addressed by applying methods that are unique to NIL. In 2018, Hiura et al. reported a mix and match overlay (MMO) of 3.4 nm and a single machine overlay (SMO) across the wafer was 2.5nm using an FPA-1200 NZ2C four station cluster tool. These results were achieved by combining a magnification actuator system with a High Order Distortion Correction (HODC) system, thereby enabling correction of high order distortion terms up to K30. The HODC system utilizes a digital micro mirror array to correct distortion on a field-by-field basis. Further improvements to the system have been achieved by extending the range of the HODC system by applying a diamond like carbon film to the wafer chuck in order to reduce friction. Other process variables that are unique to NIL and that can be considered as process tunable variables include imprint force and tip/tilt of the imprint head relative to the wafer substrate during exposure. These variables can be used to modulate and control the overlay errors near the imprint field edges and provide good overlay control. An additional method to improve overlay is Drop Pattern Compensation (DPC). DPC is used to create a resist drop pattern designed to remove non-flatness originating either from the wafer/wafer chuck or pattern topography, so as to minimize mask bending. Finally, it is also possible to correct distortion signatures on wafer by fabricating a “refined” mask which takes into account the distortion signature. The purpose of this paper is to describe the application of the improvements discussed above to realize a mix and match overlay of less than 3nm.

c-Kit receptor tyrosine kinase and its ligand stem cell factor (SCF) play critical roles in regulating the development and proliferation of various cells, including the interstitial cells of Cajal (ICC) in the gastrointestinal tract. Many subtypes of ICC are known to be lacking in c-Kit-SCF-insufficient mice, such as W/Wv and Sl/Sld, whereas ICC-deep muscular plexus (DMP) in small intestine are not lacking. In this study, we examine ICC-DMP development in normal and c-Kit-SCF signal-insufficient mice. In normal mice, numerous ICC-DMP labeled with c-Kit and neurokinin 1 receptor (NK1R) antibodies were observed only in the duodenum on the day of birth, in the duodenum and the jejunum on postnatal day 4 and throughout the small intestine after postnatal day 6. In W mutant mice (W/Wv, Wv/Wv, W/W), ICC-DMP investigated using c-Kit and NK1R immunoreactivities were similar to that in normal mice. c-Kit ligand SCF-deficient mice (Sl/Sl) also showed almost identical ICC-DMP development and proliferation as normal mice. These results show that the development and proliferation of ICC-DMP occur in the postnatal period independent of c-Kit-SCF signaling.

A metabolic shift to glycolysis is reportedly involved in radioresistance. We examined whether pretreatment 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), which can detect enhanced glucose uptake, was able to predict the therapeutic response to chemoradiotherapy (CRT) in patients with pancreatic cancer (PC). Of 125 PC patients (75 unresectable and 50 borderline resectable), 37 and 26 underwent induction chemotherapy before CRT and surgical resection after CRT, respectively. FDG-PET was performed at three different institutions. Of the 88 patients who underwent upfront CRT, 31 (35%), 34 (39%), and 23 (26%) showed a partial response (PR), stable disease, and progressive disease, respectively. The tumor PR rate was an independent factor associated with longer overall survival (OS) on multivariate analysis. We evaluated the optimal cut-off of maximum standardized uptake values (SUVmax) at initial diagnosis to detect the tumor PR rate at the three institutions separately. The SUVmax was independently associated with tumor response rate on multivariate analysis. In the low SUVmax group, induction chemotherapy had no significant impact on OS. In contrast, induction chemotherapy was significantly associated with longer OS in the high SUVmax group. FDG-PET SUVmax was significantly associated with the therapeutic response to CRT in PC patients. Moreover, induction chemotherapy may improve the prognosis of patients with a high SUVmax tumor.

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.

Background The clamp crushing method and the use of the Cavitron ultrasonic surgical aspirator (CUSA) are widely accepted techniques for hepatic parenchymal transection. The actuator-driven pulsed water jet (ADPJ) with high tissue selectivity is a new technology that was shown as a safe transection tool in preclinical models, although not much is known about its safety criteria in patients. Therefore, its strongest advantage, the best indications for its use, and its performance in comparison with other transection methods remain to be clarified. In this report, we present several representative cases to help answer these questions. Methods We started using the ADPJ in December 2017, only in cases where the tumor was very close to major vessels or attached to them, along a considerable length, to preserve vessels and prevent postoperative liver failure. All the cases underwent highly demanding procedures. We avoided using this device in cases such as liver cirrhosis, where the hepatic parenchyma was very hard. Results Six cases fulfilled our limited indications for using ADPJ. The median age and number of tumors were 55 years (10 to 69 y) and 2.5 years (1 to 4 y), respectively. The mean tumor size was 7.8 cm (2.8 to 21 cm), the minimum distance between the tumor and major vessels to be preserved was 0 mm (0 to 4 mm), and the contact length of the tumor and major vessels was 26 mm (19 to 40 mm). Regarding the surgical outcome, the median operation time and blood loss were 559 minutes (508 to 919 min) and 620 mL (230 to 860 mL), respectively. We achieved a negative surgical margin (R0 resection) in all cases. Conclusions Using ADPJ, we could perform R0 hepatectomy in all cases, which preoperatively were considered to have a high chance of being margin positive. We consider the best indication for using ADPJ is when the tumor and vessels to be preserved are attached or very close over a long distance.

A woman in her 50s received a detailed examination for her abdominal pain. CT indicated intestinal wall thickening of the ascending colon, lymphadenopathy, and tumor embolism in the superior mesenteric vein. Colonoscopy revealed type 2 tumor in the hepatic flexure of the colon, and she was diagnosed as having moderately differentiated adenocarcinoma by biopsy specimen. She received 12 courses of FOLFOXIRI plus BV therapy after ileostomy. As the tumor embolism disappeared and the primary lesion shrank after chemotherapy, right hemicolectomy and lymph node dissection were performed. Six months after surgery, she has had no recurrent disease. This case suggests that FOLFOXIRI plus BV therapy could be an effective treatment for right colon cancer with tumor embolism.

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.

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). 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. 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. HMS was superior to VS for preventing early postoperative complications and did not affect pancreatic function.

As the most aggressive features in advanced memory designs continue to shrink, so does the overlay budget. The number of layer stacks also creates unwanted topography, and the alignment robustness of lithography tools becomes much more important for on-product overly. Canon developed a through-the-mask moire alignment system for the FPA-1200NZ2C nanoimprint lithography (NIL) system allowing high-speed measurement of several alignment marks within each imprint field and alignment compensation to be completed during the imprinting sequence. To provide increased process flexibility and overlay accuracy while maintaining high-productivity, we have developed a new low-noise and high-resolution moire diffraction alignment system based on spatial phase interferometry. In this paper, we report on the TTM detection system used in FPA-1200NZ2C. In particular, the principle of moire detection and the improvement of the detection method will be described. The measurement error of moire is analyzed by a simplified model calculation and we confirmed the relationship between process change and alignment error. Results of analyses proved that selection of the wavelength are key factors for optimizing alignment accuracy. Based on these results we applied the following improvement items: 1) Dual Dipole illumination, 2) Optimization of the alignment wavelength. We evaluated the new alignment system measurement error by comparing the moire measurement value with the measured overlay values for 24 wafers and confirmed that new TTM alignment system can reduce to the measurement error more than 40%. The data shows that our moire measurement system can provide process robustness and can support mass-production of leading-edge memory products.

Imprint lithography is a promising technology for replication of nano-scale features. For semiconductor device applications, Canon deposits a low viscosity resist on a field by field basis using jetting technology. A patterned mask is lowered into the resist fluid, which then quickly flows into the relief patterns in the mask by capillary action. Following this filling step, the resist is crosslinked under UV radiation, and then the mask is removed, leaving a patterned resist on the substrate. Overlay budgets play a large role in defining production readiness. As an example, DRAM devices require overlay on the order of 15-20% of the half pitch. Canon uses a through the mask (TTM) alignment system to measure a Moire image anywhere in the field. This system can also record alignment errors of all fields and all marks. The data collected by the TTM system correlates very closely with an Archer measurement tool. In addition, a High Order Distortion Correction (HODC) system, which applies a heat input on a field by field basis through the use of a DMD array has been combined with magnification actuators to correct high order distortion terms up to K30. There is an additional distortion term that must also be addressed for the case of nanoimprint lithography. NIL drop patterns are typically designed to minimize resist fill time and create a uniform residual layer beneath the resist pattern. For device wafers, however, it is important to recognize that there are both long wavelength flatness errors coming from the wafer chuck and existing pattern topography from previously patterned levels that cause out of plane errors. When the mask comes in contact with the resist on the wafer, these out of plane errors can then induce mask bending, resulting in an additional distortion term. To minimize this distortion, a Drop Pattern Compensation (DPC) Model has been implemented to minimize the added distortion terms. In this paper we present an updated study and report on nanoimprint mix and match overlay improvements using DPC. In addition, we describe how the mode array and peak to valley thickness of the resist impacts distortion correction.

Aim Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a very rare subtype of primary liver carcinoma; therefore, its clinicopathological characteristics have not yet been elucidated in detail. The aim of the study was to reveal the clinicopathological characteristics and prognostic factors of cHCC-CCA after hepatic resection (HR) METHODS: A total of 124 patients who underwent curative HR for cHCC-CCA between 2000 and 2016 were enrolled in this multi-institutional study conducted by the Kyushu Study Group of Liver Surgery. Clinicopathological analysis was performed from the viewpoint of patient prognosis. Results A total of 62 patients (50%) had early recurrence within 1.5 years after HR, including 36 patients (58%) with extrahepatic recurrence. In contrast, just four patients (3%) had late recurrence occurring >3 years after HR. The independent predictors of early recurrence were as follows: des-gamma carboxyprothrombin >40 mAU/mL (odds ratio 26.2, P = 0.0117), carbohydrate antigen 19-9>37 IU/l (odds ratio 18.0, P = 0.0200), and poorly differentiated HCC or CCA (odds ratio 11.2, P = 0.0259). Conclusions Half of the patients with cHCC-CCA had early recurrence after HR. Preoperative elevation of des-gamma carboxyprothrombin or carbohydrate antigen 19-9 and the existence of poorly differentiated components of HCC or CCA in resected specimens are predictors of its early recurrence.

Background/aim High mobility group box-1 (HMGB1) induces the release of proinflammatory cytokines and chemokines as a late-acting mediator of inflammation. Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer. However, little is known about the relationship between HCC and HMGB1 and its receptor RAGE (receptor for advanced glycation end products). This study analyzes the clinicopathological relevance of HMGB1 expression level and the effect of HMGB1 expression on the characteristics of HCC. Materials and methods Samples from 75 HCC patients including 13 with positive hepatitis B surface antigen and 36 with hepatitis C antibody were studied. The expression of HMGB1 in paired cancer and non-cancerous tissues from patients with HCC was assessed using reverse-transcription polymerase chain reaction (RT-PCR) and western blotting. Quantitative RT-PCR data were analyzed in association with the clinicopathological factors of patients with HCC. Results The expression of HMGB1 mRNA in HCC was high in well-differentiated tumors, but declined as tumors dedifferentiated to moderately and poorly differentiated HCC. The levels of HMGB1 mRNA showed a negative correlation with the presence of portal invasion (p=0.005) and the rise of serum PIVKA-II (p=0.034). There was no clear correlation between HMGB1 expression and proliferation activity of HCC using Ki-67 staining. Conclusion In HCC, HMGB1 expression level correlated inversely with tumor differentiation. The RAGE-HMGB1 interaction may play a greater role in the early stages of HCC tumorigenesis than during cancer development.

BACKGROUND The aim of this study was to confirm whether intraoperative fluorescence vascular imaging using indocyanine green (FVI-ICG) is useful for evaluating splenic perfusion after spleen-preserving distal pancreatectomy (SPDP) performed with the Warshaw technique (SPDP-W). METHODS We evaluated the blood perfusion of the spleen with an intraoperative FVI-ICG system after SPDP-W. All of the patients underwent dynamic computed tomography (CT) scans at one post-operative week and one post-operative month to evaluate the post-operative blood perfusion of the spleen. Then, the post-operative perfusion status of the spleen according to CT and the intraoperative fluorescence status of the spleen were compared. RESULTS Five patients were enrolled in this study. None of the patients required secondary splenectomies. We detected a tendency towards a close relationship between the intraoperative fluorescence level of the spleen according to FVI-ICG performed after SPDP-W and post-operative splenic perfusion as evaluated by CT. Improved splenic perfusion was seen at one post-operative month in all cases, including a case in which poor splenic perfusion was initially detected. CONCLUSION We detected a close relationship between the fluorescence level of the spleen on intraoperative FVI-ICG and the post-operative perfusion status of the spleen among patients who underwent SPDP-W. Intraoperative FVI-ICG could help surgeons to safely preserve the spleen after SPDP-W.

Highlights • Severe acute pancreatitis with necrotizing colonic perforation is refractory and the mortality is high. • Step-up approach for severe acute pancreatitis with infectious walled-off necrosis has been increasingly used. • We performed percutaneous drainage, ileostomy, and video-assisted retroperitoneal debridement (VARD) as a step-up approach. • VARD enable sufficient washing of the abscess and radical debridement of the necrotic tissues under direct view., Introduction Colorectal complications including penetration and perforation in acute pancreatitis often become severe and fatal. Effective drainage is pivotal for successful treatment. We present a case of large retroperitoneal abscess with colonic necrotizing perforation due to severe acute pancreatitis treated with video-assisted retroperitoneal debridement (VARD) in a step-up approach. Presentation of case A 31-year-old man was admitted to a general hospital with a diagnosis of severe acute pancreatitis. Ten days after onset, he was referred to our hospital for more intensive treatment. On day 16, he experienced melena and shock, and embolization of the three straight arteries of the descending colon was performed. On day 30, percutaneous drainage was performed for large retroperitoneal abscess. On day 36, ileostomy was performed because the drained pus from the retroperitoneal abscess became feces-like. On day 58, VARD was performed to treat the refractory retroperitoneal abscesses causing high systemic inflammation due to insufficient drainage. On day 85, fluoroscopic examination showed disappearance of the abscess cavity. He was transferred to the previous hospital on day 89. Discussion Colonic perforation due to severe acute pancreatitis often causes sepsis and fatal condition of patients, and drainage of the retroperitoneal abscesses via laparotomy is thought to be highly invasive and risky. VARD enables radical necrosectomy and drainage less invasively. Conclusions VARD enabled less invasive treatment for patients with large retroperitoneal abscess due to colonic necrotizing perforation in severe pancreatitis.

Laparoscopic surgical training using a box trainer facilitates mastery of laparoscopic surgery. Few studies have investigated whether visualizing the surgical field in the box trainer improves performance of laparoscopic surgical procedures during laparoscopic training. An original box trainer equipped with a transparent top made of mesh covered with a latticed structure was developed and used for evaluation of novices during laparoscopic training. Three tasks (levels 1 to 3) involving organ handling while setting the surgical field were arranged to evaluate the efficacy of training. Forty‐five students were divided into three groups: group A, students without practical training; group B, students trained using the covered box trainer; and group C, students trained using the transparent box trainer. Completion time of each task before and after training was compared. Training significantly reduced the operating time, with a significant difference between the level 1 task and the levels 2 (P

Background:Stratification of pancreatic cancer patients based on early recurrence and prognosis is essential for selecting optimal therapeutic strategies. The aim of this study was to investigate whether serum carbohydrate antigen (CA) 19-9 levels can be better used to predict early recurrence and prognosis.Methods:Patients whose CA 19-9 levels obtained in association with total bilirubin >2.0 mg/dL and whose CA 19-9 levels Results:Larger tumor size, higher serum CA 19-9 level, higher C-reactive protein (CRP) level, more advanced T status, and lymph node metastasis were significantly associated with recurrence within 1 year after surgery (early recurrence). The rate of early recurrence in patients with CA 19-9 levels >100 U/mL (76.9%) was significantly higher than that of patients with CA 19-9 levels ≤100 U/mL (27.9%). We performed combination analysis of 2 additional risk factors, CRP level (cutoff: 1.0 mg/dL) and tumor size (cutoff: 3.0 cm), with serum CA 19-9 level (cutoff: 100 U/mL). Patients were divided into 3 groups according to their number of risk factors. Rates of early recurrence in patients with 0, 1, and 2 or 3 risk factors were 22.0%, 45.2%, and 91.7%, respectively. Moreover, overall survival was significantly different in each group.Conclusion:Serum CA 19-9 level, in addition to CRP level and tumor size, improve patient stratification in early recurrence as well as prognosis.

Regulation of inflammation in intestinal mesothelial cells in the abdominal cavity is important for the pathogeny of clinical conditions, such as postoperative ileus, peritonitis and encapsulating peritoneal sclerosis. Here we have examined the inflammatory effect of lipopolysaccharide (LPS) and the anti-inflammatory effect of nicotinic acetylcholine receptor stimulation in rat intestinal mesothelial cells. LPS upregulated mRNA expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1) and inducible nitric oxide synthase (iNOS). The α7, α9 and α10 subunits of nicotinic acetylcholine receptor were detected in intestinal mesothelial cells. Nicotine (10 nM) significantly inhibited LPS-induced mRNA expression of IL-1β and iNOS, but not TNF-α and MCP-1. In addition, the α7 nicotinic acetylcholine receptor selective agonist, PNU-282987 (10 nM), significantly inhibited LPS-induced mRNA expression of IL-1β but not TNF-α, iNOS and MCP-1. Finally, we found that enteric nerves adhered to intestinal mesothelial cells located under the ileal serosa. In conclusion, intestinal mesothelial cells react to LPS to induce the production of nitric oxide from iNOS. The anti-inflammatory action of intestinal mesothelial cells expressing α7nAChR may be mediated via their connectivity with enteric nerves.

Highlights • There is anomaly that bile ducts and portal veins of the Spiegel lobe do not run together. • Incidence of bile leakage after hepatic surgery was reported to be 2.6–15.6%. • A number of treatment strategies for excluded bile leakage have been reported. • Surgical treatment for excluded bile leakage is a quick and reliable procedure., Inroduction The treatments of excluded bile duct leakage after hepatectomy are not easy and various strategies have been reported, such as surgery, ethanol or fibrin glue injection, and portal vein embolization. Presentation of case A 72-year-old man with a surgical history of laparoscopic ileocecal resection for diverticular bleeding was diagnosed as having hepatocellular carcinoma. Right hemihepatectomy was performed, and computed tomography examination on postoperative day 9 showed abdominal fluid collection in the right subphrenic space. Percutaneous intra-abdominal fluid drainage was performed and it was diagnosed as bile leakage. After that it was diagnosed as excluded bile leakage from the Spiegel lobe by drip infusion cholangiographic-computed tomography and endoscopic retrograde cholangiography. To improve this clinical condition, we performed the Spiegel lobe excision on postoperative day 48. The postoperative course was uneventful and the patient was discharged. Discussion According to the postoperative examination, it appeared that the bile duct from the Spiegel lobe joined to the right main bile duct or the bile duct of the right posterior section. This bile duct anomaly was not detected preoperatively on imaging examination. It is most likely that the bile duct from the Spiegel lobe was cut when the hepatoduodenal ligament in the hepatic hilum was peeled. To prevent excluded bile leakage, the hepatoduodenal ligament should be carefully peeled and ligated instead of using energy devices. Conclusion We consider that surgical treatment for postoperative excluded bile leakage is both a quick and reliable procedure in patients with acceptable liver function and anatomical subject.

Background Gemcitabine and S-1 are drugs commonly used for treating locally advanced pancreatic cancer (LAPC). However, the safety and efficacy of combination of these agents for induction chemotherapy (IC) followed by chemoradiotherapy are not well-defined. Patients and methods Fifteen patients with LAPC (IC-CRT group) were treated with gemcitabine and S-1 IC, followed by S-1 chemoradiotherapy. The clinical outcomes were compared to a cohort of 38 patients who received chemoradiotherapy alone (CRT group). Results Disease control rates in the CRT and IC-CRT groups were 84% and 93%, respectively (p=0.024). The median time of disease progression was 10.8 and 15.4 months in the CRT and IC-CRT group, respectively (p=0.043). The median overall survival time was longer in the IC-CRT group compared to CRT (23.4 vs. 17.3 months), but this increase was not statistically significant. Conclusion Gemcitabine and S-1 combination chemotherapy, followed by CRT, is a promising IC regimen for treating LAPC.

This study describes our experience with a new method of identifying and cannulating the main pancreatic duct (MPD) using only an ultrasonically activated scalpel that overcomes the disadvantages of previously used methods. The main difference between our new method and that of previous methods is the greater ability to identify the MPD (success rate was greater than 81.3%). This technique is easy to learn, even for inexperienced surgeons, and is a reliable way of identifying the MPD.

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.

This study was performed primarily to clarify whether pathological analysis of cadavers for anatomical dissection is possible using postmortem imaging (PMI), and whether this is worthwhile. A total of 33 cadavers that underwent systematic anatomical dissection at our medical school also underwent PMI. Fixative solution was injected into the corpus 3-4 days after death. PMI was then performed using an 8-slice multi-detector CT scanner 3 months before dissection. Before dissection, a conference was held to discuss the findings of the PMI. First, two radiologists read the postmortem images without any medical information and deduced the immediate cause of death. Then, the anatomy instructor revealed the medical information available. Based on this information, the radiologist, anatomy instructor, and pathologists suggested candidate sampling sites for pathological examination. On the last day of the dissection period, the pathologists resected the sample tissues and processed them for pathological examination. In 12 of 33 cases, the presumed causes of death could be determined based on PMI alone, and revision of the cause of death described in the death certificate was considered in five (15.2%) cases, based on PMI and pathological analysis. This article presents a novel method of pathological analysis of cadavers for anatomical dissection using PMI without disturbing the anatomy education of medical students.

Imprint lithography is a promising technology for replication of nano-scale features. For semiconductor device applications, Canon deposits a low viscosity resist on a field by field basis using jetting technology. A patterned mask is lowered into the resist fluid, which then quickly flows into the relief patterns in the mask by capillary action. Following this filling step, the resist is crosslinked under UV radiation, and then the mask is removed, leaving a patterned resist on the substrate. Overlay budgets play a large role in defining production readiness. As an example, DRAM devices require overlay on the order of 20% of the half pitch. Canon uses a through the mask (TTM) alignment system to measure a Moire image anywhere in the field. This system can also record alignment errors of all fields and all marks. The data collected by the TTM system correlates very closely with an Archer measurement tool. In addition, a High Order Distortion Correction (HODC) system, which applies a heat input on a field by field basis through the use of a DMD array has been combined with magnification actuators to correct high order distortion terms up to K30. There is an additional distortion term that must also be addressed for the case of nanoimprint lithography. NIL drop patterns are typically designed to minimize resist fill time and create a uniform residual layer beneath the resist pattern. For device wafers, however, it is important to recognize that there are both long wavelength flatness errors coming from the wafer chuck and existing pattern topography from previously patterned levels that cause out of plane errors. When the mask comes in contact with the resist on the wafer, these out of plane errors can then induce mask bending, resulting in an additional distortion term. To minimize this distortion, a Drop Pattern Compensation (DPC) Model has been implemented to minimize the added distortion terms. In this paper we describe the origins of the out of plane errors, and describe the model used to correct these errors along with some examples. Finally, results are presented for a device like wafer in which the overlay errors within a field are reduced from 5.4nm to 3.4nm, 3 sigma.