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Objective The goal of this retrospective study was to clarify the clinical implications of immunohistochemically detected protein expression for genes that are frequently mutated in pancreatic neuroendocrine tumors (PNETs). Background The clinical management of PNETs is hindered by their heterogenous biological behavior. Whole-exome sequencing recently showed that 5 genes (DAXX/ATRX, MEN1, TSC2, and PTEN) are frequently mutated in PNETs. However, the clinical implications of the associated alterations in protein expression remain unclear. Methods We collected Grade 1 and 2 (World Health Organization 2017 Classification) primary PNETs samples from 100 patients who underwent surgical resection. ATRX, DAXX, MEN1, TSC2, and PTEN expression were determined immunohistochemically to clarify their relationships with prognosis and clinicopathological findings. Results Kaplan-Meier analysis indicated that loss of TSC2 (n = 58) or PTEN (n = 37) was associated with significantly shorter overall survival, and that loss of TSC2 or ATRX (n = 41) was associated with significantly shorter recurrence-free survival. Additionally, loss of ATRX or TSC2 was significantly associated with nodal metastasis. In a multivariate analysis, combined loss of TSC2 and ATRX (n = 31) was an independent prognostic factor for shorter recurrence-free survival (hazard ratio 10.1, 95% confidence interval 2.1-66.9, P = 0.003) in G2 PNETs. Conclusions Loss of ATRX, TSC2, and PTEN expression might be useful as a method of clarifying the behavior and clinical outcomes of Grade 1 and 2 PNETs in routine clinical practice. Combined loss of TSC2 and ATRX had an especially strong, independent association with shorter recurrence-free survival in patients with G2 PNETs. Loss of pairs in ATRX, TSC2, or PTEN would be useful for selecting the candidate for postoperative adjuvant therapy.

Fluoropyrimidine combined with bevacizumab is commonly used in elderly patients with metastatic colorectal cancer worldwide. However, the proportion of elderly patients who discontinued treatment due to toxicities was higher than that of younger patients. The aim of this study is to develop a less toxic schedule of S-1, while maintaining the anti-tumor effect. This phase II study is aimed to evaluate an alternate-day administration of S-1 combined with bevacizumab in untreated elderly patients (aged ≥75 years) with metastatic colorectal cancer. The primary endpoint is progression-free survival, and the secondary endpoints are safety, response rate, and overall survival. The expected median progression-free survival is 8.5 months, and the minimum efficacy threshold is 5.0 months. The total required sample size is calculated as 50 patients, with a 2-sided type I error of 0.10 and a power of more than 80%. This study is ongoing, and fifty-four patients were enrolled until October 2016. We hope that S-1 on alternate days combined with bevacizumab for elderly patients with colorectal cancer is well tolerated and can maintain effectiveness. Trial registration: UMIN clinical trials UMIN000010402.

Background Carcinoma of the ampulla of Vater is uncommon. This study aimed to clarify predictors of survival for ampullary adenocarcinoma and to identify characteristics of its two major pathological subtypes. Methods Medical records were reviewed for 86 patients who underwent curative resection for ampullary adenocarcinoma between 2000 and 2012 at 12 principal hospitals in Kagawa, Japan. Results Resection was most common among 75–79-year-old patients. Actuarial 1-, 3-, and 5-year postoperative survival rates for ampullary adenocarcinoma were 90%, 72.3%, and 69.1%, respectively. Preoperative biliary drainage; serum CA19-9 and total bilirubin levels; pathological grade; perineural, vascular, pancreatic, and duodenal invasion; nodal metastasis; UICC-T stage; and pancreatobiliary subtype were predictors of poor survival. An elevated serum CA19-9 level; an elevated total bilirubin level; lymphatic, vascular, perineural, and pancreatic invasion; and advanced overall tumor stage were more common in patients with pancreatobiliary-type tumors than in patients with intestinal-type tumors. Additionally, pathologic subtype analysis showed that each subtype had distinct prognostic factors. Conclusions Preoperative elevated serum CA19-9 and total bilirubin levels are prognostic factors for ampullary adenocarcinoma, and are both associated with pancreatobiliary-type tumors. Surgeons should be aware of these factors because pancreatobiliary-type adenocarcinoma is aggressively invasive and is associated with poor survival. J. Surg. Oncol. 2014; 110:156–162. © 2014 Wiley Periodicals, Inc.

Oral uracil-tegafur and leucovorin (UFT/LV) therapy for elderly patients with metastatic colorectal cancer (mCRC) requires careful handling in Western countries because of a high incidence (≥20 %) of grade 3 diarrhea. However, its efficacy and safety for elderly Asian patients have not been investigated. In this multicenter cooperative phase II study, the eligibility criteria were: age of 75 years or older, no prior chemotherapy, and histologically confirmed colorectal cancer with one or more measurable lesions. UFT 300 mg/m2/day and LV 75 mg/day were administered orally for 28 days followed by a 7-day rest period. Twenty-one patients were enrolled in this study (prior to study termination after approval of bevacizumab), and all patients were eligible for efficacy and safety analysis. The median age was 79 years (range, 75–83 years). The majority of patients (95 %) had ECOG Performance Status 0 or 1. The overall response rate was 33 % (95 % confidence interval [CI], 18–53 %). The median progression-free and overall survivals were 5.3 months (95 % CI 4.0–7.9 months) and 18 months (95 % CI 13–21 months), respectively. Grade 3 or greater adverse events included anorexia (10 %), diarrhea (10 %), and leukopenia (5 %). These results were compatible with those seen in Japanese patients in a previous bridging study between Japan and the US, in which patients under 75 years old were evaluated. UFT/LV therapy was safe and feasible in elderly Japanese patients with mCRC, and further study of UFT/LV therapy in combination with bevacizumab is warranted.

Background We previously reported that uracil-tegafur with oral leucovorin (UFT/LV) treatment for elderly patients (aged ≥ 75 years) was well-tolerated in a phase II study. In the present study, the efficacy and safety of a modified (1-week shorter administration period) UFT/LV schedule combined with bevacizumab for a similar population are reported. Patients and Methods The present study was a single-arm, open-label, multicenter, cooperative group clinical trial. The key eligibility criteria included age ≥ 75 years, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, first-line chemotherapy, measurable lesions, and preserved organ function. Patients received UFT 300 mg/m2/d and LV 75 mg/d on days 1 to 21 and intravenous bevacizumab 5 mg/kg on days 1 and 15. Treatment was repeated every 28 days. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR), overall survival (OS), and safety. Results Of the 55 patients enrolled from 15 Japanese institutions, 52 eligible patients were evaluated. Their median age was 80 years (range, 75-87 years), and 73% had an ECOG performance status of 0. The median PFS was 8.2 months (95% confidence interval [CI], 6.2-10 months). The ORR was 40% (95% CI, 27%-55%). The median OS was 23 months (95% CI, 12-33 months). The most common grade 3 and 4 treatment-related adverse events were hypertension (12%), fatigue (8%), anemia (8%), nausea (6%), and diarrhea (6%). Treatment-related death occurred in 2 patients. Conclusion UFT/LV (3 weeks of therapy and 1 week without) combined with biweekly bevacizumab is a tolerable and effective treatment option for elderly patients (aged ≥ 75 years) with metastatic colorectal cancer.

Background. This study aimed to evaluate the integrity of anastomotic wound healing after digestive surgery under septic conditions and define the participation of local expression of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) around the anastomotic segment. Materials and methods. Experimental animals were divided into lipopolysaccharide (LPS) and control groups, which had either LPS or normal saline solution injected into the peritoneal cavity 24 h before transection and anastomosis of the colon. Anastomotic bursting pressure (ABP) and tissue hydroxyproline concentration (HP) were measured as indicators of wound healing. Immunohistochemical staining for TNF-α and IL-10 on tissue samples obtained from the anastomotic segment were examined 1, 6, and 24 h after the operation. The reactive cells were counted under light microscopy. Results. ABP and HP were significantly lower in the LPS group than in the control group 7 days after surgery. In the LPS group, TNF-α expression increased about threefold over that in the control group 1 h after the operation. TNF-α-reactive cells were observed until 24 h after the operation in the LPS group, but not in the control group. On the other hand, IL-10 was not expressed in the control group during the observed period, whereas IL-10 was observed 24 h after the operation in the LPS group. Conclusions. It is suggested that anastomotic wound healing was impaired after the digestive surgery in animals treated with intraperitoneal LPS, and that local expression of TNF-α and IL-10 at the anastomotic site acts as an inhibitory factor in the wound healing process.

Background. The effect of age on functioning hepatocyte mass and liver blood flow was examined using 99mTc-galactosyl-human serum albumin (GSA) liver scintigraphy in patients with liver tumors awaiting surgery. Materials and methods. Seventy-two patients with liver tumors, but normal liver parenchyma, were included in this study; patients with compromised hepatic blood flow as a result of vascular invasion or thrombus were excluded. The liver volume, calculated liver volume, and liver blood flow index (K value) were preoperatively determined by liver scintigraphy using GSA. These three parameters and liver volume measured by computed tomography volumetry (CT-LV) and the standard liver volume (ST-LV), calculated from the patient's body surface area, were examined for correlations with the patient's age. The K value was compared with the indocyanine green dye retention rate, and both sets of results were examined for correlation with the patient's age. Results. Both the CT-LV and the ST-LV decreased with age, resulting in an unchanged CT-LV/ST-LV ratio with aging. The liver volume and calculated liver volume measured by scintigraphy both decreased with age, even when body size was taken into account. Therefore, in elderly patients, the liver was not morphologically smaller, but the hepatocyte mass in the liver decreased. Furthermore, liver blood flow per unit of functional liver volume determined from the blood flow index did not change with age. Conclusions. These results, suggesting a discrepancy between liver volume estimated by CT and actual functioning hepatocyte volume in the elderly, may have a critical impact on preoperative liver functional reserve evaluation prior to hepatic resection in elderly patients.

症例は59歳の男性. 2日間持続する右下腹部痛で来院. ACTH単独欠損症でヒドロコルチゾンを内服していた. 来院時右下腹部に圧痛と反跳圧痛を認め, 白血球数7,100/μl, CRP 14.1mg/dlであった. 腹部超音波検査で内部に高エコー領域を伴う腫大した径10mmの虫垂を確認した. 急性虫垂炎と診断, 緊急手術を施行した. 虫垂の壁側腹膜への癒着と魚骨2cm長の穿通を認め, 虫垂切除術を施行した. 本邦の魚骨による消化管穿通は, 下部消化管に多く虫垂は少ない. 慢性炎症による膿瘍と腫瘍との鑑別は難しく, 広範切除となる症例もある. 腹部超音波検査やCT検査で虫垂内部に高エコー領域を認めた時は, 本疾患の可能性も考え術前鑑別診断が重要である.

We evaluated the changes in hepatic arterial and portal perfusion in nonembolized as well as in embolized lobes after portal venous branch embolization (PVE) with dynamic helical computed tomography (CT). Six patients with hepatic malignancies, who underwent PVE prior to a subsequent hepatectomy, were the subjects of this study. We performed CT examinations before PVE and 2 weeks after PVE to make a volumetric analysis. At the same time, we performed single-location dynamic sequences after the injection of a 50-ml bolus of contrast medium, and we then created time-density curves from circular regions of interest drawn over the aorta, parenchyma of the right and left lobe of the liver, and spleen. We calculated the arterial perfusion index (ml/min per ml of tissue) and the portal perfusion index by dividing the maximum rate of enhancement of the liver before and after the splenic peak by the peak aortic enhancement. We then calculated the arterial and portal flows (ml/min) from the perfusion index and values of CT volumetry. In the right lobe, where the portal flow was occluded, the arterial perfusion index and flow increased significantly after PVE. In contrast, the arterial perfusion index and flow both decreased in the left lobe after PVE in a reverse response to the increase in the portal perfusion index and flow. The total arterial flow of the liver thus seemed to slightly increase; however, the change was not significant. By performing PVE an increased arterial perfusion was induced in the embolized lobe, with a concomitant decrease in arterial perfusion in the nonembolized lobe.

症例は64歳,男性. 37歳時に十二指腸潰瘍のため幽門側胃切除術の既往を有していた.食物つかえ感,心窩部痛のため上部消化管造影,胃内視鏡検査を施行したところ胃噴門部にほぼ全周性のBorrmann III型腫瘍を認めた.生検でgroup Vと診断され,手術を施行した.総肝動脈,膵頭領域,大動脈周囲のリンパ節が一塊となり,著明に腫大していたため,根治術は不可能と判断し,姑息的な残胃全摘術を施行した.病理組織検査では細胞質に乏しい,小型から中型の核を有する異型細胞が索状,充実性に増殖しており,著明な核分裂像,脈管侵襲像を認めた.腫瘍細胞は好銀顆粒を有し,酵素抗体法でsynaptophisin, chromogranin, gastrinが陽性なことから,内分泌細胞癌と診断された.術後4カ月に多発肝転移を生じ1年で癌死した.胃内分泌細胞癌は稀な疾患であるが,残胃に発生したとする報告は少なく,極めて稀な症例と考えられた.

胃軸捻転を伴った成人Bochdalek孔ヘルニアは,検索しえた限り本邦では自験例を含め7例と非常に稀な病態である. 症例は72歳,女性で,平成8年7月に左上腹部痛と嘔吐が出現して当院へ入院した.胸部X線撮影で左胸腔内に胃泡像があり,上部消化管造影で混合型胃軸捻転を伴う横隔膜ヘルニアを認め,胸腹部MRI所見からBochdalek孔ヘルニアと診断した.手術は開腹アプローチで行った.左横隔膜の外側後方に横隔膜欠損を認め,同部より軸捻転を伴った胃体部と横行結腸の一部が左胸腔内に脱出していた.ヘルニア孔は大きく(7cm×5cm),その背側は非常に脆弱であったためダクロンメッシュを用いてヘルニア孔を閉鎖した.術後経過は順調で3年3カ月の現在までヘルニアの再発は認めていない.

症例は開腹術の既往のない32歳の女性で,妊娠21週目に閉塞性イレウスを発症した.開腹所見では,肝臓と前腹壁の問の癒着による線維性索状物が,妊娠で挙上した40cmの小腸を絞拒していた.索状物を切離し虚血腸管を切除した.術後の回復は順調で,妊娠38週に自然分娩で健康な女児を出産した. 妊娠中のイレウスは稀であり,多くの場合開腹術の既往による癒着性イレウスである.本症例の肝臓周囲の癒着の原因は不明であったが,手術の既往がなくても妊娠中の癒着によるイレウスは除外できないと考えられた.

症例は85歳の女性で,上行結腸癌および術後の癒着性イレウスに対する手術既往歴を有していた.検診の便潜血陽性に対する精査の結果,回腸・横行結腸の端側吻合によって生じた長さ17cmの盲管内に1型の大腸癌が発見された.手術は盲管のみの切除を行った.病理組織学的にはmp, ly0, v0, n(-)の中分化腺癌であった.また盲管内には径5mm大までの腺管腺腫を7個認めた. Blind loop内に発生した大腸癌の本邦報告例は,自験例を含めて7例であった.このうち短絡型が4例,盲管型が3例で,前者の壁深達度はse以深が多く診断の困難さが示唆された. Blind loop内では細菌叢の変化がみられるために発癌のpotentialが高いとは考えられたが, blind loopが発癌に関与するのか,あるいは偶発的にblind loop内に癌が発生したのかについての判定は,報告症例数が極めて少ないため,今後の症例の集積が必要である.

イレウスに合併し,胃石イレウスとの鑑別が困難であった巨大腹腔内遊離体の1例を経験した.症例は88歳,男性.腹痛,嘔吐を主訴として近医を受診,腹部単純X線で腹腔内に石灰化を伴う腫瘤像とイレウス像がみられ,開腹手術の既往がないことから胆石イレウスと診断された.しかし,当院のCTでは胆道系に異常所見を認めなかったことから,胃石イレウスと診断し,手術を施行した.手術所見では腸管の広範な癒着による閉塞性イレウスを認め,その近傍に6.8cm×6.5cmの巨大な腹腔内遊離体が存在した.病理組織学的にも腹腔内遊離体に合致する所見であった.腹腔内遊離体は腹膜垂の炎症・脱落を発生原因とする説がもっとも有力で,本症例の腹腔内遊離体の成因および腸管癒着の原因としても腹膜垂が関与しているものと思われた.

最大腫瘍径3cm以下, 3病巣以下の肝細胞癌(HCC)切除49例, 56結節を対象に,腫瘍および腫瘍周囲の病理組織像を腫瘍径別(径15mm以下; 12結節, 16-20mm; 20結節, 21-25mm; 16結節, 26-30; 8結節)に検討し,選択すべき治療法を考察した.腫瘍径15mm以下のHCCでは,腫瘍周囲進展像(被膜外浸潤・脈管侵襲・肝内転移)陽性が1結節(8.3%)のみであったため,経皮的エタノール注入療法(PEIT)が第一選択と考えられた.しかし,中・低分化型が6結節(50%)に混在していたこと,被膜形成陰性が5結節(41.7%)にみられたことは, PEIT後の局所再発へのrisk factorとして留意すべきと思われた.腫瘍径16mm以上のHCCでは被膜浸潤が59.1%, 腫瘍から1cm以内の腫瘍周囲進展像が45.5%と高率にみられ,またPEIT施行後肝切除例の4結節中の1例(腫瘍径22mm)に肝内転移の組織学的遺残がみられたことから,腫瘍周囲を含めた確実な局所コントロールが可能な治療法,すなわち肝切除術やマイクロ波凝固壊死療法が第一選択となると考えられた.

閉鎖孔ヘルニアは高齢者の女性に好発する比較的稀な疾患で,穿孔例の報告は少ない.今回,閉鎖孔に嵌頓した象徴が穿孔し,大腿部に巨大な膿瘍をきたした1例を経験したので報告する.症例は82歳女性で,腹痛,嘔吐,左大腿部痛のため,近医を受診.同医でイレウスと診断され保存的治療が行われるも改善せず,左大腿部の腫脹が出現した.画像上,大腿部にガス像を認めたことよりガス壊疸の疑いで当科に紹介された. CTでは,左大腿部に膿瘍を認め,その上方は左閉鎖孔に近接していた.また前医で挿入されたイレウス管の先端は左閉鎖孔付近で停止していた.膿瘍穿刺液にenterococcusが検出されたことより,閉鎖孔ヘルニア嵌頓による小腸穿孔と診断した.術中所見では回盲部より75cm口側の小腸が左閉鎖孔に嵌頓・穿孔し,大腿側に穿破していた.小腸部分切除とヘルニア門の修復を行い軽快退院した

Serum hyaluronate can be used as an index of hepatic sinusoidal endothelial cell function. This study was designed to evaluate its application as a predictor of liver failure after major hepatectomy. Thirty-six patients who underwent right liver lobectomy after percutaneous transhepatic right branch portal vein embolization were divided into two groups based on their postoperative clinical course (groups 1 and 2, with and without postoperative liver failure, n = 6 and n = 30, respectively). We serially measured serum hyaluronate levels using a sandwich binding protein assay system before and after hepatectomy and determined relations with progression of the underlying chronic liver disorder, portal venous pressure, and liver growth of the left lobe after portal embolization. Serum hyaluronate levels were significantly elevated, in line with the degree of severity of the underlying chronic liver disorder, and correlated well with the portal venous pressure and the hypertrophic ratio of the left lobe subsequent to portal embolization. Serum hyaluronate levels in group 1 were significantly higher than those in group 2 before surgery and increased steeply during the early period after hepatectomy. These results suggest that the serum hyaluronate reflects the hepatic functional reserve, and serial measurement of this parameter after hepatectomy can serve as a simple indicator for early detection of posthepatectomy liver failure.

Background: Criteria for selection of patients for portal vein embolization (PVE) before major hepatectomy for advanced-stage hepatocellular carcinoma (HCC) have not been clarified in detail. This study was aimed at defining those benefiting from this therapy in a retrospective fashion. Patients and Methods: Firstly, to determine liver functional criteria for applying this approach 26 patients with stage III (17 patients) or IV (9 patients) disease, who underwent major hepatectomies after PVE, were divided into those without major complications (20 patients) and a postoperative liver failure group (6 patients). Clinical, analytical, and hemodynamic parameters obtained before and after PVE were compared between the groups. Secondly, to define the application of this approach with regard to tumor progression survival rates of patients were also obtained, taking into account factors which affect tumor development, i.e. lesion size, intrahepatic metastasis and vascular invasion. Results: With regard to liver function 4 nonindications were obtained: (1) a portal pressure measured right after PVE >25 cm H2O; (2) post-PVE serum hyaluronate >200 ng/ml; (3) pre-PVE serum cholinesterase Conclusions: When laboratory data fulfill 3 or more of the criteria, the extent of hepatic resection may have to be carefully reconsidered. Patients with HCCs featuring IM3 intrahepatic metastasis may not benefit from the aggressive approach described here.

The effect of warm ischemia on lidocaine-metabolizing activity was examined in vivo. Total liver ischemia was produced for 1 hr in Sprague-Dawley rats by clamping the portal vein and hepatic artery at the hilum. Livers were then reperfused, and liver microsomes were prepared before and 0, 2, 6, and 24 hr, and 3, 6, and 10 days after reperfusion. Microsomal lidocaine-metabolizing activity and cytochrome P-450 content were examined. Lidocaine N-deethylase activity was decreased from 2.25 +/- 0.33 to 0.97 +/- 0.21 nmol/mg protein/min (mean +/- SD) 24 hr after reperfusion. This inhibition was prolonged, and activity gradually recovered after 10 days. The cytochrome P-450 content showed the same tendency. On the other hand, serum levels of alanine aminotransferase increased significantly 2 hr after reperfusion and returned to control levels 3 days after reperfusion. Liver blood flow recovered rapidly after unclamping and reached baseline levels within 6 hr. Our results suggest that after warm ischemia, prolonged hepatic dysfunction in drug metabolism, which cannot be detected by evaluating serum enzymes or liver blood flow, exists at the microsomal level.

Colonic stenosis associated with ulcerative colitis without malignant tumor is very rare with only eight cases reported in Japan. A case of total colonic type of ulcerative colitis with severe stenosis of the transverse colon is reported. A 37-year-old man had been complaining of abdominal pain and diarrhea, and diagnosed as having ulcerative colitis since 1979. In 1998, he was admitted to the department because of vomiting and abdominal pain. Barium enema and colonoscopy revealed stenosis around the entire circumference of the transverse colon measuring about 10cm in length. Right hemicolectomy was performed because possible association of malignant tumor could not be ruled out. Histopathologically, inflammatory cells like polymorphonuclear leukocytes which infiltrated into mucosa and submucosa, hypertrophy of muscle layer, and fibrosis covering from submucosa to subserosa were observed. No malignancy was seen.

Background: Laparoscopic surgery has proven to be safe and effective. However, the value of laparoscopic resection for malignancy in terms of cancer outcome can only be assessed by large prospective randomized clinical trials with sufficient follow-up. Methods: COLOR (COlon carcinoma Laparoscopic or Open Resection) is a European multicenter randomized trial which has started in September 1997. In 24 hospitals in Sweden, The Netherlands, Germany, France, Italy and Spain, 1,200 patients will be included. The primary end point of the study is cancer-free survival after 3 years. Results: Within Conclusions: Although laparoscopic surgery appears of value in colorectal malignancy, results of randomized trials have to be awaited to determine the definitive place of laparoscopy in colorectal cancer. Considering the current accrual rate, the COLOR study will be completed in 2002.

We describe a rare case of quadruple cancer arising from the renal pelvis, stomach, rectum and lung. A 68-year-old man who was pointed out having hematuria at a medical check up underwent a left nephroureterectomy for transitional cell carcinoma of the renal pelvis (pT1N0M0) in November 1993. In April 1996, an endoscopic mucosal resection for early gastric cancer (m, ly0, v0) was performed. After discharge, a colonoscopy showed a protruding tumor of the rectum in June 1996. This tumor was resected endoscopically, but the resected margins were positive for tumor cells. Anterior resection for rectal cancer (sm, lyl, v0, pT1N0M0) was performed. In March 1997, an abnormal shadow 10mm in diameter in the lower lobe of the left lung was pointed out and a left lower lobectomy was performed by videoassisted thoracoscopic surgery (moderately differentiated adenocarcinoma, pT1N0M0). This rare case of guadruple cancer in which all tumors were found in an early stage and curatively treated is presented here.

A 50-year-old man who had been operated on for fibrosarcoma of the right upper arm, was admitted to the hospital because of a right adrenal tumor. Abdominal ultrasonography and computed tomography disclosed an abnormal tumor in the right adrenal gland. Bone scintigraphy showed metastatic bone tumor. The adrenal tumor was enlarging quickly, and so we considered that operation was indispensable. Under a suspicion of adrenal metastatic tumor, a right adrenalectomy was performed. Resected specimen showed a 5.4×4.4cm tumor, contained coagulating tissue. Histological findings were the same as those of fibrosarcoma of the right arm. Adrenal metastasis of fibrosarcoma was diagnosed. The metastatic adrenal tumor is rare, especially that of fibrosarcoma. Although the prognosis of metastatic adrenal tumor is usually poor, a better prognosis can be expected by positive excision of the tumor, if the original foci is well controlled and no other prominent metastasis is present.

To review the significance of the indocyanine green dye retention rate 15 minutes after injection of 0.5mg/kg (ICGR15) for the evaluation of the liver functional reserve, relationships between ICGR15 and other liver function tests in 200 patients with hepatocellular carcinoma, and between ICGR15 and histological fibrosis (F0-3) in 40 patients of chronic hepatitis, were evaluated. Furthermore, correlations between liver functional parameters including ICGR15 and postoperative liver function were studied in patients who had undergone right lobectomy or extended right lobectomy. Although statistically significant correlations were found between ICGR15 and the values of serum albumin, cholinesterase, prothrombin time, GOT, platelet count, and portal pressure, these data distributed with some widths. Degrees of histological fibrosis distributed from 0 to 3 even in about same ICGR15, regardless with a statistically significant correlation between ICGR15 and the degree of fibrosis. Between patients groups which were divided based on their postoperative course, there found statistically significant differences in regard with their preoperative values of Alb, ChE, GOT, and ICGR15. However, a multivariate regression analysis of correlation between the postoperative course and values revealed a significance for only ChE and ICGR15. These results demonstrate the importance of ICGR15 in preoperative evaluation of liver function. However, when there is a gap between the values of ICGR15 and other parameters, liver function should carefully be appreciated.

Background. The functional heterogeneity of the cell adhesion molecule family CD44 is explained by differences in its activity, which is regulated by alterations in the distribution of its cellular localization. The aim of the current study was to evaluate the functional differences in cancer cells according to variations in the cellular localization of CD44.

径30mm以下肝細胞癌 (HCC) 切除例のうち単発38例と多発24例の第1・第2結節を対象に, 組織分化型面積比と組織学的浸潤度を比較し, 小型HCCにおける多中心性多発 (MC) と転移性多発 (IM) の相違点を検討した.第2結節に高分化型が存在する例をMC群, 存在しない例をIM群と分類した. この分類によると, MC群が9例, IM群が15例と後者が多数を占めた. MC群の第1結節は単発結節と同等の分化型面積比と組織学的進展性を示したが, IM群の第1結節は中・低分化面積比, fc-inf陽性率, vp陽性率ともに有意に高率であった. MC群とIM群の画像上の存在部位や第1-第2結節径差には有意差を認めなかったが, DSA血管造影でIM群第2結節の濃染像が有意に高率であった.多発する小型HCCでは, 第2結節の高分化型組織像の存在の有無が, IMとMCの鑑別の一助になるものと思われる.

Percutaneous transhepatic portal vein embolization (PTPE) has been used to decrease the risk of hepatic failure after hepatectomy in patients with poor liver function. The effect of PTPE on hepatic drug-metabolizing activities is not clear. Therefore we examined the effect of portal vein branch ligation, a model of PTPE, on hepatic drug-metabolizing activities in Sprague-Dawley rats. Ligated and nonligated lobes were harvested separately. Drug-metabolizing activities and concentrations of components of the microsomal cytochrome P-450 monooxygenase system were examined. In ligated lobes, drug-metabolizing activities (lidocaine and aminopyrine) and enzymatic concentrations of the microsomal cytochrome P-450 monooxygenase system gradually decreased over 10 days. In nonligated lobes these functions were depressed rapidly to 60% of those before PBL but then recovered 10 days after PBL. From the viewpoint of drug metabolism, hepatic dysfunction occurred in both ligated and nonligated lobes.

We consider that the usefulness of percutaneous transhepatic right branch of portal vein embolization (PTRPE) is to reduce acute and remarkable change in portal circulation before and after right lobectomy of the liver. The pressure (cmH2O) of portal vein in patients group without preoperative PTRPE elevated from 14.2±4.2 to 22.3±4.3 before and after right lobectomy of the liver. On the other side, in patients group with preoperative PTRPE, lesser change in the pressure was shown, from 21.2±4.6 to 22.8±4.7 before and after right lobectomy of the liver. The portal blood flow in the group without preoperative PTRPE elevated to 121% on an average before and after right lobectomy of the liver. On the other side, in the group with preoperative PTRPE, a lesser change was shown, elevating to 102% on an average before and after right lobectomy of the liver. Regardless of preoperative PTRPE, portal circulation after right lobectomy of the liver was similar to prehepatectomy status. In the group with preoperative PTRPE, portal circulation showed a ramarkable change before and after PTRPE, and it was taken to posthepatectomy status. Irrespectively of the association of liver cirrhosis, the same result was acquired.

The effects of an immunosuppressive agent, tacrolimus (FK-506), on the activities of cytochrome P-450-linked monooxygenase systems with respect to three cytochrome P-450 isozymes in rat liver microsomes were investigated. FK-506 non-competitively inhibited the aniline p-hydroxylase, p-nitroanisole O-demethylase and lidocaine N-deethylase activities of cytochrome P-450-linked monooxygenase systems, these activities being mainly catalyzed by cytochromes P-450 CYP2E1, CYP2C11 and CYP3A4, respectively, and the Ki values of the activities for FK-506 were determined to be 605, 491 and 97 microM, respectively. The inhibition of cytochrome P-450-linked monooxygenase systems by FK-506 seemed to involve the direct inhibition of cytochromes P-450 because the NADPH-cytochrome c reductase and NADPH-ferricyanide reductase activities of NADPH-cytochrome P-450 reductase were not affected by the presence of 1 mM FK-506 at all. A spectrophotometric study showed that a reverse type I spectral change was induced on the addition of FK-506 to rat liver microsomes, and the Ks value was apparently 125 microM. On the other hand, the EPR spectra of cytochromes P-450 in rat liver microsomes were not affected by 1 mM FK-506. These results suggest direct interaction between FK-506 and cytochrome P-450 apoproteins, except for the heme iron regions of cytochromes P-450, resulting in inhibition of the drug-metabolism activities catalyzed by cytochromes P-450.

To evaluate the effects of hepatopancreatectomy on the regenerative process of the liver, the serum protein changes, hepatic protein synthesis (HPS), and bromodeoxyuridine (BrdU) labeling index were measured in rats. Sprague-Dawley rats were divided into four groups according to the type of resection: A simple laparotomy was performed in the sham group; 68% of the liver was excised in the Hx group; 45% of the pancreas was excised in the Px group; and 45% of the pancreas and 68% of the liver were excised simultaneously in the HPx group. Serum total protein and albumin levels were significantly lower in the HPx group compared to the other three groups on postoperative day (POD) 3 (P

With the aim of minimizing postoperative liver dysfunction and promoting increased resectability, we employed portal vein embolization (PVE). In this study, the effect of PVE on major hepatic resection for advanced-stage hepatocellular carcinoma (HCC) in injured livers was evaluated. PVE was performed prior to hepatectomy in 13 patients with stage III and IV HCCs. Following PVE, right trisegmentectomy was performed in 3 patients, extended right lobectomy in 3 and right lobectomy in 7. To evaluate the effect of PVE, the changes in liver functional capacity and estimated remnant liver volume (ERLV), determined by computed tomography, were examined before and after PVE. The operative morbility, mortality, and survival rates after hepatectomy were also assessed. By 2 weeks after PVE, ERLV had increased in all patients, by an average of 28%, and the mean resection rates had decreased from 70.0% to 62.2%. Postoperatively, the 30-day mortality rate was 15.3%, and the 1- and 2-year survival rates were 69% and 46%, respectively. The results of this study indicate that resectability can be increased, and major hepatectomy can be made safer by employing PVE preoperatively, in view of the fact that major hepatectomy was not considered feasible without PVE in these patients.

Insulinomas are comparatively rare. We successfully operated on a cases of insulinoma of which localization was revealed by preoperative as well as intraoperative examinations. A 20-year-old man was admitted because of an unconsciousness attack. By magnetic resonance imaging and ultrasonography, a tumor with the size of 2cm in diameter was found in the tail of the pancreas. We performed percutaneous transhepatic portal catheterization (PTPC) and selective arterial calcium injection (SACI), in which the localization of the tumor was diagnosed by observing the marked increase in the insulin concentration of the portal venous blood sampled near the tumor site. Partial resection of the tail of the pancreas without splenectomy was performed. In our case, hypoglycemic attacks did not occur any more after the operation. Because the surgical resection is the primary choice for the treatment of insulinoma it is necessary to diagnose the localization of the tumor preoperatively and intraoperatively for a successful resection. It is though that PTPC and SACI were useful examinations for insulinoma.

We report herein 4 cases of lactic acidosis found in patients with gastrointestinal cancer, who were being given total parenteral nutrition (TPN). The first patient had advanced gastric cancer, the second patient hepatocellular carcinoma with lung and bone metastasis. Both were treated with chemotherapy, and refused meals because of severe nausea. The third and fourth cases refused meals because of poor appetite after having undergone pancreatoduodenectomy. In each case, the patient received TPN without vitamins. At 25 days on average after they had stopped eating, clouding of consciousness, peripheral circulatory failure, and tachypnea suddenly occurred. Severe metabolic acidosis was disclosed. Serum lactate was 127.9mg/dl on average. Upon giving thiamine intravenously these symptoms dramatically resolved. It was considered that in patients who were being treated with chemotherapy, and who were exhausted after having undergone major surgery, TPN should be performed carefully to avoid lactic acidosis.

Leiomyosarcoma of the ascending colon is an extremely rare disease. This paper describes a case of leiomyosarcoma of the ascending colon associated with colocolic type intussusception. A 61-year-old woman was admitted to the hospital because of abdominal pain around the navel. An infant fist sized tumor was felt at the right side of the navel. Barium enema revealed a tumbler like tumor. CT revealed a lobulated tumor which was unevenly enhanced. On colonoscopic examination, the pointed end of the apparatus did not pass through the intestine at the lesion. With biopsy a leiomyosarcoma was suspected. While the patient was waiting for operation, her abdominal pain was intensified and had vomiting. Emergency operation was carried out with a diagnosis of intestinal obstruction. There were a large volume of slightly hemorrhagic ascites in the abdomen and intussusception headed by tumor. Right hemicolectomy with lymph bnode dissection (D2) was performed. About forty percent of leiomyosarcomas of the colon grow into the lumen of the bowel, which are called “Intracolic type”, although more than ninety percent are “Extra type” in the small intestine. So intussusception is a significant complication in the colonic leiomyosarcoma.

慢性肝炎 (CH) 併存肝細胞癌36切除例の再発様式を検討し, CHと異時性多中心性発癌の関連性と肝切除の意義を考察した. 対象の61%が組織学的stage III, IV-A進行癌であり, 術後9年目の1例以外は全て3年以内に再発した. 異時性多中心性再発の条件を, (1) 初発巣が早期肝細胞癌で絶対治癒切除が得られた例, (2) 初発巣に浸潤像のない術後3年以降単発再発例, (3) 術後5年以降再発例, (4) 再発再肝切除病巣に高分化型組織像が存在する例とすると, 異時性多中心性発癌例は術後9年目再発の1例 (肝硬変進展例) のみであった. 累積5年再発率・生存率はそれぞれ37.7%・70.8%と良好な成績であり, この理由は対象の64%に葉単位以上の広範肝切除を適用したこと, 異時性多中心性再発例が1例に過ぎなかったことの2点が考えられた. CH併存例は単中心性に発生する可能性が強く, とくに径30mmを越える肝癌では広範肝切除による根治性の追及で良好な遠隔成績が得られている.

Carcinoma of the ampulla of Vater is uncommon. This study aimed to clarify predictors of survival for ampullary adenocarcinoma and to identify characteristics of its two major pathological subtypes.Medical records were reviewed for 86 patients who underwent curative resection for ampullary adenocarcinoma between 2000 and 2012 at 12 principal hospitals in Kagawa, Japan.Resection was most common among 75-79-year-old patients. Actuarial 1-, 3-, and 5-year postoperative survival rates for ampullary adenocarcinoma were 90%, 72.3%, and 69.1%, respectively. Preoperative biliary drainage; serum CA19-9 and total bilirubin levels; pathological grade; perineural, vascular, pancreatic, and duodenal invasion; nodal metastasis; UICC-T stage; and pancreatobiliary subtype were predictors of poor survival. An elevated serum CA19-9 level; an elevated total bilirubin level; lymphatic, vascular, perineural, and pancreatic invasion; and advanced overall tumor stage were more common in patients with pancreatobiliary-type tumors than in patients with intestinal-type tumors. Additionally, pathologic subtype analysis showed that each subtype had distinct prognostic factors.Preoperative elevated serum CA19-9 and total bilirubin levels are prognostic factors for ampullary adenocarcinoma, and are both associated with pancreatobiliary-type tumors. Surgeons should be aware of these factors because pancreatobiliary-type adenocarcinoma is aggressively invasive and is associated with poor survival.

The goal of this retrospective study was to clarify the clinical implications of the status of the 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4).Recent whole-exome sequencing had shown that the landscape of the pancreatic ductal adenocarcinoma (PDAC) genome is notable for 4 frequently mutated genes (KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4).We determined immunohistochemically the status of TP53, CDKN2A/p16, and SMAD4/DPC4 among the 4 genes because the KRAS gene is mutated in virtually all PDAC patients, and analyzed relationships with clinicopathological findings, including survival and patterns of disease progression, in 106 patients with PDAC undergoing radical surgery.Abnormal immunolabeling of p53 was detected in 81.1% of PDACs and was significantly associated with tumor dedifferentiation (P = 0.022) and the presence of locoregional recurrence (P = 0.020). Loss of p16 and Smad4/Dpc4 immunolabeling was identified in 67.0% and 60.4%, respectively. Loss of p16 immunolabeling was associated with lymphatic invasion (P = 0.012) and postoperative widespread metastases (P0.001). A significant correlation was found between Smad4/Dpc4 immunolabeling and tumor size (P = 0.006), lymphatic invasion (P = 0.033), and lymph node metastasis (P = 0.006). Interestingly, all of the 6 patients demonstrating 5-year survival had intact SMAD4/DPC4. Kaplan-Meier survival analysis showed that lymph node metastasis (P = 0.001), lymphatic invasion (P = 0.008), the tumor (T) factor (T3 vs. T1/T2, P = 0.004), loss of p16 immunolabeling (P = 0.029), and loss of Smad4/Dpc4 immunolabeling (P0.001) were significantly associated with shorter overall survival. Multivariate analysis revealed that loss of Smad4/Dpc4 immunolabeling was an independent and significant poor prognostic factor for overall and disease-free survival. On analysis of combinations of the status of these 3 genes, increasing number of alterations reflected poorer survival.Genetic alterations of these 3 genes and their accumulation are strongly associated with malignant behavior of PDAC. Their immunohistochemical assessment at the time of diagnosis may provide a new prognostic tool, assisting in deciding optimal therapeutic strategies for patients.

To determine whether cytokines produced in the operative field during digestive surgery selectively spill over into the portal blood, the changes in interleukin-6 (IL-6) levels in portal and peripheral venous blood were assayed at several points in time from the commencement of surgery until 14 days later, in 11 patients. Similar changes in the IL-6 levels were observed in the portal and peripheral blood samples; however, the IL-6 levels in the portal blood reached a maximum 6–12 h after the commencement of surgery, being earlier than in the peripheral venous blood. In fact, between 3 and 12 h after the commencement of surgery, the IL-6 levels were higher in the portal blood by 33–81 pg/ml. By 24 h or more after the commencement of surgery, the IL-6 levels did not differ significantly in the two types of blood samples. Moreover, the C-reactive protein levels 2 days after surgery were even more closely correlated to the maximum IL-6 levels in the portal blood than to those in the peripheral venous blood. These results suggest that IL-6 produced during intraabdominal digestive surgery initially enters the portal blood, being trapped by IL-6 receptors in the liver, where it may regulate the synthesis of acute-phase proteins as a hepatocyte-stimulating factor.

The effectiveness of University of Wisconsin (UW) and University of Pittsburgh (UP) solutions for the preservation of rat hearts was compared. Lewis rat hearts were preserved with UW (group A, n = 45) or UP (group B, n = 45) solution for 0 or 24 h and then transplanted heterotopically into the recipients' abdomen. Ten recipients in each group were observed to obtain 1-week graft survival rates. Tissue water content and tissue content of adenine nucleotides were measured 2 h after transplantation in six grafts from each group. Six hearts preserved for 0 h and seven hearts preserved for 24 h were taken from each group 24 h after grafting for histopathology. The 1-week graft survival rates of groups A24 and B24 were 60% and 10%, respectively. In the 24-h preserved grafts, adenosine triphosphate (ATP) and energy charge [(ATP + adenosine diphosphate/2)/(ATP + adenosine diphosphate + adenosine monophosphate)] of groups A and B were 0.972 +/- 0.165 and 0.200 +/- 0.123 mg/g wet tissue (P0.05) and 74.4% and 61.1% (P0.05), respectively. The tissue water content of group A24 was 71.7%, whereas that of group B24 was 74.1% (P0.05). Histopathology revealed more severe muscle edema and necrosis and infiltration of polymorphonuclear cells in group B24 than in group A24. We conclude that UW solution is more appropriate for rat heart preservation than UP solution.

Annexin (AX) constitutes a new family of Ca2+-dependent membrane-binding proteins; 13 of them have been described. Among these, annexin-1 (AX-I) has displayed many biological functions in vitro. Its actual role in vivo, however, remains unknown. We already reported that AX-I was expressed in proliferating (regenerating) hepatocytes at both protein and messenger RNA (mRNA) levels. The role of AX-I in human hepatocellular carcinoma (HCC) remains obscure. In this study, the amounts of AX-I at protein and mRNA levels, as well as its localization, have been determined in the normal human liver, chronic hepatitis liver, and nontumorous and tumorous portions of HCC. AX-I was rarely found in normal and chronic liver tissues, whereas it is overexpressed at both the transcriptional and translational levels in tumorous and nontumorous regions of HCC. In addition, more AX-I was expressed in the tumorous portion than the nontumorous portion of HCC. AX-I was present in the hepatocytes and HCC cells, localized mainly in the cytoplasm. AX-I was expressed in poorly differentiated cancer cells. Furthermore, AX-I was tyrosine-phosphorylated in HCC. We also found that some of the AX-I- positive hepatocytes in the nontumorous tissues were derived from a particular subset of parenchymal cells (stem or oval cells). These results indicate that AX-I plays an important role in the malignant transformation process leading to HCC and that it is closely related to the histological grade of HCC. HCC would offer a novel tool with which to study the function of AX-I in malignant transformation.

A lymphoepithelial cyst is reported. A 68-year-old man consulted a surgeon, presenting with a sense of abdominal fullness. Ultrasonography and computed tomography revealed a large tumor, 10 cm in diameter, behind the head of the pancreas. Celiac arteriography at our hospital showed feeding arteries from the dorsal pancreatic artery and the pancreatic arcades. CA19-9 was elevated to 178 U/ml. Laparotomy was performed. The tumor was well demarcated from the surrounding tissue by a fibrous capsule and there was no continuity to the pancreatic parenchyma. Simple tumorectomy and distal gastrectomy for peptic gastric ulcer disease were performed. The cut surface revealed a multicystic lesion containing atheromatous substances. Histopathologically, the internal surface of the cyst was lined with stratified squamous epithelium containing mucin-producing cells; many germinal centers were observed in the cyst wall.