[A Case of Unresectable Advanced Lower Esophageal Adenocarcinoma That Achieved Pathological Complete Response after Conversion Surgery following Nivolumab plus SOX Therapy].

An 80-year-old woman presented with epigastric discomfort and dysphagia, underwent upper gastrointestinal endoscopy, and was diagnosed with type 2 advanced lower esophageal adenocarcinoma. Computed tomography data revealed that there was the lower esophageal tumor is T3, but a large carina lymph node invading the left bronchus. We diagnosed this patient unresectable cT4bN1M0, cStage ⅣA advanced esophageal adenocarcinoma, and we administered nivolumab plus S-1 plus oxaliplatin(SOX)therapy. After 3 courses of the therapy, imaging showed marked reduction in the size of primary tumor and carina lymph node. We diagnosed partial response(PR)and attempted conversion surgery. Video-assisted thoracoscopic esophagectomy with 2 fields lymphadenectomy was performed. The pathological examination demonstrated no residual tumors and no lymph node metastases, and the histological response of primary tumor was determined to be Grade 3, with a pathological complete response(pCR). Currently, the patient is alive without recurrence for 1 year after surgery.

[A Case of Early Ascending Colon Cancer Complicated the Mesenteric Phlebosclerosis Who Underwent Laparoscopic Subtotal Colectomy].

A 71-year-old woman who have been taking Sanshishi for 50 years until the age of 70 for dermatitis underwent colonoscopy( CS)to reveal the reason of abdominal pain. CS showed ascending colon tumor(AT)with major axis 3 cm and suspicious of the mesenteric phlebosclerosis. Although endoscopic submucosal dissection(ESD)was performed for AT, colon perforation due to colonic wall fibrosis was occurred and ESD was suspended. Therefore, surgical resection was planned. Intraoperative observations by laparoscopy showed that the color of colon serosa from the cecum to the splenic flexure was grayish white and colonic wall thickening with lead tubular change was observed. From the descending colon to the sigmoid colon, wall thickening was mild, and Haustra was confirmed. Although the tumor location was in the ascending colon, laparoscopic subtotal colectomy and functional end-to-end anastomosis of ileum and sigmoid colon was performed for safe intestinal anastomosis. For treat of colon cancer complicated mesenteric phlebosclerosis(MP), endoscopic resection is considered difficult due to fibrosis and extended resection of the colon may be required to reduce the risk of anastomotic leakage. Herein, we report our case and details of past reported literatures.

Short-term outcomes of laparoscopic lateral pelvic node dissection for advanced lower rectal cancer.

BACKGROUND: The laparoscopic magnified visual effects and evolution of the laparoscopic camera system have recently enabled us to observe details in the deep pelvic floor. Indications of laparoscopic surgery for colorectal cancer have been expanded, and laparoscopic (Lap) lateral pelvic node dissection (LLND) has been introduced in some institutions. We investigated the feasibility of Lap LLND in patients with locally advanced rectal cancer (LARC). METHODS: Lap LLND was performed in 38 patients diagnosed with cT3-4 or cN1-2 cancer during 2014-2018. We retrospectively analyzed their surgical and short-term outcomes. RESULTS: Laparoscopic surgery was performed in all patients. cStages II/III/IV were found in 6/31/1 patients, respectively. Among them, 25 patients underwent neoadjuvant chemotherapy without radiotherapy. Lap unilateral LLND was performed in 6 patients and Lap bilateral LLND was performed 32 patients. The number of harvested lymph nodes (LNs) were 4 in the unilateral group and 15 in the bilateral group. Operation time was 531 min, and blood loss was 105 ml. Oral intake has started on postoperative day (POD) 3, and pelvic drain was removed on POD 7. Hospital stay was 18.5 days. Seven patients developed a neurogenic bladder (all Clavien-Dindo grade (CD) II and all occured in the bilateral LLND group), one patient developed abdominal bleeding (CD IIIb) and one patient developed anastomotic leakage (CD IIIb). Pathological results revealed 2/5/16/14/1 patients with pStages 0/I/II/III/IV, respectively. Four patients had histopathologically verified lateral pelvic lymph node metastases. There were no local recurrences after curative surgery (median follow-up 24.2 months). CONCLUSION: Although the median follow-up period is relatively short and further follow-up is necessary, oncologically, especially in the point of local control rate, Lap LLND appears to have acceptable in the treatment of LARC without radiotherapy in experienced centers. Further investigations focusing on indications and the Lap LLND procedural technique are required.

[Two Cases of Locally Advanced Lower Rectal Cancer with Pathological Complete Response after Cetuximab plus SOX as Neoadjuvant Chemotherapy].

We have introduced neoadjuvant chemotherapy(NAC)for locally advanced lower rectal cancer(LARC)since 2014. We report 2 LARC cases in which a pathological complete response(pCR)was obtained by using cetuximab(Cmab)plus oxaliplatin plus S-1(SOX)for NAC. Case 1: A 68-year-old woman underwent 4 courses of Cmab plus SOX for Rb rectal cancer (well-differentiated adenocarcinoma, cStage Ⅲc: cT4b[vagina]N3M0). Lap posterior pelvic exenteration was performed. The pathological findings of the resected specimen revealed no carcinoma and we diagnosed it as pCR. As of 31 months after the operation, she is alive without recurrence. Case 2: A 72-year-old man underwent 4 courses of Cmab plus SOX for middle and lower rectal cancer(Rab, moderately differentiated tubular adenocarcinoma, cStage Ⅲc: cT3N3M0). After NAC, with the diagnosis of ycT3N0M0, laparoscopic-assisted(Lap)super-low anterior resection with bilateral lateral pelvic node dissection was performed. The pathological findings of the resected specimen revealed no carcinoma and we diagnosed it as pCR. As of 37 months after the operation, he is alive without recurrence. NAC with Cmab plus SOX may be an effective treatment for LARC.

[Laparoscopic Total Pelvic Exenteration of Locally Advanced Rectal Cancer Invading Urogenital Organs].

Application of laparoscopic surgery(Lap)for colorectal cancer has expanded, and laparoscopic total pelvic exenteration (TPE)of locally advanced rectal cancer(LARC)invading the urogenital organs has been introduced in some institutions. In our institute, we have performed Lap TPE and posterior-TPE(PPE)in a total of 6 LARC patients so far. Here, we report the surgical technique of Lap TPE, and the associated surgical and short-term outcomes. We performed Lap TPE and Lap PPE in 3 patients each. Operation time was approximately 562 min, and the blood loss was 310 mL on an average. No patient developed postoperative complications above Clavien-Dindo Grade Ⅲ. One patient exhibited recurrence in the liver and another in peritoneum in the Lap PPE group. No recurrence was observed in the Lap TPE group(median follow-up period: 24.5 months). Although Lap TPE and PPE are difficult to perform and time consuming, it is suggested that these procedures may help reduce the intraoperative bleeding volume and shorten the length of postoperative hospital stay compared to open TPE and PPE.

[A Case of Recurrent Gastric Cancer with Durable Complete Response after Short-Term Nivolumab Therapy].

We report the case of a patient with recurrent gastric cancer that showed a complete response(CR)after short-term nivolumab administration. A 76-year-old woman was diagnosed with unresectable advanced gastric cancer(T4b, N+, M0, cStage ⅣA). The patient was administered 7 courses of SOX. Since the primary lesion was reduced significantly after the chemotherapy, radical gastrectomy was performed. Although postoperative adjuvant chemotherapy with weekly nab-PTX was performed, cancer recurrence occurred in the abdominal cavity, and another surgery was performed. However, complete resection was difficult to achieve. Postoperatively, chemotherapy was continued; however, CEA levels increased, and thus RAM+PTX was administered as second-line treatment. Stable disease was maintained for a while; however, disease progression occurred eventually. Thus, RAM+PTX was discontinued after 8 courses, and nivolumab was administered as the third-line treatment. However, due to the rapid deterioration of renal function, nivolumab could not be continued after 3 courses. After nivolumab discontinuation, CEA levels normalized and the image showed CR. Approximately 1.5 years have passed since then, with no report of recurrence without any treatment. Although nivolumab has been shown to be useful as a third-line treatment for unresectable advanced/recurrent gastric cancer, there are few reports demonstrating CR and none showing maintenance of CR after short-term nivolumab administration. Moreover, the rationale of continuing nivolumab is unclear once clinical CR is achieved. Our experience shows the feasibility of discontinuation of short-term nivolumab if CR is achieved.

[A Case of Intraperitoneal Bleeding Due to Vitamin K Deficiency after Laparoscopic Total Pelvic Exenteration for Advanced Rectal Cancer].

A 70-year-old man underwent a colonoscopy and enhanced CT for scrutiny of his anemia. These examinations revealed rectal cancer(cT4b[rectal mesenteric infiltration], N3M0, cStage Ⅲc). We introduced neoadjuvant chemotherapy(NAC) (cetuximab plus oxaliplatin plus S-1, 4 courses)for this patient and diagnosed ycStage Ⅲc(ycT4bN3M0)after the therapy. We performed laparoscopic total pelvic exenteration with bilateral pelvic lymph node dissection. Cefmetazole was administered as a preventive antibiotic in the perioperative period(intraoperatively to postoperative day 3). On postoperative day 4, intra-abdominal heavy bleeding occurred. Blood examination revealed remarkable coagulation disorder with parameters such as APTT 58.9 sec, PT-INR 3.33, and a remarkably high PIVKA- / Ⅱ score of 11,754 mAU/mL. Based on these findings, the patient was diagnosed with complicated vitamin K(VK)deficiency. The coagulation disorders improved following the administration of VK. VK is a fat-soluble vitamin, and the main absorption pathways are dietary, intestinal bacterial production, and recycling in the VK metabolic cycle. In our case, it was considered that the causes of VK deficiency were a marked decrease in VK intake, impairment of the VK metabolic cycle due to taking antibiotics with a N-methyl-thiotetrazole group, and deficiency of VK accompanying suppression of the intestinal flora by antibiotics. We should also consider VK deficiency when patients are diagnosed with postoperative bleeding.

Active Hexose Correlated Compound Has Protective Effects in Ischemia-Reperfusion Injury of the Rat Small Intestine.

BACKGROUND: Ischemia-reperfusion (IR) injury of the small intestine is a serious problem in abdominal aortic aneurysm surgery or small intestine transplantation. Active hexose correlated compound (AHCC) is a popular anti-inflammatory drug in complementary and alternative medicine. The aim of this study was to examine whether pretreatment with AHCC reduces intestinal IR injury. METHODS: Rats were given a normal diet (IR group) or normal diet supplemented with 2% AHCC (IR + AHCC group) ad libitum for 10 d. After 1 d of fasting, the superior mesenteric artery was occluded by clipping for 45 min. Intestinal and blood samples were collected for 1-6 h after reperfusion. The messenger RNA (mRNA) and protein levels of inflammatory factors were analyzed. RESULTS: The IR + AHCC group had reduced mucosal abrasion and significantly increased mucosal thickness of the intestinal tissues 6 h after reperfusion, compared with the IR group. AHCC decreased mRNA expression of inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant 1 and interleukin 6 in the mucosa of the small intestine. AHCC also decreased expression of iNOS protein. Serum levels of cytokine-induced neutrophil chemoattractant 1 and tumor necrosis factor α were decreased in the IR + AHCC group compared with the IR group. Electrophoretic mobility shift assay of mucosal nuclear extracts revealed that AHCC inhibited the activation of nuclear factor kappa B. AHCC also inhibited the expression of iNOS antisense transcript, which stabilizes iNOS mRNA. CONCLUSIONS: Our findings suggest that AHCC reduces expression of inflammatory mediators, in part, by inhibiting nuclear factor kappa B activation. AHCC may have anti-inflammatory effect in patients with intestinal IR injury.

Outcomes of neoadjuvant chemoradiotherapy in Japanese locally advanced rectal carcinoma patients.

BACKGROUND: We investigated the efficacy and prognosis of neoadjuvant chemoradiotherapy (NACRT) for Japanese locally advanced rectal carcinoma patients. METHODS: Fifty-seven patients diagnosed with cT3-4 or any cT/cN+ disease using enhanced computed tomography or magnetic resonance imaging from 2002 to 2014 were enrolled. The male/female ratio was 42/15, and the median age was 67 years. Ra/Rb/Rb-P/P was expressed by 6/35/14/2 patients. Histological tumor types were tub1/tub2/por/muc in 22/30/4/1 patients. For NACRT, radiotherapy doses were 40-50.4 Gy chemotherapy consisted of 5'-DFUR, capecitabine, or S1. RESULTS: All 57 patients received curative surgical treatment. The anal preservation rate was 65.0%. The ypStage of 0/I/II/IIIa/IIIb was 7/10/25/11/4 cases. The histological antitumor effect (HATE) was ≥grade (G) 2 and G3 in 31 (54.4%) and 7 (12.3%) cases, respectively. Postoperative complications occurred in 17 patients and exceeded GIII (Clavien-Dindo classification) in four patients. Recurrence was observed in 19 patients; the primary local recurrence rate was 5.3%. The 3-year relapse-free survival (RFS) and overall survival (OS) rates were 64.8 and 95.5%, respectively; the 5-year RFS and OS rates were 60.2 and 61.0%, respectively. In multivariate analysis, ypN+ was a high-risk factor for distant organ recurrence. As predictive factors regarding the efficacy of NACRT, a neutrophil concentration <70% and a neutrophil/lymphocyte ratio <3.0 in peripheral blood prior to treatment indicated that NACRT would be significantly more effective. CONCLUSIONS: NACRT was effective in reducing local recurrence but did not suppress distant organ recurrence in Japanese locally advanced rectal carcinoma patients. A further investigation of an extension of the NACRT regimen is required.

pyroGlu-Leu inhibits the induction of inducible nitric oxide synthase in interleukin-1ß-stimulated primary cultured rat hepatocytes.

Pyroglutamyl leucine (pyroGlu-Leu), which is a peptide isolated from wheat gluten hydrolysate, has been reported to be a hepatoprotective compound in acute liver failure. In inflamed liver, proinflammatory cytokines including interleukin (IL)-1ß and tumor necrosis factor (TNF)-α stimulate the induction of inducible nitric oxide synthase (iNOS). Excess production of nitric oxide (NO) by iNOS is an inflammatory biomarker in liver injury. We examined proinflammatory cytokine-stimulated hepatocytes as a simple "in vitro inflammation model" to determine liver protective effects of pyroGlu-Leu and its mechanisms of action. We hypothesized that pyroGlu-Leu inhibits the induction of iNOS gene expression, resulting in the attenuation of hepatic inflammation. Hepatocytes were isolated from rats by collagenase perfusion and cultured. Primary cultured cells were treated with IL-1ß in the presence or absence of pyroGlu-Leu. The induction of iNOS and its signaling pathway were analyzed. IL-1ß stimulated the enhancement of NO production in hepatocytes and this effect was inhibited by pyroGlu-Leu. pyroGlu-Leu decreased the expression of iNOS protein and its mRNA. Transfection experiments with iNOS-luciferase constructs revealed that pyroGlu-Leu inhibited both of iNOS promoter transactivation and its mRNA stabilization. pyroGlu-Leu also decreased the expression of an iNOS gene antisense transcript, which is involved in iNOS mRNA stability. However, pyroGlu-Leu had no effects on IκB degradation and NF-κB activation. Results demonstrate that pyroGlu-Leu inhibited the induction of iNOS gene expression at transcriptional and post-transcriptional steps through IκB/NF-κB-independent pathway, leading to the prevention of NO production. pyroGlu-Leu may have therapeutic potential for liver injury through the suppression of iNOS.

Alpha-lipoic acid exerts a liver-protective effect in acute liver injury rats.

BACKGROUND: Recent evidence indicates that alpha-lipoic acid (α-LA) has a variety of liver-protective effects through the suppression of inflammatory mediators including tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS). However, there are few reports that α-LA markedly enhanced the survival rate in animal models of liver injury with more than 90% death. The aim of this study was to investigate the beneficial effects of α-LA in a rat model of acute liver injury and to clarify the mechanisms of α-LA action. METHODS: Rats were treated with d-galactosamine and lipopolysaccharide (GalN and LPS) to induce acute liver injury. α-LA (100 mg/kg) was administered intraperitoneally 1 h before GalN and LPS injection. Inflammatory mediators including TNF-α and iNOS were analyzed. RESULTS: A single injection of α-LA improved the survival rate by more than 80%. α-LA prevented serum transaminase increases, histopathologic changes, and apoptosis in the liver. In the serum, α-LA decreased TNF-α production and increased interleukin (IL)-10 production. In the liver, α-LA reduced TNF-α and IL-6 messenger RNA (mRNA) but enhanced IL-10 mRNA. α-LA decreased the expression of iNOS mRNA and its antisense transcript, leading to the reduction of iNOS protein expression and resulting in the inhibition of nitric oxide production. An electrophoretic mobility shift assay revealed that α-LA reduced the activation of nuclear factor-kappa B induced by GalN and LPS. CONCLUSIONS: α-LA inhibited the induction of inflammatory mediators, such as TNF-α and iNOS, in part through the inhibition of nuclear factor-kappa B activation and enhanced the induction of IL-10. α-LA may have therapeutic potential for use in the prevention of acute liver injury.

Influence of Rictor and Raptor Expression of mTOR Signaling on Long-Term Outcomes of Patients with Hepatocellular Carcinoma.

BACKGROUND: Aberrant signaling mediated by the mammalian target of rapamycin (mTOR) occurs at high frequency in hepatocellular carcinoma (HCC), indicating that mTOR is a candidate for targeted therapy. mTOR forms two complexes called mTORC1 (mTOR complexed with raptor) and mTORC2 (mTOR complexed with rictor). There are minor studies of the expression kinetics of mTORC1 and mTORC2 in HCC. METHODS: We studied 62 patients with HCC who underwent curative resection. We used univariate and multivariate analyses to identify factors that potentially influence disease and overall survival after hepatectomy. The mRNA and protein levels of mTOR, rictor and raptor in cancer and non-cancer tissues were analyzed using quantitative RT-PCR, immunohistochemistry and Western blotting. RESULTS/CONCLUSION: High ratio of the levels of rictor and raptor mRNAs in tumors was identified as independent prognostic indicators for disease-free survival. Low and high levels of preoperative serum albumin and mTOR mRNA in the tumor, respectively, were identified as independent indicators of overall survival. HCC is likely to recur early after hepatic resection in patients with high levels of mTOR and rictor mRNAs and high rictor/raptor ratios in cancer tissues. We conclude that analysis of mTOR expression in cancer tissues represents an essential strategy to predict HCC recurrence after curative treatment.

[A Case of Adenosquamous Carcinoma of the Ascending Colon].

We report a case of adenosquamous carcinoma of the colon. A 70-year-old woman underwent a colonoscopic examination because of a positive fecal occult blood test. Colonoscopy demonstrated a type 2 tumor of the ascending colon, and a biopsy specimen showed poorly-moderately differentiated tubular adenocarcinoma. We performed a right hemicolectomy with D2 lymphadenectomy. The histopathology of the tumor demonstrated adenosquamous adenocarcinoma. Primary adenosquamous carcinoma of the colon is relatively rare and has a poor prognosis. Therefore, adenosquamous carcinoma of the colon may require strict follow-up.

Adenosine, a hepato-protective component in active hexose correlated compound: its identification and iNOS suppression mechanism.

Supplementation of active hexose correlated compound (AHCC) improved the prognosis of postoperative hepatocellular carcinoma patients. Excess production of nitric oxide (NO) by inducible NO synthase (iNOS) is an inflammatory biomarker in liver injury. AHCC suppressed iNOS induction in hepatocytes, suggesting that AHCC has a potential liver-protective effect. However, the active component in AHCC responsible for NO suppressive activities has not been identified. The objective of this study was to identify this NO suppressive component and to investigate its mechanisms of action. AHCC was subjected to fractionation by cation exchanger, size exclusion chromatography, and normal- and reversed-phase HPLC. Aliquots of the fractions were added to primary cultured rat hepatocytes stimulated with interleukin (IL)-1ß, and NO production was assayed. By activity-guided fractionation and electron spray ionization mass spectrometry analysis, adenosine was identified as one of the NO suppressive components in AHCC. Adenosine inhibited NO production, and reduced the expression of iNOS protein and mRNA. It had no effects on IκB degradation, but it inhibited NF-κB activation. Adenosine also inhibited the upregulation of type I IL-1 receptor (IL-1RI). Experiments with iNOS promoter-luciferase constructs revealed that adenosine decreased the levels of iNOS mRNA at the promoter transactivation and mRNA stabilization steps. Adenosine decreased the expression of the iNOS gene antisense transcript, which is involved in iNOS mRNA stability. Adenosine in AHCC suppressed iNOS induction by blocking NF-κB activation and the upregulation of the IL-1RI pathways, resulting in the inhibition of NO production.

Bone marrow cells enhance liver regeneration after massive hepatectomy in mice.

BACKGROUND: Recent evidence indicates that transplanted autologous bone marrow cells (BMCs) can be converted into functional liver cells. BMC therapy can improve hepatic function and increase the potential for liver regeneration in patients with serious liver damage. We investigated whether BMC therapy influenced liver regeneration after massive hepatectomy in mice. METHODS: Male C57/BL6 mice underwent 70 % hepatectomy, followed by injection of BMCs via the portal vein (PV group), BMCs via the tail vein (IV group), or saline via the portal vein (control group). Analysis of serum enzyme levels and liver histology was performed on postoperative days (POD) 1, 3, and 5. RESULTS: Compared with the control group, the rate of liver regeneration on POD 3 and 5 was significantly higher in the PV group, but not in the IV group. Examination of the mitotic index and Ki-67 labeling index revealed that the increased liver regeneration resulted from stimulation of DNA synthesis. On POD 3, the serum levels of interleukin (IL)-6 and hepatocyte growth factor (HGF) were significantly higher and the expression of IL-6 and HGF mRNA in the remnant liver tended to be higher in the PV group than in the control group. Histological examination showed BMCs in the liver of the PV group, as well as conversion of BMCs into liver cells. CONCLUSIONS: Our findings indicate that the injection of BMCs via the portal vein, but not the injection of BMCs via the tail, enhances liver regeneration after massive hepatectomy in mice.

Temporal and spatial dependence of inflammatory biomarkers and suppression by fluvastatin in dextran sodium sulfate-induced rat colitis model.

BACKGROUND: Dextran sodium sulfate (DSS)-induced colitis in rats is widely used as an experimental model for elucidating the etiology of ulcerative colitis (UC) and developing its novel remedy. We investigated the temporal and spatial changes in inflammatory mediators such as tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS) in the regions of rectum and distal colon and examined whether statins, which were designed to lower plasma cholesterol levels, influenced those mediators. METHODS: Colitis was induced in rats by oral administration of 5 % DSS for 5 days, followed by 2 % DSS for 10 days. 5 % DSS rats were treated with fluvastatin (20 mg/kg) concomitantly for 5 days. The expression of inflammatory mediators of a sequence of four regions in rectum (R) and distal colon (D0, D1, and D2) was determined by quantitative RT-PCR. RESULTS: The peak of colitic damage, which was confirmed clinically and histopathologically, was found on days 4-6. The expression of TNF-α, iNOS, cytokine-induced neutrophil chemoattractant-1, interleukin (IL)-1ß, and IL-6 mRNA increased in R time dependently, showing the peak on days 4-6, and then decreased thereafter. The levels of mRNAs reduced from R to D0, D1, and D2 region dependently. Fluvastatin decreased the expression of these markers in addition to the prevention of DSS-induced damage. CONCLUSIONS: Results demonstrated that the expression of inflammatory biomarkers had time and region specificity and was markedly inhibited by fluvastatin. To obtain a precise drug effect for UC, it is important to elucidate the temporal and spatial dependence of inflammatory biomarkers in DSS colitis model.