[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.

[Diagnosis of Serous Adenocarcinoma following Pneumatosis Intestinalis Development during Bevacizumab Therapy for Cancer of Unknown Primary-A Case Report].

A 75-year-old woman was treated with TC plus Bev for cancer of unknown primary. During treatment, she presented to the clinic with chief complaints of general malaise and anorexia. On presentation, abdominal distention and upper abdominal tenderness were noted, and sepsis was suspected. A thoracoabdominal CT scan revealed prominent intramural emphysema and mesenteric gas in the ascending colon. An emergency laparotomy was performed for suspected pneumatosis intestinalis non-obstructive intestinal ischemia. However, no intra-abdominal contamination or ischemic changes were observed intraoperatively. Histological examination revealed a small adenocarcinoma on the serous surface of the ascending colon, and immunochemical staining confirmed the diagnosis of serous adenocarcinoma as the patient's primary cancer. This report describes a case in which the patient achieved long-term survival after diagnosis. It also emphasizes the importance of identifying the subset of patients with cancer of unknown primary who have a good prognosis in order to provide appropriate treatment.

Near-Infrared Fluorescence Imaging and Photodynamic Therapy for Liver Tumors.

Surgery with fluorescence equipment has improved to treat the malignant viscera, including hepatobiliary and pancreatic neoplasms. In both open and minimally invasive surgeries, optical imaging using near-infrared (NIR) fluorescence is used to assess anatomy and function in real time. Here, we review a variety of publications related to clinical applications of NIR fluorescence imaging in liver surgery. We have developed a novel nanoparticle (indocyanine green lactosome) that is biocompatible and can be used for imaging cancer tissues and also as a drug delivery system. To date, stable particles are formed in blood and have an ~10-20 h half-life. Particles labeled with a NIR fluorescent agent have been applied to cancer tissues by the enhanced permeability and retention effect in animals. Furthermore, this article reviews recent developments in photodynamic therapy with NIR fluorescence imaging, which may contribute and accelerate the innovative treatments for liver tumors.

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.

[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.

[Intussusception Due to Inflammatory Polyp in the Ileum after ESD for Rectal LST].

A 69-year-woman was admitted to the clinic in August 2018 because of general fatigue and low appetite.She had occult blood-positive and was referred to our hospital for further investigations.There was LST in the rectum for which colonoscopy and ESD were performed.She had abdominal pain and slight fever on postoperative day 1.Abdominal CT showed an intussusception in the ileum.We could not achieve endoscopic de-torsion and carried out laparotomy.The intussusception was found to be strangulated due to inflammatory polyp and mesenteric adhesion.The affected portion was resected.Although treatment for low hypoalbuminemia and neurogenic cystitis was required, she was discharged on postoperative day 28.

Near-infrared fluorescence imaging and photodynamic therapy with indocyanine green lactosomes has antineoplastic effects for gallbladder cancer.

BACKGROUND: The diagnostic use and therapeutic effect of near infrared fluorescence (NIF) imaging and photodynamic therapy (PDT) was investigated for gallbladder cancer using indocyanine green (ICG)-lactosomes. RESULTS: PDT was toxic for NOZ cells treated with ICG-lactosomes. Fluorescence intensity in the tumor region of mice administered ICG-lactosomes, but not ICG alone, was higher than the healthy contralateral region ≥24 hours after injection. PDT exerted immediate and continuous phototoxic effects in NOZ implanted mice injected with ICG-lactosomes. Enhanced antitumor effects were observed in the twice irradiated group compared with the once irradiated group. METHOD: ICG or ICG-lactosomes were added to the human gallbladder cancer cell line NOZ followed by PDT and cell viability was measured. Mass spectrometry of ICG and ICG-lactosomes was performed after PDT. ICG or ICG-lactosomes were intravenously administered to BALB/c nude mice implanted subcutaneously with NOZ cells and fluorescence was evaluated by NIF imaging. Implanted tumors underwent PDT and antitumor effects were analyzed after performing irradiation once or twice in ICG-lactosome groups. CONCLUSIONS: ICG-lactosomes accumulated in xenograft tumors and PDT had an antitumor effect on these malignant tumors. NIF imaging with ICG-lactosomes and PDT may be useful diagnostic and/or therapeutic agents for gallbladder cancer.

Levosimendan pretreatment improves survival of septic rats after partial hepatectomy and suppresses iNOS induction in cytokine-stimulated hepatocytes.

We evaluated the survival effects and biochemical profiles of levosimendan in septic rats after partial hepatectomy and investigated its effects in cultured hepatocytes. Thirty-two rats underwent 70% hepatectomy and were randomised equally into four groups, followed by lipopolysaccharide (LPS) injection (250 µg/kg, i.v.) after 48 h. Levosimendan was given (i.p.) 1 h before LPS injection [group (A) levosimendan 2 mg/kg; (B) 1; (C) 0.5; (D) vehicle]. Survival at 7 days was increased significantly in group A compared with that in group D [A: 63%; B: 38%; C: 13%; D: 0%]. In serum, levosimendan decreased the level of tumour necrosis factor-α, interleukin (IL)-1ß, IL-6 and nitric oxide (NO). In remnant livers, levosimendan inhibited inducible nitric oxide synthase (iNOS) gene expression. In primary cultured rat hepatocytes stimulated by IL-1ß, levosimendan suppressed NO production by inhibiting iNOS promoter activity and stability of its mRNA.

Peritoneal dissemination of ascending colon cancer demonstrating relapse-free survival for 40 months with panitumumab monotherapy: A case report.

INTRODUCTION: The prognosis of metastatic colorectal cancer (mCRC) patients receiving multiple cytotoxic agents and targeted therapies (CATT) has improved, but a complete cure by CATT is still very rare. PRESENTATION OF CASE: We report the successful treatment of ascending colon cancer complicated by peritoneal disseminations (PDs) with panitumumab (Pmab) plus mFOLFOX6 therapy. A 67-year-old male patient was diagnosed with clinical stage IV cancer of the ascending colon with PDs, and underwent ileostomy. Eighteen courses of Pmab plus mFOLFOX6 caused remarkable tumor shrinkage and the disappearance of PDs on ECT. Laparotomy revealed tumor shrinkage and scarring at the PD sites. We performed right hemicolectomy, subtotal omentectomy, and ileostomy closure as curability B surgery. Seven months later, new PDs were detected by ECT so we resumed Pmab plus mFOLFOX6 therapy. After nine courses of treatment, the target lesion had completely disappeared. After a total of 20 courses, we changed to Pmab monotherapy as maintenance therapy because there was no recurrence. Forty months after the initiation of Pmab monotherapy, there has been no oncologic progression. DISCUSSION: Pmab plus mFOLFOX6 treatment resulted in a complete response for PDs, which is extremely rare for CATT. CONCLUSION: We consider that Pmab therapy should be introduced for the treatment of mCRC complicated by PDs.

The Proton Pump Inhibitor Lansoprazole Has Hepatoprotective Effects in In Vitro and In Vivo Rat Models of Acute Liver Injury.

BACKGROUND/AIMS: The proton pump inhibitor lansoprazole (LPZ) is clinically used to reduce gastric acid secretion, but little is known about its possible hepatoprotective effects. This study aimed to investigate the hepatoprotective effects of LPZ and its potential mechanisms using in vitro and in vivo rat models of liver injury. METHODS: For the in vitro model of liver injury, primary cultured rat hepatocytes were treated with interleukin-1ß in the presence or absence of LPZ. The influence of LPZ on inducible nitric oxide synthase (iNOS) induction and nitric oxide (NO) production and on the associated signaling pathways was analyzed. For the in vivo model, rats were treated with D-galactosamine (GalN) and lipopolysaccharide (LPS). The effects of LPZ on survival and proinflammatory mediator expression (including iNOS and tumor necrosis factor-α) in these rats were examined. RESULTS: LPZ inhibited iNOS induction partially through suppression of the nuclear factor-kappa B signaling pathway in hepatocytes, thereby reducing potential liver injury from excessive NO levels. Additionally, LPZ increased survival by 50% and decreased iNOS, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-1 mRNA expression in the livers of GalN/LPS-treated rats. LPZ also inhibited nuclear factor-kappa B activation by GalN/LPS. CONCLUSIONS: LPZ inhibits the induction of several inflammatory mediators (including cytokines, chemokines, and NO) partially through suppression of nuclear factor-kappa B, resulting in the prevention of fulminant liver failure. The therapeutic potential of LPZ for liver injuries warrants further investigation.

Near-infrared fluorescence imaging and photodynamic therapy with indocyanine green lactosome has antineoplastic effects for hepatocellular carcinoma.

BACKGROUND: Anticancer agents and operating procedures have been developed for hepatocellular carcinoma (HCC) patients, but their prognosis remains poor. It is necessary to develop novel diagnostic and therapeutic strategies for HCC to improve its prognosis. Lactosome is a core-shell-type polymeric micelle, and enclosing labeling or anticancer agents into this micelle enables drug delivery. In this study, we investigated the diagnostic and therapeutic efficacies of indocyanine green (ICG)-loaded lactosome for near-infrared fluorescence (NIF) imaging and photodynamic therapy (PDT) for HCC. METHODS: The human HCC cell line HuH-7 was treated with ICG or ICG-lactosome, followed by PDT, and the cell viabilities were measured (in vitro PDT efficiency). For NIF imaging, HuH-7 cells were subcutaneously transplanted into BALB/c nude mice, followed by intravenous administration of ICG or ICG-lactosome. The transplanted animals were treated with PDT, and the antineoplastic effects were analyzed (in vivo PDT efficiency). RESULTS: PDT had toxic effects on HuH-7 cells treated with ICG-lactosome, but not ICG alone. NIF imaging revealed that the fluorescence of tumor areas in ICG-lactosome-treated animals was higher than that of contralateral regions at 24 h after injection and thereafter. PDT exerted immediate and continuous phototoxic effects in the transplanted mice treated with ICG-lactosome. CONCLUSIONS: Our results demonstrate that ICG-lactosome accumulated in xenograft tumors, and that PDT had antineoplastic effects on these malignant implants. NIF imaging and PDT with ICG-lactosome could be useful diagnostic and/or therapeutic strategies for HCC.

Genipin Inhibits the Induction of Inducible Nitric Oxide Synthase Through the Inhibition of NF-κB Activation in Rat Hepatocytes.

BACKGROUND/AIMS: Genipin is a component of Japanese traditional herbal medicine (Kampo), inchinkoto, and is used for the treatment of various liver injuries. However, there are few scientific evidence for its anti-inflammatory effects and mechanisms. In inflamed liver, proinflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1ß stimulate liver cells, followed by the expression of inducible nitric oxide synthase (iNOS). Excessive levels of NO produced by iNOS have been implicated as one of the factors in liver injury. Thus it is essential to inhibit iNOS induction for the prevention of liver injury. In this study, we examined IL-1ß-stimulated hepatocytes as a simple "in vitro liver injury model" to investigate liver protective effects of genipin. METHODS: Primary cultured rat hepatocytes were treated with IL-1ß in the presence or absence of genipin. The induction of NO production and iNOS, and its signaling pathway were analyzed. RESULTS: In IL-1ß-stimulated hepatocytes, genipin inhibited the production of NO dose- and timedependently, and reduced the levels of iNOS protein and its mRNA expression. Genipin also reduced mRNA expressions of TNF-α and IL-6. Genipin inhibited two essential signaling pathways for iNOS induction, IκB degradation/NF-κB activation and type I IL-1 receptor upregulation. Transfection experiments revealed that genipin decreased the expression of iNOS mRNA through both inhibitions of the promoter activation and mRNA stabilization. Delayed administration of genipin after IL-1ß addition also inhibited iNOS induction. CONCLUSION: Genipin influenced the induction of inflammatory mediators, iNOS and TNF-α, in part through the inhibition of NF-κB activation in hepatocytes. Genipin may have therapeutic potential for organ injuries including liver.

[Introduction and PDCA-Management of a Liaison-Clinical Pathway with Cancer Patients after a Curative Operation].

Our hospital was appointed as an Osaka designated cancer care hospital in April 2012. At that time, we introduced the same liaison-clinical pathway with cancer patients after a curative operation in all of Osaka. Based on the management of the plan-do-check-act cycle, we found problems in the clinical pathway. These problems included the following: the clinical pathway was not known, was complicated, was troubling for patients, and not well understood by doctors. To solve these problems, we planned and carried out the following five measures. The first was public information, followed by practice processes, informed consent, patient referral documents, and clinical pathway investigation reports. We were able to promote the use of the liaison-clinical pathway by constantly improving these measures.

[A Case of Local Recurrence of Bile Duct Cancer Completely Responding to Chemoradiotherapy with S-1].

An 80-year-old man with common bile duct cancer was treated by pancreaticoduodenectomy with D2 lymph node dissection in October 2005. The patient presented with frequent episodes of bloody-mucous rectal discharge in July 2009. An abdominal CT demonstrated local recurrence at the hepatoduodenal ligament. We treated him with concurrent chemoradiotherapy (CRT) with single-dose S-1 chemotherapy. After 6 months, we diagnosed a complete response (CR) by follow-up CT. The patient was treated with S-1 for 3 years after the diagnosis of a CR. He is alive without disease 6 years after the diagnosis of the recurrence. Concurrent CRT with S-1 chemotherapy may be the therapy of choice for recurrence of bile duct cancer.