A Case of Gallbladder Metastasis of Malignant Melanoma.

In the clinical course of malignant melanoma, which can metastasize to multiple organs, gallbladder metastases are rarely detected. A 69-year-old man who underwent resection of a primary malignant melanoma was subsequently treated with nivolumab for lung metastases and achieved complete response. Seven years after surgery, multiple nodules were found in the gallbladder, and he underwent laparoscopic cholecystectomy. The postoperative diagnosis was metastases of malignant melanoma. He has been recurrence-free 8 months after surgery. If radical resection is possible, such surgery should be performed for gallbladder metastases found in patients with other controlled lesions of malignant melanoma.

Functional remodeling of intraperitoneal macrophages by oncolytic adenovirus restores anti-tumor immunity for peritoneal metastasis of gastric cancer.

Intraperitoneal tumor-associated macrophages (TAMs) are involved in evading anti-tumor immunity and promoting the peritoneal metastasis (PM) of gastric cancer (GC). Oncolytic viruses are known to induce the activation of host anti-tumor immunity in addition to tumor lysis. This study investigated whether a wild-type p53-loading telomerase-specific oncolytic adenovirus (OBP-702) could elicit the remodeling of intraperitoneal macrophages and enhance the efficacy of immune therapy. Increased numbers of CD163 TAMs and few CD8+ lymphocytes were immunohistochemically observed in clinical samples with PM, which suggested that TAMs were associated with the suppression of anti-tumor immunity. OBP-702 induced immunogenic cell death and upregulated PD-L1 expression in human and murine GC cell lines. Intraperitoneal administration of OBP-702 increased recruitment of CD8+ lymphocytes into the PM via the functional remodeling of intraperitoneal macrophages from TAM toward a pro-inflammatory phenotype, resulting in significantly suppressed tumor growth for the in vivo model. Furthermore, the combination of intraperitoneal OBP-702 with anti-programmed cell death-1 antibody enhanced anti-tumor immunity and prolonged the survival of mice bearing PM. Intraperitoneal immunotherapy using OBP-702 restores anti-tumor immunity via the remodeling of intraperitoneal macrophages in addition to direct tumor lysis and cooperates with immune checkpoint inhibitors to suppress PM in GC.

Rare case of retroperitoneal mitotically active leiomyoma in a postmenopausal woman.

Leiomyomas are benign smooth muscle tumors, and retroperitoneal leiomyomas without coexisting uterine leiomyomas are extremely rare. Mitotically active leiomyomas, which are leiomyomas with increased mitotic activity, are rarely observed in postmenopausal women, except under the influence of exogenous hormones. This report presents a rare case of a retroperitoneal mitotically active leiomyoma in a postmenopausal woman. The patient presented with an abdominal mass and underwent surgical resection of the retroperitoneal tumor. Pathological examination revealed a mitotically active retroperitoneal leiomyoma with 31 mitotic figures per 10 high-power fields. The patient did not experience recurrence during the 2-year follow-up period. This case highlights the need to consider retroperitoneal mitotically active leiomyomas in postmenopausal women and suggests that myomectomy can prevent their recurrence.

[Two Cases of Closed LECS for Early Gastric Cancer].

In recent years, laparoscopy and endoscopy cooperative surgery(LECS)is reported as the treatment of gastric cancer. We report closed LECS performed for an elderly patient with remnant gastric cancer and gastric cancer in a patient with lung cancer. Case 1 is an 85-year-old male. Early gastric cancer was pointed out in the remnant stomach after distal gastrectomy. ESD was not indicated because of the size of tumor. Because of his age and many comorbidities, closed LECS was performed. Postoperative pathological diagnosis was pT1a(M), pPM0, pDM0, Ly0, v0. Case 2 is a 56-year-old male. He was undergoing chemotherapy for lung cancer with pleural dissemination. Upper gastrointestinal endoscopy revealed early gastric cancer. ESD was not indicated for this lesion because of the depth of tumor. Pleural dissemination of lung cancer is his prognostic factor, and gastrectomy with lymph node dissection was considered excessively invasive. Therefore, closed LECS was performed. Postoperative pathological diagnosis was pT1b2(SM2), pPM0, pDM0, Ly1c, v1a. Closed LECS could be useful therapeutic option for early gastric cancer.

Modulation of p53 expression in cancer-associated fibroblasts prevents peritoneal metastasis of gastric cancer.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are associated with the establishment and progression of peritoneal metastasis. This study investigated the efficacy of replicative oncolytic adenovirus-mediated p53 gene therapy (OBP-702) against CAFs and peritoneal metastasis of gastric cancer (GC). Higher CAF expression in the primary tumor was associated with poor prognosis of GC, and higher CAF expression was also observed with peritoneal metastasis in immunohistochemical analysis of clinical samples. And, we found transcriptional alteration of p53 in CAFs relative to normal gastric fibroblasts (NGFs). CAFs increased the secretion of cancer-promoting cytokines, including interleukin-6, and gained resistance to chemotherapy relative to NGFs. OBP-702 showed cytotoxicity to both GC cells and CAFs but not to NGFs. Overexpression of wild-type p53 by OBP-702 infection caused apoptosis and autophagy of CAFs and decreased the secretion of cancer-promoting cytokines by CAFs. Combination therapy using intraperitoneal administration of OBP-702 and paclitaxel synergistically inhibited the tumor growth of peritoneal metastases and decreased CAFs in peritoneal metastases. OBP-702, a replicative oncolytic adenovirus-mediated p53 gene therapy, offers a promising biological therapeutic strategy for peritoneal metastasis, modulating CAFs in addition to achieving tumor lysis.

[A Case of Inverted LECS for GIST Near the Pylorus Ring].

Laparoscopy and endoscopy cooperative surgery(LECS)is a surgical procedure to avoid excessive resection of the gastrointestinal wall and preserve its function. For gastrointestinal stromal tumors(GIST)near the cardia and pylorus ring, the function of the cardia and pylorus can be preserved by minimum excision and hand-sewn suture closures. Here, we report a case successfully treated with inverted LECS for GIST near the pylorus ring. The patient was a 58-year-old male. Upper gastrointestinal endoscopy had revealed a 45 mm sized SMT near the pylorus ring. Biopsy by EUS-FNA indicated gastric GIST. The tumor was separated from the pylorus ring and inverted LECS was performed. The defect was closed with hand-sewn sutures, forming an L-shape. The postoperative course was good and he was discharged from hospital 10 days after surgery. It is considered that devising the direction of closure by means of the LECS procedure can preserve the pyloric function without passage obstruction or stasis, even for gastric GIST near the pylorus ring.

[Unresectable Advanced HER2-Positive Gastric Cancer Leading to a Perforation during Chemotherapy with Trastuzumab plus Paclitaxel].

The patient was a 70s female with gastric cancer. CT and PET scans revealed metastases of para-aortic lymph nodes, hepatoduodenal ligament lymph nodes, and left supraclavicular lymph nodes. She was diagnosed with T4a, N2, M1(LYM), and cStage ⅣB and was given chemotherapy with paclitaxel due to chronic kidney disease and trastuzumab treatment. We planned to perform radical gastrectomy with lymph node dissection due to the disappearance of FDG uptake except for primary gastric cancer on PET scans 5 months after chemotherapy. However, the patient developed pan-peritonitis due to gastric cancer perforation; therefore, emergency distal gastrectomy with Billroth Ⅱ reconstruction was performed. She received chemotherapy(only trastuzumab)after getting discharged. Reports about gastric cancer perforation during chemotherapy using trastuzumab are rare. We should consider the possibility of perforated gastric cancer during chemotherapy and optimal surgical procedures, including the extent of lymph node dissection in the case of Stage Ⅳ gastric cancer.

[A Case of Laparoscopic Subtotal Gastrectomy with a Very Small Remnant Stomach in an Elderly Patient with Multiple Malignant Gastric Tumors].

An 85-year-old man was referred to our hospital for anemia. Upper gastrointestinal endoscopy showed 6 malignant gastric lesions. Abdominal CT showed a primary tumor. We treated early gastric cancer at the upper stomach with endoscopic submucosal dissection(ESD)to avoid total gastrectomy. We then performed laparoscopic subtotal gastrectomy with a very small remnant stomach. In elderly patients with multiple gastric cancer, it is useful to combine ESD with laparoscopic subtotal gastrectomy with a very small remnant stomach.

[A Case of Colon Cancer with Suspected DPD Deficiency Causing Severe Adverse Effects following Adjuvant Chemotherapy with Capecitabine].

The present study reports a case of colon cancer in a 76-year-old female who underwent laparoscopic right colectomy. Pathological findings revealed pT3(SS), pN2a, cM0, and pStage Ⅲb. Hence, we administered adjuvant chemotherapy with capecitabine. On day 18, she was urgently hospitalized because of severe oral mucositis(grade 3), diarrhea(grade 3), and leukocytopenia(grade 4). Furthermore, the patient experienced DIC, which gradually improved through intensive conservative treatment. From the clinical course, we suspected that the severe adverse effects were caused due to a deficiency of DPD. We were able to save the patient through early treatment.

Boosting Replication and Penetration of Oncolytic Adenovirus by Paclitaxel Eradicate Peritoneal Metastasis of Gastric Cancer.

Peritoneal metastasis is the most frequent form of distant metastasis and recurrence in gastric cancer, and the prognosis is extremely poor due to the resistance of systemic chemotherapy. Here, we demonstrate that intraperitoneal (i.p.) administration of a green fluorescence protein (GFP)-expressing attenuated adenovirus with oncolytic potency (OBP-401) synergistically suppressed the peritoneal metastasis of gastric cancer in combination with paclitaxel (PTX). OBP-401 synergistically suppressed the viability of human gastric cancer cells in combination with PTX. PTX enhanced the antitumor effect of OBP-401 due to enhanced viral replication in cancer cells. The combination therapy increased induction of mitotic catastrophe, resulting in accelerated autophagy and apoptosis. Peritoneally disseminated nodules were selectively visualized as GFP-positive spots by i.p. administration of OBP-401 in an orthotopic human gastric cancer peritoneal dissemination model. PTX enhanced the deep penetration of OBP-401 into the disseminated nodules. Moreover, a non-invasive in vivo imaging system demonstrated that the combination therapy of i.p. OBP-401 administration with PTX significantly inhibited growth of peritoneal metastatic tumors and the amount of malignant ascites. i.p. virotherapy with PTX may be a promising treatment strategy for the peritoneal metastasis of gastric cancer.

[A Rare Case of Abdominal Malignant Triton Tumor].

A 60-year-old woman presented at our hospital with abdominal pain and vomiting.Three abdominal tumors were detected, and she was referred to our department for surgery.She underwent an enterectomy including 2 of the tumors.The third tumor could not be resected because it had invaded the superior mesenteric artery(SMA)and superior mesenteric vein(SMV). Based on positive immunohistochemistry results for S-100 protein and desmin, nerve sheath differentiation with rhabdomyoblastic differentiation was confirmed, and she was diagnosed with a malignant triton tumor(MTT).She received postoperative chemotherapy with adriamycin and dacarbazine.However, she died 7 months after surgery, with multiple peritoneal metastases.MTT is a subtype of malignant peripheral nerve sheath tumor and is very rare.MTT has a poor prognosis with a high tendency of local recurrence and early metastasis.The most common treatment strategy is radical resection followed by postoperative chemoradiotherapy.When preoperative diagnosis is possible, radical resection with clear margins should be performed.

[Assessment of Endoscopic Resection and Partial Duodenectomy for Duodenal Mucosal Tumor].

INTRODUCTION: The risk of perforation following endoscopic resection is high. We analyzed the outcome of partial duodenectomy and discussed the therapeutic strategy for duodenal mucosal tumor(DMT). PATIENTS AND METHODS: We analyzed 19 cases who have undergone endoscopic resection, and 11 cases who have undergone partial duodenectomy for DMT in our institute since 2007. We divided them into the first period(ESD actively indicated)and late period(ESD carefully indicated according to the alteration of indication of ESD for DMT in 2013)groups. RESULTS: In the first period, all 17 cases initially underwent endoscopic resection and 4 cases were complicated by perforation. On the other hand, in the late period, 6 of 12 cases initially underwent endoscopic resection and 1 case was complicated by perforation. Emergent partial duodenectomy was performed with additional resection in the perforation cases. There were no complications associated with surgery, and all 29 cases achieved curative resection, based on the histology results. CONCLUSION: We can safely indicate endoscopic resection for DMT with surgical back-up and cooperation with the endoscopic internal department.

[A Case of Advanced Gastric Cancer with Para-Aortic Lymph Node Dissection after Neoadjuvant Chemotherapy].

The patient was a 49-year-old woman with advanced gastric cancer.CT and PET-CT revealed para-aortic lymph node metastases.She was diagnosed with Stage IV T4aN3M1(LYM)and underwent neoadjuvant chemotherapy with S-1 plus CDDP.After 3 courses, both the tumor and para-aortic lymph node metastases decreased in size.Because radical resection was considered possible, she underwent distal gastrectomy with D3(D2+No.1 6a2-b1)dissection and Roux-en-Y reconstruction. Histopathological findings revealed the cancer was Stage I B(yp T1b N1)with the disappearance of cancer cells in the para-aortic lymph nodes.She was discharged on POD 32.She underwent adjuvant chemotherapy with S-1 and was followed up for 3 years with no recurrence.Para -aortic lymph node metastases are factors predicting a poor outcome; however, when neoadjuvant chemotherapy is effective, long-term survival can be expected from gastrectomy with curative PAND.

[Two Cases of Locally Recurrent Rectal Cancer after Intersphincteric Resection That Were Controlled with a Combination of Chemoradiotherapy and Abdominoperineal Resection].

We report 2 cases of locally recurrent rectal cancer after intersphincteric resection(ISR)that were controlled with a combination of chemoradiotherapy and abdominoperineal resection(APR). In Case 1, we performed preoperative chemoradiotherapy( TS-1 plus RT 45 Gy)and APR for the local recurrence of ISR. On pathology, viable neoplastic cells were noted. In Case 2, we performed preoperative chemotherapy(Bmab plus mFOLFOX6)and APR for the local recurrence of ISR. On pathology, no viable neoplastic cells were noted. However, a local recurrence developed again 3 months later. Therefore, we performed chemoradiotherapy(TS-1 plus RT 53 Gy). The 2 patients survived without recurrence until now. Their pathology tissues and clinical courses showed that control of local recurrence with only chemoradiotherapy or surgical resection was likely to be difficult. We might be able to improve the prognosis of patients with a combination of chemoradiotherapy and surgical resection.

[A Long-Surviving Case of Unresectable Gall Bladder Carcinoma Treated with Gemcitabine-Based Chemotherapy].

We report a 5-year surviving patient with unresectable gall bladder carcinoma treated with gemcitabine(GEM)-based chemotherapy. A 64-year-old man was diagnosed with unresectable gall bladder carcinoma with peritoneal dissemination based on laparotomy findings. Two months later, he started to receive GEM chemotherapy. Twelve months after surgery, the patient chose to suspend GEM treatment. One year and 10 months later, multiple lung metastases appeared and GEM was restarted in combination with UFT. Although the primary lesion and lung metastases gradually progressed, the patient maintained a good quality of life. After 3 years and 2 months, chemotherapy was changed to GEM plus S-1 because of progressive disease. Five years and 2 months after surgery, his condition was complicated by a secondary pneumothorax, and the patient received home oxygen therapy. Five years and 8 months after surgery he died of respiratory distress caused by the progression of lung metastases. Even in the case of unresectable advanced gall bladder carcinoma, effective chemotherapy could improve quality of life and prolong survival.

[Report of a Case of Long-Term Survival with Mulitidisciplinary Therapy for a Patient with Multiple Liver Metastases from Rectal Cancer].

Multidisciplinary therapy is necessary to prevent recurrence of advanced rectal cancer and advanced cancer with metastases. Here we report a case of long-term survival of a patient with advanced rectal cancer with multiple liver metastases. An 80's woman had previously undergone both Hartmann's operation and a partial hepatectomy for advanced rectal cancer with multiple liver metastases. A year after chemotherapy, a CT scan revealed multiple liver metastases. Thus, we performed partial liver resection. After another round of chemotherapy, a CT scan revealed lung metastases and local recurrence of the rectal cancer; therefore, we performed partial lung resection and a Miles operation. These procedures were conducted 4 years after her first operation. The following year, PET-CT revealed a mediastinum lymph node metastasis; consequently, we performed radiation therapy. New lung metastases and local recurrences of rectal cancer were identified after the radiation therapy; thus, we resumed the therapy, including a molecular targeting drug. Although the patient is in a tumor-bearing state, she is still alive 10 years after her first operation.

[Outcome of Pulmonary Metastasectomy for Hepatocellular Carcinoma].

Pulmonary metastasis of hepatocellular carcinoma (HCC) is considered a poor prognostic feature of the disease, and the utility of pulmonary resection is unclear. We evaluated clinical outcomes following pulmonary resection in 7 patients. All patients underwent video-assisted thoracic surgery (VATS). The median disease-free interval (DFI) was 14 (6-23) months. During pulmonary resection in 1 of the patients, intrahepatic recurrence was discovered and, 18 months later, this patient died of the recurrence. Of the remaining 6 patients, 2 patients developed intrahepatic recurrence and brain metastasis and died at 66 months and 10 months after pulmonary resection. Three patients are still alive and disease-free to date with a median follow-up duration of 42 (18-55) months. Of these 3 surviving patients, 2 patients had solitary pulmonary metastases and 1 patient had multiple bilateral pulmonary metastases; these patients underwent VATS once. The 7th patient underwent VATS 3 times for pulmonary metastasis and had no evidence of intrahepatic or extrahepatic recurrence. This patient died of an unrelated cause 15 months after the last pulmonary resection (47 months after the primary pulmonary resection). This study indicates that surgical resection of metachronous pulmonary metastases is associated with a favorable outcome in selected patients.

In vitro proliferation and chondrogenic differentiation of rat bone marrow stem cells cultured with gelatin hydrogel microspheres for TGF-beta1 release.

The objective of this study was to evaluate the proliferation and chondrogenic differentiation of rat bone marrow-derived mesenchymal stem cells (MSCs) cultured with gelatin hydrogel microspheres of cell scaffold which can release transforming growth factor-beta1 (TGF-beta1). Gelatin was dehydrothermally cross-linked in different conditions in a water-in-oil emulsion state to obtain gelatin hydrogel microspheres with different water content. The microspheres functioned not only as the scaffold of MSC, but also the carrier matrix of TGF-beta1 release. The MSC proliferation depended on the water content of microspheres. Higher MSC proliferation was observed for the gelatin microspheres with lower water content. When cultured with the gelatin hydrogel microspheres, MSC formed their aggregates, in contrast to culturing with hydrogel sheets. The cell viability was significantly high compared with that of the hydrogel sheet. The production of sulfated glycosaminaglycan (sGAG) from MSC was examined as a measure of chondrogenic differentiation, after their culturing in a normal and chondrogenic differentiation media. For both the cultures, the amount of sGAG produced was significantly higher for MSC cultured with the gelatin microspheres than that of the gelatin sheet. Stronger differentiation of MSC was achieved in culture with the microspheres incorporating TGF-beta1 than that of MSC cultured in the medium containing the same amount of TGF-beta1. It is concluded that the gelatin hydrogel microspheres function well as both the scaffold of MSC and the matrix of TGF-beta1 release, resulting in enhanced MSC aggregation and the consequent promotion of cell proliferation and differentiation.

Development of a novel antimicrobial peptide, AG-30, with angiogenic properties.

The utility of various synthetic peptides has been investigated in clinical trials of the treatment of cancers, infectious diseases and endocrine diseases. In the process of functional gene screening with in silico analysis for molecules with angiogenic properties, we generated a small peptide, angiogenic peptide (AG)-30, that possesses both antimicrobial and pro-inflammatory activities. AG-30 has an alpha-helix structure with a number of hydrophobic or net positively charged amino acids and a propensity to fold into amphipathic structures. Indeed, AG-30 exhibited antimicrobial activity against various bacteria, induced vascular endothelial cell growth and tube formation in a dose-dependent manner and increased neovascularization in a Matrigel plug assay. As a result, AG-30 up-regulated expression of angiogenesis-related cytokines and growth factors for up to 72 hrs in human aortic endothelial cells. To further evaluate the angiogenic effect of AG-30 in vivo, we developed a slow-release AG-30 system utilizing biodegradable gelatin microspheres. In the ischaemic mouse hind limb, slow-release AG-30 treatment results in an increase in angiogenic score, an increase in blood flow (as demonstrated by laser Doppler imaging) and an increase in capillary density (as demonstrated by immunostaining with anti-CD31 antibody). These data suggest that the novel peptide, AG-30, may have therapeutic potential for ischaemic diseases.

The impact of coronary artery disease risk factors on intravascular ultrasound-derived morphologic indices of human coronaries.

OBJECTIVE: The relationship of intravascular ultrasound (IVUS)-derived measurements of atherosclerotic plaque to various coronary artery disease (CAD) risk factors is not well known. The purpose of this study was to examine the relationship of percent coronary luminal stenosis by IVUS to other IVUS measures of CAD, as well as the relationship of common IVUS measures of CAD to traditional CAD risk factors. We hypothesized that one or more IVUS measures of CAD might relate more strongly to CAD risk factors than does percent luminal coronary stenosis. METHODS: The records of 897 consecutive patients (57% men, mean age 62 years) who underwent IVUS investigation of their coronary arteries from 1996 through 2001 were retrospectively reviewed. IVUS was performed using a 20-MHz probe (Jomed, Rancho Cordoba, CA) and a manual pull-back technique to image the coronary arteries. Coronary artery remodeling ratio-i.e., the ratio of coronary lesion external elastic membrane cross-sectional area (EEM CSA) to proximal reference artery EEM CSA; plaque burden-i.e., plaque plus media CSA divided by EEM CSA; calcium arc; and percent stenosis of luminal cross-sectional area were measured by a single reader. RESULTS: Percent area stenosis, the most commonly used IVUS parameter, did not correlate with the other three IVUS-derived parameters, nor was it related to any of the CAD risk factors considered. In contrast, remodeling ratio was directly correlated with plaque burden (r=0.22, P<0.001), but inversely related to calcium arc (r=-0.13, P=0.01). IVUS plaque burden was significantly correlated with male gender (P<0.0001) and diabetes mellitus (DM) (P=0.003). In multivariate analyses including age, gender, and CAD risk factors, plaque burden was significantly associated with age, male gender, and DM, but not with chronic renal failure, hypertension, or hypercholesterolemia. The multivariate model also revealed that the calcium arc was significantly associated with male gender and age. These IVUS findings provide anatomic documentation that the traditional CAD risk factors relate more strongly to plaque burden than to percent coronary arterial luminal narrowing.