Reduced port laparoscopic subtotal cholecystectomy for Mirizzi syndrome with a bilio-biliary fistula: A case report.

A 65-year-old male diagnosed with Mirizzi syndrome with a bilio-biliary fistula was referred to our department and underwent single-incision laparoscopic surgery with an assistant trocar. As typical laparoscopic cholecystectomy could not be performed due to the coexistence of a bilio-biliary fistula, we performed laparoscopic subtotal cholecystectomy as a bail-out procedure according to the recommendation of the recent Tokyo Guidelines (TG18). The neck of the remnant gallbladder could be easily sutured with the effective use of an assistant trocar, and the surgery was completed without any complications. The patient was discharged 5 days after surgery without any complications. While little has been reported on the efficacy of reduced port surgery for Mirizzi syndrome, our surgical approach, i.e. reduced port surgery with an assistant trocar, enabled secure and easy suturing as a bail-out procedure and seemed to be an efficient method that is both less-invasive and safe.

[Two Cases of Lower Rectal Cancer in Which Temporary Ileostomy Could Be Avoided by Using the Pull Through Procedure].

We report 2 cases of lower rectal cancer in which temporary ileostomy was avoided by using the Pull through procedure. Case 1 was a 59-year-old man with a BMI of 29.67 who was diagnosed as having lower rectal cancer after a positive stool occult blood test. He had a strong refusal to use a ileostomy and was obese, so he underwent laparoscopic intersphincteric resection using the Pull through procedure. Reconstruction was performed on the 7th postoperative day. He was discharged from the hospital on the 14th day after the initial surgery. Case 2 was a 65-year-old woman with a BMI of 27.65 who was referred to our department for additional resection after ESD for a lesion in the lower rectum. As in the previous case, she was obese and refused to use a ileostomy, so we chose to perform a laparoscopic intersphincteric resection using the Pull through procedure. Reconstruction was performed on the 7th postoperative day, and she was discharged on the 25th day after the initial surgery. Patient satisfaction was high, and the Pull through procedure may be an option for patients with lower rectal cancer who have difficulty in undergoing temporary ileostomy.

[A Case of Surgical Resection for Ascending Colon Cancer with Protein-Losing Gastroenteropathy].

An 84-year-old man visited our department for further examination of anemia and elevation of tumor marker levels. Colonoscopy revealed a huge circumferential type 3 tumor in the ascending colon. Significant hypoalbuminemia was observed at 1.1 g/dL, and prolonged hypoalbuminemia was considered to be caused by protein-losing gastroenteropathy due to the large tumor. In this case, we performed right hemicolectomy, and performed single-stage anastomosis. The resected specimen showed a huge type 3 lesion with a diameter of 140×120 mm in the ascending colon, which directory invaded to the cecum and ileum. After the operation, there were no particular complications, and albumin levels gradually improved. Although hypoalbuminemia is one of the risks of anastomotic leakage, there are many reports with one-stage anastomosis and with a good course, including our case. Therefore, it was considered necessary to examine each case regarding the surgical procedure.

[A Case of Low-Grade Appendiceal Mucinous Neoplasm with Extra-Appendiceal Mucin Extrusion Successfully Treated with Laparoscopic Surgery].

A 49-year-old male patient, who presented with abdominal pain, was suspected of having acute appendicitis. Abdominal computed tomography revealed a swollen appendix, accompanied by a 40 mm low-density mass located behind the appendix. He was diagnosed with an appendiceal mucinous neoplasm, and laparoscopic ileocecal resection was performed. A soft tumor was found proximal to the swollen appendix and was adhered tightly to the iliopsoas muscle. The tumor cells were exfoliated carefully, and the tumor was excised en bloc without any injury. Histopathological examination revealed a low- grade appendiceal mucinous neoplasm(LAMN)accompanied by extra-appendiceal mucin extrusion due to the lack of epithelial lining. Because LAMN is potentially malignant, surgical excision was performed as first-line therapy. In the surgical management of LAMN, preventing intraoperative rupture is essential to avoid pseudomyxoma peritonei. To achieve this, a magnified laparoscopic surgery may be useful. Although no definitive guidelines describing the indications of lymph node dissection or the appropriate extent of resection exist, laparoscopic ileocecal resection may be used to manage cases of LAMN.

Foreign body granulomas mimic peritoneal dissemination caused by incarcerated femoral hernia perforation: A case report.

BACKGROUND: Foreign body granuloma (FBG) is a well-known type of granulomatous formation, and intraabdominal FBG (IFBG) is primarily caused by surgical residues. Multifocal IFBGs caused by gastrointestinal perforation is an extremely rare and interesting clinicopathological condition that resembles peritoneal dissemination. Here, we present a case of IFBGs mimicking peritoneal dissemination caused by bowel perforation and describe the value of intraoperative pathological examinations for rapid IFBG diagnosis. CASE SUMMARY: An 86-year-old woman with an incarcerated femoral hernia was admitted to the hospital and underwent operation. During the operation, the incarcerated ileum was perforated during repair due to hemorrhage necrosis, and a small volume of enteric fluid leaked from the perforation. The incarcerated ileum was resected, and the femoral hernia was repaired without mesh. Four months later, a second operation was performed for an umbilical incisional hernia. During the second operation, multiple small, white nodules were observed throughout the abdominal cavity, resembling peritoneal dissemination. The results of peritoneal washing cytology in Douglas' pouch and the examination of frozen nodule sections were compatible with IFBG diagnosis, and incisional hernia repair was performed. CONCLUSION: IFBGs can mimic malignancy. Intraoperative pathological examinations and operation history are valuable for the rapid diagnosis to avoid excessive treatments.

[A Case of Initially Unresectable Advanced Gastric Cancer Radically Resected by Conversion Surgery after Nivolumab Immunotherapy].

A 77-year-old man was admitted to our hospital with symptoms of epigastralgia and vomiting. Detailed investigation revealed unresectable advanced gastric cancer accompanied by multiple lymph node metastases and invasion of the pancreas(UM, type 3, cT4b, N3, M0, Stage ⅢC). The patient received nivolumab immunotherapy after first-line S-1 plus oxaliplatin(SOX)chemotherapy and second-line nab-paclitaxel(PTX)plus ramucirumab(RAM)chemotherapy. Remarkable tumor reduction was observed after 3 courses of nivolumab immunotherapy, and the patient subsequently underwent radical total gastrectomy with splenectomy and D2 lymphadenectomy. Histopathological examination of the resected stomach showed a near complete response, and only small metastatic foci remained in No. 2 lymph nodes, resulting in R0 resection. The patient was followed up without adjuvant therapy, and he is alive 6 months after the treatment without any symptoms of recurrence. The mechanism of action of immune checkpoint inhibitors is fundamentally different from that of conventional cytotoxic chemotherapeutic agents. Recently, several reports have described good responses to immune checkpoint inhibitors in cases where conventional chemotherapy has been unsuccessful. When predictive biomarkers of response to immune checkpoint inhibitors are identified, a combination therapy of preceding immunotherapy and subsequent surgery might provide an efficient radical therapeutic effect even in cases of unresectable advanced gastric cancer.

[A Case of Local Recurrence of Transverse Colon Cancer Radically Resected by Extended Surgery].

A 71-year-old male with a past history of Stage Ⅱb transverse colon cancer was pointed out a mass lesion penetrating into the stomach on abdominal computed tomography 1 year after surgery. The mass lesion was pathologically diagnosed as local recurrence of the previous colon cancer by upper gastrointestinal endoscopy. As he presented progressive anemia due to persistent tumor bleeding and no other recurrent lesion was recognized, surgical treatment was performed. Since intraoperative inspection suspected direct invasion to the pancreas, the patient underwent tumor resection in combination with distal pancreatectomy and partial resection of the stomach. Histopathological examination revealed negative surgical margins, resulting in R0 resection. Loco-regional therapies such as surgery and radiotherapy are considered appropriate for the treatment of local recurrence since pathogenesis of local recurrence is different from that of distant metastasis. As local recurrence may show various symptoms, we should aggressively consider surgical resection. Especially, complete resection of recurrent lesion is the only therapeutic strategy which can achieve radical cure. Although worsening of QOL might be a matter of concern depending on the site of recurrence, extended surgery with secure surgical margins is encouraged in cases of solitary recurrence.

[A Case of Primary Gastrointestinal Stromal Tumor with First Recurrence 13 Years after Surgery and Second Recurrence in the Omentum 6 Years Later].

A 63-year-old man underwent proximal gastrectomy for gastrointestinal stromal tumor(GIST)of the stomach 19 years ago. Local recurrence of GIST of the stomach occurred 13 years later, and the tumor was resected. Since then, he had adjuvant chemotherapy. Six years later, computed tomography revealed a soft-tissue shadow at the left lateral side of the stomach, and positron emission tomography also revealed fluorodeoxyglucose uptake at the same site. The recurrence of GIST was suspected, and therefore laparoscopic resection was performed. The operative time was 70 minutes. Blood loss was 10 g. Immunohistochemical examination showed positivity for c-kit and CD34, leading to a diagnosis of recurrence of GIST. The postoperative course was uneventful, and the patient was discharged on the fifth postoperative day. At present, the patient is alive without adjuvant chemotherapy 13 months since surgery. GIST may recur 10 years or more after surgery. Therefore, long-term surveillance seems to be mandatory.

Needlescopic surgery for broad ligament hernia: A case report.

Broad ligament hernia is a rare type of internal hernia. We herein report a case of broad ligament hernia successfully treated by needlescopic surgery. A 41-year-old woman was referred to our hospital with a complaint of nausea and vomiting. Abdominal contrast-enhanced computed tomography showed diffuse dilatation of the small bowel accompanied by a caliber change at the right side of the uterus. She was thus diagnosed with small bowel obstruction due to incarceration through right broad ligament hernia. After bowel decompression, she underwent elective needlescopic surgery using 2- and 3-mm instruments. The defect in the right broad ligament was closed with sutures, and she was discharged 2 days after surgery. In the treatment of broad ligament hernia without bowel ischemia, neither an abdominal incision nor any energy devices are required. In this respect, needlescopic surgery seems to be a promising approach among minimally invasive surgeries.

[A Case of Esophageal Gastrointestinal Stromal Tumor Resected by Mediastinoscope-Assisted Transhiatal Esophagectomy].

A 58-year-old man was followed up for esophageal submucosal tumor at our hospital. Esophagogastroduodenoscopy showed the tumor was located on the left side of the thoracic esophagus and had gradually increased in size. Endoscopic ultrasonography revealed an 18×11.5mm hypoechoic tumor connected to the fourth layer of the esophagus and fine needle biopsy revealed c-kit(+), desmin(-)and a-SMA(-). Double-contrast barium study detected a tumor of diameter 20 mm in the middle-lower thoracic esophagus. We diagnosed an esophageal gastrointestinal stromal tumor(GIST)and performed mediastinoscope-assisted transhiatal esophagectomy with gastric tube reconstruction. The maximum tumor diameter was 25mm and pathological evaluation showed c-kit(+), Ki-67 index of less than 5%, and low-risk GIST by the Fletcher classification. Mediastinoscope-assisted transhiatal esophagectomy might be a useful approach for esophageal GIST, because dissection along the esophagus can be performed without thoracotomy.

Flt3 ligand promotes myeloid dendritic cell differentiation of human hematopoietic progenitor cells: possible application for cancer immunotherapy.

Current in vitro culture systems allow the generation of human dendritic progenitor cells (CFU-DCs). The aim of this study was to assess the effect of Flt3 ligand (FL) on the proliferation of human peripheral blood-derived myeloid CFU-DCs and their differentiation into more committed precursor cells (pDCs) using in vitro culture systems. Immunomagnetically separated CD34+ cells were cultured in serum-free, as well as in serum-containing, liquid suspension cultures to investigate the expansion and/or proliferation/differentiation of CFU-DCs, pDCs, and more mature dendritic cells (DCs). FACS-sorted CD34+Flt3+/- cells were cultured in methylcellulose to assay hematopoietic progenitors, including CFU-DCs. In the clonal cell culture supplemented with granulocyte/macrophage (GM) colony-stimulating factor (CSF), interleukin-4, and tumor necrosis factor alpha, the frequency of CFU-DCs was significantly higher in the CD34+Flt3+ fraction than in the CD34+Flt3- population, thus suggesting functional Flt3 expression on CFU-DCs. Serum-free suspension culture of CD34+ cells revealed the potent effect of FL on the expansion of CFU-DCs in synergy with GM-CSF and thrombopoietin (TPO). In addition, FL strongly induced the maturation of CFU-DCs into functional CD1a+ pDCs in serum-containing liquid suspension culture. Moreover, these FL-generated pDCs showed remarkable potential to differentiate into mature DCs with surface CD83/CD86 expression, which induced a distinct allogeneic T-cell response. These results clearly demonstrate that FL supports not only the proliferation of early hematopoietic progenitor cells, but also the maturation process of committed precursor cells along with the DC-lineage differentiation. Therefore, it is possible to develop a more efficient DC-based cancer immunotherapy using this specific cytokine combination, GM-CSF+TPO+FL in vitro in the near future.

Successful induction of clinically competent dendritic cells from granulocyte colony-stimulating factor-mobilized monocytes for cancer vaccine therapy.

Recent studies have suggested that dendritic cell (DC)-based immunotherapy is one promising approach for the treatment of cancer. We previously studied the clinical toxicity, feasibility, and efficacy of cancer vaccine therapy with peptide-pulsed DCs. In that study, we used granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood monocytes as a cell source of DCs. However, previous investigations have suggested that G-CSF-mobilized peripheral blood monocytes produce reduced levels of proinflammatory cytokines such as interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha. These T helper (Th)-1-type cytokines are thought to promote antitumor immune response. In this study, we assessed the functional abilities of DCs generated from G-CSF-mobilized monocytes obtained from 13 patients with CEA-positive advanced solid cancers. Peripheral blood mononuclear cells were obtained from leukapheresis products collected before and after systemic administration of G-CSF (subcutaneous administration of high-dose [5-10 microg/kg] human recombinant G-CSF for five consecutive days). In vitro cytokine production profiles after stimulation with lipopolysaccharide (LPS) were compared between monocytes with and without G-CSF mobilization. DCs generated from monocytes were also examined with respect to cytokine production and the capacity to induce peptide-specific T cell responses. Administration of G-CSF was found to efficiently mobilize peripheral blood monocytes. Although G-CSF-mobilized monocytes (G/Mo) less effectively produced Th-1-type cytokines than control monocytes (C/Mo), DCs generated from G/Mo restored the same level of IL-12 production as that seen in DCs generated from C/Mo. T cell induction assay using recall antigen peptide and phenotypic analyses also demonstrated that DCs generated from G/Mo retained characteristics identical to those generated from C/Mo. Our results suggest that G-CSF mobilization can be used to collect monocytes as a cell source for the generation of DCs for cancer immunotherapy. DCs generated in this fashion were pulsed with HLA-A24-restricted CEA epitope peptide and administered to patients safely; immunological responses were induced in some patients.

[A case of scirrhous carcinoma of the stomach with malignant pleural and peritoneal carcinomatosis responding to the local administration of docetaxel (TXT)].

We report the case of a 34-year-old woman who underwent total gastrectomy for scirrhous carcinoma in the stomach (T4, N0, H0, CY1, P1, Stage IV). Despite adjuvant chemotherapy with TS-1 and/or CDDP, ascites caused by peritoneal carcinomatosis increased four months after gastrectomy. Therefore, intraperitoneal administration of docetaxel (TXT) at a dosage of 45 mg/m2 was applied. This therapy successfully maintained her good quality of life by inhibiting the increase of ascites without any severe adverse side effects for more than six months. When the left effusion from pleural carcinomatosis appeared nine months after the surgery, the intrathoracic administration of TXT succeeded in inhibiting the increase of pleural effusion over five months or more. In this case, intraperitoneal and intrapleural administrations of TXT were effective and temporarily improved the patient's quality of life without any side effects. We thought that the local administration of TXT was a useful treatment without severe toxicities for malignant pleural effusion and ascites in scirrhous carcinoma of the stomach.

Mobilization of peripheral blood stem cells (PBSCs) after etoposide, adriamycin and cisplatin therapy, and a multimodal cell therapy approach with PBSCs in advanced gastric cancer.

The EAP combination of etoposide (ETP), doxorubicin (ADM) and cisplatin (CDDP) has been reported to be highly active for advanced gastric cancer. However, it is associated with severe myelotoxicity, and its use has declined. We examined whether peripheral blood stem cells (PBSCs) could be mobilized during hematopoietic recovery after EAP, and assessed the possibility of using multimodal cell therapy with PBSCs for the treatment of advanced gastric cancer. Five men with advanced gastric adenocarcinoma were enrolled. All patients were chemotherapy-naïve. EAP (ETP, 360 mg/m2; ADM, 40 mg/m2; CDDP, 80 mg/m2) was given to each patient, and myelotoxicity was carefully monitored. Granulocyte colony-stimulating factor was administered after the neutrophil nadir, and PBSCs were collected by leukapheresis during hematopoietic recovery. The median nadir of the neutrophil count after EAP was 225/ml, occurring between day 17 and 20. Sufficient numbers of PBSCs [CD34(+) cells, CFU-GM] could be mobilized in 4/5 patients. A 45-year-old patient with extended lymph node metastasis received high-dose EAP with peripheral blood stem cell transplantation (PBSCT), followed by cancer vaccine therapy with dendritic cells (DCs), induced from cryopreserved PBSCs. Both high-dose EAP with PBSCT and DC-based immunotherapy was safely performed for the first time against gastric cancer. Although associated with severe myelotoxicity, EAP can mobilize sufficient numbers of PBSCs during hematopoietic recovery. Multimodal cell therapy combining high-dose chemotherapy with PBSCT and DC-based immunotherapy is feasible and can be a reasonable approach in advanced gastric cancer.

Streptococcal preparation OK432 promotes functional maturation of human monocyte-derived dendritic cells.

Streptococcal preparation OK432 is an immunomodulatory agent extensively used as adjuvant therapy for gastric cancer in Japan. OK432 augments the cytotoxic activity of various effector cells such as lymphocytes, macrophages and (natural killer) NK cells and induces the production of multiple cytokines. Dendritic cells (DC) are professional antigen-presenting cells (APC) that can be used for cancer vaccine therapy. In the present study, we investigated the effect of OK432 on the activation of DC. Here we report that OK432 induced phenotypic and functional maturation of human monocyte-derived DC. In vitro culture of immature DC generated from adherent peripheral blood mononuclear cells (PBMC) using granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) with OK432 at various doses (0.01 to 0.1 KE/ml) for 2 days resulted in increased cell surface expression of CD80, CD83, CD86 and ICAM-1 in a dose-dependent manner. The expression of CD83, a selective marker of mature DC, on DC activated by OK432 (OK-DC) was maximally enhanced after 3 days of incubation. Assay of cytokine production in OK-DC after 2 days in culture revealed that OK432 was a strong inducer of IL-12 and interferon-gamma (IFN-gamma). OK432 efficiently augmented the primary allogeneic T-cell responses by DC. This distinct phenotypic profile and allostimulatory capacity of OK-DC was stable for at least 48 h of additional culture in the absence of any cytokines. Moreover, the antiviral cytotoxic T lymphocytes (CTL) response in vitro was also enhanced by the addition of OK432 to the cultures. These findings suggest that OK432 is a potent stimulator of DC, and that stimulated DC are strong inducers of the T helper 1 (Th1)-type response. We conclude that OK-DC are likely candidates for use as an adjuvant for DC-based cancer immunotherapy.

Role of human interleukin-9 as a megakaryocyte potentiator in culture.

OBJECTIVE: This study investigated the effect of interleukin-9 (IL-9) on the proliferation and differentiation of human colony-forming unit megakaryocytic progenitor cells (CFU-Meg). MATERIALS AND METHODS: Peripheral blood-derived CD34(+)IL-6R(-) cells were sorted and cultured in the presence of IL-9, erythropoietin (Epo), stem cell factor (SCF), and thrombopoietin (TPO) alone or in combination. The number of pure and mixed megakaryocyte colonies, the size of pure megakaryocyte colonies, the ploidy distribution of megakaryocytes, and proplatelet formation were investigated. RESULTS: Apart from TPO, no single factor could support CFU-Meg-derived colony formation, but each two-factor combination among IL-9, Epo, and SCF supported a few CFU-Meg colonies. Interestingly, the combination of Epo+SCF+IL-9 induced four to six times as many CFU-Meg colonies as any of the two-factor combinations. Neutralizing monoclonal antibodies (mAbs) for IL-9 receptor and c-kit completely abolished this synergistic effect. In contrast, addition of neutralizing anti-c-Mpl or anti-CXCR4 Abs did not influence colony formation, indicating that this synergistic effect was independent of TPO or SDF-1. Moreover, the endogenous production of TPO by cultured CD34(+)IL-6R(-) cells in the presence of Epo+SCF+IL-9 was ruled out by reverse transcriptase polymerase chain reaction for TPO mRNA. Interestingly, the combination of TPO, Epo, SCF, and IL-9 supported the largest number of pure and mixed megakaryocyte colonies, suggesting that this combination of cytokines might recruit primitive megakaryocytic as well as multipotential progenitors. This combination also potently enhanced proplatelet formation compared with TPO alone or a combination of Epo, SCF, and IL-9. CONCLUSION: This study demonstrated for the first time that human IL-9 can potentiate human megakaryocytopoiesis in the presence of Epo and/or SCF.