[Brain Metastasis and Leptomeningeal Carcinomatosis after Surgery for Esophageal Cancer-A Case Report].

A 70-year-old man had undergone thoracoscopic esophagectomy following neoadjuvant chemotherapy for thoracic esophageal squamous cell carcinoma 3 years before presentation. He was undergoing whole-brain irradiation following surgery for a solitary brain metastatic tumor. The chief complaint was left leg pain during irradiation. FDG-PET/CT and MRI revealed metastases in bilateral cauda equina S1 nerve roots. Cerebrospinal fluid examination also revealed malignant cells. He received chemotherapy with 2 courses of 5-fluorouracil and cisplatin following 30 Gy of spinal irradiation. To control neurological symptoms, 4 courses of intrathecal chemotherapy with methotrexate, cytarabine, and betamethasone were performed. However, he gradually weakened and died 8 months after brain metastasis and 7 months after leptomeningeal carcinomatosis. The multidisciplinary treatment using irradiation and systemic and intrathecal chemotherapies could improve the survival of patients with leptomeningeal carcinomatosis of esophageal squamous cell carcinoma.

[Effect of Proteinuria in Patients Receiving Anti-VEGF Therapy for Advanced Colorectal Cancer].

Grade 2 or 3 proteinuria was observed in 54 patients out of 158 metastatic colorectal cancer patients receiving anti-VEGF therapy. Patients with diabetes and hypertension were risk for severe proteinuria. ARBs were more frequently used in patients with severe proteinuria. However, they could not reduce proteinuria. The examination of protein/creatinine ratio was useful for continuing anti-VEGF therapy.

Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo.

Several chemotherapeutic drugs have immune-modulating effects. For example, cyclophosphamide (CP) and gemcitabine (GEM) diminish immunosuppression by regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), respectively. Here, we show that intermittent (metronomic) chemotherapy with low-dose CP plus GEM can induce anti-tumor T cell immunity in CT26 colon carcinoma-bearing mice. Although no significant growth suppression was observed by injections of CP (100 mg/kg) at 8-day intervals or those of CP (50 mg/kg) at 4-day intervals, CP injection (100 mg/kg) increased the frequency of tumor peptide-specific T lymphocytes in draining lymph nodes, which was abolished by two injections of CP (50 mg/kg) at a 4-day interval. Alternatively, injection of GEM (50 mg/kg) was superior to that of GEM (100 mg/kg) in suppressing tumor growth in vivo, despite the smaller dose. When CT26-bearing mice were treated with low-dose (50 mg/kg) CP plus (50 mg/kg) GEM at 8-day intervals, tumor growth was suppressed without impairing T cell function; the effect was mainly T cell dependent. The metronomic combination chemotherapy cured one-third of CT26-bearing mice that acquired tumor-specific T cell immunity. The combination therapy decreased Foxp3 and arginase-1 mRNA levels but increased IFN-γ mRNA expression in tumor tissues. The percentages of tumor-infiltrating CD45(+) cells, especially Gr-1(high) CD11b(+) MDSCs, were decreased. These results indicate that metronomic chemotherapy with low-dose CP plus GEM is a promising protocol to mitigate totally Treg- and MDSC-mediated immunosuppression and elicit anti-tumor T cell immunity in vivo.

Antitumor effects of cytoplasmic delivery of an innate adjuvant receptor ligand, poly(I:C), on human breast cancer.

Innate adjuvant receptors are expressed in immune cells and some types of cancers. If antitumor therapies targeting these receptors are established, it is likely that they will be therapeutically beneficial because antitumor effects and immune-cell activation can be induced simultaneously. In this study, we tested this possibility of using an innate adjuvant receptor ligand, polyinosinic-polycytidylic acid [poly(I:C)], to treat human breast cancer cell lines. Three breast cancer cell lines (MCF-7, MDA-MB-231, and BT-549) were used in this study. Poly(I:C) was transfected into these cancer cells to stimulate melanoma differentiation-associated gene (MDA) 5, which is a cytoplasmic adjuvant receptor. Poly(I:C) transfection significantly reduced the viability of all cell lines in a manner partially dependent on MDA5. Flow cytometeric analyses and immunoblot assays revealed that the antitumor effect depended on both caspase-dependent apoptosis and c-Myc- and cyclinD1-dependent growth arrest. Interestingly, poly(I:C) transfection was accompanied by autophagy, which is thought to protect cancer cells from apoptosis after poly(I:C) transfection. In a xenograft mouse model, local transfection of poly(I:C) significantly inhibited the growth of xenografted MDA-MB-231 cells. Our findings indicate that cytoplasmic delivery of poly(I:C) can induce apoptosis and growth arrest of human breast cancer cells, and that therapy-associated autophagy prevents apoptosis. The results of this study suggest that the innate adjuvant receptors are promising targets and that their ligands could serve as antitumor reagents, which have the potential to simultaneously induce antitumor effects and activate immune cells.

Reconstruction of the esophagojejunostomy by double stapling method using EEA™ OrVil™ in laparoscopic total gastrectomy and proximal gastrectomy.

Here we report the method of anastomosis based on double stapling technique (hereinafter, DST) using a trans-oral anvil delivery system (EEATM OrVilTM) for reconstructing the esophagus and lifted jejunum following laparoscopic total gastrectomy or proximal gastric resection. As a basic technique, laparoscopic total gastrectomy employed Roux-en-Y reconstruction, laparoscopic proximal gastrectomy employed double tract reconstruction, and end-to-side anastomosis was used for the cut-off stump of the esophagus and lifted jejunum. We used EEATM OrVilTM as a device that permitted mechanical purse-string suture similarly to conventional EEA, and endo-Surgitie. After the gastric lymph node dissection, the esophagus was cut off using an automated stapler. EEATM OrVilTM was orally and slowly inserted from the valve tip, and a small hole was created at the tip of the obliquely cut-off stump with scissors to let the valve tip pass through. Yarn was cut to disconnect the anvil from a tube and the anvil head was retained in the esophagus. The end-Surgitie was inserted at the right subcostal margin, and after the looped-shaped thread was wrapped around the esophageal stump opening, assisting Maryland forceps inserted at the left subcostal and left abdomen were used to grasp the left and right esophageal stump. The surgeon inserted anvil grasping forceps into the right abdomen, and after grasping the esophagus with the forceps, tightened the end Surgitie, thereby completing the purse-string suture on the esophageal stump. The main unit of the automated stapler was inserted from the cut-off stump of the lifted jejunum, and a trocar was made to pass through. To prevent dropout of the small intestines from the automated stapler, the automated stapler and the lifted jejunum were fastened with silk thread, the abdomen was again inflated, and the lifted jejunum was led into the abdominal cavity. When it was confirmed that the automated stapler and center rod were made completely linear, the anvil and the main unit were connected with each other and firing was carried out. Then, DST-based anastomosis was completed with no dog-ear. The method may facilitate safe laparoscopic anastomosis between the esophagus and reconstructed intestine. This is also considered to serve as a useful anastomosis technique for upper levels of the esophagus in laparotomy.

A case of Spigelian hernia after laparoscopic incisional hernia repair.

Laparoscopic ventral hernia repair with intraperitoneal onlay mesh reinforcement is often performed in clinical practice. We herein describe a patient who developed a Spigelian hernia at the edge of the mesh due to rupture of the muscular layer in the abdominal wall. A 69-year-old woman developed a left-sided abdominal bulge 15 months after laparoscopic ventral hernia repair. CT showed a 33-mm defect in the abdominal wall at the lateral edge of the left abdominal rectus muscle with an intestinal prolapse through the defect. She was diagnosed with a Spigelian hernia and underwent operation. The hernia orifice was located at the aponeurosis of the transverse abdominal muscle where the thread had been used to fix the mesh through all layers of the abdominal wall. This report details a case of a Spigelian hernia after laparoscopic ventral hernia repair.

Adenocarcinoma Arising From a Gastric Duplication Cyst With Lymph Node Metastasis.

Gastric duplication cysts (GDCs) are a relatively rare congenital anomalies and are mostly diagnosed in the early years of life. Herein, we report a very rare surgical case of adenocarcinoma arising from a GDC with lymph node metastasis. A 78-year-old woman was referred to our hospital because of elevated serum levels of cancer antigen (CA) 19-9. Endoscopic ultrasound, contrast fistulography, and computed tomography showed a cystic lesion communicating with the lesser curvature of the stomach. The serum levels of CA 19-9 were high, and fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging demonstrated a slightly enlarged lymph node with high FDG uptake after four months. The size of the cyst was unchanged. It was diagnosed as a GDC. The enlarged lymph node was highly likely to be malignant. Hence, we performed a distal gastrectomy involving the origin of entry and whole body of the GDC with en bloc regional lymphadenectomy. The postoperative pathology was consistent with GDC with moderately differentiated adenocarcinoma and lymph node metastasis. Adjuvant chemotherapy with tegafur-gimeracil-oteracil potassium (S-1) was administered for 12 months. At present, the patient is alive, with no recurrence of the lesion even four years after the operation. GDCs in adults are rare and may predispose to malignancy. Early diagnosis and prompt surgical intervention are important for favorable outcomes.

First Case Report of a Huge Giant Cell Tumor of Soft Tissue Originating from the Retroperitoneum.

BACKGROUND Giant cell tumor of soft tissue (GCT-ST) is a rare disease generally generated from superficial tissue. We report an extremely rare case of giant cell tumor of soft tissue arising from retroperitoneal tissue. CASE REPORT A 78-year-old man visited our medical center with the chief complaint of fatigue and weight loss for 1 month. He had a hard and immobilized mass without pain in the left upper quadrant. Contrast-enhanced CT showed a huge tumor (22×20×16 cm) in the retroperitoneal space, and it invaded into the stomach, colon, pancreas, spleen, and left kidney. MRI demonstrated the tumor had a serous cystic component as T1 was low, T2 was high, and DWI was slightly high. We diagnosed the retroperitoneal malignant tumor, and tumor resection was performed with total gastrectomy, partial colectomy, distal pancreatectomy, left nephrectomy, and left adrenalectomy for complete resection, without any postoperative complications. The tumor predominantly consisted of a solid mass, and had necrotic lesions, cystic lesions, and calcification. The histological exam showed it was composed of spindle and multinucleated giant cells; however, there was no cellular atypia or pleomorphism. Immunohistochemical staining characterized the tumor with CD68+, SMA+, CD34-, Desmin-, and S-100-. We finally diagnosed it as GCT-ST with the intermediate group of malignancy, according to WHO criteria. Thereafter, the patient had no recurrence at 1 year after resection. CONCLUSIONS The huge GCT-ST arising from the retroperitoneal space, which has never before been reported, was successfully resected. We report it with pathological findings to add to the relevant literature.

Chloroquine augments TRAIL-induced apoptosis and induces G2/M phase arrest in human pancreatic cancer cells.

Autophagy contributes to the treatment-resistance of many types of cancers, and chloroquine (CQ) inhibits autophagy. The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) kills cancer cells but is minimally cytotoxic to normal cells. However, because the therapeutic efficacy of TRAIL is limited, it is necessary to augment TRAIL-induced anti-tumor effects. In this study, we explored the anti-tumor effects of a combination of CQ and TRAIL on two human pancreatic cancer cell lines: TRAIL-sensitive MiaPaCa-2 cells and Panc-1 cells that are less sensitive to TRAIL. Although both CQ and TRAIL reduced cancer cell viability in a dose-dependent manner, the combination acted synergistically. CQ increased the expression level of type-II LC3B without decreasing the expression of p62, an autophagic substrate, thus indicating inhibition of autophagy. CQ did not increase the levels of death receptors on cancer cells but reduced the expression of anti-apoptotic proteins. A combination of CQ and TRAIL significantly increased cancer cell apoptosis. CQ induced cell-cycle arrest in the G2/M phase. Also, CQ increased the p21 level but reduced that of cyclin B1. A combination of CQ and TRAIL reduced the colony-forming abilities of cancer cells to extents greater than either material alone. In xenograft models, combination CQ and TRAIL therapy significantly suppressed the growth of subcutaneously established MiaPaCa-2 and Panc-1 cells, compared with the untreated or monotherapy groups. Together, the results indicate that CQ in combination with TRAIL may be useful to treat human pancreatic cancer.

The HSP70 and autophagy inhibitor pifithrin-µ enhances the antitumor effects of TRAIL on human pancreatic cancer.

TRAIL and agonistic death receptor-specific antibodies can induce apoptosis in cancer cells with little cytotoxicity to normal cells. To improve TRAIL-induced antitumor effects, we tested its effectiveness in combination with pifithrin (PFT)-µ, which has the potential to inhibit HSP70 function and autophagy, both of which participate in TRAIL resistance in cancer cells. Among the four human pancreatic cancer cell lines tested, MiaPaca-2, Panc-1, and BxPC-3 cells showed varying sensitivities to TRAIL. In MiaPaca-2 and Panc-1 cells, knockdown of HSP70 or beclin-1, the latter an autophagy-related molecule, by RNA interference augmented TRAIL-induced antitumor effects, decreasing cell viability, and increasing apoptosis. On the basis of these findings, we next determined whether the TRAIL-induced antitumor effects could be augmented by its combination with PFT-µ. The combination of TRAIL plus PFT-µ significantly decreased the viability and colony-forming ability of MiaPaca-2 and Panc-1 cells compared with cells treated with either agent alone. When applied alone, PFT-µ increased Annexin V(+) cells in both caspase-dependent and -independent manners. It also promoted TRAIL-induced apoptosis and arrested cancer cell growth. Furthermore, PFT-µ antagonized TRAIL-associated NF-κB activation in cancer cells. In a xenograft mouse model, combination therapy significantly inhibited MiaPaca-2 tumor growth compared with treatment with either agent alone. The results of this study suggest protective roles for HSP70 and autophagy in TRAIL resistance in pancreatic cancer cells and suggest that PFT-µ is a promising agent for use in therapies intended to enhance the antitumor effects of TRAIL.