Gastric Small Cell Neuroendocrine Carcinoma With Loss of Epithelial Markers Expression.

Background/Aim: Given that gastric small cell neuroendocrine carcinoma (SCNEC) is notably more aggressive than conventional adenocarcinoma, and a platinum-based regimen aligned with the treatment for pulmonary SCNEC is advocated when chemotherapy is needed, ensuring an accurate pathological diagnosis is paramount. Case Report: A 63-year-old man, examined for melena, underwent gastroscopy which revealed a total circumferential Borrmann type 3 lesion extending from the pylorus to the antrum of the stomach. He underwent a distal gastrectomy with D2 lymphadenectomy. The microscopic examination revealed SCNEC with a minor adenocarcinoma component. Immunohistochemically, the SCNEC was diffusely positive for synaptophysin, CD56, and INSM1, very focally positive for chromogranin A, and negative for leukocyte common antigen, CD3, and CD20. A significant observation in this case was the complete negativity for epithelial markers including keratin (CK7, CK8, CK20, CAM5.2, and AE1/AE3) and epithelial membrane antigen. Conclusion: Diffuse positivity for neuroendocrine markers, negativity for other lineage markers, and a transition from the adenocarcinoma component, if present, serve as significant diagnostic clues for gastric SCNEC with loss of epithelial markers expression. SCNEC should not be excluded solely based on the negative result for epithelial markers.

A useful modality of CT angiography image to identify medical emergency in isolated celiac artery dissection type I: A case report with longest follow-up and literature review.

Symptomatic isolated celiac artery (CA) dissection (SICAD) is an extremely rare form of visceral artery dissection. It is diagnosed by a contrast abdominal computed tomography (CT) scan showing a CA dissection (CAD). There are 4 types of CAD: Type I-IV. Type I has entry and re-entry and no true luminal narrowing. All types other than type I have entry and re-entry. They have true lumen compression and true lumen constriction due to false lumen. We report a case with the longest follow-up, 120 months after symptom onset, without evidence of CAD exacerbation. A 56-year-old man presented with a sudden onset of abdominal and back pain. He had a past medical history of left pneumothorax, pulmonary tuberculosis at the age of 23, and hypertension on medication since the age of 46. On physical examination, he had mild muscle rebound tenderness in the epigastric region. The curved multiplanar reconstruction (MPR) of the urgent 3-dimensional contrast-enhanced abdominal computed tomography angiography (CTA) showed an isolated celiac artery dissection type I. Given the risk of emergency surgery for total occlusion of the CA, conservative management with analgesics during hospitalization resolved the abdominal pain, and the patient was discharged 3 days later. Subsequently, a total of 5 CTAs were performed over 120 months, but no worsening of CA arterial dissection and CA occlusion findings were observed. In type I SICAD cases, arterial dissection, and CA occlusion may progress, in which case emergency stenting or endovascular treatment may be indicated, and close follow-up such as CTA is required.

GM-CSF derived from the inflammatory microenvironment potentially enhanced PD-L1 expression on tumor-associated macrophages in human breast cancer.

Ever since immune checkpoint inhibitors have been approved for anti-cancer therapy in several cancers, including triple-negative breast cancer, the significance of programmed death-1 ligand 1 (PD-L1) expression in the tumor immune microenvironment has been a topic of interest. In the present study, we investigated the detailed mechanisms of PD-L1 overexpression on tumor-associated macrophages (TAMs) in breast cancer. In in vitro culture studies using human monocyte-derived macrophages, lymphocytes, and breast cancer cell lines, PD-L1 overexpression on macrophages was induced by the conditioned medium (CM) of activated lymphocytes, but not that of cancer cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) derived from activated lymphocytes was found to be involved in PD-L1 overexpression, in addition to interferon (IFN)-γ, via STAT3 pathway activation. Macrophages suppressed lymphocyte activation, and this inhibition was impaired by PD-1 blocking. The CM of activated lymphocytes also induced the overexpression of PD-L2, but GM-CSF did not affect PD-L2 expression. In the murine E0771 breast cancer model, anti-GM-CSF therapy did not affect PD-L1 expression on TAMs, and the mechanisms of PD-L1 expression on TAMs might differ between humans and mice. However, not only PD-L1, but also PD-L2 was overexpressed on TAMs in the E0771 tumor model, and their expression levels were significantly lower in the tumors in nude mice than in wild-type mice. Anti-PD-L1 antibody and anti-PD-L2 antibody synergistically inhibited E0771 tumor development. In conclusion, PD-L1 and PD-L2 were overexpressed on TAMs, and they potentially contributed to immunosuppression. The GM-CSF-STAT3 pathway is thought to represent a new mechanism of PD-L1 overexpression on TAMs in human breast cancer microenvironment.

Soluble Factors Involved in Cancer Cell-Macrophage Interaction Promote Breast Cancer Growth.

BACKGROUND/AIM: Recent studies have indicated the clinical significance of tumor-associated macrophages (TAMs) in breast cancer; however, the detailed mechanisms of cell-cell interactions between TAMs and cancer cells remain unclear. MATERIALS AND METHODS: In vitro cell culture studies using human monocyte-derived macrophages and breast cancer cell lines were performed to test which cytokines would be involved in cell-cell interactions between cancer cells and macrophages. In addition, studies using human resected samples and animal breast cancer models were performed to examine the significance of TAMs in cancer development. RESULTS: Osteopontin, HB-EGF, and IL-6 were suggested to be macrophage-derived growth factors for breast cancer cells. FROUNT inhibitor significantly blocked TAM infiltration and subcutaneous tumor growth in an E0771 mouse breast cancer model. CONCLUSION: TAMs express growth factors, such as osteopontin, for cancer cells, and targeting of TAM infiltration might be a promising approach for anti-breast cancer therapy.

[Large bowel malignant obstruction treated with SEMS placement as a bridge to surgery procedure].

We treated 5 cases of preoperative decompression using the self-expandable metallic stent (SEMS) against obstructive left side colon cancer since October 2013. The obstruction site was the descending colon in one patient, sigmoid colon in 2, rectal-sigmoid colon in 1, and rectum in 1. Colonic stent placements were successful in all cases. Oral intake started an average of 3.7 days after SEMS placement. All patients underwent radical surgery an average of 17.2 days after SEMS placement. Two patients waited for surgery while out of the hospital. All patients underwent colonoscopy. One patient had advanced colon cancer. Our findings show that SEMS placement can treat obstructive left-sided colon cancer.

[A case of carcinoma arising in a diverticulum of the transverse colon].

A 64 year-old woman presented with advanced, transverse colon cancer arising in the diverticulum. Tumor invasion extended beyond the serosa to the anal side of the colon. Anemia and fatigue progressed after 6 months of iron administration. The hemoglobin value was 5.3 g/dL and carcinoembryonic antigen (CEA) level was elevated to 44.2 ng/mL. A palpable and tender fist-sized mass was found in the right upper abdomen. Computed tomography (CT) revealed a low-density mass in the transverse colon invading beyond the serosa to the anal side of the colon. Right hemi-colectomy with lymph node dissection was performed. The resected specimen contained multiple diverticula including the one from which the tumor arose. Histological examination revealed a well-differentiated, tubular adenocarcinoma (UICC TNM T4bN0M0) arising in a transverse colon diverticulum. There has been no recurrence for 2 years. Colon cancer arising in a diverticulum may expand to the extra-serosa and easily invade to the adjacent organ. In such cases, malignancy should be considered.

[A case of juvenile colon cancer with peritoneal dissemination treated effectively by use of resection and chemotherapy].

A 37 -year-old man experienced abdominal pain and vomiting. Computed tomography showed massive ascites and obstruction of the colon by a tumor at the left colic flexure. The tumor was classified as advanced Borrmann type 3 on the basis of a colonoscopy. Palliative resection of the colon and colostomy on the oral side were performed. Operative findings showed massive peritoneal dissemination of the tumor. We administered palliative chemotherapy consisting of capecitabine/oxaliplatin (XELOX) and bevacizumab. After 4 courses of chemotherapy, the primary and disseminated tumors and ascites had disappeared, and tumor marker expression levels were within normal range. Palliative resection and subsequent chemotherapy was effective for this young patient with very advanced colon cancer that had disseminated and caused obstruction.

[A case of small intestinal gastrointestinal stromal tumor (GIST) with peritoneal dissemination, treated effectively with molecular target drug after operation].

A 54-year-old man, presenting with sudden onset of abdominal pain, was admitted to our hospital. Blood examination revealed high white blood cell counts and elevated C-reactive protein (CRP) levels. Ultrasonography and computed tomography detected a 12 cm mass in the lower abdomen, some ascites, and multiple small nodules spread through the abdomen. The preoperative diagnosis of the tumor was either a gastrointestinal stromal tumor (GIST) or a possible lymphoma. The 12 cm tumor and greater omentum with multiple nodules were resected. Upon pathological examination, the tumor was diagnosed as a GIST, and appeared KIT positive by immunostaining. After the operation, imatinib was administered; however, psoriasis vulgaris developed within 5 months. As the next line of therapy, sunitinib treatment was initiated; however, since peripheral nerve disorder developed, sunitinib dose was halved and maintained. Two years after the operation, the patient is still alive. Small intestinal GISTs, which make up only 20-30% of all GISTs, are considered to be more malignant than others. We report a rare case of GIST with peritoneal metastases originating from the small intestine, which was treated effectively with molecular target drugs.

Development of a novel controllable, multidirectional, reusable metallic port with a wide working space.

BACKGROUND: Endoscopic surgery is currently a standard procedure in many countries. Furthermore, conventional four-port laparoscopic cholecystectomy is developing into a single-port procedure. However, in many developing countries, disposable medical products are expensive and adequate medical waste disposable facilities are absent. Advanced medical treatments such as laparoscopic or single-port surgeries are not readily available in many areas of developing countries, and there are often no other sterilization methods besides autoclaving. Moreover, existing reusable metallic ports are impractical and are thus not widely used. MATERIAL AND METHODS: We developed a novel controllable, multidirectional single-port device that can be autoclaved, and with a wide working space, which was employed in five patients. RESULTS: In all patients, laparoscopic cholecystectomy was accomplished without complications. CONCLUSION: Our device facilitates single-port surgery in areas of the world with limited sterilization methods and offers a novel alternative to conventional tools for creating a smaller incision, decrease postoperative pain, and improve cosmesis. This novel device can also lower the cost of medical treatment and offers a promising tool for major surgeries requiring a wide working space.

[A case of delayed subcutaneous metastases of gastric carcinoma effectively treated with S-1 plus cisplatin chemotherapy].

We encountered a case of delayed subcutaneous metastases of gastric carcinoma. The patient underwent distal gastrectomy for advanced gastric carcinoma 11 years ago. Postoperative pathological diagnosis indicated stage IIIB disease, poorly differentiated adenocarcinoma (scirrhous, T4a, ly2, v2, N2, H0, P0). Three courses of adjuvant chemotherapy with 5-fluorouracil (5-FU)+cisplatin (CDDP) were administered; however, the patient discontinued the treatment. No signs of recurrence were observed for 11 years after the treatment. However, subcutaneous metastases in the front portion of the head and the back and an ovarian tumor were detected after the remission period. The specimen from the resected subcutaneous tumor from the back indicated signet-ring cell carcinoma, and delayed subcutaneous and ovarian metastases of the gastric carcinoma was diagnosed. Therefore, 8 courses of the S-1+CDDP combination therapy were administered. The cutaneous metastases disappeared, but the ovarian tumor progressed and was therefore resected. Analysis of the resected ovarian tumor also indicated signet-ring cell carcinoma. We report a case of delayed recurrence of gastric carcinoma that was effectively treated with chemotherapy.

[A case of solitary ectopic medullary carcinoma in the right submandibular region].

A 77-year-old woman consulted our hospital because of an indolent mass in the right submandibular region, which developed approximately 4 months previously. Ultrasonography revealed a 19.5×9.2 mm homogeneous low echoic mass in the submandibular region and a 9.8×3.1 mm low echoic mass in the left thyroid lobe. Blood examinations revealed high levels of carcinoembryonic antigen (CEA) and calcitonin. Analysis of the cytological specimens obtained from the submandibular tumors indicated class IV disease. First, we resected the mandibular tumor for diagnosis, and the specimen showed medullary carcinoma. Later, the patient underwent left thyroid lobe resection. The pathological diagnosis was adenomatous goiter. We report a rare case of ectopic medullary carcinoma in the right mandibular region.

[A case of advanced gastric cancer with esophageal severe dysplasia resected after neoadjuvant S-1+cisplatin therapy].

A 72-year-old man was admitted to our hospital complaining of upper abdominal pain and back pain. Advanced gastric cancer was found at the fundus of the stomach, and severe dysplasia was found at the lower esophagus. We proceeded with neoadjuvant chemotherapy (S-1+CDDP) because the lymph nodes in the lesser curvature of the stomach were metastasized and invasion of the pancreas and some vessels was suspected by computed tomography. The tumor size was reduced remarkably, the esophageal dysplasia disappeared after preoperative chemotherapy, and we were able to perform total gastrectomy.

[A case of ruptured gastrointestinal stromal tumor of the duodenum with intraabdominal bleeding].

We report a case of ruptured gastrointestinal stromal tumor (GIST) of the duodenum with intraabdominal bleeding. A 50-year-old man was admitted to our hospital because of sudden epigastralgia. Enhanced computed tomography (CT) showed a tumor measuring about 14 cm in diameter on the ventral side of the right kidney and intrapelvic fluid collection. We performed an emergency operation. At laparotomy, the tumor was originated from the 2nd portion of the duodenum without attaching to the retroperitoneum. We resected the tumor radically. Histopathologically, the tumor arose from the proper muscle layer of the duodenum, and was positive for c-kit and negative for CD34 and α-SMA on immunostaining. Then the tumor was diagnosed as GIST of the duodenum. Adjuvant therapy by imatinib 400 mg/day is now being done because this case is thought to be clinically malignant GIST.

[A case of mucinous adenocarcinoma of descending colon with abscess formation and solitary metastasis at right side of the abdomen].

A 59-year-old man realized a left lower abdominal pain and palpable mass about a month ago. He was admitted to our hospital because of the pain and high fever. Blood examinations revealed high levels of white blood cell count and CRP. Ultrasonography showed a wall thickness of the descending colon and 7 cm cystic mass with air around. Moreover, a 6 cm cystic mass was found an outside of the ascending colon. We first treated with antibiotics under the diagnosis of abscesses because of perforation of diverticulum. Colonoscopy revealed an obstructing tumor in descending colon and biopsy specimens of the tumor showed adenocarcinoma. The preoperative diagnosis of the right side tumor was unclear. We performed a partial resection of the descending colon, and the tumor outside of the ascending colon was resected. The pathological diagnosis of the tumors was both mucinous carcinoma of the colon. Mucinous carcinoma tends to be more found in the right side of the colon than in the left side. The rate of lymph node metastasis and dissemination is higher than that in differentiated adenocarcinoma. We report a rare case of mucinous carcinoma originated from the left side of the colon with a solitary dissemination in opposite side of the abdomen.

[A case of giant presacral neurilemoma resected without blood transfusion after embolization of tumor vessels].

A 71-year-old man began feeling a lower abdominal pain at bowel movement about one year ago. He was found to have a pelvic tumor during a health examination and referred to our hospital for further evaluation. CT and MRI scans demonstrated a giant pelvic tumor, 10 cm in size, which compressed the rectum. The likely preoperative diagnosis was leiomyosarcoma from the rectum or neurilemoma. To regulate intraoperative hemorrhaging and to reduce the tumor size, angiography was performed at two days before the operation and embolization of the tumor vessels was done. He had a tumor resection and a low anterior resection of the rectum and a transient colostomy of the ascending colon without blood transfusion. The resected tumor was covered with thin yellowish-white capsule with smooth surface, elastic hard on palpation, and was measured 10.5 × 9 × 10.5 cm, and weighted 320 g. The pathological diagnosis was neurilemoma (schwannoma) consisting both Antoni type A and Antoni type B sections.

Synthetic small interfering RNA targeting heat shock protein 105 induces apoptosis of various cancer cells both in vitro and in vivo.

We previously reported that heat shock protein 105 (HSP105), identified by serological analysis of a recombinant cDNA expression library (SEREX) using serum from a pancreatic cancer patient, was overexpressed in various human tumors and in the testis of adult men by immunohistochemical analysis. In the present study, to elucidate the biological function of the HSP105 protein in cancer cells, we first established NIH3T3 cells overexpressing murine HSP105 (NIH3T3-HSP105). The NIH3T3-HSP105 cells acquired resistance to apoptosis induced by heat shock or doxorubicin. The small interfering RNA (siRNA)-mediated suppression of HSP105 protein expression induced apoptosis in human cancer cells but not in fibroblasts. By a combination of siRNA introduction and doxorubicin or heat shock treatment, apoptosis was induced synergistically in a human colon cancer cell line, HCT116. In vivo, siRNA inoculation into the human gastric cancer cell line KATO-3 established in the flank of an NOD SCID mouse suppressed the tumor growth. This siRNA-induced apoptosis was mediated through caspases, but not the p53 tumor suppressor protein, even though the HSP105 protein was bound to wild-type p53 protein in HCT116 cells. These findings suggest that the constitutive overexpression of HSP105 in cancer cells is involved in malignant transformation by protecting tumor cells from apoptosis. HSP105 may thus be a novel target molecule for cancer therapy and a treatment regimen using synthetic siRNA to suppress the expression of HSP105 protein may provide a new strategy for cancer therapy.

[A long-term survival case of liver and mediastinal LN metastases from colon cancer treated with intensive multimodal therapy].

A 50-year-old man with multiple liver and mediastinal LN metastases from sigmoid colon cancer was admitted to our hospital in May 2005. In October 2002, a radical resection of the original tumor and liver metastases were performed at a previous hospital. Histologically, the tumor was diagnosed as Stage IV. He was treated with an oral anticancer agent as an adjuvant therapy. In January 2005, the CEA level was increased to 3.2 ng/ml and CT scan revealed a solitary liver metastasis. Partial resection of the liver was performed. On admission to our hospital, a systemic chemotherapy by FOLFOX4 was begun. The liver metastases showed 61% reduction in size and were judged to be PR. However, the intrathoracic lymph node size was not changed. Therefore, VATS extirpation of the mediastinal lymph node was performed. After 10 courses of FOLFOX4, abdominal CT revealed liver metastases remained to be almost the same size. In January 2006, radio frequency ablation (RFA) and partial hepatectomy were enforced and then, the tumor marker returned to normal. There were no serious adverse events or postoperative complications. He has been alive without any sign of recurrence for 42 months from the initial treatment. In conclusion, intensive combination therapies for remote metastases of colon cancer might be promising to obtain a long-term survival without ruining QOL.

[Thoracoscopic radio-frequency ablation therapy for liver surface tumor located under the diaphragm].

It is necessary to select a proper method for radio-frequency ablation (RFA) therapy of the liver tumor. Especially, treating the tumor under the diaphragm is usually difficult to approach by percutaneous puncture. We have done thoracoscopic RFA in 48 cases (43 HCC, 1 adenomatous hyperplasia, and 4 metastatic liver tumors) to treat the tumor located on the surface of the liver under the diaphragma since January 1st, 2000. The average operation time was 237 minutes, the average blood loss was 29.0 ml and the average tumor diameter were 2.6 cm, and the average frequency of coagulation was 4.5 times. The cases which thoracoscopic RFA was possible with diaphragm incision were 27 cases (56%). However, there were 15 cases in which diaphragm incision was difficult by the adhesion under the diaphragm. Moreover, there were six cases with severe adhesion that was impossible by the thoracoscopic operation to convert an open chest method. There were 25 cases, which had some adhesion either in the chest or under the diaphragm, and those adhesions were considered to be related to the previous treatments such as the operation, ablation, and chemotherapy. The average length of the hospital stay post operation was 9.7 days. Only 3 cases (6%) needed additional treatments for tumor where the severe postoperative complication did not occur. Therefore, thoracoscopic RFA for tumor on the liver surface located under the diaphragm is suggested to be a feasible technique. On the other hand, it is necessary to pay attention to two kinds of adhesion taking a critical role for thoracoscopic operation procedures.

[A long term survival case of advanced intrahepatic cholangiocarcinoma treated with multidisciplinary treatment].

A 56-year-old man was admitted to our hospital for liver tumor of 7 cm in diameter, located mainly in the anterior segment. He underwent a hepatic resection of anterior and median segment of the liver in January 2002. Pathologically, the tumor was moderately differentiated intrahepatic cholangiocarcinoma (ICC) with vascular invasion. Hepatic arterial chemotherapy as a neoadjuvant therapy was performed. In December 2002, bone metastases in the 12th thoracic spine and iliac bone were found. Therefore, he received radiotherapy (total of 30 Gy) and a monthly bisphosphonate infusion. In May 2003, multiple intrahepatic recurrences were diagnosed. Transarterial chemoembolization for twice and an additional radio-frequency ablation were performed. Four months later, lung metastases were found, thus, he was administered TS-1. He has been alive with PS 0 for 4 and half years after the hepatic resection. No new intrahepatic recurrences were found and bone and lung metastases remained to be stable. Although only a hepatic resection is a useful therapy for ICC, such a multidisciplinary treatment may have an effect to improve the prognosis of patients with ICC.

DNA vaccination of HSP105 leads to tumor rejection of colorectal cancer and melanoma in mice through activation of both CD4 T cells and CD8 T cells.

We report that HSP105, identified by serological identification of antigens by recombinant expression cloning (SEREX), is overexpressed in a variety of human cancers, including colorectal, pancreatic, thyroid, esophageal, and breast carcinoma, but is not expressed in normal tissues except for the testis. The amino acid sequences and expression patterns of HSP105 are very similar in humans and mice. In this study, we set up a preclinical study to investigate the usefulness of a DNA vaccine producing mouse HSP105 whole protein for cancer immunotherapy in vivo using BALB/c and C57BL/6 mice, Colon26, a syngeneic endogenously HSP105-expressing colorectal cancer cell line, and B16.F10, a melanoma cell line. The DNA vaccine was used to stimulate HSP105-specific T-cell responses. Fifty percent of mice immunized with the HSP105 DNA vaccine completely suppressed the growth of subcutaneous Colon26 or B16.F10 cells accompanied by massive infiltration of both CD4+ T cells and CD8+ T cells into tumors. In cell transfer or depletion experiments we proved that both CD4+ T cells and CD8+ T cells induced by these vaccines play critical roles in the activation of antitumor immunity. Evidence of autoimmune reactions was not present in surviving mice that had rejected tumor cell challenges. We found that HSP105 was highly immunogenic in mice and that the HSP105 DNA vaccination induced antitumor immunity without causing autoimmunity. Therefore, HSP105 is an ideal tumor antigen that could be useful for immunotherapy or the prevention of various human tumors that overexpress HSP105, including colorectal cancer and melanoma.