[A Case of Medullary Carcinoma of the Colon with Poor Prognosis].

An 87-year-oldwoman was referredowing to lightheadedness. Severe anemia(Hb 3.9 g/dL)was detected, and colonoscopy revealeda circumferential elevatedlesion at the transverse colon(Group 5, por). The patient was diagnosed with colon cancer(cT4a, N0, M0, Stage Ⅱ), andright hemicolectomy was performed. Immunochemical analysis showedthat the lesion was MLH1- andPMS2- and confirmed a diagnosis of medullary carcinoma. Although the patient was discharged 48 days after surgery without any incident, she was readmitted because of lower leg edema. Liver metastasis and peritoneal dissemination were suspectedon performing computedtomography, andthe patient died3 5 days after readmission. Medullary carcinoma has molecular pathological features such as methylation of the promoter region andassociatedattenuation of MLH1 protein expression, as well as microsatellite instability. The prognosis for medullary carcinoma is relatively good comparedto that for poorly differentiatedad enocarcinoma, though the present case hada poor prognosis. Herein, we report a literature review.

[A Case of a Duodenal GIST Observed as a Non-Functional Pancreatic Neuroendocrine Tumor].

A 67-year-oldman was referredto our hospital because his CEA level was increasing. In March 2007, abdominal computed tomography(CT)showedthe presence of a tumor(30mm in diameter)in the pancreatic head. Upon close inspection, the patient was diagnosed with a non-functional pancreatic neuroendocrine tumor and was observed. In September 2016, the patient showedhyperglycemia, liver dysfunction, andelevation of tumor markers. CT revealeda tumor(42mm in diameter) in the pancreatic head. It hadincreasedmore than before. We diagnosedhim with a gastrointestinal stromal tumor(GIST)of the duodenum based on endoscopic ultrasound-guided fine-needle aspiration biopsy and performed pancreaticoduodenectomy. Immunohistochemical staining showedpositive c-kit, andmore than 10%positive MIB-1. Currently, the patient is alive after the surgery.

[A Case of Extramedullary Plasmacytoma of the Stomach Detected Due to Severe Anemia].

A 78-year-oldwoman was referredfor exertional dyspnea. Severe anemia(Hb 4.2 g/dL)was detected, and upper endoscopy revealeda giant ulcer at the posterior wall of the gastric body. Computedtomography showeda mass protruding from the gastric wall, suggestive of a submucosal tumor. Although biopsy did not confirm a diagnosis, we performed distal gastrectomy to control the bleeding. The pathological findings and systemic examination confirmed a diagnosis of extramedullary plasmacytoma of the stomach. Plasmacytoma is a tumor of the bone marrow derived from plasma cells that mature from B cells. The frequency of extramedullary plasmacytoma for all plasmacytoma is about 5% and plasmacytoma derived from the stomach occurs in approximately 2%of these cases. Complete resection with lymph node dissection according to the surgical treatment of gastric cancer is recommended. Large tumors, such as that in the present case, may have a poor prognosis; thus, careful follow-up is required for the early detection of recurrence. We report a case of extramedullary plasmacytoma of the stomach with a literature review.

[A Case of Long-Term Control of Stage â £ Gastric Cancer by Multimodal Therapy].

An 82-year-oldwoman was admittedto our hospital because of appetite loss andwas diagnosedwith a Type 3 tumor in the lower gastric body. Pathological examination suggested moderately differentiated adenocarcinoma with negative staining for HER2 by immunohistochemistry. An abdominal CT revealedthickening of the gastric wall andparaaortic lymph node metastases. The clinical findings suggested Stage Ⅳ disease(T4aN3M1). Chemotherapy was administered with a combination of S-1 plus oxaliplatin(SOX). After 2 courses of the SOX regimen, an abdominal CT showed a reduction of the paraaor- tic lymph node metastases, and the CEA level hadd ecreasedto 6.2 ng/mL. After 7 courses of the SOX regimen, the CEA level hadincreasedto 10.1 ng/mL, and the treatment schedule was changed to a regimen of paclitaxel plus ramucirumab(PTX/ RAM). However, grade 4 neutropenia was observed after the first treatment. Distal gastrectomy with D1+lymph node dissection was performedfor local control in September 2016. The post-operative pathological findings were ypT1b2ypN2M1, ypStage Ⅳ and the chemotherapeutic effect was grade 1a. A CT scan revealedregrowth of the paraaortic lymph node 3 months after the operation. Chemotherapy was administered with a combination of capecitabine plus oxaliplatin(CapeOX). At present, the patient is being treatedwith capecitabine monotherapy in the outpatient department with no signs of tumor regrowth.

[Curative Resection for Liver Metastasis Ten Years after Surgery for Rectosigmoid Cancer-A Case Report].

Here, we report the case of a 73-year-oldfemale patient, who previously underwent high anterior resection for rectosigmoidcancer at the age of 63. Her scheduled5 years of follow-up after colorectal surgery hadbeen finished, but she kept undergoing endoscopic mucosal resection for colorectal polyps every 1 or 2 years since then. Blood examination 10 years 6 months after surgery for rectosigmoidcancer revealedthat the value of her serum CEA was 5.5 ng/mL, which was slightly higher than the normal range. Contrast-enhancedCT showedan irregular-shapedtumor with a diameter of 3 cm in which the contrast of the peripheral area was mainly emphasized. When combining the results of MRI and PET-CT examinations, the liver tumor was clinically diagnosed as either intrahepatic cholangiocarcinoma or metastatic liver cancer. Since the first choice of therapy was tumor resection for both diagnoses, S8 subsegmental hepatectomy was performed 10 years 8 months after surgery for rectosigmoidcancer. HE staining of the resectedspecimen showedwell or moderately differentiatedad enocarcinoma, andits immunostaining findings were as follows: CDX-2: positive, CK20: positive, CK7: negative. It was pathologically diagnosed as liver metastasis from rectal cancer. It is rare for colorectal cancer to have metachronous liver metastasis more than 10 years after surgery. However, in any case where a tumor marker for colorectal cancer increases, it is necessary to examine carefully with the possibility of any metastasis in mind.

[Pregnancy-Associated Stage â £ Gastric Cancer with No Recurrence for a Long Time-A Case Report].

A 28-year-oldwoman visiteda clinic with a complaint of epigastralgia 3 months after delivery. She was diagnosedwith gastritis andtreatedwith medication. Two months later, in January 2006, she was admittedto our hospital with a complaint of dysphagia. Upper gastrointestinal endoscopy revealed type 3 gastric cancer in the lesser curvature of the cardia, and abdominal CT scan showed wall thickening of the upper gastric body. No apparent distant metastases were found. The patient underwent total gastrectomy with D2 lymph node dissection in February 2006. Although there was no peritoneal dissemination, the patient testedpositive in peritoneal lavage cytology. The postoperative pathological diagnosis was gastric cancer pT4aN2M1(P0CY1H0), Stage Ⅳ. She was discharged on postoperative day 22. S-1 monotherapy(100mg/day, day 1- 28q6wks)was performedfor 1 year on an outpatient basis. For 13 years and1 0 months after the surgery, no apparent recurrences of gastric cancer have been observed. In gastric cancers associated with pregnancy, it is difficult to distinguish between perinatal symptoms andsymptoms of gastric disease. Therefore, endoscopic examination shouldbe performedfor perinatal patients presenting with persistent gastrointestinal symptoms.

[Resection of a Desmoid Tumor Originating from the Greater Omentum after Surgery for Colon Cancer and Liver Metastasis-A Case Report].

Here, we report the case of a 66-year-old male patient who previously underwent resection of sigmoid colon cancer and its liver metastasis. His follow-up contrast-enhanced CT scan revealed a mass shadow at around the gastrosplenic ligament, which gradually increased in size. Because it could not be pathologically diagnosed by transgastric EUS-FNA, en bloc resection wasperformed surgically for the tumor in the greater omentum. Hematoxylin-eosin staining of the resected specimen showed fibroblast-like cellswith hyperplasia of bold collagen fibersand spindle-shaped nucleus. While the immunostaining findings denied a diagnosis of mesenchymal neoplasm such as GIST, leiomyosarcoma, or schwannoma, it was pathologically diagnosed as a desmoid tumor. He has been followed up without any recurrence for 2-and-a-half years after the surgical resection. Desmoid tumors tend to be locally invasive; thus, there is the potential for local recurrence, although the frequency of distant metastasis is very low. In cases in which the tumor increases in size, en bloc resection with sufficient surgical margin should be performed. Cases of desmoid tumors originating from the greater omentum are reportedly rare; however, en bloc resection may be useful for both diagnosis and treatment of tumors of the greater omentum showing increased size that are also surgically resectable.

[A Case of Advanced Gastric Cancer with Synchronous Liver Metastases Responding to Preoperative Combination Chemotherapy with S-1 plus Oxaliplatin(SOX)].

A 67-year-old man was admitted to our hospital because of anemia and weight loss, and diagnosed with a type 3 tumor in the upper gastric body. Pathological examination suggested moderately differentiated adenocarcinoma with immunohistochemically negative staining for HER2. Abdominal CT revealed thickening of the gastric wall and multiple liver metastases. The clinical findings suggested Stage IV disease(T4aN0M1). Chemotherapy was administered with a combination of S-1 plus CDDP(SP). However, the level of CEA(ng/mL)increased from 49.2 to 634.6, and the treatment schedule was changed to a combination of S-1 plus oxaliplatin(SOX). After 3 courses of the SOX regimen, abdominal CT showed a reduction of liver metastases and the level of CEA decreased to 8.4 ng/mL. We performed total gastrectomy with D1 lymph node dissection in September 2016. Post-operative pathological findings were ypStage IV (T3N0M1)and chemotherapeutic effect was grade 2. CT scan revealed regrowth of the tumor in S2 3 months after the operation. The patient underwent transcatheter arterial chemoembolization(TACE)followed by a regimen of paclitaxel plus ramucirumab(PTX/RAM). At present, he is being treated with the PTX/RAM regimen in the outpatient department with no signs of tumor growth. Although the prognosis of gastric cancer with synchronous liver metastases is very poor, it is possible for survival to be prolonged with multimodality therapy.

[Curative Resection for Metastatic Lower Rectal Tumor from Ovarian Cancer - Report of a Case].

We here report the case of a 56-year-old female patient who underwent curative resection for right ovarian cancer with intraperitoneal dissemination and liver metastases. She received following adjuvant chemotherapy, and had been visited hospital for regular follow-up since then. One and half a year after surgery, blood examination showed increasing value of CA125. Contrast-enhanced CT scan revealed a tumor whose long diameter was 5 cm at front side of lower rectum. Following MRI and PET-CT examinations indicated the pelvic tumor as recurrence of ovarian cancer, so that laparotomy was carried out. As the tumor was palped through Douglas cavum, we performed low-anterior rectal resection for en bloc tumor extirpation. Tumor cells mainly developed at peri-rectal wall and proper muscle by HE staining of pathological findings, and ER(positive), vimentin(positive), CD56(positive), synaptophysin(negative)and chromogranin A(negative)by immunostaining indicated the tumor as metastasis of ovarian cancer. Though rectal metastasis from ovarian cancer is basically rare, it might be necessary to rule out possibility of metastatic colon tumor from ovarian cancer when treating patient with rectal tumor who had underwent surgery for ovarian cancer before.

[A Case of Advanced Rectal Cancer Resulting in a Pathologically Complete Response after Neoadjuvant Chemotherapy].

A 61-years-old man was admitted to our hospital because of abdominal pain. Colonoscopy revealed a type 2 tumor in the rectum, which was diagnosed as low differentiated adenocarcinoma. At least 8 abdominal lymph adenopathies were enhanced on contrast-enhanced CT. We diagnosed stage cT3N2H0M0P0, cStage III b. Because of the risk of a poor prognosis, we tried neoadjuvant chemotherapy for the purpose of down staging. A CRT was prevented by Clostridium difficile enteritis, but we completed 80% of the regimen. Laparoscopic abdominoperineal resection was performed after 4 months of chemotherapy. The specimen contained no tumor lesion, and the pathology results were no residue of adenocarcinoma, status postchemoradiation therapy, Grade 3.

[A Case of T1a Early Gastric Cancer That Metastasized to the Right Femoral Muscles Six Years and Seven Months after Radical Surgery].

A 49-year-old woman presented to our hospital complaining of abdominal distension and right thigh edema 6 years and 7 months after undergoing total gastrectomy for early gastric cancer in December 2008. The histopathological type of the tumor was poorly differentiated adenocarcinoma. The pathological findings led to a diagnosis of T1aN2M0, Stage II A disease. In August 2015, abdominal CT and MRI revealed para-aortic lymph node swelling, ascites, and a tumor on the right femoral muscles. We performed a needle biopsy of the femoral muscle, and the final diagnosis was intramuscular metastasis from the primary gastric cancer. We initiated chemotherapy using TS-1 plus docetaxel. TS-1(80mg/m2/day)was orally administered for 2 weeks followed by a 1-week drug-free period, and 1 course of docetaxel(40mg/m2)was administered intravenously on day 1. After 2 courses of this regimen, the tumor on the right femoral muscles was reduced in size. However, diarrhea and leukopenia were observed, and the treatment schedule was changed to several other chemotherapy regimens. The patient died of progressive disease 6 months after the diagnosis of muscle metastasis. We report a rare case of late recurrence after curative resection in a patient treated for T1a early gastric cancer.

[Right Hemi-Colectomy for a Metastatic Transverse Colon Tumor from Breast Cancer Following Bilateral Breast Cancer Resection - A Case Report].

We herein report the case of a 75-year-old female patient who underwent 4 surgeries for bilateral breast cancer and its recurrence. When she presented at a clinic with an irritable colon, a fist-sized tumor was palpated in the right upper abdomen at her first medical examination. Abdominal CT scan at the clinic revealed a tumor with a maximum diameter of 10 cm on the right side of the transverse colon and multiple swollen mesenteric lymph nodes. Therefore, the patient was referred to our hospital for surgery. Colonoscopy revealed stenosis of the same lesion with an edematous mucosa and sclerosis. Using immunohistochemistry, a biopsy specimen from the lesion tested positive for CK AE1+AE3, and negative for CD20(-)and CD3 (-). As a result, the tumor was diagnosed as a poorly differentiated adenocarcinoma. We performed right hemicolectomy to avoid her intestinal obstruction. Tumor cells were mainly present at the subserosa, according to HEstaining. Using immunostaining, the cells were tested for the following markers: CDX2(-), GCDFP15(weakly positive), CK7(strongly positive), CD20(partially positive), E R(+), PgR(-), and HER2(1+), characterizing the tumor as metastasis of breast cancer. Although gastro-intestinal metastasis from breast cancer is rare, and colon metastasis is even rarer, it might be necessary to rule out the possibility of a metastatic colon tumor from breast cancer when treating patients with a colon tumor who have undergone surgery for breast cancer.

Deletions in the cytoplasmic domain of iRhom1 and iRhom2 promote shedding of the TNF receptor by the protease ADAM17.

The protease ADAM17 (a disintegrin and metalloproteinase 17) catalyzes the shedding of various transmembrane proteins from the surface of cells, including tumor necrosis factor (TNF) and its receptors. Liberation of TNF receptors (TNFRs) from cell surfaces can dampen the cellular response to TNF, a cytokine that is critical in the innate immune response and promotes programmed cell death but can also promote sepsis. Catalytically inactive members of the rhomboid family of proteases, iRhom1 and iRhom2, mediate the intracellular transport and maturation of ADAM17. Using a genetic screen, we found that the presence of either iRhom1 or iRhom2 lacking part of their extended amino-terminal cytoplasmic domain (herein referred to as ΔN) increases ADAM17 activity, TNFR shedding, and resistance to TNF-induced cell death in fibrosarcoma cells. Inhibitors of ADAM17, but not of other ADAM family members, prevented the effects of iRhom-ΔN expression. iRhom1 and iRhom2 were functionally redundant, suggesting a conserved role for the iRhom amino termini. Cells from patients with a dominantly inherited cancer susceptibility syndrome called tylosis with esophageal cancer (TOC) have amino-terminal mutations in iRhom2. Keratinocytes from TOC patients exhibited increased TNFR1 shedding compared with cells from healthy donors. Our results explain how loss of the amino terminus in iRhom1 and iRhom2 impairs TNF signaling, despite enhancing ADAM17 activity, and may explain how mutations in the amino-terminal region contribute to the cancer predisposition syndrome TOC.

[Pulmonary Mucoepidermoid Carcinoma--A Case Report].

Mucoepidermoid carcinoma (MEC) of the lungs is a rare type of lung cancer, mainly arising from the submucosal salivary type mucous glands of the large bronchi. MEC is classified into low- and high-grade subtypes based on its cytological and histological features, and this classification correlates well with prognosis. We report the case of a 36-year-old man diagnosed after an initial episode of obstructive pneumonia. CT and bronchoscopy revealed an endobronchial mass in the right S3 bronchus and distal atelectasis. Although biopsy is important for deciding the treatment plan, both pre- and intraoperative biopsy resulted in false negativity in this patient. The tumor was completely resected via right upper lobectomy, and the final pathological diagnosis was low-grade MEC. No evidence of disease was found 2 years after the operation without any adjuvant therapy. At (11; 19) translocation with the associated CRTC1-MAML2 fusion oncogene is often recognized in cases of both salivary and pulmonary MEC. It is speculated that MEC is sensitive to EGFR-TKI therapy, which disrupts CRTC1-MAML2-induced proliferation signals via upregulation of the EGFR ligand amphiregulin.

A forward genetic screen to study mammalian RNA interference: essential role of RNase IIIa domain of Dicer1 in 3' strand cleavage of dsRNA in vivo.

RNA interference is a major post-transcriptional regulatory pathway in many eukaryotes. The RNase III enzyme Dicer1 processes precursor RNAs into small RNA duplexes to be loaded onto Argonaute proteins, the effector components of RNA-induced silencing complex. Biochemical studies have shown that the RNase IIIa and RNase IIIb domains of Dicer1 cleave the 3' and 5' strands of dsRNAs, respectively, although the in vivo functional significance of this activity remains unclear. Genetic screening of mammalian cells is useful for studying molecular mechanisms at the cellular level. In the present study, we conducted a novel forward genetic screen for mammalian RNA interference components using Chinese hamster ovary cells and successfully obtained several Dicer1 mutant lines. One mutant bore an intriguing Dicer1 allele in which a conserved glutamic acid in the RNase IIIa domain was substituted with a lysine. Our detailed cell biological study demonstrated that the RNase IIIa domain of Dicer1 was essential for generating small RNAs embedded in the 3' stem of exogenous hairpin-like RNAs. In the mutant cells, the expression of endogenous mature microRNAs derived from the 3' stem of pre-microRNA was repressed more severely than that from the 5' stem. Moreover, appropriate processing and loading of small RNAs were required for the dissociation of Argonaute 2 from Dicer1. The data obtained in the present study demonstrate that this screening method represents a promising strategy for the identification of unknown components of mammalian RNA interference pathways and the study of the biological significance of these components at the cellular level.

iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS.

Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. A key mediator of septic shock is tumor necrosis factor-α (TNFα), which is shed from the plasma membrane after cleavage by the TNFα convertase (TACE). We report that the rhomboid family member iRhom2 interacted with TACE and regulated TNFα shedding. iRhom2 was critical for TACE maturation and trafficking to the cell surface in hematopoietic cells. Gene-targeted iRhom2-deficient mice showed reduced serum TNFα in response to lipopolysaccharide (LPS) and could survive a lethal LPS dose. Furthermore, iRhom2-deficient mice failed to control the replication of Listeria monocytogenes. Our study has identified iRhom2 as a regulator of innate immunity that may be an important target for modulating sepsis and pathogen defense.

TbGPI16 is an essential component of GPI transamidase in Trypanosoma brucei.

Glycosylphosphatidylinositol (GPI) is widely used by eukaryotic cell surface proteins for membrane attachment. De novo synthesized GPI precursors are attached to proteins post-translationally by the enzyme complex, GPI transamidase. TbGPI16, a component of the trypanosome transamidase, shares similarity with human PIG-T. Here, we show that TbGPI16 is the orthologue of PIG-T and an essential component of GPI transamidase by creating a TbGPI16 knockout. TbGPI16 forms a disulfide-linked complex with TbGPI8. A cysteine to serine mutant of TbGPI16 was unable to fully restore the surface expression of GPI-anchored proteins upon transfection into the knockout cells, indicating that its disulfide linkage with TbGPI8 is important for the full transamidase activity.

GPI7 is the second partner of PIG-F and involved in modification of glycosylphosphatidylinositol.

Many eukaryotic cell surface proteins are anchored to the membrane via glycosylphosphatidylinositol (GPI). GPI is synthesized from phosphatidylinositol by stepwise reactions and attached en bloc to nascent proteins. In mammalian cells, the major GPI species transferred to proteins is termed H7. By attachment of an additional ethanolamine phosphate (EtNP) to the second mannose, H7 can be converted to H8, which acts as a minor type of protein-linked GPI and also exists as a free GPI on the cell surface. Yeast GPI7 is involved in the transfer of EtNP to the second mannose, but the corresponding mammalian enzyme has not yet been clarified. Here, we report that the human homolog of Gpi7p (hGPI7) forms a protein complex with PIG-F and is involved in the H7-to-H8 conversion. We knocked down hGPI7 by RNA interference and found that H7 accumulated with little production of H8. Immunoprecipitation experiments revealed that hGPI7 was associated with and stabilized by PIG-F, which is known to bind to and stabilize PIG-O, a protein homologous to hGPI7. PIG-O is a transferase that adds EtNP to the third mannose, rendering GPI capable of attaching to proteins. We further found that the overexpression of hGPI7 decreased the level of PIG-O and, therefore, decreased the level of EtNP transferred to the third mannose. Finally, we propose a mechanism for the regulation of GPI biosynthesis through competition between the two independent enzymes, PIG-O and hGPI7, for the common stabilizer, PIG-F.

GPI transamidase of Trypanosoma brucei has two previously uncharacterized (trypanosomatid transamidase 1 and 2) and three common subunits.

Glycosylphosphatidylinositol (GPI) anchor is a membrane attachment mechanism for cell surface proteins widely used in eukaryotes. GPIs are added to proteins posttranslationally by a complex enzyme, GPI transamidase. Previous studies have shown that human and Saccharomyces cerevisiae GPI transamidases are similar and consist of five homologous components: GAA1, GPI8, PIG-S, PIG-T, and PIG-U in humans and Gaa1p, Gpi8p, Gpi17p, Gpi16p, and Cdc91p in S. cerevisiae. We report that GPI transamidase of Trypanosoma brucei (Tb), a causative agent of African sleeping sickness, shares only three components (TbGAA1, TbGPI8, and TbGPI16) with humans and S. cerevisiae but has two other specific components, trypanosomatid transamidase 1 (TTA1) and TTA2. GPI transamidases of both bloodstream form (growing in mammalian blood) and procyclic form (growing in tsetse fly vector) of the parasite have the same five components. Homologues of TTA1 and TTA2 are present in Leishmania and Trypanosoma cruzi but not in mammals, yeasts, flies, nematodes, plants, or malaria parasites, suggesting that these components may play unique roles in attachment of GPI anchors in trypanosomatid parasites and provide good targets for antitrypanosome drugs.