Targeted Metabolite Fingerprints of Thirteen Gambierdiscus, Five Coolia and Two Fukuyoa Species.

The genus Gambierdiscus produces an array of bioactive hydrophilic and lipophilic secondary metabolites that range in mode of action and toxicity. In this study, the metabolite fingerprint was mapped for thirteen Gambierdiscus, five Coolia and two Fukuyoa species (34 isolates) by assessing the production of 56 characterised secondary metabolites. Gambierdiscus polynesiensis was the only species to produce Pacific-ciguatoxin-3B (P-CTX3B), P-CTX3C, iso-P-CTX3B/C, P-CTX4A, P-CTX4B and iso-P-CTX4A/B. G. australes produced maitotoxin-1 (MTX-1) and MTX-5, G. cheloniae produced MTX-6 and G. honu produced MTX-7. Ubiquitous production of 44-methylgambierone was observed amongst all the Gambierdiscus isolates, with nine species also producing gambierone. Additional gambierone analogues, including anhydrogambierone (tentatively described herein), were also detected in all Gambierdiscus species, two Coolia and two Fukuyoa species. Gambieroxide was detected in G. lewisii and G. pacificus and gambieric acid A was detected in ten Gambierdiscus species, with G. australes (CAWD381) being the only isolate to produce gambieric acids A-D. This study has demonstrated that the isolates tested to date produce the known CTXs or MTXs, but not both, and highlighted several species that produced 'unknown' compounds displaying characteristics of cyclic polyethers, which will be the focus of future compound discovery efforts.

Local resection of the stomach for gastric cancer.

The local resection of the stomach is an ideal method for preventing postoperative symptoms. There are various procedures for performing local resection, such as the laparoscopic lesion lifting method, non-touch lesion lifting method, endoscopic full-thickness resection, and laparoscopic endoscopic cooperative surgery. After the invention and widespread use of endoscopic submucosal dissection, local resection has become outdated as a curative surgical technique for gastric cancer. Nevertheless, local resection of the stomach in the treatment of gastric cancer in now expected to make a comeback with the clinical use of sentinel node navigation surgery. However, there are many issues associated with local resection for gastric cancer, other than the normal indications. These include gastric deformation, functional impairment, ensuring a safe surgical margin, the possibility of inducing peritoneal dissemination, and the associated increase in the risk of metachronous gastric cancer. In view of these issues, there is a tendency to regard local resection as an investigative treatment, to be applied only in carefully selected cases. The ideal model for local resection of the stomach for gastric cancer would be a combination of endoscopic full-thickness resection of the stomach using an ESD device and hand sutured closure using a laparoscope or a surgical robot, for achieving both oncological safety and preserved functions.

[Remission of Advanced Gastric Cancer with Concurrent Portal Vein Tumor Thrombosis via Chemotherapy - A Case Report].

The following is a case report of moderately differentiated tubular adenocarcinoma of the stomach with widespread thrombosis of the portal vein, for which chemotherapy proved effective. A 75-year-old man presented to the clinic with a new onset ofmalaise. The patient had anemia, elevation ofliver and biliary enzymes, and significantly elevated CA19-9 levels at 43,581 U/mL and CEA levels at 2,560 ng/mL. An upper endoscopy revealed a mass lesion extending from the fundus to the pylorus as well as to the duodenum along the smaller curvature of the stomach. A biopsy revealed moderately differentiated tubular adenocarcinoma. Abdominal CT showed a mass lesion extending from the body of the stomach and penetrating through the gastric wall, and extensive lymphadenopathy in the surrounding areas. In addition, multiple thromboses were identified in the portal vein and its tributaries, including the inferior mesenteric vein, splenic vein, and intrahepatic capillaries. The patient subsequently received a single round ofS -1 and CDDP. The tumor demonstrated a marked response; the tumor size and lymphadenopathy showed a significant improvement and the CA19-9 level decreased. Because the patient's condition deteriorated, this chemotherapy regimen was discontinued. The patient was switched to S-1 monotherapy and is still alive today, 2 years 10 months after the initial diagnosis.

[Radical Resection of cT3a Gallbladder Cancer after Neoadjuvant Chemotherapy - A Case Report].

We report a case of a radical resection of cT3a gallbladder cancer after neoadjuvant chemotherapy(NAC). A 68-year-old man was referred to our hospital with a chief complaint of right hypochondralgia.Imaging findings were consistent with acute cholecystitis with a stone at the neck of the gallbladder, and advanced gallbladder cancer with infiltration into segments 4 and 5 from the fundus of the gallbladder, Gfb, cT3a(liver), cN1(8a), cM0, cStage III B, was diagnosed on staging laparoscopy. The patient received 3 courses of GEM plus CDDP NAC.The response to the treatment included reduction of the main tumor by 35%, diminished accumulation of FDG at the 8a lymph node, and decrease in serum CA19-9, from 163 U/mL to 75 U/mL. Cholecystectomy with the gallbladder bed and regional lymphadenectomy were performed.The histologic examination revealed extensive necrosis and degeneration of cancer cells in the infiltrating lesions, and the therapeutic effect was judged as Grade I b.The patient has now survived for 11 months without recurrence.

[Treatment Outcomes of Advanced Gastric Cancer after Neoadjuvant Chemotherapy with S-1 and Cisplatin].

BACKGROUND: The prognosis after neoadjuvant chemotherapy(NAC)is expected to improve in patients with resectable advanced gastric cancer who are at high risk of recurrence or those with unfavorable prognostic factors. PATIENTS AND METHODS: This retrospective study examined treatment outcomes and survival of 25 patients with advanced gastric cancer who received NAC with S-1 and cisplatin(CDDP)between October 2008 and December 2015. RESULTS: Among patients with clinical Stage II (4 patients)and III (21 patients)tumors, 13 had partial response(PR)and 12 had stable disease(SD). Neither complete response(CR)nor progressive disease(PD)was noted. CR of lymph node metastases was observed in 6 patients, PR in 9 patients, and SD in 7 patients. R0 resection was performed in 16 patients, R1 in 3 patients, and R2 in 6 patients. Histologic grades of primary tumors were Grade 0(1 patient), Grade 1a(16 patients), Grade 1b(5 patients), Grade 2(3 patients), and Grade 3(none). The 3-year survival rate after R0 resection was 46%, 3-year progression-free survival rate was 68%, and 3-year recurrence-free survival rate was 69%. Significant differences were observed for pathologic stages ypN0/1, 2, and 3(p=0.04), tumor down-stage(p=0.02), and overall tumor fStage I , II / III , and IV (p<0.01). CONCLUSION: It is conceivable that R0 resection and downstaging after NAC will improve prognosis.

[Clinical Analysis of Esophageal Bypass Surgery with Nutritional Assessment in Patients with Unresectable Esophageal Cancer].

BACKGROUND: Esophageal bypass surgery is palliative surgery for unresectable esophageal cancer with esophageal stenosis, which often leads to poor nutrition. We investigated the clinical characteristics, nutritional status, and outcomes of patients who underwent esophageal bypass surgery. PATIENTS AND METHODS: We reviewed 11 cases of esophageal bypass surgery for unresectable esophageal cancer performed in our hospital between 1992 and 2015, and we examined the surgical outcome along with preoperative nutritional assessment. RESULTS: There were 1, 9, and 1 cases of cStage Ⅲ, Ⅳa, and Ⅳb, respectively. For the bypass, a gastric tube was used in 8 cases and colon reconstruction in 3. Postoperative complications were 1 case of recurrent laryngeal nerve palsy (9%), 4 cases of anastomotic leakage (36%), and 4 cases of pneumonia (36%). The preoperative nutritional status (total protein, albumin, and cholinesterase levels) in the esophageal bypass group (n=11) was significantly worse than that in the esophagectomy group (n=40). The median survival of all patients (n=11) was 5.7 months. Patients receiving induction chemoradiotherapy followed by bypass surgery (n=7) had a median survival of 15.2 months. CONCLUSION: Since patients undergoing esophageal bypass surgery often present with malnutrition, attention to anastomotic leakage and infectious complications is necessary.

[A Case of Gastric and Pancreatic Cancer Resected with Curative Intent while Preserving Organ Function].

A 57-year-old woman was diagnosed with a pancreatic tumor. Abdominal computed tomography showed cStage Ⅳa pancreatic cancer with a 20×16 mm tumor near the base of the celiac artery. Since the tumor contacted the SMA at an angle of 90 degrees, it was judged as a borderline resectable tumor. In addition, cStage ⅠB gastric cancer was found in the corpus ventriculi. Since the patient had a respiratory complication, a distal pancreatectomy with celiac axis resection in combination with a total gastrectomy was considered too aggressive for this patient. Therefore, she received chemoradiotherapy prior to the surgery. Distal pancreatectomy with D2 lymphadenectomy and subtotal gastrectomy with lower left phrenic artery preservation was performed. This case involved a considerable extension of the disease and radical surgery; however, currently the patient's prognosis and QOL are good.

[A Successful Case of Treatment of Colonic Metastasis and Peritoneal Recurrence of Type 4 Gastric Cancer by Using Colectomy and Chemotherapy].

We present a successful case of treatment of colonic metastasis and peritoneal recurrence of type 4 gastric cancer by using colectomy and chemotherapy. A 70-year-old woman with a diagnosis of type 4 advanced gastric cancer underwent distal gastrectomy. The final pathological diagnosis was LM, circ, type 4, sig, pT4a (SE), ly1, v1, pN1, M0, P0, CY0, pStage Ⅲa. Adjuvant chemotherapy was conducted with oral administration of S-1, though regrettably the chemotherapy was interrupted because of diarrhea, an adverse effect of S-1. Metastatic recurrence occurred on the transverse colon, for which she underwent transverse colectomy 2.9 years after the initial surgery. Another colonic metastasis in the ascending colon along with peritoneal recurrence was diagnosed 3.11 years after the initial surgery, and the patient underwent a palliative colostomy and received chemotherapy with S-1 plus docetaxel. She was successfully treated up to a clinical CR with chemotherapy, and she died 5.10 years after the initial surgery. In this case, a good prognosis was obtained through the combination of resection of the recurrence sites, palliative surgery for avoiding obstruction, and chemotherapy using S-1 plus docetaxel for metachronous multiple metastases.

[A patient with invasive carcinoma derived from IPMN who achieved long-term survival despite lymph node metastasis].

A woman in her 70s was referred for examination of liver dysfunction. A cystic lesion with irregular contrast was observed at the pancreas head. The bile and pancreatic ducts were obstructed by the lesion. Part of the branch of the pancreatic duct at the pancreas head, continuous with the main pancreatic duct, was observed to be extended by using pancreatography. Pancreaticoduodenectomy was performed, and a diagnosis of invasive carcinoma from an intraductal papillary-mucinous neoplasm (IPMN) was made. Postoperative pathological diagnosis showed 16b1 inter-node metastasis. Liver and lung metastases were also detected after surgery; nevertheless, long-term survival was achieved for 5 years and 2 months by using various treatment modalities.

[Evaluation of combination chemotherapy with docetaxel and nedaplatin in patients with advanced or recurrent esophageal cancer].

BACKGROUND: There is no standard regimen after failure of 5-fluorouracil and cisplatin-based first-line chemotherapy in patients with advanced or recurrent esophageal cancer. The feasibility of combination chemotherapy with docetaxel (DOC) and nedaplatin (CDGP) for these patients was retrospectively evaluated. METHODS: Patients received DOC (30 mg/m² intra- venously) and CDGP (30-40 mg/m² intravenously) on days 1 and 15 of each 4-week period. The efficacy and toxicity of combination chemotherapy with DOC and CDGP in 13 patients was analyzed. RESULTS: The patients received a median of 2 cycles of treatment(range, 1-23). The response and disease control rates were 8% and 54%, respectively. Grade 3 or 4 hematological toxicities were neutropenia, anemia, and thrombocytopenia, observed in 4(31%), 11(15%), and 2 patients (15%), respectively. Non-hematological toxicity, anorexia, was detected in only 1 patient(8%). No treatment-related death was observed. The median progression-free survival and overall survival were 3.2 and 11.6 months, respectively. CONCLUSIONS: Combination chemotherapy with DOC and CDGP is considered a feasible regimen for refractory esophageal cancer.

[Evaluation of conversion gastrectomy for treatment of Stage IV advanced gastric cancer].

BACKGROUND: The standard treatment for Stage IV advanced gastric cancer (AGC) is systemic chemotherapy. Because patients who respond to induction chemotherapy seem to have a good prognosis, we converted the treatment strategy to gastrectomy( termed as conversion gastrectomy) in such patients. In this study, we estimated the outcomes of patients who underwent conversion gastrectomy for Stage IV AGC. METHODS: We evaluated patients with Stage IV AGC who underwent conversion gastrectomy from October 2008 through September 2012 and retrospectively analyzed their clinicopathological variables and oncologic outcomes. RESULTS: Twenty patients underwent conversion gastrectomy with an R0 resection rate of 45% (9/20). The median survival time (MST) was 18.0 months overall and did not differ significantly between patients with clinically stable disease( SD) and those with a partial response( PR)( 22.0 months vs 18.0 months, p=0.64). The MST was longer in patients with pathological Grade 1b-3 tumors than in those with Grade 1a tumors (47.8 months vs 16.3 months), and this difference was significant (p=0.04). Patients with R0 resection had a significantly longer MST than those with R1-2 ( 47.8 months vs 14.1 months ). CONCLUSIONS: The present study provides evidence that patients with Stage IV AGC who undergo conversion gastrectomy with a histopathological response have a good prognosis and that R0 resection predicts longer survival.

[A case of jejnal cancer who was controlled peritoneal metastasis, successfully by combination therapy with docetaxel and S-1].

The patient was a 60-year-old man who had been admitted to our hospital because of elevated serum CA19-9 levels. Endoscopy revealed a Borrmann type 2 tumor of the jejunum. Computed tomography (CT) revealed lymph node metastases and peritoneal seeding. Hence, he was diagnosed with advanced jejunal cancer with distant metastasis (T4N1M0 stage). We performed partial resection of the jejunum, and he underwent chemotherapy with docetaxel( DOC) and S-1 for the peritoneal seeding postoperatively. Follow-up CT revealed that the chemotherapy was effective, and the patient achieved complete remission following 9 months of treatment.

[Surgical resection of multiple liver metastases of rectal neuroendocrine tumors].

We report a case of surgically resected multiple liver metastases of rectal neuroendocrine tumors (NET), which could not be controlled by medical treatment. A 66-year-old man was diagnosed as having multiple liver metastases of rectal NET 5 years after the initial diagnosis. Although we performed 5 rounds of transcatheter arterial infusion (TAI) and administered 4 cycles of 5-fluorouracil, Leucovorin, and oxaliplatin( mFOLFOX6), the metastasis gradually spread. The patient was admitted to our hospital to undergo hepatectomy. Extended right hepatectomy and partial resection of the lateral segment were performed. The pathological diagnosis was metastasis of rectal NET and it was classified as grade 2 NET according to the 2010 World Health Organization (WHO) classification. The patient received intramuscular injections of sustained-release octreotide( 30 mg every 4 weeks) after surgery. One year and 2 months after surgery, he shows no signs of recurrence.

Long-term survival by surgery and adjuvant chemotherapy in a patient with perforated extranodal NK/T-cell lymphoma of the small intestine: a retrospective case study.

BACKGROUND: Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) of the small intestine, is a disease with extremely poor prognosis. We describe treatment in a case which is novel in that it demonstrated long-term survival. CASE PRESENTATION: A 68-year-old man was admitted to the emergency department of our hospital with the complaint of severe umbilical pain with tenderness and muscular defense. An abdominal computed tomography scan revealed a thick-wall mass on the small intestine and intra-abdominal free air. He was suspected of perforation of a small intestinal tumor and underwent emergency surgery. The surgery revealed a perforated tumor ulcer, and ENKL was diagnosed from the postoperative pathological findings. The patient's postoperative course was uneventful. He was further treated with adjuvant chemotherapy by hematologist comprising six courses of dexamethasone, etoposide, ifosfamide, and carboplatin. The patient demonstrated long-term survival and was in remission at the time of writing, four years and five months after surgery. CONCLUSIONS: We report a rare case of long-term survival of perforated ENKL of the small intestine achieved by surgery and adjuvant chemotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin. It is essential to consult with a hematologist to determine the most appropriate chemotherapy such as DeVIC if one encounters rare postoperative pathological findings of ENKL. To elucidate the pathophysiology of this disease and to prolong survival of affected patients, accumulation of cases of long-term survival and examination of associated characteristics is necessary.

[A case of port site recurrence after thoracoscopic resection for lung metastasis of cecal cancer].

We experienced a case of port site recurrence after thoracoscopic resection for lung metastasis of cecal cancer. The patient was a 57-year-old woman who underwent right hemicolectomy at the age of 51 following a diagnosis of cecal carcinoma. She underwent video-assisted thoracic surgery for pulmonary metastasis 2 years after the first surgery. She underwent local resection for a retroperitoneal pelvic wall recurrence 3.5 years after the first surgery. Chest wall port site recurrence occurred 5.5 years after the first surgery, and she underwent partial resection of the left lung and chest wall. Subsequent treatment has been performed with adjuvant chemotherapy, and she is healthy with no evidence of recurrence 7 years and 11 months after the initial surgery. In this case, a good prognosis was obtained by frequent local resection and adjuvant chemotherapy for metachronous multiple metastases.

[A case of gastric endocrine cell carcinoma that responded to chemotherapy with CPT-11+CDDP].

A 57-year-old male patient was referred to our department with a diagnosis of #3 lymph node recurrence of early gastric cancer after treatment of endoscopic submucosal dissection (ESD). The pathological diagnosis of the ESD specimen was neuroendocrine cell carcinoma of the stomach with positive immunohistochemical staining of chromogranin A. The diameter of the tumor was 10 mm and the depth of invasion was pSM2. Distal partial gastrectomy with standard lymph node dissection (D2) was performed. The pathological findings were negative for malignancy in the resected stomach and positive in 2 of the #3 lymph nodes. Adjuvant chemotherapy of S-1 was administered, but a recurrence in the paraaortic lymph nodes was revealed by follow up X-ray computed tomography (X-CT) 3 months later. The case was considered as a S-1 failure, and the chemotherapy was changed to the irinotecan(CPT-11) +cisplatin(CDDP). A clinical complete response (CR) was obtained after two courses and maintained for up to twenty months.

[A case of drug resistant recurrent gastrointestinal stromal tumor treated surgically by resection, partial hepatectomy and diaphragmectomy].

This 69-year-old man underwent a partial jejunectomy for gastrointestinal stromal tumor(GIST) at the age of 60, and subsequently hepatectomy of segment 5, 6, 7 for liver metastasis of GIST a year later. An irregular mass close to the cutting stump of the liver, and a mass that showed enhanced-effect at segment 4 was discovered 28 months after hepatectomy. In order to treat this second recurrence, we administered imatinib and sunitinib sequentially. The tumor subsequently became drug-resistant, so we removed it surgically together with the liver and a portion of right diaphragm, and a tumor in segment 4. The patient shows no recurrent sign 4 months after surgery. This case suggests that surgical resection should be considered for partially drug resistant GIST.

Toxicity and growth characteristics of epiphytic dinoflagellate Gambierdiscus silvae in Japan.

The genus Gambierdiscus is a marine benthic/epiphytic dinoflagellate that has been investigated worldwide as the causative agent of ciguatera poisoning (CP). In Japan, CP occurs mainly in the subtropical region and sporadically in the temperate region. To understand the mechanism of CP outbreaks in the coastal regions, identifying the species of Gambierdiscus occurring in the regions and determining their toxicity and growth characteristics, such as growth responses to temperature, salinity, and light intensity, are important. Recently, the occurrence of G. silvae in the Japanese temperate and subtropical regions has been revealed through metabarcoding. However, the toxicity and growth characteristics of G. silvae have not yet been investigated. In this study, three strains of Gambierdiscus were isolated from a depth of 30 m in subtropical waters in Japan and were identified as Gambierdiscus silvae based on morphological characteristics and phylogenetic positions. A dichloromethane soluble fraction (DSF) and aqueous methanol soluble fraction (MSF) of the three strains showed high mouse toxicity by intraperitoneal injection, but only the DSF of the three strains showed toxicity by gavage. All strains grew in the range of 17.5-30 °C and salinity range of 25-40, and grew well at 25 °C and salinity 30. The optimal light intensity for growth of the strains was 42.0-83.0 µmol photons/m2/s. These results suggest that G. silvae has the potential to be widely distributed from temperate to subtropical/ regions and in shallow to deep coastal waters of Japan. Understanding the growth characteristics of this species would be useful in predicting the occurrence of this species in Japanese coastal waters. Finally, the results obtained in this study suggest that G. silvae showing high toxicity is one of the causative agents of CP in Japan, and knowledge of this species would be useful in understanding the mechanism of CP outbreaks in Japan.

Horizontal and vertical distribution of Gambierdiscus spp. (Dinophyceae) including novel phylotypes in Japan identified by 18S rDNA metabarcoding.

The genus Gambierdiscus is a marine benthic/epiphytic dinoflagellate considered the causative agent of ciguatera poisoning (CP). Clarifying the geographical distribution of this genus to understand the potential risk of CP is important. Many studies have focused only on the species/phylotype composition of Gambierdiscus in shallow waters, but no study has investigated the species/phylotype composition of the genus in deep waters. In the present study, the distributions of Gambierdiscus species/phylotypes at two depths (2-8 and 30 m) and two sampling sites (temperate and subtropical) in Japan was investigated using high throughput sequencing (HTS) with a newly developed primer set that preferentially amplifies the 18S rDNA V8-V9 region of Alveolata. A phylogenetic analysis using 89 samples collected over three years revealed of ten Gambierdiscus species/phylotypes including not only two species that have not been reported in Japan (G. caribaeus and G. silvae) but also four novel phylotypes (Gambierdiscus spp. Clade II_1, Clade II_2, Clade II_3, and Clade VI_1). Uncorrected genetic distances also supported that these new phylotypes clearly diverged from other Gambierdiscus species. All four new phylotypes, G. caribaeus, and G. silvae were distributed in the subtropical region. Among them, Clade II_2, Clade VI_1, and G. silvae were also distributed in the temperate region. Four species/phylotypes previously reported from Japan showed a similar distribution as reported previously. Among the ten species/phylotypes, Gambierdiscus sp. type 3 and Clade VI_1 were found only in deep waters, whereas five species/phylotypes were observed only in shallow waters. The other three species/phylotypes were found in both deep and shallow waters. The results of the horizontal and vertical distribution suggest that the growth characteristics of each species/phylotypes found in Japan might adapt to the ambient environmental conditions. This study revealed an inclusive assemblage of Gambierdiscus species/phylotypes in Japan through metabarcoding using the Alveolata primer set. In the future, the abundance and toxicities/toxin productions of the newly reported species/phylotypes need to be clarified to understand the mechanism of CP outbreaks in Japan.

[A case of Castleman disease with status epileptics originating from focal cortical dysplasia].

A 55-year-old man was admitted to our hospital because of prolonged consciousness disturbance after generalized convulsions. He had been afflicted with chronic inflammatory symptoms since 43 years of age, while multiple abdominal lymphadenopathy with a high level of serum IL-6 was revealed at the age of 53. FDG-PET/CT showed hypermetabolism in the left medial portion of the frontal lobe. Biopsy specimens of this lesion revealed a pathology of focal cortical dysplasia (FCD). Non-convulsive status epileptics continued despite enhanced treatment with antiepileptic drugs, while cortical T2 hyperintense lesions developed and expanded. Castleman disease was confirmed by pathological findings of abdominal lymph node biopsy specimens. The patient showed a higher level of IL-6 in cerebrospinal fluid (1,400 pg/dl) than in serum (720 pg/dl), thus indicating intrathecal production of this proinflammatory cytokine. We concluded that continuous exposure of FCD tissue to IL-6 may have augmented epileptogenesis of the originally silent congenital lesion.