[Analysis of Chemotherapy-Induced Nausea and Vomiting during Chemotherapy for Gastric Cancer].

BACKGROUND: Chemotherapy-induced nausea and vomiting(CINV)are typical side effects caused by chemotherapy. We analyzed CINV during first-line chemotherapy for gastric cancer. MATERIALS AND METHOD: Thirty-one patients who received first-line chemotherapy for gastric cancer were retrospectively assessed for CINV. RESULTS: The median age was 70 years, and the gender(male/female)was 23/8 cases. NK1 receptor antagonist, 5-HT3 receptor antagonist, and dexamethasone were used as antiemetic agents in 29 patients(94%). Sixteen patients(52%)had Grade 1 or higher nausea, and 6 patients (19%)had Grade 1 or higher vomiting, and complete control of nausea and vomiting was achieved in 21 patients(68%). Nausea was significantly more frequent in patients with liver metastasis(p=0.0008), but there was no significant difference in vomiting(p=1.0000). There was no significant difference in the occurrence of CINV between chemotherapy regimens or combination of olanzapine. CONCLUSION: During first-line chemotherapy for gastric cancer, 3 antiemetic agents were used in 94% of cases, and the complete control rate of CINV was 67.8%.

[A Case of Early Gastric Cancer with Adachi Type â ¥ Vascular Anomaly Treated by Laparoscopic Distal Gastrectomy].

We report a case of early gastric cancer with Adachi Type Ⅵ vascular anomaly treated by laparoscopic distal gastrectomy. An 81-year-old woman was admitted because of anorexia, and was diagnosed with early gastric cancer. Preoperative MDCT revealed Adachi Type Ⅵ vascular anomaly, where the hepatic artery does not appear at the superior border of the pancreas. The patient was treated successfully with laparoscopic distal gastrectomy with D1+lymph node dissection. At surgery, we identified the portal vein, then, dissection of No. 8a lymph nodes was performed. The postoperative course was uneventful and the patient was discharged 10 days after surgery. The final pathology result showed gastric cancer, M, Less, Type 0-Ⅱc+Ⅲ, 58×50 mm, tub1>pap, pT1a(M), Ly0, V0, pN0(0/40), H0, P0, M0, pStage ⅠA. We understand the arterial running pattern before surgery by using MDCT, and performed laparoscopic surgery safely.

[Two Cases of Advanced Gastric Cancer with Para‒Aortic Lymph Node Metastasis or Recurrence for Which Nivolumab Therapy Were Effective].

A 74‒year‒old man was diagnosed with advanced gastric cancer with para‒aortic lymph node metastasis and ascites. He has been treated with S‒1 plus oxaliplatin as the primary treatment, paclitaxel plus ramucirumab as the secondary treatment and CPT‒11 as the third‒line treatment, but the effect of all treatments were temporary and left adrenal metastasis appeared during the course. Nivolumab was started as the fourth‒line treatment. Two months later, para‒aortic lymph nodes and left adrenal metastasis were markedly shrank and ascites disappeared. A 79 years old woman was performed proximal gastrectomy for advanced gastric cancer of the upper stomach. S‒1 therapy was started as adjuvant chemotherapy, but tumor markers have been increased and para‒aortic lymph node recurrence was observed 4 months after the operation. After ramucirumab as the primary treatment was ineffective, nivolumab was started as the secondary treatment. Two months later, para‒aortic lymph nodes shrank below the significant size and tumor markers were normalized.

[A Case of Advanced Gastric Cancer Successfully Treated with mFOLFOX6 Therapy].

We report a case of advanced gastric cancer that was successfully treated with mFOLFOX6 therapy. A 78-year-old man presented to our hospital with a chief complaint of weight loss. Esophagogastroduodenoscopy(EGD)and computed tomography( CT)revealed the presence of type 3 advanced gastric cancer with distant lymph node metastasis and peritoneal dissemination. Biopsy specimen examination revealed moderately differentiated adenocarcinoma with a HER2 score of 1. Chemotherapy comprising 5-fluorouracil, Leucovorin, and oxaliplatin(mFOLFOX6)was administered because of renal failure. Subsequently, the gastric lesion, distant lymph node metastasis, and peritoneal dissemination were seen to be reduced on EGD and CT. After 7 courses, the regimen was changed to 5-fluorouracil and Leucovorin(5-FU/l -LV)chemotherapy because of thrombocytopenia. For more than 10 months, he has continued to receive chemotherapy without the recurrence of metastasis.

[A Case of Gastrointestinal Submucosal Tumor with an Intraluminal Growth Pattern Resected by Laparoscopic Wedge Resection].

We report a case of gastrointestinal submucosal tumor with an intraluminal growth pattern resected by laparoscopic wedge resection. A 62-year-old man was admitted because of melena. Upper gastrointestinal endoscopy revealed gastrointestinal submucosal tumor with an intraluminal growth pattern just below the gastric junction, and the pathological diagnosis was GIST. A laparoscopic wedge resections(percutaneous endoscopic intragastric surgery)was performed by a single access port. After laparotomy 5 cm above the umbilicus, the anterior wall of the middle part of the stomach was incised and fixed to the skin, and the tumor was dissected with a linear stapler. The final pathology result showed a high risk GIST of 70×40 mm with 110 mitotic images/50 HPF, and the patient was treated with imatinib mesylate adjuvant chemotherapy. There were no complications, including postoperative transit disturbances, and there were no local or distant metastatic recurrences.

[Surgical Resection of the Lymph Node Metastasis after Liver Resection for Hepatocellular Carcinoma].

A 76-year-old man had undergone right lobectomy after transcatheter arterial chemoembolization(TACE)for hepatocellular carcinoma(HCC)in segment 5/6 of the liver. He had undergone TACE for intrahepatic recurrence in segment 1 eight months after the operation. Abdominal CT revealed intrahepatic recurrence in segment 2 and segment 3 and a hepatic portal lymph node swelling 13 months after the operation, he underwent TACE and radiofrequency ablation for intrahepatic lesions. There was neither intrahepatic recurrences nor new extrahepatic lesions, and the hepatic portal lymph node resection was performed. He was discharged on postoperative day 8, and there has been no subsequent recurrence over 42 months after initial treatment. The lymph node metastasis of HCC is rare and systemic chemotherapy such as molecular targeted argent is the standard treatment, but its prognosis is poor. When a patient has a resectable metastasis with controlled intrahepatic lesions, lymph node resection appears to be an effective option.

[A Case of Rapidly Progressive Gallbladder Cancer Presented with Gallbladder Hemorrhage].

A 96-year-old woman was brought to our hospital for epigastric pain. Abdominal contrast-enhanced CT and MRCP showed wall thickness of the fundus and extravasation in the gallbladder. With a diagnosis of gallbladder hemorrhage from the tumors, we performed laparoscopic cholecystectomy. The histopathological diagnosis was gallbladder cancer. Herein, we report on this case and also provide a literature review.

[Laparoscopic Repair of Incarcerated Diaphragmatic Hernia as a Complication of Left Hepatectomy for Liver Cancer].

We report a case of laparoscopic repair of a diaphragmatic hernia after left hepatectomy for liver cancer. A woman in her 70s had undergone left hepatectomy for liver cancer 9 months earlier, and she was admitted because of epigastric pain after vomiting immediately following contrast-enhanced CT. On the next day, contrast-enhanced CT revealed an incarcerated diaphragmatic hernia, for which laparoscopic diaphragmatic hernia repair was performed. The incarcerated stomach was pushed back into the abdominal cavity, and the diaphragm was closed with 2-0 proline sutures. Gastric resection was not performed because the blood flow gradually improved. The postoperative course was good; the patient was discharged on the 7th postoperative day and is under outpatient follow-up.

[A Case of Late-Onset Recurrent Rectal Cancer Associated with Anal Fistulas].

A 71-year-old man underwent laparoscopic lower anterior resection(D3 dissection)for rectal cancer and bilateral lung metastases. Histopathological findings indicated Ra, type 2, tub2, ly0, v2, pN0, pM1(PUL1), pStage Ⅳ. The lung metastases had disappeared after postoperative chemotherapy and the patient entered cCR. Two years after the surgery, the patient's anal fistulas appeared sclerotic. Biopsy revealed recurrent rectal cancer. We performed an abdominoperineal resection and rectus abdominis muscle flap. Currently, the patient is alive at 9 months after surgery with no re-recurrence.

[A Case of Recurrence in the Lateral Pelvic Lymph Node after Local Excision of Lower Rectal pT1a Cancer].

The patient was a man in his 70s who visited our hospital to undergo an examination for fecal occult blood, which detected a 20 mm, Ⅱa lesion in the lower rectum on colonoscopy. He was diagnosed with SM-invasive cancer and was planned to undergo trans-anal local excision. After the surgery, he had a good postoperative course without complications. The pathological findings were Ⅱa, tub1, 22×16 mm, pT1a(950 mm), int, INF a, ly0, v0, pHM0, pVM0(300 mm). He was followed up after the surgery, but was diagnosed with lateral lymph node recurrence 4 years after a local surgery. The surgery involved right-sided lateral lymphadenectomy with resection of the ureter, spermatic duct, seminal vesicle, and piriformis muscle. He was diagnosed with lymph node metastasis with invasion of the spermatic duct based on pathology. Eight courses of adjuvant chemotherapy containing CapeOX was administered. Unfortunately, primary squamous cell lung cancer was detected, and he died after surgery for recurrence in the second year. It is suggested that it is necessary to note lateral lymph node recurrence on postoperative follow-up for lower rectal cancer at any stage.

[A Case of Pulmonary Metastases of Colon Cancer with Submucosal Invasion].

In general, distant metastasis is uncommon in colorectal submucosal(SM)invasion without lymph node metastasis. We experienced an extremely rare case of synchronous pulmonary metastases for colon cancer in SM invasion. A man in his 70s was seen at the hospital for a positive fecal occult blood test. Colonoscopy revealed 3 lesions in the sigmoid colon and endoscopic mucosalresection revealed 2,000 mm SM invasion in all 3 lesions. Computed tomography showed no signs of distant lymph node or liver metastasis but showed small nodules in both lungs. Radical treatment included laparoscopic anterior resection with lymph node dissection. Histological examination showed no residual tumor in the colon and no lymph node metastasis. Two years after surgery, the number of lung nodules gradually increased and we performed partial resection of the left lung, which was diagnosed as pulmonary metastasis from colon cancer by histological examination. Therefore, we resected the opposite-side pulmonary metastases. The patient has exhibited no other signs of recurrence in the 2 years since the last operation.

[Advanced Gastric Cancer with Liver Metastasis and Para-Aortic Lymph Node Metastases Treated Effectively Using Neoadjuvant CapeOX Therapy].

A 60-year-old man was diagnosed with advanced gastric cancer(cT4a, N1, M1[No. 16LYM], cStage Ⅳ). He was treated with a neoadjuvant chemotherapy of a regimen consisting of capecitabine plus oxaliplatin, followed by distal gastrectomy with D2 and No. 16lymph node dissection and partial hepatectomy of S3 and S6. He had an uncomplicated postoperative course and was discharged early from hospital. Capecitabine was started at POD 40 as an adjuvant chemotherapy. Postoperatively, the histological effect was determined to be Grade 2, and hepatic tumors and lymph nodes showed no residual cancer. He started capecitabine monotherapy as adjuvant chemotherapy. At 10 months postoperatively, the patient was alive and relapse-free.

[A Case of Long-Term Survival of Liver Metastasis from Biliary Carcinoma after Pancreaticoduodenectomy Treated by Multimodal Therapy].

A 73-year-old man underwent a subtotal stomach preserving pancreaticoduodenectomy(SSPPD)for biliary carcinoma without regional lymph node metastasis. Although S-1 was administrated as adjuvant chemotherapy after the operation, the serum CA19-9 level was gradually elevated, and a liver metastasis of 27mm in diameter was detected in Couinaud's segment 8 during chemotherapy. We administrated gemcitabine(GEM)and cisplatin(CDDP)combination therapy(GC therapy). The liver tumor was immediately shrunk to 6mm and kept up the PR state after 15 courses of GC therapy. A stereotactic body radiation therapy(SBRT)was performed 1 year 8 months after the operation. The patient has been alive without recurrence for 4 years since the SBRT. Although systemic chemotherapy is the standard treatment for the recurrence of biliary carcinoma, a loco-regional therapy such as SBRT may be an effective alternative when a patient has a solitary metastasis to the liver with no other evidence of recurrence.

Asymmetric Synthesis of Spiroketals with Aminothiourea Catalysts.

Chiral spiroketal skeletons are found as core structures in a range of bioactive compounds. These natural compounds and their analogues have attracted much attention in the field of drug discovery. However, methods for their enantioselective construction are limited, and easily available optically active spiroketals are rare. We demonstrate a novel catalytic asymmetric synthesis of spiroketal compounds that proceeds through an intramolecular hemiacetalization/oxy-Michael addition cascade mediated by a bifunctional aminothiourea catalyst. This results in spiroketal structures through the relay formation of contiguous oxacycles, in which multipoint recognition by the catalyst through hydrogen bonding imparts high enantioselectivity. This method offers facile access to spiroketal frameworks bearing an alkyl group at the 2-position, which are prevalent in insect pheromones. Optically active (2S,5S)-chalcogran, a pheromone of the six-spined spruce bark beetle, and an azide derivative could be readily synthesized from the bicyclic reaction product.

Ten-Gram-Scale Total Synthesis of the Anticancer Drug Candidate E7130 to Supply Clinical Trials.

E7130 is a novel drug candidate with an exceedingly complex chemical structure of the halichondrin class, discovered by a total synthesis approach through joint research between the Kishi group at Harvard University and Eisai. Only 18 months after completion of the initial milligram-scale synthesis, ten-gram-scale synthesis of E7130 was achieved, providing the first good manufacturing practice (GMP) batch to supply clinical trials. This paper highlights the challenges in developing ten-gram-scale synthesis from the milligram-scale synthesis.

E7386, a Selective Inhibitor of the Interaction between ß-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling.

The Wnt/ß-catenin signaling pathway plays crucial roles in embryonic development and the development of multiple types of cancer, and its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor of the interaction between ß-catenin and CREB binding protein, which is part of the Wnt/ß-catenin signaling pathway, disrupts the Wnt/ß-catenin signaling pathway in HEK293 and adenomatous polyposis coli (APC)-mutated human gastric cancer ECC10 cells. It also inhibited tumor growth in an ECC10 xenograft model and suppressed polyp formation in the intestinal tract of ApcMin /+ mice, in which mutation of Apc activates the Wnt/ß-catenin signaling pathway. E7386 demonstrated antitumor activity against mouse mammary tumors developed in mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice. Gene expression profiling using RNA sequencing data of MMTV-Wnt1 tumor tissue from mice treated with E7386 showed that E7386 downregulated genes in the hypoxia signaling pathway and immune responses related to the CCL2, and IHC analysis showed that E7386 induced infiltration of CD8+ cells into tumor tissues. Furthermore, E7386 showed synergistic antitumor activity against MMTV-Wnt1 tumor in combination with anti-PD-1 antibody. In conclusion, E7386 demonstrates clear antitumor activity via modulation of the Wnt/ß-catenin signaling pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody. SIGNIFICANCE: These findings demonstrate that the novel anticancer agent, E7386, modulates Wnt/ß-catenin signaling, altering the tumor immune microenvironment and exhibiting synergistic antitumor activity in combination with anti-PD-1 antibody.

Discovery of anti-inflammatory clinical candidate E6201, inspired from resorcylic lactone LL-Z1640-2, III.

Inspired by natural product, LL-Z1640-2, clinical candidate, E6201 (22) was discovered in a medicinal chemistry effort through total synthesis. The modification on C14-position to N-alkyl substitution showed to be potent in vitro and orally active in vivo in anti-inflammatory assays.

Combined exposure to dinotefuran and chronic mild stress counteracts the change of the emotional and monoaminergic neuronal activity induced by either exposure singly despite corticosterone elevation in mice.

Dinotefuran (DIN) belongs to the neonicotinoids (NNs), a class of globally applied pesticides originally developed to exhibit selective toxicity in insects. However, several reports have suggested that NNs also exert neurotoxic effects in mammals. We previously demonstrated neurobehavioral effects of DIN on mice under non-stressful conditions. For further toxicity assessments in the present study, we investigated the effects of DIN on mice exposed to stressful conditions. After subacutely administering a no-observed-effect-level (NOEL) dose of DIN and/or chronic unpredictable mild stress (CUMS) to mice, we conducted three behavioral tests (i.e., open field test [OFT], tail suspension test [TST] and forced swimming test [FST]). In addition, serotonin (5-HT) and tryptophan hydroxylase 2 (TPH2) of the dorsal raphe nuclei (DRN) and median raphe nuclei (MRN) and tyrosine hydroxylase (TH) of the ventral tegmental area and substantia nigra (SN) were evaluated immunohistochemically. A NOEL dose of DIN or CUMS alone increased of the total distance in OFT, decreased or increased the immobility time in TST or FST, respectively, and increased the positive intensity of 5-HT and TPH2 in the DRN/MRN, and TH in the SN. These changes were suppressed under the conditions of combined exposure to DIN and CUMS, though the blood corticosterone level was increased depending on the blood DIN values and the presence of CUMS. The present study suggests the multifaceted toxicity of the neurotoxin DIN.

Peripubertal exposure to the neonicotinoid pesticide dinotefuran affects dopaminergic neurons and causes hyperactivity in male mice.

Although neonicotinoid pesticides are expected to have harmful influence on mammals, there is little animal experimental data to support the effect and mechanisms. Since acetylcholine causes the release of dopamine, neonicotinoids may confer a risk of developmental disorders via a disturbance in the monoamine systems. Male mice were peripubertally administered dinotefuran (DIN) referring to no observed effect level (NOEL) and performed behavioral and immunohistological analyses. In an open field test, the total locomotor activity was increased in a dose-dependent manner. The immunoreactivity of tyrosine hydroxylase in the substantia nigra was increased in DIN-exposed mice. These results suggest that exposure to DIN in peripubertal male mice causes hyperactivity and a disturbance of dopaminergic signaling.

Verification of the causal relationship between subchronic exposures to dinotefuran and depression-related phenotype in juvenile mice.

It has been suggested that an increase in the use of pesticides affects neurodevelopment, but there has been no animal experiment showing a causal relation between neonicotinoid pesticides (NNs) and depression. We examined whether dinotefuran (DIN), the most widely used NN in Japan, induces depression. Male mice were administered DIN between 3 and 8 weeks of age, referring to the no-observed-effect level (NOEL). The mice were then subjected to a tail suspension test (TST) and a forced swimming test (FST). After these tests, their brains were dissected for immunohistochemical analyses of serotonin (5-HT). Antidepressant activity in TST and no decrease in 5-HT-positive cells were observed. The subchronic exposure to DIN alone in juvenile male mice may not cause depression-like indication.