Long-term survival of HER2 positive gastric cancer patient with multiple liver metastases who obtained pathological complete response after systemic chemotherapy: A case report.

INTRODUCTION AND IMPORTANCE: Advanced gastric cancer with liver metastasis is classified as stage IV disease and is generally treated with systemic chemotherapy. Despite recent advances in chemotherapy regimens, the prognosis for gastric cancer with liver metastasis is poor. Recent studies reported the effectiveness of upfront chemotherapy followed by conversion surgery for gastric cancer with liver metastasis. Here, we report a case of an advanced stage IV gastric cancer with liver metastasis treated with upfront systemic chemotherapy followed by conversion surgery, which resulted in pathological complete response and good prognosis. CASE PRESENTATION: A 79-year-old man diagnosed with human epidermal growth factor receptor type 2 (HER2)-positive gastric cancer with multiple liver metastases. He underwent systemic chemotherapy with capecitabine, cisplatin, and trastuzumab. After 14 courses of chemotherapy, the primary tumor and liver metastases shrank, suggesting a partial response. We performed distal gastrectomy with D2 dissection plus lateral hepatic segment resection. Pathological examination revealed no residual tumor cells in the primary or metastatic sites, which indicated a pathological complete response. The postoperative course was uneventful. The patient was discharged on postoperative day 8. Adjuvant S-1 chemotherapy was started on postoperative day 46 and given for 1 year. The patient has been alive and recurrence-free for approximately 5 years after surgery. CONCLUSION: This case shows the possibility of conversion surgery after systemic chemotherapy for stage IV advanced gastric cancer with liver metastasis.

[A Case of Complete Response to Chemotherapy and Radical Resection of Unresectable Advanced Gastric Cancer].

The patient was a 75-year-old woman who was referred to our department because she had type 3 advanced gastric cancer on the posterior wall of the gastric body. Following a thorough examination, she was diagnosed as cT4aN3M1 (#16a1 int, #16b2 lat), cStage Ⅳ, an unresectable advanced gastric cancer with multiple extranodal lymph node metastases. As radical resection was not possible, chemotherapy(SOX therapy)was started. After the start of chemotherapy, the main lesion and metastatic lymph nodes shrank markedly. At the time of 7 courses, it was judged that R0 resection by conversion surgery was possible, and surgical treatment was performed. The patient underwent sub-total gastrectomy with D2 dissection and para-aortic lymph node dissection. The specimen was submitted for pathological examination and showed no residual tumor component including the main lesion and dissected lymph nodes, indicating a complete pathological response. She was started on S-1 as adjuvant chemotherapy on postoperative day 51 and has been recurrence-free for approximately 5 months after surgery.

[Deviation of Peripherally Inserted Central Catheter(PICC)during Total Parenteral Nutrition(TPN)for a Gastric Cancer Patient-A Case of Report].

A 90s woman was diagnosed as having cT4aN2M0, cStage ⅢA, advanced gastric cancer. As she was severely malnourished owing to pyloric stenosis, a peripherally inserted central catheter (PICC)was placed in her left arm, and total parenteral nutrition(TPN)was initiated. She complained of dyspnea, and radiography revealed right pleural effusion on day 4 of TPN. Contrast computed tomography revealed that the tip of the catheter had perforated the vessel wall of the superior vena cava and had migrated into the mediastinal space. After thoracocentesis, the catheter was removed under fluoroscopic guidance after hemostasis was achieved. Thus, the possibility of catheter deviation should be considered in case of dyspnea and pleural effusion during TPN.

[A Long-Term Survival Case of Locally Advanced Unresectable Pancreatic Adenocarcinoma after Chemoradiotherapy and Conversion Surgery].

A 62-year-old man was referred to our hospital with complaints of upper abdominal pain and weight loss while being treated for diabetes mellitus at his family doctor. He was diagnosed as locally advanced unresectable pancreatic adenocarcinoma that involved superior mesenteric artery(SMA). Gemcitabine(GEM)and S-1 combined chemoradiotherapy(CRT) was administered. After CRT, CT test showed improved involvement of SMA, and radical resection was possible. We performed the radical pancreaticoduodenectomy and adjuvant chemotherapy, and he has been followed up for more than 5 years after the operation without recurrence. For locally advanced unresectable pancreatic adenocarcinoma, CRT or chemotherapy is recommended in the Pancreatic Cancer Practice Guidelines(2019 edition). However, the prognosis is extremely poor. We report a case of locally advanced unresectable pancreatic adenocarcinoma that was successfully curatively resected due to the good response of CRT.

[A Case of Cholangiocellular Carcinoma in Lynch Syndrome Treated by an Immune Checkpoint Inhibitor].

We report a case of cholangiocellular carcinoma(CCC)with high-frequency microsatellite instability(MSI-H)in Lynch syndrome that was managed using a multimodal treatment approach including an immune checkpoint inhibitor. The patient was a 74-year-old man who presented with fever as the chief complaint. He had a history of Vater's papilla cancer and colorectal cancer in Lynch syndrome. A diagnosis of CCC in the left lobe of the liver was made, and left hepatectomy and left caudate lobectomy were performed. From about 2 years and 5 months after the operation, the patient developed several episodes of cholangitis, and recurrence of CCC was diagnosed based on the results of biliary cytology. Gemcitabine and cisplatin therapy was started, but exacerbation of bile duct stenosis associated with cancer progression was observed, and pembrolizumab, an immune checkpoint inhibitor, was started as the solid cancer had an MSI-H status. The tumor markers then improved and the cholangitis subsided. We experienced a case of recurrence of CCC with MSI-H in Lynch syndrome managed by multimodal treatment including an immune checkpoint inhibitor.

[Laparoscopic Liver Resection for Cholangiolocellular Carcinoma-A Single Institutional Experience].

Cholangiolocellular carcinoma(CoCC)was first reported by Steiner et al in 1959. CoCC resembles cholangiocellular carcinoma( CCC)grossly and presents a variety of imaging findings, which often makes preoperative diagnosis difficult. In Japan, CoCC is rare, accounting for only 0.56% of primary liver cancers. We report the results of laparoscopic liver resection (LLR)for CoCC at our institution. Among 845 liver resections(678 LLR and 167 open liver resections)performed at Kansai Rosai Hospital from 2010 to 2020, only 13 were CoCC. Eight patients underwent LLR except for 5 patients who required vascular reconstruction and lymph node dissection. Median age was 71 years (55-77), gender was male/female(7/1), stage was Ⅰ/Ⅱ/Ⅲ/ⅣA(3/3/1/1), liver function was Child-Pugh A/B/C(7/1/0), and liver damage A/B/C(6/2/0). The preoperative diagnosis was 1 CoCC, 3 CCC and 4 HCC. The operative procedure was 3 Hr 0, 3 Hr 1 and 2 Hr 2. The operative time was 342 minutes(168-488), the blood loss was 51.3 g(0-400), and the postoperative hospital stay was 14 days(5- 53). The 5-year disease-free survival rate was 83.3%, and the 5-year overall survival rate was 85.7%. Recurrence was seen in 1 patient. The 5-year survival rate after curative resection of CoCC has been reported to be 73-83%, compared with 28- 36% for CCC. LLR for CoCC at our institution showed good perioperative results. Long-term results were comparable to those reported for liver resection. LLR for CoCC was considered an appropriate technique with good perioperative and long- term results.

[Short-Term Outcomes of Laparoscopic Surgery for Gallbladder Cancer-A Single Institutional Experience].

INTRODUCTION: Laparoscopic surgery is a safe, minimally invasive, and effective approach in managing abdominal malignancies. Laparoscopic anatomical resection has been covered by insurance in Japan since 2016. Here, we have reported the short-term outcomes of gallbladder cancer in laparoscopic cholecystectomy, gallbladder bed resection, or S4a/S5 liver resection with lymph node dissection. PATIENTS: Between May 2012 and December 2020, 28 patients underwent laparoscopic cholecystectomy for gallbladder cancer at Kansai Rosai Hospital. Two patients underwent laparoscopic choledochotomy with lymph node dissection, 6 patients underwent gallbladder bed resection, and 7 patients underwent S4a/S5 liver resection. The control group included 13 patients who received open surgery between July 2010 and November 2019. The patient age was 74.2 and 74.4 years, while the male to female ratio was 19/24 and 8/5 in the laparoscopic and open surgery groups, respectively. According to the Japanese Society of Hepato-Biliary-Pancreatic Surgery, the pathological stage was 0/Ⅰ/Ⅱ/Ⅲ A/ⅢB/ⅣA/ⅣB in 4/17/13/4/2/1/2 and 0/1/2/3/1/1/5 patients(p=0.0100)in the laparoscopic and open surgery groups, respectively. This study was approved by the Human Ethics Review Committee of Kansai Rosai Hospital(Certificate Number: 2101001). RESULTS: The laparoscopic surgery group had an average operation time of 223.3 minutes, an estimated blood loss of 18.7 g, and a hospital stay of 8.5 days. The open surgery group had an average operation time of 514.5 minutes, an estimated blood loss of 1,274.3 g, and a hospital stay of 33.9 days. There was no postoperative bleeding or bile leakage in both groups. After laparoscopic cholecystectomy, the 5-year disease-free survival rate was 100% among Stage 0 or Ⅰ patients, 64.8% among Stage Ⅱ patients, and 0% in Stage Ⅲ or Ⅳ patients. The 5-year overall survival rate was 100% among Stage 0 or Ⅰ patient and 66.7% among Stage Ⅱ patients. The 1-year overall survival rate was 50% among Stage Ⅲ or Ⅳ patients. After laparoscopic liver resection with lymph node dissection, the 5-year disease-free survival rate was 100% among Stage Ⅰ or Ⅱ patients and 66.7% among Stage Ⅲ or Ⅳ patients. The 5-year overall survival rate was 100% among Stage Ⅰ or Ⅱ patients and 62.5% among Stage Ⅲ or Ⅳ patients. CONCLUSION: Laparoscopic cholecystectomy in Stage 0 or Ⅰ patients and laparoscopic gallbladder bed resection or S4a/S5 liver resection with lymph node dissection were safe and effective approaches to gallbladder cancer management.

Synthesis and Biological Evaluation of Cyclopentaquinoline Derivatives as Nonsteroidal Glucocorticoid Receptor Antagonists.

The steroidal glucocorticoid antagonist mifepristone has been reported to improve the symptoms of depression. We report the discovery of 6-(3,5-dimethylisoxazol-4-yl)-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one 3d (QCA-1093) as a novel nonsteroidal glucocorticoid receptor antagonist. The compound displayed potent in vitro activity, high selectivity over other steroid hormone receptors, and significant antidepressant-like activity in vivo.

Cuprizone short-term exposure: astrocytic IL-6 activation and behavioral changes relevant to psychosis.

A growing body of evidence suggests the involvement of inflammatory processes in the pathophysiology of schizophrenia. Four- to 8-week exposure to cuprizone, a copper chelator, causes robust demyelination and has been used to build a model for multiple sclerosis. In contrast, we report here the effects of 1-week cuprizone exposure in mice. This short-term cuprizone exposure elicits behavioral changes that include augmented responsiveness to methamphetamine and phencyclidine, as well as impaired working memory. The cellular effects of 1-week cuprizone exposure differ substantially from the longer-term exposure; perturbation of astrocytes and microglia is induced without any sign of demyelination. Furthermore, the proinflammatory cytokine interleukin-6 was significantly up-regulated in glial fibrillary acidic protein (GFAP)-positive cells. We propose that this cuprizone short-term exposure may offer a model to study some aspects of biology relevant to schizophrenia and related conditions.

The 5-HT1A receptor agonist MKC-242 reverses isolation rearing-induced deficits of prepulse inhibition in mice.

RATIONALE: Prepulse inhibition (PPI) of startle provides an operational measure of sensorimotor gating in which a weak stimulus presented prior to a startling stimulus reduces the startle response. PPI deficits observed in schizophrenia patients can be modeled in rats by individual housing from weaning until adulthood. The deficits in PPI produced by isolation rearing can be reversed by antipsychotics. We previously found that (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242), a highly potent 5-HT(1A) receptor agonist, reduced aggressive behavior selectively in isolation-reared mice. OBJECTIVE: This study examines whether isolation rearing of mice produces PPI deficits and whether PPI deficits are attenuated by 5-HT(1A) receptor activation. METHODS: Male ddY mice, 4 weeks old, were housed for more than 6 weeks singly or in groups of five or six. The PPI of the acoustic startle response was measured using SR-LAB systems. RESULTS: The PPI was less in isolation-reared mice than in group-reared mice. Oral administration of MKC-242 at 0.1-0.3 mg/kg reversed PPI deficits in isolation-reared mice, although it did not affect PPI in group-reared mice. MKC-242 did not affect MK-801-induced and apomorphine-induced PPI deficits in group-reared mice. The reversal by MKC-242 of isolation-induced PPI deficits was antagonized by the 5-HT(1A) receptor antagonist WAY100635 at low doses. CONCLUSION: These results suggest that isolation rearing produces deficits in sensorimotor gating in mice that are reversible by activation of 5-HT(1A) receptors, probably somatodendritic 5-HT(1A) autoreceptors.

The 5-HT1A receptor agonist MKC-242 increases the exploratory activity of mice in the elevated plus-maze.

The effect of (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242), a 5-HT(1A) receptor agonist, on mouse behavior was examined in the elevated plus-maze. MKC-242 significantly increased the percentage of open-arm entries and the percentage of open-arm time, indices of anxiety reduction, while it did not increase the enclosed-arm entries and time spent in enclosed arms. The effect of MKC-242 was antagonized by a low dose of the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide which alone did not affect the behavior. These findings suggest that MKC-242 increases the exploratory activity of mice in the elevated plus-maze via activation of 5-HT(1A) receptors, probably the presynaptic autoreceptors.

Modulation by 5-hT2A receptors of aggressive behavior in isolated mice.

The present study examines whether isolation-rearing affects sensitivity of 5-hydroxytryptamine (5-HT)2A receptors and the functional interaction between 5-HTIA and 5-HT2A receptors in mice. The 5-HT2A-receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI)-induced head twitch response was significantly greater in isolated mice than in grouped mice. DOI increased isolation-induced aggressive behavior, and the 5-HT2A-receptor antagonist ritanserin decreased it. The 5-HTIA-receptor agonist (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242) inhibited the DOI-enhanced aggressive behavior. MKC-242 inhibited DOI-induced head twitch response. These findings suggest that 5-HT2A receptors play a role in aggressive behavior in isolated mice and imply that the antiaggressive effect of MKC-242 may be mediated partly by the inhibition of 5-HT2A-receptor function.