Multicenter phase II study of capecitabine plus oxaliplatin in older patients with advanced gastric cancer: the Tokyo Cooperative Oncology Group (TCOG) GI-1601 study.

BACKGROUND: Capecitabine plus oxaliplatin (CapeOX) is a standard treatment option for advanced gastric cancer (AGC). We conducted a prospective multicenter phase II study to evaluate the efficacy and safety of CapeOX as a first-line therapy for AGC in older patients. METHODS: Chemotherapy-naive patients aged ≥ 70 years with AGC were eligible. Initial treatment comprised capecitabine (2000 mg/m2 on days 1-14) and oxaliplatin (130 mg/m2 on day 1) every 3 weeks. After the initial feasibility assessment, the dose was reduced considering toxicity (capecitabine, 1500 mg/m2 on days 1-14; and oxaliplatin, 100 mg/m2 on day 1 every 3 weeks). The primary endpoint was overall survival (OS). RESULTS: In total, 108 patients were enrolled, of whom 104 were evaluated. Thirty-nine patients received the original-dose treatment, whereas 65 received the reduced-dose treatment. The median OS, progression-free survival (PFS), and time to treatment failure (TTF) were 12.9 (95% CI 11.6-14.8), 5.7 (95% CI 5.0-7.0), and 4.3 (95% CI 3.9-5.7) months, respectively, for all patients; 13.4 (95% CI 9.5-16.0), 5.8 (95% CI 4.1-7.8), and 5.3 (95% CI 3.5-7.2) months in the original-dose group; and 12.8 (95% CI 11.3-15.3), 5.7 (95% CI 4.4-7.0), and 4.1 (95% CI 3.7-5.7) months in the reduced-dose group. The most common grade 3/4 toxicities were neutropenia (17.9%), anemia (12.8%), and thrombocytopenia (12.8%) in the original-dose group and neutropenia (13.8%) and anorexia (12.3%) in the reduced-dose group. CONCLUSIONS: These findings demonstrate CapeOX's efficacy and safety in older AGC patients.

[A case of pancreatic cancer with clusters of invasive micropapillary carcinoma markedly reduced by chemotherapy].

A man in his 60s was hospitalized with multiple cerebral infarctions and referred for Trousseau's syndrome. Computerized tomography confirmed a 60-mm mass in the pancreatic head and swollen lymph nodes around the abdominal aorta. Fine needle aspiration cytology of the pancreatic lesion and laparoscopic para-aortic lymph node biopsy revealed adenocarcinoma, including clusters of invasive micropapillary carcinoma (IMPC). Chemotherapy (gemcitabine and nab-paclitaxel) markedly decreased the primary and metastatic lesions, and no recurrence was clinically detected 24 months later. To the best of our knowledge, reports of pancreatic IMPCs are rare. Our case was the seventeenth case of pancreatic cancer with IMPC. In this case, chemotherapy was markedly effective.

The effects of the herbal medicine Daikenchuto (TJ-100) after esophageal cancer resection, open-label, randomized controlled trial.

BACKGROUND: Daikenchuto (TJ-100), a traditional Japanese herbal medicine, is widely used in Japan. Its effects on gastrointestinal motility and microcirculation and its anti-inflammatory effect are known. The purpose of this prospective randomized controlled trial was to investigate the effect of TJ-100 after esophagectomy in esophageal cancer patients. METHODS: Forty patients for whom subtotal esophageal resection for esophageal cancer was planned at our institute from March 2011 to August 2013 were enrolled and divided into two groups at the point of determination of the operation schedule after informed consent was obtained: a TJ-100 (15 g/day)-treated group (n = 20) and a control group (n = 20). The primary efficacy end-points were maintenance of the nutrition condition and the recovery of gastrointestinal function. The secondary efficacy end-points were the serum C-reactive protein (CRP) level and adrenomedullin level during the postoperative course, the incidence of postoperative complications, and the length of hospital stay after surgery. RESULTS: We examined 39 patients because one patient in the TJ-100 group was judged as having unresectable cancer after surgery. The mean age of the TJ-100 group patients was significantly older than that of the control group patients.The rate of body weight decrease at postoperative day 21 was significantly suppressed in the TJ-100 group (3.6% vs. the control group: 7.0%, p = 0.014), but the serum albumin level was not significantly different between the groups. The recovery of gastrointestinal function regarding flatus, defecation, and oral intake showed no significant between-group differences, but postoperative bowel symptoms tended to be rare in the TJ-100 group. There was no significant between-group difference in the length of hospital stay after surgery. The serum CRP level at postoperative day 3 was 4.9 mg/dl in the TJ-100 group and 6.9 mg/dl in the control group, showing a tendency of a suppressed serum CRP level in the TJ-100 group (p = 0.126). The rate of increase in adrenomedullin tended to be high postoperatively, but there was no significant difference between the two groups. CONCLUSIONS: TJ-100 treatment after esophageal cancer resection has the effects of prompting the recovery of gastrointestinal motility and minimizing body weight loss, and it might suppress the excess inflammatory reaction related to surgery.

CXCR4 Expression is Associated with Poor Prognosis in Patients with Esophageal Squamous Cell Carcinoma.

BACKGROUND: Chemokines and their receptors are known to play important roles in the tumorigenesis of many malignancies. The chemokine CXCL12 and its receptors CXCR4 and CXCR7 were suggested to be involved in cancer invasion and metastasis. The aim of this retrospective study was to evaluate the prognostic impact of the expressions of CXCL12, CXCR4 and CXCR7 in patients with esophageal squamous cell carcinoma (ESCC). METHODS: We used immunohistochemistry (IHC) and reverse transcriptase-polymerase chain reaction (RT-PCR) to evaluate the expressions of CXCL12, CXCR4, and CXCR7 in ESCC patients' tumor biopsy specimens obtained during preoperative endoscopy or surgery. These results were compared with the patients' clinicopathological parameters and survival. RESULTS: IHC was conducted for 172 patients. High expression of CXCR4 in the cytoplasm and nuclei and that of CXCR7 were associated with poor cause-specific survival (CSS) (P= .002 and .010, respectively). The specimens from 52 of the 172 patients were examined by RT-PCR and quantitative real-time PCR. The expression levels of messenger RNA (mRNA) of CXCR4 and CXCR7 were significantly increased in the tumors compared with normal esophageal mucosae (P < .0001). The expression level of mRNA of CXCR4 was associated with poor recurrence-free survival and CSS (P = .012 and .038, respectively). CONCLUSIONS: CXCR4 expression is associated with poor prognosis in patients with ESCC.

[Tension Hemothorax Associated with Spontaneous Rupture of the Thoracic Aorta;Report of a Case].

A 94-year-old woman was admitted to our hospital with sudden onset of chest pain without any episode of trauma. Computed tomography(CT) revealed left massive pleural effusion and extravasation of contrast medium from the side chest wall to the back. Neither aortic aneurysm nor dissection was evident. During the investigation, the patient went into hypovolemic shock. Hemothorax due to bleeding from an intercostal artery was diagnosed, and emergency surgery was performed. A 1-mm hole was detected in the descending aorta, and closed by a single suture. The final diagnosis was spontaneous rupture of the thoracic aorta. Three-dimensional CT (3D-CT), reconstructed postoperatively, revealed extravasation of the contrast medium from the descending aorta. The postoperative course was satisfactory, and the patient was discharged on the 20th postoperative day. 3D-CT may be useful for identifying the source of bleeding in such cases.

Aldehyde dehydrogenase 1 expression is associated with poor prognosis in patients with esophageal squamous cell carcinoma.

BACKGROUND: Aldehyde dehydrogenase 1 (ALDH1) and CD44 act as important biomarkers in several solid tumors. However, few studies have examined the relationships between ALDH1 expression and the prognosis and clinical characteristics of esophageal squamous cell carcinoma (ESCC). METHODS: This study was a retrospective case-control study and included 152 patients with ESCC. A total of 56 patients underwent surgery (OP group), 40 patients received neoadjuvant chemotherapy involving weekly docetaxel plus 5-fluorouracil and low-dose cisplatin (DFP therapy) prior to undergoing surgery (NAC group), and 56 patients received initial systemic DFP therapy (CT group). The ALDH1 and CD44 immunohistochemical expression levels of each tumor were evaluated and compared with the prognosis and clinical characteristics of the ESCC patients. RESULTS: In the OP and NAC groups, multivariate analysis found that ALDH1 was independently associated with postoperative recurrence and prognosis (OP group, P=0.004 and 0.016, respectively; NAC group, P=0.026 and 0.014, respectively). In addition, CD44 was found to be associated with postoperative recurrence in the OP group and prognosis in the NAC group (P=0.024 and 0.047, respectively). Among the ALDH1-negative clinical stage II/III patients, the OP and NAC groups displayed better prognoses than the CT group (P<0.001). However, among the ALDH1-positive clinical stage II/III patients, the OP and NAC groups displayed poorer prognoses than the CT group (P=0.049). CONCLUSIONS: ALDH1 was found to be a predictor of postoperative recurrence and prognosis in ESCC, and CD44 might be a predictor of recurrence and prognosis. ALDH1 expression might affect the treatment strategy for ESCC.

Primary syphilis presenting as a painful unilateral inguinal lymphadenopathy, without cutaneous manifestations, in a 71-year-old Japanese man: A case report.

Syphilitic infection is usually observed in young patients, and the first stage of the disease (primary syphilis) is characterized by painless cutaneous and lymph node lesions. Herein, we describe a 71-year-old Japanese man with primary syphilis that presented as unilateral inguinal lymphadenopathy without skin lesions. Originally, an incarcerated hernia was clinically suspected. The lymph node pathologically showed suppurative lymphadenitis with vague granulomas; immunohistochemistry was highly suggestive of a syphilitic infection. Primary syphilis was confirmed by positive serological tests. Syphilitic infection should be included in the clinicopathological differential diagnoses for patients with inguinal lymphadenopathy, even in elderly patients without skin lesions.

Stone removal by percutaneous papillary balloon dilatation for cystic duct and bile duct stones after cholecystectomy and distal gastrectomy with Roux-en-Y gastrojejunostomy.

A 71-year-old woman was referred to our department for abdominal pain. She was diagnosed with acute obstructive cholangitis due to cystic duct and bile duct stones after cholecystectomy and Roux-en-Y gastrojejunostomy. Two years ago, the patient underwent endoscopic and laparoscopic treatment for cystic duct and bile duct stones, however, the stones remained. This time, she was treated with stone removal using percutaneous papillary balloon dilatation (PPBD). Large stones in the common hepatic and bile ducts were crushed by electrohydraulic lithotripsy and then pushed out into the duodenum through the dilated papilla of Vater using a balloon catheter covered with the sheath and cholangioscopy. Stone in the cystic duct was pulled to the common bile duct and pushed to the duodenum. Stone removal using PPBD is an excellent alternative for patients with cystic duct and bile duct stones unable to be treated with endoscopic or laparoscopic stone removal.

Navigation by modified and dynamic intraoperative cholangiography during laparoscopic subtotal cholecystectomy for difficult gallbladder.

We used modified and dynamic intraoperative cholangiography (IOC) navigation during laparoscopic subtotal cholecystectomy for difficult gallbladders. We have defined an IOC that does not open the cystic duct as a modified IOC. Modified IOC methods include the percutaneous transhepatic gallbladder drainage (PTGBD) tube method, the infundibulum puncture method, and the infundibulum cannulation method. Case 1 was chronic cholecystitis after PTGBD for acute cholecystitis with pericholecystic abscess. In this case, modified IOC was performed via PTGBD, and biliary anatomy and incarcerated stone were confirmed. Case 2 was chronic cholecystitis after endoscopic sphincterotomy for cholecystocholedocholithiasis. In this case, modified IOC was performed via gallbladder puncture needle, and biliary anatomy and incision line were confirmed. The target point on the laparoscopic image was determined by moving the tip of the grasping forceps under modified IOC, which we call modified and dynamic IOC. We conclude that the navigation by the modified and dynamic IOC via PTGBD tube or puncture needle is useful to identify biliary anatomy, incarcerated gallbladder stone, and safe incision line during laparoscopic subtotal cholecystectomy .

Robot-assisted total remnant gastrectomy for interposed jejunal pouch dysfunction 25 years after proximal gastrectomy for gastric cancer: A case report.

Proximal gastrectomy (PG) in combination with jejunal pouch interposition is a technique aimed at improving the postoperative dietary outcomes; however, some cases are reported to require surgical intervention owing to difficulty of food intake caused by pouch dysfunction. Herein, we present a case of robot-assisted surgery for interposed jejunal pouch (IJP) dysfunction in a 79-year-old male, occurring 25 years after the initial PG for gastric cancer. The patient had chronic anorexia for 2 years and was treated with medications and dietary guidance; however, 3 months prior to admission his quality of life had reduced, owing to worsening symptoms. The patient was diagnosed with pouch dysfunction due to extremely dilated IJP identified using computed tomography and underwent robot-assisted total remnant gastrectomy (RATRG) with IJP resection. After an uneventful course of intraoperative and postoperative treatment, he was discharged with sufficient food intake on postoperative day 9. RATRG can, thus, be considered in patients with IJP dysfunction after PG.

Identification and verification of communicating accessory bile duct associated with a biliary circuit by modified and dynamic intraoperative cholangiography during laparoscopic cholecystectomy.

Communicating accessory bile duct (CABD) is a rare anatomical anomaly of the bile duct and forms a biliary circuit. It is difficult to identify during laparoscopic cholecystectomy (LC) without the use of intraoperative cholangiography (IOC). A modified IOC, in which tube insertion was performed through the infundibulum of the gallbladder, was evaluated dynamically. This procedure allowed us to accurately identify and verify the presence of CABD, a biliary circuit, and the short cystic duct. The short cystic duct could be separated safely without damaging the biliary circuit. Modified and dynamic IOC is recommended for identifying and verifying the presence of CABD during LC.

Prognosis of esophageal squamous cell carcinoma in patients positive for human epidermal growth factor receptor family can be improved by initial chemotherapy with docetaxel, fluorouracil, and cisplatin.

BACKGROUND: The human epidermal growth factor receptor (HER) family, Ki-67 and p53 are important biomarkers for several malignancies. However, few studies have examined the role of these in prognosis and therapeutic sensitivity of esophageal squamous cell carcinoma (ESCC). The efficacy of triple-drug combination therapy with docetaxel, fluorouracil and cisplatin has recently been expected for ESCC. METHODS: Subjects comprised 142 patients with ESCC who underwent operation (OP group, n = 54), neoadjuvant chemotherapy with docetaxel, fluorouracil, and cisplatin (DFP therapy) followed by operation (NAC group, n = 37) or initial systemic DFP therapy (CT group, n = 51) between January 2004 and December 2010. Immunohistochemical expressions of epidermal growth factor receptor (EGFR), HER2, HER3, Ki-67, and p53 were evaluated and compared with prognosis and sensitivity to DFP therapy. RESULTS: Positive correlations existed between EGFR, HER2, and HER3 expressions. In the OP group, EGFR was independently associated with postoperative recurrence in multivariate analysis (P = .036). In the NAC group, EGFR correlated with pathological response to DFP therapy (P = .004). In the CT group, EGFR, HER2, and HER3 correlated with clinical response to DFP therapy and EGFR was independently associated with favorable prognosis in multivariate analysis (P = .022). CONCLUSION: EGFR represents a predictor of postoperative recurrence and sensitivity to triple-drug combination therapy including a taxane. EGFR-positive patients may show improved prognosis with taxane combination chemotherapy and molecular targeted therapy for HER family members.

Sentinel lymph node biopsy using intraoperative indocyanine green fluorescence imaging navigated with preoperative CT lymphography for superficial esophageal cancer.

BACKGROUND: The sentinel lymph node (SLN) concept has been gaining attention for gastrointestinal neoplasms but remains controversial for esophageal cancer. This study evaluated the feasibility of SLN identification using intraoperative indocyanine green (ICG) fluorescence imaging (IGFI) navigated by preoperative computed tomographic lymphography (CTLG) to treat superficial esophageal cancer. METHODS: Subjects comprised 20 patients clinically diagnosed with superficial esophageal cancer. Five minutes after endoscopic submucosal injection of iopamidol around the primary lesion using a four-quadrant injection pattern with a 23-gauge endoscopic injection sclerotherapy needle, three-dimensional multidetector computed tomography was performed to identify SLNs and lymphatic routes. ICG solution was injected intraoperatively around the tumor. Fluorescence imaging was obtained by infrared ray electronic endoscopy. Thoracoscope-assisted standard radical esophagectomy with lymphadenectomy was performed to confirm fluorescent lymph nodes detected by CTLG. RESULTS: Lymphatic vessels and SLNs were identified preoperatively using CTLG in all cases. Intraoperative detection rates were 100% using CTLG and 95% using IGFI. Lymph node metastases were found in four cases, including one false-negative case with SLNs occupied by bulky metastatic tumor that were not enhanced with both methods. The other 19 cases, including three cases of metastatic lymph nodes, were accurately identified by both procedures. CONCLUSIONS: Preoperative CTLG visualized the correct number and site of SLNs in surrounding anatomy during routine computed tomography to evaluate distant metastases. Referring to CTLG, SLNs were identified using IGFI, resulting in successful SLN navigation and saving time and cost. This method appears clinically applicable as a less-invasive method for treating superficial esophageal cancer.

Stepwise partial splenic embolization for portal hypertension based on a new concept: Splanchnic caput Medusae.

Management of splenomegaly with thrombocytopenia is important in the treatment of portal hypertension. We propose a new concept: "Splanchnic Caput Medusae" in which enlarged spleen is her face and portal collateral pathways are her snake hairs. We report 2 demonstrable cases who were treated based on this new concept. Case 1 with refractory esophageal varices and splenomegaly was treated by stepwise partial splenic embolization (PSE) and endoscopic injection sclerotherapy with ligation. Spleen/liver volume ratio changed from 0.33 to 0.10. Hepatic venous pressure gradient changed from 19 to 14 mmHg. Case 2 with mesenteric shunt and splenomegaly was treated by stepwise PSE and retrograde obliteration. Spleen/liver volume ratio changed from 0.70 to 0.05. Hepatic venous pressure gradient changed from 11 to 7 mmHg. In these 2 cases, 3D-CT reconstruction images after treatment revealed that spleen- portal system reversed almost to normal form. We conclude that splenomegaly and portal collateral pathways could be considered as "Splanchnic Caput Medusae" and have to be treated by stepwise PSE.

Sarcoidosis-lymphoma syndrome with portal hypertension: diagnostic clues and approach.

Sarcoidosis-lymphoma syndrome associated with portal hypertension is very rare. A 68-year-old female presented with a 5 kg weight loss in 6 months. Soluble interleukin-2 receptor activity was increased and total platelet count was decreased. Contrast-enhanced computed tomography showed the presence of hepatosplenomegaly and a 3 cm-sized tumor in segment 3 of the liver. The hepatic venous catheterization showed mild portal hypertension. On fluorodeoxyglucose-positron emission tomography/computed tomography, progressive malignant lymphoma was suspected. However, bone marrow biopsy showed multiple noncaseating granulomas. A laparoscopic liver biopsy revealed that the liver tumor had features of Hodgkin lymphoma. There were multiple noncaseating epithelioid granulomas in the portal tracts of the liver. Splenectomy for splenomegaly and partial hepatectomy for the liver tumor were performed. Pathological examination of the resected specimens revealed multiple noncaseating epithelioid granulomas in the liver and spleen. Histopathology of the liver tumor confirmed classic Hodgkin lymphoma with mixed cellularity. We conclude that hepatic venous catheterization, positron emission tomography/computed tomography, and pathological examinations of bone marrow, liver, and spleen are crucial for the diagnosis of sarcoidosis-lymphoma syndrome associated with portal hypertension.

Flood syndrome managed by partial splenic embolization and percutaneous peritoneal drainage.

Flood syndrome is a rare complication of cirrhosis of liver accompanied by ascites and a sudden rupture of umbilical hernia causing drainage of ascitic fluid from abdominal cavity. We report management of a case of Flood syndrome which was caused by rupture of incisional hernia. The clinical picture was similar to well described and widely accepted Flood syndrome. A 70-year-old female with decompensated hepatitis C cirrhosis was transported to the emergency department with a sudden drainage of ascitic fluid after sudden dehiscence of pre-existing incisional hernia and diffuse abdominal tenderness. Initially, she was managed by applying ostomy bag and diuretics to reduce the ascites. On 8th day of admission, a 16 Fr. drain was percutaneously placed in the left lower abdominal quadrant to divert the fluid from the abdominal wall defect. On 13th day, 80% partial splenic embolization (PSE) was attempted to control portal hypertension to reduce the ascites volume. After PSE, the hepatic venous pressure gradient reduced from 28 to 21cm H2O. The peritoneal drain was removed on 16th day and she was discharged on 22nd day. We conclude that PSE and temporary percutaneous peritoneal drainage are useful option to manage Flood syndrome.

Hemoperitoneum and sepsis from transhepatic gallbladder perforation of acute cholecystitis: A case report.

We report a case of hemoperitoneum and sepsis from transhepatic gallbladder perforation in an 87-year-old male with acute cholecystitis who had past history of endoscopic sphincterotomy for common bile duct stone. Contrast-enhanced computed tomography (CT) showed intrahepatic and subcapsular low density areas. A wall defect of gallbladder was seen in coronal and sagittal - sections at the liver bed. Fluids obtained through the paracentesis were hemorrhagic. Percutaneous transhepatic gallbladder drainage (PTGBD) was attempted. First cholangiography revealed an orifice of fistula. Further injection of contrast medium drained into the intrahepatic secondary abscess and intraperitoneal cavity confirming the diagnosis of transhepatic gallbladder perforation. We conclude that contrast-enhanced CT with coronal and sagittal - sections and cholangiography via PTGBD tube are useful to confirm diagnosis of transhepatic gallbladder perforation.

Triterpenes augment the inhibitory effects of anticancer drugs on growth of human esophageal carcinoma cells in vitro and suppress experimental metastasis in vivo.

The antineoplastic effects of combinations of anticancer drugs (5-fluorouracil, irinotecan and cisplatin) and triterpenes (ursolic acid, betulinic acid, oleanolic acid and a Japanese apricot extract (JAE) containing triterpenes) on esophageal squamous carcinoma cells were examined by the WST-8 (2-(2-methoxy- 4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt) assay in vitro and by an animal model in vivo. Triterpenes and JAE showed additive and synergistic cytotoxic effects, respectively, on esophageal squamous carcinoma cells (YES-2 cells) by combinational use of 5-fluorouracil. JAE and 5-fluorouracil induced cell cycle arrest at G2/M phase and at S phase, respectively, and caused apoptosis in YES-2 cells. A new animal model of esophageal cancer causing tumor colonization of the peritoneal cavity and producing bloody ascites was made by injecting YES-2 cells into the peritoneal cavity of a severe combined immunodeficiency mouse. In this model, 5-fluorouracil inhibited colonization of tumor cells in the peritoneum. The addition of JAE to 5-fluorouracil augmented the suppression of experimental metastasis of the peritoneum. The numbers of peritoneal nodules of more than 2 mm in diameter in mice treated with 5-fluorouracil and JAE were less than those in mice treated with 5-fluorouracil alone or JAE alone. These results suggest that triterpenes, especially JAE, are effective supplements for enhancing the chemotherapeutic effect of 5-fluorouracil on esophageal cancer.