[A Study of the Safety of Chemotherapy with Generic Oxaliplatin for the Treatment of Colorectal Cancer].

BACKGROUND: Generic oxaliplatin is widely used in colorectal cancer chemotherapy; however, studies on the adverse events of generic drugs are limited. We investigated the safety of brand-name and generic oxaliplatin used in capecitabine plus oxaliplatin(plus bevacizumab: Bmab)for colorectal cancer treatment. PARTICIPANTS AND METHODS: A total of 86 patients who newly started CAPOX(plus Bmab)between January 2018 and January 2022 were included in this retrospective study, excluding those who changed to generic from the brand-name drug during the chemotherapy course. RESULTS: Forty-seven patients(54.6%)were in the generic drug(GE)group, while 39 patients(45.4%)were in the brand drug(EP)group. No significant difference was observed in the patient characteristics between the GE and EP groups. The median number of oxaliplatin administrations were 4 and 5 cycles in the GE and EP groups, respectively. Neutropenia of Grade 2 or higher was observed in 51.1%(24 patients)and 33.3%(13 patients)in the GE and EP groups, respectively. Hypersensitivity was observed in 14.9%(7 patients)and 7.7%(3 patients)in the GE and EP groups, respectively. CONCLUSION: There were no statistically significant differences between generic and brand-name oxaliplatin in the frequency of adverse events.

[Effects of Conservative or Surgical Treatment of Anastomotic Leakage after Colorectal Surgery].

BACKGROUND: Anastomotic leakage is associated with short- and long-term mortality and an increased risk of local and distant cancer recurrence. This study aimed to investigate the short- and long-term outcomes after surgical or conservative therapy for anastomotic leakage. METHODS: Patients with anastomotic leakage after undergoing colorectal resection between January 2011 and December 2018 were identified and grouped according to the therapy for anastomotic leakage: surgical or conservative. We analyzed the intergroup differences in clinicopathological factors and outcomes. RESULTS: Of the 33 patients with anastomotic leakage, 21(64%)and 12(36%)patients received surgical therapy and conservative therapy, respectively. Patients in the conservative therapy group had a shorter length of hospital stay after the first operation. In patients with UICC Stage Ⅱ/Ⅲ, both overall and recurrence-free survival were significantly worse in those who were treated conservatively than in patients who were surgically treated(p<0.01). CONCLUSION: Conservative therapy for anastomotic leakage could shorten the length of hospital stay, but could negatively affect long-term outcomes.

[A Case of Laparoscopic Gastrectomy for Gastric Cancer Occurring after Coronary Artery Bypass Grafting Using the Right Gastroepiploic Artery].

We present a case of 72-year-old man who was diagnosed with gastric cancer that occurred after coronary artery bypass grafting(CABG)with the right gastroepiploic artery(RGEA). Gastrointestinal endoscopy revealed a 0-Ⅱc lesion at the posterior wall of gastric angle, and diagnosis was cStage Ⅰ(T2N0M0). Cardiac computed-tomography showed an occlusion of the RGEA graft, suggesting that the RGEA graft could be ligated and dissected. Coronary angiography showed no severe stenosis of the right coronary artery, suggesting that coronary revascularization was not necessary. He underwent laparoscopic distal gastrectomy with D2 lymph node dissection. During the operation, the RGEA graft was dissected after clamp test for 20 minutes to confirm no cardiac event. In such cases, it is crucial to consider whether it is possible or not to dissect the RGEA graft and whether to restore the coronary flow with preoperative meticulous examination.

[A Case of Laparoscopic Cholecystectomy(TANKO)for Gallbladder Cancer with Torsion].

Gallbladder torsion is comparatively rare. Gallbladder cancer is found in 1.5% of cases of acute cholecystitis. We report a case of laparoscopic cholecystectomy(TANKO)for gallbladder cancer with torsion. CASE: A 54-year-old woman with epigastric pain underwent enhanced computed tomography. Gallbladder torsion and a tumor at the gallbladder neck were suspected, and ascites was observed. She was diagnosed with gallbladder torsion, and surgery was performed the same day. Intraoperative findings: The gallbladder was movable, minimally attached to the liver bed, rotated 360°around the cystic duct and cystic artery, and appeared necrotic. The torsion was relieved and laparoscopic cholecystectomy(TANKO)was performed. We accidentally perforated the gallbladder and bile leaked out. COURSE: The patient did well postoperatively. Pathological diagnosis revealed gallbladder cancer. DISCUSSION: Gallbladder cancer with torsion has been reported in 14 cases, not including ours. Among these, none were performed using laparoscopic cholecystectomy(TANKO). We believe that laparoscopic cholecystectomy is appropriate for such cases, but the approach must be carefully considered because of the risk of perforation.

[Efficacy of Palliative Radiotherapy for Unresectable Advanced Gastric Cancer with Bleeding].

Bleeding and obstruction negativelyimpact qualityof life for patients with unresectable advanced gastric cancer. There are several choices against bleeding and obstruction such as surgery, endoscopic therapy, radiotherapy and interventional radiology. We report on an 85-year-old woman with StageIV gastric cancer with tumor bleeding. Radiation therapyof 30 Gyin 10 fractions was performed. Anyadverse events were not confirmed. Bleeding or obstruction did not occur for 7 months after radiation therapy. Palliative radiation therapy to gastric cancer can be a reasonable option for patients with unsuitable general conditions for surgical intervention.

[A Case of Gemcitabine and Nab-Paclitaxel Therapy for Multiple Metastatic Pancreatic Cancer].

Pancreatic cancer is one of the leading causes of cancer-related death in Japan. Nab-paclitaxel(nab-PTX)and gemcitabine( GEM)combination chemotherapysignificantlyimproved overall survival in a phase III trial(MPACT). This combination chemotherapyhas become one of the first-line treatments for patients with metastatic pancreatic cancer since December 2014. We report a case of a patient who underwent this chemotherapyfor recurrence of pancreatic head cancer. A 64-yearold man, who underwent curative resection of pancreatic cancer 2 years ago, relapsed with multiple lung metastases and a para-aortic nodal metastasis. The patient was treated with combination chemotherapyof nab-PTX 125mg/m2 plus GEM 1,000mg/m2. He died from carcinomatous pleurisy1 9 months after starting the chemotherapy. The patient skipped scheduled chemotherapyonly3 times due to Grade 3 neutropenia during his clinical course over 19 months. The combination regimen of nab-paclitaxel and gemcitabine is thought to be a well-tolerated and standard treatment for metastatic pancreatic cancer.

[A Case of Giant Liver Metastasis from Gastric Cancer after Surgery for Which Transcatheter Arterial Embolization and Chemotherapy Made Hepatic Resection Possible].

The prognosis of liver metastasis from gastric cancer, which often exhibits incurable factors, is dismal, and no effective therapy exists. We report a case of giant liver metastasis from gastric cancer after surgery, for which transcatheter arterial embolism and chemotherapy(G-SOX)made it possible to perform hepatic resection. The patient was a 78-year-old woman who underwent distal gastrectomy combined with D2 lymphadenectomy at our department in August 2014. She complained of abdominal distension, and a liver metastasis measuring more than 16 cm in diameter was found on computed tomography in April 2015. Transcatheter arterial embolization was performed followed by chemotherapy(9 courses of G-SOX were administered). These therapies were effective, enabling partial hepatic resection to be performed. The patient remains alive and free from recurrence 4 months after surgery. Although no effective therapy exists for liver metastasis from gastric cancer, intensive therapies may enable curative resection.

[Metastatic breast cancer with microangiopathic hemolytic anemia successfully treated by using eribulin].

A 48-year-old woman was diagnosed with metastatic breast carcinoma and multiple bone metastases as well as a brain metastasis in 2004. Multiple bone metastases and brain metastases were also diagnosed in 2005, 2006, and 2010, but she remained stable with the use of chemotherapy and hormonal therapy for about 8 years. In 2013, severe anemia occurred, and the patient was diagnosed with microangiopathic hemolytic anemia (MHA). She was treated with eribulin(1.4 mg/m²), and recovered successfully after treatment. Approximately 8 months have elapsed after initiating the therapy, and there has been no recurrence. MHA associated with breast cancer is very rare, and is regarded as a disease with a poor prognosis. However, eribulin could be a valid treatment for prolonging the survival of patients with MHA associated with breast cancer.

[Squamous cell carcinoma of the anal canal showing complete response after concurrent chemoradiotherapy and S-1 plus mitomycin C - a case report].

The patient was a 65-year-old man who underwent colonoscopy for melena. Following a biopsy, the patient was diagnosed with anal canal squamous cell carcinoma. A computed tomography (CT) scan revealed metastasis to the regional lymph nodes. The proposed treatment regimen comprised radiotherapy combined with S-1 and mitomycin C (MMC). Dur- ing radiotherapy (59.6 Gy in 32 fractions), 10mg/m² MMC was administered, as an intravenous bolus injection, on days 1 and 29. S-1 was administered orally, at a dose of 80 mg/m², on days 1-14 and 29-42. No serious adverse events were observed during chemoradiotherapy; the observed adverse events were leukemia (Grade 2), diarrhea (Grade 1), anorexia (Grade 1), and radiation dermatitis (Grade 1). After 8 weeks of treatment, no tumors, only scar tissue could be detected by using colonoscopy, and a CT scan revealed a remarkable reduction in regional lymph node metastases. The patient achieved a complete response.

[Two cases of surgical resection of rectal gastrointestinal stromal tumor after neoadjuvant therapy with imatinib mesylate].

Case 1: A 58-year-old man who initially presented with diarrhea was diagnosed with rectal gastrointestinal stromal tumor (GIST). The patient initially received neoadjuvant therapy with imatinib mesylate. After imatinib therapy( 400 mg/day) for 23 weeks, the patient's abdominal computed tomography (CT) and magnetic resonance imaging (MRI) scans showed a reduction of approximately 67% in tumor size. He underwent sphincter-preserving surgery with intersphincteric resection, and the tumor was resected radically and safely. Case 2: A 66-year-old man with a complaint of hematochezia was diagnosed with rectal GIST during treatment for infective endocarditis. Neoadjuvant imatinib therapy (400 mg/day) was started. However, the treatment was stopped after 11 weeks because of rhabdomyolysis, which was suspected to be an adverse effect of imatinib administration. Abdominal CT and MRI revealed a reduction of approximately 53% in tumor size. A radical operation was considered feasible and sphincter-preserving surgery with intersphincteric resection was performed. Currently, neoadjuvant imatinib mesylate therapy is performed in the setting of clinical trials, but the cases suggest that it can be a promising strategy for locally advanced rectal GIST, improving the complete resection rate and the safety of operations by reducing the size of the tumor.

The first case of phenytoin intoxication associated with the concomitant use of phenytoin and TS-1, a combination preparation of tegafur, gimeracil, and oteracil potassium.

PURPOSE: We reported the first case of phenytoin intoxication due to the concomitant use of phenytoin and TS-1, together with a review of the literature regarding the occurrence of phenytoin intoxication due to the concomitant use of phenytoin and fluoropyrimidine antitumor drugs such as fluorouracil (5-FU) and tegafur (FT). METHODS: We showed the clinical course of our patient. Reports of phenytoin intoxication due to the concomitant use of phenytoin and fluoropyrimidine antitumor drugs in the English and Japanese language literature up to 2007 were identified by searching Medline and ICHUSHI Web (Japana Centra Revuo Medicina). RESULTS: A patient taking phenytoin and TS-1, a combination preparation of tegafur, gimeracil, and oteracil potassium, experienced lightheadedness and repeated falls associated with an increase in serum phenytoin concentration (32.8 mug/ml) at 1 month after the start of TS-1 treatment. The time lag between initiation of combined treatment and onset of adverse symptoms suggests the presence of an indirect mechanism, rather than direct inhibition of drug-metabolizing enzymes by drugs in TS-1 or their active metabolites. CONCLUSIONS: Plasma phenytoin concentration should be closely monitored in patients receiving TS-1 and phenytoin concomitantly.

Dextran sulfate suppresses cell adhesion and cell cycle progression of melanoma cells.

We have reported that dextran sulfate is a possible candidate for an antimetastatic drug because it inhibits cell adhesion. It has been demonstrated that dextran sulfate can detach cancer cells adhering to the bottom of plastic flasks, and that the detached cells do not readhere or proliferate. In this study, we investigated the effects of dextran sulfate on cancer cells, focusing on cell cycle regulators as well as cell adhesion molecules. The effects of dextran sulfate on the cell cycle were examined by flow cytometry, and changes in gene expression caused by dextran sulfate were analyzed by cDNA microarray to identify changes in adhesion and cell cycle genes. By flow cytometry, treatment with dextran sulfate increased the percentage of cells in the G1/G0-phase, and decreased those in the S- and G2/M-phases. Analysis by cDNA microarray revealed decreased expression of several genes essential for progression of the G1- and S-phases. The expression of the adhesion factors involved in metastases was also suppressed. Furthermore, we confirmed these changes in the gene expression by Northern and Western blotting. Our results indicate that dextran sulfate suppresses cell adhesion and cell cycle progression, both of which are essential for metastasis, suggesting that dextran sulfate could be used as an antimetastatic agent.

Cisplatin incorporated in microspheres: development and fundamental studies for its clinical application.

A new drug delivery formulation, biodegradable glycolic acid-lactic acid copolymer (PGLA) microspheres incorporating cisplatin (CDDP-MS) has been developed for the treatment of peritoneal carcinomatosis. Scanning electron microscopy showed that CDDP-MS has a smooth surface and few cisplatin crystals in the hollow. An electron probe micro analyzer revealed that cisplatin was located mainly in the matrix in the state of a molecule. Release profile in vitro of CDDP from microspheres showed that the initial burst was 21.2% and the remaining CDDP was released slowly thenceforth over 14 days. Hydrolysis of CDDP-MS progresses very slowly during the 14 days, but there was no morphological change in the SEM views. The dimethylformamide content entrapped within CDDP-MS, determined by a gas chromatography, was 136 ppm at the evaporation temperature of 47 degrees C. The 50% lethal dose value of CDDP-MS, calculated by the Litchfield-Wilcoxon method, was reduced to 57% of the cisplatin solution. Therapeutic experiment on mice with peritoneal carcinomatosis showed that CDDP-MS did not enhance therapeutic effect as compared with the same dose dosage of a cisplatin aqueous solution but large quantities of cisplatin could be given in case of CDDP-MS owing to less toxicity.

Local administration of methotrexate bound to activated carbon particles (MTX-CH) for treating cancers in mice.

PURPOSE: A new dosage formulation of methotrexate (MTX-CH) was developed to control cancer growth by local administration. MATERIALS AND METHODS: BALB/c mice received a subcutaneous inoculation with transplantable Colon 26 cancer cells on the back. When cancerous tumor became 7 mm in diameter, MTX-CH or MTX aqueous solution (MTX-sol) was injected into the tumor. The MTX concentration in the tumor was compared between the MTX-CH group and the MTX-sol group. The tumor growth was assessed in single or repeated local administration experiments. RESULTS: The MTX concentrations were significantly higher for longer periods in the MTX-CH group than those in the MTX-sol group. Repeated MTX-CH administration was significantly more effective for suppressing the tumor growth compared with repeated MTX-sol administration. CONCLUSION: MTX-CH is superior to MTX-sol in controlling the tumor growth by local administration because of its long-acting effect.

Possible involvement of inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) in the peritoneal dissemination of gastric cancers.

Our previous study using cDNA microarray showed that differentially expressed genes among gastric cancer cells involved in peritoneal dissemination could be positively identified. One of these genes, which is overexpressed, is inositol 1,4,5-trisphosphate receptor type 3 (IP3R3). IP3R3 is responsible for the intracellular Ca2+ release channel and for mobilizing stored Ca2+. Three different receptor types have been molecularly cloned and their genes have been classified into a family. However, the role of the IP3 signaling pathway in the peritoneal dissemination of gastric cancer is still unclear. In the study presented here, the IP3R3 is showed to be overexpressed in gastric cancer cell lines established from malignant ascites, but weakly expressed in a gastric cancer cell line established from primary tumor as well as normal gastric epithelial cells. IP3R1 and 2 are only weakly or not expressed in these cells. The antagonist of IP3R, 2APB, inhibited cell proliferation and induced apoptosis in gastric cancer cells from malignant ascites at concentrations of 100 nM to 100 microM in a dose-dependent manner. On the other hand, 2APB showed a weak effect on other gastric cancer cells established from primary tumors (SNU1), lymph node metastases or liver metastases (MKN1 or 74), methothelial cell lines Met5A and myeloid leukemia HL60 cells. This suggests that this inhibitory effect depends on the level of IP3R3 expression. As cells which express IP3R3 mRNA (i.e. pancreas ascinar cells) are known to have a secretory function in which IP3/Ca2+ signaling has been shown to be involved, IP3R3 may be a prerequisite for secretion of an enzyme, such as protease, in gastric cancer cells. These results indicate that IP3R3 may be specifically involved in gastric cancer peritoneal dissemination and that IP3R3 may be a molecular target of the peritoneal dissemination of gastric cancer. Its antagonist, 2APB, may thus be useful for the specific treatment of peritoneal dissemination of gastric cancer.

Combination of L-3-phosphoserine phosphatase and CEA using real-time RT-PCR improves accuracy in detection of peritoneal micrometastasis of gastric cancer.

Peritoneal metastasis is the most frequent form of recurrence for advanced gastric cancer. We previously performed a global analysis of the gene expression of gastric cancer cell lines established from peritoneal metastasis with cDNA microarray. One of the up-regulated genes is L-3-phosphoserine phosphatase (L3-PP). We have examined its potential as a novel marker for the detection of peritoneal micrometastasis of gastric cancer. L3-PP mRNA in peritoneal wash from 88 gastric cancer patients was quantified for comparison of carcinoembryonic antigen (CEA) mRNA by means of real-time RT-PCR with a fluorescently-labeled probe to predict peritoneal recurrence. The quantity of L3-PP and CEA correlated with wall penetration. The cut-off value was set at the upper limit of the quantitative value of T1 cases (tumor invades within submucosa) and those above the cut-off value constituted the micrometastasis (MM+) group; eight out of 14 cases with peritoneal dissemination were MM+ L3-PP (57.1% sensitivity) and two out of 57 T1 and T2 cases were MM+ (93% specificity). For two out of 14 cases of peritoneal dissemination only L3-PP could detect micrometastasis of gastric cancer, indicating that L3-PP is superior to CEA especially in poorly-differentiated adenocarcinoma. The combination of CEA and L3-PP improved the accuracy of diagnosis up to 85.7%. Consequently, free cancer cells that cannot be detected by CEA mRNA could be detected using L3-PP mRNA. CEA alone was not sufficient, but L3-PP and CEA in combination can attain a higher accuracy of detection.

[Fundamental studies on locally injected methotrexate bound to activated carbon particles (MTX-CH)].

We developed a new dosage formulation of methotrexate bound to activated carbon particles (MTX-CH). In this study, subcutaneous injection of MTX-CH was examined for its long-acting effect at the injection sites, anti-tumor effect and acute toxicity in mice. MTX-CH- or MTX aqueous solution (MTX-SOL)- was injected locally into tumors growing on the back of BALB/c mice at a dosage of 30 mg/kg as methotrexate (MTX). (1) The MTX concentration at the injection sites remained higher in mice with MTX-CH than that with MTX-SOL. (2) A marked effect on the control of tumor growth by MTX-CH was noted after repeated injections throughout the observation period. These results suggest that MTX-CH is superior to MTX-SOL due to longer-acting effects at the administration site and have a better control of tumor growth than MTX aqueous solution (MTX-SOL).

[Detection of sentinel lymphatic region with activated carbon particles in lymph node dissection for colorectal cancer].

Sentinel node navigation surgery (SNNS) for gastrointestinal cancer has been examined using various methods, but the SN concept has not been established. For 18 patients who had colorectal cancer without macroscopic nodal metastases, we had attempted to detect sentinel lymph nodes (SNs) with activated carbon particles and investigate the existence of nodal metastases histologically. SNs were detected in 17 of 18 patients. Thus activated carbon particles are a useful tracer for SN detection. Three patients had microscopic nodal metastases, and two had nodal metastases in SNs. Although the remaining patient was a false negative case which had nodal metastases in non-SNs only, the nodal metastases were within the sentinel lymphatic region (SLR) which includes SNs. It is considered possible to safely perform minimally invasive lymphadenectomy for colorectal cancer without macroscopic nodal metastases, by means of SLR dissection using activated carbon particles.

[Possible involvement of inositol 1, 4, 5-trisphosphate receptor type 3 (IP3R3) in the peritoneal dissemination of gastric cancers].

Our previous study using a cDNA microarray demonstrated that positive identification of differently expressed genes among gastric cancer cells involved in peritoneal dissemination could be accomplished. One of these genes with overexpression is inositol 1, 4, 5-trisphosphate receptor type 3 (IP3R3). IP3R3 is an intracellular Ca2+ release channel responsible for mobilizing stored Ca2+. Three different receptor types have been molecularly cloned, and their genes have been classified into a family. But the role of the IP3 signaling pathway in the peritoneal dissemination of gastric cancers is still unclear. In this study, IP3R3 is overexpressed in gastric cancer cell lines established from malignant ascites, but weakly expressed in gastric cancer cell lines established from primary tumor as well as in normal gastric epithelial cells. IP3R1 and 2 are expressed only weakly or not at all in these cells. The antagonist of IP3R, 2-APB, inhibited cell proliferation and induced apoptosis of gastric cancer cells from malignant ascites at concentrations of 100 nM to 100 microM in a dose dependent manner. Conversely, 2-APB showed a weak effect on other gastric cancer cells established from primary tumors (SNU1), lymph node metastases or liver metastases (MKN1 or 74), methothelial cell lines Met5A and myeloid leukemia cell HL60 cells. This suggests that this inhibitory effect depends on the level of IP3R3 expression. As cells that express IP3R3 mRNA (i.e., pancreatic aciner cells) are known to have a secretory function in which IP3/Ca2+ signaling has been shown to be involved, IP3R3 may be a prerequisite for secretion in gastric cancer cells. These results indicate that IP3R3 may be specifically involved in gastric cancer peritoneal dissemination and that IP3R3 may be a molecular target of the peritoneal dissemination of gastric cancer. Its antagonist, 2-APB, may thus be useful for the treatment of gastric cancer, especially for peritoneal dissemination.

[Endoscopic local injection of anticancer drugs bound to carbon particles for treatment of advanced rectal cancer, when surgical treatment was contraindicated].

Generally, patients with advanced rectal cancer in whom surgical treatment is contraindicated receive radiation or chemotherapy. In such patients, we have administered local injection of methotrexate and mitomycin C bound to activated carbon particles. Four patients received intratumoral injection of the dosage formulation (total dose 100-400 mg of methotrexate or 8-32 mg of mitomycin C) under colonofiberscope. After the treatment, bleeding and pain were lessened in all 4 patients. In two patients, the tumor markedly decreased in size and there was no regrowth prior to death 12-14 months after the treatment. In another patient, bleeding and pain disappeared until the patient died of pulmonary and liver metastases. The fourth patient is alive without regrowth 5 months after treatment. Side effects were not severe.