[Gastric varices treated by balloon-occluded retrograde transvenous obliteration following oxaliplatin-based chemotherapy for gastric cancer].

A 78-year-old female patient with stomach cancer (with hepatic metastasis and peritoneal dissemination) had received eight courses of an S-1 and oxaliplatin regimen as palliative chemotherapy. Computed tomography revealed liver deformities and incidental gastric varices. Esophagogastroduodenoscopy confirmed the findings of gastric varices in the cardia and fornix. It was suspected that oxaliplatin-based chemotherapy had induced non-variceal portal hypertension in the patient-similar to that which is seen in patients with colon cancer who are treated with oxaliplatin-based chemotherapy. We had chosen balloon-occluded retrograde transvenous obliteration (BRTO) for the preventive treatment of gastric varices because the patient had a gastro-renal shunt, which enabled access to the gastric varices via the vena cava. Our patient had undergone BRTO, which resulted in the endoscopic disappearance of gastric varices. Currently, the patient is continuing chemotherapy without bleeding from gastric varices. Our case suggests that patients with gastric cancer treated with oxaliplatin-based chemotherapy require careful follow-up for portal hypertension.

The utility of two-dimensional real-time shear wave elastography for assessing liver fibrosis in patients with chronic hepatitis C virus infection.

OBJECTIVE: Two-dimensional shear wave elastography (2D-SWE) is a new ultrasound-based elastography method to evaluate liver fibrosis in the daily practice. However, the utility of 2D-SWE among the other liver fibrosis markers is unclear. METHODS: We enrolled 141 consecutive patients with hepatitis C virus infection, 66 men and 75 women (median age, 67 years), who underwent liver biopsy and 2D-SWE (LOGIQ E9, GE Healthcare, Wauwatosa, WI, USA). We compared the diagnostic accuracy of the 2D-SWE with those of magnetic resonance elastography (MRE; MR-Touch, GE Healthcare, Milwaukee, WI, USA), Mac-2 binding protein glycosylation isomer (M2BPGi), fibrosis-4 index (FIB-4) and platelet counts (PLT), using the histologic METAVIR scoring as the reference standard. RESULTS: The areas under the receiver operating characteristics curves (AUROCs) of 2D-SWE, MRE, M2BPGi, FIB-4 and PLT for ≥F2, ≥F3 and F4 were 0.86, 0.88, 0.79, 0.81 and 0.77; 0.92, 0.93, 0.86, 0.87 and 0.83; and 0.91, 0.97, 0.85, 0.85 and 0.82, respectively. For diagnosing ≥F2 and ≥F3, the AUROCs of 2D-SWE and those of MRE showed no significant differences, and both 2D-SWE and MRE showed significantly higher AUROCs than the other markers. For diagnosing F4, the AUROC of MRE was significantly higher than those of other fibrosis markers. CONCLUSION: 2D-SWE has an excellent diagnostic accuracy equivalent to that of MRE for assessing significant (≥F2) and severe (≥F3) fibrosis. MRE demonstrated a higher AUROC than 2D-SWE, but this last one has advantages such as lower cost, fewer contraindications and greater ease of performance than MRE.

Successful Treatment with 5-fluorouracil and Levofolinate Calcium in Advanced Gastric Cancer Patient with Disseminated Intravascular Coagulation.

A 32-year-old woman was found to have a gastric adenocarcinoma with multiple bone metastases. Chemotherapy in the first, second and third-line was not effective. Blood examinations showed disseminated intravascular coagulation(DIC)at the end of the second-line chemotherapy. The fourth-line chemotherapy, infusional 5-fluorouracil and levofolinate calcium was performed. This resulted in a good response for DIC. This palliative therapy was effective and safety.

Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer.

BACKGROUND: This multicenter, randomized phase II trial was conducted to compare the efficacy and safety of nimotuzumab plus irinotecan (N-IRI) versus irinotecan alone (IRI) in patients with advanced gastric cancer (AGC) showing disease progression after previous 5-fluorouracil-based therapy. METHODS: Irinotecan-naive patients (n = 82) received N-IRI (nimotuzumab 400 mg weekly plus irinotecan 150 mg/m(2) biweekly) or IRI (irinotecan 150 mg/m(2) biweekly) until disease progression. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), response rate (RR), safety, tolerability, and the correlation between efficacy and tumor epidermal growth factor receptor (EGFR) expression. RESULTS: Of 83 patients, 40 and 43 patients were randomly assigned to the N-IRI and IRI groups, respectively. In the N-IRI/IRI treatment group, median PFS was 73.0/85.0 days (P = 0.5668), and median OS and RR at 18 months were 250.5/232.0 days (P = 0.9778) and 18.4/10.3 %, respectively. Median PFS and OS in the EGFR 2+/3+ subgroups were 118.5/59.0 and 358.5/229.5 days, respectively. The RR was 33.3/0.0 % in the N-IRI/IRI treatment group. The incidence of grade 3 or higher adverse events was 77.5/64.3 %. No adverse events of grade 3 or higher skin rash or grade 3 or higher infusion-related reaction were reported. CONCLUSIONS: There was no superiority of N-IRI over IRI alone in terms of PFS in 5-fluorouracil-refractory AGC patients. However, N-IRI showed potential improvement in the EGFR 2+/3+ subgroup based on improved RR, PFS, and OS.

Phase II study of combined chemotherapy with irinotecan and S-1 (IRIS) plus bevacizumab in patients with inoperable recurrent or advanced colorectal cancer.

BACKGROUND: In Japan, a study comparing the effectiveness and safety of irinotecan plus S-1 (IRIS) with those of a combination of 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as second-line treatment in patients with advanced or recurrent colorectal cancer demonstrated that IRIS was non-inferior to FOLFIRI. We previously reported that IRIS is also effective as first-line treatment. PATIENTS AND METHODS: Eligibility criteria included inoperable recurrent colorectal cancer with a confirmed diagnosis of adenocarcinoma, age ≥20 years, and no history of prior chemotherapy. S-1 (40-60 mg twice daily) was given orally on Days 1 to 14, and irinotecan (100 mg/m(2)) and bevacizumab (5 mg/kg) were given intravenously on Days 1 and 15 of a 28-day cycle. The primary endpoint was safety. The secondary endpoints included overall response (OR), progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 52 eligible patients were enrolled from October 2007 through March 2009. In safety analysis, the incidences of grade 3 or 4 adverse reactions were as follows: neutropenia, 27%; hypertension, 21%; and diarrhea, 17%. The overall response rate was 57.7%. Median progression-free survival was 16.7 months. CONCLUSION: IRIS plus bevacizumab is a well-tolerated, highly effective chemotherapeutic regimen that is easy to administer.

[A case of advanced gastric cancer with liver metastases successively treated with S-1/CDDP combination therapy followed by curative resection].

The patient was a 67-year-old male with type-3 gastric cancer from the upper body of the stomach to the cardia. An abdominal computed tomography scan revealed liver metastases(S8)(T2N0M0H1, Stage IV). The patient received neoadjuvant combined chemotherapy with S-1 and CDDP. S-1(120mg/body/day)was orally administered for 3 weeks followed by 2 drug-free weeks as a course, and CDDP(60mg/m2)was administered by intravenous infusion on day 8. After the second course, significant tumor reduction and disappearance of liver metastases resulted. Total gastrectomy, splenectomy, cholecystectomy, and D2 nodal dissection were performed. The histological diagnosis revealed no metastases in all lymph nodes: Stage I B. The combined neoadjuvant chemotherapy with S-1 and CDDP can be considered an effective treatment for advanced gastric cancer.

Genotype-directed, dose-finding study of irinotecan in cancer patients with UGT1A1*28 and/or UGT1A1*6 polymorphisms.

Irinotecan-induced severe neutropenia is associated with homozygosity for the UGT1A1*28 or UGT1A1*6 alleles. In this study, we determined the maximum-tolerated dose (MTD) of irinotecan in patients with UGT1A1 polymorphisms. Patients who had received chemotherapy other than irinotecan for metastatic gastrointestinal cancer were enrolled. Patients were divided into three groups according to UGT1A1 genotypes: wild-type (*1/*1); heterozygous (*28/*1, *6/*1); or homozygous (*28/*28, *6/*6, *28/*6). Irinotecan was given every 2 weeks for two cycles. The wild-type group received a fixed dose of irinotecan (150 mg/m(2)) to serve as a reference. The MTD was guided from 75 to 150 mg/m(2) by the continual reassessment method in the heterozygous and homozygous groups. Dose-limiting toxicity (DLT) and pharmacokinetics were evaluated during cycle 1. Of 82 patients enrolled, DLT was assessable in 79 patients (wild-type, 40; heterozygous, 20; and homozygous, 19). Dose-limiting toxicity occurred in one patient in the wild-type group, none in the heterozygous group, and six patients (grade 4 neutropenia) in the homozygous group. In the homozygous group, the MTD was 150 mg/m(2) and the probability of DLT was 37.4%. The second cycle was delayed because of neutropenia in 56.3% of the patients given the MTD. The AUC(0-24 h) of SN-38 was significantly greater (P < 0.001) and more widely distributed in the homozygous group. Patients homozygous for the UGT1A1*28 or UGT1A1*6 allele can receive irinotecan in a starting dose of 150 mg/m(2), but many required dose reductions or delayed treatment in subsequent cycles. UMIN Clinical Trial Registration number: UMIN000000618.

Successful treatment of gastric adenocarcinoma in a Meckel's diverticulum with pemetrexed plus carboplatin.

A 42-year-old man was found to have an adenocarcinoma arising from ectopic gastric mucosa in Meckel's diverticulum, as diagnosed with surgical pathology. Recurrence was recognized with massive ascites at 1 year and 6 months after surgery. Chemotherapy in the first and second lines was not effective. In the third line of chemotherapy, pemetrexed and carboplatin were both administered and this resulted in a good response for massive ascites. This palliative therapy was effective and safe.

Disturbance of the growth hormone-insulin-like growth factor-1 axis associated with poor performance status in patients with solid tumors.

OBJECTIVE: Hormonal imbalance characterized by excessive production of growth hormone (GH) and a low circulating concentration of insulin-like growth factor (IGF)-1 has been demonstrated in individuals with various serious conditions. However, little is known about changes in the GH-IGF-1 axis in cancer patients. METHODS: We prospectively examined the circulating levels of several hormones in 58 patients with solid tumors who were classified according to Eastern Cooperative Oncology Group performance status (PS): PS 0-1, n = 15; PS 2, n = 15; PS 3, n = 15; and PS 4, n = 13. The relations of hormone concentrations, with a focus on the GH-IGF-1 system, to PS were evaluated by Spearman's rank correlation test and regression analysis. RESULTS: The circulating levels of IGF-1, IGF-binding protein-3 and thyroid hormones (total T(3) and T(4)) were inversely correlated with PS score. The concentration of GH was increased irrespective of PS but not statistically significant. The ratio of IGF-I to GH was inversely correlated with PS. The levels of GH and IGF-1 in all patients were also inversely correlated. CONCLUSIONS: The present study suggests that the GH-IGF-1 axis is disturbed in patients with cancer.

[A case report--gastric stenosis due to primary gastric malignant lymphoma after administration of R-CHOP].

A 67-year-old man was diagnosed with primary gastric malignant lymphoma by an endoscopic examination. Endoscopy revealed irregular ulcerative regions from body to antrum of the stomach. With a diagnosis of diffuse large B-cell lymphoma based on the biopsy finding, the patient was treated with R-CHOP chemotherapy. After three cycles of chemotherapy, a tight stenosis was located at the antrum of the stomach. Total gastrectomy was performed due to an obstruction. Pathological diagnosis was complete response. It was thought that the tumor organization rapidly disappeared due to the effectiveness of the chemotherapy, and that the origin of the stricture caused fibrosis.

Chemotherapy for patients with advanced gastric cancer with performance status 2.

METHODS: We retrospectively analyzed 657 patients with advanced gastric cancer who received first-line chemotherapy. Baseline patient characteristics and treatment results were compared between Eastern Cooperative Oncology Group performance status (PS) 0-1 and PS 2 patients. RESULTS: Prior to beginning first-line chemotherapy, 513, 112, and 32 patients were PS 0-1, PS 2, and PS 3-4, respectively. Patients with massive ascites (42% vs. 3%; P < .001) or inability to eat (39% vs. 4%; P < .001) were more likely to be PS 2 than PS 0-1. Significantly fewer PS 2 patients received first-line chemotherapy regimens containing oral agents (40% vs. 77%; P < .001) or combination chemotherapy (19% vs. 40%; P < .001) compared to PS 0-1 patients. Median survival time was significantly shorter in PS 2 patients (5.8 vs. 13.9 months; P < .001). Multivariate survival analysis revealed that use of oral agents was associated with a better prognosis in PS 0-1 patients (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59-0.97, P = .03), while it was associated with poorer survival in PS 2 patients (HR 1.52, 95% CI 1.0-2.3, P = .046). CONCLUSION: Advanced gastric cancer patients with PS 2 not only had a poorer prognosis but also differed in several baseline characteristics compared to PS 0-1 patients. These results indicate that additional clinical trials that specifically target gastric cancer patients with PS 2 may be required to evaluate optimal treatment regimens for this patient population.

Pilot study of combination chemotherapy using irinotecan plus S-1 for metastatic pancreatic cancer.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of a combination regimen using irinotecan plus S-1 in patients with metastatic pancreatic cancer. METHODS: Based on the results of our previous phase I/II study in patients with gastric and colorectal cancer, we initiated a regimen with irinotecan at 100 mg/m(2) on days 1 and 15 and S-1 at 80 mg/m(2) starting at day 1 for 14 consecutive days, followed by a 14-day rest period. This treatment was repeated every 28 days. RESULTS: From November 2003 to December 2006, a total of 16 patients were enrolled. All patients presented with metastatic disease. Six patients had received prior gemcitabine. The median number of treatment cycles was 4 (range 1-16) and the response rate was 43.7% (95% confidence interval 19.5-68.1). The median time to progression was 4.9 months, and the median survival time was 11.3 months. Grade 3-4 neutropenia developed in 5 of 16 patients and grade 3 diarrhea in 1 patient. CONCLUSIONS: The combination of irinotecan and S-1 is feasible and promising for pancreatic cancer. Further evaluation of this combination chemotherapy is required.

Prolongation of survival and improvement in performance status following palliative chemotherapy in gastrointestinal cancer patients with a poor performance status.

BACKGROUND: The prognosis of advanced gastrointestinal cancer, especially in patients with poor performance status (PS), is generally dismal. Patients with PS 3-4 are almost ineligible for participation in clinical studies. PATIENTS AND METHODS: From June 2000 to February 2007, 116 patients with poor PS (PS 3 = 73 and PS 4 = 43) were treated with chemotherapy. Retrospective analysis was performed. RESULTS: Of the 107 patients with at least one measurable lesion, a partial response was obtained in 15 patients (14.0%). Of 65 patients with ascites and/or pleural effusion, 12 patients achieved decreased fluid accumulation. A decline in tumor markers was observed in 30 patients. As a result, 38 patients (32.7%) achieved tumor response, a decrease in fluid accumulation or a decline in tumor markers (responders), which resulted in a survival benefit compared to the other 78 patients without effect (6.9 vs. 2.2 months, p < 0.001). PS improvement was seen in 16 patients (13.8%). CONCLUSIONS: The results suggest that chemotherapy may be beneficial in gastrointestinal cancer patients with poor PS, as demonstrated by a certain degree of improvement in PS and survival in responders. Further study is required to confirm the benefit of chemotherapy in this patient population.

A case of advanced breast cancer associated with development of liver atrophy with progressive liver failure during treatment.

A 44-year-old-female came to our hospital with abdominal distension in April 2005. She had been diagnosed with breast cancer in 1991, which was treated with mastectomy, postoperative radiation therapy,and a five-year course of hormonal therapy. An abdominal computed tomography (CT) scan revealed multiple hypoattenuated lesions in both lobes of her liver, which were diagnosed as metastatic breast cancer by liver biopsy. Weekly chemotherapy with paclitaxel was initiated on May 13. Trastuzumab and tamoxifen were added after two weeks. After six months of treatment, the CT scans showed reductions in the size of her multiple liver metastases along with the development of slight irregularities in the liver surface. Liver dysfunction was improved,and tumor marker BCA225 levels significantly decreased. After ten months of treatment, the CT scan showed nodular irregularity of the hepatic borders with deformation and atrophic changes. After twelve months of treatment,she was readmitted with abdominal distension and lower extremity edema. Increased ascites and appearance of esophageal varices were observed. Laboratory values were compatible with decompensation of liver function,although BCA225 levels still remained low. Despite discontinuation of chemotherapy and hormonal therapy at this time, she died from liver failure less than two weeks later. The atrophic changes and liver failure are suspected to have resulted from the chemotherapy and/or hormonal therapy.

Metastatic rectal cancer responding to third-line therapy employing bevacizumab after failure of oxaliplatin and irinotecan: case report.

A 61-year-old female with surgically treated rectal cancer that had metastasized to lung and lymph nodes was treated with bevacizumab (BV) plus 5-fluorouracil (5-FU) and leucovorin (LV) as third-line chemotherapy after treatment failures with infusional 5-FU, LV and oxaliplatin (FOLFOX regimen); and infusional 5-FU, LV and irinotecan (FOLFIRI regimen). After four cycles of treatment, a computed tomography scan revealed reduced sizes of the lung and lymph node metastases. Tumor response has still been maintained after six cycles of treatment, and the chemotherapeutic response was evaluated as partial response according to the Response Evaluation Criteria In Solid Tumor guidelines. Manageable toxicity included grade 2 hypertension, grade 1 epistaxis and grade 1 stomatitis. Although there are no clinical trial results supporting the use of BV-containing therapy as third-line chemotherapy for advanced colorectal cancer, BV plus 5-FU and LV was effective and feasible in our patient with colon cancer that had progressed after treatment with 5-FU, irinotecan and oxaliplatin.

[A feasibility study of oxaliplatin (L-OHP) in combination with infusional 5-FU/l-LV (FOLFOX4 regimen) for advanced colorectal cancer].

This trial was performed to evaluate the safety and tolerability of the FOLFOX4 regimen in Japanese patients with ACRC until the end of the third cycle according to the regulation of the Japanese Ministry of Health and Welfare. Thirty-nine patients received FOLFOX4 and 38 patients were evaluable for safety analysis. Thirty-four patients completed all three cycles, 18 of whom did not need dose reduction or prolongation of administration. The most frequent of grade 3/ 4 adverse events (the Common Terminology Criteria for Adverse Events v3.0) were neutropenia (42.1%), nausea (5.3%), and anorexia (5.3%). There were no treatment-related deaths. Neuro-sensory toxicity was a highly-frequent adverse event (78.9%), but no grade 3/4 neurotoxicity was seen. The FOLFOX4 regimen was acceptable to Japanese patients with ACRC in at least 3 cycles.

A case of suspected vasospastic angina related to S-1 administration.

A 58-year-old male with advanced gastric cancer underwent a total gastrectomy after neoadjuvant chemotherapy with paclitaxel and cisplatin. The combination chemotherapy was resumed postoperatively as adjuvant chemotherapy. Although no recurrence was observed after 6 months of adjuvant chemotherapy,the patient elected to receive further adjuvant chemotherapy with an oral drug. On the night of November 9,2006, he began taking S-1 at a dose of 50 mg twice daily. Fifty minutes after taking the first 50 mg of S-1,he experienced a squeezing chest pain at rest that was later accompanied by diaphoresis and nausea. The pain continued for approximately one hour,but had subsided by the time he reached an emergency room. Coronary angiography revealed a 50% eccentric stenosis in the proximal site of the right coronary artery,but there was no coronary lesion which could caused myocardial ischemia. Cardiac scintigraphy using 123I-BMIPP (123I-labeled beta-methyl-p-iodophenyl-pentadecanoic acid) showed a decreased uptake of BMIPP within the posterior wall,which improved one month later,so transient myocardial ischemia was confirmed. Since vasospastic angina related to S-1 administration was highly suspected,re-administration of S-1 was not performed. The patient is not currently receiving chemotherapy and remains under surveillance for relapse.