Postoperative long-term evaluation of interposition reconstruction compared with Roux-en-Y after total gastrectomy in gastric cancer: prospective randomized controlled trial.

BACKGROUND: The postoperative clinical superiority of the interposition of jejunum reconstruction (INT) to Roux-en-Y reconstruction (RY) after total gastrectomy has not been clarified. Postoperative quality of life (QOL) was evaluated between the 2 methods by a multi-institutional prospective randomized trial. METHODS: A total of 103 patients with gastric cancer were prospectively randomly divided into groups for RY (n = 51) or INT reconstruction (n = 52) after total gastrectomy. They were stratified by sex, age, institute, histology, and degree of lymph node dissection. Postoperatively, body mass index (BMI) and nutritional conditions were measured serially, and QOL and postoperative squalor scores were evaluated at 3, 12, and 60 months and compared between the 2 groups. RESULTS: After removing patients who did not complete the follow-up survey or censured cases, 24 patients in the RY group and 18 patients in the INT group were clinically available and their postoperative status was assessed. QOL scores were increased and complication scores were improved in the postoperative periods (P < .01). Postoperative BMI significantly deteriorated compared with preoperative BMI in each group. The postoperative QOL and complication scores at 60 months after surgery were significantly better than those at 3 months after surgery in each group (P < .01). However, there was no significant difference of QOL scores and postoperative complication scores between the 2 reconstruction groups. The nutritional condition in the INT group was nearly the same as that in the RY group. CONCLUSIONS: Although our patient sample was small and patients who did not complete the follow-up survey were present, we could not identify any clinical difference between INT and RY after total gastrectomy 60 months after surgery. The safer and simpler RY method may be a more suitable reconstruction method than INT after total gastrectomy.

[Strategy for patients with GIST after failure of imatinib].

Sunitinib malate(SU11248)is an oral multitargeted receptor tyrosine kinase inhibitor(MTI)that has antitumor activities for patients with gastrointestinal stromal tumor; GIST after failure of Imatinib. Sunitinib has demonstrated significant clinical benefits, including PFS, RR and OS in the USA and Japan. However, cis-mutations in the activation loop of the KIT gene tend to develop Sunitinib-resistant GIST. Two clinical trials revealed that new multitargeted receptor tyrosine kinase inhibitors, Sorafenib and Nilotinib, had antitumor activities for Sunitinib-resistant GIST with longer PFS and a different spectrum. Now, clinical trials of several new MTIs are ongoing in Western countries. Inhibition of the KIT gene cis-mutations and antiangiogenesis activities may be essential for the strategy for Imatinib/Sunitinibresistant GIST.

Dynamic alteration of gene expression induced by anticancer-agent exposure in gastric cancer cell lines.

The prognosis for advanced gastric cancer remains very poor due to the limited effectiveness of chemotherapy agents. The range in efficacy of these chemotherapy agents is likely the result of various factors including gene expression. In addition, the emergence of drug resistance during chemotherapy can result in the undesirable outcome of patients experiencing the side effects of chemotherapy without benefiting in terms of tumor response. Gene expression profiling provides a unique opportunity to gain insight into the development of different types of gastric cancer. We applied the TaqMan low density array to investigate the expression of 96 genes in four gastric cancer cell lines (TMK-1, MKN-45, MKN-74 and CDDP-resistant MKN-74). The cell lines displayed different patterns of gene expression alteration after exposure to the chemotherapeutic drugs cisplatin and 5-fluorouracil. We also established that cisplatin-resistant MKN-74 cells do not show the same gene expression patterns as the parental MKN-74 cell line at 0, 8 and 24 h after CDDP exposure. This study reveals the underlying complexity of biological and pathological events and could, perhaps, contribute to new experimental protocols or treatments that would achieve a consistent and desirable outcome of chemotherapy.

Combination chemotherapy of biweekly irinotecan (CPT-11) plus tegafur/uracil (UFT) and leucovorin (LV) for patients with metastatic colorectal cancer: phase I/II study in Japanese patients.

PURPOSE: We aimed to evaluate the safety and efficacy of combination chemotherapy with biweekly irinotecan (CPT-11) plus oral tegafur/uracil (UFT) and leucovorin (LV) in patients with previously untreated metastatic colorectal adenocarcinoma in phase I/II setting. PATIENTS AND METHODS: We recruited 37 patients with histologically proven metastatic colorectal adenocarcinoma. UFT (300 mg/m(2) per day) and LV (75 mg/day) were administered orally on days 1-21. CPT-11 was administered intravenously on day 1 and 15, at an initial dose of 60 mg/m(2), stepping up to 150 mg/m(2) in a traditional phase I fashion. The treatment was repeated every 4 weeks. After patients enrolled into a phase II portion, the efficacy and toxicity of this regimen were also assessed. RESULTS: The recommended dose of CPT-11 was determined to be 150 mg/m(2). Although one patient had a pulmonary embolism after 60 mg/m(2) of CPT-11, the treatment was well tolerated in general. The overall objective response rate was 37.8% (14/37; 95% CI, 22.5-55.2) in all patients. Median progression-free survival was 226 days (95% CI, 133-276). CONCLUSIONS: Biweekly CPT-11 plus UFT and LV had a reasonable safety profile with manageable toxicity, and had a promising activity in patients with metastatic colorectal cancer. Further trials are indicated based on the promising results observed in this study.

Surgical site infection risk factors identified by multivariate analysis for patient undergoing laparoscopic, open colon, and gastric surgery.

BACKGROUND: Surgical site infection (SSI) is an important clinical indicator of quality of patient care and infection control; therefore, we aimed to assess risk factors SSI in colon and gastric surgeries. METHODS: SSI was assessed according to the National Nosocomial Infection Surveillance (NNIS) system (1999). Risk factors examined included operative approach, operative procedure, duration of operation, diabetes mellitus (DM), body mass index (BMI), age, and sex. RESULTS: Among 3152 operated patients, 1675 patients were included in the study. The univariate analysis showed that male sex, high BMI, and long duration of operation were significant risk factors for colon surgery and that advanced age, presence of DM and long duration of operation were significant risk factors for gastric surgery. The multivariate analysis indicated that significant risk factors for SSI were BMI of 25 or above, open surgery, and long duration of operation for colon surgery and open surgery for gastric surgery. The SSI rate of laparoscopic colon surgery was 40%, less than that of open colon surgery, and that of laparoscopic gastric surgery was 75%, less than that of open gastric surgery. CONCLUSION: The risk factors for SSI depend on whether the operation is laparoscopic or open and duration of operation. In addition, BMI (25 or above) and age (70 years or above) are risk factors for colon and gastric surgery, respectively.

Heat shock protein 27, a novel regulator of 5-fluorouracil resistance in colon cancer.

The resistance of colon cancer to 5-fluorouracil (5-FU) is a critical issue, and the cause of this resistance cannot always be explained based on the known molecules. Heat shock protein 27 (HSP27) mRNA expression has recently been shown to be correlated with 5-FU resistance in 5-FU-resistant cell lines. In this study, we attempted to elucidate the functional mechanism of HSP27 in 5-FU resistance in colon cancer. HSP27 protein levels in several human colon cancer cell lines (LoVo, HCT15, WiDr, HCT116, HT-29 and SW480) were determined by immunoblot and densitometry analysis. The in vitro growth inhibition rates (IR) of the cell lines at various concentrations of 5-FU were assessed by MTT assay. The degree of 5-FU resistance was estimated as the drug concentration inducing 50% IR (IC50). The HSP27 protein level and IC50 were significantly correlated in these cell lines (p=0.010). The effect of HSP27 overexpression on IC50 was evaluated in LoVo cells. HSP27 transfectants significantly increased IC50 and reduced HSP27 resistance. The effect of HSP27 down-regulation by HSP27 siRNA on IC50 was confirmed in HCT15 cells. HSP27 siRNA suppressed HSP27 protein levels and reduced IC50 in a dose-dependent manner. These data indicated that HSP27 is closely connected with 5-FU resistance in colon cancer and suggested that HSP27 levels predicted 5-FU resistance. HSP27 down-regulation overcame 5-FU resistance and HSP27 may be a clinical target in patients with 5-FU-resistant colon cancer.

Clinical practice guidelines for gastrointestinal stromal tumor (GIST) in Japan: English version.

Diagnostic and treatment strategies for gastrointestinal stromal tumors (GISTs) have evolved greatly since the introduction of molecularly targeted therapies. Although several clinical practice guidelines are extant, such as those published by the National Comprehensive Cancer Network and the European Society of Medical Oncology, it is not clear as to whether these are appropriate for clinical practice in Japan. Therefore, clinical practice guidelines for the optimal diagnosis and treatment of GIST tailored for the Japanese situation have often been requested. For this reason, the Japanese Clinical Practice Guideline for GIST was proposed by the GIST Guideline Subcommittee, with the official approval of the Clinical Practice Guidelines Committee for Cancer of the Japan Society of Clinical Oncology (JSCO), and was published after assessment by the Guideline Evaluation Committee of JSCO. The GIST Guideline Subcommittee consists of members from JSCO, the Japanese Gastric Cancer Association (JGCA), and the Japanese Study Group on GIST, with the official approval of these organizations. The GIST Guideline Subcommittee is not influenced by any other organizations or third parties. Revision of the guideline may be done periodically, with the approval of the GIST Guideline Subcommittee, either every 3 years or when important new evidence that might alter the optimal diagnosis and treatment of GIST emerges. Here we present the English version of the Japanese Clinical Practice Guideline for GIST prepared by the GIST Guideline Subcommittee.

New chemotherapy strategies for gastric cancer.

Gastric cancer chemotherapy has entered a new era with the introduction of new drugs such as S-1, irinotecan (CPT-11), paclitaxel and docetaxel. Recent phase III studies have indicated that S-1 monotherapy, a remnant reference arm from a previous study, was not inferior to 5-FU alone, and that the combination of S-1 with cisplatin and CPT-11 showed higher efficacy than S-1 alone with tolerable side-effects for advanced and recurrent gastric cancer. In the adjuvant setting, S-1 monotherapy prolonged survival following surgery compared with surgery alone after curative extended (D2) lymph-node dissection for stage II/III gastric cancer. However, some issues remain, such as the sequence of several duplet chemotherapies, treatment following cases of S-1 failure, the relative efficacy of doublet and triplet therapies, and the impact of molecular-targeting.

Development of 36 clones producing human monoclonal antibodies specific to cancer cells and their ability to inhibit cancer cell growth.

The development of a specific antibody for cancer therapy could enable a potent strategy for overcoming cancer. As ideal immunotherapy, a human monoclonal antibody (HuMoAb) might have a useful antitumor effect without any lethal toxicities. Thirty-six unique clones producing HuMoAbs were successfully developed using tumor infiltrating lymphocytes collected from 28 patients with several malignant solid tumors. The 36 tumor-specific immunoglobins were found among 9,450 clones after 43 fusions by the conventional hybridoma method. Among these 36 HuMoAbs, 9 had a remarkable tumor-specific reaction and no reaction with normal tissues, as determined with quantum dots-streptavidin and a fluorescence microscope. The inhibition of cell proliferation by the HuMoAbs was evaluated with the MTT assay. Over 40% cell growth inhibition was confirmed with 4 of the 36 HuMoAbs. Two of the antibodies had highly-specific reactivity to carcinomatous lesions with strong growth inhibition and up to 94.3% inhibition of the control growth. In conclusion, 36 clones with HuMoAbs that have specific reactions with cancer cells were successfully established. These HuMoAbs might be utilized as either anticancer or drug delivery agents.

Candida albicans infection delays duodenal ulcer healing in cysteamine-induced duodenal ulcers in rats.

A low curability of ulcers infected with Candida has been reported in the literature. The aim of the study reported here was to investigate experimentally whether Candida infection affects the healing of ulcers. Candida albicans (the Candida group) or saline (the control group) was administered intragastrically into rats with a cysteamine-induced duodenal ulcer. The duodenal lesions, vascular endothelial growth factor A (VEGF-A) and proliferating cell nuclear antigen (PCNA) were assessed. On Day 7 post-administration, 70.4% rats of the Candida group had a duodenal ulcer compared with 33.3% in the control group (P < 0.05). The duodenal ulcer in the Candida group was significantly larger and deeper than that in the control group. The number of VEGF-A- and PCNA-positive cells was smaller and the area of VEGF-A expression was lower in the Candida group. Using a rat model, we have demonstrated that Candida infection can delay the wound healing process of duodenal ulcers by means of a low expression of VEGF-A and PCNA.

[Individualized tumor response assay].

The accuracy of an individualized tumor response (ITR) assay in Japan was reportedly 74% (30th Annual Meeting of Japan Research Society for Appropriate Cancer Chemotherapy). Based upon the hypothesis according to which the appropriate adjuvant cancer chemotherapy will increase the survival outcome after surgery of advanced gastric cancer, we have clarified the usefulness of an ITR assay in evaluating the appropriate adjuvant chemotherapy for gastric cancer. While recent reports indicate the standard therapy for gastric cancer, the gastric cancer cohort includes responder and non-responder to adjuvant cancer chemotherapy. The ITR assay will be useful to differentiate the responder and nonresponder to cancer chemotherapy.

[Clinical experience of second-line chemotherapy with S-1/CPT-11 for highly advanced gastric cancer].

We have performed chemoradiation with S-1 and low-dose CDDP as an initial treatment for 27 patients with incurable or unresectable highly advanced gastric cancer since 2002. Twelve out of 27 patients received combination chemotherapy of S-1 and CPT-11 as the second-line chemotherapy. On this regimen, S-1 was administered orally at a dose of 80 mg-120 mg daily, and CPT-11 at a dose of 60 mg/m(2) once in 2 or 3 weeks for outpatients. Clinical effects after therapy showed a response rate of 30.0%. Considering the prognostic outcome of the regimen, the one-year survival rate of the therapy was 66.7%, and the median survival time was more than 1 year, suggesting second-line chemotherapy will be one of the beneficial regimens in gastric cancer patients. Although 4 patients showed grade 3 bone marrow suppression (33.3%), they were all able to continue the therapy, after recovering from toxicity by means of G-CSF and/ or cessation of chemotherapy. The incidence and level of toxicity accompanying subjective symptoms, however, were relatively low, and the regimen was useful as an outpatient treatment maintaining good quality of life and improving their prognosis. Treatment with an appropriate regimen at an appropriate time will enable these patients to have good quality of life and survival.

Intravenous injection of micafungin counteracts Candida albicans-induced aggravation of duodenal ulcers caused by cysteamine in rats.

BACKGROUND: We have reported previously that Candida albicans is involved in the pathogenesis of peptic ulcer perforation; it was shown that C. albicans aggravated the severity of duodenal ulceration and increased the rate of perforation. We considered it incumbent upon us to ascertain whether C. albicans is a virulence factor involved in peptic ulcer perforation. In the present study, we administered an antifungal drug (micafungin) intravenously to rats that had received intragastric (i.g.) administration of C. albicans and cysteamine, in order to examine that micafungin could counteract the C. albicans-aggravation of duodenal ulcers. METHODS: Cysteamine was administered thrice on day 1 to male Wistar rats. C. albicans was administered to the animals 1 h before, and 12 and 24 h after the first administration of cysteamine. Micafungin (n = 22) or saline (n = 24) was administered 12, 24, and 48 h after the administration of cysteamine. RESULTS: The area of the duodenal ulcers was also significantly smaller in the micafungin group (P < 0.05). In addition, the survival rate of the rats was significantly higher in the micafungin group (P < 0.05). While in the control group, the ulcer base was found to be colonized by C. albicans, there was no evidence of the presence of C. albicans in the micafungin group. CONCLUSION: It was shown that intravenous injection of micafungin counteracted the aggravation by C. albicans of cysteamine-induced duodenal ulcers in rats. This finding supports the concept that C. albicans is an aggravating factor for peptic ulcers.

Phase II study of chemoradiotherapy with S-1 and low-dose cisplatin for inoperable advanced gastric cancer.

PURPOSE: The results of a pilot study using S-1/low-dose cisplatin/radiotherapy led us to hypothesize that the initial chemoradiotherapy regimen would induce a 70% efficacy rate with a 10% pathologic complete response rate. PATIENTS AND METHODS: Only patients with unresectable or incurable advanced gastric cancer were eligible. The patients received induction S-1 and cisplatin therapy with radiotherapy followed by chemotherapy alone. RESULTS: Of the 30 patients recruited and assessed, 29 were eligible for clinical evaluation of measurable lesions. The response rate was 65.5%, with 19 with a partial response, 8 with no change, and 2 with progressive disease of 29 patients. Of the 30 patients recruited, 10 (33.3%) underwent stomach resection and D2 LN dissections. The pathologic complete response rate was 13.3% (4 patients), and the R0 resection rate was 100% (10 patients). The survival analysis showed a median survival time of 25 months. Grade 3 toxicity occurred in 66.7% for leukocytopenia, 33.3% for thrombocytopenia, 23.3% for nausea and appetite loss, and 6.7% for anemia, diarrhea, and renal dysfunction. Although all the patients had been hospitalized with a poor performance status with a giant tumor, 97% (29 of 30) could be discharged after the first cycle, resulting in an improvement in quality of life. CONCLUSION: Chemoradiotherapy could be a powerful regimen for controlling tumor progression in advanced gastric cancer, improving patients' quality of life with tolerable toxicity. A complete histologic response rate of >10% would be expected, even for large tumors with metastatic lesions.

Pioglitazone, a ligand for peroxisome proliferator-activated receptor-gamma acts as an inhibitor of colon cancer liver metastasis.

BACKGROUND: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the steroid receptor superfamily. Liganded PPARgamma can inhibit cancer cell proliferation. The in vitro and in vivo inhibitory effect of the synthetic ligands, ciglitazone (CGZ) and pioglitazone (PGZ), on human colon cancer was investigated. MATERIALS AND METHODS: Cell proliferation and the expression of PPARgamma, cyclooxygenase (COX)-2 and cyclin D1 were assessed in colon cancer cells treated with CGZ or PGZ. After subcutaneous or splenic inoculation of severe combined immunodeficient (SCID) mice using colon cancer HT-29 and SW480 cells, PGZ was administered orally and tumor growth inhibition was assessed by xenograft volume. The COX-2, cyclin D1 and PPARgamma expression in the HT-29 cells was evaluated. RESULTS: Cultured HT-29 and SW480 cells expressed PPARgamma and proliferation was inhibited by CGZ and PGZ. Oral PGZ inhibited xenograft tumor growth and liver metastases in the SCID mouse and suppressed expression of COX-2 and cyclin D1 in HT-29 cells. CONCLUSION: PGZ down-regulates COX-2 and cyclin D1 and inhibits colon cancer proliferation and liver metastasis, making PPARgamma a candidate target for the treatment/prevention of colon cancer metastasis.

Subclassification of superficial cardia cancer in relation to the endoscopic esophagogastric junction.

BACKGROUND: The incidence of adenocarcinoma of the gastric cardia has been reported to be increasing, but the endoscopic characteristics of the mucosal background of the tumor remain unclear. The purpose of the present study was to evaluate the relationship between the location of the adenocarcinoma according to the esophagogastric junction (EGJ) and mucosal characteristics. METHODS: Patients with superficial adenocarcinoma of the gastric cardia diagnosed pathologically were enrolled and divided into the above-EGJ group and the below-EGJ group according to tumor location. The EGJ was judged as the lower end of the esophageal longitudinal vessels. We retrospectively reviewed endoscopic findings with respect to the classification of reflux esophagitis, hiatus hernia, valvular appearance of the cardia and the pattern of atrophic gastritis. RESULTS: The incidence of reflux esophagitis in the above-EGJ group and below-EGJ group was 75.0% and 30.0%, respectively. The severity of hiatus hernia and the valvular appearance of the cardia of patients in the above-EGJ group were worse than in the patients in the below-EGJ group. The pattern of atrophic gastritis in the patients in the above-EGJ group was the closed type, whereas patients in the below-EGJ group had the open type. CONCLUSION: There were significant differences between cancers above or below the EGJ, so classification of adenocarcinoma of the gastric cardia according to location is recommended.

[Retrospective analysis of treatment for advanced gastric cancer with peritoneal dissemination].

Recent development and clinical application of novel anticancer agents like S-1 have been reported to show a good outcome against gastric cancer (GC) with peritoneal dissemination (P). In our study, a retrospective analysis of the treatment for GC with P was performed. Since 1989, a chemosensitivity test with MTT assay (MTTA) using surgical specimen was performed to choose chemotherapy after surgery, resulting in good prognosis in patients who received drugs which were determined effective by the MTTA. Since 1999, S-1 was introduced as adjuvant chemotherapy, and, since 2002, initial treatment with S-1/CDDP was used for GC with P, suggesting a better prognostic outcome compared with previous results with ineffective chemotherapy or surgery alone. In conclusion, prognosis of GC with P has been improving by effective regimens with novel anticancer agents like S-1. Further research and clinical trials will be necessary to achieve a more satisfactory outcome with the treatment of GC with P.

Retrospective analysis of prognosis for scirrhous-type gastric cancer: one institution's experience.

BACKGROUND: Scirrhous gastric cancer is biologically aggressive, and the prognosis is poor even with curative surgery. We compared outcomes with different therapies in order to identify prognostic factors. METHODS: Records for 83 patients, who were treated between 1991 and 2004, were evaluated for survival and stage, treatment, and clinicopathological factors. RESULTS: Cumulative 5-year overall survival was 10.2% for all 83 patients, including 27 (32.5%) patients with stage II/III disease and 56 (67.4%) with stage IV disease. The 5-year overall survival rate and median survival time for patients with stage II/III disease after curative surgery were 24.3% and 1150 days. For patients with stage IV disease, 2-year and 5-year survival rates after initial surgery were 13.7% and 0% and median survival was 250 days. In contrast, preoperative chemotherapy for advanced, unresectable disease produced 2-year and 3-year overall survival rates of 53.6% and 26.8% and medican survival was 910 days. CONCLUSION: Aggressive surgery alone does not seem to improve outcome, but preoperative chemotherapy might be beneficial and should be investigated further.

A patient with gastric cancer and liver metastases successfully treated with combination chemotherapy including S-1.

We report the case of a 62-year-old man with advanced gastric cancer and multiple liver metastases who was successfully treated with combined chemotherapy including S-1. The patient was clinically diagnosed with stage IV (T3 N2 H1 P0) disease and was initially treated with 100 mg/body per day S-1 administered orally for 21 days and 10 mg/body per day cisplatin (CDDP) infused on days 1-5, 8-12, and 15-19. This chemotherapy resulted in significant reduction of the liver and gastric tumors. After receiving additional CDDP/S-1 administration as an outpatient, the patient's liver masses disappeared as shown on abdominal computed tomography (CT). With the patient's desire and informed consent, he underwent curative surgery with total gastrectomy, D1+alpha lymph node dissection, and partial resection of liver S4. After discharge without any surgical complication, CT revealed regrowth of the S4 liver mass, and combined docetaxel and CDDP was selected as second-line chemotherapy with local radiation therapy against the hepatic metastasis. Additionally, a third regimen with irinotecan and S-1 was given. At 2 years 7 months after the initial treatment, no sign of cancer (including liver metastasis and peritoneal dissemination) has been identified by radiological follow-up examinations.

Candida albicans aggravates duodenal ulcer perforation induced by administration of cysteamine in rats.

BACKGROUND: Candida sp are frequently isolated from the ascitic fluid of patients with perforated ulcers. The present study was performed to examine whether Candida infection may be involved in the process of ulcer perforation. METHODS: Male Wistar rats were divided into a saline group (n = 15) and a Candida group (n = 17). Cysteamine-HCl (Sigma; 31 mg/100 g) was administered thrice on day 1 to both groups of animals. Candida albicans at a density of 10(8) in 0.5 mL of saline was administered 1 h before, and 12 h and 24 h after the first administration of cysteamine in the Candida group. RESULTS: Perforated duodenal ulcers were observed in 94.1% of the rats in the Candida group, but only 26.7% of the rats in the saline group (P < 0.01). The area of the duodenal ulcers in the Candida group was 40.89 +/- 33.07 mm2, whereas that in the saline group was 16.53 +/- 20.4 mm2 (P < 0.05). The mortality rate was significantly higher in the Candida group than in the saline group. In the Candida group, colonization by C. albicans was recognized at the ulcer base, surrounded by marked granulocytic infiltration. The number of eosinophils infiltrating the ulcer base was also significantly greater in the Candida group than in the saline group. Immunohistochemical analysis revealed the expression of secretory aspartyl protease (SAP) in the region of the ulcer showing colonization by C. albicans in the Candida group. CONCLUSION: Candida albicans aggravates duodenal ulcer perforation in the experimental model of cysteamine-induced duodenal ulcer perforation. The present findings suggest that SAP and host-parasite relationships, including granulocyte-dependent mechanisms, may be involved in the aggravation of ulcer perforation by C. albicans.