Findings of in vitro Analyses of Basophil Functions May Help Us Better Understand Drug Desensitization.

Drug hypersensitivity can be an important problem during pharmacological management of various diseases. Patients diagnosed as having a drug allergy usually need to avoid the offending drug, either temporarily or for life. Another way of overcoming a drug allergy is to establish desensitization using the allergen drug itself. We previously investigated in vitro desensitization of human basophils using a subthreshold dose of an IgE-crosslinking reagent. We found that basophil desensitization occurred in a dose-dependent manner over a period of one to several hours. We think that inducible basophil desensitization occurring without histamine release may explain, at least in part, the clinical features of drug desensitization in type 1 drug allergy.

Evaluation of Preoperative Chemotherapy with Modified OPTIMOX-1 Plus Bevacizumab in Patients with Advanced Rectal Cancer with Factors Contraindicative of Curative Surgery.

BACKGROUND/AIMS: The efficacy and safety of neoadjuvant chemotherapy in patients with highly advanced rectal cancer for whom radical surgery was considered difficult were evaluated. METHODOLOGY: From June 2007 to February 2011, 10 advanced lower rectal cancer patients with factors contraindicative of curative surgery with total mesenteric excision were eligible for this study. Neoadjuvant chemotherapy consisting of modified OPTIMOX1 (mFOLFOX6 and sLV5FU2 alternating administration) plus bevacizumab was administered. RESULTS: Adverse events seen with chemotherapy consisted of grade 2 leukopenia in 1 patient, but there were no cases of delayed administration or dosage reduction due to grade 2 neurotoxicity. The surgical procedures were anus-preserving resection in 8 patients, total pelvic exenteration in 1 patient, and posterior pelvic exenteration in 1 patient. A positive radial margin was confirmed in 3 patients, but radical surgery was performed, histologically as well, in the other patients. Upon comparing the clinical and postoperative histological stages, primary tumor and node downstaging was achieved in 20.0% and 70.0% of the patients, respectively. CONCLUSIONS: These findings suggest the potential utility of neoadjuvant chemotherapy consisting of modified OPTIMOX1 plus bevacizumab prior to permitting radical resection or anus-preserving surgery in patients with highly advanced rectal cancer.

Serotonin (5-HT3) receptor antagonists for the reduction of symptoms of low anterior resection syndrome.

PURPOSE: Serotonin (5-hydroxytryptamine [5-HT])3 receptor antagonists are effective for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), in which exaggerated intestinal/colonic hypermotility is often observed. Recent studies have suggested that the motility disorder, especially spastic hypermotility, seen in the neorectum following sphincter-preserving operations for rectal cancer may be the basis of the postoperative defecatory malfunction seen in these patients. We investigated the efficacy of 5-HT3 receptor antagonists in patients suffering from severe low anterior resection syndrome. PATIENTS AND METHODS: A total of 25 male patients with complaints of uncontrollable urgency or fecal incontinence following sphincter-preserving operations were enrolled in this study. Defecatory status, assessed on the basis of incontinence score (0-20), urgency grade (0-3), and number of toilet visits per day, was evaluated using a questionnaire before and 1 month after the administration of the 5-HT3 antagonist ramosetron. RESULTS: All the parameters assessed improved significantly after taking ramosetron for 1 month. The effect was more prominent in cases whose anastomotic line was lower, ie, inside the anal canal. Defecatory function was better in patients who commenced ramosetron therapy within 6 months postoperatively, as compared to those who were not prescribed ramosetron for more than 7 months postoperatively. CONCLUSION: These results suggest that 5-HT3 antagonists are effective for the treatment of low anterior resection syndrome, as in diarrhea-predominant irritable bowel syndrome. The improvement in symptoms is not merely time dependent, but it is related to treatment with 5-HT3 antagonists.

Antitumor effect of 1, 8-cineole against colon cancer.

Several essential oils possess pharmacological effects. Among the various constituents of essential oils, 1, 8-cineole has been shown to possess pharmacological effects such as anti-bacterial and anti-inflammatory effects. The effect of 1, 8-cineole on human colorectal cancer cells, however, has not reported previously. In this study, we have investigated the anti-proliferative effect of 1, 8-cineole on human colon cancer cell lines HCT116 and RKO by WST-8 and BrdU assays. The cytotoxicity of 1, 8-cineole was investigated by LDH activity and TUNEL staining. The mechanism of apoptosis by 1, 8-cineole was determined by western blot analyses. In in vivo study, RKO cells were injected into the SCID mice and the effect of 1, 8-cineole was investigated. Specific induction of apoptosis, not necrosis, was observed in human colon cancer cell lines HCT116 and RKO by 1, 8-cineole. The treatment with 1, 8-cineole was associated with inactivation of survivin and Akt and activation of p38. These molecules induced cleaved PARP and caspase-3, finally causing apoptosis. In xenotransplanted SCID mice, the 1, 8-cineole group showed significantly inhibited tumor progression compared to the control group. These results indicated 1, 8-cineole suppressed human colorectal cancer proliferation by inducing apoptosis. Based on these studies 1, 8-cineole would be an effective strategy to treat colorectal cancer.

Enhanced antitumor activity of cerulenin combined with oxaliplatin in human colon cancer cells.

Fatty acid synthase is highly expressed in many types of human cancers. Cerulenin, a natural inhibitor of fatty acid synthase, induced apoptosis in the human colon cancer cell lines HCT116 and RKO. Oxaliplatin also induced cell death in these cell lines. Cerulenin treatment was associated with reduced levels of phosphorylated Akt, activation of p38 and induced caspase-3 cleavage and finally caused apoptosis. Oxaliplatin induced activation of the p53-p21 pathway and p38. In combination with cerulenin and oxaliplatin, activation of the p53-p21 pathway and p38 occurred in a smaller concentration and finally induced caspase-3 cleavage in a smaller concentration of cerulenin and oxaliplatin. In xenotransplanted SCID mice, the cerulenin + oxaliplatin group significantly inhibited tumor progression compared to the control, cerulenin and oxaliplatin groups. Based on these studies, inhibiting fatty acid synthase would be an effective strategy to treat unresectable colorectal cancer tumors in combination with oxaliplatin. Fatty acid synthase inhibitor would be one of the best counterparts of oxaliplatin, which reduces the dose and side-effects of oxaliplatin and would make it possible to endure the chemotherapy over a longer period.

[Evaluation of modified OPTIMOX1 plus bevacizumab as the neoadjuvant therapy for highly advanced rectal cancers].

UNLABELLED: We evaluated the efficacy and safety of neoadjuvant chemotherapy using modified OPTIMOX1 plus bevacizumab for advanced rectal cancer. PATIENTS AND METHODS: Nine cases with highly advanced rectal cancer for which curative surgery was potentially difficult were enrolled(clinical T4 in 7 cases, lateral node metastasis in 3 cases, M1 in 2 cases). RESULTS: The number of courses of modified OPTIMOX1(mFOLFOX6 and sLV5FU2, alternating administration)plus bevacizumab ranged from 1 to 21(median: 10). Surgical procedures consisted of internal sphincter resection(ISR)in 4 patients, ultra-low anterior resection(ULAR)in 2 patients, pelvic exenteration(TPE)in 2 patients, and Hartmann's procedure in 1 patient. Liver resection was conducted in 2 patients. RM1 was confirmed in 2 patients, but curative surgery was performed in the other patients. Histological efficacy of grade x/1a/1b/2were seen in the above 1/4/2/2 cases, respectively. Neurotoxicity associated with oxaliplatin was mild; no grade 3 neurotoxicity was noted. Recurrence has been confirmed in 5 patients at the median follow-up period of 650 days. CONCLUSION: It was suggested that modified OPTIMOX1 plus bevacizumab is effective and safe to administer as a neoadjuvant chemotherapy for curative resection or anus-preserving surgery in patients with highly advanced rectal cancer.

[An analysis of palliative surgery for the patients with malignant bowel obstruction].

PURPOSE: The objective of this study was to clarify the surgical outcome of patients with palliative surgery for malignant bowel obstruction. OBJECTIVE AND METHODS: This study investigated the clinical features, operative procedures and postoperative course of 35 patients who underwent a palliative surgery for malignant bowel obstruction. And then the patients were divided into two groups; Patients in A group were consisted of 4 patients with hospital death and 7 patients with postoperative complications. Patients in B group were consisted of 24 patients without hospital death or postoperative complications. RESULT: Eighteen patients who had been inserted nasogastric tube or ileus tube in the preoperative state could be removed. Thirty-three of 35 patients(94.3%)could become an oral ingestion. Four of 35 patients(11.4%)could not be discharged; 3 patients died of cancer and 1 patient died of acute myocardial infarction. Postoperative complications were seen in 7 patients except 4 patients with hospital death. The median postoperative stay was 18 days(3-58). Twenty six of 35 patients(74.3%) underwent chemotherapy. The median survival time was 137 days(3-1,614). The patients in A group showed a lower level of albumin(p=0.0071)and hemoglobin,(p=0.0006)and poorer performance status(p=0.0178)than the patients in B group. The median hospital stay of the patients in A group and B group were 28 days and 16 days, respectively(p=0.0823). The median survival time of the patients in A group and B group were 42 days and 119 days, respectively(p=0.0035). CONCLUSION: We concluded that the palliative surgery made an oral ingestion possible and improved a quality of life of the patients with malignant bowel obstruction. However, the surgical indication should be carefully decided for the patients with low albumin, hemoglobin and poor performance status.