[Comparative survey on current status and the differences of treatment using modified FOLFOX6 regimen in patients with colorectal cancer in two general hospitals].

We surveyed the current status and the differences of treatment of colorectal cancer using modified FOLFOX6 regimen, in two general hospitals, Sakai City Hospital (A hospital) and Takarazuka Municipal Hospital (B hospital) between April 2005 and November 2006, retrospectively. The numbers of examined patients were 33 and 17 in A and B hospitals, respectively. The grade of myelosuppression and peripheral neuropathy were evaluated according to Common Terminology Criteria for Adverse Events v 3.0(CTCAE v 3.0)and Neurotoxicity Criteria of DEBIOPHARM(DEB-NTC). The setting of dosage was differed in two hospitals. In A hospital, the dosages of oxaliplatin, 5-FU bolus and 5-FU continuous infusion were more than 90% of the standard one at first time, and were reduced with almost same degree in the appearance of adverse effects. On the other hand, in B hospital, the dosages of these drugs were reduced about 20% even at first administration and, especially, the dose of 5-FU bolus tended to be remarkable reduction. Of adverse events, the rates of the appearance of neutropenia more than grade 3 was 21.2% and 47.1%, in A and B hospitals, respectively. No difference in peripheral neuropathy was detected at both hospitals. In conclusion, the differences in these two hospitals were detected in the dosage setting and myelosuppression, not in non-hematological adverse effects.

[Determining S-1 dosage at hospitals prioritizing cancer chemotherapy].

Although it is recommended that the standard S-1 dosage should be based on how large the body surface area is, an on-site setting of the appropriate dosage is often lower than the standard one, depending on the individual's condition and considering possible side effects and so, on. Here, we investigated usage conditions for S-1 as a part of field training for expert pharmacists at our hospital that performs total clinical treatments. Decreases in dosage per day for elderly patients were although the standard dosage is generally determined according to the amount of a patient's body surface. We conducted a retrospective survey with a total 90 patients by creating a tree-diagram to identify a reduction standard. It was found that the S-1 dosage was decreased when there were side effects, aggravation in performance status, decrease in kidney function, old age, combined injection chemotherapy, and a decrease in radiation therapy performance. The dosage decreases without such medical reasons were seen in only 4 of the 90 patients. The individual target dosage on the basis of daily medical examination.

[Equalization of spread of breast cancer chemotherapy regimen at general hospitals--with EC and FEC regimens].

We investigated the differences in safety and management of adverse events of chemotherapy among three hospitals, Sakai Municipal Hospital, Takarazuka Municipal Hospital and National Hospital Organization Osaka-minami Medical Center. The main purpose of this study was to equalize the spread of breast cancer chemotherapy regimen. The following three regimens were evaluated; epirubicin (75 mg/m(2)) /cyclophosphamide (500 mg/m(2)) (EC75), epirubicin (75 mg/m(2)) /cyclophosphamide (500 mg/m(2)) /5-fluorouracil (500 mg/m(2)) (FEC75) and epirubicin (100 mg/m(2)) / cyclophosphamide (500 mg/m(2)) /5-fluorouracil (500 mg/m(2)) (FEC100). Sixty-three patients were evaluated. We studied the level of myelosuppression after each regimen. As a result, there was no significant difference in neutrocyte counts at nadir after chemotherapy among hospitals and regimens. However, the values tended to be ranked EC75>FEC75>FEC100. In addition, we examined the risk of febrile neutropenia (FN) according to the multi- national association for supportive care in cancer (MASCC) scoring system. Almost all patients (61/63) were in the low risk group of FN, and only two patients had developed FN. At one hospital, patients receiving chemotherapy were prescribed ciprofloxacin tablets prophylactically for prexia over 38 deg C, and the patients learned from it. Thus, no marked difference in the safety (side effects such as myelosuppression) was recognized. However, management of side effects was different among these hospitals. In conclusion, it is very important to provide patients with adequate information on side effects.

Oxaliplatin-induced hypersensitivity reaction displaying marked elevation of immunoglobulin E.

A 74-year-old female has been diagnosed with stage IIIB rectal cancer in 2003. Following anterior resection, she received adjuvant chemotherapy with three different regimens. In August 2005, she was started on a modified FOLFOX6 regimen, and the sixth cycle of chemotherapy induced a severe hypersensitivity reaction (HSR). Immediate cessation of the infusion resulted in a disappearance of the allergic reaction 60 min later. Blood tests just after the reaction demonstrated a marked elevation of immunoglobulin E to 300 IU L(-1) (normal range: <170 IU L(-1)). This change implies the involvement of a type I reaction in the HSR. In addition, a drug lymphocyte stimulating test against oxaliplatin and levofolinate calcium (an isomer of leucovorin calcium) gave values of 696% and 107 % respectively, as compared with control serum. This suggests that the patient had an adverse reaction not only of type I but partly of type IV allergic reaction also. Oxaliplatin appears to have caused a HSR in this Japanese patient, and thus pharmacists, physicians, and other medical staff must keep a careful watch of a patient's clinical condition during chemotherapy including oxaliplatin.

Upregulation of enzymes metabolizing 5-fluorouracil in colorectal cancer.

BACKGROUND: The purpose of this study was to compare the activities of various enzymes, participating in the metabolism of 5-fluorouracil, between colorectal cancer and nontumor tissues and to investigate the association of the enzyme activities with clinicopathological backgrounds. METHODS: Activities of seven enzymes involved in nucleic acid metabolism--orotate phosphoribosyltransferase (OPRT), ribonucleotide reductase (RNR), thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, uridine phosphorylase and thymidine kinase (TK)--were measured in tumor and nontumor tissues from 28 patients who were operated on for colorectal cancers. RESULTS: OPRT, thymidylate synthase, RNR, thymidine phosphorylase, uridine phosphorylase and thymidine kinase activities were significantly higher in tumor areas than in nontumor areas. OPRT showed the highest T/N ratio (the ratio of each enzyme activity in tumor areas to that in nontumor areas). The T/N ratio of RNR activity showed a tendency to be associated with lymph node metastasis and Dukes classification. CONCLUSION: The results suggest that OPRT is a main enzyme participating in the phosphorylation of 5-fluorouracil and has an important role in tumor growth. The T/N ratio of RNR may be predictive of tumor progression.

Does cisplatin (CDDP) function as a modulator of 5-fluorouracil (5-FU) antitumor action? A study based on a clinical trial.

OBJECTIVE: To clarify whether CDDP acts as a modulator of 5-FU antitumor action in gastric cancer, patients were treated preoperatively with 5-FU + CDDP (FP) chemotherapy. PATIENTS AND METHODS: From September 2000 to November 2001 at Takarazuka Municipal Hospital, 29 patients preoperatively diagnosed with stages II-IV gastric cancer were enrolled. Written informed consent was obtained from all patients. The patients were randomly assigned to two groups: the FU group, in which patients received a continuous intravenous infusion of 5-FU 320 mg/m2 per day over 24 h a day for 5 days beginning 5 days prior to surgery, and the FP group, in which patients received bolus intravenous injections of CDDP 3.5 mg/m2 per day for 5 days prior to surgery in addition to the same infusion of 5-FU as the FU group. As indicators of the intracellular effect of 5-FU treatment, thymidylate synthase (TS) inhibition rates, TS protein levels, TS and dihydropyrimidine dehydrogenase (DPD) activity, and F-RNA concentrations were measured. RESULTS: Using Scheffe's multiple comparison test, in both treatment groups the tumor regions were found to have significantly higher TS inhibition rates than the nontumor regions (P<0.05). No significant differences in TS protein levels, TS activity, DPD activity or F-RNA concentrations were found between the four regions. CONCLUSIONS: Our results show that CDDP clinically may act to enhance the antitumor effects of 5-FU in terms of the inhibition of DNA synthesis and could therefore act as a modulator of 5-FU.

Occult gallbladder carcinoma diagnosed by a laparoscopic cholecystectomy.

PURPOSE: A laparoscopic cholecystectomy (LC) has become a common treatment modality. The incidence of occult gallbladder carcinoma (GC) diagnosed by LC has increased; however, the effects of a radical second operation after LC have not yet been demonstrated. In this study we examine the outcome of such further surgical intervention. METHODS: We clinicopathologically studied occult GC diagnosed by LC. We analyzed the results to establish a therapeutic protocol for repeated surgical intervention, and to determine whether the incidence of occult GC has increased. RESULTS: GC, which invaded the mucosa and exhibited a noninvading biliary wedge (m+/bm-), did not recur during the follow-up. GC, which invaded the subserosa (ss)+/bm- and thus required a second operation, did not recur, and the patients had a satisfactory prognosis, both short-term and long-term. One of the patients with ss+/bm+ developed peritoneal dissemination after secondary surgical intervention. CONCLUSION: After evaluating the clinical outcome of a second operation for the treatment of GC, we concluded that, even for advanced stage patients, repeated surgical intervention may improve the prognosis of GC and thus should be considered, when encountering such patients.

Immunohistochemical evaluation for intraoperative rapid pathological assessment of the gastric margin.

In patients undergoing surgery for gastric cancer, as the resection area is difficult to define preoperatively, we define the resection area by intraoperative rapid pathological assessment of the resected margin. In some patients, however, the result of postoperative assessment of a permanent section differs from the result obtained intraoperatively. In this study we explored methods of improving the accuracy of intraoperative pathological assessment. Of the patients who underwent surgery for gastric cancer at Takarazuka Municipal Hospital, between April 2000 and July 2001, intraoperative pathological assessment of the resection margin was performed in 34 because it could not be accurately defined preoperatively. The intraoperative assessment consisted of touch smear cytological examination and hematoxylin and eosin (HE) and cytokeratin (CK) histological examination. The time required to perform cytological examination and HE and CK immunohistochemistry by this modified method, which uses an ENVISION Kit/HRP, was approximately 20 minutes for each procedure. Touch smear cytological examination gave false positive results in 3 of 34 patients (8.8%). Of the 14 patients preoperatively diagnosed with signet-ring cell carcinoma, intraoperative HE histological analysis yielded a false negative result in one (7.1%). The results of CK histological assessment of these patients were all consistent with those of postoperative examination of permanent sections. Of the 20 patients preoperatively diagnosed with non-signet-ring cell carcinoma, HE analysis yielded a false negative result in one (5%). The results of CK histological assessment of these patients were all consistent with those of postoperative examination of permanent sections. Our modified CK staining method with the ENVISION Kit/HRP allows intraoperative pathological assessment to be performed accurately and rapidly. This method is more useful than HE immunohistochemistry for the assessment of resected gastric margins.

Differential effects of two fluorouracil administration regimens for colorectal cancer.

Mechanisms of anti-tumor action of 5-fluorouracil (5-FU) are presumed to inhibit DNA synthesis and RNA function, and the balance of these mechanisms is presumed to depend on the modalities of administration. On the other hand, variability of 5-FU sensitivity of the tumors is also presumed to depend on the enzymes of 5-FU metabolism (e.g. dihydropyrimidine dehydrogenase; DPD, rate limiting enzyme of catabolism) and action target (e.g. thymidylate synthase; TS). We studied the effects of modalities of administration and enzyme activities related to metabolism and target of 5-FU on the mechanism of anti-tumor action in patients with colorectal cancer. Thirty-eight patients who were diagnosed at stage II to IV preoperatively were enrolled. Patients were randomly assigned to receive 24-h protracted IV infusion of 5-FU at 320 mg/m(2)/day for 5 days (CIV group: 18 patients) or 10-min bolus IV infusion of 5-FU at the same dosage for 5 days (BIV group: 20 patients) administered from the 5th preoperative day. Specimens from the tumor and non-tumor regions were obtained by operation. F-RNA (fraudulent-RNA, or 5-FU in RNA) concentration, an indicator for action of 5-FU to RNA, and the enzyme activities of DPD and TS, an indicator for action of 5-FU to DNA, in the collected specimens were measured by GC-MS or RI-HPLC. F-RNA concentration (ng/mg-RNA) in the tumor and non-tumor region in the CIV group was 100.58+/-16.88 and 50.11+/-6.03, respectively, with a significant difference between them (P<0.05), and in the tumor and non-tumor region in the BIV group was 195.32+/-16.26 and 121.05+/-10.62, respectively, with a significant difference between them (P<0.01). F-RNA concentration in the tumor and non-tumor regions in the BIV group was significantly higher than those in the CIV group (P<0.05). DPD activity and TS activity were not significantly different between the CIV and the BIV groups in the tumor and non-tumor region, respectively. F-RNA concentration was negatively correlated to DPD activity (r=-0.540, P<0.05) in the tumor region in the CIV group. F-RNA was not correlated to DPD activity in the non-tumor region in the CIV group or in the tumor and non-tumor region in the BIV group. F-RNA was not correlated to TS activity in the tumor or non-tumor region of the two groups. DPD activity was not correlated to TS activity in the tumor or non-tumor region of the two groups. BIV inhibited RNA function more potently than CIV and this was not dependent on TS or DPD activity. As for the inhibition of DNA synthesis, other indicators should be considered further.

[A case of rectal cancer with multiple liver metastases that responded dramatically to pharmacokinetic modulating chemotherapy/CPT-11 therapy].

A 67-year-old male patient suffering from rectal cancer complicated by multiple hepatic metastases underwent low anterior resection, cholecystectomy and hepatic arterial cannulation. He was treated postoperatively with arterial infusion pharmacokinetic modulating chemotherapy (PMC) and venous infusion CPT-11 (modified PMC). After three courses of modified PMC, a complete response (CR) of the hepatic metastatic lesions was noted. PMC/CPT-11 therapy was managed at our outpatient clinic, and seems to be a useful treatment option.