A case of insulin allergy successfully managed using multihexamer-forming insulin degludec combined with liraglutide.

BACKGROUND: Insulin allergy, one of insulin's adverse effects, is rare, especially in patients with Type 2 diabetes, but management is difficult and no effective strategy has yet been established. We experienced an insulin allergy case successfully managed with a novel combination of insulins. CASE REPORT: A 38-year-old woman started insulin therapy when diabetes was diagnosed at age 19 years. Despite poorly controlled diabetes because of poor adherence, she hoped to conceive a child and continuous subcutaneous insulin infusion was introduced using insulin aspart at age 32 years. One month thereafter, she developed skin reactions at the subcutaneous insulin infusion catheter insertion site. The patient was then tested for all rapid-acting insulin formulations, all of which triggered local reactions. She decided to continue the continuous subcutaneous infusion of human regular insulin, accompanied by oral cetirizine hydrochloride and betamethasone valerate ointment. The patient was admitted to our hospital at age 38 years with high HbA1c levels. She was tested for all long-acting insulin analogues. All results, except for insulin degludec, were positive. She discontinued continuous subcutaneous insulin infusion and switched to insulin degludec combined with liraglutide. The allergic reactions had completely disappeared and her blood glucose was well controlled by the time of discharge. CONCLUSION: Our patient was allergic to all insulin formulations except insulin degludec. Her allergic reactions completely disappeared after switching to insulin degludec. The crystallized structure of this insulin might mask its skin allergen antigenicity. Furthermore, her postprandial hyperglycaemia was successfully controlled with liraglutide. We propose multihexamer-forming ultra-long-acting insulin plus glucagon-like peptide-1 analogues as a therapeutic option for patients with insulin allergy.

Feasibility of a novel weekday-on/weekend-off oral UFT schedule as postoperative adjuvant chemotherapy for colorectal cancer. UFT Compliance Study Group, Kanagawa, Japan.

PURPOSE: When oral anticancer agents are used for adjuvant chemotherapy of colorectal cancer, compliance and feasibility become issues because of the long treatment time. Appropriate studies of these issues are lacking. We investigated compliance and feasibility during a weekday-on/weekend-off schedule of oral UFT (uracil-tegafur) over a period of 1 year administered as adjuvant chemotherapy to patients with colorectal cancer. PATIENTS AND METHODS: A UFT dose of 600 mg/day was prescribed according to a weekday-on/weekend-off schedule to 87 patients after potentially curative resection. Compliance was investigated in three ways: physician interview, patient self-report, and chemical analysis of urine. The results were compared with the dose prescribed. Feasibility was evaluated on the basis of two indices: relative performance (RP), which was the ratio of the actual total dose taken to the total dose planned, and individual dose intensity (IDI), which was the ratio of the actual dose taken to the dose planned during a given period. RESULTS: The compliance assessed by physician interview and by patient self-report conformed well with the prescribed dose, the rate of agreement among the three compliance measures being more than 94%. Chemical analysis of urine in 38 of the patients revealed that they were actually taking the drug. The RP was 0.72, and the IDI was 0.8. CONCLUSION: From these results, the feasibility of the weekday-on/weekend-off schedule was judged to be good. It is suggested that the feasibility would be even better if the dose of UFT was set according to body surface area.

Secondary aneurysm due to arterial injury during surgical procedures.

Most secondary aneurysms following trauma to the cerebral artery were reported as a complication of head injury. Three cases of aneurysm due to arterial injury during operations are reported. A search of the world literature revealed ten other cases. The responsible surgical procedure and the location of these aneurysms varied. Rupture of these aneurysms was observed in four cases at 10 to 23 days following the primary operation. Only two patients died.

Congenital absence of the portal vein and role of liver transplantation in children.

BACKGROUND/PURPOSE: Congenital absence of the portal vein (CAPV) is a subtype of congenital portosystemic shunt, which can cause a broad spectrum of clinical manifestations. The authors report on 4 patients with CAPV including a boy with CAPV-associated encephalopathy, which was resolved effectively by liver transplantation (LT). METHODS: The case records of 4 pediatric patients with CAPV who were referred to the author's institution between 1984 and 1999 were reviewed. RESULTS: The patients (3 boys and 1 girl) ranged in age at diagnosis from 0.8 to 14 years. Two patients had growth retardation or disturbed consciousness, and the other 2 had no specific manifestations. Not only high serum levels of bile acids, ammonia, and transaminases but also low plasma levels of branched-chain amino acids were common laboratory findings. The absent portal vein was replaced by a large portosystemic shunt, which connected the splanchnic vein to the inferior vena cava or the left renal vein. Two patients survived without any symptoms, but 1 with growth retardation died of hepatic failure. The other with encephalopathy did not respond to medical therapy and underwent LT, which resolved symptoms and metabolic disorders effectively. CONCLUSIONS: Patients with CAPV do not always have a good prognosis. They should be followed up with careful observation of their symptoms, hepatic function, and metabolic abnormalities. LT might be indicated for patients with symptomatic CAPV unresponsive to medical therapy.

Angiogenesis in hepatocellular carcinoma as evaluated by alpha smooth muscle actin immunohistochemistry.

BACKGROUND/AIMS: Angiogenesis has been known to be associated with tumor development. In this study, neovascularization in small hepatocellular carcinoma was investigated by evaluation of intratumoral arteriole counts, using alpha smooth muscle actin antibody immunohistochemistry. METHODOLOGY: Surgical specimens from 38 patients with small hepatocellular carcinoma were immunostained for alpha smooth muscle actin and proliferating cell nuclear antigen. The correlation between intratumoral arteriole density and clinicopathological factors including angiographic findings, proliferative activity, and patient prognosis were analyzed. RESULTS: Significant difference in intratumoral arteriole density were observed between well-differentiated hepatocellular carcinoma and poorly differentiated hepatocellular carcinoma (P = 0.004) or moderately differentiated hepatocellular carcinoma and poorly differentiated hepatocellular carcinoma (P = 0.011). The mean intratumoral arteriole count in the tumors showing angiographic hypervascularity was significantly higher than that in the tumors without angiographic hypervascularity (P = 0.011). A significant and positive correlation was found between proliferating cell nuclear antigen labeling index and intratumoral arteriole density (r = 0.5232, P = 0.001). A high intratumoral arteriole density in tumor was significantly correlated with shorter patients survival (P = 0.018). Cox's multivariate regression analysis showed that the intratumoral arteriole density was independent prognostic factors (P = 0.0306). CONCLUSIONS: Intratumoral arteriole density was found to be significantly associated with histological grade, proliferative activity, and patient survival. It also reflected the angiographic findings. Alpha smooth muscle actin antibody immunohistochemistry would provide a simple and biologically significant method which is usable to screen neovascularization and arterial blood supply in hepatocellular carcinoma, and may have predicting utility for patients outcome. This technique is applicable to routine paraffin sections, and may be useful as an adjunct to surgical pathology of hepatocellular carcinoma.

Visualization of nasopharyngeal carcinoma with Tl-201 chloride and a three-head rotating gamma camera SPECT system.

Tl-201 SPECT was performed on 12 patients with nasopharyngeal carcinoma (NPC) by means of a three-head rotating gamma camera to evaluate whether or not Tl-201 SPECT was useful and reliable for assessing the tumor viability of NPC. Tl-201 clearly accumulated in the tumor in 3 patients before radiation treatment and increased Tl-201 uptake by the lesion ceased after the treatment. Three of 9 patients who were followed up after radiotherapy developed apparent local recurrence and Tl-201 SPECT clearly visualized these recurrent lesions. Tl-201 SPECT was very useful for assessing the tumor response to irradiation and for detecting local recurrent tumor. A high resolution SPECT system employing Tl-201 chloride is a new reliable and accurate diagnostic tool for the assessment of NPC.

Voice preservation technique in the surgical treatment of postcricoid cancer.

In patients with freedom from invasion to anterior half of the larynx in postcricoid and cervical esophageal cancer, reconstruction of vocal tract with preservation of the anterior half of the larynx is applied with oncologic rationality and we performed the procedure in three cases of T2N1. At neck dissection bilateral superior thyroid neurovascular pedicles and unilateral inferior thyroid vessels were preserved. The larynx and upper part of the trachea were devided on the frontal plane and the posterior half with the hypopharynx and cervical esophagus was removed. The anterior half of the part was preserved and the mucosal edges of the cut surface extending from the appropriate margin of membranous portion of the trachea to the aryepiglottic folds were longitudinally approximated to reconstruct a thin tube to rehabilitate the voice. The pharyngoesophagus was replaced by either deltopectoral flap or forearm flap. Postoperative aspiration was minimal and voice rehabilitation was satisfactory.

Dissection of parapharyngeal space in head and neck cancer.

The parapharyngeal space is a potential space located lateral to the upper pharynx and tonsillar area. This space can be involved either by direct extension, by perineural or neural spread, or by lymph node metastasis from cancers originating in adjacent sites. Between 1978 and 1984, 22 patients with T3 or T4 carcinoma of the head and neck region underwent dissection of the parapharyngeal space in conjunction with ablation of the primary tumor and standard radical neck dissection. Twelve of these patients had carcinoma arising in the oral cavity, 4 in the oropharynx, and 6 in the major salivary glands. Surgical approaches applied to the dissection of the space were the submandibular route combined with the transoral approach in 1 patient, transparotid in 3, the mandibular "swing" approach in 9, and mandibular composite resection in 9. The last 2 approaches allowed excellent control of the neurovascular structures up to their entrance into the skull base. In 18 patients of this series, the tumor was locoregionally controlled in 5 to 77 months (median 23 months) of follow-up. Dissection of the parapharyngeal space improves locoregional control rate of advanced head and neck cancers involving this space.

[A case of multiple chemodectoma: clinical and electron microscopical studies]. / Ein Fall des multiplen Chemodektoms. --Klinische und elektronenmikroskopische Untersuchungen--.

We observed electronmicroscopically and clinically a case of multiple chemodectoma, which has occurred from glomus caroticum sinistra and glomus jugularis sinistra of a 18 year old boy. The diagnosis was especially made by an angiography of the left common carotid artery and by a retrograde venography of the left internal jugular vein. Electronmicroscopically two kinds of tumor cells in this chemodectoma were identified. These cytoplasmas showed cored neurosecretory granules measured 125 to 250 A in diameter markedly increasing in number. Moreover in the island of the tumor cells of the carotid body tumor we happened to observe the nerve ending.

Parathyroid gland adenoma in primary hyperparathyroidism: report of two cases--chief and oxyphil cell adenoma.

Parathyroid adenomas are classified into two types: chief cell and oxyphil cell variants. In this report two types of parathyroid adenoma in association with hyperparathyroidism were examined. Both cases had suffered from renal calculi, and underwent operation. The laboratory tests showed high serum calcium and parathyroid hormone (PTH) levels. An exploratory surgery revealed a solitary tumor in each case. After extirpation of the parathyroid tumor these data returned to normal values. Electronmicroscopically, oxyphil cell adenoma in this report was characterized by numerous mitochondria and annulate lamellae in the cytoplasm. In some tumor cells secretory-like granules were observed.

[Efficacy of hepatic arterial and intraportal infusion chemotherapy for liver metastasis of colorectal cancer].

We evaluated the effect of hepatic arterial infusion chemotherapy (HAI) and intraportal infusion chemotherapy (IPI) for liver metastasis of colorectal cancer. Since 1980, 89 patients with colorectal cancer showed liver metastasis. Seven of these cases had undergone curative resection of colon tumor and hepatectomy (5 cases with HAI). Eleven cases had undergone colon tumor resection and HAI. Among the former, 3 cases with HAI are alive, and the postoperative survival rate after 2 years improved among the latter. Curative removal was carried out in 567 patients in the same period. Recurrence of liver metastasis was observed in 30 cases, in 13 cases of which hepatectomy with HAI was performed, with HAI only in another 9 cases. The three-year survival rate among the former was 41.1% and the one-year survival rate of the latter was 16.2%. From 1986 to 1988, we performed IPI in 24 cases of colorectal cancer to prevent liver metastasis. They had undergone curative resection. Recurrence of liver metastasis was observed in one case (4.2%), which was less than in the control group (9.3%). It is concluded that HAI and IPI are effective treatment for liver metastasis in colorectal cancer.

[Hepatocyte growth factor (HGF) in fluid from operation fields of breast surgery].

Recently, it is suggested that hepatocyte growth factor (HGF) is produced by fibroblasts with Interleukin-1. Therefore tumor cells seem to be promoted by HGF in the operation fields. We measured HGF in serum and fluid from operation fields, and evaluated its clinical significance. Fifty-one breast cancer patients who underwent breast surgery were enrolled. Serum HGF was measured on the day before operation and on the first, fifth and seventh postoperative days and fluid HGF on the first and fifth postoperative days, both by ELISA method. Fluid HGF was 10-12 fold higher than serum HGF. This result indicated that fibroblasts in the operation fields probably produced HGF. Moreover, invasive surgery and long operation time induced higher HGF concentrations. Serum HGF concentrations were higher in stage IV cases than in stage I-III cases. This probably means that not only fibroblasts but also breast cancer tissues secrete HGF. Fluid addition to the culture promoted MCF-7 cells in cultivation. We suggest that HGF was produced in the operation fields by fibroblasts and that HGF promotes tumor cells.

[Therapeutic strategy for hepatic metastasis of primary colon cancer].

PURPOSE: To analyze the clinical results of treatments for hepatic metastasis of primary colon cancer for an evaluation of treatment strategies. MATERIALS AND METHODS: Two hundred and twenty-five patients with only hepatic metastasis of primary colon cancer (synchronous tumors, 164 patients: metachronous tumors, 61 patients) between 1983 and 1999 were studied. Of these 225 patients, 68 patients (synchronous tumors, 39 patients: metachronous tumors, 29 patients) were treated with curative resection. These 225 patients were categorized into group A (chemotherapy only), group B (hepatic arterial infusion only), group C (curative resection + hepatic arterial infusion), and group D (curative resection only). The therapeutic results were compared. RESULTS: The five-year survival rate and five-year recurrence-free rate of 68 patients with curative resection were 40.6% and 31.0%. By therapeutic modality, the five-year survival rate and five-year recurrence-free rate of the 36 patients of group C were 40.7% and 29.5%, and those of the 32 patients of group D were 43.4% and 33.0%, respectively. No significant difference was found between these two groups. However, in the patients with synchronous tumors, the five-year survival rate and five-year recurrence-free rate of group C and group D were 65.7, 49.6% and 13.8, 15.9%, respectively. The results of group C were significantly better than those of group D. Recurrence was found in 36 patients (52.2%). Among these patients, 25 (36.8%) recurred within one year from the end of treatment(s). Twenty-one patients (32.4) had the recurrence in the residual liver, and 14 (17.6%) had metastasis to the lung. In group B, in which curative resection was impossible, the one-year and two-year survival rates in the patients with synchronous tumors were good in comparison with those of group A. Herein we report two cases in which hepatic arterial infusion was effective. CONCLUSION: It is important to set aggressive resection and hepatic infusion as a fundamental treatment policy, and to perform not only hepatic infusion but to combine other treatments with consideration of the next recurrence.

[Intraoperative radiation therapy (IORT) for locally unresectable pancreatic cancer].

To evaluate the therapeutic effect of IORT for unresectable locally advanced pancreatic cancer, 11 patients treated with IORT and 15 patients treated with palliative therapy only were retrospectively examined. The mean age of the IORT group was 61.9 years, 5 cases were classified into surgical stage IVa, and 6 into stage IVb. The mean age of the palliative therapy group was 69.1 years; 5 cases were classified into surgical stage IVa and 10 into stage IVb. The tumor size was measured in 6 cases in the IORT group, before and after IORT. The tumor was enlarged in 1 case, not changed in 4 cases, and reduced in 1 case. The serum CA19-9 level was measured in 8 cases of the IORT group. Serum CA19-9 was increased in 3 cases, not changed in 4 cases, and decreased in 1 case after IORT. ECOG pain scores were obtained in 9 patients who had complained of pain before IORT, and the score decreased in 7 cases. The median survival was 7.6 months in the IORT group and 3.0 months in the palliative therapy group. IORT may improve patients' QOL by decreasing their pain. However, further studies are necessary to confirm the efficacy of IORT for survival of locally unresectable pancreatic cancer patients, because the patient profile in this study was different in the two groups.

[Clinical effects of Juzendaiho-to on immunologic and fatty metabolic states in postoperative patients with gastrointestinal cancer].

Juzen-daiho-to is one of the Chinese traditional medicines which is usually applied with patients suffering from anemia or chronic exhaustive disease. Twenty-three patients after gastrectomy and 16 patients after colectomy were studied for NK cell activity, blastogenesis by PHA, several T-lymphocyte subsets, serum triglyceride and serum lipo-protein before drug administration at one, three, six, nine months and one year after the start of drug administration respectively. A remarkable elevation in NK cell activity was noted 3 and 6 months after the drug administration. Statistical analysis shows a significant converse correlation between NK cell activity and lipo-protein value in the group given Juzendaiho-to.

[Preoperative treatment of lymph node metastases of gastric cancer by local injection of 5-FU adsorbed on activated carbon--clinical study of 5-FU concentration in resected lymph nodes].

The concentration of 5-fluorouracil (5-FU) in blood and lymph node of 55 patients with gastric cancer who were endoscopically injected 250 mg of 5-FU alone or adsorbed on activated carbon into the gastric wall or 300 mg of 5-FU dry syrup orally before operation, were measured chronologically. The concentration of 5-FU in blood were similar in all cases but higher in lymph node in the group given adsorbed preparation than other cases. In the cases given adsorbed preparation, the lymph node concentration was remained high 7 days after injection, and in 37% cases more than the minimum inhibitory concentration of 5-FU remained. Therefore, for the purpose to elicit anticancer effect on micrometastasis in lymph nodes in the patients with gastric cancer, endoscopically preoperative injection of 5-FU adsorbed on activated carbon seemed to be useful.

[Phase II study of carboplatin in head and neck cancer].

To evaluate the clinical efficacy and safety of carboplatin for head and neck cancer, a phase II study was conducted in 21 institutions. Eighty-eight patients were entered into this trial, of which 70 were evaluable. Carboplatin was administered intravenously over 0.5-1 hr at the dose of 400 mg/m2 in good risk cases and 300 mg/m2 in poor risk cases. One patient achieved complete response(CR) and 13 achieved partial response(PR) with an overall response rate of 20%. In terms of response by histology, the response rate was 22% in cases of squamous cell carcinoma. The response rate was 26% in previously untreated patients and 16% in previously treated patients. One CR and 2 PR were achieved in 14 patients with prior cisplatin treatment. Toxicity was observed in 47% of the 70 evaluable patients. Nausea and vomiting were the most common toxicity observed (36%) followed by anorexia in 27%. Concerning hematologic toxicity, thrombocytopenia was noted in 32% and leukopenia in 29%. Elevation of BUN and creatinine was observed in only 2 cases and 1 case, respectively. It was concluded that carboplatin suggested activity similar to cisplatin, and also could be safely used at the outpatient level.

[Optimal dosage of UFT in a weekday-on/weekend-off schedule as a postoperative adjuvant chemotherapy for colorectal cancer].

In evaluations of adjuvant chemotherapy with oral anticancer agents, compliance in taking the drug as prescribed (compliance), adverse reactions, and feasibility are important factors in setting the dose. A weekday-on/weekend-off schedule, in which 600 mg/day of UFT was taken for 5 consecutive days and not taken on the following 2 days, was carried out as a postoperative adjuvant chemotherapy for one year in 87 patients with colorectal cancer who had undergone potentially curative resection. The prescribed dose and the dose of ingestion confirmed by physician interview were both highly consistent with the dose of ingestion according to the patients' self reports, with consistency rates of more than 94% for both. Relative performance (RP) yielded a value of 0.72, and individual dose intensity (IDI) yielded 0.8 on average. Female gender, low body weight, and low body surface area were factors that negatively affected feasibility. None of the adverse reactions was serious. Based on the feasibility and adverse reactions, the dosage of UFT should be set according to the body surface area at 375-425 mg/m2/day. When this schedule is used as one arm of a controlled study, it is suggested that the dose should be decided with 400 mg/m2 as a guideline.

[Effect of levamisole in postoperative adjuvant immunochemotherapy of stomach cancer--randomized controlled study of MMC-5-FU combination therapy with or without levamisole. 1].

A randomized controlled study by envelope method was carried out with the purpose of evaluating effects and side effects of levamisole in patients with resectable stomach cancer. The patients were randomly allocated to the treatment either with control or levamisole according to the indication of the envelope opened at least 3 days prior to surgery. The control group was treated with Mitomycin C (day 0, 20 mg day 1, 10 mg, one shot i.v.) and 5-FU(150 mg/day, p.o.). The levamisole group was treated with Mitomycin C, 5-FU and levamisole. Levamisole was administered at a daily dose of 150 mg for 3 consecutive days before surgery, and the 3 consecutive days administration schedule was repeated every fortnight for one year after surgery. Four hundred and forty-six patients were entered in this trial. However, with the exclusion of 104 patients as exceptions and dropouts, the total eligible patients were 342, consisting of 167 in the control group and 175 in the levamisole group. The effects were evaluated by comparing the disease-free interval or the survival time of both groups. There was no significant difference in the disease-free interval and survival. In this study, we have not yet reached the conclusion that levamisole is effective in prolonging disease-free interval and survival time, because high survival rates are still maintained in both groups for 2 years after surgery. The final conclusion would be drawn with the follow-up results in the future.

[Moderate dose methotrexate with citrovorum factor rescue therapy in the treatment of head and neck cancer].

A clinical trial of moderate dose methotrexate (MTX)-CF rescue was conducted in 12 institutions. Thirty-seven patients with head and neck carcinoma entered this trial, of which 32 were evaluable. MTX was administered 350 mg/m2 (500 mg/body) by i.v. drip over 6 hours. Three hours after completion of MTX infusion, CF rescue was started. There was no complete response in 32 patients. Nine patients showed partial response with the response rate of 28%. The response rates were 21% for the group of patients treated previously, and 75% for the group untreated previously. MTX concentration in plasma was determined at 6, 24, 48 and 72 hours after the initiation of MTX infusion, and the assay results revealed a safe range. GI disturbances were seen at the rates of 11 to 38%. Bone marrow suppression was mild and no renal toxicity was observed. We concluded that the moderate dose MTX-CF rescue therapy was useful for head and neck carcinoma. As a next step, we are planning to conduct a clinical trial of high-dose MTX.