Intra-arterial chemotherapy with gemcitabine (GEM) for unresectable pancreatic cancer

PURPOSE: Most patients with pancreatic cancer are unresectable because of local invasion and liver metastasis at the time of diagnosis. To date, no treatment has had a significant impact on this disease. To deliver a high concentration of drug to the cancer, intra-arterial chemotherapy with GEM was performed in two patients with unresectable advanced cancer. PATIENTS AND METHODS: One patient, a 70-year-old man with liver metastasis, was treated with arterial infusion of GEM 1,000 mg/body. Another patient, a 55-year-old woman with local invasion and distant metastatic lymphadenopathy, was given intra-arterial infusion of GEM 400 mg and intra-venous infusion of GEM 1,000 mg/body. The patients were given GEM weekly for 3 weeks followed by a week of rest. RESULTS: In the first patient, the pain went away and CEA was decreased for 6 months. After that, the patient died due to intra-abdominal dissemination within 4 months. In the other patient, the pain went away. Tumor markers, such as CEA and CA19-9, were normalized and primary pancreatic cancer was reduced locally. The patient currently has a metastatic liver tumor, but she has had a significant improvement in performance status. CONCLUSION: Intra-arterial chemotherapy with GEM may be tolerated in patients with unresectable pancreatic cancer.     

A novel sustained release system for aqueous cis-platinum

The authors devised a novel sustained release system for aqueous cis-platinum (CDDP) to study in vitro the degradability of the carrier materials and the release profile of the CDDP. We first prepared fibrin hydrogels with clinically used biomedical materials, and irradiated the gels with ultraviolet (UV)-rays to form gradually degradable drug carriers. We then loaded aqueous CDDP into the carriers under negative pressure. These prepared materials were incubated in fibrinolytic test medium at 37 degrees C for the in vitro studies. The UV-irradiated materials slowly degraded and dissolved within 10-15 days, while non-UV-treated carriers disintegrated in 4-5 days. Each carrier showed a sustained release of CDDP. Most of the CDDP delivered was revealed to be the protein-binding (larger than 10 kDa) form. Free-CDDP was almost nil. The antineoplastic efficacies of this new drug delivery system developed using an original technique are now being investigated.     

A case of vulval extramammary Paget's disease associated with pancreatic cancer that was successfully treated with chemotherapy

We report the case of an 84-year-old woman with vulval extramammary Paget's disease associated with pancreatic cancer who was successfully treated. At first, biweekly low-dose FP (cisplatin 10 mg/body, 5-fluorouracil 250 mg/body) was administered by intravenous infusion. Next, we attempted a regimen of gemcitabine (1,000 mg/body) was administered weekly by intravenous infusion. As a result, the size of the pruritic lesion of the vulva was reduced more than 50%, and the serum level of CA19-9 decreased clearly. These treatments would be a valid option in certain cases of pancreas cancer and extramammary Paget's disease.     

Treatment of hypercalcemia of malignancy with pamidronate in a patient with advanced recurrent oral cancer

Hypercalcemia of malignancy is a common problem for cancer clinicians. Treatment of hypercalcemia of malignancy with pamidronate in a patient with advanced recurrent oral cancer is reported herein. The patient was a 36-year-old man who had neck lymph node metastases due to recurrence of squamous cell carcinoma of the buccal mucosa and complained of cloudiness of consciousness due to hypercalcemia. The patient was administered pamidronate. A fine reduction in serum calcium was observed and cloudiness of consciousness was also alleviated. Although treatment of hypercalcemia with pamidronate is palliative, it is effective against the deterioration of quality of life.     

Different genetic alterations in rat forestomach tumors induced by genotoxic and non-genotoxic carcinogens

Human beings are exposed to a multitude of carcinogens in their environment, and most cancers are considered to be chemically induced. Here we examined differences in genetic alterations in rat forestomach tumors induced by repeated exposure to a genotoxic carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or N-methylnitrosourethane (MNUR), and chronic treatment with a non-genotoxic carcinogen, butylated hydroxyanisole (BHA) or caffeic acid (CA). A total of 132, 6-week-old male F344 rats were employed. Forty rats were treated with MNNG by intragastric administration at a dose of 20 mg/kg body wt once a week for 32 weeks, and 20 rats received 20 p.p.m. MNUR in their drinking water for 48 weeks. Further groups of 20 animals were administered 2% BHA or 2% CA in the diet for 104 weeks. The remaining rats were maintained without any supplement as controls. Multiple forestomach tumors were observed in all rats of the MNNG-, MNUR-, BHA- and CA-treated groups. Histopathologically, MNUR- and CA-treated groups showed almost the same pattern. On polymerase chain reaction-single strand conformation polymorphism analysis, H-ras and p53 gene mutations were observed at high and relatively low frequencies, respectively, in forestomach tumors induced by MNNG and MNUR. Most H-ras gene mutations were G-->A transitions in codons 7 and 12 of exon 1. On the other hand, forestomach tumors due to the non-genotoxic carcinogens, BHA and CA, had almost no mutations of the H-ras and p53 genes. Moreover, relative overexpression of cyclin D1 and p53 was detected in forestomach tumors induced by the genotoxic carcinogens, while their non-genotoxic counterparts had a tendency to show low expression of those molecules. Mutations of the beta-catenin gene were not detected in any group. The present study demonstrates that rat forestomach tumors induced by genotoxic and non-genotoxic carcinogens have different underlying genetic alterations, even if their pathological features are similar.     

Enhanced Apoptosis in Pilocytic Astrocytoma: A Comparative Study of Apoptosis and Proliferation in Astrocytic Tumors

Both cell proliferation and cell death occur simultaneously in tumor tissue, and extent of tumor growth reflects the net balance of these events. We correlated cell proliferation, spontaneous cell death, and alterations in tumor suppressor proteins with one another and with survival of patients with primary astrocytic tumors. In 39 astrocytic tumor specimens (6 pilocytic astrocytomas, 14 fibrillary astrocytomas, 9 anaplastic astrocytomas, and 10 glioblastomas), we determined the MIB-1 labeling index, the apoptotic ratio according to nick end labeling with morphologic confirmation, the p53 labeling index, and the presence of p53 or PTEN mutations.MIB-1 labeling indices of pilocytic astrocytomas, fibrillary astrocytomas, anaplastic astrocytomas, and glioblastomas were 0.30±0.32; 1.84±1.87; 19.3±6.42; and 28.0±14.5 (mean±SD), respectively. Corresponding apoptotic ratios were 17.9±5.16; 3.96±3.57; 1.18±0.93; and 2.11± 1.60 (mean±SD). The apoptotic ratio in pilocytic astrocytomas was significantly higher than in other astrocytic tumors (fibrillary astrocytomas, p<0.05; anaplastic astrocytomas and glioblastomas, p<0.01). MIB-1 showed a significant negative correlation with apoptosis (p<0.01). MIB-1 and apoptosis showed significant negative and positive correlations with patient survival (p<0.01). Mutations of p53 and PTEN show no correlation with survival and apoptotic ratio.The apoptotic ratio can clearly distinguish pilocytic astrocytomas from other tumors, and this biological feature may reflect less aggressive growth of pilocytic astrocytomas.     

Immunomodulatory effects of low dose cis-Diaminedichloroplatinum (cisplatin) combined with UFT and PSK in patients with advanced colorectal cancer

It is well known that cell-mediated immunity is suppressed in patients with neoplastic diseases. We have reported that soluble receptors for interleukin-2 (sIL-2R) and tumor necrosis factor (sTNF-R1) are elevated in the serum of patients with advanced colorectal cancer. The presence of these soluble receptors and immunosuppressive cytokines, including interleukin-10 (IL-10), might be important in the mechanisms of immunosuppression. cis-Diaminedichloroplatinum (cisplatin) has been reported to immunomodulate, especially when used in low dose in combination with 5-Fluorouracil (5-FU). In this study, cisplatin and UFT, a form of uracil and tegafur which is a prodrug of 5-FU, were administered with immunomodulator Polysaccharide K (PSK) to ten patients with colorectal cancer, who showed distant metastasis in the liver or lung, and the serum levels of sIL-2R and sTNF-R1 and the production of gamma-interferon (gamma-INF) and interleukin-10 by peripheral blood mononuclear cells were measured. The serum concentrations of sIL-2R and the production of IL-10 were reduced (p < 0.05) after 2 months of treatment. Thus, this combination appeared to have immunomodulative potential in patients with advanced colorectal cancer.     

Cortical functional abnormality assessed by auditory-evoked magnetic fields and therapeutic approach in patients with chronic dizziness

A long-lasting dizzy sensation is a common complaint in elderly subjects. The pathogenesis and effective treatment of such chronic dizziness (CD), however, have not yet been fully elucidated because of lack of methods for evaluating this sensation. On the basis of assumption that CD may be attributable partly to cortical functional abnormality, we attempted to estimate the function of auditory cortex by measurements of auditory-evoked magnetic fields (AEFs). Magnetic field signals in the parieto-temporal cortex were evoked by 1000-Hz tone-burst with 90-dB normal hearing level sounds, and the highest-amplitude magnetic waveforms at approximately 100-ms (N100m) were analyzed as electrical current arrows in normal subjects (n=11), patients with CD (n=27) and patients with cerebral infarction but no dizzy sensation (n=9). In the normal subjects, the current arrows pointed to a nearly straight line with small directional distortion as indicated by a rotation-degree parameter, dI(rot) of 1.59+/-0.46. In 17 of 27 CD patients, the directions of current arrows were markedly distorted showing abnormally high dI(rot) values greater than 2.50 (the mean plus two standard deviations of normal values) and disclosed a clockwise or counter-clockwise rotation in either side or both sides of parieto-temporal cortex. In all the patients with cerebral infarction, the current arrows exhibited the similar pattern as the normal subjects. None of them exhibited abnormally high dI(rot) values. We hypothesized that the rotational abnormality may be caused by abnormal neuronal excitation, since non-evoked magnetic fields in temporal lobe epilepsy demonstrated the similar current rotational abnormality as reported previously. Seven CD patients were treated with anticonvulsants, and four showed remarkable amelioration of dizzy sensation. In all the four patients with symptomatic amelioration, the disappearance of rotational abnormality in AEFs or the tendency towards disappearance was observed following symptomatic amelioration. The results of the present study suggest that the auditory center may contribute to the maintenance of equilibrium, and its dysfunction may lead to the development of CD. AEFs measurements may make it possible to evaluate the functional abnormality of auditory center and may be useful for studying the pathophysiology and treatment of CD.     

Voxel-based comparison of regional cerebral glucose metabolism between PSP and corticobasal degeneration

OBJECTIVES: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative disorders that may be accompanied by dementia and parkinsonism as clinical symptoms. The purpose of this study was to elucidate cerebral metabolic differences of these two diseases with cognitive impairments by [18F] fluorodeoxyglucose (FDG) and positron emission tomography (PET). METHODS: A total of 12 patients with PSP (age: 62.8+/-6.0 years old, m: 7, f: 5, Mini-Mental State Examination (MMSE): 23.4+/-2.6), 12 patients with CBD (age: 64.8+/-6.3 years old, m: 6, f: 6, MMSE: 22.9+/-4.5), and age-matched healthy subjects (normal control (NC)) (age: 63.8+/-7.7 years old, m: 7, f: 5) were subjected to FDG-PET to obtain glucose metabolic images. We compared regional cerebral metabolic images by a voxel-by-voxel analysis with statistical parametric mapping (SPM) among PSP, CBD, and NC subjects, and evaluated differences of hypometabolic regions. RESULTS: The patients with PSP showed reduced cerebral glucose metabolism in the medial and lateral frontal gyri, basal ganglia, and midbrain compared with NC, whereas the patients with CBD showed significant reduction in the parietal lobes (p<0.001). SPM also revealed parietal hypometabolism in CBD patients compared with PSP patients (p<0.001). CONCLUSIONS: The predominant parietal glucose metabolic reduction in CBD patients was different from previously reported findings. This finding would be the characteristic substance of patients with CBD accompanying cognitive impairments. Our findings suggest that measurement of glucose metabolism by PET and a voxel-based analysis is useful to understand the pathophysiology of these two diseases with cognitive impairments.