Treatment of recurrent malignant supratentorial astrocytomas with carboplatin and etoposide combined with recombinant mutant human tumor necrosis factor-alpha

BACKGROUND: This study assesses the safety, tolerance and preliminary efficacy of combined treatment with carboplatin, etoposide and recombinant human mutant tumor necrosis factor-alpha (TNF-SAM2) for recurrent malignant supratentorial astrocytomas at first relapse. MATERIALS AND METHODS: Carboplatin was administered intravenously at a dose of 400 mg/m2 on Day 1, while etoposide was administered intravenously at a dose of 100 mg/m2 from Day 1 to Day 3 for 3 days. From Day 7, 80x10(4) U/m2 TNF-SAM2 was given intravenously for up to 5 injections for 2 weeks. Treatment was repeated every 8 to 12 weeks. RESULTS: Ten patients previously treated with surgery, radiation therapy and chemotherapy with a nitrosourea (ranimustine: MCNU) for malignant astrocytomas received this regimen for up to four cycles. Three patients with anaplastic astrocytomas, one patient with anaplastic oligoastrocytoma and 6 patients with glioblastomas (3 men and 7 women), aged 27 to 69 years, were eligible and were evaluated for response and toxicity. Grade 2 and 3 hematological toxicities occurred in 4 (40%) and 2 patients (20%), respectively. Grade 2 hepatic toxicity was observed in two patients. Of 9 evaluable patients, three (33%), including one glioblastoma, partially responded to the treatment (PR) with time to tumor progression (TTP) of 231, 121 and 57 weeks, respectively. Two patients had stable disease (SD), while 4 glioblastomas (44%) had progressive disease (PD) with TTP values of 11, 15, 6 and 12 weeks, respectively. CONCLUSION: These results suggest that combined therapy with carboplatin, etoposide and recombinant mutant TNF-alpha in this patient population seems to be safe and acceptable and may benefit those with recurrent anaplastic astrocytomas. These intriguing clinical observations warrant a properly stratified randomized trial to determine whether this approach can provide therapeutic benefits and improve survival.     

Genetic alterations in adenoma-carcinoma sequencing of intraductal papillary-mucinous neoplasm of the pancreas

We investigated the adenoma-carcinoma sequence in intraductal papillary-mucinous neoplasm from the aspect of genetic changes. The formalin-fixed paraffin-embedded tumors and surrounding normal pancreatic tissues from patients with 16 intraductal papillary-mucinous adenoma of the pancreas (IPMA) and 10 intraductal papillary-mucinous carcinoma of the pancreas (IPMC) were provided for DNA extraction after microdissection. SSCP-DNA sequencing analysis demonstrated K-ras mutations at codon 12 in 75% of IPMA and 70% of IPMC, while those at codon 13 were observed neither in IPMA nor IPMC. There were no characteristic K-ras mutation types in IPMA and IPMC and no significant differences in incidence of K-ras mutations between the two categories. The frequencies of p53 mutations analyzed by SSCP-DNA sequencing were not high in IPMA (18.8%) and IPMC (30%), showing no significant difference between them. LOHs of APC in IPMA and IPMC were infrequent (6.3 and 20%, respectively) and showed no significant difference in incidence between the two categories. The LOH frequencies of DCC in IPMA and IPMC were 31.3 and 40%, respectively, and were not statistically different from each other. Taken together, genetic changes such as K-ras, p53, APC and DCC mutations may not be associated with adenoma-carcinoma sequence in intraductal papillary-mucinous neoplasm of pancreas.     

Serum squamous cell carcinoma antigen is a useful biologic marker in patients with inverted papillomas of the sinonasal tract

BACKGROUND: Inverted papilloma (IP) is a frequent benign sinonasal tumor that is characterized histologically by squamous metaplasia, epithelial acanthosis, and hyperplasia of the nasal epithelium. Because of its high recurrence rate and malignant transformation potential, careful long-term follow up is necessary. METHODS: The purpose of the current report was to study the expression of squamous cell carcinoma (SCC) antigen in sinonasal IPs and to evaluate the usefulness of SCC antigen as a biologic marker for the follow-up of patients with sinonasal IP. The expression of SCCA1 in three sinonasal IP cases, three sinonasal SCC cases, and cases of normal nasal epithelium were examined by Western blot analysis, and the SCCA1 expression pattern in 31 IP specimens and 4 carcinoma in IP specimens were evaluated immunohistochemically. The serum levels of SCC antigen in 11 patients with sinonasal IP also were analyzed. RESULTS: SCCA1 was overexpressed in all three sinonasal IP tissues compared with sinonasal SCC tissues or normal nasal epithelium. SCCA1 cytoplasmic immunoreactivity was detected in the suprabasal epidermal keratinocytes of all 31 sinonasal IP cases. In the four carcinoma in IP specimens, SCCA1 expression in the papillomatous lesion was more intense than in the cancerous lesion. The serum SCC antigen level was high in 10 of 11 patients with IP (91%) and significantly decreased after surgical resection of the tumors. CONCLUSIONS: The results of the current study indicate that SCCA1 frequently is overexpressed and may play a biologic role in the development of sinonasal IPs. Serum SCC antigen may be a useful biologic marker in patients with sinonasal IP.     

Very low incidence of microsatellite instability in intraductal papillary-mucinous neoplasm of the pancreas

Intraductal papillary-mucinous carcinoma (IPMC) of the pancreas, a new entity of pancreatic cancer with a favorable prognosis, has shown a gradual increase in the number of reported cases. Patients with high-frequency microsatellite instability (MSI-H) tumors have been shown to survive longer than those with low-frequency MSI (MSI-L) or microsatellite stable (MSS) tumors in colorectal and gastric cancer. We investigated whether MSI-H in patients with IPMC can contribute to a good prognosis. The formalin-fixed paraffin-embedded tumors and surrounding normal pancreatic tissues from 10 patients with IPMCs and 16 with intraductal papillary-mucinous adenomas (IPMAs) were provided for DNA extraction after microdissection. Polymerase chain reaction (PCR) was carried out using 8 microsatellite primer marker sets. The mixed PCR samples were analyzed using a genetic analyzer. MSI-H was determined by assessment of microsatellite variations in 3 or more of the 8 tested markers. Immunohistochemical staining of the MSI-responsible proteins hMLH1 and hMSH2 was conducted for both the IPMC and IPMA samples. Ten percent of IPMC harbored MSI-H tumors, whereas no MSI-H tumors were detected in the IPMAs. Thirty percent of IPMC tumors and 25% of IPMA tumors showed MSI-L. All IPMCs and IPMAs showed normal expression of both hMLH1 and hMSH2. MSI-H and loss of hMLH1 and hMSH2 are very rare events in both IPMCs and IPMAs. We conclude that a good prognosis for patients with IPMC is not associated with MSI-H.     

Early postnatal protein malnutrition affects learning and memory in the distal but not in the proximal cue version of the Morris water maze

Learning and memory of early postnatal protein malnourished rats were investigated in the Morris water maze. During the lactation period (21 days) each litter (mother plus six male and two female pups) was provided with 16% (well-nourished) or 6% (malnourished) protein diets. After weaning, rats remained on the same diet until 49 days of age. From day 50 on all animals were fed a commercial lab chow. Experiments started on day 70. In experiment I (proximal cue version) the animals were trained to escape from water to a visible platform (3 cm above the water level) in six trials daily for four consecutive days, completing 24 trials. In experiment II (distal cue version) the animals were trained to escape from water to a submerged platform using the same procedure as in experiment II. After the 24th trial, the platform was removed and the animals were submitted to a 60-s trial (probe trial). Seven and twenty-eight days after training, the retention test was conducted in one 180-s trial. The results showed no impairment of the learning or memory of malnourished animals tested in the proximal cue version but an increased latency and distance traveled to find the submerged platform in the distal cue version of the procedure. In the distal cue version the malnourished animals also showed increased latency to find the platform 7 and 28 days after the test training. No difference due to diet was found in the probe trial test indicating that, once the task is acquired, malnourished rats can manage extra-maze cues as easily as well-nourished rats. It is suggested that the present results can be due to alterations produced by protein malnutrition in the hippocampal formation or also to reflect the higher emotionality of rats following early malnutrition, specially considering the fact that postnatally malnourished animals are more reactive to unpleasant or aversive stimuli as cold water.     

Prevention of progression of interstitial lung lesions by early combination therapy with corticosteroids and cyclosporine/cyclophosphamide in two patients with amyopathic dermatomyositis

Two patients with amyopathic dermatomyositis complicated by interstitial lung lesions were effectively treated with a combination of corticosteroids and cyclosporine and/or cyclophosphamide. A 48-year-old female patient was treated with pulse methylprednisolone and cyclosporine 2 months after onset of dermal symptoms. A 45-year-old male patient was treated with oral prednisolone and pulse cyclophosphamide 2 1/2 months after onset of dermal symptoms. Early evaluation of interstitial lung lesions and early extensive therapy may improve prognosis of interstitial lung lesions in patients with amyopathic dermatomyositis.     

Early Diagnosis of Postoperative Infection: Assessment of Whole Blood Chemiluminescence

(Received for publication on Oct. 19, 1998; accepted on Nov. 11, 1999)     

Peroxisome proliferator-activated receptor gamma activation induces cell cycle arrest via the p53-independent pathway in human anaplastic thyroid cancer cells.

Anaplastic thyroid carcinoma is one of the most aggressive human malignancies. Outcomes of intensive multimodal therapy have been far from satisfactory. Furthermore, p53 gene dysfunction, often found in this type of cancer, is known to impair the efficacy of the therapeutic agents. Specific ligands for peroxisome proliferator activated receptor gamma (PPAR-gamma) induce growth suppression in some tumor cells. In this study, we investigated the role of PPAR-gamma in anaplastic thyroid cancer cell lines (OCUT-1, ACT-1). PPAR-gamma was expressed and functional in both cell lines. Activation of PPAR-gamma with its specific ligands, troglitazone and 15-deoxy-delta 12,14-prostaglandin J2, inhibited cell growth in a dose-dependent manner through inducing G1 cell cycle arrest. P53 protein expression differed in OCUT-1 and in ACT-1, though the levels stayed constant irrespective of ligand exposure in both cell lines. In contrast, p21 and p27 proteins were induced in a dose-dependent manner in both situations. This study showed that PPAR-gamma ligands were able to induce growth suppression in anaplastic thyroid cancer cells via a p53-independent, but p21- and p27-dependent cytostatic pathway. These tumor-suppressive effects of PPAR-gamma may provide a novel approach to the treatment of anaplastic thyroid cancer.     

A case of urachal xanthogranuloma causing recurrent intestinal obstruction

A 68-year-old male was admitted to our hospital with the chief complaints of lower abdominal pain and fever. There was a tender mass palpable in the lower abdomen. Plain abdominal X-ray film revealed multiple air-fluid levels with dilated small bowel loops, suggesting intestinal obstruction. Abdominal ultrasonography, computed tomography and magnetic resonance imaging revealed a solid mass extending from umbilicus to the bladder dome beneath the rectal muscle. There was normal mucosa of the bladder by cystoscopic examination. A urachal tumor was clinically suspected and en bloc removal of the mass, the remaining urachus, umbilicus, omentum and bladder dome was performed. The histological diagnosis was urachal xanthogranuloma. The patient has remained in good health without any recurrence for 6 months since the surgery. We discuss urachal xanthogranuloma in the literature.