A case of cerebral toxoplasmosis

A histopathologically proven case of cerebral toxoplasmosis in a young HIV positive patient has been presented. The clinical problems in management are highlighted.     

Radical Resection of Periampullary Tumors in the Elderly: Evaluation of Long-term Results

Increasingly, patients of advanced age are coming for evaluation of periampullary tumors. Although several studies have demonstrated the safety of resecting periampullary tumors in older patients, few long-term survival data have been reported. Between 1983 and 1992 various periampullary masses were resected in 70 patients over age 65 (range 65–87 years). Total pancreatectomy was performed in 11 patients, and 59 patients underwent pancreaticoduodenectomy. The mean duration of hospitalization was 17 ± 15 days. Major complications occurred in 27 patients (39%), and operative mortality rate was 8.5%. Overall median survival was 24 months; and 5-year survival was 25%. Perioperative outcome was compared in patients aged 65 to 74 years and in patients ≥75 years old. The older age group required longer periods in the surgical intensive care unit postoperatively, but the long-term survival was similar in the two age groups. Radical resection with the intent to cure periampullary tumors is safe in selected patients of advanced age, and long-term survival is in the range of expected survival for younger patients with the same tumors.     

Dismal rehabilitation in predominantly type II diabetics on dialysis in Inner-City Brooklyn

AIM: In order to define their demographics and medical conditions, 218 diabetic patients undergoing hemodialysis in Brooklyn were interviewed and their charts reviewed. METHODS: Patient rehabilitation was assessed with the Karnofsky score, and the urea reduction rate as well as serum albumin and hematocrit levels evaluated adequacy of hemodialysis. RESULTS: The majority of patients (167) were African-American, 25 were Whites, 19 patients were Hispanic and 6 were Asian. One patient was a Native American. The mean age was 60.5 years (range 16-88), and the majority, 52%, were women. Rehabilitation was poor, the mean Karnofsky score being 65.1+/-20.8, and only 6% of patients were working. By linear regression, there was no difference in the Karnofsky score according to gender, age, race, type of diabetes, education, family income or hematocrit level. Only the patients' self-perception of their psyche function, or how well they thought they were doing, was significant. CONCLUSION: Further work is needed to examine the reasons for the poor rehabilitation of diabetics on dialysis in Brooklyn.     

Expression of the tumor suppressor gene ARHI in epithelial ovarian cancer is associated with increased expression of p21WAF1/CIP1 and prolonged progression-free survival.

PURPOSE: ARHI, an imprinted putative tumor suppressor gene, is expressed in normal ovarian epithelial cells, but its expression is down-regulated or lost in most ovarian cancer cell lines. Reexpression of ARHI in cancer cells induces p21(WAF1/CIP1), down-regulates cyclin D1 promoter activity and inhibits growth in cell culture and in heterografts. To determine the relevance of these observations to clinical cancer, we have now measured ARHI expression in normal, benign and malignant ovarian tissues using immunohistochemistry and in situ hybridization. EXPERIMENTAL DESIGN: Paraffin embedded tissues from 7 normal ovaries, 22 cystadenomas and 42 borderline lesions were analyzed using standard immunoperoxidase and in situ hybridization techniques to assess ARHI expression. In addition, immunohistochemistry against ARHI was performed on a tissue microarray containing 441 consecutive cases of ovarian carcinoma. RESULTS: Strong ARHI expression was found in normal ovarian surface epithelial cells, cysts and follicles using immunohistochemistry and in situ hybridization. Reduced ARHI expression was observed in tumors of low malignant potential as well as in invasive cancers. ARHI expression was down-regulated in 63% of invasive ovarian cancer specimens and could not be detected in 47%. When immunohistochemistry and in situ hybridization were compared, ARHI protein expression could be down-regulated in the presence of ARHI mRNA. ARHI expression was correlated with expression of p21(WAF1/CIP1) (P = 0.0074) but not with cyclin D1 and associated with prolonged disease free survival (P = 0.001). On multivariate analysis, ARHI expression, grade and stage were independent prognostic factors. ARHI expression did not correlate with overall survival. CONCLUSIONS: Persistence of ARHI expression in epithelial ovarian cancers correlated with prolonged disease free survival and expression of the cyclin dependent kinase inhibitor p21(WAF1/CIP1).     

Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial.

PURPOSE: Gemcitabine remains the standard therapy for metastatic pancreatic adenocarcinoma (ACA), but has limited activity. ISIS-2503 is an antisense compound directed against H-ras with preclinical activity against pancreatic ACA in tumor models. The combination of ISIS-2503 and gemcitabine has been evaluated in a prior phase I study. METHODS: Patients with metastatic or locally advanced pancreatic ACA not amenable to surgery or local radiation received gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1 and 8 and ISIS-2503 6 mg/kg/d as a continuous intravenous infusion over 14 days of an every-3-weeks cycle. Responses were monitored by radiologic imaging every 6 weeks. RESULTS: Forty-eight eligible patients were enrolled, 43 with metastatic disease. Median follow-up was 12.6 months (range, 2.2 to 16.8 months) for living patients. A median of four cycles of treatment was given (range, 1 to 18 cycles). All patients were assessable for response and toxicity. The 6-month survival percentage was 57.5% (95% CI, 44.9% to 73.5%) and the median survival was 6.6 months. The response rate was 10.4% (one complete response, four partial responses). Clinically significant toxicity was limited except for one fatal pulmonary embolism. CONCLUSION: This study shows a promising response rate to the combination of gemcitabine and ISIS-2503 in patients with pancreatic ACA. The observed 6-month survival rate in these patients met our protocol-defined criteria for success. This regimen is tolerable, but is of unclear benefit. Additional studies evaluating the role of gemcitabine and ISIS-2503 in the treatment of pancreatic ACA should be considered.     

p21-activated kinase signaling in breast cancer

The p21-activated kinases signal through a number of cellular pathways fundamental to growth, differentiation and apoptosis. A wealth of information has accumulated at an impressive pace in the recent past, both with regard to previously identified targets for p21-activated kinases that regulate the actin cytoskeleton and cellular stress pathways and with regard to newly identified targets and their role in cancer. Emerging data also provide new clues towards a previously unappreciated link between these various cellular processes. The present review attempts to provide a quick tutorial to the reader about the evolving significance of p21-activated kinases and small GTPases in breast cancer, using information from mouse models, tissue culture studies, and human materials.     

Pharmacokinetics of the hypoxic cell cytotoxic agent tirapazamine and its major bioreductive metabolites in mice and humans: retrospective analysis of a pharmacokinetically guided dose-escalation strategy in a phase I trial

 Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide; SR 259075) is a selective hypoxic cell cytotoxic agent that is bioreductively activated in tumours to a reactive-drug free radical. Preclinically the agent has been shown to possess additive and synergistic anti-tumour activity in combination with radiotherapy and chemotherapy regimens. In the present study the pharmacokinetics and metabolism of tirapazamine were investigated in mice and patients as part of pre-clinical and phase I investigations. The objectives of this work were twofold; firstly, to evaluate retrospectively the utility of a pharmacokinetically guided dose-escalation (PGDE) strategy for tirapazamine, and secondly, to investigate if pharmacologically relevant plasma concentrations could be achieved at tolerable doses. Pharmacokinetic studies for PGDE were conducted in mice at four dose levels ranging from one-tenth of the LD₁₀ to the LD₅₀. The AUC at the LD₁₀ (2932 μg ml^-1min) was used to determine a target AUC value of 1173 μg ml^-1min (equivalent to 40% of the mouse LD₁₀ AUC) for clinical studies. A phase I study to investigate the tolerance of a single i.v. infusion of tirapazamine (once every 3 weeks) was initiated with close pharmacokinetic monitoring. The starting dose (36 mg/m²) was based on toxicity data obtained in the mouse, rat and dog. Doses were escalated by increases in the volume and duration of infusion. A retrospective analysis of the pharmacokinetic and toxicity data was then made to determine the utility of a PGDE approach. The drug exhibited a steep dose-lethality relationship in mice (LD₁₀ 294 mg/m², LD₅₀ 303 mg/m²). The major gross toxicities were body-weight loss (15–20%), pilo-erection and hypoactivity at all dose levels. Sporadic ptosis and conjunctivitis were observed at doses of >300 mg/m². The plasma elimination of tirapazamine fitted a monoexponential open model, with rapid elimination from the plasma (t _1/2=36±0.65 min) occuring at the LD₁₀ dose of 294 mg/m². A 10.3-fold increase in dose resulted in a 25.0-fold increase in AUC. Clinically, doses were escalated over the range of 36–450 mg/m². Ototoxicity (tinnitus and reversible hearing loss) was dose-limiting at 450 mg/m² and the MTD was 390 mg/m² for this schedule. Pharmacokinetic analyses in patients revealed that the elimination of tirapazamine in patients was generally bi-phasic, with low inter-patient variability being found in clearance. A 12.5-fold increase in dose resulted in a 19.0-fold increase in AUC. There was good quantitative agreement in metabolite formation between mice and humans with respect to the two- and four-electron bioreductive metabolites. AUC values recorded for tirapazamine at the MTD of 390 mg/m² (range 1035–1611 μg ml^-1min) were similar to the target AUC in mice. Importantly, these levels are consistent with the levels required for radiation-dose enhancement and effective combination with cisplatin in mice. Given (a) the similarities in plasma pharmacokinetics and metabolism observed at the target AUC/MTD in mice, rats, dogs and humans, (b) the similar degree of plasma protein binding seen between species and (c) the relatively low inter-patient variability noted in drug clearance, a successful PGDE approach should have been feasible. The results also indicate that potentially therapeutic levels of tirapazamine are achievable in patients at tolerable doses. Received: 27 May 1996 / Accepted: 30 September 1996     

A rare case of primary Ewings sarcoma of the nasal bone

Primary Ewing’s sarcoma of the nasal bone has not been previously described. This case presented as a mass in the left ala of the nose in a five year old female child. The clinical, radiological, microscopic features are described and a review of literature is presented. The case was treated with neoadjuvant chemotherapy and local electron beam radiation therapy. The child was free of disease when she reported for follow up in July 1997. Although wide excision is part of the treatment approach in Ewing’s sarcoma, in sites where surgery is not suitable local radiotherapy and chemotherapy adequately controls primary disease.     

A rare case of primary Ewings sarcoma of the nasal bone

Primary Ewing’s sarcoma of the nasal bone has not been previously described. This case presented as a mass in the left ala of the nose in a five year old female child. The clinical, radiological, microscopic features are described and a review of literature is presented. The case was treated with neoadjuvant chemotherapy and local electron beam radiation therapy. The child was free of disease when she reported for follow up in July 1997. Although wide excision is part of the treatment approach in Ewing’s sarcoma, in sites where surgery is not suitable local radiotherapy and chemotherapy adequately controls primary disease.