Temozolomide in combination with celecoxib in patients with advanced melanoma. A phase II study of the Hellenic Cooperative Oncology Group.

BACKGROUND: There is now increasing evidence that a constitutive expression of cyclooxygenase (COX)-2 plays a role in the development and progression of malignant epithelial tumors. Expression of COX-2 is seen in 93% of melanomas, as determined by immunohistochemistry. Temozolomide (TMZ) has demonstrated activity against melanoma and has been investigated as single agent or in combination. We designed a phase II study to assess the efficacy and toxicity of the combination of TMZ and celecoxib (a COX-2 inhibitor) in patients with advanced melanoma. PATIENTS AND METHODS: From January 2003 to July 2004, 52 patients were enrolled in the study. Nineteen patients were M1a, six M1b and 27 M1c. Patients received TMZ 200 mg/m(2) per day p.o. for 5 consecutive days every 4 weeks and celecoxib 400 mg b.i.d. p.o. for a maximum of six cycles. Celecoxib was continued until progression. RESULTS: The median age was 63 years. There were 29 males and 23 females. Among 50 assessable patients, there were 11 (21.5%) objective responses including five complete responses and six partial responses. Twenty patients (38.5%) had stabilization of their disease, and 19 (36.5%) progressed. The median time to progression was 4.6 months and the median survival 9.5 months. Twenty-two patients (41.5%) completed all cycles of treatment. Median relative dose intensity of TMZ was 0.99 (range 0.6-1.2). Most commonly seen toxic effects included anemia (27.5%), neutropenia (17.5%), thrombocytopenia (33%), nausea/vomiting (75%), gastrointestinal (52%) and fatigue (46.5%). One patient discontinued due to severe toxicity. COX-2 was determined by immunohistochemistry and was expressed in all cases. CONCLUSION: The combination of TMZ and celecoxib is safe and potentially effective in the treatment of metastatic melanoma. Randomized studies are needed to explore the role of celecoxib in combination with chemotherapy or as maintenance treatment in these patients.

Coinfection of Schistosoma mansoni and Strongyloides stercoralis in a patient with variceal bleeding.

We report a case of hepatosplenic schistosomiasis with portal hypertension and variceal bleeding in an immigrant patient from Egypt, coinfected with Strongyloides stercoralis. The diagnosis was based on the following: (a) identification of Schistosoma mansoni ova in the stools and colonic biopsy specimens, (b) portal hypertension and esophageal varices with normal liver function and the absence of hepatic cirrhosis stigmata, (c) history of migration from an endemic area and (d) ultrasonographic findings of spleen and liver enlargement, fibrosed portal tracts, and normal lobular architecture of liver parenchyma. Hepatosplenic schistosomiasis should be suspected in any patient from an endemic area who has splenomegaly, portal hypertension, and esophageal varices bleeding in the absence of stigmata of liver cirrhosis and hepatic insufficiency. Coinfection with S. stercoralis could be attributed to common epidemiological features of the parasites and the patient's habits.

Vinorelbine in combination with interleukin-2 as second-line treatment in patients with metastatic melanoma. A phase II study of the Hellenic Cooperative Oncology Group.

OBJECTIVES: To evaluate the efficacy and toxicity of the combination of vinorelbine and interleukin (IL)-2 in patients with metastatic melanoma as second-line chemotherapy. PATIENTS AND METHODS: Twenty-two patients with histologically confirmed stage IV melanoma previously treated with temozolomide-based chemotherapy--only one regimen of chemotherapy for disseminated disease was allowed--were treated with vinorelbine 30 mg/m2 on days 1 and 15 and IL-2 subcutaneous 9 x 10(6) once daily on days 2-6 and 16-19 every 4 weeks for maximum of six cycles. RESULTS: From January 2000 to July 2001, 22 patients entered the study; the median age was 56 years. Among 20 evaluable patients there were 2 (9.1%) objective responses including 1 complete response and 1 partial response. Five (22.7%) had stabilization of their disease, and 13 (59.1%) progressed. The median time to progression (TTP) was 2.9 months and the median overall survival was 9.1 months. There was a significant difference in TTP in patients who responded or remained stable (median TTP 10.75 months) and those who progressed (median TTP 2.1 months) (p<0.05). There was also a difference in survival in the two groups (p<0.05 (28 vs. 8 months). The most common side effects were flulike symptoms, such as fever, chills, fatigue, and injection site reaction. Grade 3 hematological toxicity rarely occurred. One patient discontinued therapy because of fatigue and anorexia. There were no treatment-related deaths. CONCLUSIONS: The combination of vinorelbine and IL-2 provides clinical benefit in patients recurring or progressing on first-line chemotherapy for metastatic melanoma, with manageable toxicity.

Prognostic significance of the sequential detection of circulating melanoma cells by RT-PCR in high-risk melanoma patients receiving adjuvant interferon.

The purpose of this study was to address the prognostic significance of circulating melanoma cells by reverse transcriptase-polymerase chain reaction in the peripheral blood of stage IIB and III melanoma patients on high-dose adjuvant interferon at multiple sequential time points from initiation of treatment. Tyrosinase mRNA in peripheral blood from these patients was assayed by reverse transcriptase polymerase chain reaction prior to initiation of adjuvant interferon, at completion of 1 month of intravenous interferon and at 3 monthly intervals until progression. Four hundred and eighteen blood samples from 60 melanoma patients were analysed. The median follow-up time calculated from the time of inclusion in the study was 23 months (range 2-38 months). Tyrosinase mRNA in blood was detected in 42 (70%) of 60 patients: 16 (76%) of 21 stage IIB patients and 26 (66% ) of 39 stage III patients. The presence of tyrosinase mRNA in blood was correlated with a shorter disease-free survival (P : 0.03) and in multivariante analysis was an independent prognostic factor for relapse. Patients who seroconverted to a negative reverse-transcriptase-polymerase chain reaction after induction treatment had a significantly lower probability of recurrence. The presence of circulating melanoma cells is a marker of a high relapse risk and shorter disease-free survival whether detected postoperatively or during follow-up. Tyrosinase mRNA amplification by reverse-transcriptase-polymerase chain reaction may be a useful tool for monitoring the efficacy of adjuvant treatment in stage IIB and III melanoma patients.

Microsurgical repair after crush-avulsion injury of the femoral vein in rats: prevention of microvascular thrombosis with recombinant human tissue-type plasminogen activator (rt-PA).

Vein thrombosis is often encountered in microsurgery, especially in the case of crush-avulsion injuries. The aim of this study was to investigate the effect of systemic administration of recombinant tissue-type plasminogen activator (rt-PA) on the patency of the femoral vein of the rat, which had previously sustained a crush-avulsion injury. The study consisted of 3 groups of male Wistar rats, 20 animals each. A standardized crush-avulsion injury model was used. After microvascular repair of the femoral vein, the animals received either normal saline (group A), heparin 100 U/kg body weight (group B), or rt-PA 3.5 mg/kg body weight (group C) systemically. Patency tests were performed at 20 minutes, 48 hours, and 1 week after blood flow reestablishment. According to our results, the patency rate of the rt-PA group was significantly higher than in both the control and heparin groups.

Microvascular repair with 1-mm polytetrafluoroethylene (PTFE) grafts: effect of recombinant tissue-type plasminogen activator (rt-PA) on the patency rate and healing process.

The present study assesses the effect of recombinant tissue-type plasminogen activator (rt-PA) on the patency rate and healing process of microvascular polytetrafluoroethylene (PTFE) grafts. Wistar rats were used, divided into four groups of 25 animals each. After dissection of the carotid artery a segment of the vessel, 1 cm long, was resected and replaced by equal length graft. Two different type fibril length (30- or 60-microm) grafts of the same wall thickness (0.18 mm) were used. Normal saline or 3 mg/kg of body weight of rt-PA was applied locally in each group of different fibril length grafts. Patency tests were performed at 15 min and 4 weeks after blood flow was reestablished. All grafts were harvested and examined histologically. The results showed that local application of rt-PA improves patency statistically significantly in both types of fibril length grafts. Patency in 60-microm fibril length grafts was statistically significantly higher than that of 30-microm fibril length grafts, whether rt-PA was used or not. The use of rt-PA had no influence on the healing process of either type of graft.

Prefabrication of an axial bio-synthetic flap for circumferential tracheal defect reconstruction.

The aim of this study was to prefabricate an axial bio-synthetic flap for reconstruction of circumferential tracheal defects in a rabbit model. Two series of experiments were performed. In the first set of experiments axial island bio-synthetic flaps were prefabricated. These consisted of an inner island de-epithelialised fasciocutaneous flap from a rabbit's ear and an outer polytetrafluoroethylene vascular graft. The flaps were buried at the base of the rabbit's ear for periods of 1, 2 and 3 weeks (groups A, B and C, respectively), 10 flaps per group. Only one flap in group C failed to survive. Clinical and histological assessment, at the completion of each time period, showed that only the viable flaps of group C developed all the characteristics needed for a tracheal substitute. In the second set of experiments the prefabricated bio-synthetic flaps were transferred to the rabbit's neck by means of microvascular anastomoses. Ten such free flaps were buried at the rabbit's neck for 3 weeks (group D). Eight of the flaps remained viable and all the viable flaps had characteristics similar to those of group C. These results demonstrate the feasibility of creating a prefabricated axial bio-synthetic flap (island or free), over a 3-week period, possessing the characteristics needed for a tracheal substitute in a rabbit model.

Lectin-binding pattern of primary malignant melanomas and melanocytic nevi.

A panel of six biotinylated lectins was applied in order to study the composition and distribution of plasma membrane carbohydrate residues in 83 primary cutaneous melanomas (MMs) and in 85 melanocytic nevi (MN) with the avidin-biotin peroxidase technique. No clear-cut differences between MN and MMs were observed with regard to the staining with lectins. In MN and MMs derived from different patients, the lectin-binding pattern was variable and heterogeneous even within the individual nevi or melanomas. It seems reasonable, therefore, to assume that the lectin-binding pattern cannot be regarded as a reliable histochemical marker for the differentiation of MN from MMs. Moreover, because the pattern reveals no statistically significant correlation with the thickness or the depth of invasion of MM, it seems to lack prognostic significance.

Microvascular repair following a modified crush-avulsion injury in a rat model: effect of recombinant human tissue-type plasminogen activator on the patency rate.

The failure rate of replantations following a crush-avulsion type injury is high. This study has been designed to reproduce an effective standardized crush-avulsion injury model to the femoral artery of the rat and evaluate the antithrombotic efficacy of systemic intravenous administration of recombinant human tissue-type plasminogen activator (rt-PA). The crush-avulsion injury was reproduced by using a bulldog clamp and two hemostats and followed by microvascular repair. The animals were divided into three groups of 20 rats each and received either normal saline, heparin 100 U/kg body weight, or rt-PA 3.5 mg/kg body weight intravenously. Patency tests were performed 20 min and 48 h after blood flow reestablishment. Results showed that this experimental crush-avulsion injury model ensures low patency in the control group, whereas systemic rt-PA administration improves the patency rate statistically significantly compared to control and heparin groups at both 20 min and 48 h postrevascularization.

Effect of fixation on interphase cytogenetic analysis by direct fluorescence in situ hybridization on cell imprints.

The direct fluorescent in situ hybridization (FISH) technique using a centromerespecific DNA probe for chromosome 11 was applied on fresh tissue imprints from melanomas and pituitary adenomas. The cell imprints were fixed in acetone and formalin, and the influence of fixation was evaluated. Acetone fixed imprints gave a sharp and intense fluorescent signal in a large number of cells from both tumors without any pretreatment. In contrast, formalin fixed imprints disclosed a weak hybridization signal in a few cells even after careful enzymatic digestion. Direct FISH on acetone fixed cell imprints represents a simple and time saving technique applicable to any laboratory for the study of numerical chromosomal abnormalities.

Tumor induced osteomalacia.

We describe a case of mesenchymal tumor induced osteomalacia. Our patient presented a typical clinical and radiological picture of osteomalacia, with low serum phosphate. With the excision of the tumor, which was located in the right forearm, the serum phosphate concentrations increased to normal values within a week postoperatively and the symptoms improved dramatically.