Biomedical subjects
C Karakousis
Publications and source records attributed to C Karakousis.
Prognostic factors in malignant melanoma patients with solitary or multiple brain metastases. Is there a role for surgery?
BACKGROUND: The aim of this study is to evaluate the prognostic parameters and treatment modalities of malignant melanoma patients with brain metastases. METHODS EXPERIMENTAL DESIGN: a retrospective study with a mean follow-up of 46 months. SETTING: specialized Cancer Center. PATIENTS: the charts of 136 patients, treated in Roswell Park Cancer Institute, for melanoma brain metastases, were analyzed. INTERVENTIONS: all patients were treated surgically and in the majority adjuvant therapy was applied. MEASURES: survival and time of recurrence of patients and possible prognostic factors. RESULTS: PATIENTS who were treated surgically had a better one-year survival rate (28.3%), than patients who received radiotherapy and/or chemotherapy (6.67%) or patients who refused any kind of treatment (3.45%), (p=0.006). Prolonged survival after surgical treatment was found in patients with single metastatic lesions and in patients with multiple metastatic lesions. CONCLUSIONS: Melanoma patients with single metastatic lesions to the brain seem to do better after surgical treatment. The role of surgical intervention in patients with multiple brain metastases needs re-evaluation from a big multicenter, prospective trial.
Results of aggressive treatment of gastric sarcoma.
BACKGROUND: Leiomyosarcoma and leiomyoblastoma and subtypes of gastric smooth muscle tumors. These rare tumors are usually treated with surgical resection. However, there is controversy regarding the optimal surgical management for these malignancies and little information is available on the efficacy of radiation and chemotherapy in the adjuvant or palliative setting. METHODS: The records of 32 patients with gastric leiomyosarcoma or leiomyoblastoma were reviewed. Survival data were obtained and patient outcome was analyzed with respect to the type of treatment given. Four different staging systems were compared for their ability to predict survival. RESULTS: Thirty patients with leiomyosarcoma and two patients with leiomyoblastoma were followed after surgery. All 32 patients were explored, and 21 curative and 11 palliative procedures were performed. Adjacent organs were included in 38% of resections. Only three patients did not undergo gastric resection. Local recurrence developed in eight patients after curative resection for a local control rate of 62%. Eight other patients developed metastatic disease for an overall recurrence rate of 76% after curative resection. Median survival of patients undergoing curative resection was 40 months compared with 8 months for those having a palliative procedure. The estimated 5-year survival was 34% and 10%, respectively (p = 0.05). Twenty-five patients with advanced disease received systemic, hepatic arterial, or intraperitoneal chemotherapy. Eighty percent of patients received a regimen including doxorubicin. Four partial and one complete response were noted. Seven patients received postoperative radiation therapy. Fourteen patients underwent debulking surgery of recurrent or persistent disease in conjunction with chemotherapy. Chemotherapy, radiation therapy, and debulking surgery did not result in statistically significant prolongation of survival. Seven patients remain alive, two with liver metastases. Four different staging systems for gastric sarcomas were compared, but none of them were found to be clearly superior in predicting survival. CONCLUSIONS: Curative gastric resection was achieved in 66% of patients and resulted in a significant prolongation of survival as compared with patients who had a palliative procedure. Wedge resection of tumor or partial gastric resection appears to be an acceptable surgical approach to these tumors as long as negative margins can be obtained. Chemotherapy, radiation therapy and debulking surgery did not result in significant prolongation of survival in the face of advanced disease. None of the staging systems for gastric sarcoma currently in use is completely satisfactory. Tumor grade and extent of disease seem to be the most important factors when determining prognosis or considering adjuvant therapy.
Cytogenetic findings in 21 malignant melanomas.
Cytogenetic analysis was performed on 21 tumor samples of malignant melanoma to identify the presence of consistent chromosome abnormalities. Four cases had a normal karyotype, and 17 were cytogenetically abnormal. Numerical chromosome alterations were observed in 15 tumors: 12 were hyperdiploid and three were hypodiploid. The most frequent losses consisted of chromosomes 5, 9, 17 and Y. The structural abnormalities were usually complex, consisting mainly of nonreciprocal translocations and deletions affecting 1p, 1q, 3p, and 9p. This study adds further data to previously reported melanoma cases, confirming that chromosomes 1, 3, 6, and 9 are nonrandomly affected.
Thick cutaneous melanoma of the trunk and extremities: an institutional review.
The objective of this study was to review our experience with thick cutaneous melanoma of the trunk and extremities and to identify subgroups of long-term survivors. Ninety-one patients admitted between the years 1977 and 1987, with cutaneous melanoma of the trunk or extremities, Breslow thickness > or = 4.0 mm, or a Clark's level V lesion form the basis of this review. Node positive clinical stage II patients had a 5-year survival rate of 32%. Five-year survival for node positive clinical stage III patients was 0% (P < 0.0001). Node negative clinical stage II patients, and those found to be histologically node positive, had no survival difference, P = 0.88. Sixty per cent of node negative patients with an extremity primary survived 5 years, while patients with a node positive truncal primary had a survival of 14%, P = 0.005. In conclusion, most patients present with local-regional disease. Patients with node negative extremity lesions have the best chance for cure.
Staging and grading in the survival of adrenal carcinomas.
In 53 patients with histologically proven adrenal cortical carcinomas the most common metastatic sites, at the time of diagnosis, were the liver, lymph nodes, bone and lungs, and during the course of the disease, the lungs. At the time of diagnosis six (11%) of our patients were in Stage S1, seven (13%) in S2, 11 (21%) in S3 and 29 (55%) in S4. Histologic grading (G) in 43 patients showed G1 grade in 11 (26%), G2 in seven (16%) and G3 in 25 patients (58%). Median survival in months (estimated 5-year survival rate) for the various stages were: S1 46 (33%), S2 84 (57%), S3 eight (18%) and S4 seven (7% at 2 years) (P = 0.01). Median survival in months (estimated 5-year survival rate) for the various grades were: G1 46 (46%), G2 24 (43%), G3 five (4% at 2 years) (P = 0.003). In this series, tumor stage (P = 0.01) and grade (P = 0.003) were predictors of survival and the two were closely correlated (P = 0.02).
[Stage-dependent surgical resection of malignant melanoma].
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Adjuvant chemotherapy with a nitrosourea-based protocol in advanced malignant melanoma.
173 patients with regional lymphatic metastases (n = 139) or distant disease (n = 34) were prospectively randomised, following resection of all clinically detectable tumour, to observation (n = 88) or adjuvant chemotherapy (n = 85). The treatment group received 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) 80 mg/m2 intravenously (i.v.) every 4 weeks, and actinomycin-D 10 micrograms/kg, vincristine 1.0 mg/m2 i.v. every 2 weeks for 6 months. The disease-free survival curves between the two groups were significantly different (P = 0.03). The estimated 5-year disease-free survival rate for the observation group was 9% and for the treatment group 29%. However, the overall survival curves were not significantly different for the two groups. Nitrosoureas may have a weak effect as adjuvant treatment in malignant melanoma.
Resection of lung metastases from soft-tissue sarcomas. A multivariate analysis.
From 1970 through 1986, 78 patients underwent 162 thoracotomies for removal of lung metastases from soft-tissue sarcomas. A multivariate analysis showed that the presence of a local recurrence, an incomplete pulmonary resection, and a shorter disease-free interval were poor prognostic factors. Patients who underwent multiple thoracotomies survived longer from the time of initial thoracotomy. The histologic type of sarcoma and the number of metastases resected showed no statistical significance. The median survival of the 61 patients who had a complete resection was 21 months. Patients with five or fewer metastases resected had an overall 5-year survival of 22% compared with 21% for patients who had six or more metastases resected. However, patients with five or fewer metastases showed a trend toward a higher 10-year disease-free survival. A complete resection of pulmonary metastases from soft-tissue sarcoma can prolong survival even if multiple metastases are present, although patients with fewer metastases may have a longer disease-free survival.
Comparison of an immunoperoxidase "sandwich" staining method and western blot detection of P-glycoprotein in human cell lines and sarcomas.
The applicability of a multilayer immunoperoxidase "sandwich" method (IpS) developed by Chan14 for the amplified detection of P-glycoprotein (Pgp) was investigated. The authors examined 15 formalin-fixed cell lines, as well as formalin-fixed, paraffin-embedded sections from single biopsies of 46 sarcomas. The cell lines included sensitive and multidrug resistant sublines (KB, A2780, MCF-7, HeLa) with various relative degrees of resistance to doxorubicin (Dox). The sarcoma biopsy specimens were selected on the basis of the results obtained in Western blot (WB) detection of Pgp (22 positive and 24 negative by WB) using C219 and C494 monoclonal antibodies to Pgp. The IpS method employed C219. The least resistant cell line in which Pgp could be detected by IpS was fivefold resistant to doxorubicin, whereas Pgp was detected by WB in cells greater than twofold resistant. Cell lines having greater than fivefold resistance to Dox were positive by both IpS and WB analyses. The less resistant cell lines contained more nonreactive cells whereas the highly resistant cell lines showed more homogeneous strong membrane reactions. Among the six cell lines determined to be Pgp negative by WB analysis, no false positive immunostaining by IpS existed. One of 22 WB positive and 7 of 24 WB-negative sarcoma biopsy specimens were positive by IpS methods. Reaction varied and was always focal (a minimum of 3-5 cells, ranging up to 3-4 high power fields) indicating pronounced heterogeneous distribution of Pgp. Thus, WB can detect low average (overall) levels of Pgp in tumor samples but such low concentrations of PgP at the single cell are not detectable by IpS methods. However, IpS can discern among many Pgp-negative cells small subpopulations of immunoreactive cells, which are not detected by WB analysis due to Pgp dilution by the membrane protein of numerous Pgp negative cells. IpS and WB used together as complementary methods can provide more complete information about Pgp distribution and content, particularly in the case of heterogeneous human tumors. The IpS method is more suitable for less drastically treated (not embedded) cell line specimens than for paraffin-embedded (routine) sections. Some modification of the present IpS protocol seems necessary to increase its sensitivity and reduce the disparity with WB results.
Chromosomes in the diagnosis of soft tissue tumors. I. Synovial sarcoma.
It has been established that nonrandom chromosome rearrangements are characteristic of specific types of neoplasia. We present six new cases of sarcoma that had in common the same chromosome abnormality, i.e., a balanced translocation between chromosomes X and 18, t(X;18)(p11.2;q11.2), and evaluate the 15 cases with this translocation in the literature. The histological diagnosis was synovial sarcoma in 19 cases and malignant fibrous histiocytoma and fibrosarcoma in the remaining two tumors, respectively. The translocation was found in tumors of both the biphasic and monophasic types, as well as in poorly differentiated synovial sarcoma. The two nonsynovial sarcomas with the t(X;18) were described as spindle cell tumors but failed to show the presence of cytokeratins by immunohistochemical stains. Even with the numerous variabilities on which this test depends, the cytogenetic analysis holds great promise as a tool for the diagnosis of synovial sarcoma.
Spouse adjustment to cancer surgery: distress and coping responses.
Although often acknowledged, the impact of the surgical treatment of cancer on the spouse of the adult cancer patient is a largely unexplored area. The present study examined distress, coping, and appraisal among spouses (N = 36) and patients (N = 43) assessed prior to and following surgery. The results indicated that at both the presurgical and postsurgical period, spouses were exhibiting significantly greater distress than patients. Surprisingly, spouses' levels of distress remained fairly constant across the presurgery to postsurgery period, while the patients' distress decreased. Escape and avoidance behaviors were found to be maladaptive for spouses coping with their partners' surgical treatment. Appraisal was also found to be a critical factor in understanding individual reactions to the stress of cancer surgery. Spouses of cancer patients undergoing surgical treatment appear to be an underacknowledged population at risk.
Initial clinical trial of the macrophage activator muramyl tripeptide-phosphatidylethanolamine encapsulated in liposomes in patients with advanced cancer.
A phase I clinical trial of the macrophage activator, muramyl tripeptide-phosphatidylethanolamine has been carried out in 37 patients (47 courses) at doses of 0.01-6.0 mg/m2 intravenously twice weekly for 4 weeks. Activation of peripheral blood monocytes and drug toxicity were used as the parameters to monitor the trial. Toxicity was acute systemic responses of fever, chills, and hypertension without a clear dose response. No major organ-related toxicity was seen. A dose of 4.0 mg/m2 biweekly produced activation of blood monocytes; a dose of 6.0 mg/m2 produced inhibition. There was one complete response of 3 months duration in a patient with renal cell carcinoma with pulmonary metastases. The optimum dose for phase II studies is in the range of 1-4 mg/m2 twice weekly for 4 weeks, a dose that is well tolerated.
Phase I trial of a new nitrosourea, CGP 6809, given every 2 weeks.
A phase I study was carried out on a new water-soluble nitrosourea, 6-deoxy-3,5 di-O-methyl 6-(3 methyl-3-nitrosoureido)-alpha-D-glucofuranoside (EDMN, CGP 6809), given every 2 weeks. A total of 18 patients received doses of 1, 2, 3, and 3.75 g/m2 as a 2- to 5-h infusion. Toxicity principally involved nausea and vomiting, hepatotoxicity, and abdominal pain. There was no evidence of cumulative toxicity. The dose of 3.75 g/m2 was not exceeded because in a previous phase I study, 4.5 g/m2 every 6 weeks was not tolerated; the recommended dose for phase II studies is 3.75 g/m2 every 2 weeks.
Involvement of 6p in benign lipomas. A new cytogenetic entity?
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Three possible cytogenetic subgroups of leiomyosarcoma.
Cytogenetic analysis was performed on short-term cultured tumor cells from ten patients diagnosed as having leiomyosarcoma. Of these, five tumors from five unrelated patients had clonal chromosome abnormalities. The combined data from this report and previous studies on leiomyosarcomas indicate that at least three subtypes may be identified chromosomally within leiomyosarcomas. One subtype is characterized by a hypodiploid chromosome number ranging from 41 to 43 and a common chromosome pattern of monosomies of chromosomes specific to this subgroup, including partial monosomy of the short arm of chromosome 1 (1p13----pter), monosomy 18, and consistent monosomy 22. In contrast to the previous subtype, for the pathogenesis of which the "tumor suppressor gene" hypothesis may be suggested, another subtype was characterized by a pseudodiploid chromosome number associated with simple reciprocal translocations; so far, these translocations are unique to individual tumors, the pathogenesis of which may involve a translocation-mediated gene deregulation pathway. A third subtype contained tumors with heterogeneous karyotypic findings.
Phase I clinical trial and human pharmacokinetics of 2,4-diamino-5-adamantyl-6-methyl pyrimidine ethane sulfonate (DAMP-ES): a lipid-soluble antifolate.
A phase I and pharmacokinetic study of a novel lipid-soluble antifolate, 2,4 diamino-5-adamantyl-6-methyl pyrimidine ethane sulfonate (DAMP-ES) has been carried out on two schedules: I--daily x5; II--24-h continuous infusion. In schedule I, doses of 10-90 mg/m2 per day were evaluated. Dose-limiting toxicity was hematologic, but nausea and vomiting, skin rash, diarrhea, anorexia, alopecia, mucositis, and neurotoxicity were also noted. In schedule II, doses of 192 and 240 mg/m2 were evaluated. Dose-limiting toxicity was neurotoxicity, but hematologic toxicity was also marked. Recommended starting doses for phase II studies are 75 mg/m2 per day for 5 days or 192 mg/m2 by continuous infusion for 24 h. Pharmacokinetic studies indicated a beta-phase plasma half-life of 12.4-24 h and a large and variable volume of distribution.
Recurrent breakpoints at 9q31 and 22q12.2 in extraskeletal myxoid chondrosarcoma.
A cytogenetic study of extraskeletal myxoid chondrosarcoma cells revealed a complex t(9;22;15)(q31;q12.2;q25) as a primary chromosome change. A reciprocal translocation involving identical breakpoints on chromosomes #9 and #22 in this tumor has been reported in the literature. We suggest that the breakpoints 9q31 and 22.q12.2 are associated with extraskeletal myxoid chondrosarcoma, a comparatively rare tumor of adulthood.