Biomedical subjects
C J Logothetis
Publications and source records attributed to C J Logothetis.
Preoperative chemotherapy in the treatment of germinal tumors.
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Combined intravenous and intra-arterial cyclophosphamide, doxorubicin, and cisplatin (CISCA) in the management of select patients with invasive urothelial tumors.
Twenty-eight patients with unresectable urothelial tumors who had no evidence of distant visceral metastasis were managed with iv CISCA (cyclophosphamide, doxorubicin, and cisplatin) and intra-arterial (ia) CISCA chemotherapy. Ten patients had locally advanced disease only and 18 had locally advanced disease with nodal metastasis (ten in pelvic nodes; seven in pelvic and para-aortic nodes; and one in pelvic, para-aortic, and mesenteric nodes). Eleven patients (39%) achieved a complete remission, with a median duration of 49 weeks (range, 25-108). Seven patients (25%) achieved on objective response and ten patients (36%) failed to respond. Iv and ia CISCA chemotherapy is effective in the management of advanced urothelial tumors. Patients with locally advanced disease with or without the presence of nodal metastasis are a select population in whom frequent complete remissions can be achieved.
Perioperative chemotherapy for the management of primary local regional urothelial tumors.
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The prognostic significance of endodermal sinus tumor histology among patients treated for stage III nonseminomatous germ cell tumors of the testes.
A retrospective study was undertaken to determine the prognostic significance of endodermal sinus tumor (EST) elements in 56 patients with Stage III nonseminatous germ cell tumors of the testes (NSGCTT). The study patients were treated with conventional vinblastine, bleomycin and cisplatinum chemotherapy prior to our recognition of EST as a distinct entity. Twenty-one (37.5%) of the patients had EST elements in their tumors. Nineteen patients had EST in their primary testis tumor, whereas two had EST in metastatic sites only. Prognostic criteria (tumor volume, Dixon-Moore classification and chemotherapy vinblastin and bleomycin [VB] and VB plus cisplatin [VB + P] ) were similar in EST and non-EST patients. Long-term disease-free survival was significantly poorer for patients with Stage III NSGCTT containing EST (38%) compared with those not containing EST (71%) (P = 0.04). All 12 patients with small volume disease (III-B1-III-B2), independent of the presence of EST, are alive and free of disease for more than 2 years. Only 6 of 18 patients (33%) with advanced disease and EST are alive and free of disease, whereas 17 of 26 (65%) of patients with advanced disease not containing EST are alive and free of disease (P = 0.074). The addition of single agent bolus cisplatin to the treatment of patients with advanced disease achieved no improvement in survival. Endodermal sinus tumor must be included in future studies of advanced Stage III NSGCTT as an important prognostic variable.
Surgery in the management of stage III germinal cell tumors. Observations on the M.D. Anderson Hospital experience, 1971-1979.
Sixty patients with initial stage III germinal tumors treated with conventional vinblastine, bleomycin and cisplatin chemotherapy (VB + P) were surgically explored. Twenty-two patients not treated with an initial retroperitoneal node dissection were surgically explored to pathologically confirm a complete remission following chemotherapy. Thirty-eight patients had a persistent mass in the absence of elevated serum markers. Seventeen (28%) patients had viable carcinoma at surgery. Eight (47%) of the 17 patients with viable carcinoma at surgery died of recurrent tumor. All but three patients with persistent viable carcinoma at surgery were treated with surgery followed by chemotherapy. Fourteen patients were found to have mature teratoma and one (7%) developed recurrent carcinomatosis. Two (8%) of the 25 patients found to have scar died. One patient died of recurrent carcinomatosis and one of postoperative complications. Ten additional patients with a suboptimal response to chemotherapy were surgically explored for attempted salvage. All ten died of recurrent tumor, with a median postoperative survival of 7 months. We believe optimal individualized chemotherapy is required for the management of stage III testis cancer. Therapeutic benefit for surgery can be demonstrated only in unusual circumstances. Attempted surgical excision of a clinically active germinal tumor is futile; hence patients with elevated serum biomarkers should not be explored. Patients with non-seminomatous germinal tumors and a residual postchemotherapy mass must be explored. The excision of mature teratoma is mandatory, as is documentation of the absence of viable carcinoma prior to cessation of therapy.
The role of surgery following chemotherapy in stage III germ cell neoplasms.
After curative chemotherapy 58 patients with metastatic germinal tumors and 2 with extragonadal germinal tumors underwent an operation either to confirm a clinical complete response or to remove a residual mass. Biomarker status was converted to negative in all patients. Retroperitoneal lymphadenectomy was done in 22 patients after a complete clinical response was achieved and in 23 after an apparent complete response was achieved except for a residual retroperitoneal mass. Thoracotomy was done for a residual mass in 13 patients, while 2 underwent bilateral thoracotomy. Scarring was found in 25 patients (42 per cent), teratoma in 14 (23 per cent) and active tumor in 17 (28 per cent). One patient with scarring and primary seminoma died of disseminated seminoma, while 1 with primary teratocarcinoma died of disseminated disease, for a false negative rate of 3 per cent. Four patients with a residual mass showed unexpected findings: 2 had granulomas in the lung, 1 had carcinoid of the lung and 1 had retroperitoneal neurofibroma. Thus, there was a 7 per cent incidence of a mass being other than scar, teratoma or residual tumor. There was 1 operative death and 10 deaths of tumor, for an 18 per cent death rate. Of the 17 patients with active tumor 9 responded to salvage chemotherapy with stable complete remission and a minimum followup of 18 months. In addition to the 60 patients the advanced disease in 10 was surgically debulked after failure of chemotherapy and this procedure was followed by salvage chemotherapy. All 10 patients died, with a median survival of 7 months. The lack of responsiveness to chemotherapy was not improved by incomplete removal of tumor.
Doxorubicin, mitomycin-C, and 5-fluorouracil (DMF) in the treatment of metastatic hormonal refractory adenocarcinoma of the prostate, with a note on the staging of metastatic prostate cancer.
Sixty-two patients with metastatic hormonal refractory adenocarcinoma of the prostate received a combination of doxorubicin, mitomycin-C, and 5-fluorouracil (DMF). Thirty (48%) of the patients achieved an objective response. Response criteria excluded disease "stabilization" as a manifestation of response. Four clinical prognostic categories were identified: osseous I (OI) had metastatic axial skeletal involvement (23 patients); osseous II (OII) had axial and extremity skeletaL involvement (18 patients); visceral I (VI) had pulmonary metastasis (9 patients); and visceral II (VII) had pulmonary metastasis and involvement of other viscera (12 patients). The 20 responding patients survived a median of 47.5 weeks, whereas the 32 nonresponding patients survived a median of 23.8 weeks (n = 0.002). Response rates were highest among patients with OI (52%) and VI (88%) disease; response rates were lower amont patients with OII (33%) and VII (33%) disease. Responding patients in each clinical category survived longer than nonresponding patients except for those patients with VII disease. The median duration of response for patients with OI disease was 11 months, for OII 9.5 months, for VI patients it was 6.5 months, and VII patients it was 5 months. DMF is an effective treatment of metastatic hormonal refractory prostate cancer, resulting in consistent objective responses. The staging system employed identifies four clinical categories of metastatic prostate cancer and allows for accurate comparison of diet and stratification of study populations.
Sterilized metastases: a diagnostic and therapeutic dilemma.
The usual indication of improvement in metastatic cancer is diminution of the mass. When a mass persists after treatment, it is presumed the lesion either does not respond or has stopped responding to the therapy. Two patients with brain metastases, one biopsy proven, from breast cancer and eight patients with presumed metastatic testicular cancer to the lung, liver, or retroperitoneum have been identified in whom surgery or autopsy revealed only necrosis and/or fibrosis in the persistent mass; the mass had been "sterilized." Although this phenomenon is not frequent, it is not uncommon in testicular cancer. Our observations are offered to make others aware that persistent mass need not indicate viable tumor. When sufficient examples are accumulated, some clues to predicting this phenomenon may help resolve the therapeutic dilemma it presents.
The growing teratoma syndrome.
Six patients with metastatic mixed germ-cell tumors who had been treated successfully with chemotherapy had recurring solitary enlarging masses. Four had enlarging pulmonary masses and two patients had enlarging abdominal masses. Each had the presumed chemotherapy refractory mass surgically resected and was found to have mature teratoma with absence of malignant histologies. The growth in two patients can be attributed to tense and expansile cysts; the remaining four had firm masses. All patients remain free of disease without further therapy at 5, 13, 14, 25, 66, and 108 months. Early recognition of this previously unreported and unusual clinical circumstance of a benign teratoma to grow after chemotherapy will allow for surgical salvage.
The management of brain metastases in germ cell tumors.
Twelve patients, with brain metastases from germ cell tumors were treated with combined whole brain irradiation and systemic chemotherapy. Two prognostic categories were identified. Patients with single brain metastases had a mean survival of 29.9 months, while patients with multiple brain lesions had a mean survival of 13.7 months. Four of the six patients with single brain lesions remain alive at 13, 14, 35 and 41 months following the clinical diagnosis of brain metastasis. The improved survival among patients with single lesions can be attributed to the sensitivity to chemotherapy of their tumors. Meningeal carcinomatosis, a previously unreported complication of metastatic germ cell tumor, developed in two patients who were initially treated for single brain metastasis. Both patients developed a clinical picture suggesting meningeal invasion by tumor and both had cytologic evidence in the cerebrospinal fluid of malignant cells.
Management of pelvic complications of malignant urothelial tumors with combined intra-arterial and iv chemotherapy.
Twenty-nine patients with local-regional pelvic recurrences of malignant urothelial tumors were treated with combined intra-arterial and iv chemotherapy. 5-FU (1 g/m2) was infused daily for 5 days via bilateral percutaneously placed hypogastric catheters. Doxorubicin (25 mg/m2) was infused iv on Days 1 and 2 and mitomycin (5 mg/m2) was infused iv on Days 3 and 4 of each course. Seventeen patients (58%) demonstrated an objective decrease in the size of the pelvic mass. All four patients with one of the adenocarcinoma variants of malignant urothelial tumors responded to therapy, while the three patients with squamous transformation of a transitional cell carcinoma failed to respond. The median survival of the responding patients was significantly longer (52 weeks) than that of nonresponding patients (28 weeks) (P = 0.002). Patients with initial low-volume pelvic disease demonstrated durable control of local residual tumors, with four of six patients having negative repeat cystoscopic examinations.
Doxorubicin, mitomycin, and 5-FU (DMF) in the treatment of hormone-resistant stage D prostate cancer: a preliminary report.
Fifteen patients with advanced stage D hormone-resistant prostate cancer were treated with the combination of doxorubicin, mitomycin, and 5-FU. Nine patients (60%) had objective responses, with a mean duration of 27.9 weeks. No responding patient had relapsed. Although three patients developed a culture-negative leukopenic fever, no deaths from chemotherapy occurred. Preliminary results with doxorubicin, mitomycin, and 5-FU indicate that this is a very effective chemotherapy regimen, resulting in a high objective response rate in metastatic prostate cancer.
Chemotherapy of carcinoma of renal pelvis: preliminary report.
Seven patients with metastatic and/or recurrent transitional cell carcinoma of the renal pelvis treated with systemic chemotherapy are evaluated. The median age of the patients was fifty-five; 6 were men, 6 of the tumors were histologic grade III and Stage C at the time of nephroureterectomy. Most of the patients presented with a large recurrent mass at the original site of surgery in addition to bone and/or pulmonary metastases. Four patients were treated with CISCA combination chemotherapy (cis-platinum, cyclophosphamide, and doxorubicin), and responded with 1 partial remission, 1 less than partial remission, and 2 symptomatic improvement. Two patients were treated with FAM combination chemotherapy (5-fluorouracil, doxorubicin, and mitomycin C) and demonstrated an objective response. One patient had a less than partial remission (30 per cent) and the second patient a partial remission. The seventh patient was treated with alternating courses of CISCA and FAM and thus far has received 8 courses and is in complete remission. The median survival time of the 7 patients is seven months (range four to fourteen months). Transitional cell carcinoma of the renal pelvis is responsive to chemotherapy; therefore, trials are indicated.
Model systems of prostate cancer: uses and limitations.
A valid experimental model system reflects the system under study and is reproducible. Model systems of prostate cancer that accurately reflect the different disease stages are necessary to ensure a proper experimental design aimed at increasing our understanding of the biology of the disease and such models are essential tools to accelerate development of new therapies for prostate cancer. Until recently, a limited number of experimental systems were available and more suitable models derived from human specimens have only recently been developed and become available for use. In addition, transgenic techniques have also permitted the development of unique mouse models. The difficulty in establishing model systems may reflect the complex requirements necessary for cancer progression and should lead us to interpret results from model systems with caution. It is unlikely that a single model system that faithfully reflects the whole process of cancer development and progression will be developed. However, thoughtful use of the available model systems will permit the study of a significant portion of prostate cancer progression. In this review we summarize the properties of the prostate cancer model systems in use and defined their utility and limitations. This review will guide the investigator seeking models with which to test specific hypotheses pertaining to prostate cancer.
Molecular regulation of cell death and therapeutic strategies for cell death induction in prostate carcinoma.
Many of the common molecular alterations associated with prostate cancer progression involve genes known to regulate cell death susceptibility. The significance of these molecular events is discussed in the context of developing and implementing new strategies designed to restore cell death susceptibility in prostate cancer cells and overcome therapeutic resistance.
Tumor-suppressive activity of CD66a in prostate cancer.
CD66a (human homolog of rat cell-cell adhesion molecule, also known as biliary glycoprotein) is a cell surface protein of the immunoglobulin family. CD66a has been shown to mediate homotypic cell adhesion. Aside from this, no other functions of this molecule have been demonstrated. We have observed previously that CD66a protein expression is lost in most prostate tumors, suggesting that the down-regulation of CD66a is associated with the abnormal growth of prostate cells. CD66a is homologous (65% identity) to rat cell-cell adhesion molecule, which has been shown to have tumor-suppressive activity. This homology suggests the possibility that CD66a might also be a tumor suppressor. In this report, we show that restoring CD66a expression in DU145 human prostate cancer cells by adenovirus (Ad)-mediated gene transfer dramatically altered the malignant phenotype of these cells, as evidenced by their reduced ability to form tumors in a xenograft animal model. This result suggests that loss of CD66a protein plays an important role in the development of prostate cancer, and that restoring CD66a expression might provide an effective treatment for prostate cancer. We further explored the possibility of using Ad vectors to deliver CD66a as a potential therapeutic agent for prostate cancer. Direct injection of Ad-CD66a, an Ad vector carrying the CD66a gene, into DU145 tumors in mice significantly suppressed the growth of these tumors. This antitumor activity of CD66a was found to be dose-dependent. These results suggest that CD66a has tumor-suppressive activity and that Ad-CD66a is a potential therapeutic agent for prostate cancer treatment.
Schedule-dependence of C-CAM1 adenovirus gene therapy in a prostate cancer model.
BACKGROUND: C-CAM1 functions as a tumor suppressor in prostate cancer. Thus C-CAM1 recombinant adenovirus therapy may be a promising treatment for prostate cancer. Understanding the time course of C-CAM1's antitumor activity is essential for designing an optimal schedule for C-CAM1 gene therapy. MATERIALS AND METHODS: PC3 cells were exposed to Ad-C-CAM1 and the time course of C-CAM1 expression was monitored by flow cytometry. Tumors generated in nude mice by subcutaneous injection of PC-3 cells were used for in vivo testing of C-CAM1's antitumor activity. Intratumoral injections of viruses (either Ad-C-CAM1 or Ad-beta-gal) or buffer only (control) were performed according to two different schedules. Mice in Schedule A received a single injection, while mice in Schedule B received the same total amount of viruses in 3 equal doses at 2-week intervals. RESULTS: After single exposure to Ad-C-CAM1, PC-3 cells expressed abundant C-CAM1 protein which reached the highest level on day 3 and persisted for up to 5 days. PC-3 tumors in nude mice exhibited 2 to 3-week lag in tumor growth curves after a single Ad-C-CAM1 injection. In contrast, 14 of the 18 tumors receiving 3 fractionated Ad-C-CAM1 injections regressed completely, while the other 4 tumors shrank to significantly smaller sizes. CONCLUSIONS: Sustained expression of C-CAM1 is required for optimal tumor suppression. The schedule-dependence of C-CAM1's antitumor activity should be taken into account in optimizing gene therapy in clinical settings.