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G J Bosl

Publications and source records attributed to G J Bosl.

At least 19 recordsLinked to original sources
PubMed1998

Chromosomal amplification is associated with cisplatin resistance of human male germ cell tumors.

Chemotherapy resistance of tumors is an important biological and clinical problem. Studies from many tumor types have indicated that resistance may be based on multiple genetic pathways. Human male germa cell tumors (GCTs) are an especially good model system to study the genetic basis of tumor sensitivity and resistance to chemotherapy. GCTs are exquisitely sensitive to treatment with DNA-damaging drugs such as cisplatin, rarely exhibit TP53 gene mutations, express normal p53 protein, and undergo p53-mediated apoptosis upon drug treatment. A small proportion of tumors (20-30% of metastatic lesions) escape the apoptotic response and result in treatment resistance. We have recently shown (J. Houldsworth, et al., Oncogene, 16: 2345-2359, 1998) that in a subset of such tumors, resistance is linked to TP53 gene mutations. In a further search for genetic mechanisms underlying resistance, we subjected a panel of 17 tumors from relapse-free patients (sensitive) and 17 chemotherapy-resistant tumors to comparative genomic hybridization analysis to identify possible amplified regions (implying amplified/overexpressed genes) associated with resistance. With the exception of 12p11.2-12, high level amplification was not detected in any of the sensitive tumors. We have identified eight amplified regions (1q31-32, 2p23-24, 7q21, 7q31, 9q22, 9q32-34, 15q23-24, and 20q11.2-12) in five resistant tumors, which suggests that chromosomal and, hence, gene amplification may comprise a pathway to drug resistance. Identification of amplified/overexpressed genes at these sites may elucidate new genetic pathways of chemotherapy resistance in GCTs and possibly also in other tumors.

Chromosome Mapping↗
PubMed1998

FGF4 dissociates anti-tumorigenic from differentiation signals of retinoic acid in human embryonal carcinomas.

A subset of male germ cell cancers presenting with advanced stage abundantly express the fibroblast growth factor-4 (FGF4). FGF4 expression is restricted in vitro to undifferentiated embryonal carcinomas (ECs). During induced differentiation, FGF4 expression is repressed in maturation sensitive but not resistant human ECs, suggesting FGF4 plays an important role in malignant growth or differentiation of ECs. To explore these FGF4 signals in male germ cell cancers, the multipotent human EC NTERA-2 clone D1 (NT2/D1) cell line was studied. All-trans-retinoic acid (RA)-treatment of these cells induces a neuronal phenotype and represses tumorigenicity and FGF4 expression. In contrast, RA-treatment of retinoid resistant lines derived from NT2/D1 cells failed to repress FGF4 expression. This implicated FGF4 directly in regulating human EC growth or differentiation. To evaluate further this FGF4 role, FGF4 was constitutively over-expressed in NT2/D1 cells using a CMV-driven expression vector containing the neomycin resistance gene. Three stable transfectants expressing exogenous FGF4 were studied as was a control transfectant only expressing the neomycin resistance gene. RA-treatment repressed endogenous but not exogenous FGF4 expression. RA-treatment of these transfectants induced morphologic and immunophenotypic maturation, changes in RA-regulated genes, and a G1 cell cycle arrest in a manner similar to parental NT2/D1 cells. This indicated FGF4 over-expression did not block RA-mediated differentiation. As expected, RA-treatment repressed tumorigenicity of the control transfectant after subcutaneous injection into athymic mice. Despite RA-treatment, this repressed tumorigenicity was overcome in all the transfectants over-expressing FGF4. The histopathology and neovascularization did not appreciably differ between xenograft tumors derived from FGF4 over-expressing versus control transfectants. FGF4 expression studies were extended to patient-derived germ cell tumors using total cellular RNA Northern analysis and an immunohistochemical assay developed to detect FGF4 protein expression. Germ cell tumors with EC components were significantly more likely to express FGF4 mRNA (P < or = 0.0179) than other examined germ cell tumors without EC components. Immunohistochemical results from 43 germ cell tumors demonstrated increased FGF4 expression especially in non-seminomas having EC components. Thus, FGF4 promotes directly malignant growth of cultured ECs, overcomes the antitumorigenic actions of RA, and is selectively expressed in specific histopathologic subsets of germ cell tumors. Taken together, these findings indicate how differentiation and anti-tumorigenic retinoic acid signals can be dissociated in germ cell cancer.

Antineoplastic Agents↗
PubMed1998

Human male germ cell tumor resistance to cisplatin is linked to TP53 gene mutation.

Male germ cell tumors (GCTs) are uniquely sensitive to cisplatin-based chemotherapy, with more than 90% of newly diagnosed cases cured. The underlying cause for resistance to treatment in 20-30% of metastatic lesions remains to be identified. Unlike other solid tumors, no mutations in the TP53 gene have been identified to date in random panels of GCT specimens, which could account for the exquisite sensitivity of these tumors to genotoxic insult. However, in a panel of resistant GCTs that did either not respond to cisplatin-based chemotherapy or subsequently relapsed and resulted in the death of the patient, we have now identified a subset of tumors to contain TP53 mutations within exons 6-9. A cell line derived from one of these tumors (228A) displayed the same TP53 mutation as the tumor specimen, expressed only mutant TP53 mRNA, and exhibited a relative resistance to cisplatin in vitro in comparison to a cell line (218A) derived from a responsive tumor with wild-type TP53. The resistant cell line displayed a much reduced apoptotic cell death and did not exhibit an induction of transcription of the p53-responsive genes WAF1 and MDM2 following cisplatin treatment, compared to that observed in the sensitive cell line. The levels of bax, an agonist of apoptosis, were found to be reduced in the resistant cell line. The simplest explanation for the resistance of this subset of GCTs that are resistant to cisplatin-based chemotherapy, is the inability of the cells to mount an apoptotic response following exposure due to a functionally inactivating mutation in the TP53 gene.

Antineoplastic Agents↗
PubMed1998

Pulmonary metastasectomy for testicular germ cell tumors: a 28-year experience.

BACKGROUND: The role of surgery in patients with pulmonary metastatic germ cell tumors has been evolving since the 1970s. To evaluate the results of pulmonary resection, we reviewed our 28-year experience. METHODS: Between July 1967 and May 1995, 157 patients with testicular germ cell tumors underwent pulmonary resections for suspected metastases. Their clinical and pathological data were reviewed. Kaplan-Meier and Cox regression models were used to analyze prognostic factors for survival after resection of metastatic disease. RESULTS: All patients were male with median age of 27 years (range 15-65). Complete resection was accomplished in 155 (99%) patients. Viable carcinoma was present in 44% (70) of the patients. Forty-one (26%) patients had metastases to other sites after pulmonary metastasectomy. The overall actuarial survival 5 years after pulmonary resection was 68% for the entire group and 82% for patients diagnosed after 1985. On multivariate analysis, the adverse prognostic factors were metastases to nonpulmonary visceral sites (p = 0.0069) and the presence of viable carcinoma in the resected specimen (p < 0.0001). CONCLUSIONS: With current chemotherapy regimens, almost 85% of the patients with testicular germ cell tumors undergoing complete resection of their pulmonary metastases can be expected to achieve long-term survival.

Adolescent↗
PubMed1998

Teratoma with malignant transformation: diverse malignant histologies arising in men with germ cell tumors.

PURPOSE: Teratoma with malignant transformation refers to a form of germ cell tumor in which a somatic teratomatous component becomes morphologically malignant and develops aggressive growth. We evaluated the spectrum of histologies, chromosomal abnormalities and clinical outcome in patients with teratoma with malignant transformation. MATERIALS AND METHODS: We identified 46 patients with germ cell tumor meeting morphologic criteria for malignant transformation. Histology, disease extent and treatment were correlated with survival. Tumors in 12 patients were studied by conventional cytogenetics or molecular genetic techniques for the isochromosome 12p [i(12p)], a marker for germ cell tumor, as well as other chromosomal abnormalities. RESULTS: The site of first detection of malignant transformation occurred in the primary tumor of 21 cases (44%), at a metastatic site in 20 (43%) and in both sites in 5 (10%). Sarcoma was the most frequent histology, identified in 29 patients (63%) with rhabdomyosarcoma the most common subtype. Seventeen tumors (37%) contained a solid tumor histology other than sarcoma, with adenocarcinoma and primitive neuroectodermal tumor as the most common histologies. Four patients with mediastinal germ cell tumor containing sarcoma also had hematological malignancies, including a focus of nonHodgkin's lymphoma in the mediastinal primary tumor (1) and nonlymphocytic leukemia in spleen or bone marrow (3). Patients who had teratoma with malignant transformation components confined to the testis or retroperitoneum completely resected experienced a longer survival than those with distant metastases or incompletely resected tumors (p = 0.003). Chromosomal abnormalities associated with germ cell tumor (i[12p]) were identified in 11 of 12 tumors containing adenocarcinoma, primitive neuroectodermal tumor, sarcoma and leukemia. In addition to i (12p), chromosomal rearrangements characteristic of the transformed histology were detected in 4 tumors. CONCLUSIONS: A variety of nongerm cell histologies, including sarcoma, adenocarcinoma, primitive neuroectodermal tumor and leukemia, may occur in association with germ cell tumor. Chromosomal abnormalities in these tumors include i (12p), reflecting germ cell tumor clonality, as well as chromosomal abnormalities associated with the transformed histology. These tumors do not respond like germ cell tumor to cisplatin-containing chemotherapy regimens. Treatment should be tailored according to that used in standard management of the transformed histology, and surgical resection is the mainstay of therapy.

Adenocarcinoma↗
PubMed1998

Metastatic germ cell tumors: modeling for response to chemotherapy.

PURPOSE: This study sought to determine factors that predict response to chemotherapy for patients with advanced germ cell tumors (GCTs), to evaluate different methods by which serum tumor markers can be used to predict response independent of assay method, and to develop criteria to guide allocation to clinical trials. METHODS: Pretreatment data from 796 patients treated with platinum-based chemotherapy on Memorial Hospital protocols from 1975 to 1990 were analyzed. Multivariate analyses were performed on a developmental data set (n = 597) to assess for independently significant predictors of response. Predictive models developed using these methods were confirmed on the validation set (n = 199). RESULTS: Independently significant factors for response included a mediastinal primary tumor (.015), pure seminomatous histology (.002), metastases to nonpulmonary visceral sites (bone, liver, and brain; .0001), and the pretreatment values of lactate dehydrogenase (LDH; .0001) and human chorionic gonadotropin (HCG; .0001). The likelihood of complete response (CR) was increased by seminomatous histology and decreased by the other factors. Serum levels of HCG and LDH could predict outcome independent of assay methodology. A model to predict good-, intermediate-, and poor-risk categories with CR rates of 92%, 76%, and 39%, respectively, was developed. CONCLUSION: The independent prognostic factors of serum tumor markers LDH and HCG, the sites of metastases, and the primary origin of GCTs can predict outcome in patients with advanced GCT. These factors should be considered in the allocation of patients with advanced disease to clinical trials and have been included in the new tumor-node-metastasis (TNM) staging systems developed for the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Mediastinal growing teratoma syndrome.

BACKGROUND: The growing teratoma syndrome refers to the phenomenon whereby germ cell tumors enlarge after chemotherapy despite complete eradication of malignant cells and normalization of serum tumor markers. This clinical scenario must be differentiated from that in which germ cell tumors maintain their malignant characteristics with elevated levels of serum tumor markers. METHODS: Hospital record review was conducted of 2 cases. RESULTS: Two male patients are presented, 1 with a metastatic germ cell tumor of both the retroperitoneum and mediastinum (with elevated alpha-fetoprotein level) and 1 with a primary germ cell tumor of the mediastinum (with elevated alpha-fetoprotein and beta-human chorionic gonadotropin levels). After completion of chemotherapy and normalization of tumor markers, both patients presented with pulmonary symptoms attributable to their massively enlarging mediastinal teratomas. The clinical and roentgenographic features of patients with thoracic manifestations of the growing teratoma syndrome, as well as its management, are reviewed. CONCLUSIONS: After chemotherapy in patients with primary or metastatic mediastinal germ cell tumors whose tumor markers normalize, a growing mass in the mediastinum may represent the growing teratoma syndrome.

Adult↗
PubMed1997

High-dose carboplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors.

PURPOSE: A treatment program that included high-dose carboplatin, etoposide, and cyclophosphamide (CEC) followed by autologous bone marrow transplantation (AuBMT) was investigated as first-line therapy in patients with poor-risk germ cell tumors (GCTs). PATIENTS AND METHODS: Previously untreated GCT patients with poor-risk features were treated with etoposide, ifosfamide, and cisplatin (VIP) with or without high-dose CEC plus AuBMT. Patients qualified for a change to high-dose CEC if a prolonged clearance of elevated serum tumor markers was observed after two cycles of the cisplatin-containing regimen. RESULTS: Sixteen patients were treated with VIP alone and 14 with VIP and high-dose CEC. Seventeen patients (57%) achieved a complete response. Twenty are alive (67%) and 15 (50%) are free of disease at a median follow-up time of 30 months. For 23 cycles of high-dose CEC, the median time from AuBMT to a granulocyte count > or = 0.5/microL was 11 days (range, 0 to 14) and to a platelet count 50,000/microL, 19 days (range, 14 to 34). The survival of 58 patients treated in two of our center's programs that incorporated high-dose chemotherapy (high-dose carboplatin plus etoposide [CE] and CEC) was compared with our prior experience with conventional-dose cisplatin chemotherapy alone in poor-risk GCT. Patients treated with marker-dependent, early-intervention high-dose chemotherapy experienced longer survival (P = .001). CONCLUSION: In this setting, high-dose CEC was well tolerated, cumulative toxicity was lacking, and the recovery of blood counts after AuBMT was rapid. A randomized trial has been initiated to investigate further the role of high-dose CEC in first-line therapy for patients with poor-risk GCT.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Long-term follow-up of patients with good-risk germ cell tumors treated with etoposide and cisplatin.

PURPOSE: To assess the durability of response and overall survival for patients with good-risk metastatic germ cell tumors (GCT) treated with four cycles of etoposide and cisplatin (EP). PATIENTS AND METHODS: Two hundred fourteen patients treated with EP on two consecutive randomized trials for good-risk metastatic GCT were the subject of this retrospective study. The response to therapy, relapse and survival status, and results of salvage therapy are reported. RESULTS: One hundred ninety-five patients (91%) achieved a complete response (CR). This included 182 patients (85%) who achieved a CR to chemotherapy alone and 13 patients (6%) who achieved a CR to chemotherapy plus surgical resection of viable GCT. Seventeen patients (9%) have relapsed from CR. The median time to relapse was 10 months, and the longest duration from treatment to relapse was 36 months in a patient who received three of four planned courses of therapy. Eight patients who either achieved an incomplete response (IR) or relapsed were rendered continuously disease-free by salvage therapy and are alive. One hundred eighty-three patients (86%) are alive at a median follow-up of 7.6 years. CONCLUSION: Four cycles of EP constitute effective therapy and can be offered to patients with good-risk GCT. In patients with intermediate- and poor-risk GCT, clinical trials remain a priority to identify more effective treatment.

Adolescent↗
PubMed1997

Ifosfamide- and cisplatin-containing chemotherapy as first-line salvage therapy in germ cell tumors: response and survival.

PURPOSE: To evaluate the efficacy and toxicity of ifosfamide- and cisplatin-containing chemotherapy as first-line salvage treatment for patients with germ cell tumors (GCT). PATIENTS AND METHODS: Fifty-six patients with advanced GCT resistant to one prior cisplatin-containing regimen were treated with a salvage chemotherapy regimen of ifosfamide, cisplatin, and either vinblastine or etoposide (VeIP/VIP). RESULTS: Twenty of 56 (36%) assessable patients achieved a complete response (CR). Thirteen (23%) are alive and continuously free of disease at a median follow-up time of 52 months; the median survival duration was 18 months. Among patients with a testis primary tumor site and a prior CR to first-line therapy, 65% are alive and 41% continuously disease-free, and the median survival time has not been reached. In contrast, for patients with an extragonadal primary tumor or with a testis primary tumor site and an incomplete response (IR) to first-line therapy, 31% are alive and 15% continuously free of disease, with a median survival time of 12 months (P < .03). CONCLUSION: Ifosfamide- and cisplatin-containing therapy achieves a durable CR in a minority of patients with resistant GCT as first-line therapy. Patients with a primary testis site who relapsed from a CR to first-line cisplatin therapy have a better prognosis than patients with an extragonadal primary tumor site or an IR to first-line therapy. Risk-directed clinical trials to improve response and survival in both subsets are warranted.

Adolescent↗
PubMed1997

Aberrant expression of cyclin D2 is an early event in human male germ cell tumorigenesis.

Human male germ cell tumors (GCTs) arise in the spermatocytic lineage, and subsets display embryonal-like differentiation. Virtually all GCTs exhibit multiple copies of the short arm of chromosome 12, even in carcinoma in situ/intratubular germ cell neoplasia, the earliest recognizable neoplastic lesion of germ cells. Among the candidate amplified genes mapped to 12p, expression of the cyclin D2 gene (CCND2) was deregulated in a panel of GCT cell lines, with the relative level of steady-state mRNA and protein inversely correlated with the pattern of differentiation characteristic of the cell line. GCT cell lines with a more differentiated phenotype, as indicated by an immunophenotypic analysis, displayed lower cyclin D2 expression with a concurrent increase in expression of the cell cycle inhibitor p21. In the GCT cell lines in which cyclin D2 was highly expressed, cyclin D2 was in complex with its expected catalytic partners (Cdk4 and Cdk6). Whereas no detectable cyclin D2 expression was evident in normal human germ cells, cyclin D2 was expressed in the abnormal germ cells of all carcinoma in situ/intratubular germ cell neoplasia lesions studied. In GCT specimens that displayed no evidence of differentiation (seminoma) or primitive differentiation (embryonal carcinoma), cyclin D2 expression was detected. However, in tumor specimens with certain patterns of differentiation (teratoma and yolk sac tumor), expression was down- or up-regulated depending on the pattern. Our data suggest that aberrant cyclin D2 expression is an early event in germ cell tumorigenesis.

Blotting, Northern↗
PubMed1997

Surgery for a post-chemotherapy residual mass in seminoma.

PURPOSE: We attempted to select patients for surgery of post-chemotherapy residual mass in advanced seminoma. MATERIALS AND METHODS: A total of 55 patients with advanced seminoma underwent surgical exploration of a mass seen on computerized tomography (CT) after chemotherapy. Residual masses were defined radiographically as smaller or larger than 3 cm. and as well defined or poorly defined. Surgery consisted of complete resection of the mass and surrounding lymph nodes or multiple biopsies at sites of disease. RESULTS: Of the 55 patients 32 (58%) had masses resected and 23 (42%) underwent multiple biopsies. Of 27 patients with a post-chemotherapy 3 cm. or larger mass on CT 8 (30%) had residual tumor (seminoma in 6 and teratoma in 2), whereas necrotic tissue was found in the other 28 patients having a mass smaller than 3 cm. Well defined masses on CT were resected in 78% of patients and poorly defined masses could be resected in only 44%. Of the 8 patients with positive histology 6 remain alive and disease-free after complete resection of a well defined, larger than 3 cm. mass containing viable tumor, and 2 with a poorly defined mass died after biopsy only of residual seminoma despite salvage therapy. Three other patients who underwent complete resection of necrotic masses subsequently had relapse at distant sites and died. Median followup was 47 months (range 5 +/- 153+ months). CONCLUSIONS: Patients with advanced seminoma who have a residual mass smaller than 3 cm. after chemotherapy do not benefit from surgery. For patients with a residual mass 3 cm. or larger we prefer surgery to define response, resect viable tumor when possible and direct further treatment.

Follow-Up Studies↗
PubMed1997

Germ cell tumors.

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Adolescent↗
PubMed1997

Combined-modality therapy for bladder cancer.

Radical cystectomy remains standard management for patients with locally advanced T2 through T4, N0, M0 transitional cell carcinoma of the urinary bladder. Although radical cystectomy results in excellent local control, 50% or more of patients relapse. Studies have shown that multidrug cisplatin (Platinol)-based chemotherapy prolongs disease-free survival in 10% to 15% of cases and is superior to single-agent cisplatin. These studies led to the application of these regimens in conjunction with surgery and/or radiation therapy in an attempt to preserve bladder function. With this approach, the decision to leave the bladder in place, remove a portion (partial cystectomy), or perform a radical cystectomy is made after assessing the initial response to therapy. Results from neoadjuvant studies have shown that: major responses are observed in at least 50% of patients; bladder preservation can be achieved in 25% to 50%; a pathologic complete response predicts long survival; and patients with deeply invasive lesions (T3b to T4) usually are not candidates for bladder preservation. Whether overall survival is improved has been difficult to ascertain due to such issues as small sample size and case selection. Concurrently, newer surgical approaches with continent diversions have reduced, to some extent, the need for ileal conduits, a factor influencing the bladder preservation approach. Adjuvant chemotherapy, although less well studied, suggests a possible survival benefit for selected patients with a high likelihood of relapse. To optimize patients selection, new prognostic factors are necessary. Many biologic variables based on expression of tumor-related proteins are under study. Combined-modality therapy is not standard management for the majority of bladder-cancer patients. However, it is a viable alternative for those who are committed to preserving bladder function. Additional research is required to determine whether these approaches improve survival and to identify better markers of treatment outcome.

Carcinoma, Transitional Cell↗
PubMed1997

Implementation of practice guidelines.

Memorial Sloan-Kettering Cancer Center staff, in conjunction with Cambridge Technology Partners, has designed, developed, and begun to implement a disease management system (DMS) as a means of standardizing the care of the center's patients with cancer. The disease management system is centrally coordinated through disease management teams, which include physicians from each of the major oncology disciplines--radiation, medicine, and surgery--as well as specialists and other professionals involved in patient care. The system is comprised of four modules: system administration, treatment pathways, patient management, and outcomes analysis. In July 1966, the gynecology team began to pilot this program, and the remaining 16 disease management teams were incorporated, in phases, during the rest of 1996. The regional sites are being incorporated in 1997. After a brief summary of the basic features of the disease management system, this article describes the implementation process and the accomplishments to date.

Databases, Factual↗