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S Rodenhuis

Publications and source records attributed to S Rodenhuis.

At least 109 records · Page 6Linked to original sources

Bone marrow reconstitution after high-dose chemotherapy and autologous peripheral blood progenitor cell transplantation: effect of graft size.

BACKGROUND: Peripheral blood progenitor cell transplantation is rapidly replacing autologous bone marrow transplantation as hematological support after high-dose chemotherapy for lymphoma or solid tumors. Controversy exists concerning the number of progenitor cells required for rapid and sustained bone marrow recovery, and as to which of the widely available methods for estimating this number should be employed. METHODS: Forty consecutive patients with solid tumors or lymphomas received high-dose chemotherapy followed by autologous peripheral stem cell reinfusion. All stem cell harvests had been performed after mobilization with standard-dose chemotherapy followed by 300 micrograms G-CSF daily. Hematopoietic reconstitution was studied in relation to pertinent patient characteristics, to the size of the graft (in terms of the total number of mononuclear cells (MNC), the number of granulocyte/macrophage colony-forming units (CFU-GM) and the number of CD34+ cells, and to the use of G-CSF after stem cell reinfusion. RESULTS: Both the numbers of CFU-GM and CD34+ cells reinfused, but not those of the MNC, correlated with granulocyte and platelet recovery. Patients who received at least 5 x 10(6) CD34+ cells/kg body weight achieved platelet transfusion independence on day 12 after reinfusion (range: day 7-37), significantly earlier than patients who had received less (p = 0.001). Thirty patients who received G-CSF (300 micrograms s.c. daily) after reinfusion achieved granulocyte recovery (> or = 500 x 10(6)/l) on day 9 (range: day 8-12), while this took a median of 15 days (range: day 10-28) in 10 consecutive patients not receiving G-CSF (p = 0.0003). In one patient who had received 1.4 x 10(6) CD34+ cells/kg, secondary bone marrow failure developed 3 months after transplantation. Reinfusion of cryopreserved autologous bone marrow was followed by prompt recovery. CONCLUSION: Peripheral stem cells, mobilized by moderate-dose chemotherapy and G-CSF, lead to rapid and durable engraftment after high-dose chemotherapy when at least 3-5 x 10(6) CD34+ cells/kg are reinfused. Lower numbers may also be satisfactory, but are associated with slower granulocyte and platelet recoveries. A moderate dose of G-CSF after reinfusion significantly hastens granulocyte recovery without interfering with platelet recovery.

Adult↗

C-erbB-2 expression and codon 12 K-ras mutations both predict shortened survival for patients with pulmonary adenocarcinomas.

We evaluated the prognostic significance of p185c-erbB-2 expression and ras gene mutations in all patients diagnosed with a pulmonary adenocarcinoma between 1982 and 1985 at the University of Iowa. p185c-erbB-2 expression was detected in 15 cases (34%). A ras gene mutation was found in 16 cases (36%) and all were in codon-12 of K-ras. No N-ras mutations were identified. Both p185c-erbB-2 expression and a K-ras mutation were found only in codon-12 and present in six cases (14%). By univariate analysis p185c-erbB-2 expression was associated with shortened survival (P = 0.02) while the presence of a K-ras mutation was not (P = 0.16). Multivariate analysis by the Cox proportional hazards model, controlling for patient age and tumor stage, also continued to identify p185c-erbB-2 expression as an independent unfavorable prognostic factor (P = 0.01). In this model a K-ras mutation also approached significance as a poor prognostic indicator (P = 0.06). The impact of both p185c-erbB-2 expression and a K-ras mutation on survival was additive and highly significant (P = 0.004). This additive nature suggests that together these two markers identify a high-risk population of lung adenocarcinoma patients that may benefit from aggressive therapy.

Actuarial Analysis↗

Catheter-related complications in 52 patients treated with continuous infusion of low dose recombinant interleukin-2 via an implanted central venous catheter.

In this study we evaluated the catheter-related complications in 52 patients with advanced melanoma, renal cell cancer or non-Hodgkin's lymphoma treated with continuous infusion of low-dose recombinant interleukin-2 by central venous access (CVA) of the port-a-cath type. We noted a high incidence (55.5%) of catheter infection, defined as positive blood cultures drawn from the CVA in symptomatic or asymptomatic patients. Six infections were noted before rIL-2 treatment was started. Twelve of the 30 documented infections were symptomatic (fever and/or chills), with only four documented bacteraemias. The most frequently cultured microorganism was Staphylococcus epidermidis (73%). Treatment initially consisted of systemic antibiotics via the CVA, but as experience increased, the mostly asymptomatic CVA infections were not treated. In 30% of the documented CVA infections a thrombus at the tip of the catheter was found by radiological contrast examination. Local thrombosis can be effectively treated with constant infusion of low dose streptokinase via the CVA.

Adult↗

K-ras oncogene activation in lung adenocarcinomas from former smokers. Evidence that K-ras mutations are an early and irreversible event in the development of adenocarcinoma of the lung.

BACKGROUND: Point mutations in codon 12 of the K-ras protooncogene occur more frequently in lung adenocarcinomas from smokers (30%) than they do in lung adenocarcinomas from nonsmokers (7%), suggesting that smoking is an important factor in the induction of these mutations. The lack of well defined "early" premalignant or in situ glandular neoplasms of the lung, however, has not permitted direct evaluation of the chronology of ras activation in the development of lung adenocarcinomas. To circumvent the need to evaluate precursor lesions, we examined lung adenocarcinomas from former smokers for point mutations in K-ras. METHODS: Mutations in codon 12 of K-ras were detected using polymerase chain reaction amplification and mutation-specific oligonucleotide probes. The types and frequencies of mutations found in adenocarcinomas obtained from 57 former smokers were compared to those found in 27 adenocarcinomas from patients who never smoked and to those found in 27 adenocarcinomas from patients who were current smokers. RESULTS: The overall prevalence of K-ras point mutations in lung adenocarcinomas obtained from former smokers (32%) was not different from that seen in adenocarcinomas from patients who were current smokers (30%, P = 0.83), and was greater than that seen in adenocarcinomas from patients who never smoked (7%, P = 0.015). This pattern was independent of the duration of abstinence from smoking. Furthermore, the predominant type of mutation found in tumors from former smokers was a guanine-to-thymine transversion, the specific type of mutation induced by benzo(a)pyrene, one of the chemical carcinogens found in tobacco smoke. CONCLUSIONS: These findings support previous findings that suggest that codon 12 of the K-ras oncogene may be a specific target of the mutagenic activity of tobacco smoke, and suggest that DNA alterations at this site can occur early and irreversibly during the development of adenocarcinomas of the lung.

Adenocarcinoma↗

[Favorable effect of hematopoietic stem cells isolated from blood on hematologic recovery following high-dosage chemotherapy].

Peripheral blood stem cells can reconstitute bone marrow function after high-dose chemo-/radiotherapy. We describe 17 patients treated with a three-day course of chemotherapy consisting of cyclophosphamide or ifosfamide and etoposide (malignant lymphoma and germ cell tumor) or a one-day course of 5-fluorouracil, epidoxorubicin and cyclophosphamide (breast cancer), followed by the administration of recombinant human granulocyte colony-stimulating factor (G-CSF). Maximum numbers of peripheral blood stem cells were recruited on day 9-10 of the G-CSF administration with 0.1 x 10(9)/l CD34+ cells (median; range 0-0.36). The total number of peripheral stem cells harvested with two-three leukaphereses was 40 x 10(4)/kg CFU-GM (4-257) or 8 x 10(6)/kg CD34+ cells (1-39). Ten patients with malignant lymphoma or solid tumours received high-dose chemotherapy followed by bone marrow and peripheral stem cell infusion (n = 7) or peripheral stem cell infusion alone (n = 3). The recovery of granulocytes, platelets and reticulocytes after peripheral stem cell infusion, in addition to or instead of bone marrow, was markedly accelerated compared with the infusion of BM alone. The accelerated haemopoietic recovery was associated with a reduction in platelet and red blood cell transfusion, reduction in fever periods and earlier discharge from hospital. Peripheral stem cell transplantation may become an important alternative to autologous bone marrow transplantation. This transplantation technique may also allow application of multiple-cycle intensive chemotherapy.

Adult↗

A phase I study of prolonged continuous infusion of low dose recombinant interleukin-2 in melanoma and renal cell cancer. Part II: Immunological aspects.

Previously we described the clinical aspects of a phase I study of prolonged continuous infusion of low-dose recombinant interleukin-2 (rIL-2). In the present paper we report several immunological effects in 13 patients with melanoma and renal cell cancer treated on an out-patient basis with rIL-2 for uninterrupted periods ranging from 5 to 18 weeks. Groups of three patients were treated at following dose levels 0.18, 0.6, 1.8 or 6 x 10(6) IU m-2 24 h-1 and one patient was treated with 3 x 10(6) IU m-2 24 h-1. Prolonged rIL-2 treatment resulted in a dose-dependent and sustained increase in the percentage and absolute number of (CD56+, CD8dim) natural killer cells. Within this population a preferential increase in the CD56bright cells with low expression of CD16 was observed. The CD27 antigen was also upregulated in the CD56bright CD16dim population. This increase of NK cells was accompanied by an enhancement of the cytotoxic capacity of the peripheral lymphocytes. No consistent signs of T cell activation or expansion were noted.

Adult↗

Combination chemotherapy with tauromustine (TCNU), 5-fluorouracil and leucovorin in advanced colorectal carcinoma: a dose-finding study.

BACKGROUND: In preparation for a phase II trial we performed a dose-finding study involving tauromustine (TCNU), fluorouracil (5-FU) and leucovorin (LV), applied in patients with colon cancer. To prevent TCNU/5-FU antagonism, a phenomenon recently demonstrated in vitro, special attention was paid to the sequencing of these agents. PATIENTS AND METHODS: In 25 patients with advanced colorectal carcinoma (13 M, 12 F, median age 51 yrs), four dose levels of TCNU (25, 30, 35 or 40 mg/m2) were investigated. The agent was administered orally once per week in weeks 1 through 4, in combination with fixed i.v. doses of 400 mg/m2 5-FU and 80 mg/m2 LV, once a week, weeks 1 through 8. Unless progression occurred, two 8-week cycles were applied. TCNU was administered at least 24 hours prior to 5-FU, because recent in vitro studies suggested that such an interval is required to obtain additive cytotoxicity. RESULTS: All 25 patients were evaluable for toxicity; 23 patients received at least one full 8-week course, and 13 were eligible for second cycles. Significant haematologic toxicity, predominantly thrombocytopenia WHO grade 3 or 4, was mainly encountered at the 35 and 40 mg/m2 dose levels. Although occasionally severe, myelosuppression did not result in toxic deaths; spontaneous haemorrhage was never observed, and platelet transfusions were not required. Additional toxicity, also related to the two higher dose levels, consisted of diarrhea (WHO grade 3) and the 'hand and foot syndrome', both occurring in a single patient; two patients developed fever of undetermined origin, but only one of them required hospitalization and antibiotic treatment. The overall response rate was 20% (7 partial responses in 25 evaluable patients). CONCLUSIONS: For phase II studies, we recommend a weekly oral dose of 40 mg/m2 TCNU, weeks 1 through 4, in combination with 400 mg/m2 5-FU and 80 mg/m2 LV (IV), once a week, weeks 1 through 8.

Adult↗

Epirubicin in patients with advanced or recurrent adenoid cystic carcinoma of the head and neck: a phase II study of the EORTC Head and Neck Cancer Cooperative Group.

BACKGROUND: Because of the rarity of salivary gland cancer, little is known about the single-agent activity of most anticancer agents in the different histologic types of these cancers. PATIENTS AND METHODS: Twenty patients with advanced or recurrent adenoid cystic carcinoma of the head and neck were treated with epirubicin on a low-dose weekly schedule (30 mg/m2/week) for eight weeks and, in instances of no response, a high-dose three-weekly schedule (> or = 90 mg/m2). Thirteen patients had locoregional disease (12 recurrences), seven of them also had distant metastases and seven had distant metastases only. All had documented progressive disease, and 17 were symptomatic. RESULTS: Two objective responses of 7.5 and 20 months were observed in patients with locally recurrent disease, and ten patients showed disease stabilization. The median time to progression was 16 weeks (range 2-250 weeks) and the median survival 67 weeks (range 13-272+ weeks), with three patients still alive more than five years after the initiation of chemotherapy. Contrary to the rather modest objective response rate, symptomatic improvement occurred more frequently (29.4%) and was evident within 8 weeks of treatment. CONCLUSIONS: This type of chemotherapy should be reserved for patients with rapidly progressive disease or those with symptomatic disease.

Adult↗

Feasibility study of FEC-chemotherapy with dose-intensive epirubicin as initial treatment in high-risk breast cancer.

BACKGROUND: The prognosis of patients with stage III B breast carcinoma with metastasis to the apical axillary lymph nodes is poor despite adequate local control achieved by surgery and/or radiation therapy. This study evaluated the feasibility of a dose-intensive up-front chemotherapy regimen in this subgroup of patients. PATIENTS AND METHODS: A preoperative chemotherapy regimen consisting of 3 courses of fluorouracil 500 mg/m2, dose-intensive epidoxorubicin 120 mg/m2 and cyclophosphamide 500 mg/m2 (DIE-FEC), was administered at 21-day intervals without hematopoietic growth factors to 31 patients with apex-positive disease. All patients were below 60 years of age and none had had prior chemotherapy or radiotherapy. RESULTS: Seven patients achieved clinical complete responses (23%), and 21 achieved clinical partial responses (68%); three patients had stable disease (10%), one of whom had only ductal carcinoma in situ at histopathologic evaluation, which suggested an additional response to therapy. The major toxicity was moderate bone marrow suppression with a median WBC nadir of 1650/microliters (range 500-4600). Other toxic effects were mild. CONCLUSION: DIE-FEC is well-tolerated and highly effective as up-front chemotherapy in relatively young patients with high-risk breast cancer, with a 90% (CI 74%-98%) clinical objective response rate.

Adult↗

Overexpression of the p53 tumor suppressor gene product in primary lung adenocarcinomas is associated with cigarette smoking.

Mutations in the p53 tumor suppressor gene are frequently observed in primary lung adenocarcinomas, suggesting that these mutations are critical events in the malignant transformation of airway cells. These mutations are often associated with stabilization of the p53 gene product, resulting in the accumulation of p53 protein. In this study, 70 formalin-fixed, paraffin-embedded primary lung adenocarcinomas resected for potential cure were examined for p53 overexpression. These 70 lung adenocarcinomas were obtained from a series of patients with well-documented clinical histories, and all 70 carcinomas had been previously evaluated for point mutations in codon 12 of the K-ras oncogene. Overexpression of the p53 protein was detected using an antigen retrieval system (Target Unmasking Fluid) and the anti-p53 antibody CM-1. CM-1 is a polyclonal antibody directed against the wild-type p53 protein. Overexpression of the p53 protein was found in 23 (33%) of the 70 lung adenocarcinomas. In all 23 cases, overexpression was confined to neoplastic cells. Overexpression of the p53 protein correlated with cigarette smoking: 10 (56%) of the 18 adenocarcinomas from patients who were current smokers overexpressed p53 compared with 13 (33%) of the 40 adenocarcinomas from patients who had quit smoking and 0 (0%) of the 12 adenocarcinomas from patients who had never smoked (p = 0.002, trend test). Overexpression of the p53 protein was also related to the degree of histologic differentiation: 48% of the p53 negative carcinomas were well differentiated, whereas only 13% (p = 0.003) of the carcinomas in which p53 was overexpressed were well differentiated. Overexpression of the p53 protein did not correlate with point mutations in codon 12 of the K-ras oncogene, nor did it correlate with tumor stage or patient survival. These findings indicate that p53 protein is frequently overexpressed in primary lung adenocarcinomas. Furthermore, the association of tobacco smoking with this overexpression suggests that the p53 gene is a target of specific mutagens in tobacco smoke.

Adenocarcinoma↗

Central venous catheter associated thrombosis of major veins: thrombolytic treatment with recombinant tissue plasminogen activator.

OBJECTIVE: Major thromboses can occur in the venous system in association with central venous catheters. This usually necessitates removal of the catheter. METHODS: The effectiveness of low dose recombinant tissue type plasminogen activator (rt-PA) in combination with heparin was assessed in patients with central venous catheter associated thrombosis. RESULTS: In five patients, all suffering from cancer, a 5-7 day continuous infusion resulted in complete lysis of the thrombus without complications in three. In the other two patients moderately severe haemorrhage was observed with only partial lysis, of the thrombus. CONCLUSIONS: The infusion of heparin and rt-PA is potentially effective in thrombosis related to use of central venous catheters, but the risk of haemorrhage is not inconsiderable.

Adult↗

Peripheral blood stem cell (PBSC) mobilization and transplantation (PSCT) in patients with malignant lymphomas and solid tumors.

Peripheral blood stem cells can reconstitute bone marrow function after high-dose chemo-/radiotherapy. We describe 44 patients related with a three-day course of chemotherapy, for hematopoietic stem cell mobilization, consisting of cyclophosphamide or ifosfamide and etoposide (malignant lymphoma and germ cell tumor) or a one-day course of 5-fluorouracil, epirubicin and cyclophosphamide (breast cancer), followed by the administration of recombinant human granulocyte colony-stimulating factor (G-CSF). Maximum numbers peripheral blood stem cells (PBSC) were recruited on day 9-10 of the G-CSF administration. The total number of PBSC cells harvested with median 3.6 leukaphereses was 46 x 10(4)/kg (7.5-136) CFU-GM or 8 x 10(6)/kg (0.7-25.0)CD34+ cells for patients with solid tumors and 26 (4.5-258) CFU-GM's or 6.1 (1-0-39.2) CD34+ cells for patients with malignant lymphomas. Thirty-five patients with malignant lymphomas or solid tumors received high-dose chemotherapy followed by bone marrow and PBSC infusion (n = 8) or PBSC cell infusion alone (n = 27). The recovery of granulocytes, platelets and reticulocytes after peripheral stem cell transplantation (-PSCT) in addition to or instead of bone marrow, was markedly accelerated compared with the infusion of BM alone. The accelerated haemopoietic recovery was associated with a reduction in platelet and red blood cell transfusion, reduction in fever periods and earlier discharge from hospital. PSCT is an important alternative to autologous bone marrow transplantation (ABMT). This transplantation technique may also allows application of multiple-cycle intensive chemotherapy.

Adult↗

Clinical significance of ras oncogene activation in human lung cancer.

Activation of ras oncogenes is commonly found in human neoplasms. We have investigated 280 human lung cancer specimens for ras activation, including 38 that have not been reported previously, using an oligonucleotide detection assay. From a total of 141 adenocarcinoma samples from smokers, 41 tested positive for a point mutation in codon 12 of K-ras (30%), while three tumors had another type of ras activation. Only two of 40 cases from nonsmokers had a K-ras mutation (5%), suggesting that K-ras mutations may be directly caused by exposure to carcinogens in tobacco smoke. The majority of the point mutations in adenocarcinomas were guanine to thymine transversions in codon 12 of the K-ras oncogene. Occasional point mutations in ras oncogenes were detected in adenosquamous carcinomas (one of five cases) and large cell carcinoma (one of 24 cases), but no ras activations were found in small cell carcinomas (six cases), squamous carcinomas (48 cases), carcinoid carcinomas (15 cases), or thymoma (one case). Analysis of the clinical and pathological features of the adenocarcinoma cases showed no apparent associations between the K-ras activation and age at diagnosis, sex, disease stage, and the occurrence of other neoplasms. K-ras-positive adenocarcinomas tended to be less differentiated than the K-ras-negative ones (P = 0.044, chi 2 test for trend). K-ras mutations identify a subgroup of patients with adenocarcinoma of the lung who have a very poor prognosis despite radical resection of their tumor. Although K-ras has been proposed as a target for antitumor therapy, its major clinical significance could be to aid in the selection of patients for specific therapeutic interventions, such as adjuvant chemotherapy.

Genes, ras↗

Intestinal obstruction due to diffuse peritoneal fibrosis at 2 years after the successful treatment of malignant peritoneal mesothelioma with intraperitoneal mitoxantrone.

A 44-year-old man who had achieved a complete remission of malignant peritoneal mesothelioma after the intraperitoneal administration of 25 mg/m2 mitoxantrone presented with clinical and radiological signs of intestinal obstruction suggestive of recurrent disease at about 2 years following the initial treatment. However, laparotomy revealed extensive adhesive fibrosis but no sign of malignant mesothelioma. The peritoneal complications of intraperitoneal cytostatic treatment are discussed.

Adult↗

A phase I study of prolonged continuous infusion of low dose recombinant interleukin-2 in melanoma and renal cell cancer. Part I: Clinical aspects.

The optimal schedule for recombinant interleukin-2 (rIL-2) administration is unclear. Because the clinical and immunological effects of prolonged continuous exposure to rIL-2 are unknown, we have conducted a phase I study to assess the toxicity and feasibility of continuous low dose infusion of rIL-2 (EuroCetus) using central venous access with a portable infusion device on an out-patient basis. Twenty-two patients entered the study, 13 with melanoma and nine with renal cell cancer, age range 26-66 years (median 51), performance status less than or equal to 1. They were treated with one of the following doses per m2 per 24 h: 0.18 x 10(6) IU, 0.6 x 10(6) IU, 1.8 x 10(6) IU, 3 x 10(6) IU, 6 x 10(6) IU and 9 x 10(6) IU. Toxicity was evaluable in 20 patients receiving greater than or equal to 3 weeks treatment duration or in whom treatment was discontinued prematurely because of toxicity. Constitutional symptoms consisting of fatigue, malaise and fever up to 40 degrees C without significant organ dysfunction occurred with doses greater than or equal to 1.8 x 10(6) IU m-2. The maximum tolerated dose was 6 x 10(6) IU m-2 24 h-1. In all patients toxicity reached a peak at 3 weeks and resolved thereafter despite continued rIL-2 treatment. Peripheral blood eosinophilia (up to 66% of white blood cell count) followed the same pattern. An infection of the central venous access occurred in 55% of the patients but this was mostly asymptomatic. Thirteen patients were treated greater than or equal to 6 weeks and were evaluable for tumour response. A partial remission occurred in a patient with melanoma with a dose of 1.8 x 10(6) IU rIL-2 m-2 24 h-1.

Adult↗

Feasibility and toxicity study of a high-dose chemotherapy regimen for autotransplantation incorporating carboplatin, cyclophosphamide and thiotepa.

Sixteen patients received a high-dose chemotherapy regimen consisting of carboplatin (1600 mg/m2) and cyclophosphamide (6000 mg/m2) as daily two-hour infusions over four days (CC). All but two of them also received thiotepa (480 mg/m2) in eight 30-minute infusions given every 12 hours (CTC). Bone marrow and/or peripheral stem cell (PSC) reinfusions took place 72 hours after the last course of chemotherapy. The major toxicity was bone marrow suppression, the duration of which was markedly reduced in the patients receiving PSC reinfusions. Non-hematological toxicity was relatively mild and consisted of nausea and vomiting, minor mucositis and skin rashes. All but one patient had mild and completely reversible elevations of serum ALAT and/or LDH levels. One patient, who had received full-dose chemotherapy despite a creatinine clearance of 56 ml/min, developed significant toxicity consisting of transient cyclophosphamide-associated pancarditis, reversible neurotoxicity and partially reversible hearing loss and renal function impairment. There were no toxic deaths. In view of the high carboplatin dose, the CTC regimen may be particularly suitable for use in the salvage treatment of germ cell cancer. Since CTC causes no serious organ toxicity, further studies to determine its suitability for double or even triple transplantation programs are warranted.

Adult↗

Feasibility study of high-dose carboplatin and etoposide in the salvage treatment of testicular cancer.

Eleven patients with testicular cancer, either relapsing after or refractory to cisplatin-based chemotherapy, underwent salvage chemotherapy with high-dose carboplatin (800 mg/m2 on day 1) and high-dose etoposide (500 mg/m2 on days 1, 3 and 5). A total of 21 courses were administered. The major toxicity consisted of profound myelosuppression. There were two toxic deaths, both caused by infection during neutropenia. Bone marrow recovery was usually complete around day 26 (range 19-129). Other toxicities included mild mucositis, nausea and vomiting, and alopecia. No significant neurotoxicity or hearing loss were observed and only one patient had a moderate decrease in renal function. Nine of ten evaluable patients responded, with one complete remission, 6 partial remissions with normalization of tumor markers, and two partial remissions with over one log decrease of tumor markers. The duration of these remissions was not evaluable, since only three evaluable and responding patients did not receive additional therapy after HD-CE. All three relapsed after discontinuing chemotherapy. HD-CE has activity in relapsing or refractory testicular cancer and can be administered without bone marrow support. The regimen may thus be suitable to be used as a remission induction regimen prior to consolidation with intensive chemotherapy and autologous bone marrow transplantation.

Adult↗