melphalan and Kidney-Neoplasms

Nonablative hematopoietic cell transplantation (HCT) is becoming a preferred treatment for those recipients in whom the potential toxicity risk of standard ablative allogeneic therapy may be unacceptable. Graft-versus-malignancy effects may be generated against epithelial malignancies which are similar to the graft-versus-leukemia activity that is well documented in human hematological malignancies. Renal cell carcinoma has been shown to be responsive to immunotherapy with recombinant human cytokines and may be an ideal model for exploring this novel therapy. Clinical investigations have demonstrated regression of metastatic renal cell carcinoma occurs in some patients following nonablative allogeneic HCT. However, graft-versus-host disease remains a significant toxicity of nonablative transplantation, and further investigations are warranted to further evaluate this promising approach and to improve its safety.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Cytokines; Graft Survival; Graft vs Host Disease; Graft vs Tumor Effect; Humans; Immunotherapy, Adoptive; Kidney Neoplasms; Melphalan; Multicenter Studies as Topic; Nephrectomy; Peripheral Blood Stem Cell Transplantation; Recombinant Proteins; Survival Analysis; Thiotepa; Transplantation Chimera; Transplantation Conditioning; Treatment Outcome; Vidarabine

Although cytotoxic immunosuppressive agents play an unquestionably useful role in treating many neoplastic and non-neoplastic disorders, there is accumulating evidence that the toxicity associated with their use is considerable. The therapeutic successes obtained with antitumor agents have led to increases in the life span of cancer patients, but have also provided the opportunity for this toxicity to become manifest. A search of the available literature was carried out, with emphasis on cases in which a malignancy developed in patients following chemotherapy for either neoplastic or non-neoplastic (e.g., renal transplantation, psoriasis) conditions; particular focus was given to the incidence of acute myelogenous leukemia in various groups of Hodgkin's disease and multiple myeloma patients. That patients with nonmalignant conditions treated with cytotoxic immunosuppressive agents are also at increased risk of developing a malignancy raises the possibility that these agents may have oncogenic potential. Therefore, one may be faced with the paradox that the patients benefiting most from chemotherapy may be at highest risk of suffering its consequences.

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Azathioprine; Burkitt Lymphoma; Choriocarcinoma; Cyclophosphamide; Dactinomycin; Female; Hodgkin Disease; Humans; Immunosuppressive Agents; Kidney Neoplasms; Leukemia, Myeloid, Acute; Lymphoma; Mechlorethamine; Melphalan; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Prednisone; Pregnancy; Procarbazine; Time Factors; Vincristine

Limited information is available regarding the use of amifostine in pediatric hematopoietic stem cell transplant (HSCT) patients. Melphalan, carboplatin, etoposide +/- cyclophosphamide is a commonly used preparatory regimen in pediatric solid tumor HSCT. Therefore, we decided to determine the feasibility of the addition of amifostine (750 mg/m b.i.d. x 4 d) to melphalan (200 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) (level 1) and escalating doses of cyclophosphamide (3000 mg/m and 3800 mg/m, levels 2 and 3, respectively) followed by autologous HSCT. Thirty-two patients with a variety of pediatric solid tumors were studied. Seventeen patients were accrued at level 1, 9 at level 2, and 6 at level 3. Major toxicities during the administration of the preparatory regimen were hypocalcemia, emesis, and hypotension. Hypocalcemia required aggressive calcium supplementation during the conditioning phase. No dose limiting toxicities were encountered at level 3. Amifostine at 750 mg/m b.i.d. for 4 days can be administered with a double alkylator regimen consisting of melphalan (200 mg/m), cyclophosphamide (up to 3800 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) with manageable toxicities.

Topics: Adolescent; Adult; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Bone Neoplasms; Carboplatin; Central Nervous System Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Etoposide; Feasibility Studies; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Hypocalcemia; Kidney Neoplasms; Melphalan; Neoplasms; Neuroblastoma; Pilot Projects; Recurrence; Risk Factors; Sarcoma; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Wilms Tumor

Normalized glomerular filtration rate (nGFR) <60 mL/min/1.73 m(2) often precludes hematopoietic stem cell transplant (HSCT) in pediatric patients. Three patients with nGFR < 60 mL/min/1.73 m(2) enrolled on an institutional phase I trial of HSCT preparative therapy for advanced and recurrent solid tumors with escalating melphalan, ranging from 135 to 180 mg/m(2), thiotepa (600 mg/m(2)), and vincristine (2 mg/m(2)). An additional patient with low nGFR was treated with the same preparative therapy. None of the patients developed acute renal failure, excess toxicities during HSCT or delayed engraftment. These cases demonstrate that it is feasible and safe to perform HSCT in pediatric patients with low nGFR using melphalan- and thiotepa-based preparative therapy.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Combined Modality Therapy; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Hematopoietic Stem Cell Transplantation; Humans; Infant; Kidney Neoplasms; Melphalan; Neuroblastoma; Thiotepa; Transplantation, Autologous; Treatment Outcome; Wilms Tumor

Current 5-year survival after complete resection of pulmonary metastases is 20% to 40%, and many patients develop intrathoracic recurrences. Isolated lung perfusion is an experimental technique to deliver high-dose chemotherapy to the lung without systemic exposure. A phase I trial of isolated lung perfusion with melphalan (MN) combined with pulmonary metastasectomy for resectable lung metastases was conducted to define the dose-limiting toxicity and maximum tolerated dose.. From May 2001 to August 2003, 16 patients underwent isolated lung perfusion with MN, followed by surgical resection of lung metastases. Patients were treated with increasing MN doses (15, 30, 45, and 60 mg). For each dose level, normothermia (37 degrees C) and hyperthermia (42 degrees C) were evaluated (n = 3 per level). Serum samples were obtained during the procedure. Pulmonary, hematologic, and nonhematologic toxicities were recorded. The primary tumor was colorectal in 7 patients, renal in 5, sarcoma in 3, and salivary gland in 1. Isolated lung perfusion was performed unilaterally in 11 patients, and staged bilaterally in 5.. In total, 21 procedures of isolated lung perfusion with complete metastasectomy were performed without technical difficulties. Operative mortality was 0%, and no systemic toxicity was encountered. Grade 3 pulmonary toxicity developed at a dose of 60 mg of MN at 37 degrees C in 2 of 3 patients at this dose, terminating the trial.. Isolated lung perfusion with MN combined with pulmonary metastasectomy is feasible. Dose-limiting toxicity occurred at a dose of 60 mg of MN at 37 degrees C, and the maximum tolerated dose was set at 45 mg of MN at 42 degrees C.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Female; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Melphalan; Middle Aged; Pulmonary Surgical Procedures; Salivary Gland Neoplasms; Sarcoma

Regionally advanced cancer is a common, often unresolved problem. Effective local control with chemotherapy is limited by the toxicity following systemic administration. Chemofiltration (CF) is a form of regional perfusion that enables the administration of cytotoxic drugs into one body area while limiting systemic toxicity. The drug is infused into the artery supplying the involved area. The venous effluent of the same organ is pumped out into a hemofiltration unit at a high flow rate. The drug is then filtered away and the blood returned to systemic circulation.. Forty-one patients underwent 45 CF. Twenty-four patients had CF of the pelvis for advanced rectal carcinoma (10), malignant melanoma (6), and cancers of the uterine cervix (3), ovary (2), vulva (1), endometrium (1), and anus (1). Seventeen patients underwent CF of the liver for metastatic colon (10), breast (4), pancreas (1), ovary (1), and unknown primary (1) cancer. 5-fluorouracil (1 g/m2) and mitomycin-C (30 mg/m2); cisplatinum (200 mg/m2) alone or combined with bleomycin (50 mg/m2) and mitomycin-C (20 mg/m2); or melphalan (1 mg/kg) were the combinations used.. Generally the procedure was well tolerated. Complications included transient leukopenia (18), paralytic ileus (2), hair loss (2), renal failure (1). Two patients died within 40 days following CF. Of 36 evaluable patients, 16 (44%) had partial response, 14 (38%) had stable disease, and 6 (18%) had disease progression. A decrease of at least 30% in carcinoembryonic antigen levels occurred in 12 of 24 patients (50%). Median time to progression was 7 months. Ten of 13 patients (77%) achieved good symptomatic palliation.. The results of CF in our study are not superior to alternative methods of drug delivery to the liver and pelvis. However, considering that previous systemic chemotherapy had failed two-thirds of the patients, some benefit may be attributed to this regional delivery modality. Furthermore, pelvic CF afforded very significant symptomatic relief which was definitely superior to other methods.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Renal Cell; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Digestive System Neoplasms; Female; Fluorouracil; Genital Neoplasms, Female; Hemofiltration; Humans; Kidney Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Mitomycin; Prognosis; Survival Rate

Topics: Aged; Drugs, Investigational; Female; Humans; Infusions, Intravenous; Kidney Neoplasms; Male; Melphalan; Middle Aged; Neoplasm Metastasis

A trial of melphalan and methyl-gag was undertaken in 16 patients with metastatic renal cell carcinoma. Among 14 evaluable patients, 6 had stabilization of disease. No significant responses were observed. While both drugs have produced occasional responses in renal cancer, their combination shows no therapeutic advantage.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Melphalan; Middle Aged; Mitoguazone

Topics: Aged; Bence Jones Protein; Clinical Trials as Topic; Cyclophosphamide; Diagnosis, Differential; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Kidney Neoplasms; Melphalan; Multiple Myeloma; Nitrosourea Compounds

Survival for subgroups of patients with Wilms tumor (WT), such as those who suffer from relapse, is disappointing. Some patients' treatment plans include high-dose chemotherapy (HDT) with autologous hematopoietic cell transplantation (aHCT), although proof for its benefit is lacking. To increase the level of evidence regarding children with WT receiving aHCT as consolidation of first or second remission (after first relapse), we extracted relevant data from the European Blood and Marrow Transplantation Registry concerning 69 patients. Different HDT regimens were administered, mostly either melphalan-containing (n = 34) or thiotepa-containing (n = 14). For the whole population, 5-year overall survival (OS) and event-free survival (EFS) probabilities were 0.67 (±0.06) and 0.63 (±0.06), respectively (median observation time 7.8 years); for children transplanted in first remission, OS and EFS were 0.69 (±0.09) and 0.72 (±0.08). In univariate analysis, male gender and relapse in multiple sites were associated with lower OS probabilities. The use of a given pretransplant regimen (i.e. melphalan alone versus regimens with multiple drugs) did not seem to influence EFS/OS probability after aHCT, but significantly influenced platelet engraftment (more delayed with thiotepa). We here provide further data to improve the basis for future evidence-based clinical decision-making when using HDT and aHCT in relapsed/refractory WT.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Kidney Neoplasms; Male; Melphalan; Neoplasm Recurrence, Local; Transplantation, Autologous; Treatment Outcome; Wilms Tumor

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chemoradiotherapy; Etoposide; Humans; Infant; Kidney Neoplasms; Lung Neoplasms; Male; Melphalan; Wilms Tumor

An increasing number of children with advanced malignancies have recently received high-dose chemotherapy (HDC) with hematopoietic stem cell transplantation (HSCT), followed by surgery. In this study, we reviewed our experience with surgery after HDC and autologous (auto) or allogeneic (allo) HSCT to elucidate the problems associated with this treatment and establish the optimum surgical management strategy.. We retrospectively reviewed the cases of 24 children with advanced malignancy treated with HDC and HSCT before tumor resection at our institution. The tumors included 18 neuroblastomas, 5 soft tissue sarcomas, 2 hepatoblastomas, and 1 Wilms tumor. The source of hematopoietic stem cells was auto-HSCT in 19 patients and allo-HSCT in 5 patients. To be able to undergo surgery, it was necessary that the patient's general condition, including hemostasis, should be fairly good and that the results of hematological examinations should include a white blood cell (WBC) count of>1,000/µL, hemoglobin level of>10 g/dL and platelet count of>5 × 10(4)/µL.. The mean duration before WBC recovery after HSCT was 14.5 ± 1.4 days after auto-HSCT and 23.8 ± 1.2 days after allo-HSCT, respectively (p<0.01). The mean duration before platelet recovery after HSCT was 46.5 ± 5.2 days for auto-HSCT and 48.6 ± 5.5 days for allo-HSCT (not significant [n.s.]). The mean interval between allo-HSCT and surgery was significantly longer (92.8 ± 6.2 days) than that between auto-HSCT and surgery (57.0 ± 3.9 days) (p<0.01), likely because of the use of steroids and immunosuppressants after HSCT. The tumors were completely resected in all cases without severe complications. All the patients treated with allo-HSCT had an acute graft versus host (aGVH) reaction at 2 to 3 weeks after HSCT, and specifically required the administration of steroids and immunosuppressants to prevent aGVH. The postoperative complications included paralytic ileus in two cases and a tacrolimus-associated encephalopathy in one case involving allo-HSCT. In half of the patients, the WBC count was not elevated after surgery, whereas the postoperative serum C-reactive protein (CRP) level was elevated in all cases.. Our data indicate that surgical treatment can be safely performed even after HDC with HSCT if attention is paid to myelosuppression and the adverse effects of both chemotherapeutic agents and immunosuppressants.

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Child; Child, Preschool; Drug Administration Schedule; Female; Hematopoietic Stem Cell Transplantation; Hepatoblastoma; Humans; Infant; Kidney Neoplasms; Liver Neoplasms; Male; Melphalan; Neoadjuvant Therapy; Neoplasms, Complex and Mixed; Neuroblastoma; Perioperative Care; Retrospective Studies; Sarcoma; Thiotepa; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Wilms Tumor

High-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) is a treatment option for pediatric patients with relapsed nephroblastoma. We present long term results of 9 patients treated between 1993 and 2013 at our center.. Reinduction therapy was carried out according to GPOH and SIOP recommendations. The conditioning regimen consisted of carboplatin (1 200 mg/m²), etoposide (800 mg/m² or 40 mg/kg) and melphalan (180 mg/m²). Purging of the grafts with immunomagnetic CD34 positive selection was performed in 5 patients.. 8 of 9 Patients (90%) are alive without evidence of disease after a median follow-up of 8.5 years. Leukocyte engraftment occurred after a median of 10 days (range 8-12). Median numbers of 667/µl CD3+, 329/µl CD4+, 369/µl CD8+T cells and 949/µl B cells were reached after 180 days. No negative impact of CD34 selection was observed. No transplantation-related death occurred. Acute toxicity comprised mucositis III°-IV° in all and veno-occlusive disease in one patient. Long term effects probably related to treatment occurred in 3/7 evaluable patients and comprised hearing impairment, reduced renal phosphate reabsorption, mild creatinine elevation and hypothyroidism (n=1, each).. Thus, in our experience HDC with ASCR is an effective treatment of recurrent or refractory nephroblastoma with acceptable side effects. However, a randomized trial proving its efficiency with a high level of evidence is needed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Dactinomycin; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Kidney Neoplasms; Male; Melphalan; Neoplasm Recurrence, Local; Transplantation Conditioning; Vincristine; Wilms Tumor

High-dose chemotherapy and hematopoietic stem cell support remains a valuable treatment option for the rare patient population with relapsed Wilms' tumor. Here we report the case of a 22-year-old male patient treated with two cycles of high-dose chemotherapy at relapse after nephrectomy and adjuvant chemotherapy; the first cycle with melphalan--etoposide--carboplatin and the second with a novel preparative regimen incorporating high-dose topotecan (topotecan--cyclophosphamide--melphalan). A detailed discussion and literature review pertaining to that case is provided.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chemotherapy, Adjuvant; Cyclophosphamide; Dose-Response Relationship, Drug; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Kidney Neoplasms; Male; Melphalan; Nephrectomy; Topotecan; Wilms Tumor; Young Adult

Wilms tumor relapses are infrequent, occurring in approximately 15% of favorable histology patients. Very few cases of late recurrent relapse exist in the literature. Long-term survival after autologous stem cell rescue ranges from 40% to 73%, but there are very few reports of patients transplanted in their third complete response. We report a late recurrent relapse of Wilms tumor successfully treated with high-dose chemotherapy and autologous stem cell rescue in his third complete response who remains disease free 15 months posttransplant.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child, Preschool; Combined Modality Therapy; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Kidney Neoplasms; Male; Melphalan; Neoplasm Recurrence, Local; Salvage Therapy; Wilms Tumor

A 52-year-old woman was admitted to our hospital for treatment of nephrotic syndrome. Funduscopic findings showed fundal hemorrhage and soft exudates, and serologic analysis showed a monoclonal serum component that was identified as Bence Jones protein-k type. A bone marrow biopsy showed diffuse proliferation of atypical plasma cells, while a renal biopsy showed diffuse and nodular mesangial proliferation. Immunohistochemical staining confirmed the presence of k chains along the glomerular basement membrane and in mesangial areas. The patient was diagnosed as multiple myeloma (Bence Jones k type) with light chain deposition disease (LCDD). After high-dose melphalan and autologous peripheral blood stem cell transplantation (PBSCT), the multiple myeloma and nephrotic syndrome were in complete remission; her renal function was improved, but a renal biopsy performed 6 months after PBSCT showed the persistence of diffuse and nodular lesions. By contrast, a renal biopsy performed 3 years later showed complete resolution of the diffuse and nodular mesangial proliferation.

Topics: Antineoplastic Agents, Alkylating; Bence Jones Protein; Biopsy; Female; Humans; Immunoglobulin Light Chains; Immunohistochemistry; Kidney Neoplasms; Melphalan; Mesangial Cells; Middle Aged; Multiple Myeloma; Nephrotic Syndrome; Peripheral Blood Stem Cell Transplantation; Remission Induction; Time Factors; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Renal cell carcinoma (RCC) is usually chemoresistant. This chemoresistance could be overcome if specific cytostatics are applied for which the RCC expresses an uptake transporter. In the present study, we investigated the expression of solute carrier (SLC) transporters in different RCC lines and their ability to interact with chemotherapeutics. We tested five RCC lines for the expression of different SLCs by reverse transcription-PCR and TaqMan real-time PCR. In two of five RCC lines, A498 and 7860, we observed a highly significant expression of SLC22A3 (hOCT3). Uptake of the organic cation [(3)H]MPP (4-methyl-pyridinium iodide) into these cells and also into hOCT3 stably transfected Chinese hamster ovary (CHO) cells was inhibited by irinotecan, vincristine, and melphalan. The K(i) values [determined from Dixon plots] for irinotecan, vincristine, and melphalan were 1.72 +/- 0.45 micromol/L, 17 +/- 4.81 micromol/L, and 366 +/- 51 micromol/L, respectively. Cytotoxic activities of the selected drugs were tested by [(3)H]thymidine incorporation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays on CHO-hOCT3, A498 (high expression of hOCT3), and ACHN cell lines (low expression of hOCT3). The growth of CHO-hOCT3 was inhibited by 20% more with irinotecan and by 50% more with vincristine compared with nontransfected CHO cells. Melphalan produced 20% to 30% more inhibition in hOCT3-expressing cells compared with nonexpressing control cells. Similar results were obtained for A498 and ACHN cells. Thus, our data support the hypothesis that the sensitivity of tumor cells to chemotherapeutic treatment depends on the expression of transporter proteins mediating specific drug accumulation into target cells.

Topics: Animals; Antineoplastic Agents; Camptothecin; Cell Division; Cell Line, Tumor; Cell Survival; CHO Cells; Cricetinae; Cricetulus; DNA Primers; Humans; Irinotecan; Kidney Neoplasms; Melphalan; Organic Cation Transport Proteins; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Vincristine

A 5-month-old male with stage II malignant rhabdoid tumor of the kidney (MRTK) and a 24-month-old male with stage III MRTK were treated with surgical resection of tumors and chemotherapy of alternating ICE (ifosfamide, carboplatin, and etoposide) and VDC (vincristine, doxorubicin, and cyclophosphamide), followed by high-dose chemotherapy using etoposide, carboplatin, and melphalan with autologous hematopoietic stem cell transplantation (SCT). Two patients have been alive without any evidence of disease for 30 and 37 months after diagnosis, respectively, and require no medication. Consolidation with SCT should be further studies for selected patients with high-risk MRTK.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Infant; Kidney Neoplasms; Male; Melphalan; Prognosis; Rhabdoid Tumor; Survival Rate; Tomography, X-Ray Computed; Transplantation, Autologous; Treatment Outcome; Vincristine

Sunitinib demonstrating efficacy in pancreatic islet cell carcinomas will pave the way for further trials in other neuroendocrine tumor types such as carcinoid, poorly differentiated neuroendocrine disease, and several other endocrine tumors that are dependent on VEGF/VEGFR for angiogenesis. In addition, other drugs with distinct mechanisms of action, such as mTOR inhibitors, currently investigated in phase III trials, may also supply novel options in those diseases to control tumor growth and metastasis.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoid Tumor; Cell Line, Tumor; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Indoles; Kidney Neoplasms; Lung Neoplasms; Melphalan; Neovascularization, Pathologic; Neuroendocrine Tumors; Pancreatic Neoplasms; Procarbazine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyrroles; Sunitinib; Vinblastine; Xenograft Model Antitumor Assays

Topics: Acute Kidney Injury; Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Fatal Outcome; Humans; Kidney Neoplasms; Male; Melphalan; Multiple Myeloma; Paraproteinemias; Plasma Cells; Plasmacytoma; Prednisolone; Thalidomide; Urine

Drug resistance remains one of the primary causes of suboptimal outcomes in cancer chemotherapy. This study reports the development of a drug resistant cell line with over-expression of glutathione S-transferase (GST). The resistant tumor cell model was established by continuous exposure of UOK130, a human renal tumor cell line, to escalating concentrations of cisplatin. By immunoblotting the cisplatin-resistant cells (UOK(CR)) were found to express an elevated level of GST-pi isozyme. Neither alpha nor mu isozyme was detected by the corresponding polyclonal antibodies. A significant increase in cellular glutathione (GSH) was also observed in UOK(CR) cells comparative to the parental cells. In addition, the continuous exposure to cisplatin resulted in decreased cell susceptibility not only to cisplatin (resistant factor: 5.7) but also to melphalan (resistant factor: 2.9) and chlorambucil (resistant factor: 2.3). A transgenic cell line was developed by transfecting of UOK130 cells with GST-pi cDNA. The transfection of the GST-pi virus into UOK130 cell apparently increased its intracellular GST-pi activity. The resistance of the transfectants to cisplatin was consistently increased, compared with that of mock transfectants. A haloenol lactone (HEL) derivative known as a selective inhibitor of GST-pi was applied to evaluate the suitableness of the cell model for GST-pi-mediated drug resistance studies. The inhibitor was found to potentiate the cytoxicity of cisplatin to both UOK130 and UOK(CR) cell lines and to reverse their resistance to cisplatin. In conclusion, we developed a multiple drug resistant tumor cell line with selective over-expression of GST-pi. The cell model provides a unique tool for mechanistic studies of drug resistance mediated by over-expression of GST-pi.

Topics: 4-Butyrolactone; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line, Tumor; Chlorambucil; Cisplatin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Glutathione; Glutathione S-Transferase pi; Humans; Isoenzymes; Kidney Neoplasms; Melphalan; Transfection

A 52-year-old patient with atypical plasmocytoma presented with a bilateral serous detachment of the retina as well as a huge detachment of the pigment epithelium (PE) in the periphery. Shortly thereafter the PE ruptured. In the left eye this led to substantial central macular fibrosis.. The clinically healthy patient showed a nephrotic syndrome; neither typical monoclonality was detectable nor was erythropoiesis or myelopoiesis reduced.. To avoid further reduction of VA pars plana vitrectomy (ppV) with silicone oil tamponade and laser coagulation was performed. Clinical findings were reduced significantly and VA was stabilized for 2.5 years.. PE detachments and serous retinal detachments in patients with nephrotic syndrome are only mentioned in a few cases. However, a peripheral rupture of the PE to this extent seems to be very rare. Early ppV with silicone oil and laser coagulation may prevent further macular fibrosis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Choroidal Neovascularization; Comorbidity; Female; Fluorescein Angiography; Follow-Up Studies; Humans; Kidney Neoplasms; Laser Coagulation; Lenses, Intraocular; Melphalan; Middle Aged; Nephrotic Syndrome; Ophthalmoscopy; Plasmacytoma; Postoperative Complications; Prednisolone; Recurrence; Renal Insufficiency; Reoperation; Retinal Detachment; Retinal Perforations; Silicone Oils; Visual Acuity; Vitrectomy

To investigate whether high-dose therapy with hematopoietic stem-cell rescue (HSCR) will improve survival for patients with relapsed Wilms' tumor.. Thirteen children with relapsed Wilms' tumor were treated with one or two cycles of high-dose chemotherapy (HDT) followed by autologous HSCR. Twelve of 13 patients received reinduction chemotherapy before HDT and HSCR. The median age at diagnosis was 4.8 years, and the median time to relapse was 12 months. The histology was favorable in 12 of 13 patients. The ablative regimens included: (1) thiotepa (TT)/cyclophosphamide (CTX)/carboplatin (CP; n = 2); (2) TT/CTX (n = 5); (3) TT/etoposide (ETP; n = 1); and (4) CP/ETP/CTX (n = 1). Four patients received two cycles of HDT and HSCR. Cycle 1 consisted of CP/ETP/CTX, and melphalan/CTX were used in cycle 2.. Seven of 13 patients are alive without evidence of disease, with a median follow-up of 30 months. The 4-year estimated event-free survival (EFS) rate is 60% (95% CI, 0.40 to 6.88), and the overall survival (OS) at 4 years is 73% (95% CI, 0.40 to 6.86). There was no transplant-related mortality. All patients engrafted to an absolute neutrophil count 500/microL at a median of 13 days (range, 8 to 62 days) and had an unsustained platelet count > 20.0 micro at a median of 16 days (range, 10 to 202 days).. Our results suggest that HDT with HSCR is an effective treatment for patients with Wilms' tumor who experience relapse.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Cyclophosphamide; Dose-Response Relationship, Drug; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Kidney Neoplasms; Male; Melphalan; Neoplasm Recurrence, Local; Survival Analysis; Thiotepa; Transplantation, Autologous; Treatment Outcome; Wilms Tumor

Adult Wilms' tumor (AWT) is a very rare and aggressive malignancy, and little information is available on effective therapy in adults. Although mutations in WT1 have been found in 10% to 15% of childhood Wilms' tumor patients, to date WT1 mutations in AWT patients have not been described. The authors describe a 47-year-old man with relapsed AWT and a novel germline alteration in intron 1 of WT1: IVS1-6 C-->A. This alteration may reduce the splicing efficiency for exon 2 and possibly results in exon skipping. The effective salvage chemotherapy contained ifosfamide, carboplatin, and etoposide and was followed by a high-dose chemotherapy that contained melphalan, carboplatin, and etoposide. Both chemotherapy regimens showed moderate treatment-related toxicity. This report is the first that indicates that adult nephroblastoma patients also may carry WT1 germline mutations.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Dose-Response Relationship, Drug; Etoposide; Genes, Wilms Tumor; Germ-Line Mutation; Humans; Kidney Neoplasms; Male; Melphalan; Middle Aged; Salvage Therapy; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome; Wilms Tumor

Children with Wilms tumor who have a particular risk of failure at relapse or at primary diagnosis were treated with high-dose chemotherapy (HDC) and autologous peripheral blood stem cell rescue in order to improve their probability of survival. From April 1992 to December 1998, 23 evaluable patients received HDC within the German Cooperative Wilms Tumor Studies. Nineteen were given melphalan, etoposide and carboplatin (MEC); the others received different regimens. The dose of carboplatin was adjusted according to renal function. Indications for HDC were high-risk relapse in 20 patients, bone metastases in two patients and no response in one patient. Fourteen of 23 patients are alive after a median observation time of 41 months, 11 of 14 in continuous complete remission, three in CR after relapse post HDC. The estimated survival and event-free survival for these patients are 60.9% and 48.2%. Twelve children relapsed after HDC; nine of them died within 12 months and three are surviving from 20 to 33 months after relapse. The main toxicities were hematologic, mucositis and renal (tubular dysfunction; intermittent hemodialysis in one patient). There were no toxic deaths. About half of the children suffering from Wilms tumor with very unfavorable prognostic factors survive disease-free after HDC for over 3 years. Besides hematological toxicity, mucositis and infections, renal function is at risk during HDC. With dose adjustment on glomerular filtration rate, however, no permanent renal failure was observed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Etoposide; Female; Germany; Hematologic Diseases; Humans; Ifosfamide; Infant; Kidney Diseases; Kidney Neoplasms; Life Tables; Lung Neoplasms; Male; Melphalan; Peripheral Blood Stem Cell Transplantation; Prognosis; Stomatitis; Survival Analysis; Thiotepa; Transplantation, Autologous; Wilms Tumor

In children with bilateral Wilms' tumor, the therapy should aim at maximal preservation of renal parenchyma and function. Local radiotherapy may give rise to second malignant neoplasms and may impair renal function. We present a therapeutic strategy without any irradiation. Three children were diagnosed with bilateral Wilms' tumor at ages from 6 months to 5 years. Each patient had a massive tumor with local stage III on one side; one had pulmonary metastases. The therapeutic strategy was first to obtain tissue for histology by percutaneous needle biopsy, to administer pre-operative chemotherapy until desired tumor shrinkage, and then to perform kidney-sparing resective surgery. After a period of conventional chemotherapy, the patients were consolidated with high-dose (HD) melphalan and ABMT. Renal parenchyma spared post-surgery (right/left) was 0%/70%, 60%/40% and 40%/60% of the original kidney volumes. The toxicity of the ABMT procedure was mild, the patients engrafted promptly, and were discharged on days +14 to +27. All patients survive disease-free, 3 years 4 months to 4 years 5 months post-transplant. Our program resulted in good preservation of renal parenchyma and normal function, and we consider the risk of this ABMT program smaller than the late consequences of local radiotherapy for children with bilateral Wilms' tumor. The therapeutic strategy described merits further evaluation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Doxorubicin; Drug Administration Schedule; Female; Humans; Infant; Kidney Neoplasms; Male; Melphalan; Pilot Projects; Rhabdomyoma; Vincristine; Wilms Tumor

The three-drug combination of melphalan (M), etoposide (E), and carboplatin (C) followed by autologous stem-cell (ASC) rescue has been evaluated prospectively by the French Society of Pediatric Oncology (SFOP) in pediatric high-risk recurrent (HRR) Wilms' tumor (WT) patients with chemotherapy-responsive disease.. From October 1988 to October 1994, 29 patients with HRR WT were treated in nine SFOP centers. Two additional patients with stage IV anaplastic WT were consolidated in first complete response (CR) with the same regimen and have been studied separately. The regimen consisted of M 180 mg/m2 for 1 day, E 200 mg/m2/d for 5 days, and C at a daily targeted area under the concentration-time curve (AUC) of 4 mg x min/mL for 5 days. ASCs were reinfused 48 hours after M.. Twelve of 28 assessable patients with HRR WT are still in continuous CR at a median of 48.5 months (range, 36 to 96) after consolidation. Disease-free survival (DFS) and overall survival (OS) estimated by the Kaplan-Meier method at 3 years were 50%+/-17% and 60%+/-18%, respectively. Sixteen patients relapsed at a median of 8.5 months (range, 3 to 53) after consolidation. Toxicity data are available in 31 grafted patients. Grade III and IV toxicities included hematologic side effects (n=31), hemorrhage (n=8), mucositis (n=24), diarrhea (n=12), renal disorders (n=8), and pneumonitis (n=3).. The adverse prognostic factors (APF) used to select patients for this dose-intensive chemotherapy define children with very-poor-risk recurrent WT. Despite high treatment-related toxicity, about half of these patients remain disease-free at 3 years. Patient outcome is statistically better when high-dose chemotherapy (HDCT) is performed as early as the second CR or partial response (PR). Novel therapeutic approaches with innovative preparative regimens are warranted for the remaining high-risk patients.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Combined Modality Therapy; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Infant; Kidney Neoplasms; Male; Melphalan; Neoplasm Recurrence, Local; Wilms Tumor

Multidrug resistance (MDR) in human cancer cells is multifactorial. Previously, we reported on the association between expression of P-glycoprotein (Pgp), the multidrug resistance-associated protein (MRP), and the lung resistance protein (LRP) with the MDR phenotype in the NCI panel of 60 human cancer cell lines used for in vitro anticancer drug screening. Eight cell lines from this panel, manifesting widely divergent levels of in vitro drug resistance were chosen to investigate the role of MRP and LRP expression at the molecular level. LRP mRNA levels, as determined by ribonuclease protection assay, varied significantly among the 8 cell lines, and correlated closely with in vitro drug resistance to both MDR and non-MDR related drugs. LRP mRNA expression was determined to be a stronger correlate of drug sensitivity than protein expression. In contrast, MRP mRNA levels were not significantly correlated with drug sensitivity. The rates of newly transcribed LRP or MRP mRNA did not correlate with mRNA levels, indicating that mRNA stability or other features of processing may be important in regulation of LRP and MRP mRNA levels. Using Southern blot analysis, LRP gene amplification was shown not to be associated with LRP overexpression. These data suggest that LRP expression may be an important determinant of the MDR phenotype in cell lines intrinsically resistant to cancer chemotherapeutic agents.

Topics: Amsacrine; Antineoplastic Agents; ATP-Binding Cassette Transporters; Cell Nucleus; Cisplatin; Colonic Neoplasms; Doxorubicin; Drug Resistance, Multiple; Female; Glycoproteins; Humans; Kidney Neoplasms; Leukemia; Lung Neoplasms; Melphalan; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Ovarian Neoplasms; Phenotype; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured; Vault Ribonucleoprotein Particles

Topics: Acute Kidney Injury; Adult; Diuresis; Humans; Kidney Neoplasms; Male; Melphalan; Multiple Myeloma; Peritoneal Dialysis; Plasmapheresis

Topics: Aged; Autopsy; Biopsy; Bone Marrow Cells; Cyclophosphamide; Female; Heart Neoplasms; Humans; Kidney Neoplasms; Leukemia, Lymphoid; Lymphocytes; Male; Melphalan; Middle Aged; Multiple Myeloma; Nasal Polyps; Nose Neoplasms; Osteitis Deformans; Plasmacytoma; Pleural Effusion; Prednisolone; Radiography

Topics: Adenocarcinoma; Bleomycin; Carcinoma, Squamous Cell; Castration; Dactinomycin; Estrogens; Female; Humans; Kidney Neoplasms; Male; Melphalan; Nitrosourea Compounds; Phosphorus Isotopes; Plicamycin; Prostatic Neoplasms; Testicular Neoplasms; Urinary Bladder Neoplasms; Urogenital Neoplasms; Vinblastine; Vincristine

Topics: Adenoma; Adolescent; Adult; Aged; Anemia, Hypochromic; Anemia, Macrocytic; Anemia, Sideroblastic; Blood Protein Disorders; Chlorambucil; Female; Hemoglobinometry; Humans; Immunosuppressive Agents; Kidney Neoplasms; Leukemia; Lupus Erythematosus, Systemic; Male; Melphalan; Multiple Myeloma; Polycythemia; Pyridoxine; Waldenstrom Macroglobulinemia

Topics: Carcinoma; Cecal Neoplasms; Cobalt Isotopes; Female; Fibrosarcoma; Humans; Kidney Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Maxillary Neoplasms; Melanoma; Melphalan; Multiple Myeloma; Myxosarcoma; Palliative Care; Radioisotope Teletherapy; Testicular Neoplasms

Topics: Adrenalectomy; Aged; Antineoplastic Agents; Breast Neoplasms; Bronchial Neoplasms; Cortisone; Cyclophosphamide; Drug Synergism; Ethinyl Estradiol; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Hydrazines; Hypophysectomy; Kidney Neoplasms; Lung Neoplasms; Male; Melanoma; Melphalan; Mesothelioma; Methotrexate; Middle Aged; Nandrolone; Neoplasm Metastasis; Ovarian Neoplasms; Podophyllin; Sarcoma; Thiotepa; Vinblastine

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Carcinoma; Drug Therapy; Humans; Kidney Neoplasms; Kidney Pelvis; Melphalan; Neoplasms; Nephrectomy