High-dose cyclophosphamide or melphalan with escalating doses of mitoxantrone and autologous bone marrow transplantation for refractory solid tumors.

As the dose-limiting toxicity of mitoxantrone is hematological, the drug is suitable for dose escalation and use in intensive chemotherapy followed by autologous bone marrow rescue. Adult patients with therapy-resistant solid tumors received a regimen of high-dose cyclophosphamide (7 g/m2) and escalating doses of mitoxantrone in dose steps of 30, 45, 60, and 75 mg/m2. Both drugs were given i.v. on 3 consecutive days. Despite the addition of mesnum (3.5 to 7 g/m2), hemorrhagic cystitis occurred on the second day in four of eight patients, irrespective of the mesnum or mitoxantrone dose. Therefore, the cyclophosphamide in the combination regimen was replaced by high-dose melphalan (180 mg/m2). Mucositis was dose limiting at 75 mg/m2 of mitoxantrone. Responses were seen in eight of ten evaluable patients with four complete responses. Three responders received, after the autologous bone marrow transplantation program, radiotherapy or surgery on pretreatment bulky tumor localizations. Five patients still have disease-free survival after 9 to 36 mo. Pharmacokinetic studies of mitoxantrone were performed by high-performance liquid chromatography with UV detection. The plasma disappearance of mitoxantrone fitted into a three-compartment model with a mean t1/2 alpha of 10 min, a mean t1/2 beta of 96 min, and a slow elimination phase of 172 h. The mean distribution volume was 4294 +/- 3836 liters. We conclude that the high-dose cyclophosphamide-mitoxantrone regimen led to unexpected bladder toxicity, but the combination of melphalan (180 mg/m2) and mitoxantrone (60 mg/m2) can probably be given without major extramedullary toxicity. However, more patients should be evaluated at this dose before definite conclusions can be drawn about toxicity.

Induction chemotherapy and intensification with autologous bone marrow reinfusion in patients with locally advanced and disseminated breast cancer.

In 56 patients with disseminated or locally advanced breast cancer it was attempted to reach a state of no evidence of disease by a remission induction regime containing prednisone, 5-fluorouracil, methotrexate, doxorubicin and vincristine. If successful, patients received an intensification regimen consisting of cyclophosphamide (7 g/m2) and etoposide (1.5 g/m2) with autologous bone marrow reinfusion. The complete remission rate of the induction regimen was 52% and the partial remission rate 42%. 32 patients received the intensification regimen. Two toxic deaths occurred. The median time to disease progression in the group with disseminated disease was 15 months. After a median observation of 4 years, 11 out of 19 patients with locally advanced breast cancer were free of disease. It is concluded that this approach may lead to prolonged disease-free survival in patients with locally advanced breast cancer, but does not influence the survival in disseminated disease.

Intensive chemotherapy with autologous bone marrow transfusion as primary treatment in women with breast cancer and more than five involved axillary lymph nodes.

Patients with breast cancer and a high number of involved axillary lymph nodes have a poor prognosis, despite adjuvant chemotherapy. The 5-year disease-free survival (DFS) in this group amounts to 30-40% and the 10-year DFS is only 15-20%. Therefore, new treatment modalities are being sought for this group of patients. The aim of the present study was the evaluation of the efficacy of high-dose chemotherapy combined with autologous bone marrow support. 24 patients with a primary breast cancer with more than five involved axillary lymph nodes received, after surgery, six courses of induction chemotherapy followed by ablative chemotherapy and reinfusion of autologous bone marrow. All patients were premenopausal or less than 2 years postmenopausal. Induction chemotherapy consisted of methotrexate (MTX) 1.5 g/m2 intravenous (i.v.) and 5-fluorouracil (5-FU) 1.5 g/m2 i.v. on day 1, prednisone 40 mg/m2 orally on days 2-14, doxorubicin 50 mg/m2 i.v. and vincristine 1 mg/m2 i.v. on day 14. Courses were repeated six times every 4 weeks. 10 patients received cyclophosphamide 7 g/m2 i.v. and etoposide 1.5 g/m2 i.v. as intensive regimen, in 14 patients this comprised mitoxantrone 50 mg/m2 i.v. and thiotepa 800 mg/m2 i.v. Reinfusion of autologous marrow followed on day 7. Finally, patients received locoregional radiotherapy for extranodal disease and tamoxifen 40 mg daily orally over a period of 2 years. The median age of patients was 42 years, range 29-54. The median number of involved nodes was 10. During induction therapy, fever requiring i.v. antibiotics occurred in 4% of 144 courses, 14% of patients suffered from mucositis WHO grade 2-3, and the other patients had mucositis grade 1. During the ablative chemotherapy, 1 patient died, 6 developed septicaemia, 5 showed mucositis grade 3-4 and the other patients had mucositis grade 1 or 2. In the follow-up, 1 patient died from acute cardiac failure. Reversible radiation-induced pneumonitis occurred in 7 out of 14 irradiated patients; symptoms started directly following radiotherapy and lasted for several weeks, but disappeared in due course. During follow-up, 2 patients with six and > 10 positive nodes, respectively, have relapsed after 18 and 36 months, both in the cyclophosphamide/etoposide regimen. Median observation is 3 years, disease-free survival at 5 years is predicted to be 84%. Intensive treatment in these patients with high numbers of involved axillary lymph nodes is a toxic regimen, but may improve the chance of surviving free of disease.

Renal dysfunction following high-dose carboplatin treatment.

A case history is reported or renal failure during and after treatment with carboplatin for 3 days, total dose 750 mg/m2, in a conditioning regimen prior to autologous bone marrow transplantation. Pretreatment renal function was compromised after nephrectomy and chemotherapy with cisplatin. A decrease in glomerular filtration rate concurred with a decrease in excretion of platinum in the urine and an increase in urinary beta 2 microglobulin. Treatment with high-dose carboplatin in patients with impaired renal function and previous treatment with cisplatin may lead to further loss of renal function.

Absence of relation between nutritional parameters and renal function in non-seminomatous testicular cancer patients.

Earlier studies revealed that renal function is reduced in non-cancer patients with a malnutritional status. We have studied the effect of nutritional status on renal function in 46 patients with disseminated non-seminomatous testicular cancer treated with combination chemotherapy including cis-diammine dichloroplatinum (cDDP) according to the Einhorn regimen. The renal function was expressed as glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and filtration fraction (FF) measured by radioisotope infusion methods. Nutritional assessment of the patients was performed by means of three nutritional parameters: weight-for-height index (WHI), creatinine height index (CHI), and serum albumin concentration (Salb). The patients were also divided into two groups: group 1, patients with a sufficient nutritional status, defined as patients with only one abnormal nutritional parameter or none at all (n = 30); group 2, patients with an insufficient nutritional status, defined as patients with two or three abnormal nutritional parameters (n = 16). Median values of WHI, CHI and Salb in group 2 patients were significantly lower than the median values in group 1. Before treatment no correlation was found between the individual nutritional parameters and GFR, ERPF and FF respectively. The median GFR, ERPF and FF of both group 1 and group 2 did not differ significantly. Although the renal function of the total group of patients was reduced as a result of cDDP, this reduction was not influenced by the individual parameters and not higher in the group with an initially insufficient nutritional status. In this study no relation was found between nutritional status and renal function of patients with disseminated non-seminomatous testicular cancer.

Pharmacokinetics of piperacillin and tazobactam in critically ill patients with renal failure, treated with continuous veno-venous hemofiltration (CVVH).

OBJECTIVE: Kinetics of piperacillin (pip), in combination with the beta-lactamase inhibitor tazobactam (taz) have been studied in volunteers and patients in relatively stable conditions. The fixed drug preparation appeared to have ideal pharmacokinetic properties if renal function was normal or slightly impaired, but no data are available for critically ill patients in anuric renal failure. This study should provide such data. PATIENTS, DESIGN: We studied the pharmacokinetics in nine patients with multiple organ failure, including anuric renal failure, treated with continuous veno-venous hemofiltration (CVVH). Patients received a standard schedule of 4 g pip and 0.5 g taz administered over 0.5 h intravenously, 8 hourly. During 2 consecutive days, the serum levels of both compounds were determined, and total clearance (CIT) was calculated from serum concentrations. RESULTS: All nine patients completed day 1, and 8 completed day 2 of the protocol. On day 1, single-dose kinetics showed considerable spread, but pip/taz serum levels followed the pattern as expected, with a pip/taz concentration ratio of 20:1. On day 2, however, taz serum concentrations showed a relative increase as compared to pip, resulting in a change in the serum pip/taz concentration ratio to 10:1 on day 2. The CIT of pip was 2.52 +/- 1.38 l/h (t 1/2: 5.9 +/- 2.9 h), and CIT of taz 4.44 +/- 2.28 l/h (t 1/2: 8.1 +/- 3.7 h). The CIT and t 1/2 of pip and taz correlated highly significantly with clearance by CVVH. Despite a higher CIT, taz has a longer half-life, because of a higher volume of distribution. CONCLUSION: In CVVH dependent patients, pip/taz fixed drug preparations can be used initially, but the pip dosage should be increased relative to that of taz (or interval-adjusted) to prevent cumulation of taz, as compared to the active antimicrobial agent pip.

Long-term results of induction- and intensification chemotherapy supported with autologous bone marrow reinfusion in patients with disseminated or T4 breast cancer.

Twenty-nine patients with metastatic or T4 breast cancer who were in pathologically proven complete remission after induction chemotherapy, received intensification chemotherapy with autologous bone marrow support. Twelve patients had T4 breast cancer, 17 had metastatic disease. The median age was 42 years (27-52). Intensification consisted of cyclophosphamide 7 g/m2 i.v. and etoposide 1.5 g/m2 i.v. in 24 patients, or thiotepa 800 mg/m2 i.v. and mitoxantrone 50-75 mg/m2 i.v. in 5 patients. The median observation is 7 years. Median survival is 36 months. Ten year relapse-free survival is 20%. For patients with metastatic disease median survival is 34 months, time to relapse 18 months; two patients (12%) have survived disease-free for more than 6 years. The patients with T4 cancer have a median survival of 80 months and a median time to relapse of 53 months; four patients (33%) have survived more than 5 years disease-free.

Pulmonary function after high-dose chemotherapy with autologous bone marrow transplantation and radiotherapy in patients with advanced loco-regional breast cancer.

Our aim was to study the extent of pulmonary toxicity after high-dose chemotherapy and radiotherapy in breast cancer patients. In a retrospective study the pulmonary symptoms and chest X-rays were analyzed before, during and after treatment in 17 patients, treated with loco-regional radiotherapy to the breast/chest wall and the regional lymph nodes after the completion of high-dose chemotherapy and autologous bone marrow transplantation for locally advanced breast cancer. Lung function was evaluated between 15 and 46 months after completion of the irradiation. Nine patients (53%) had pulmonary symptoms during and/or within two months from irradiation. Radiographic changes were seen in twelve patients (71%) and a decreased diffusion capacity occurred in nine patients (53%). The spirometric values (VC and FEV1) were abnormal in two patients (12%). There is a high incidence of radiation pneumonitis, although no consistent correlation between the various parameters (pulmonary symptoms, chest X-rays and lung function tests) could be found.

Tumour necrosis factor (cachectin) and other cytokines in septic shock: a review of the literature.

The role of bacterial endotoxin in the pathogenesis of septic shock has been studied extensively. Endotoxin does not seem to exert most of its effects on the host directly, but rather it elicits the production of host factors that may in turn lead to shock and death. These factors, called cytokines, appear to be produced by cells of haematopoietic origin such as macrophages/monocytes, but can also be produced by other cells such as endothelium and fibroblasts. Three important cytokines associated with septic shock are tumour necrosis factor/cachectin (TNF), interleukin 1 (IL-1) and interleukin 6 (IL-6). The macrophage-derived TNF has been implicated as the most important host mediator in the pathogenesis of septic shock. TNF, alone or together with endotoxin or IL-1, is capable of inducing lethal shock and tissue injury resembling that of septic shock. It has also been suggested that IL-6 is involved in the pathogenesis of septic shock. The major biologic activities of IL-6 include B-cell differentiation and induction of the acute-phase proteins. In the present paper, reports addressing the current understanding of the biological, regulatory and clinical aspects of these cytokines are reviewed.

Incidence and effects of herpes simplex virus infection after autologous bone marrow transplantation for solid tumours.

In a prospective study of 44 patients, who underwent autologous bone marrow transplantation (ABMT) for solid tumours, the results of serial viral cultures and determination of complement-fixing antibodies to herpes simplex virus (HSV) were analysed. No primary infections with HSV occurred. Of 31 initially HSV-seropositive ABMT patients, 61% developed positive HSV cultures. Half of these patients showed a significant antibody rise. Active HSV infection did not influence the recovery of the bone marrow after ABMT, but coincided with a significantly increased number of febrile days.

Amanita phalloides, a potentially lethal mushroom: its clinical presentation and therapeutic options.

Mushroom poisoning with Amanita phalloides, a rare phenomenon in everyday clinical practice in the Netherlands, must be recognized early in view of its potential morbidity and mortality. In this article 2 cases of amanita intoxication are presented and the pharmacological basis and clinical manifestations discussed. Furthermore, the rationale of various treatment modalities, including the role of liver transplantation, is outlined.

[Hypothermia in patients with a high spinal cord lesion]. / Hypothermie bij patiënten met een hoge dwarslaesie.

Two women aged 54 and 69 years with high spinal cord injuries and tetraparesis developed hypothermia (30.4 and 29.4 degrees C, respectively); normalization was accomplished by external heating using insulation blankets. Even moderately lowered environmental temperatures may lead to hypothermia in these patients with abnormal temperature sensation, incapacity to compensate and autonomous dysfunction. The symptoms are aspecific and the differential diagnosis is extensive. Recommendations for prevention of hypothermia include daily measurement of the core temperature, adjustment of the environmental temperature and humidity of the air, adequate closing and avoidance of vasodilator drugs.

Lactate monitoring with subcutaneous microdialysis in patients with shock: a pilot study.

We describe the use of subcutaneous microdialysis for continuous sampling of lactate to monitor the plasma lactate concentration in eight patients with shock. The dialysate lactate concentrations were significantly correlated with the plasma lactate concentrations (r = 0.8229), but the linear regression lines varied between patients. Therefore, we used the individual regression line of each patient for calibration to calculate estimated plasma values from the dialysate concentrations. While the estimated values were linearly correlated to the plasma lactate values (r = 0.912), the 95% confidence interval of the estimated values was +/- 2.8 mmol/L. Thus, subcutaneous microdialysis does not allow accurate estimation of the plasma lactate concentration. In 3 of the 8 patients, there was a significant negative correlation between the dialysate/plasma lactate ratio and the plasma lactate concentration. This suggests that besides plasma lactate, other factors such as subcutaneous adipose tissue metabolism and blood flow, may influence subcutaneous sampling and dialysate lactate concentration as well. While microdialysis can be used for on-line sampling and continuous monitoring of the concentration of extracellular substances, for the purpose of plasma lactate monitoring, sampling probes should be designed that permit intravascular placement.

Effects of different types and combinations of antimicrobial agents on endotoxin release from gram-negative bacteria: an in-vitro and in-vivo study.

Total and free endotoxin release in time from cultures of Escherichia coli by different antibiotics was studied in vitro for 4 h in relation to the antibiotic effect on viable counts and morphological features of the test cultures. The most rapid fall in viable counts was seen after treatment with imipenem or the combination of imipenem with tobramycin, accompanied by an early, but minimal increase (1.8-fold) of the total (free plus cell-bound) endotoxin level at 1 h. Total endotoxin levels increased approximately 5-fold upon incubation with ceftazidime, tobramycin or the combination of tobramycin with cefuroxime, whereas incubation with cefuroxime or aztreonam alone caused a late 22-and 49-fold increase in total endotoxin, respectively, at 4 h. In chloramphenicol treated cultures there was still an increase in viable counts during therapy, resulting in an ultimately 78-fold increase of mean levels of total endotoxin. Free endotoxin levels increased approximately 6-fold within 1 h upon treatment with imipenem, alone or in combination with tobramycin, or ceftazidime as the result of rapid lysis of bacteria. Treatment with cefuroxime or aztreonam induced a relatively late but much higher release of free endotoxin (118-and 222-fold, respectively), which was due to the formation of long filamentous structures during the first 2 h of incubation and eventually cell lysis. Both tobramycin and the combination of tobramycin with cefuroxime caused a more gradual rise in free endotoxin, with a +/- 15-fold increase in free endotoxin at 4 h. In chloramphenicol treated cultures, as in the control cultures, the level of free endotoxin remained proportional to the amount of viable organisms. We also studied plasma endotoxin levels in 20 patients with septic shock. 10 out of these 20 patients had a detectable endotoxemia (greater than 5 ng/l) on admission. We describe the patterns of plasma endotoxin in these patients during the first 24 h of antibiotic treatment. We conclude that, in the in-vitro study, values of total endotoxin, free endotoxin, and the rate of release of endotoxin varies with the antibiotic used. We also demonstrate that in patients under treatment for septic shock endotoxin release can be related to the administration of antibiotics.

Chemotherapy with maximally tolerable doses of VP 16-213 and cyclophosphamide followed by autologous bone marrow transplantation for the treatment of relapsed or refractory germ cell tumors.

Eleven patients with advanced nonseminomatous germ cell tumors (NSGCT), who relapsed after or were refractory to standard dose cisplatin-based remission induction chemotherapy, were treated in a phase II clinical trial with VP 16-213 2500 mg/m2 and cyclophosphamide 7 g/m2. Both drugs were given in maximally tolerable doses regarding extramedullary toxicity. Urothelial damage due to cyclophosphamide was prevented by the administration of mesnum. Autologous bone marrow was infused on day 7 to prevent long lasting medullary toxicity. Because of the disappointing results in the first three patients, a second treatment step was added. The next eight patients were treated with 2500 mg/m2 VP 16-213 divided and given on days 1-2-3 and after full bone marrow recovery with total doses of VP 16-213 2000 mg/m2 plus cyclophosphamide 7 g/m2 divided and given on days 29-30-31, followed by autologous bone marrow transplantation (ABMT) on day 35. Toxicity to high-dose VP 16-213 plus cyclophosphamide followed by ABMT consisted of mucositis, nausea, vomiting and diarrhea. No cardiac toxicity or hemorrhagic cystitis occurred. The mean duration of leukopenia and thrombopenia was 14 and 13 days respectively. The additional, preceding treatment with VP 16-213 as a single agent caused mucositis, and leukopenia and thrombopenia for a mean number of 9 and 6 days respectively. Seven responses were obtained: two complete responses of 46 and 66+ weeks respectively and five partial responses with a median response duration of 12 weeks. The median survival time was 40 weeks. This regimen of one or two courses with maximally tolerable doses of VP 16-213 plus cyclophosphamide and ABMT is not sufficient to salvage a substantial number of patients with relapsing or refractory NSGCT.

Hyperalimentation in autologous bone marrow transplantation for solid tumors. Comparison of total parenteral versus partial parenteral plus enteral nutrition.

Recipients of autologous bone marrow transplantation (ABMT) for solid tumors need nutritional support to maintain their body weight (BW). Severe BW-reduction (9.9%) was noticed retrospectively in ten ABMT patients fed orally, despite intensive counseling or occasional tube feeding. A prospective, randomized study of hyperalimentation (25 g nitrogen (N) and 3400 nonprotein kilocalories) with total parenteral nutrition (TPN) or partial parenteral plus enteral nutrition by tube feeding (PPN/EN) was done in 22 patients. Nutritional assessment included balance measurements of N, Na, K, Cl, P, Ca, Mg, Cu, and Zn, and serial measurements of BW, serum albumin, prealbumin, and transferrin. Both regimens were effective in maintaining BW (maximum percent of change, 2.5) and N-balance. Blood products accounted for an additional N-intake of 13% in both groups. The TPN group had a higher dietary N-intake versus PPN/EN, a positive K balance but negative Ca, Mg, Cu, and Zn balances. More mineral supplementation was given in the PPN/EN group where positive K, Mg, and Zn balances were seen. Visceral proteins and IgG, IgA, and IgM levels were decreased on days 7, 14, and 21. Creatinine clearance increased significantly in both groups. Compared with TPN, the PPN/EN group showed a twofold number of patients with a positive blood culture, although this observation did not reach statistical significance and patients had fewer days of diarrhea (31.1% versus 54.3%, P less than 0.01). Hyperalimentation with PPN/EN is an acceptable alternative to TPN in the nutritional support of ABMT recipients.

Patterns of cytokines, plasma endotoxin, plasminogen activator inhibitor, and acute-phase proteins during the treatment of severe sepsis in humans.

OBJECTIVE: To study the patterns of plasma concentrations of endotoxin, tumor necrosis factor-alpha (TNF), interleukin-6 (IL-6), plasminogen activator inhibitor-1, C-reactive protein, and serum amyloid A during the treatment of human sepsis. DESIGN: A prospective case series study. SETTING: ICU of the Department of Internal Medicine, University Hospital Groningen, The Netherlands. PATIENTS: Twenty consecutive patients (11 female, 9 male, mean age 67 yrs) with clinically defined sepsis. Eighteen patients were admitted from the outpatient emergency ward; two patients were already inpatients. The control group (n = 7) comprised patients with nonseptic shock. MEASUREMENTS AND MAIN RESULTS: Ten (50%) septic patients had detectable endotoxemia (greater than 5 (ng/L). TNF concentrations on admission were increased in 94% of the septic patients, whereas IL-6 and plasminogen activator inhibitor plasma concentrations were increased in all septic patients. The septic group showed significantly (p less than .05) higher concentrations of TNF, IL-6, plasminogen activator inhibitor-1, C-reactive protein, and serum amyloid A compared with the nonseptic patients. In the septic group, we found a correlation of both IL-6 and plasminogen activator inhibitor concentrations with severity of illness (r2 = .33, p less than .05; r2 = .22, p less than .05, respectively). After the start of antibiotic treatment, high concentrations of TNF and plasminogen activator inhibitor persisted in the nonsurvivors in contrast to decreasing concentrations in most of the survivors. After an initial increase in seven patients, IL-6 concentrations decreased in all septic patients and also in nonsurvivors. CONCLUSIONS: This study confirms previous findings that: a) TNF is a major mediator involved in the pathogenesis of septic shock; b) plasminogen activator inhibitor activity is significantly increased in septic patients and might be involved in the pathogenesis of disseminated intravascular coagulation associated with sepsis; and c) IL-6 is involved in the pathophysiology of septic shock, although further studies are needed to determine whether IL-6 is directly involved in mediating the lethal complications of septic shock or whether it should be considered an "alarm hormone" that reflects endothelial cell injury. Our findings also suggest that the concentrations and trends of these mediators during treatment are valuable for monitoring septic patients.

Bleeding prophylaxis in autologous bone marrow transplantation for solid tumors. Comparison of cryopreserved autologous and fresh allogeneic single-donor platelets.

Bleeding prophylaxis with cryopreserved autologous thrombocytes was evaluated in 43 patients treated with high-dose chemotherapy and autologous bone marrow transplantation. Platelet transfusions were given prophylactically. Nineteen patients received only autologous, 10 only fresh allogeneic single-donor, and 14 both types of transfusions. The effects of 104 autologous versus 93 allogeneic thrombocyte transfusions were compared. The increment at 1 h was for allogeneic platelets twice that for autologous platelets (30.6 versus 15.2 x 10(9)/l), but the interval between transfusions in days (2.3) was the same. Twelve patients received alternating autologous platelet transfusion after washing out the cryoprotectant dimethyl sulfoxide (18 transfusions) and non-washed autologous platelets (24 transfusions). Platelet increments, corrected increments, and predicted recovery were not influenced by omitting the washing procedure, and no side effects of dimethyl sulfoxide occurred.