Transplantation for primary hyperoxaluria in the USA.

US data were sought for transplantation in primary hyperoxaluria (PH). The USRDS recorded 194 patients since 1974. By lifetable analysis, survival was better for transplanted than for non-transplanted patients (P < 0.001), even after trimming data for age < 55 and end-stage renal disease since 1985 (63 patients, 39 transplanted, 24 not transplanted). Transplant survival was longer for living related donor (21) vs cadaveric (17) transplants. Twenty-nine kidney transplants in 22 children were registered in NAPRTCS. Interview data with physicians showed that eight of 17 living related donor kidneys functioned well, three were borderline and six were lost. All six cadaver kidneys were lost. Four of six kidney-liver transplants functioned, and two died. United Network for Organ Sharing recorded 13 kidney-liver transplants in 11 patients. Six initially functioned well; two were retransplanted. Ultimately seven lived and four died. Overall, transplant is better than no transplant; cadaver donation results are poor; living related kidney donation can succeed; and kidney-liver transplant is still problematic in the US, and rarely follows appropriate investigation. Until more cooperative effort can be achieved, isolated kidney living related donor transplant is preferable, and does not preclude kidney-liver transplant later.

Treatment outcomes in patients with adult thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.

BACKGROUND: Plasma treatment has improved the outcomes in adults with thrombotic thrombocytopenic purpura (TTP)-hemolytic uremic syndrome (HUS). We reviewed our experience in treating unselected patients to determine the clinical outcomes and to evaluate the treatments given in addition to plasma. METHODS: A chart review of all cases of TTP and HUS in adults treated at the Toronto (Ontario) Hospital, the largest treatment center for adults with TTP-HUS in the province of Ontario, was conducted. RESULTS: Sixty-seven episodes of TTP-HUS in 52 consecutive adult patients were treated during a 12-year period. Plasma was the primary form of therapy, and most patients received plasma exchange. A complete hematologic remission was achieved in 65 of 67 episodes; however, two patients in remission were brain-dead. The time to complete remission varied from 3 to 58 days (median, 13 days). The death rate during the acute illness was 8%. Long-term sequelae included relapses, persisting renal impairment, hepatitis, and transfusion-associated acquired immunodeficiency syndrome. Relapses occurred in 21% of patients during a median follow-up of 1.1 years (range, 0.1 to 18 years). Analyses of the treatment given in addition to plasma did not demonstrate a significant benefit in terms of reducing the illness duration, mortality, or long-term sequelae. CONCLUSION: While most patients recovered from TTP-HUS, deaths still occurred and many patients suffered long-term complications. The role of the treatments given in addition to plasma is uncertain.

Multiple drug chemotherapy combined with multiple fractions per day (MFD) radiotherapy in an experimental solid tumor model.

A series of multi-drug chemotherapy studies combined with multi fractions per day (MFD) radiotherapy have been carried out in an experimental solid tumor model to provide information on how drugs contribute in combinations, both for effect on tumor and with regard to host toxicity. Twenty-five different combinations of cyclophosphamide (CP) and 5-fluorouracil (FU) were evaluated in this initial study. All tumors received a total dose of 6000 cGy of radiation given in multiple fractions per day for three courses one week after combined chemotherapy. Doses of each drug in the combinations ranged from 25 to 100% of the LD10 (150 mg/kg or .9 mg/m2) of each drug when given as a single agent. Proportional hazards analysis of the survival data yielded optimal doses of 132.8 mg/kg FU and 115.0 mg/kg CP, that is, approximately 3/4 of the LD10 of each drug in the combination. The group close to the optimum combination had a median GD of 295.3 days. Among the 5 rats in this group there were 4 partial responses and 1 cure for a 100% response rate. Excessive toxicity occurred in the group given the highest doses of FU and CP along with the 6000 cGy radiotherapy. These experimental cancer treatment studies in well defined solid tumor models demonstrate how the quantitative inter-relationship between anti-tumor effects and host toxicity to tumor burden and total therapeutic dose chemotherapy (single or multiple combinations) and radiotherapy alone or in combination can be obtained. These major determinants on treatment outcome are difficult or impossible to determine in clinical studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of tumor regrowth to tumor cell survival, tumor cure rates and host survival in a solid tumor model following combined chemotherapy and radiotherapy.

Endpoints available for comparison of two or more treatment arms in a clinical cancer trial include response rates (complete and partial), time to progression, and patient survival. In experimental systems, similar endpoints are available (tumor cell survival, tumor regrowth, tumor cure rates, and host survival), but there is opportunity for more precise measurements and a wider range for varying the independent variables. Radiotherapy alone was compared with an alternating schedule in which both radiotherapy and cyclophosphamide (CP) were given intermittently for a total of 3 courses of each. Radiotherapy was given as multiple, 250 cGy fractions per day (MFD) in 2-day courses. Cyclophosphamide alone (3 x 150 mg/kg) was equivalent in tumor effect to 3600 cGy of irradiation given with the MFD schedule. The experimental points for the combined modality treatments fell along the lower edge of the zone of additivity. Exprapolation of the plots of log surviving fraction vs. total radiation for the combined treatment predicted a 37% cure rate at 6000 cGy + CP. There was a high probability for long term control and tumor cures only with the highest total doses of radiation (6000, 7000 and 8000 cGy) when combined with CP. The results obtained in well defined experimental tumor models provide quantitative information of the interrelationship of the major determinants on end results of the effectiveness of treatment and acceptable host toxicity of combined chemotherapy and radiotherapy. The quantitative evaluation of these major determinants on treatment outcome in relationship to host toxicity is often difficult or impossible to obtain in clinical host toxicity is often difficult or impossible to obtain in clinical studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationships between various uses of antineoplastic drug-interaction terms.

In in vitro testing, no pharmacologic synergism has been found for the combination of cisplatin and etoposide in P388 leukemia in contrast to the demonstration of therapeutic synergism in the same model. No pharmacologic synergism has been found for the same combination in the treatment of four small-cell lung-cancer cell lines, although clinical results obtained using this combination in small-cell lung cancer and other cancers suggest a therapeutic advantage. The popular concept of synergy, implying a therapeutic advantage, is different from the pharmacologic meaning, which generally implies that less drug is required in a combination for an equal effect. Therapeutic advantage may be obtained regardless of whether drugs are synergistic in the pharmacologic sense in the treatment of a tumor. To gain a more comprehensive insight into concepts of drug interaction, it is important to recognize that the type of drug interaction seen is dependent on the drug doses used and may vary with the treatment of different cell lines. All of these factors complicate the use of the word synergism, or any associated term, in a categorical manner to describe the effects of combinations of antineoplastic drugs.

A method for determining schedule dependency in tissue culture.

A dual-exposure drug treatment of cell lines in tissue culture provides a possible method for determining schedule dependency. This is suggested by results of treatment of human small cell lung carcinoma NIH H209 and murine L1210 leukemia cell lines with cisplatin, a non-schedule-dependent drug, and etoposide, a schedule-dependent drug. Nonlinear least squares was used to estimate the dose-response surface. The estimated regression coefficients for the effect of the first dose compared to that of the second dose support the premise that cisplatin is not schedule dependent. Unlike cisplatin, the second dose of etoposide was shown to be more effective than the first dose in the human small cell carcinoma line. This agrees with known clinical results where multiple etoposide dosing has been shown to be more effective and confirms schedule dependency. This methodology, or a refinement, may offer another tool for studying schedule dependency of drugs using tissue culture methods.

An asymptomatic confidence interval for the response at the stationary point of a quadratic response surface.

The delta method is utilized to construct an asymptotic 100(1 - alpha)% confidence interval for the response at the stationary point of a quadratic response surface. The end-points of the interval can be found directly, compared to other more, computationally intense procedures that result in a conservative interval. The coverage probability associated with intervals constructed in this manner from studies with relatively small numbers of observations is investigated via a simulation study. Finally, the methodology is illustrated with an example involving the evaluation of a combination of cytotoxic agents in the treatment of murine L1210 leukemia.

Assessing the efficacy of azaprophen and physostigmine as a pretreatment for soman-induced incapacitation in guinea pigs by response-surface modeling.

Physostigmine (PHY) has the advantage over pyridostigmine of minimizing OP-induced incapacitation because it penetrates into the CNS. However, physostigmine is behaviorally toxic at relatively low concentrations. It is anticipated that this could be offset by a cholinolytic to prevent behavioral deficit due to the carbamate pretreatment alone. The therapeutic efficacy of physostigmine/azaprophen pretreatment therapy was evaluated in soman-challenged guinea pigs. Response surface methodology was employed to describe the relationship of the pretreatment combination with duration of incapacitation. The significance of the combination relative to PHY alone was evaluated in addition to dose combinations that yield optimal time to recovery. Analysis of the fitted response surface indicated that combination pretreatment with these compounds significantly reduces the time to recovery after soman challenge versus pretreatment with PHY alone.

Isobolographic characterization of drug interactions incorporating biological variability.

Isobolograms have been widely used to characterize the nature of the interaction between combinations of drugs or chemicals. Some authors have applied this technique without accounting for the variability in the data or without adjusting for multiple comparisons to the line of additivity. This paper develops a graphical procedure which takes into account the variability of the data and which maintains favorable statistical properties. The isobolographic procedure utilized is illustrated by using three classical pharmacological drug combinations in female ICR mice. An additive relationship is illustrated with the loss of righting reflex after combinations of doses of sodium hexobarbital with itself. An antagonistic relationship is illustrated with the protection by mecamylamine of nicotine-induced lethality. A synergistic relationship is illustrated with the loss of righting reflex after combinations of ethanol and chloral hydrate. The procedure's statistical properties (level of significance and power) were determined using a simulation study. The isobolographic procedures developed here are applicable for quantal, continuous and count data. These procedures are applicable for identifying beneficial drug combinations, or conversely, identifying hazards resulting from exposure to multiple toxicants.

Office evaluation and treatment of lower extremity injuries in the runner.

Lower extremity problems in the runner are common and often perplexing. Although many problems such as acute tendinitis and mild sprains can be treated with short periods of rest and nonsteroidal anti-inflammatory drugs, some will be chronic or recurrent in nature. These persistent problems can cause even a serious runner to reduce his activity greatly or even give up the sport entirely. Chronic recurring ailments should be examined carefully with a high suspicion of a biomechanical imbalance in the foot or lower extremity. With a basic understanding of the biomechanics of the foot and ankle and the stresses incurred during running, most of the problems can be managed conservatively.

The survival of the cemented femoral component of a total hip replacement.

A series of 1321 total hip arthroplasties including 238 primary revisions (18%) were evaluated to identify intrinsic factors of the femoral canal that might influence the success of a cemented total hip replacement. A survival analysis was used to compare the success rates of cemented femoral components. These were classified into five groups according to the condition of the medullary canal at the time of surgery: primary surgery, aseptic cemented loosening, failed noncemented hemiarthroplasty, previous septic failure, or fractured femoral prosthesis with rigid distally fixed cement. The overall survival rates of the five groups were found to be significantly different (p less than 0.01). Specifically, the success rates of recemented revisions for aseptic loosening were significantly lower than those for primary total hip replacements (p less than 0.01). No statistical difference was found between the success rates of primary surgeries and the revision success rates for septic failure or for a fractured femoral component.

Retrospective evaluation of an iodophor-incorporated antimicrobial plastic adhesive wound drape.

The incidence of postoperative wound infection following the use of an iodophor-incorporated adhesive wound drape with a preliminary one-minute alcohol cleanse was observed in 649 total arthroplasties. The patients were followed for a minimum of one year to detect signs of infection. An infection rate of 0.46% was comparable to the incidence previously observed for conventional methods using an iodine spray as a skin preparation.

A model for easy location of the center of the femoral head during total knee arthroplasty.

Demographic data and radiographs of 115 patients (230 hips) were evaluated to determine factors significantly related to the location of the center of the femoral head, the point critical in determining proper knee alignment during total knee arthroplasty. Separate regression analysis for men and women showed the distance between the anterior iliac spines to be the only clinically significant factor related to the position of the femoral head center (P less than .0001). A model for each sex was then developed, which allowed easy location of the center point from this readily available distance.

Demonstration of a schedule-dependent therapeutic synergism utilizing the interacting drugs methotrexate and teniposide in L1210 leukemia.

When three variables require simultaneous adjustment for treatment optimization, the experimental determination of the optimum treatment becomes more complicated than generally appreciated, especially when one variable is the interval between drug administrations. Molecular pharmacological studies at this institution suggest that teniposide, in doses that are achievable in vivo, blocks methotrexate efflux from cells, enhancing formation of methotrexate polyglutamates which are active retentive forms of the drug. Hence, the combination might show a synergistic effect if teniposide is given at an appropriate time in relation to administration of methotrexate. This paper considers the problem of estimating the optimal dose levels and timing of administration of these drugs in B6D2F1 mice bearing L1210 leukemia in vivo as a model for the analysis of multidrug regimens when time and dose are variables. Because of the complexity of these experiments, an adaptive approach was applied. Three cycles of treatment were given using methotrexate at 0-400 mg/kg, teniposide at 0-60 mg/kg, and an interval of 0-54 hours between the two drugs. The single drugs prolonged median survival up to 24 days under the conditions of these experiments. The combination given simultaneously resulted in median survival of up to 33.5 days, while use of an appropriate interval between drugs prolonged median survival to greater than 50 days. An analysis of the underlying dose-time response gives a much better appreciation of the relationships among the variables. The concept that optimal doses included less methotrexate and more teniposide as the interval between drugs is increased was developed only through modeling. This finding is critical in demonstrating the importance of including all nonnegligible variables in the experimental design if the results are to be considered valid. Confidence regions about the optimum dose and about the response at the optimum provide a sound basis for a claim of therapeutic synergism as demonstrated by use of a scheduling variable in the experiment design. A nonproportional hazards analysis permits the conclusion of nonproportionality and emphasizes the contribution of methotrexate to optimal short-term survival (15-24 days) and teniposide to long-term survival (24-39 days).

Postoperative patellar complications with or without lateral release during total knee arthroplasty.

Between 1975 and 1984, 84 knees in which an intraoperative lateral release had been performed with total knee arthroplasty (TKA) were compared with 471 knees that, having sufficient patellar tracking at the time of surgery, had not required a lateral release. The lateral superior geniculate artery was routinely sacrificed in all knees in which a lateral release was necessary. The results showed no complications associated with a possible loss of blood supply secondary to the lateral release. No increased evidence of osteonecrosis, patellar bone-cement radiolucency, or patellar fracture was discovered. Clinically, there was no difference in pain, ambulation, or range of motion. Seventeen patellar fractures (3.6%) were observed in patients for whom a lateral release had not been performed, yet only one patellar fracture (1.5%) was encountered among the patients who had required a lateral release. In TKA, lateral release was associated with a relatively high degree of patellar tilting.

Arthroscopy in total knee replacements.

The purpose of this presentation is to relate to the author's experience in treating eight patients for fibroarthrosis following total knee replacements from June 1983 to September 1986. Patients were obtained from referrals by independent orthopedists who had performed total knee replacements and believed that their patients' range of motion (ROM) and pain level were unsatisfactory after trying all standard treatment modalities. Patients evaluated their results through questionnaires and patients were also evaluated by an independent examiner. Improvement in flexion was consistent, yet extension was not generally improved. Postoperative pain level was reduced as compared with preoperative pain level, and there were no major complications. Indications for arthroscopy in total knee arthroplasties are not well defined, but results appear promising for the fibroarthrotic patient with regard to improvement in flexion and subjective pain reduction.

Effect of range of motion on the success of a total knee arthroplasty.

Five hundred fifty posterior cruciate condylar total knee replacements rated on the Hospital for Special Surgery knee rating scale were evaluated to determine whether postoperative range of motion had any detrimental effects on the total score. The amount of flexion significantly influenced the total score (P less than .0003), the stair climbing score (P less than .004), and the walking ability score (P less than .02). Pain, the main determinant of success, was not affected by range of motion unless there was a flexion contracture when there was a significant effect (P less than .05).

Combination of 5-fluorouracil and cyclophosphamide in L1210 and P388 leukemias with changes in optimum treatments as a function of the age of the L1210 tumor at first treatment.

The interaction of 5-fluorouracil and cyclophosphamide in the treatment of L1210 and P388 leukemias was studied using response surface methodology. Single dose treatment of each drug was administered simultaneously or with a 24-hr interval between 5-fluorouracil and cyclophosphamide to the advanced tumors or at various times after L1210 inoculation. While at low doses the action of the combination of the two drugs was greater than expected, there was no therapeutic synergism if the drugs were given together (optimum doses cyclophosphamide 366 mg/kg and 364 mg/kg, respectively, in advanced L1210 and P388 leukemias) or in the early tumor when cyclophosphamide was given 24 hours after 5-fluorouracil. In the advanced tumor, using the regimen employing a 24-hr interval between drugs, therapeutic synergism could be demonstrated (optimum doses 5-fluorouracil 130 mg/kg followed by cyclophosphamide 248 mg/kg in advanced L1210 leukemia and 5-fluorouracil 110 mg/kg followed by cyclophosphamide 263 mg/kg in advanced P388 leukemia). The evidence generated suggested that improved therapy could be found in two separate regions of the treatment space, raising the possibility of more than one mechanism of drug interaction. The location of the optimal treatment depended on the tumor burden at the time treatment was initiated. A shift from one region to the other occurred after 4-6 days of tumor growth when the original inoculum was 10(5) i.p. L1210 cells. Another more obvious conclusion that can be drawn is that treatment was less effective as the tumor became more advanced. The notion that different tumor stages may require different ratios of drugs in a clinically useful combination should receive attention.

Long-term comparison of the Charnley, Muller, and Trapezoidal-28 total hip prostheses. A survival analysis.

Seven hundred ninety-one total hip arthroplasties (242 Charnley prostheses, 146 Muller prostheses, and 403 Trapezoidal-28) performed between 1969 and 1980 by one surgeon were evaluated using survival analysis to predict success and/or failure over time. Only 6.4% of the population was excluded because of failure to return for follow-up evaluation. All other patients were included in the analysis. It is expected that at 10 years after operation, 91% of the Charnley, 88% of the T-28, and 80% of the Muller prostheses will survive (P less than .05). The acetabular cup of the Muller prosthesis showed significant premature loosening, compared with the Charnley and T-28 prostheses (P less than .0001 and P less than .05, respectively). The Muller femoral stem was inferior only to the Charnley (P less than .025). The T-28 femoral stem showed no difference in success compared with the other two prostheses, despite 10 T-28 femoral stem fractures. Multivariate survivorship regression analysis revealed significant factors that may have predisposed the above failures. Women (P less than .0005) and older patients (P less than .0005) had significantly higher success rates. Significant intrinsic factors included radiolucency about the entire acetabular bone-cement interface (P less than .0005), fracture in the acetabular cement (P less than .005), and radiolucency about the entire femoral bone-cement interface (P less than .0005).

An evaluation of Trapezoidal-28 femoral stem fractures.

Fourteen patients sustaining femoral stem fractures of cold rolled wrought stainless steel Trapezoidal-28 prostheses (Zimmir, Warsaw, Indiana) were compared statistically with 259 successful hip replacements of the same type of prosthesis to determine possible factors predisposing to prosthetic fracture. Varus alignment was the highest contributing factor in these femoral stem fractures. Calcar resorption and insufficient distal lateral cement support also were contributory. Medial cement support was less for patients sustaining a fracture, but this was not statistically significant. Patients prone to encounter a fracture were men who were young and/or overweight. There was no significant correlation of fracture to preoperative diagnosis, laterality, trochanteric osteotomy, nonunion of the greater trochanter, or wire breakage.