Henry J. Mankin

Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease.

BACKGROUND AND METHODS Gauchers disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme replacement was proposed as a therapeutic strategy for this disorder in 1966. To assess the clinical effectiveness of this approach, we infused macrophage-targeted human placental glucocerebrosidase (60 IU per kilogram of body weight every 2 weeks for 9 to 12 months) into 12 patients with type 1 Gauchers disease who had intact spleens. The frequency of infusions was increased to once a week in two patients (children) during part of the trial because they had clinically aggressive disease. RESULTS The hemoglobin concentration increased in all 12 patients, and the platelet count in 7. Serum acid phosphatase activity decreased in 10 patients during the trial, and the plasma glucocerebroside level in 9. Splenic volume decreased in all patients after six months of treatment, and hepatic volume in five. Early signs of skeletal improvements were seen in three patients. The enzyme infusions were well tolerated, and no antibody to the exogenous enzyme developed. CONCLUSIONS Intravenous administration of macrophage-targeted glucocerebrosidase produces objective clinical improvement in patients with type 1 Gauchers disease. The hematologic and visceral responses to enzyme replacement develop more rapidly than the skeletal response.

The Hazards of the Biopsy, Revisited. For the Members of the Musculoskeletal Tumor Society*

In 1982, members of the Musculoskeletal Tumor Society, representing sixteen centers for the treatment of bone and soft-tissue cancer, compiled data regarding the hazards associated with 329 biopsies of primary malignant musculoskeletal sarcomas. The investigation showed troubling rates of errors in diagnosis and technique, which resulted in complications and also adversely affected the care of the patients. These data were quite different when the biopsy had been carried out in a treatment center rather than in a referring institution. On the basis of these observations, the Society made a series of recommendations about the technical aspects of the biopsy and stated that, whenever possible, the procedure should be done in a treatment center rather than in a referring institution. In 1992, the Musculoskeletal Tumor Society decided to perform a similar study to determine whether the rates of complications, errors, and deleterious effects related to biopsy had changed. Twenty-five surgeons from twenty-one institutions submitted the cases of 597 patients. The results were essentially the same as those in the earlier study. The rate of diagnostic error for the total series (in which cases from referring institutions and treatment centers were combined) was 17.8 per cent. There was no significant difference in the rate of patients for whom a problem with the biopsy forced the surgeon to carry out a different and often more complex operation or to use adjunctive irradiation or chemotherapy (19.3 per cent in the current study, compared with 18 per cent in the previous one). There was also no significant difference in the percentage of patients who had a change in the outcome, such as the need for a more complex resection that resulted in disability, loss of function, local recurrence, or death, attributable to problems related to the biopsy (10.1 per cent in the current study, compared with 8.5 per cent in the 1982 study). Eighteen patients in the current study had an unnecessary amputation as a result of the biopsy, compared with fifteen in the previous study. Errors, complications, and changes in the course and outcome were two to twelve times greater (p < 0.001) when the biopsy was done in a referring institution instead of in a treatment center.

Percutaneous radiofrequency coagulation of osteoid osteoma compared with operative treatment.

Osteoid osteoma, a benign bone tumor, has traditionally been treated with operative excision. A recently developed method for percutaneous ablation of the tumor has been proposed as an alternative to operative treatment. The relative outcomes of the two approaches to treatment have not previously been compared, to our knowledge. The rates of recurrence and of persistent symptoms were compared in a consecutive series of eighty-seven patients who were managed with operative excision and thirty-eight patients who were managed with percutaneous ablation with radiofrequency. Patients who had a spinal lesion were excluded. The minimum duration of follow-up was two years. There was a recurrence, defined as the need for subsequent intervention, after operative treatment in six (9 per cent) of sixty-eight patients who had been managed for a primary lesion and in two of nineteen who had been managed for a recurrent lesion. The average length of the hospital stay was 4.7 days for the patients who had a primary lesion and 5.1 days for those who had a recurrent lesion. There was a recurrence after percutaneous treatment in four (12 per cent) of thirty-three patients who had been managed for a primary lesion and in none of five who had been managed for a recurrent lesion. The average length of the hospital stay was 0.2 day for these thirty-eight patients. With the numbers available, we could detect no significant difference between the two treatments with regard to the rate of recurrence. The rate of persistent symptoms (that is, symptoms that did not necessitate additional treatment) was greater than the rate of recurrence. According to responses to a questionnaire, eight (30 per cent) of twenty-seven patients had persistent symptoms after operative treatment and six (23 per cent) of twenty-six patients had persistent symptoms after percutaneous treatment with radiofrequency. Two patients had complications after operative excision, necessitating a total of five additional operations. There were no complications associated with the percutaneous method. The results of the present study suggest that percutaneous ablation with radiofrequency is essentially equivalent to operative excision for the treatment of an osteoid osteoma in an extremity. The percutaneous method is preferred for the treatment of extraspinal osteoid osteoma because it generally does not necessitate hospitalization, it has not been associated with complications, and it is associated with a rapid convalescence.

The hazards of biopsy in patients with malignant primary bone and soft-tissue tumors.

This study was performed by the Musculoskeletal Tumour Society using questionnaires to assess the following: • The accuracy of biopsy in making a diagnosis • The incidence of complications associated with the biopsy procedure • The effects of errors in diagnosis and of complications on the treatment of patients • Whether these problems occurred with greater frequency when the initial biopsy was performed in a referring institution or in a specialist treating centre Each member of the Society submitted data on 20 sequential, unselected, newly diagnosed patients with malignant primary tumours of bone or soft tissue who underwent a biopsy and then a defi nitive procedure. The study received data from 20 orthopedic surgeons in 16 treating centres. Information on 329 patients included a wide range of diagnoses (but generally conforming to the distribution of these tumours in the general population). The mean age of the patients was 36.5 years (range, 2 weeks to 83 years). Two hundred and twenty two lesions were bone primaries and 107 were derived from soft tissue. One hundred and forty three tumours were biopsied in the referring institution and 171 in the treating centre. The authors demonstrated 60 (18.2 %) major errors in diagnosis and 34 (10.3 %) non-representative or technically poor biopsies. Fifty-seven patients (17.3 %) encountered problems in the skin, soft tissue, or bone following biopsy and the optimum treatment plan had to be altered as a result of problems related to the biopsy in 60 patients (18.2 %). In 15 patients (4.5 %) an unnecessary amputation was performed as a result of problems with the biopsy, and in 28 patients (8.5 %) the prognosis and outcome were considered to have been adversely affected. Patients undergoing a biopsy at the referring institution experienced biopsy-related problems three to fi ve times more frequently than those undergoing biopsy at a treating centre. Given these fi ndings, the authors recommend that the biopsy should be planned as carefully as defi nitive surgery. In particular, careful attention should be paid to the following: • Asepsis, skin-handling, haemostasis, and wound closure • Precise skin incision placement, which will not compromise subsequent surgery. • The tissue obtained should be suffi cient in volume and suffi ciently representative of the lesion that the pathologist can provide a defi nitive diagnosis. If the surgeon or the institution is not prepared to perform accurate diagnostic studies or proceed with defi nitive treatment for these patients, patients should be referred to a treating centre prior to biopsy. The Hazards of Biopsy in Patients with Malignant Primary Bone and SoftTissue Tumors

Infection in bone allografts. Incidence, nature, and treatment.

Of 283 patients who had a massive allograft of bone, an infection developed in thirty-three (11.7 per cent). To assess the frequency and identify the co-morbid and predisposing factors of this devastating complication, we compared demographic data for the infected and non-infected patients. Comparison of mean age, type of graft, anatomical site of the procedure, and stage of the tumor yielded no significant differences. Multiple-regression analysis of a subgroup of eighty-two patients who had a distal femoral graft showed a correlation between infection and factors that are associated with more extensive surgery (more loss of bone, soft tissue, or skin) or with multiple operations. Approximately 30 per cent of the patients who had an infected allograft had no co-morbid or predisposing factors that could be statistically correlated with an increased risk for infection. Gram-positive organisms were the most common cause of infection, with twelve infections (36 per cent) being due to Staphylococcus epidermidis. Six patients had a single gram-negative organism and nine had mixed flora. The final result in the thirty-three patients who had an infected allograft was poor compared with that of the over-all series and of the uninfected patients. Twenty-seven infected allografts (82 per cent) were considered to be failures of treatment because amputation of the limb or resection of the graft was required to control the infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Limb salvage compared with amputation for osteosarcoma of the distal end of the femur. A long-term oncological, functional, and quality-of-life study.

The outcome of treatment of nonmetastatic high-grade osteosarcoma in the distal part of the femur was studied in 227 patients from twenty-six institutions. Eight of the seventy-three patients who had had a limb-salvage procedure and nine of the 115 patients who had had an above-the-knee amputation had a local recurrence, but there was no local recurrence in the thirty-nine patients who had had a disarticulation at the hip. There were no significant differences in the rate of survival or in the duration of the postoperative disease-free period between the three groups. One hundred and nine patients (48 per cent) were alive at an average of eleven years after the operation, and ninety patients (40 per cent) remained continuously disease-free. An additional operation on the limb was necessary more often for patients who had had a limb-salvage procedure than for those who had had an amputation. Function in seventy-eight living patients was assessed with the system of the Musculoskeletal Tumor Society for evaluation of function and by the functional assessment portion of the 1989 scoring system of the Knee Society; the scores were higher for the patients who had had a limb-salvage procedure than for the two groups of patients who had had an amputation. No difference was identified between the groups with regard to the patients acceptance of the postoperative state, the ability to walk, or the amount of pain. The quality of life was evaluated for twenty-nine patients with a series of complex questionnaires.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and pathologic review of 48 cases of chordoma

The results of treatment of 48 patients with the diagnosis of chordoma during the period 1931 to 1981 at the Massachusetts General Hospital were reviewed. Fourteen patients were treated with surgery alone: eight patients with primary tumors in the sacrococcygeal region were treated with radical surgery and four are alive with no evidence of disease (NED) with follow‐up of 8 to 20 years. Recurrent tumors in six patients were treated with surgery alone resulting in long palliation (3–25 years). The actuarial survival rate at 5 years for all patients treated with surgery was 76%. Radiation therapy was used in patients after either a biopsy (15), partial excision (17), or before radical excision in 2 patients. To achieve a worthwhile level of palliation, doses greater than 4000 cGy were required. High‐dose levels (>6500 cGy) were achieved in nine cases by a combination of photon and 160 MeV proton beams. The results to date of this approach for lesions of the base of skull and cervical vertebral body are encouraging: high local control and low morbidity. The 5‐year actuarial survival rate of all patients treated with radiation was 50%.

Preoperative, intraoperative, and postoperative radiation in the treatment of primary soft tissue sarcoma.

The rationale for combining radiation with conservative surgery in the treatment of sarcoma of soft tissue is discussed, as well as the advantages for performing the radiation preoperatively on the one hand and postoperatively on the other. The results of treatment of soft tissue sarcoma by radical resectional surgery or amputation in 464 patients at four centers and by conservative surgery, and postoperative radiation in 416 patients at three centers, have been reviewed. The local failure rates were 18.1% and 18.3%, respectively. The results obtained by radiation administered postoperatively (110 patients) or preoperatively (60 patients) at the Massachusetts General Hospital during the period September 1971 to August 1982 are analyzed and discussed with reference to 5‐year actuarial local control and survival results as well as causes of failure with respect to AJC stage, histologic type, anatomic site, and size of tumor. The results which have been obtained by the preoperative approach are judged to be superior, particularly for the larger lesions and higher grades that predominated in that group. Of a total of 170 patients, there were 19 local failures; 13 of these were diagnosed at the time when metastatic disease was not evident. Of those 13, 12 have been subjected to salvage surgery and 7 remain with no evidence of disease at 1 to 3.5 years after the salvage procedure. A major problem in the management of these patients remains the occult metastatic disease.

Osteoarticular and intercalary allograft transplantation in the management of malignant tumors of bone.

Since 1971, the Orthopaedic Service at the Massachusetts General Hospital has treated 106 patients with malignant or aggressive bone tumors by wide resection and replacement with frozen cadaveric allograft. Sixty‐one of these patients have been followed for over two years (mean, 4.5 years), allowing a comprehensive end‐results analysis. In 45 patients, mostly with giant‐cell tumors or chondrosarcomas, the resection involved the articular end of a long bone and the replacement not only included bone, but glycerolized (to prevent freezing injury) articular cartilage. Ten of the segments were intercalary (bone alone) and six involved a combination of bone and a metallic joint prosthesis. Patients were graded as excellent, good, fair, or failure, depending principally on functional capacity. End‐results analysis in this group showed that five of the 61 patients had either a local recurrence (2) and/or distant metastases (3); in five additional patients the limb was amputated or the implant removed, primarily because of infection (total failure rate, 16.5%). Forty‐five (73.8%) had successful transplants (graded excellent or good) and were able to live essentially normal lives. Six of the patients (10%) required a brace or cane but three of these patients were able to return to preoperative work activities. Although the operations were arduous and difficult, and despite a high infection rate (13%) and occasional pathologic fractures (10%), the results compare favorably with other techniques used to restore the skeleton following massive segmental resection. In long‐term follow‐up, the data suggest that if no complications ensue in the first two years, the results are generally quite good and the grafts show no evidence of progressive deterioration with time.

Chondrosarcoma of Bone: An Assessment of Outcome*

BACKGROUND The data on 227 patients who had been managed for a chondrosarcoma at one institution were reviewed to determine the nature of the lesions, the predictors of outcome, and whether there were any ways to change the treatment approaches to improve the results. METHODS The patients were followed for a mean duration of six years (range, three to twenty-five years). The mean age of the patients was forty-seven years (range, nine to eighty-four years). The most prevalent sites of the tumors were the femur (seventy-eight), the pelvis (fifty-one), and the humerus (thirty-nine). The tumors were divided into two groups according to histological grade. Eighty-six tumors (sixteen atypical enchondromas and seventy grade-1 chondrosarcomas) that were locally destructive but were associated with a low likelihood of metastasis were considered to be low-grade. The remaining 141 lesions, which were locally destructive, potentially metastatic, and capable of causing death, were thought to be high-grade. One hundred and three of these 141 lesions were grade 2, and thirty-eight were grade 3 (eighteen of the thirty-eight were grade 3 only, and twenty were both grade 3 and dedifferentiated). Two hundred and twenty-four patients were managed with resection and a limb-sparing procedure; the remaining three patients had an amputation. Postoperative adjuvant radiation was used for fifty-six patients; chemotherapy, for thirty-five; and both radiation and chemotherapy, for nineteen. Flow cytometric patterns were analyzed for 105 patients. RESULTS The patients who had a high-grade tumor were older than those who had a low-grade tumor (mean age [and standard deviation], 50+/-17.0 years compared with 40+/-15.9 years; p < 0.001). Pathological fracture, metastasis, local recurrence, and death were more prevalent in the group that had a high-grade lesion (p < 0.001). Predictors of metastasis and death in that group of patients included local recurrence, a pelvic location of the tumor, a tumor that was more than 100 cubic centimeters in size, a ploidic abnormality (aneuploidy coupled with a high mean DNA index), a histological grade of 3, and a dedifferentiated type of tumor (p < 0.001). CONCLUSIONS Although the data are suggestive, with the numbers available for study we could not detect a significant difference in the rates of pulmonary metastasis and death between the patients who had a grade-3 lesion and those who had a grade-3 lesion that was also dedifferentiated. However, the interval between diagnosis and death was 32+/-22.8 months for the patients who had a grade-3 lesion compared with 5+/-3.7 months for those who had a grade-3 lesion that was also dedifferentiated (p < 0.001). Overall, patients who had had a resection with wide margins (margins extending outside the reactive zone) had a longer duration of survival than did those who had had a so-called marginal resection (margins extending outside the tumor but within the reactive zone) or an intralesional resection (margins within the lesion) (p < 0.04). Adjunctive chemotherapy or radiation, or both (which, it must be noted, was used, without a protocol, in a relatively small number of patients), after an intralesional resection, for recurrent disease, or for distant metastasis did not appear to alter the outcome.