Criteria for evaluating patient responses to treatment modalities for prostatic cancer

Criteria for evaluating response to therapy for both early and late stages of prostate cancer, as developed by the National Prostatic Cancer Project, are presented and discussed. Detection of bone metastases and monitoring of changes in existing bone lesions are critical to these criteria for early and late disease, respectively. The prognosis, or survival experience, of groups of patients for each response category is also discussed.     

Primary echinococcus infestation of the bone and muscles

Hydatid diseases of the bone and muscles are rare, generally are incurable, and have a high level of recurrence. We attempted to ascertain whether the recurrence rate decreased in patients with hydatid disease infestation of the bone and skeletal muscle who were treated with current surgical techniques and antihelminthic chemotherapy, and whether the outcomes for bone infestation were different when compared with outcomes for muscular infestation. We retrospectively reviewed 15 patients with hydatid disease of the bone (eight patients) and muscle (seven patients). The average followup was 30 months (range, 6-69 months). Recurrence was observed in four patients with bone involvement. No patient with muscle involvement had a recurrence after excision. Hydatid disease of the bone often is recurrent and progressive despite using advanced diagnostic studies, improved surgical techniques, and newly developed antihelminthic drugs. The disease status also was not as good as for patients with bone lesions when compared with patients with muscular lesions.     

Amyloid tumor. A clinicopathologic study of four cases.

Four examples of amyloid tumors were studied to determine whether there was an association with myelomatosis. Three patients had follow-up examinations of 12 years, 9 years, and 2 1/2 years, respectively. A local recurrence developed in one patient and a second lesion developed in this patient and in one other who also had a transient monoclonal 7S globulin peak. In spite of these findings, none of our patients developed myelomatosis. A study of the scanty literature on amyloid tumors reveals that only patients with lesions of the lung and urinary bladder have had long-term follow-up. They have invariably remained free of disease. Several reports of bone lesions have inferred that amyloid tumors occurring here signify solitary myeloma despite a lack of follow-up confirmation. Our longest surviving patient developed two bone lesions over a 12-year period without developing myelomatosis. Our findings lead us to conclude that there is little evidence to regard the presence of an amyloid tumor at any site as a manifestation of solitary myeloma or myelomatosis.     

Expression of measles virus nucleocapsid protein in osteoclasts induces Paget's disease-like bone lesions in mice.

We targeted the MVNP gene to the OCL lineage in transgenic mice. These mice developed abnormal OCLs and bone lesions similar to those found in Paget's patients. These results show that persistent expression of MVNP in OCLs can induce pagetic-like bone lesions in vivo. INTRODUCTION: Paget's disease (PD) of bone is the second most common bone disease. Both genetic and viral factors have been implicated in its pathogenesis, but their exact roles in vivo are unclear. We previously reported that transfection of normal human osteoclast (OCL) precursors with the measles virus nucleocapsid (MVNP) or measles virus (MV) infection of bone marrow cells from transgenic mice expressing a MV receptor results in formation of pagetic-like OCLs. MATERIALS AND METHODS: Based on these in vitro studies, we determined if the MVNP gene from either an Edmonston-related strain of MV or a MVNP gene sequence derived from a patient with PD (P-MVNP), when targeted to cells in the OCL lineage of transgenic mice with the TRACP promoter (TRACP/MVNP mice), induced changes in bone similar to those found in PD. RESULTS: Bone marrow culture studies and histomorphometric analysis of bones from these mice showed that their OCLs displayed many of the features of pagetic OCLs and that they developed bone lesions that were similar to those in patients with PD. Furthermore, IL-6 seemed to be required for the development of the pagetic phenotype in OCLs from TRACP/MVNP mice. CONCLUSIONS: These results show that persistent expression of the MVNP gene in cells of the OCL lineage can induce pagetic-like bone lesions in vivo.     

Histologically verified lung metastases in benign giant cell tumours—14 cases from a single institution

From 1975 to 1997, 649 cases of benign giant cell tumours of the bone were treated at the Istituto Rizzoli. Fourteen patients (2.1%) experienced lung metastases after a mean of 35.2 months. The time interval between the diagnosis and the appearance of the lung metastases ranged from 3 months to 11.9 years. Metastasectomy was performed in all patients. Histologically, the metastases were identical to the primary bone lesions. Two patients with unresectable multiple metastases received additional chemotherapy. After a follow-up of 70 months (range: 8.2 to 185 months), all patients are alive. Ten patients showed no evidence of disease, one of these after a second resection of metastases, and four patients presented stable disease with multiple lung metastases. Local recurrence of the bone lesion occurred in seven patients before or simultaneously to the metastases. In contrast to previous reports, we could not detect a predominance of the distal radius, but all of the patients had a stage III tumour according to the Enneking criteria of benign lesions. We conclude that even metastatic benign giant cell tumours have an excellent prognosis after adequate resection. No prognostic factors despite high-grade lesions were detectable.     

Mantle cell lymphoma involving skin: cutaneous lesions may be the first manifestation of disease and tumors often have blastoid cytologic features

We describe five cases of mantle cell lymphoma involving skin. Three patients initially presented with skin lesions but had evidence of widespread disease at time of diagnosis or with relatively short follow-up. One patient was known to have disseminated disease before he developed skin lesions. One patient presented with a solitary skin nodule on the thigh and has developed multiple smaller nodules on the same leg, but no other sites of disease over 30 months of clinical follow-up. This case fulfills the criteria for primary cutaneous lymphoma as proposed by the European Organization for Research and Treatment of Cancer. Biopsy of the skin lesions in all cases showed predominantly dermal and focally subcutaneous lymphoid infiltrates, preferentially perivascular and periadnexal in four cases, and nodular in one case. The tumors were composed of small- to medium-sized lymphocytes with irregular nuclear contours. Four cases had blastoid and one case had typical cytologic features. Immunophenotypic studies showed that all cases were positive for CD20 and cyclin D1, and four of five were positive for CD5. Four cases, including the CD5-negative case, had evidence of the t(11;14) shown by either fluorescence in situ hybridization methods performed on skin tumors or conventional cytogenetic analysis performed on involved bone marrow. We conclude that mantle cell lymphoma can involve skin, usually as a manifestation of disseminated disease, and is often associated with blastoid cytologic features. Rare cases of mantle cell lymphoma may arise in skin.     

Atypical features of primary hyperoxaluria in end-stage renal disease.

Two case histories of patients with end-stage renal disease subsequently found to have primary hyperoxaluria are reported. In the setting of renal failure, the diagnosis is both difficult, due to diminished oxalate excretion, and important, because of frequent graft loss due to oxalate deposition after renal transplantation. The diagnosis was obtained by renal and bone biopsies. Plasma oxalate levels were normal in one patient and the other patient presented with extensive cystic bone lesions. Primary hyperoxaluria should be considered whenever nephrocalcinosis and/or nephrolithiasis are associated with end-stage renal disease.     

Periprosthetic metastatic carcinoma: Pitfalls in the management of two cases initially diagnosed as osteolysis

Periprosthetic osteolysis is a well-described phenomenon associated with total hip arthroplasty. Two cases are presented in which apparently healthy patients developed lytic lesions adjacent to cementless hip implants. Despite atypical features, the lesions were initially attributed to wear debris-induced osteolysis, and it was discovered during revision surgery that metastatic tumor was present. For one patient, if the initial diagnosis had been correct, subsequent surgery and related complications may have been avoided. It is important to consider the entire differential of radiolucent bone lesions whenever a patient presents with periprosthetic osteolysis. If revision surgery is not warranted on the basis of loosening, then a thorough medical examination, close follow-up evaluation, and/or biopsy should be performed to rule out metastatic disease     

Rationale for the use of bisphosphonates in osteoblastic and osteolytic bone lesions

Various primary malignancies develop bone metastases, and the resultant skeletal complications cause significant morbidity/mortality in advanced cancer patients. Bone lesions associated with metastases are traditionally classified radiologically as either osteolytic or osteoblastic, and both types of lesions are associated with elevated levels of specific bone resorption markers. Some common aspects in the pathophysiology of bone lesions have prompted speculation that treatments for osteolytic metastases might also be effective for predominantly osteoblastic metastases, such as in prostate cancer. Potent osteoclast activity inhibitors, bisphosphonates have been successful in the treatment of osteolytic tumor bone disease. Zoledronic acid is the first bisphosphonate shown to have a direct clinical benefit in the treatment of osteoblastic bone metastases, reducing the number and rate of skeletal events in prostate cancer patients with metastatic bone disease. Moreover, the shorter, more convenient infusion time and similar safety profile of 4 mg zoledronic acid compared with 90 mg pamidronate presently make zoledronic acid the preferred therapy for treatment of bone metastases in patients with all types of advanced malignancy.     

Localized fibrocystic disease of the femur: A report of three patients treated by curettage and bone graft

We have presented three cases of fibrocystic disease of the femur. Two of these patients had a purely cystic lesion, while the third had a solid fibrous lesion. In each of the three cases, the lesion described was the only such bone lesion present, and there was no evidence of any endocrine or hormonal disturbance. Although the gross and microscopic appearance of the solid lesion differs from that of the cystic lesion, it is probably true that both have as their pathogenic basis some localized congenital abnormahty in bone development. The clinical picture in both types of fibrocystic disease is very similar, and the surgical treatment in both types is the same. Each of these three patients was treated by curettement of the fibrocystic lesion followed by insertion of multiple bone grafts. This type of operation resulted in complete obliteration of the two purely cystic lesions and almost complete obliteration of the solid lesion.     

Cardiac Behçet disease presenting as aortic valvulitis/aortitis or right heart inflammatory mass: a clinicopathologic study of 12 cases

Beh?et disease is an inflammatory disorder of unknown etiology showing diverse clinical presentations. Cardiac involvement is a critical problem that requires a timely diagnosis and management. However, clinicopathologic features have not been characterized clearly. Here, we present clinicopathologic characteristics of this uncommon disease. Patients included 8 males and 4 females, ranging from 24 to 52 years old. They were presented with abrupt heart failure and were mostly diagnosed as having cardiac Beh?et disease later in the course. Upon echocardiography, 8 patients showed severe aortic regurgitation with redundant prolapsing aortic cusps and 4 patients showed irregular mass lesions in the right ventricular cavity. No one had both lesions. The aortic root was also involved with aortic valvulitis, showing severe mixed acute and chronic inflammation of various stages. There were frequent microabscess and extensive endothelial loss with fibrinous deposit. The right heart lesions showed similar histopathologic features. Four patients who initially underwent simple aortic valve replacement developed serious postoperative complications requiring reoperations. No serious complications developed after the treatment was changed to a replacement of aortic root with extensive debridement and concomitant immunosuppressive therapy. Cardiac Beh?et disease is presented as aortic valvulitis/aortitis or inflammatory mass lesion. Characteristic echocardiographic and pathologic findings seem to be helpful for the timely diagnosis of this critical disease.     

Surgical treatment of bone metastases in patients with breast cancer

In this retrospective study, the effect of surgical therapy on a series of 70 patients with breast cancer who were surgically treated for metastasis of the bone was evaluated. At presentation, 19 patients had one osseous lesion, 19 patients had multiple bone lesions, and 32 patients had additional visceral involvement. The surgical procedures included 60 palliative procedures, six radical resections, and four biopsies. In 14 surviving patients, the mean observation period was 35.6 +/- 40.1 months. Of the six patients with radically resected solitary bone lesions, five patients had systemic progression of the disease develop. Of the 19 patients with presumably solitary bone lesions, five currently are free of tumor. Of the 19 patients with multiple bone lesions and initially no visceral tumor spread, only two are alive. Of the 32 patients with additional visceral metastases at surgery, four are alive with the disease. For the entire group, the survival rate was 59% after 1 year, 36% after 2 years, 13% after 5 years, and 7% after 10 years. The only two independent factors that were associated with survival were the extent of the disease and the duration of symptoms from bone metastasis. These findings suggest that in orthopaedic surgery in patients with bone metastases secondary to breast cancer, wide resection is not likely to be necessary. Patients with solitary bone lesions have a 39% chance of living 5 years.     

Sclerosis of lytic metastatic bone lesions during treatment with pamidronate in a patient with adenocarcinoma of unknown primary site

Pamidronate disodium is a second-generation bisphosphonate, a group of compounds that are being used increasingly to inhibit bone resorption in disorders that are characterized by excessive bone loss such, as hypercalcemia of malignancy, osteoporosis, and Paget's disease. The precise mechanisms whereby bisphosphonates inhibit bone resorption are still not completely understood. Pamidronate has previously been reported to induce sclerosis of lytic bone metastases in patients with breast cancer. We have had a similar experience in a patient with multiple bone metastases due to adenocarcinoma of unknown primary site who developed massive consolidation of lytic bone lesions after therapeutic infusions of pamidronate, leading to a satisfactory quality of life.     

A dynamic classification of Paget's disease

A new dynamic classification of Paget's disease is proposed, incorporating both the radiographic phases of bone remodelling and the scintigraphic findings. Osteolytic, mixed and osteoblastic phases are associated with increased scintigraphic activity, while the osteosclerotic phase of remodelling is associated with normal or diminished activity and an osteoblastic radiographic appearance. Abnormal modelling of bone leading to deformity is produced by accelerated apposition or absorption at the periosteal and endosteal envelopes of the bone. In 112 patients with symptoms from Paget's disease, 527 lesions were classified. The most frequent remodelling phase was the mixed one and the most common modelling state was bone expansion with endosteal and periosteal apposition. Of 88 patients treated medically, 12 had lesions which progressed to increased bone formation without a change in modelling, and the active lesions in seven patients became inactive. Prolonged treatment with disodium etidronate led to progressive osteopenia in 11 patients.     

Primary bone oxalosis: the roles of oxalate deposits and renal osteodystrophy

Primary oxalosis is a rare congenital disorder. The excessive oxalate biosynthesis induces deposits in many organs, particularly in kidney and bone. The late onset of primary oxalosis is reported in a 50-year-old man. His chronic renal failure was treated by maintenance hemodialysis for 3 years. He then developed a diffuse bone disease with osteosclerosis and roentgenographic features of hyperparathyroidism. A parathyroidectomy was performed, with debatable improvement of bone lesions. Laboratory results and histologic and histomorphometric studies before and after parathyroidectomy suggest a double histopathogenetic mechanism for this bone disease: renal osteodystrophy and massive bone oxalate deposits. Such deposits may induce both a heterogeneous osteosclerosis with dense metaphyseal bands and histologic bone lesions similar to those of hyperparathyroidism. The crystalline deposits induce in the bone tissue a granulomatous macrophagic reaction. These macrophages are unable to phagocytize the crystals and may be involved in active bone resorption. Bone lesions of oxalosis occur in patients with chronic renal failure, and hyperparathyroidism has a worsening role.     

A 27-year experience with splenectomy for Gaucher's disease

Gaucher's disease is an inherited metabolic disorder caused by the defective activity of acid beta-glucosidase and the resultant accumulation of glucosyl ceramide-laden macrophages in the liver, bone, and spleen. Splenectomy is the preferred treatment for patients with Gaucher's disease who develop massive splenomegaly with accompanying hypersplenism and/or mechanical pressure symptoms. The charts of 48 patients with Gaucher's disease undergoing splenectomy at our institution between January 1963 and December 1989 were analyzed to determine the short- and long-term results of this procedure. Thirty-five (73%) patients had total splenectomy, whereas 13 (27%) patients had partial splenectomy. There was one postoperative death (after total splenectomy), and 13 patients (27%) had postoperative complications. Eleven patients (23%) presented with accelerated bone disease after total splenectomy (mean follow-up: 96 months). No patients having partial splenectomy (mean follow-up: 25 months) developed progressive bone disease. Eight patients have died since surgery. All four deaths due to malignant disease occurred in patients after total splenectomy. The results of this largest-ever reported series of splenectomy for Gaucher's disease confirm that while either total or partial splenectomy can be performed with minimal morbidity and mortality, total splenectomy is accompanied by more aggressive bone disease and a predisposition to malignancy. Prospective, randomized trials are needed to substantiate whether partial splenectomy is indeed the treatment of choice for splenomegaly associated with Gaucher's disease.     

Hematological malignancies and the bone (myeloma excluded)

Bone involvement is a rare event in lymphomas, except in patients with adult T-cell leukemia/lymphoma associated with HTLVI. It is usually characterised by lytic bone lesions located in the metaphysis of long bones or in the axial skeleton. The occurrence of bone lesions reflects a progression of the disease affecting the prognosis that is related to lymphoma histologic features and staging. Bone lesions may occur in some lymphoproliferative disorders such as LLC or Waldenstrom's disease, or in myeloproliferative disorders. They may reflect a progression to a more aggressive disorder with a worse prognosis. The treatment of hematologic malignancies presenting with bone lesions and/or hypercalcemia is similar to the treatment of the systemic disease. In primary lymphomas of bone presenting with an isolated bone lesion, local treatment with radiation therapy and/or surgical ablation is required, and adjuvant chemotherapy may improve the prognosis of these located lymphomas. Glucocorticoid therapy and bisphosphonates are effective in treating associated hypercalcemia. Except for myeloma and ATL, the underlying mechanisms responsible for bone involvement in hematologic malignancies remain poorly understood. The unusual occurrence of bone lesions in these diseases probably implies distinct pathogenic mechanisms, but one can speculate that an increased expression of RANK/RANKL, the common final pathway in bone resorption, may be involved.     

Metachondromatosis: a report of two cases in a family.

We have described a 10-year-old Japanese boy and his father with metachondromatosis characterized by multiple exostoses, enchondromas, and periarticular calcification or ossification and reviewed the literature on this condition. The boy developed bilateral epiphyseal changes in the hips mimicking Perthes' disease. These cases are the first Japanese individuals with this disorder. The natural history and the associated disorders of metachondromatosis are also discussed in this paper. Metachondromatosis is an inherited skeletal dysplasia characterized by multiple cartilaginous exostoses, multiple enchondromas, and periarticular calcification or ossification. The mode of inheritance of the disease is autosomal dominant. In 1971, Maroteaux first described the disorder in 6 patients of 2 kindreds. Since then, 22 cases have been reported. However, no Japanese patient with this disorder has been described to date. We herein report a Japanese boy and his father with this rare bone dysplasia. The boy developed bilateral epiphyseal lesions in the femoral heads mimicking Perthes' disease.     

Glucocorticoids decrease interleukin-6 levels and induce mineralization of cultured osteogenic cells from children with fibrous dysplasia.

Fibrous dysplasia (FD) is a progressive bone disease in which abnormal fibroblast proliferation results in the replacement of normal cancellous bone with an immature fibrous tissue that is poorly mineralized. The disease manifests itself in the monostotic form in which only one bone is involved and the polyostotic form in which multiple bones at different sites are affected. The McCune-Albright syndrome is a variation of the polyostotic form in which patients demonstrate a greater extent of bone involvement and a variety of endocrinopathies. Somatic activating mutations in the GNAS gene have been demonstrated in the fibrotic lesions of patients affected with either monostotic or polyostotic FD. The increased cAMP levels caused by the G-protein mutations lead to increased interleukin-6 (IL-6) levels in the affected tissues, resulting in abnormal osteoblast differentiation and increased osteoclastic activity. Utilizing cell culture techniques that have been developed for mammalian bone marrow stromal cells, we have successfully cultured osteogenic stem cells from the affected stroma of 11 FD patients. Cells cultured from patients with polyostotic FD showed a high frequency of the Gsalpha mutation, whereas cells from monostotic FD patients showed a low frequency of the mutation. Both the normal and FD cells displayed the osteogenic phenotype when exposed to medium containing glucocorticoids. Glucocorticoids also caused a dramatic inhibition of IL-6 mRNA and protein levels in osteogenic cells cultured from the FD patients. These findings suggest that chemical alteration of cellular function may lead to new treatment options for patients with FD.