Palliative surgery for acetabular metastasis with pathological central dislocation of the hip joint after radiation therapy: a case report.

Orthopedic surgery for bone metastases is mainly a palliative treatment. Pathological central dislocation of the hip joint secondary to osteonecrosis of acetabular metastasis after radiation therapy brings severe suffering to cancer patients. We performed minimally invasive palliative surgery for an elderly woman, and excellent pain relief was achieved. An 80-year-old female suffering from right hip pain was referred to our hospital. She had undergone surgery for lung cancer 5 years previously and her right acetabulum was subsequently affected by metastasis. With the aim of controlling the metastasis, radiation therapy was performed. Two years later, pathological central dislocation of the hip joint occurred with sudden onset of severe pain, and she was unable to maintain a sitting position and became bedridden. After she was referred to our hospital, we created an intentional pseudarthrosis in the femoral neck for palliation. After the surgery, excellent pain relief and remarkably improved mobility were achieved during her limited remaining lifetime. In this report, we introduce a novel method of producing a pseudarthrosis in the femoral neck for pathological dislocation. This procedure is a minimally invasive treatment and an alternative option for palliative surgery for pathological dislocation of the hip joint due to osteonecrosis after radiation therapy.

Evaluation of clinical problems associated with bone metastases from carcinoma from unknown primary sites.

INTRODUCTION: This study focused on the evaluation of data concerning the clinical features of patients who were initially diagnosed with bone metastases of carcinoma from unknown primary sites that could not be detected, even using state of-the-art diagnostic modalities. METHOD: The oncologic outcome of these patients is discussed. PATIENTS: The clinical records of seven patients who had presented with bone metastases of carcinoma from unknown primary sites were retrospectively reviewed. Clinical features, treatment and outcome were analyzed. Extraskeletal metastases were located in the lymph nodes, liver, skeletal muscle, kidney, adrenal gland, and pleura. Six cases were observed in the pelvis, three in the femur, three in the skull, two in the rib, two in the cervical spine, two in the thoracic spine, two in the lumbar spine, one in the humerus, one in the radius, one in the clavicle, one in the scapula and one in the sternum. Four patients received systemic chemotherapy including platinum. RESULTS: At the last follow-up time of average 272 days, six patients were dead of disease and one patient was alive with disease. Although considerable progress has been made in the development of diagnostic modalities, including more recently FDG-PET, the primary tumor site cannot always be identified. Multiple bone and visceral organ metastases are often present in patients whose primary tumor was not detected. CONCLUSION: In the present study, it was found that systemic chemotherapy can appreciably increase the survival time of the patients with carcinoma metastases from unknown primary sites.

Local delivery of rolipram, a phosphodiesterase-4-specific inhibitor, augments bone morphogenetic protein-induced bone formation.

Recombinant human bone morphogenetic protein (rhBMP) is a promising therapeutic cytokine for the induction of bone formation, but a weak response in humans remains a major hurdle in its therapeutic application. We have previously reported an rhBMP-2-induced increase in the bone mass of mice receiving systemic rolipram, a specific inhibitor of phosphodiesterase-4. To overcome the side effects of systemic administration of rolipram, we examined the effects of its local release. Polyethylene glycol discs were used as a delivery system. The discs were impregnated with rhBMP-2 and rolipram and implanted into the dorsal muscle pouches in mice. Bone formation was assessed by measuring the bone mineral content (BMC) of the formed bone. First, to determine the optimal dose of rolipram, we added 0-5000 nmol rolipram and 5 microg rhBMP-2 to the pellets and found that 500 nmol rolipram was the most effective concentration for inducing bone formation after 4 weeks. Second, to examine the time course of bone formation, we implanted 5 microg rhBMP-2 with 0 or 500 nmol rolipram and killed mice 5, 7, 10, 14, or 21 days after implantation. Bone formation was accelerated in the rolipram group. Finally, to determine the rolipram-induced increase in the effect of BMP, BMC obtained after treatment with 5 microg rhBMP-2 and 500 nmol rolipram was compared with that obtained after treatment with 5-9 microg rhBMP-2 without rolipram, 4 weeks after implantation. The results indicated that 500 nmol rolipram enhanced the effect of rhBMP-2 by almost 1.5-fold. In summary, locally released rolipram enhanced the capacity of rhBMP-2 to induce bone formation, an effect previously reported with systemic administration. These findings may decrease the cost and increase the efficacy of rhBMP-2 treatment.

RNA interference for noggin enhances the biological activity of bone morphogenetic proteins in vivo and in vitro.

Noggin is a major extracellular antagonist to bone morphogenetic proteins (BMPs) which binds to BMPs and blocks binding of them to BMP-specific receptors and negatively regulates BMP-induced osteoblastic differentiation. In this study, we investigated the effect of noggin silencing by transfection of small interfering RNA (siRNA) on BMP-induced osteoblastic differentiation in vitro and ectopic bone formation in vivo induced by recombinant human BMP-2 (rhBMP-2). Noggin mRNA expression was up-regulated in response to rhBMP-2 in C2C12 cells, a myoblastic cell line, in dose- and time-dependent fashion as determined by real-time RT-PCR assay. Silencing of noggin expression by transfection of noggin siRNA suppressed BMP-stimulated noggin expression, resulting in acceleration of BMP-induced osteoblastic differentiation. For in vivo noggin silencing, siRNA was injected locally into back muscles and transfected into local cells by electroporation, where rhBMP-2-retaining (5 microg) collagen disks had been surgically placed. The implants were harvested at 2 weeks after surgery from experimental and control group mice and analyzed by radiological and histological methods. As a result, bone mineral content of ossicles ectopically induced by rhBMP-2 was significantly increased by silencing of noggin. Our findings suggest that silencing of noggin enhances the osteoblastic differentiation of BMP-responding cells in vitro and new bone formation induced by rhBMP-2 in vivo by eliminating negative regulation of the effects of BMP. RNA interference might be useful for intensifying the effects of BMP in promoting new bone (callus) formation in repair of damaged bone.

A case report of surgical debulking for a huge mass of elephantiasis neuromatosa.

Achievement of a safe outcome for an extensive mass with hypervascularity in the extremities requires a surgical team skilled in musculoskeletal oncology. We report debulking surgery for a huge mass of elephantiasis neuromatosa in the right leg of a 56-year old man using the novel Ligasure® vessel sealing system.

Clinical problems after initial unplanned resection of sarcoma.

OBJECTIVE: Unplanned resection of a sarcoma is often chosen in the early phase by general physicians without any imaging scrutiny. The present study aimed to highlight the clinical problems associated with unplanned resection of sarcomas. METHODS: Thirty-eight patients who underwent unplanned resection of a sarcoma and additional treatment were examined. The definite histological grading was high in 31 patients and low in 7 patients. RESULTS: The tumors were located in the depth of the subfascia in 13 patients. The maximal tumor sizes exceeded 5 cm in 16 patients. Preoperative MRI was only performed in six patients. The previous surgical margins were intralesional in 20 patients and marginal in 18 patients. Inappropriate transverse skin incisions were found in 21 patients. Extensive hematoma at the initial surgical site was seen in five patients. Thirty-three patients accepted additional wide resection due to the insufficient removal of malignancy. During an average follow-up of 42.7 months, seven patients died of lung and brain metastases. CONCLUSIONS: On excision of any soft tissue tumor, surgeons should be aware of the potential risk for erroneous management of malignancy. If not, careless surgery may render the treatment protocol complicated and require excessive additional tissue resection with poor function and prognosis. Appropriate salvage treatment may have a significant role to play after unplanned resection of the sarcoma.

A 60-y-old chylomicronemia patient homozygous for missense mutation (G188E) in the lipoprotein lipase gene showed no accelerated atherosclerosis.

BACKGROUND: Familial lipoprotein lipase (LPL) deficiency is a rare autosomal recessive disorder caused by mutations in the LPL gene. Patients with LPL deficiency have chylomicronemia; however, whether they develop accelerated atherosclerosis remains unclear. METHODS: We investigated clinical and mutational characteristics of a 60-y-old Japanese patient with chylomicronemia. RESULTS: The patient's fasting plasma triglyceride levels were >9.0 mmol/l. In postheparin plasma, one fifth of the normal LPL protein mass was present; however, LPL activity was undetectable. Molecular analysis of the LPL gene showed the patient to be a homozygote of missense mutation replacing glycine with glutamine at codon 188 (G188E), which had been known to produce mutant LPL protein lacking lipolytic activity. Ultrasonographic examination of the patient's carotid and femoral arteries showed no accelerated atherosclerosis. Moreover, 64-slice mechanical multidetector-row computer tomography (MDCT) angiography did not detect any accelerated atherosclerotic lesions in the patient's coronary arteries. The patient had none of the risk factors such as smoking, hypertension, and diabetes. CONCLUSIONS: Our case suggests that accelerated atherosclerosis may not develop in patients with LPL deficiency, when they have no risk factors.

Effects of 22-oxacalcitriol and calcitriol on PTH secretion and bone mineral metabolism in a crossover trial in hemodialysis patients with secondary hyperparathyroidism.

The purpose of this crossover comparison study is to elucidate the differences between the effects of a novel calcitriol analog, 22-oxacalcitriol, and calcitriol on parathyroid hormone (PTH) and bone mineral metabolism in hemodialysis patients with secondary hyperparathyroidism (SHPT). Twenty-three patients with moderate to severe SHPT were included in a random 2 x 2 crossover trial with two vitamin D analogs (12 weeks for each treatment). Two patients withdrew during the run-in period for personal reasons. Serum electrolyte, bone metabolic marker, intact PTH (iPTH) and whole PTH (wPTH) levels were measured periodically. The primary endpoint measure was a decrease in serum iPTH level, and the secondary outcome measures included changes in serum calcium (Ca), phosphate (P), and metabolic bone marker levels. Both treatments decreased iPTH and wPTH levels by similar degrees. Serum Ca, P, and Ca x P product levels at the end of each treatment were comparable and the frequencies of hypercalcemia and hyperphosphatemia were also similar during each treatment period. 22-Oxacalcitriol significantly decreased the levels of bone metabolic markers, namely, bone-specific alkaline phosphate, intact osteocalcin, pyridinoline, and cross-linked N-telopeptide of type I collagen, after a 12-week treatment. In contrast, calcitriol did not change any of the levels of bone metabolic markers. The present study showed that 22-oxacalcitriol is equally effective for PTH suppression, and Ca and P metabolism. In addition, 22-oxacalcitriol might have putative actions on bone remodeling independent of its PTH suppression. Further study is necessary to confirm the effects of 22-oxacalcitriol on bone metabolism in SHPT.

Repair of bone defects in revision hip arthroplasty by implantation of a new bone-inducing material comprised of recombinant human BMP-2, Beta-TCP powder, and a biodegradable polymer: an experimental study in dogs.

A recombinant BMP-2-retaining putty-form implant in combination with a hip prosthesis was used to reconstruct a canine hip joint with defects similar to those encountered in revision total hip arthroplasty (THA). The bone defects were made by resecting the medial half of the proximal femur and the superior acetabular bone with inner iliac wall perforation in 10 dogs. In five dogs, hip prostheses were implanted with the putty material consisting of a synthetic polymer (poly D,L-lactic acid-polyethylene glycol block copolymer), beta-tricalcium phosphate powder, and recombinant human BMP-2 in each defect (BMP/Polymer/TCP group). In the remaining five dogs, the same material without rhBMP-2 (control group) was implanted. In the BMP/Polymer/TCP group, new radiopaque shadows began to appear 4 weeks after surgery at the defects around the hip prostheses on both the femoral and acetabular sides. At 12 weeks, the defects were completely filled with new bone in contact with the prosthesis. On histology, the rhBMP-2/Polymer/beta-TCP composite putty implants had been completely resorbed and replaced by new bone. Repair of the bone defects was not seen in the control group. The ability of this material to restore bone effectively eliminates the dependency on bone grafts of autogeneic or allogeneic origin for revision hip arthroplasty and thus opens up a potential new treatment approach in hip cases requiring this type of surgery.

Reconstruction of bone defects using rhBMP-2-coated devitalized bone.

Massive bone defects often are caused by radical resection of bone tumors. Reconstruction of the defect by reimplantation of the resected bone segment after it has been devitalized is advantageous because of its ability to match the size of the defect. In addition, this technique carries a low risk for local recurrence of the tumor, avoids immunologic reaction, and is low in cost. However, limited osteogenic potential of the devitalized bone often leads to delayed union, gradual resorption, and mechanical weakness of the reimplanted segment. We applied rhBMP-2 in a biodegradable polymer delivery system to the devitalized bone. Middiaphyseal bone defects were created by resection in rat femurs. The resected segments were autoclaved at 135 degrees C for 15 minutes, coated with a rhBMP-2-retaining paste on the outer surface, and then reimplanted into the defects. In a brief time, newly formed bone was seen on the surface of the devitalized bone. After 12 weeks, a solid bone mass encasing the dead bone segments was consistently formed and abundant new bone formation was visible in the segments as they were remodeled. The amount of new bone formed could be regulated by the amount of the rhBMP-2-retaining paste applied to the bone segments. This method presents a new approach for the reconstruction of bone defects.

Cystic beta2-microglobulin amyloidoma in a patient on long-term hemodialysis.

We report a patient with beta2 microglobulin amyloidosis (beta2M) in whom cystic tumors were seen in the bilateral axillary region. The patient was a 68-year-old woman who had been on hemodialysis for more than 20 years because of IgA nephropathy. Computed tomography-guided biopsy was performed to confirm the diagnosis. Congo red staining, beta2M immunohistochemistry, and electron microscopy examination of the biopsied sample showed extended beta2M deposits in the cystic tumor. beta2M-related amyloidosis in patients with long-term dialysis commonly presents as osteoarticular disease, although a soft-tissue pseudotumor, known as amyloidoma, has been reported. This is the first report in the English-language literature of amyloidosis presenting as bilateral axillary cystic tumors.

Do vascular lesions and related risk factors influence responsiveness to donepezil chloride in patients with Alzheimer's disease?

The purpose was to identify vascular influences on the responsiveness to donepezil chloride. The study included 50 untreated probable Alzheimer's disease patients with the Modified Hachinski Ischemic Score <4. We assessed baseline cognitive status using the Revised Hasegawa Dementia Scale (HDS-R), Clinical Dementia Rating (CDR) and the clock drawing test (CDT). The response to 5 mg of donepezil was monitored by the CDT for 12 months. Patients were classified as true responders (TR), unchanged (UC) and non-responders according to changes on the CDT in response to treatment. High HDS-R scores, low CDT scores, low CDR and presence of hypertension (HBP) and periventricular hyperintensities (PVH) predicted a TR- or UC-type outcome. Aggravation of executive function by HBP and/or PVH and its improvement by donepezil may have been detected by the CDT.

[Prophylaxis and treatment of adynamic bone].

The pathogenesis of adynamic bone disease (ABD) attributes to calcium overload, active vitamin D (VD) metabolism, increase in inactive PTH (parathyroid hormone) fragments, or derangement of bone metabolism regulation factors. In particular, increased Ca overload plays a critical role in the development of ABD. Thus, alleviated Ca load by sevelamer hydrochloride and appropriate VD administration could be effective on not only prevention, and also treatment of ABD.

[Controversy of treatment for advanced colorectal cancer--intermedisine].

Until recently, few chemotherapy options were available to treat metastatic colorectalcancer. For years, the standard chemotherapy has been a Fluorouracil (5-FU) alone of 5-FU with leucovorin (LV) modulation. The newer cytotoxic drugs irinotecan (CPT-11) and oxaliplatin (L-OHP) has generated further improvement in survival. Additionally, improvement in convenience of drug administration has been achieved with the development of oral fluoropynmidines. In randomized trials, oral fluoropyrimidines were equally effective to bolus 5-FU and LV. Recently completed or ongoing clinical trials to study novel targeting agents have initiated a new generation of drug development such as angiogenesis inhibitors and epidermal growth factor inhibitors. Randomized trials will determine the impact of these newer agents on survival and quality of life.

[Management of nausea, vomiting and anorexia due to anticancer agents].

This report outlines measures for controlling nausea, vomiting, and anorexia caused by anticancer agents. Combination therapy with a 5-hydroxytryptamine (5-HT3) receptor antagonist and a steroid preparation is effective for controlling acute vomiting. In the chronic stage, however, the response to 5-HT3 receptor antagonists is less marked, so a steroid preparation is used as the major treatment in combination with a 5-HT3-receptor antagonist or metoclopramide. The antiemetic effect of recently developed tachykinin NK-1 (NK-1)-receptor antagonists has been shown to be additive to that of existing treatments for acute and chronic symptoms, especially chronic nausea/vomiting. Steroid preparations have been shown to improve anorexia, while medroxyprogesterone acetate (MPA: a synthetic progesterone) has been reported to improve anorexia and promote weight gain.

[Hypersensitivity reactions to cancer chemotherapeutic agents].

Although hypersensitivity reactions to the anticancer drug are rare, since the reactions occasionally are clinical problems enough, that measure is important. The backgrounds (the etiologic mechanisms, the frequency, and etc) differ by each, therefore the knowledge for each medicine is required for measures including prediction and the prevention. This paper reviews the sensitivity reactions of various anticancer drugs (especially, paclitaxel, cisplatin and carboplatin) also including the molecular targeting drugs (trastuzumab, rituximab).

[Mucositis].

Mucositis is a significant dose-limiting factor associated with cancer chemotherapy and radiotherapy. For exact management, an early diagnosis and precise evaluation are surely required. A basis of the prevention and care of stomatitis is maintaining cleanliness and moisture in the mouth. The medical treatment plans of oral mucositis are a measure against infection, and prevention against symptoms, and are restoration of a tissue damage, and treatment to sharp pain. However, there is no still established prevention method. As for the present condition, in the clinical practice, there are many portions depending on experiential knowledge. In this paper, it outlined including Empiric therapy about measures of oral mucositis.

[Chemotherapy of gastric cancer--a review of clinical trials in Japan].

This review focused on the clinical trials in patients with gastric cancer in Japan. Oral fluoropyrimidines have been extensively used in Japan. Through the decades, these oral fluoropyrimidines have been examined in a variety of combinations. Most of the reports are about randomized phase II trials using overall response rate as a primary endpoint, and are a few phase III trials were conducted. S-1 (TS-1), a novel oral fluoropyrimidine, has demonstrated promising activity in phase II trials. Ongoing phase III trials on S-1 would be defining this as standard chemotherapy for metastatic gastric cancer.