The remineralization of the vertebral metastases of breast carcinoma after radiotherapy

BACKGROUND: The early detection of effects caused by radiotherapy on bone mineralisation has influence on clinical treatment. Usually the follow-up is done by conventional X-rays, presenting a loss of calcification of at least 30%. Quantitative CT-measurements are much more sensitive. PATIENTS AND METHODS: In a prospective study we evaluated the CT-scans of 14 patients with multiple vertebral metastases of mamma carcinoma. Our patients underwent SEQCT (one 10 mm slice in each affected vertebral body, 80 kV, 250 mAs) before and immediately after radiation therapy (total dose 30 Gy to 36 Gy) followed by further examinations 6 weeks and 3 months later. RESULTS: While there is no significant change in increased BMD (bone mineral density) of osteosclerotic and decreased BMD of osteolytic metastases just after therapy, the following examinations present an increase of BMD in osteolytic metastases 6 weeks after therapy more distinct 3 months after. Osteosclerotic metastases show a decline in bone density. In mixed metastases is no significant change while normal bone lying in the irradiation field demineralizes. Additive chemotherapy is very important especially for mineralisation of lytic metastases. Referring to mixed metastasis in one vertebral body we suggest a separate evaluation of the left and right side. CONCLUSION: Mineralizing effects of radiation therapy depend on the characteristics of the metastases. Supported by QCT histopathological change can be documented and exactly demonstrated to the clinician.     

Transarterial immuno-embolization therapy in patients with hepatocellular carcinoma

Surgical resection, transcatheter arterial embolization (TAE) and percutaneous ethanol injection therapy (PEIT) are effective for hepatocellular carcinoma (HCC), but the recurrence rate is high. We have devised a new therapy of transarterial immuno-embolization (TIE) with OK-432, fibrinogen and thrombin, and 2 cases are reported. Case 1: A 78-year-old Japanese male with HCC (diameter, 4 cm in subsegment 5) received TIE. The tumor size was markedly decreased, and the patient survived for more than 3 years without recurrence. Case 2: A 61-year-old Japanese male with HCC (diameter, 4.5 cm in segment 5) received hepatic subsegmentectomy following TIE. Histological examination of resected specimens following TIE showed massive infiltration of mononuclear cells in the main tumor. Tumor recurrence had developed three times thereafter, but was effectively treated by TIE. TIE may be an effective therapy for HCC.     

OK-432 therapy for lymphangiomas

OBJECTIVE: To assess the efficacy of OK-432 sclerotherapy in the treatment of lymphangiomas. DESIGN: Nonrandomized trial; follow-up, 4 to 29 months. SETTING: Academic tertiary referral medical center. PATIENTS: Six children with presumed lymphangiomas; age range at initial treatment, 1 month to 7 years 10 months. INTERVENTION: Fluoroscopically guided cyst aspiration, cystography, and injection of OK-432. OUTCOME MEASURES: Clinical and radiographic comparisons before and after therapy. RESULTS: Complete response in 2 macrocystic lymphangiomas; no response in 3 microcystic lymphangiomas; and no response in 1 venous malformation. CONCLUSION: OK-432 sclerotherapy may be effective treatment for macrocystic lymphangiomas.     

Postoperative chemotherapy including intraperitoneal and intradermal administration of the streptococcal preparation OK-432 for patients with gastric cancer and peritoneal dissemination: a prospective randomized study

We studied the effects on survival time of postoperative immuno-chemotherapy, including the streptococcal preparation OK-432, in patients with gastric cancer and synchronous peritoneal dissemination. The patients were prospectively randomized and a valid statistical assessment could be made for 109. Patients randomized to group B received therapy that is widely used in Japan to treat patients with gastric cancer: mitomycin C (MMC) and UFT, a combination of tegafur and uracil in a molar ratio of 1:4, for 1 year. Patients randomized to group A received the same drugs as were given to group B patients plus OK-432 i.p. for 7 days, beginning on postoperative day 0, and OK-432 by intradermal injection for 1 year, at 2-week intervals. There were no differences between the two groups in any known prognostic factor or in the dose of any drug administered except for OK-432. There was no difference in the toxicity rate between the groups. In this negative trial, there was no improvement in survival time with the addition of OK-432 to MMC and UFT for patients with gastric cancer and peritoneal dissemination.     

Enrofloxacin-theophylline interaction: influence of enrofloxacin on theophylline steady-state pharmacokinetics in the beagle dog

We investigated the changes in cellular components and neutrophil chemotactic factors in pleural fluid from 19 lung cancer patients who received intrapleural injection of OK-432 to treat malignant pleurisy. Not only neutrophil chemotactic activity (NCA) but also neutrophil count and percentage were increased significantly at 6 hours after OK-432 injection. The neutrophil count was significantly correlated with NCA level. The levels of C5a and IL-8 in pleural fluid were increased significantly after OK-432 injection. The increased IL-8 level was associated with a increase of both NCA and neutrophil count. OK-432 treatment also induced a marked increase of IL-1 beta and IL-6 in pleural fluid. Thus, intrapleural injection of OK-432 induced production of neutrophil chemotactic factors (IL-8 and C5a) and cytokines (IL-1 beta and IL-6), which eventually attracted neutrophils into the pleural space. These observations suggest that neutrophil migration mediated by these factors and cytokines may contribute to the sclerosing effects of OK-432 treatment.     

A case report: multiple liver metastasis of gastric cancer responding to intraarterial infusion of MTX and 5-FU

In a 63-year-old male patient with gastric cancer having multiple liver metastases, the metastatic lesions responded well to postoperative staggered intraarterial infusion therapy with MTX and 5-FU. The intraarterial infusion therapy was administered once a week. A total of 5 courses of this therapy produced marked regression of liver metastases and remarkable necrosis. The effect was thus rated as PR. The patient is healthy and has been successfully rehabilitated. His dose is oral 5-FU (200 mg x 2).     

Prospective study of bacteremia rate after elastic band ligation and sclerotherapy of esophageal varices in patients with hepatosplenic schistosomiasis

Bone scintigraphy was performed in a 69-year-old male patient with adult T-cell leukemia suffering from right lower limb pain. Numerous sites of increased uptake were seen in the skull, left clavicle, bilateral humeri, bilateral radii and right femur and tibia. Bone radiographs showed multiple osteolytic lesions, most of which corresponded to the abnormal deposits on the bone scans with 740 MBq of 99mTc-hydroxymethylene diphosphonate. This pattern is rarely reported, but bone involvement of adult T-cell leukemia is not uncommon. Bone involvement was remarkable on the appendicular skeleton when compared with common metastatic bone tumors. Bone scintigraphy may be useful in detecting bone involvement in adult T-cell leukemia.     

Emergency cervical cerclage after 20 weeks'' gestation: a retrospective study of 6 years'' practice in 34 cases

Bone metastases causing pain syndromes and imminent pathologic fractures are among the main reasons for radiotherapy in patients suffering from malignant tumors. The indication is much influenced by the radiologic findings. Surgical methods are to be chosen in the first place in cases of pathologic fractures or patients with a high risk of such fractures. Different authors recommend various therapeutic regimens. Effective pain control can be achieved with one single dose of radiation. Doses of 6 to 40 Gy applied in one to 19 days are also efficient. Side effects, especially nausea and vomiting occur in 25% of cases; this number rises to 50% in cases of half body irradiation. Visible changes of bone mineral density may be noticed about 6 weeks after termination of radiotherapy. About 70% of osteolytic metastases show progressive sclerosis whereas osteosclerotic lesions may show both increase or decline of bone mass. In spite many years of experience the optimal strategy for radiation therapy of bone metastasis has not been defined; further studies are needed.     

Transarterial immuno-chemotherapy including adoptive transfer of autologous cultured lymphocytes for stage IV breast cancer patients with locally-advanced tumor

Immuno-chemotherapy via a catheter in the subclavian artery using sequential treatment with OK-432, chemotherapeutic agents (ADM, 5-FU), and cultured autologous lymphocytes, was performed for 9 Stage IV breast cancer patients with locally-advanced primary tumor. Tumor reduction of more than 50% was observed in 8 patients including 4 whose breast tumors had disappeared. Among 11 evaluable distant metastatic lesions, 7 (1 pleural effusion, 2 lung, 2 liver, 2 bone metastases) regressed after local immunotherapy of breast or additional regional immunotherapy (1 lung, 1 liver, 1 pleural effusion). Median survival time to date is 56 months. Five patients are currently alive, although 3 of them did not undergo mastectomy. Local immuno-chemotherapy may be useful because (a) toxicity is limited, (b) low doses of anti-cancer agents during the therapy (median dose of ADM, 60 mg) do not limit subsequent systemic chemotherapy, and (c) distant metastases often regress concomitantly with the primary lesions.     

Double mitral valve orifice. Two-dimensional and Doppler echocardiographic diagnosis

A thirty three-year-old male complaining of vomiting was diagnosed as having type 3 advanced gastric cancer of upper stomach and multiple liver metastasis, and had undergone total gastrectomy. The conclusive stage was P2H2n4se stage IVb. Intraoperatively, ethanol injection was performed for the liver metastasis under ultrasonography, and CDDP 100 mg was injected into the intra-abdominal cavity. Postoperative adjuvant therapy was added using oral fluorouracil and OK-432. Then we utilized FP chemotherapy (consisting of 5-FU and cisplatin) and radiotherapy for the bone metastasis. The patient survived 4 years and 4 months with good quality of life.     

Malignant bone pain

Bone pain is one of the most frequent causes of pain in patients with cancer, and the levels of metastases and bone pain are not directly correlated. Nociceptors in the periosteum are probably stimulated by halisteresis or by inflammatory oedema leading to an increase in the intraosseous pressure. Some authors believe that the nociceptors in bone are mediated via intraosseous mechanoreceptors in the bone-matrix. At a low pain level the initial treatment is acetylsalicylic acid, paracetamol or other nonsteroidal antiinflammatory drugs. At increasing pain level initial doses of oral opioids are added. In severe bone pain, where conventional therapy seems difficult, opioids are administered by invasive techniques. In localised bone pain palliative radiation is the first treatment of choice. Corticosteroids induce an analgetic effect indirectly by reducing the inflammatory oedema, inhibiting the synthesis of prostaglandins and may inhibit excitatory nerve fibres. Endocrine treatment, calcitonin and biophosphonates have shown a documented pain-relieving effect in patients with disseminated breast and prostate cancer. Chemotherapy has shown a pain-relieving effect in patients with disseminated breast cancer, surgical intervention is used in stabilizing osteolytic bones before or after a fracture ensuring a reasonable relief of pain.     

Imaging of huge lingual thyroid gland with goitre

One year after a nonspecific trauma and with a history of pain of four weeks only, an osteoid osteoma of the first phalanx of the left thumb was diagnosed in a 31-year-old man. The radiologic appearance as well as a bone scan were suggestive for an osteoid osteoma. The diagnosis was confirmed histologically after resection of the tumor. As indicated in the literature, osteoid osteoma of the hand is relatively rare. The symptoms and radiologic features (osteolytic nidus and sclerosis) of osteoid osteomas are independent of the tumor location. Surgery with resection of the nidus is the only known curative therapy. The etiological role of trauma is discussed and a review of the literature is done with 15 other cases of posttraumatic osteoid osteoma having been reported.     

Diabetes mellitus increases the severity of anemia in non-dialyzed patients with renal failure

Therapeutic means for patients with disseminated painful bone metastases in breast cancer are strongly limited. There is a big need of an effective and well tolerated therapy. The aim of this study was to evaluate the efficacy of rhenium-186 HEDP for pain palliation in patients with bone metastases in breast cancer. 17 patients with painful bone metastases taking analgesics received one or more injections of 1295 MB9 rhenium-186 HEDP. In 59% of the patients the therapy resulted in a significant reduction of pain. The duration of pain relief partially hold on up to nine weeks. The main side effects of therapy were a short decrease of platelets and leucocytes and an increase of pain for 1-2 days. As conclusion we found out that therapy with rhenium-186 HEDP can be used complementarily to analgesic therapy and radiation in patients with painful disseminated bone metastases in breast cancer.     

Streptococcal preparation OK-432 is a potent inducer of IL-12 and a T helper cell 1 dominant state

Streptococcal preparation OK-432 is a bacterial immunopotentiator extensively used in Japan for adjuvant cancer therapy. Using a C57BL/6 mouse model, OK-432 was found to induce multiple cytokines including the Th1 polarizing cytokine IL-12. Expression of IL-12 protein by murine splenocytes was restricted to macrophages and B cells and led to high levels of IFN-gamma production from both CD4+ and CD8+ T cells. Of the Th2 cytokines IL-4 and IL-10, only IL-10 protein was detected and originated primarily from the adherent cell population. Its expression was delayed relative to IL-12. A similar pattern of cytokine induction was observed from human PBMCs. OK-432-driven IFN-gamma production was inhibited by anti-IL-12 Ab, anti-IL-2 Ab, anti-TNF-alpha Ab, and anti-IL-2R alpha Ab, suggesting that IFN-gamma production from Th1 cells is induced by the cooperation action of these cytokines through the IL-2R alpha pathway. When compared with another widely used immunopotentiator bacillus Calmette-Guérin (BCG), OK-432 was a stronger IL-12 and IFN-gamma inducer. Furthermore, the mechanism of IFN-gamma induction by OK-432 differed from BCG in that coincident granulocyte-macrophage CSF and IL-1 expression played little to no role. These results suggest that OK-432 is a potent multicytokine inducer, specifically a strong inducer of IL-12, and that OK-432 may exert its antitumor effect by promoting a Th1-dominant state.     

Effects of OK-432 (picibanil) on the estrogen receptors of MCF-7 cells and potentiation of antiproliferative effects of tamoxifen in combination with OK-432

OK-432 (picibanil), a streptococcal preparation, has a strong biological response modifier (BRM) function and is expected to produce clinical improvement and prolongation of survival in treated cancer patients in Japan. We were interested in whether OK-432 augments estrogen receptor (ER) levels in breast cancer. To investigate the effect of the BRMs on cellular growth and the characteristics of ER and progesterone receptors (PgR) in the human breast cancer cell line MCF-7, we used OK-432, Krestin (PSK), a protein-bound polysaccharide extracted from Coriolus versicolor, and lentinan, a fungal branched (1...3)-beta-D-glycan. OK432 and PSK dose dependently inhibited DNA synthesis of MCF-7 cells, and the 50% inhibitory concentrations of OK-432 and PSK were 1.2 KE (klinische Einheit, clinical unit)/ml and 200 micrograms/ml, respectively. Lentinan showed no direct anticancer effect in vitro. We found that OK-432 induced a 2-fold increase in ER levels in MCF-7 cells at 0.005 KE/ml, but not in PgR. Lentinan and low-dose PSK did not change ER or PgR levels, but high-dose PSK decreased ER and PgR. We also studied the combined effect of OK-432 and antiestrogens, tamoxifen (TAM) and DP-TAT-59. The combined treatment with OK-432 and TAM showed an additive inhibitory effect on MCF-7 cells. These results suggest that OK-432 may augment the therapeutic effect of TAM in breast cancer.     

Metastatic malignant chondroblastoma

A case of malignant chondroblastoma with metastases is reported. The patient initially presented with a lytic lesion in his left pubic ramus. He was treated with curettage, but the lesion recurred 3 years later. After repeated curettage, radiation therapy, and the late development of multiple bone and soft-tissue metastases, he succumbed to his disease 13 years after diagnosis. The surgical pathology from each of his several procedures was reviewed. Although no definite malignant transformation was apparent, a metastatic deposit curetted 3 months prior to death showed some increase in mitotic activity. Flow cytometry of specimens from the patient's first local recurrence and a late distant metastasis was performed and revealed the interval development of a minor aneuploid peak between the two samples. This fatal chondroblastoma is the only one in our series of 80 patients treated over the past 25 years.     

Multidrug-resistant recurrent breast cancer which responded to medroxyprogesterone acetate showing a remarkable improvement in the quality of life: report of a case and the role of team medical care

We herein report the case of a patient with recurrent breast cancer who showed a remarkable improvement in her quality of life (QOL) as a result of a good response to medroxyprogesterone acetate (MPA). A 43-year-old Japanese woman developed bone metastases 3 years after surgery. Subsequent radiotherapy and chemoendocrine therapy with CAF (cyclophosphamide, adriamycin, 5-fluorouracil) and tamoxifen all failed, and she could not sit up because of bone metastases. The performance status (PS) on admission was grade 4. After admission, delirium accompanied with sensory and visual hallucination caused by intense anxiety occurred, and a continuous consultation by psychiatrists was necessary. MPA treatment at the dose of 1200 mg/day alleviated the bone pain, thus improving her PS to grade 1. Her appetite also improved, while her mental state stabilized. A bone scintigram revealed an improvement of bone metastases, and the tumor markers also returned to normal values. The patient thus showed a pronounced improvement in her QOL due to both MPA treatment and team medical care. The role of the medical staff as well as the importance of their cooperation in achieving an improvement in the QOL of cancer patients is also discussed.     

Respiratory depression following administration of intrathecal bupivacaine to an opioid-dependent patient

OBJECTIVE: To document two cases of respiratory depression in patients receiving morphine once the stimulating effect of pain on respiration was removed by bupivacaine. CASE SUMMARIES: Case 1: A 72-year-old 84-kg white man with cancer of the bladder and bone metastases had intense back and leg pain that was treated with intrathecal morphine for 6 months at an increasing dosage up to 10 mg twice daily. The intrathecal route was avoided for 4 days because of a suspected local infection at the site of the intrathecal catheter. During this 4-day period the patient received extended-release morphine and subcutaneous morphine daily. When the intrathecal route was used again, he received an identical dose of morphine plus bupivacaine and epinephrine. Ten minutes after the injection, fatal respiratory distress occurred. Case 2: A 92-year-old white woman was admitted for revascularization of arteritis on her left leg. To treat a painful sacrum and heel bedsores, she received extended-release oral morphine for 8 days. Induction of the intrathecal anesthesia was performed with bupivacaine. After 10 minutes, the patient became subcomatose, with miosis and apnea. Intravenous naloxone restored spontaneous respiration and normal consciousness. CONCLUSIONS: Pain is a physiologic antagonist of the respiratory depressant effects of opioid analgesics. By reducing pain stimulation, bupivacaine may make patients more susceptible to opioid respiratory depression. Such situations require titration of bupivacaine and other analgesics as well as increased monitoring of the patient.     

Bone metastases responsive to pamidronate therapy in breast cancer

A 66-year-old woman with locally advanced and metastatic breast carcinoma received combination chemotherapy, which comprised mitomycinC (total 84 mg) and anthracyclines (total : epirubicin 350 mg and pirarubicin 450 mg). She had been alive without tumor progression for more than one year thanks to these chemotherapies. Nevertheless, she thereafter complained of severe bone pain due to progression of bone disease. Since morphine administration could not give her sufficient pain relief, we tried to treat her bone pain with pamidronate in a dose of 30 mg weekly or biweekly. The pamidronate markedly relieved her bone pain and improved osteolytic bone lesions. In conclusion, pamidronate therapy can be a promising therapeutic modality for bone-derived pain in terminal patients.