A comparative effectiveness pilot study of teriparatide for medication-related osteonecrosis of the jaw: daily versus weekly administration.

We studied the effectiveness of teriparatide (TPTD) for treating medication-related osteonecrosis of the jaw (MRONJ) in patients with osteoporosis and examined differences in the clinical outcomes following daily versus weekly TPTD. The outcomes were significantly improved in the entire patient series and the daily group. PURPOSE: Teriparatide (TPTD) treatment for Stage II-III medication-related osteonecrosis of the jaw (MRONJ) in osteoporotic patients has yielded promising results in uncontrolled studies. The daily administration and the weekly administration of TPTD have been reported to improve outcomes in MRONJ. Herein, we sought to identify differences in the clinical outcomes of MRONJ patients treated with daily TPTD versus weekly TPTD. METHODS: We enrolled 13 patients and randomly assigned them to receive either of two treatments: 1×/week 56.5-µg TPTD injection for 6 months (weekly group; n = 6 patients after 1 dropout), or 20-µg TPTD injection daily for 6 months (daily group; n = 6 patients). Patients in both groups received conventional therapy plus intensive antibiotic therapy as necessary. We compared the changes in the patients' clinical stage of MRONJ, bone metabolism, percentage of bone formation, and bone turnover markers between the weekly and daily groups. RESULTS: TPTD treatment with MRONJ led to partial remission or complete remission in 5 daily-group patients and 3 weekly-group patients. The MRONJ stage was significantly improved from baseline to 6 months of treatment in the entire series of 12 patients (p = 0.008); the weekly group did not show significant improvement, but the daily group did (p = 0.01). CONCLUSIONS: This study provides the first comparison of clinical outcomes between MRONJ patients who received daily or weekly TPTD injections. Six months of treatment with TPTD realized a significant improvement of MRONJ stage in both the entire patient series and the daily group.

Comparison of antianginal activity of nicorandil, propranolol and diltiazem with reference to the antianginal mechanism.

Nicorandil was compared with placebo, propranolol and low and high doses of diltiazem therapy in 12 patients with chronic stable angina pectoris to elucidate its antianginal mechanism. A computer-assisted treadmill exercise test was performed after administration of either placebo, 30 mg of nicorandil, 40 mg of propranolol, or low-dose 60 and high-dose 120 mg of diltiazem. Exercise duration and time to the onset of ischemia were significantly increased after each drug administration and there was no significant difference in the percent increase in exercise duration between nicorandil (44 +/- 7%), propranolol (47 +/- 11%) and high-dose diltiazem (39 +/- 5%) compared with placebo. Nicorandil increased exercise duration in patients with 1-vessel disease more effectively (7.5 +/- 0.7 minutes, p less than 0.05) than either propranolol or low-dose diltiazem (6.7 +/- 0.7, 6.1 +/- 0.9 minutes, respectively). The decrease in blood pressure obtained with nicorandil was approximately the same as that with diltiazem. Nicorandil increased exercise duration associated with higher peak double product compared with low-dose diltiazem. In contrast, high-dose diltiazem increased exercise duration at the same double product as low-dose diltiazem. Propranolol increased exercise duration at a lower level of peak double product. Because our previous study demonstrated that low-dose diltiazem yielded a plasma concentration high enough to reduce coronary tone, it appears unlikely that nicorandil will reduce coronary tone further and subsequently increased coronary reserve. Therefore, left ventricular preload reduction may be the mechanism responsible for higher values of double product obtained with nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)

A long-term study of implanted artificial hydroxyapatite particles surrounding the carotid artery in adult dogs.

In this long-term study, we implanted HAP into adult dogs using a silicone chamber attached to the carotid artery to clarify tissue reaction to HAP implantation over a long period. We designed chambers and both hemispheres of the chambers were filled with HAP particles, and were placed around both carotid arteries of seven adult dogs. The implants were removed after 150, 300, 380 days, and histological and ultrastructual examination was undertaken. We observed bone-like tissue which was formed where HAP particles were implanted. Immunohistochemical findings showed that osteocalcin and osteonectin were as positive in the bone-like tissue as in normal bone. This study suggests that biological factors from the arterial wall might play an important role in new bone-like tissue forming, and that HAP has a strong osteoconductive ability even at heterogeneous sites.

Comparison of 201 Tl- with 67 Ga single photon emission tomography in the diagnosis of head and neck cancer recurrence.

The purpose of this study was to evaluate the usefulness of 201Tl single photon emission tomography (SPET) in comparison with 67Ga SPET for distinguishing recurrent tumours in patients previously treated for head and neck cancer. A total of 37 patients with suspicion of recurrent cancer were investigated. SPET images with 201Tl were acquired 10min (early) and 3h (delayed) and SPET images with 67Ga were acquired 72h, after injection. The visual and semiquantitative (T/N ratio) analysis were performed. On visual analysis, results from early 201Tl SPET were the same as those from delayed 201Tl SPET. The sensitivity, specificity and accuracy of the diagnosis of local recurrence using 201Tl SPET were all 100%. The three values using 201Tl SPET for neck lymph node metastases were 73%, 100% and 91%. The corresponding values using 67Ga SPET for local recurrence were 57%, 100% and 89%, respectively, and those using 67Ga SPET for neck lymph node metastases 55%, 100% and 84%, respectively. In the semiquantitative analysis, there was a statistically higher T/N ratio obtained using 201Tl when compared with 67Ga. 201Tl early SPET, especially, has the potential to replace 67Ga SPET in the follow-up of patients with head and neck cancer.

[A case of miliary tuberculosis (miliary TB) accompanied with adult respiratory distress syndrome (ARDS) in a patient with Cushing's syndrome].

A 74-year-old housewife was admitted to the hospital with complaints of high fever and general fatigue. The physical examinations on admission showed no particular findings except for mild hepatomegaly, but laboratory findings showed severe liver dysfunction, active inflammation and negative tuberculine test. On the 4th day, she suddenly complained of severe respiratory distress. A chest X-ray film demonstrated surprising changes in comparison with that taken on admission. On suspicion of adult respiratory distress syndrome (ARDS) associated with military tuberculosis (Miliary TB), administration of Methylpredonisolone (1000 mg a day for 3 days) in addition to antituberculous drugs was immediately started. With this therapy she was recovered from such ill condition, but the general exhaustion and slight fever continued. We suspected that her condition might be due to adrenocortical involvement of Miliary TB and hormonal examinations were performed. Unexpectedly, Cushing's syndrome was suspected on the basis of the following; high level of plasma cortisol without normal daily variation, normal ACTH level, an absent response to the Dexamethasone suppression test. Computed tomography revealed left side adrenal mass. During these examinations, renal dysfunction probably due to Miliary TB grew gradually worse and she died of renal failure on the 56th day. Necropsy revealed disseminated tuberculosis involving the lungs and the liver, but the adrenal glands were not examined.

[A case of agranulocytosis and jaundice due to cellulitis caused by insect bite].

A 58-year-old female was introduced to our hospital for admission on April 22, 1988, because of high grade fever and agranulocytosis. She had eschers on her left zygomatic region and medial region of the right thigh. The latter lesion was accompanied by cellulitis. Laboratory tests showed her WBC was 600/mm3 and T-Bil was 6.51 mg/dl. By using minocyclin, piperacillin and other drugs, her general condition and laboratory data became better in a few days. Although her skin lesions resembled "Tsutsugamushi disease", serological tests showed no evidence for Rickettia infection. So we could not rule out that another kind of insect bite may also develop such a severe clinical course. Furthermore, Staphylococcus aureus or Clostridium spp., which were detected in her pus, might have the toxic effects of inducing agranulocytosis, which might mainly be the result from the local WBC emigration, and jaundice, just like the effects of the endotoxin of Gram negative bacteria.

[Plasma beta-glucan levels in deep fungal infections accompanying hematological diseases and clinical efficacy of miconazole--a multi-institutional study].

Miconazole (400-1200 mg/day) was administered to patients with deep mycosis and suspected deep mycosis, and the efficacy evaluated. beta-Glucan was determined as the early diagnostic parameter of deep mycosis, and the relationships between the clinical efficacy of miconazole and the titers of beta-glucan were also evaluated. Forty-nine cases were evaluated, including 2 cases of deep mycosis and 47 cases of suspected deep mycosis. Most of the patients had hematological malignancies. The rate of efficacy was 100% (2/2) in deep mycosis, 66.0% (31/47) in suspected deep mycosis, and 67.3% (33/49) in total. beta-Glucan was determined in 39 cases before the administration of miconazole. The rate of beta-glucan positivity was 100% (1/1) in deep mycosis and 44.7% (17/38) in suspected deep mycosis. beta-Glucan was also determined before and after the administration of miconazole in 11 cases. The titers of beta-glucan became negative in 6 cases, decreased in 2 cases and increased in 3 cases. Thus, the beta-glucan titers became negative or decreased in 72.7% (8/11) of the cases. Efficacy of miconazole was 83.3% (5/6) in the cases in which beta-glucan became negative, 50.0% (1/2) in the cases in which the titers of beta-glucan decreased, and 33.3% (1/3) in the cases in which the titers of beta-glucan increased. Miconazole was effective in the treatment of deep mycosis, and the titers of beta-glucan correlated well with the clinical efficacy of miconazole. The determination of beta-glucan appears to be useful for the diagnosis of deep mycosis.

[Clinical study of fluconazole for systemic fungal infections with hematological disorders].

Fluconazole (FLCZ) was administered orally or intravenously to 161 patients with systemic fungal infections complicated with hematological disorders and it was possible to evaluate clinical efficacies in 109 patients. Systemic fungal infections were documented in 48 patients and suspected in 61 patients. The overall clinical efficiency rates were 43.8% (21/48) in patients with documented fungal infections, and 55.7% (34/61) in patients with suspected fungal infections. Therefore, the overall clinical efficacy rate was 50.5% (55/109). Side effects were observed in 5 patients with an incident rate of 3.1% (5/161), but there was none of them was serious. These results indicate that FLCZ is an agent with good potential in treatment of systemic fungal infections in patients with hematological disorders.

[Efficacy and safety of cefozopran (CZOP) monotherapy and combination therapy with CZOP and amikacin (AMK) for infections accompanying hematological diseases].

We evaluated efficacy and safety of monotherapy with CZOP (1-2 g x 2/day) and combination therapy with CZOP (1-2 g x 2/day) and AMK (200 mg x 2/day) for infections in patients with hematological diseases. Efficacy was evaluated in 71 patients of monotherapy group and 70 patients of combination therapy group. Underlying diseases were mostly leukemia and lymphoma. Infections included sepsis, suspected sepsis, pneumonia and so on. Efficacy in CZOP monotherapy was excellent in 21 patients (31.3%), good in 23 patients (34.3%), fair in 5 patients (7.5%) and the efficacy rate was 65.7%. On the other hand, in combination therapy, each was 14 patients (21.2%), 23 patients (34.8%), 12 patients (18.2%) and the efficacy rate was 56.1%. Side effects such as eruption were noted in 2 patients. Abnormal laboratory findings were noted in 9 patients. All side effects as well as abnormal laboratory findings were minimal. It was concluded that CZOP monotherapy was effective in the treatment of various infections accompanying hematological diseases.

Nodular sclerosing Hodgkin's disease with massive skin invasion.

Skin invasion is a rare manifestation in cases with Hodgkin's disease and if present mortality rate is very high. In general, almost all patients with advanced skin lesions die of the underlying disease in spite of any chemotherapy, however in case the patient recovered after intensive chemotherapy and irradiation. Moreover, the type of skin manifestation in this case is unique and quite different from the usual. This report describes a well-controlled case of Hodgkin's disease with massive and atypical skin invasion.

[An aplastic anemia patient died of severe anemia who refused transfusion].

A 41-year-old woman who had been given a diagnosis of aplastic anemia 14 years before was admitted because of recurrence of the disease. Despite therapy, the anemia progressed gradually. The patient refused blood product transfusions for religious reasons. Angina pectoris-like chest pain without ischemic changes on electrocardiograms appeared at a hemoglobin concentration (Hb) of 1.6 g/dl. The patient died of heart failure at Hb 1.5 g/dl. Autopsy showed enlargement of the heart, fatty changes in the myocardium and liver due to chronic hypoxia, and no changes in coronary arteries.

[Improvement of anemia by recombinant human erythropoietin in paroxysmal nocturnal hemoglobinuria].

A 32-year-old man visited Kanto Teishin Hospital complaining of general fatigue in May, 1992. He had been diagnosed as having paroxysmal nocturnal hemoglobinuria since 1980, because of brownish urine in the morning. He received blood transfusion in 1980. In 1983, he was treated with medication. There was no remarkable improvement, however, and he stopped coming to the hospital. When he was admitted to our hospital, hemolytic anemia and hemosiderinuria were noticed. Sucrose hemolysis test and acidified-serum lysis test (Ham test) were both positive. Positive rates of decay accelerating factor and CD59 were 38.8% (control 100%) and 45.4% (control 100%), respectively. His diagnosis was thus confirmed. Bone marrow was slightly hypocellular, and erythroid cells were relatively hyperplastic (M/E ratio 0.68). The oral administration of iron and oxymetholone was not effective for anemia. He was treated with daily subcutaneous administration of recombinant human erythropoietin (EPO, 3,000U/body/day). His hemoglobin level increased from 7.5g/dl to 12.0g/dl in 4 weeks, and general fatigue disappeared. Since he had concurrent chronic hepatitis C, alpha-interferon was also administered and his hemoglobin level is now controlled between 10 and 11g/dl. This case suggests that EPO can be useful for treating hemolytic anemia, even though erythroid cells in the bone marrow are hyperplastic.

[Low-dose etoposide in the treatment of chronic myelomonocytic leukemia].

Two cases of chronic myelomonocytic leukemia (CMML) which were successfully treated with low dose etoposide are reported. One case was treated with oral etoposide in daily dose of 25 mg for 3d a week, another case in dose of 50 mg/day. Their white blood cell counts became normal and monocytes decreased after the treatment with etoposide. In the second case, blasts in peripheral blood disappeared and thrombocytopenia was improved. The experience of these cases suggests that low dose etoposide is an useful treatment for CMML.

[Atypical infiltration of megakaryocytes into the liver and spleen in a case of refractory anemia].

A 72-year-old man was admitted to our hospital because of general malaise. The peripheral blood showed pancytopenia (WBC 800/microliters, RBC 970,000/microliters, Plt 95,000/microliters). The bone marrow smear revealed morphological abnormalities in three lineage without increase in blasts. He was diagnosed as having myelodysplastic syndrome (MDS). He was treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) for leukopenia, and with washed RBC transfusions for anemia. Eight months after diagnosis of MDS, blastic cells increased in peripheral blood and bone marrow showing overt leukemic state. He died of pneumonia. An autopsy revealed that atypical megakaryocytes increased in bone marrow and infiltrated into the spleen and liver. This case suggests that not only blasts but also megakaryocytes infiltrate into extramedullary organs in some cases of MDS.

[Acute promyelocytic leukemia (APL) resulting in broad cerebral infarction during all-trans retinoic acid (ATRA) treatment].

A 27-year-old woman visited Kanto Teishin Hospital complaining of fever and petechiae in September, 1992. Her fetus had suddenly died in the uterus two weeks before (in the sixth month of pregnancy). Total white blood cell (WBC) count was 3.2 x 10(3)/microliters with 80% promyelocytes. Bone marrow was hypercellular with 90% promyelocytes. Disseminated intravascular coagulation (DIC) was recognized. She was diagnosed as having acute promyelocytic leukemia (APL), and treatment with daily oral administration of all-trans retinoic acid (ATRA) (70 mg/body/day) was begun. On day 4, hemiplegia and aphasia appeared. Broad cerebral infarction was suspected from computed tomography. On day 9, the WBC count increased rapidly, standard chemotherapy was added and she achieved complete remission. ATRA is known to have stimulatory effects on the differentiation of APL cells, but some reports have described thromboembolic events during the administration of ATRA. In this case, ATRA might have affected coagulability resulting in cerebral infarction.

[Immunoblastic lymphadenopathy-like T cell lymphoma accompanied by autoimmune hemolytic anemia].

A 62-year-old man was admitted to our hospital because of generalized lymphadenopathy, fever and skin eruptions. The histology of the right cervical lymph nodes showed immunoblastic lymphadenopathy (IBL)-like T cell lymphoma. His laboratory data were as follows: hemoglobin concentration 7.1 g/dl, red blood cells 1,850,000/microliters, reticulocytes 4.2%, total bilirubin 2.6mg/dl, direct bilirubin 0.5mg/dl, haptoglobin less than 10mg/dl, positive Coombs test. He was diagnosed as having IBL-like T cell lymphoma accompanied by autoimmune hemolytic anemia. He was successfully treated with combination chemotherapy (Pro-MACE), and lymph node swelling and hemolytic anemia disappeared. He has been in complete remission for more than 1 year.

[Changes in bone marrow MRI patterns in aplastic anemia before and after successful treatment with ATG].

In order to evaluate the usefulness of MRI in estimating bone marrow cellularity, we performed MRI of the lumbar spine in two patients with severe aplastic anemia, before and after successful treatment with antithymocyte globulin (ATG). Case 1, a 25-year-old man with idiopathic aplastic anemia, was treated with ATG 6 months after the onset. One month after treatment, his peripheral blood count and bone marrow cellularity recovered, and the MRI bone marrow pattern became normal. Case 2, a 78-year-old woman with drug-induced aplastic anemia, was treated with ATG 4 months after the onset. Three months after treatment, her peripheral blood count improved. Five months after treatment, her bone marrow cellularity recovered and the MRI bone marrow pattern was normal for her age. Seven months after treatment, when her peripheral blood count was almost normal, we observed hypercellular bone marrow restoration at the periphery of the vertebrae. MRI seems to be an effective method of evaluating bone marrow recovery in aplastic anemia.

[alpha-Interferon in the treatment of essential thrombocythemia].

Two patients with essential thrombocythemia were successfully treated by administering native alpha-interferon (alpha-IFN). One patient was a 38-year-old man in whom thrombocytosis was found accidentally. His platelet count on admission was 880,000/microliters and megakaryocytes increased. Three million units of alpha-IFN was administered subcutaneously everyday, and the platelet count decreased gradually to about 500,000/microliters within 2 weeks. The other patient was a 66-year-old woman who visited our hospital complaining of tenderness and swelling of the fingertips. Her platelet count was 1,610,000/microliters, and megakaryocytes increased and showed abnormal morphology. Six million units of alpha-IFN was administered subcutaneously every other day. The tenderness and swelling of the fingertips disappeared soon after the beginning of alpha-IFN administration. The platelet count decreased to about 500,000/microliters within 10 days, but she developed itching of the skin over the entire body. Therefore, alpha-IFN treatment was discontinued. It was suggested that alpha-IFN suppresses not only the maturation and proliferation of the progenitors of megakaryocytes but also the production of platelets from megakaryocytes. Administration of alpha-IFN should be considered in treating patients with essential thrombocythemia, because effects appear soon and alpha-IFN does not induce a second malignancy.

[Acute monocytic leukemia following anti-lymphocyte immunoglobulin treatment in a patient with severe aplastic anemia].

A 57-year-old female, who had a 14-year history of rheumatoid arthritis, developed aplastic anemia. Treatment with anti-lymphocyte globulin (ALG) and methylprednisolone pulse therapy achieved complete remission. However, twenty months after ALG treatment she developed acute monocytic leukemia. In spite of the chemotherapy, consisting of cytosine arabinoside and etoposide, she died of pneumonia. Recently, reports from Western countries have claimed that patients with aplastic anemia frequently develop clonal disorders following ALG treatment. To our knowledge, this is the first report in Japan of a case developing acute leukemia following ALG treatment.

[Effects of cytarabine ocfosfate on colony-stimulating factor in myelodysplastic syndrome with monosomy 7].

A 42-year-old man was admitted to our hospital because of pancytopenia in April 1992. A diagnosis of refractory anemia was made. The karyotype was normal male type on the initial study. Subcutaneous administration of granulocyte colony-stimulating factor (G-CSF) initially increased the peripheral neutrophil count, bat in January 1993, although blast cells did not increase, neutrophils had decreased in spite of the continuation of G-CSF administration. Chromosome analysis showed 46XY, +Y, -7 at this point. By adding 50 mg of cytarabine ocfosfate (SPAC) daily, the peripheral neutrophil count again rose dramatically. However, anemia, thrombocytopenia and the chromosomal abnormality were unchanged. These results indicate that SPAC may upregulate the effect of G-CSF on granulopoiesis in patients with myelodysplastic syndrome.