The effects of teriparatide on acceleration of bone healing following atypical femoral fracture: comparison between daily and weekly administration.

We compared the effectiveness of promoting bone healing between two teriparatide preparations for atypical femoral fracture (AFF). A total of 45 AFFs were included in this study, and we compared the duration of bone union. Teriparatide administered by daily injection enhanced bone union more than weekly administration in complete AFFs. INTRODUCTION: The efficacy of teriparatide for atypical femoral fracture (AFF) has been recently reported. Although two different teriparatide preparations can be used to treat osteoporosis in Japan, daily or weekly injection, all previous reports on the effectiveness of teriparatide for AFF only examined daily injection formulations. Therefore, we compared the promotion of bone healing between the two teriparatide preparations for AFF. METHODS: A total of 45 consecutive AFFs in 43 Japanese patients were included in this study. They received either a daily 20-µg teriparatide injection (daily group; n = 32) or a once-a-week 56.5-µg teriparatide injection (weekly group; n = 13). We compared the clinical background and duration of bone union between these two groups. RESULTS: When all patents were included, the fracture healing time was not significantly different between the two groups. Only patients with complete AFFs had significantly fewer daily bisphosphonate or denosumab injections than the weekly group (P < 0.05). The fracture healing time in the daily group (6.1 ± 4.1 months) was significantly shorter than that in the weekly group (10.1 ± 4.2 months) (P < 0.05). Even if the influence of bisphosphonate or denosumab usage was excluded, a similar significant difference was observed in the fracture healing time (P < 0.05). There was no significant difference between the two groups among patients with incomplete AFFs. CONCLUSIONS: Daily teriparatide injections enhance bone union more than weekly injections in complete AFF patients.

Altered cochlear fibrocytes in a mouse model of DFN3 nonsyndromic deafness.

DFN3, an X chromosome-linked nonsyndromic mixed deafness, is caused by mutations in the BRN-4 gene, which encodes a POU transcription factor. Brn-4-deficient mice were created and found to exhibit profound deafness. No gross morphological changes were observed in the conductive ossicles or cochlea, although there was a dramatic reduction in endocochlear potential. Electron microscopy revealed severe ultrastructural alterations in cochlear spiral ligament fibrocytes. The findings suggest that these fibrocytes, which are mesenchymal in origin and for which a role in potassium ion homeostasis has been postulated, may play a critical role in auditory function.

Frequent viral infections and delayed CD4+ cell recovery following CD34+ cell-selected autologous peripheral blood stem cell transplantation.

This study compares the reconstitution of T-lymphocyte subsets and the incidence of infections following CD34+ cell-selected autologous peripheral blood stem cell transplantation (PBSCT) (n = 15) and unselected auto-PBSCT (n = 16). In the CD34+ cell-selected auto-PBSCT group, the mean count of CD4+ cells had significantly decreased at 30 days after transplantation compared with pretransplantation, and did not reach the safe minimum level of 0.2 x 10(9)/l even at 90 days after transplantation. Compared with unselected auto-PBSCT, CD4+ cell reconstitution after CD34+ cell-selected auto-PBSCT was significantly delayed within the first 90 days after transplantation. Cytomegalovirus infections developed more frequently after CD34+ cell-selected auto-PBSCT than after unselected auto-PBSCT (nine patients vs. two patients, P = 0.0057). Hemorrhagic cystitis due to adenovirus type 11 infections developed in three patients who underwent CD34+ cell-selected auto-PBSCT. Positive correlation between the counts of reinfused CD34+ cells and the counts of CD4+ cells were found at 90 days after CD34+ cell-selected auto-PBSCT. No significant difference was found in the frequency of viral infections, however, between patients transplanted with > 2 x 10(6)/kg of CD34+ cells and those transplanted with < 2 x 10(6)/kg of CD34+ cells. Careful monitoring for viral infection is necessary after CD34+ cell-selected auto-PBSCT.

Treatment of acute myeloid leukemia and myelodysplastic syndrome with orally administered cytarabine ocfosfate and granulocyte colony-stimulating factor.

Cytarabine ocfosfate (SPAC) was administered orally to 19 patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). SPAC was administered at doses of 200-300 mg/day for more than 14 days with granulocyte colony-stimulating factor (G-CSF). Four of the 12 patients with AML and 1 of the 7 patients with MDS achieved complete remission (CR) after one cycle of SPAC treatment. Especially, 3 of the 6 patients with newly diagnosed AML achieved CR. Major side effects of SPAC were myelosuppression and tolerable gastrointestinal disorders. The treatment with SPAC is a therapeutic option in elderly patients or patients with organ failure.

Induction of apoptosis in HL60 leukemic cells by anticancer drugs in combination with anti-Fas monoclonal antibody.

Some anticancer drugs kill tumor cells through the mechanism of apoptosis. Fas antigen has been generally noticed as an apoptosis-signalling receptor molecule on the surface of different cells. Recently, it has become clear that some tumor cells express Fas antigen on their surface, and apoptosis is induced in those cells by IgM-anti-Fas monoclonal antibody (IgM-anti-Fas MoAb). If it is possible to induce apoptosis in tumor cells effectively by anticancer drugs in combination with IgM-anti-Fas MoAb, then we may be able to develop a new strategy for cancer chemotherapy. HL60 human leukemic cell line was incubated with anticancer drugs adriamycin (ADM) or cytosine arabinoside (Ara-C) at different doses alone and in combination with IgM-anti-Fas MoAb. We then observed the morphologic changes of tumor cells, the DNA fragmentation by agarose gel electrophoresis, and the changes in the amount of Fas antigen expression in their cell surface by using flow cytometry. In ADM- or Ara-C-treated tumor cells, apoptotic cells increased in number time- and dose-dependently. By the combination of ADM or Ara-C with IgM-anti-Fas MoAb, the induction of apoptosis in HL60 cells was enhanced significantly. The DNA electrophoresis supported those results. The amount of Fas antigen expression was slightly increased only in cells treated with a low dose of Ara-C, not in others. Our results suggest that apoptosis is a major process of leukemic cell death induced by anticancer drugs. Furthermore, it has become clear that the combination of anticancer drugs with IgM-anti-Fas MoAb enhances leukemic cell death through apoptosis in vitro, though the mechanism remains to be resolved.

Anti-Fas IgM monoclonal antibody enhances apoptosis induced by low-dose cytosine arabinoside.

BACKGROUND: Although low-dose cytosine arabinoside (LD-Ara-C) therapy has been accepted as an effective treatment for patients with acute non-lymphocytic leukemia (ANLL) transformed from myelodysplastic syndromes or elderly patients with ANLL, the anti-leukemic mechanism remains to be resolved. Recently, the potential role of the Fas/Fas ligand system in chemotherapeutic drug-induced apoptosis has been studied. In the present study the relationship between the anti-leukemic effect of LD-Ara-C and the Fas/Fas ligand system was examined. MATERIALS AND METHODS: The human myeloid leukemia cell line HL60 was treated with LD-Ara-C in combination with anti-Fas IgM MoAb, and apoptosis in the treated cells was estimated by morphological observation, DNA electrophoresis and flow cytometry. Simultaneously, changes in Fas antigen expression on cells treated with LD-Ara-C were investigated. RESULTS: Only limited apoptosis was observed following treatment with LD-Ara-C alone or anti-Fas MoAb alone; however, a synergistic increase in apoptosis was observed by treatment with the MoAb in combination with pretreatment with LD-Ara-C. LD-Ara-C induced a slight but consistent increase in the expression of Fas antigen on the treated cells. Moreover, the expression of Fas antigen was enhanced by repeated administration of LD-Ara-C. CONCLUSIONS: These findings suggest the possible involvement of the Fas/Fas ligand system in the anti-leukemic effect of LD-Ara-C therapy.

Cavernous sinus syndrome associated with nonsecretory myeloma.

The case of a 53-year-old man who developed cavernous sinus syndrome (CSS) four years after being diagnosed as having nonsecretory myeloma is described. He was admitted with diplopia and dull pain over the right infraorbital and zygomatic region in June 1997. The cause of CSS was the intracranial involvement of myeloma, which was diagnosed by fiberscopic biopsy. The results of endocrinologic evaluation were almost normal. The response to radiotherapy and chemotherapy was mild. CSS caused by nonsecretory myeloma is rare and its prognosis is poor. More aggressive chemotherapy with stem cell support may be indicated.

[Beneficial effect of eyelid make-up (natural rubber latex) to induce a new fold in the treatment of blepharoptosis in myotonic dystrophy].

Blepharoptosis is one of the troublesome ocular complications of myotonic dystrophy. To correct drooping eyelids for two men with myotonic dystrophy, we used Eye Putti, a cosmetic made of natural rubber latex, which induces a new fold in the upper eyelid. The cosmetic rubber latex dramatically improved the sight of a 59-year-old patient who previously had a great difficulty in looking forward and had to bend his head backward to see an object because of severe blepharoptosis. The other patient aged 54 with moderate ptosis also had satisfactory improvement. Appropriate use did not prevent eye blinking and induce corneal erosion or skin rash. The cosmetic rubber latex was effective to patients who had no residual function of the levator palpebrae and frontal muscles. This daily treatment is simple and safe, therefore may have an advantage over surgical correction of blepharoptosis for patients not only with myotonic dystrophy, but with other neuromuscular disorders including oculopharyngeal muscular dystrophy.

[Clinical evaluation of lenampicillin in the treatment of superficial suppurative skin and soft tissue infection. A double-blind study comparing amoxicillin].

A double-blind controlled clinical study between lenampicillin (LAPC), a newly developed oral ampicillin (ABPC) prodrug, and amoxicillin (AMPC) was conducted for the treatment of suppurative skin and soft tissue infection as grouped in 6 disease types. LAPC or AMPC were orally administered at a daily dose of 1,000 mg, in 4 equally divided doses. Each group was treated for 14 days. The results indicated that LAPC was equal to AMPC in evaluations of effectiveness and usefulness, although incidence of severe side effects was slightly lower in LAPC. The number of cases studied was 235 (115 in the LAPC group, 120 in the AMPC group). Among these, 10 patients (4 in LAPC, 6 in AMPC) were excluded and 12 patients (5 in LAPC, 7 in AMPC) dropped out. Final global improvement rating was evaluated in 213 patients (106 in LAPC, 107 in AMPC). General usefulness rating was evaluated in 215 patients (106 in LAPC, 109 in AMPC), and overall safety rating was evaluated in 231 patients (115 in LAPC, 116 in AMPC). Final global improvement rating of LAPC was, "cured", 55.7% and "cured" and "remarkably improved", 79.2%. The rate increased to 88.7% when "improved" was included. On the other hand, in the AMPC group, "cured" was 50.5%, and "cured" and "remarkably improved" was 76.6%. The rate increased to 91.6% when "improved" was included. No significant difference was found between the 2 drug groups. In overall safety rating of LAPC, "safe" was 93.9%, while in the AMPC group, "safe" was 94.0%. No significant difference was found between the 2 drug groups. Side effects were noted in 2 of 115 patients (1.7%) among the LAPC group and in 5 of 116 patients (4.3%) among the AMPC group. Incidence of severe side effects was slightly lower in LAPC (P less than 0.1). General usefulness rating of LAPC was, "remarkably useful", 56.6% and the rate increased to 86.8% when "useful" was included. In the AMPC group, "remarkably useful" was 51.4%, and increased to 84.4% when "useful" was included. No significant difference was found between the 2 drug groups.

[Clinical studies on lenampicillin in the therapy of skin and soft tissue infections].

Clinical evaluation of newly developed oral ampicillin prodrug lenampicillin (LAPC, KBT-1585) applied to patients with superficial purulent infection at a dosage of 750 approximately 1,500 mg daily was conducted. Additionally, as part of the basic study, transition of the compound to the human skin tissue was observed. With regard to transition to human skin tissue in 11 presurgery dermatitis cases, 250 mg or 500 mg of LAPC was administered to 2 approximately 3 hours before surgery. Comparison was made between concentrations in serum and in skin tissue. Results in the case of 250 mg application showed serum concentration to be 1.28 approximately 3.32 micrograms/ml, and in skin tissue, 0.13 approximately 0.82 micrograms/g. At 500 mg, serum concentration was found to be 2.23 approximately 10.05 micrograms/ml, with skin tissue concentration at 0.45 approximately 1.34 micrograms/g. Rate of clinical efficacy in the treatment of the 183 cases of superficial purulent infection was 79.2%. By grouping of the infections (Table 3), high efficacy rates were obtained in the second group, at 85.7%; in the third at 88.9%; and in the fourth group at 96.4%. Evaluation of usefulness from the standpoint of safety was 77.6%. Good results were obtained in the third group with 88.9%; and in the fourth group with 96.4%. LAPC's efficacy rates against individual strains of bacteria in simple infection are as follows: Staphylococcus aureus, 74.6%; Staphylococcus epidermidis, 76.3%; GPC, 100%; anaerobes, 87.5%. In polymicrobial infections the rate was 84.6%. The rate of efficacy against all strains of bacteria was 76.0%. Adverse reactions were found in 13 cases (14 incidences) out of 193. The rate of incidence was 7.3%, with allergic response accounting for 5 cases, digestive tract disorders, 7 cases, and mouth odor, 1 case. There were 5 cases (6 incidences) of abnormal deviation of laboratory findings. In all cases, abnormal deviations were mild and their relation to the drug was unclear.

[Malignant lymphoma of the testis: report of two cases].

Two cases on non-Hodgkin's malignant lymphoma (NHL) of the testis are reported. A 63-year-old man with left painless scrotal swelling underwent orchiectomy. Although prophylactic irradiation was performed under the diagnosis of seminoma, subsequent immunohistochemistry revealed NHL, large diffuse cell type (B type). He had stage IEA disease. Chemotherapy with cyclophosphamide, adriamycin vincristine and prednisolone was performed. The second case was in a 63-year old man with right painless scrotal swelling. Orchiectomy revealed NHL, diffuse medium cell type (B type). Because of tumor in the retrosternum, he had stage IIIEA disease. Chemotherapy and irradiation to the contralateral testis was performed.

[Granulomatous angiitis of the central nervous system complicated by the syndrome of inappropriate antidiuretic hormone].

We report an autopsy case of granulomatous angiitis of the central nervous system (GANS) complicated by the syndrome of inappropriate antidiuretic hormone (SIADH). A 88-year old female was admitted because of progressive mental deterioration, fever, and vomiting. A computed tomogram disclosed bilateral periventricular lucency, and a low-density area in the right occipital lobe. Laboratory studies during her hospital stay, revealed hyponatremia, hypoalbuminemia, and increased antidiuretic hormone. Treatment with antibiotics, hypertonic saline solution, and steroids, and water restriction was ineffective, and the patient died six weeks after admission. Autopsy examination of the brain revealed slightly turbid meninges with multiple small infarctions in the corona raiata of both cerebral hemispheres. Microscopic study disclosed granulomatous inflammation with many giant cells in the walls of small and medium sized vessels, and the adventitia and media were more involved than the intima. Their lumens were narrowed, and many thrombi were observed. Extensive non-granulomatous inflammatory change was found mainly in the subarachnoid space. All of these findings were similar to the GANS firstly reported by Cravioto et al, in 1959. Since the blood vessels in the central nervous system play an important part in any inflammatory conditions and the blood vessels may be involved by bacterial, fungal, parasitic or viral meningitis, various microorganisms have been suspected as the cause of GANS, including mycoplasma, herpes zoster, herpes simplex viruses, cytomegalovirus, and human T-lymphotropic virus type III (HTLV-III). Some reported cases have been associated with Hodgkin's disease and cerebral amyloid angiopathy. We could not identify any cause in our case.(ABSTRACT TRUNCATED AT 250 WORDS)

[An autopsy case of membranous lipodystrophy (Nasu)].

Membranous lipodystrophy (Nasu) is characterized by polycystic osteodysplasia associated with dementia. We recently experienced a 9th autopsy case in Japan. This 50 year-old male, eldest in the reported autopsied case in Japan, presented bone fracture at 35 year of age and dementia started at 45. His parents were cousins. His sister, died with carcinoma of the bladder at 35, developed marked osteoporosis with multiple pathological fractures and "membrano-cystic" lesions were found in her adipose tissue. The roentgenogram of the patient's long bone revealed radiolucent and cystic areas with irregular boundaries at the metaphyses. Computer tomography of the brain examined during the last 3 years showed slowly progressive brain atrophy. Calcifications of the basal ganglia or low density area in the white matter were not found. Autopsy showed typical "membrano-cystic" lesions in the adipose tissue of the whole body including bone marrow. Brain weighed 1,030 g. There was a mild convolutional atrophy at the frontal lobe. White matter was diffusely atrophic. Demyelination was limited to the frontal lobe, where only small number of perivascular sudanophilic lipid-laden macrophages were found. Fibrillary astrocytes were rather diffusely proliferated, consistent with sclerosing leukoencephalopathy. Many spheroids were found in the frontal and occipital deep white matters, and external capsule. Ultrastructural study of spheroid revealed increased amount of neurofilament, vesicles with free patchy dense materials and degenerated mitochondria, which were consistent with primary axonal degeneration.

[Multidrug resistant P-glycoprotein expression on acute nonlymphocytic leukemia cells at diagnosis].

In performing cancer chemotherapy, it is essential to know the expression of multidrug resistant (MDR) P glycoprotein (p-gp) on cancer cells. In the present study, in order to clarify the relationship between MDR of leukemic cells and cytologic, immunological and clinical features of acute nonlymphocytic leukemia (ANLL), leukemic cells in peripheral blood and/or bone marrows obtained from 28 ANLL patients were examined. Each smear was stained with C219 monoclonal antibody against P-gp by the APAAP method, and then 1,000 ANLL cells in each smear were observed. Among the FAB subtypes, M4 showed the highest proportion of leukemic cells expressing P-gp. Concerning the response to chemotherapy, five of seven patients (71%) having 1.0% or more of P-gp positive leukemic cells and 11 of 19 patients (58%) having less than 1.0% of those cells achieved complete remission. However, there was no significant correlation between P-gp expression and clinical outcome. There was also no significant correlation between P-gp expression and CD7 or CD34. Furthermore, no significant correlation between chromosome 7 abnormality and P-gp expression was observed. From these results, if we can clarify the mechanism of MDR and the relationship between MDR and cytogenetic or clinical features of ANLL with further study, P-gp expression may become a useful marker for predicting the outcome of ANLL.

[MMIP chemotherapy for the treatment of the relapsed and refractory non-Hodgkin's lymphoma].

For salvage chemotherapy, 30 cases of relapsed or refractory non-Hodgkin's lymphoma (NHL) were treated with MMIP regimen (mitoxantrone 15 mg/m2, methotrexate 400 mg/m2, and ifosfamide 2 g/m2 intravenously in day 1, respectively, and prednisolone 20 mg/m2 orally from day 1 to 5). The overall complete response rate (CR rate) was 20% and the median survival duration was 153 days. In patients with favorable performance status (PS), the CR rate and survival duration were 30% and 407 days, respectively. These results were almost equivalent to previously proposed salvage regimens. The overall disease free survival rate of CR cases at 4 years was 62%, which was excellent as compared with the other salvage regimens. Five of 8 (62.5%) patients previously treated with etoposide-non-containing regimens achieved CR, and the CR rate was significantly superior to that of patients previously treated with etoposide-containing ones. These results indicate that MMIP is a useful salvage regimen for relapsed or refractory NHL, while it seems to be difficult to salvage patients previously treated with etoposide-containing regimens.

[The examination of usefulness of the disposable pump in case of cancer pain relaxation and the economic problem].

Recently, an increasing number of cancer patients being taken care of at home has been able to use morphine to treat their pain by themselves. The most suitable administration method for individual patients-oral, intravenous, subcutaneous or depository--is being investigated. When oral intake becomes difficult, the subcutaneous via of administration is best option because it is the less dangerous and easier to use compared with the other two options. These are also thought to be less useful because it is difficult to judge the exact dosage. The use of pumps might be an economic problem to some patients. We will examine this problem.