Successful pneumovaginoscopic surgery for recurrent abscess of OHVIRA syndrome, preventing further recurrence and subsequent pregnancy.

INTRODUCTION: OHVIRA syndrome is a rare congenital anomaly of Müllerian duct development characterized by uterine didelphys, obstructed hemivagina, and ipsilateral renal agenesis. The primary treatment is surgical excision of the obstructed hemivaginal septum and hematometrial drainage. In recent years, minimally invasive approaches such as hysteroscopic or vaginoscopic septum resection have been reported. Furthermore, we originally developed some novel pneumovaginoscopic gynecologic surgeries for years using a device that consists of a cylinder that fits into the vagina and a lid that mounts multiple ports, allowing the vagina to be dilated with carbon dioxide gas, similar to a single-port laparoscope. MATERIALS AND SURGICAL TECHNIQUE: We report a successful pneumovaginoscopic surgery for a complicated recurrent abscess in a patient with OHVIRA syndrome. Conventional surgery was performed with a single forceps in a liquid, as in cystoscopy or hysteroscopy. However, this new surgery allowed multiple forceps in a gas, as in laparoscopy. So pus and blood were aspirated and washed away without leaking into the abdominal cavity via fallopian tubes. The surgical smoke generated by thermal coagulation also aspirated to clean the field of vision immediately. And thick, complicated abscesses were drained successfully. The patient conceived through IVF with ICSI and delivered safely at full term. DISCUSSION: Pneumovaginoscopy could benefit complex vaginal surgery cases, such as abscess formation in patients with OHVIRA syndrome.

Immunohistochemical analysis of SOX2 expression in small-cell neuroendocrine carcinoma of the endometrium.

Small-cell neuroendocrine carcinoma (NEC) of the endometrium is an extremely rare and highly aggressive carcinoma. Sex-determining region Y-box 2 (SOX2) is a master transcription factor regulating the self-renewal, maintenance of stem cell properties and pluripotency of embryonic stem cells, and recent studies revealed that SOX2 plays important roles in cancer growth and progression in several types of carcinomas, including small-cell neuroendocrine carcinoma (NEC) of the lung and oesophagus. Few studies to date have analysed the association between SOX2 and endometrioid carcinoma, whereas the expression of SOX2 in small-cell NEC of the endometrium has not been investigated. The aim of the present study was to analyse the expression status of SOX2, p16 and paired-box gene (PAX) 8, a useful Müllerian marker, in endometrial small-cell NEC. A total of 4 patients with small-cell NEC of the endometrium were enrolled (median age, 70 years). Immunohistochemical studies revealed SOX2 expression in 3 patients and p16 expression in all patients. No patients exhibited positive immunoreactivity for PAX8. SOX2 expression has been reported to be associated with the pathogenesis of small-cell NEC of the oesophagus. Therefore, the results of the present study indicated that SOX2 expression plays an important role in the development of small-cell NEC of the endometrium and the oesophagus. Moreover, expression of p16 and loss of PAX8 do not indicate the origin of small-cell NEC of the endometrium.

Small-cell neuroendocrine carcinoma in directly sampled endometrial cytology: A monocentric retrospective study of six cases.

Small-cell neuroendocrine carcinoma (NEC) of the endometrium is extremely rare, and demonstrates an aggressive clinical course. Since reports describing its cytological features are scarce, we aimed to retrospectively analyze these features. Patients with a histopathological diagnosis of NEC who underwent preoperative cytological examination, were enrolled in this study. The cytological features including the background, arrangement, and shape of the neoplastic cells, and the nuclear and cytoplasmic features were reviewed; six patients were enrolled. The conventionally stained, directly sampled cytological specimens showed small neoplastic cell clusters in all cases, as well as isolated neoplastic cells and large clusters in 3 and 2 cases, respectively, in inflammatory or necrotic backgrounds. These neoplastic cells had a high nuclear/cytoplasmic ratio, and round to oval nuclei with powdery chromatin, inconspicuous nucleoli, and scant cytoplasm. Nuclear molding was a characteristic finding. An adenocarcinoma component was also present in 3 cases. Initial cytodiagnosis revealed small-cell NEC and adenocarcinoma or suspected adenocarcinoma in 1 and 4 cases, respectively. The one remaining case was found to be negative and was considered as degenerated endometrial stromal cells. Primarily owing to overlooking this component, the initial cytodiagnostic accuracy of small-cell NEC was low, particularly in cases with coexisting adenocarcinoma. However, the cytological features of this tumor were characteristic. Therefore, although extremely rare, careful observation is essential for an early and accurate diagnosis and to prevent overlooking the small-cell NEC component.

Cytological features of uterine carcinosarcoma: A retrospective study of 20 cases with an emphasis on the usefulness of endometrial cytology.

BACKGROUND: Carcinosarcoma of the endometrium is a relatively rare but aggressive neoplasm. Endometrial cytological features of this type of tumor have been rarely reported. This study aimed to clarify the usefulness of endometrial cytological examination in the diagnosis of endometrial carcinosarcoma. METHODS: Patients histopathologically diagnosed with endometrial carcinosarcoma who underwent preoperative endometrial or endocervical cytological examination were enrolled. The endometrial and/or endocervical specimens were conventionally stained with Papanicolaou stain, and the cytological characteristics, including arrangement and shape of the neoplastic cells, and the nuclear and cytoplasmic features were reviewed. RESULTS: Twenty patients were enrolled in the study. In the endometrial specimens, carcinomatous component was detected in almost all cases (94.4%), including those suspicious of carcinoma despite a small volume of carcinomatous cells. Sarcomatous component was observed in 6 of 18 cases (33.3%) and was significantly more frequently detected in the heterologous type (5 of 9 cases) compared to the homologous type (1 of 9 cases) (P = 0.046). In the endocervical specimens, carcinomatous component was present in 76.5% of cases, but sarcomatous component was detected in only 17.6% of cases. CONCLUSION: Although endocervical cytology can detect the carcinomatous component in more than 50% of endometrial carcinosarcoma cases, it has lesser capability to detect sarcomatous component. In conclusion, endometrial cytological examination is a more useful and accurate method to detect sarcomatous component of endometrial carcinosarcoma, particularly in the heterologous type, compared to endocervical cytological examination.

Imprint cytology of strumal carcinoid of the ovary: A case report with immunocytochemical analysis.

Strumal carcinoid is a rare ovarian tumor defined as carcinoid associated with struma ovarii. We report here the second cytological case of strumal carcinoid and performed immunocytochemical analysis for the first time. A 68-year-old Japanese female was found to have a solid tumor with small cystic components in the left ovary, and bilateral salpingo-oophorectomy was performed. The Papanicolaou smear of the imprint cytological specimen of the left ovarian tumor revealed presence of two distinct components. The first component included thyroid follicles, which was composed of flat sheets of polygonal epithelial cells without nuclear groove and intranuclear inclusion. The other component was composed of trabecular clusters of columnar cells containing round to slender nuclei with "salt and pepper" chromatin. Immunocytochemical analysis revealed that synaptophysin was expressed in the latter component. Therefore, a cytodiagnosis of strumal carcinoid was made. Histopathological analyses confirmed the diagnosis of strumal carcinoid. Albeit rare, carcinoid tumor occurs in the ovary, and the recognition of characteristic nuclear features and cellular arrangement leads to correct cytodiagnosis. Presence of struma ovarii component suggests an ovarian origin. Moreover, immunocytochemical analysis for neuroendocrine markers aids its differential diagnosis from granulosa cell tumor and carcinoma arising from struma ovarii.

Vaginal Lymphoma with Immune Thrombocytopenic Purpura: An Unusual Case Report.

The female genital tract is rarely the initial site of presentation in lymphoma or leukemia. We report a case of non-Hodgkin's lymphoma (NHL) presenting initially in the vagina. The patient, a 75-year-old woman, had a history of immune thrombocytopenic purpura (ITP). She presented with a chief complaint of genital bleeding and introital pain. On transvaginal ultrasonography, a vaginal tumor with an irregular wall was detected, and the internal echo showed a hypoechoic and echogenic pattern. Ultrasonography and magnetic resonance imaging (MRI) suggested that the vaginal tumor was likely to be a hematoma or a hemorrhagic tumor arising from ITP. Incision and resection for a hematoma or a hemorrhagic tumor were carried out in response to genital bleeding, introital pain, and pathological diagnosis. Postoperative microscopic examination confirmed that the tumor was a vaginal NHL. The final diagnosis using the Ann Arbor staging system was high-stage (stage IV) NHL. The patient received chemotherapy, and she remains in remission for 42 months after treatment.

Transformation potential of bone marrow stromal cells into undifferentiated high-grade pleomorphic sarcoma.

PURPOSE: Bone marrow adherent cells contain conventional bone marrow stromal cells and mesenchymal stem cells and these cells constitute the hematopoietic microenvironment. Mesenchymal stem cells have the capacity to give rise to multiple mesenchymal lineage cells and even ectodermal lineage cells. In the present study, we investigated what types of tumor cells are inducible from BM adherent cells by chemical carcinogens. METHODS: Bone marrow cells from neonatal C3H/HeN mice were collected within 24 h after birth and then cultured. Four days later, bone marrow adherent cells were obtained and the cells were treated with 3-methylcholanthrene. RESULTS: By this treatment, some transformed clones consisting of large spindle cells were obtained. The transformed cells were highly positive for CD44 and were positive for Sca-1, CD49d and CD106, whereas the cells were negative for hematolymphoid markers. The cell clones had the ability to support hematopoiesis in vitro. These results indicate that the transformed cell lines have the characteristics of BM stromal cells/mesenchymal stem cells. Moreover, during culture of the transformed cells, spontaneous bone nodule formation was observed. When the transformed cells were inoculated into immunodeficient mice subcutaneously, the neoplasms grew in the subcutaneous tissue of the mice. Microscopically and ultrastructurally, the neoplasms showed the typical morphology of undifferentiated high-grade pleomorphic sarcoma (UHGPS). Bone-related genes have been found to be expressed in both transformed cells and UHGPSs. CONCLUSION: The present study suggests that UHGPSs are derived from BM stromal cells, probably mesenchymal stem cells.

Mouse mesenchymal stem cells can support human hematopoiesis both in vitro and in vivo: the crucial role of neural cell adhesion molecule.

BACKGROUND: We previously established a mesenchymal stem cell line (FMS/PA6-P) from the bone marrow adherent cells of fetal mice. The cell line expresses a higher level of neural cell adhesion molecule and shows greater hematopoiesis-supporting capacity in mice than other murine stromal cell lines. DESIGN AND METHODS: Since there is 94% homology between human and murine neural cell adhesion molecule, we examined whether FMS/PA6-P cells support human hematopoiesis and whether neural cell adhesion molecules expressed on FMS/PA6-P cells contribute greatly to the human hematopoiesis-supporting ability of the cell line. RESULTS: When lineage-negative cord blood mononuclear cells were co-cultured on the FMS/PA6-P cells, a significantly greater hematopoietic stem cell-enriched population (CD34(+)CD38(-) cells) was obtained than in the culture without the FMS/PA6-P cells. Moreover, when lineage-negative cord blood mononuclear cells were cultured on FMS/PA6-P cells and transplanted into SCID mice, a significantly larger proportion of human CD45(+) cells and CD34(+)CD38(-) cells were detected in the bone marrow of SCID mice than in the bone marrow of SCID mice that had received lineage-negative cord blood mononuclear cells cultured without FMS/PA6-P cells. Furthermore, we found that direct cell-to-cell contact between the lineage-negative cord blood mononuclear cells and the FMS/PA6-P cells was essential for the maximum expansion of the mononuclear cells. The addition of anti-mouse neural cell adhesion molecule antibody to the culture significantly inhibited their contact and the proliferation of lineage-negative cord blood mononuclear cells. CONCLUSIONS: These findings suggest that neural cell adhesion molecules expressed on FMS/PA6-P cells play a crucial role in the human hematopoiesis-supporting ability of the cell line.

Preferential expansion of human umbilical cord blood-derived CD34-positive cells on major histocompatibility complex-matched amnion-derived mesenchymal stem cells.

BACKGROUND: We previously found in a murine hematopoietic system that hematopoietic stem cells show high differentiation and proliferation capacity on bone marrow-derived mesenchymal stem cells/stromal cells (microenvironment) with "self" major histocompatibility complex (MHC). DESIGN AND METHODS: We examined whether amnion-derived adherent cells have the characteristics of mesenchymal stem cells, and whether these adherent cells can support the proliferation of umbilical cord blood-derived lineage-negative and CD34-positive cells (Lin(-)CD34(+) cells) obtained from the same fetus to a greater extent than those derived from other fetuses. RESULTS: Culture-expanded amnion-derived adherent cells expressed mesenchymal stem cell markers and HLA-ABC molecules and could differentiate into osteoblasts, adipocytes and chondrocyte-like cells, indicating that the cells have the characteristics of mesenchymal stem cells. The Lin(-)CD34(+) cells purified from the frozen umbilical cord blood were strongly positive for HLA-ABC, and contained a large number of hematopoietic stem cells. When the Lin(-)CD34(+) cells were cultured on the autologous (MHC-matched) or MHC-mismatched amnion-derived adherent cells in short-term assays (hematopoietic stem cell-proliferation) and long-term culture-initiating cell assays, greater expansion of the Lin(-)CD34(+) cells was observed in the MHC-matched combination than in MHC-mismatched combinations. The concentration of granulocyte-macrophage colony-stimulating factor in the culture supernatants of the long-term culture-initiating cell assays was significantly higher in the MHC-matched combination than in MHC-mismatched combinations. CONCLUSIONS: IT is likely that a MHC restriction exists between hematopoietic stem cells and mesenchymal stem cells/stromal cells in the human hematopoietic system and that granulocute-macropage colony-stimulating factor contributes to some extent to the preferential hematopoiesis-supporting ability of the MHC-matched amnion-derived adherent cells.

Successful acceptance of adult liver allografts by intra-bone marrow-bone marrow transplantation.

Previously, we have shown that liver allografts obtained from the fetus or young mice are accepted when bone marrow cells (BMCs) from adult mice of the same strain are co-grafted. However, for practical clinical use, it is more convenient to obtain both BMCs and liver from the same adult donors. C57BL/6 mice were irradiated with a single high-dose irradiation or two low-dose irradiations and injected with donor BALB/c (8 weeks old) BMCs intravenously (IV-BMT) or directly into the recipient BM cavity (IBM-BMT). Liver tissues taken from the same donor were, on the same day, engrafted under the kidney capsules. Higher survival rates and more complete reconstitution of donor cells were achieved in the IBM-BMT group than in the IV-BMT group, and this was the case in both irradiation protocols. The acceptance of donor liver tissue was seen in all mice in which hematolymphoid cells were replaced by donor-type cells. The liver grafts of the reconstituted mice showed normal morphology and stained positively with anti-albumin antibody and Periodic Acid Schiff (PAs) staining, indicating that the grafted livers were accepted, had grown, and were functioning. These results demonstrate that the acceptance of allogeneic liver can be achieved by cografting donor BMCs via the IBM route.

Facilitation of hematopoietic recovery by bone grafts with intra-bone marrow-bone marrow transplantation.

We have previously shown that T cells can acquire donor-type major histocompatibility complex (MHC) restriction and can interact with both donor-type antigen-presenting cells (APCs) and B cells, when adult donor bones are co-grafted with intravenous (IV) injection of bone marrow cells (BMCs) in order to supply donor bone marrow (BM) stromal cells. We have also found that the direct injection of donor BMCs into recipient BM (intra-bone marrow-bone marrow transplantation: IBM-BMT) produces more rapid reconstitution (including T-cell functions) and higher survival rates than IV injection (IV-BMT) even in chimerism-resistant combinations. In the present study, we show that the co-administration of bones from suckling (2-3 days old) donor mice is also effective in the IBM-BMT system. Even when a relatively low number of BMCs were injected into adult (more than 15 weeks old) mice, complete reconstitution was achieved in the mice that had received IBM-BMT+bone grafts, but not in the mice that had received IBM-BMT alone. Most BM and splenic adherent cells obtained from the recipients that had received IBM-BMT+bone grafts were reconstituted by donor-type cells. Both T-cell proliferation and plaque-forming cell assays indicated that the T cells of such mice showed donor-type MHC restriction. Moreover, the analyses of thymic sections using confocal microscopy revealed that donor BM stromal cells had migrated into the thymus. Thus, the co-administration of donor bones has great advantages for allogeneic BMT in adult mice.

Contribution of neural cell adhesion molecule (NCAM) to hemopoietic system in monkeys.

Neural cell adhesion molecules (CD56) are important adhesion molecules that are mainly expressed on neural cells and natural killer cells. Although freshly isolated cynomolgus monkey bone marrow cells (BMCs) contained only a few CD56-positive cells, almost all the BM adherent cells (obtained after a 2- to 3-week culture of the BMCs) were stained positively with anti-CD56 monoclonal antibody (mAb). The BM adherent cells showed uniformly fibroblastic morphology and were negative for hematolymphoid markers (CD4, CD8, CD11b, CD14, CD34, and CD45). Adipogenesis and osteogenesis were observed under inductive culture conditions. The BM adherent cells had the ability to support hemopoiesis of hemopoietic stem cells (HSCs) in vitro, and the proliferation of HSCs was significantly inhibited by the addition of anti-CD56 mAb to the coculture system. CD56 molecules were also expressed on HSCs because about 20% of an HSC-enriched population (lineage-negative and blast-gated cells) was positive for CD56. In addition, the immunostaining of monkey BM sections revealed that many stromal cells were CD56-positive, and some CD56-positive stromal cells came into direct contact with CD56-positive hemopoietic cells. These results indicate that the CD56 molecule is expressed on both HSCs and BM stromal cells (containing MSCs) in monkeys, and therefore it can be speculated that CD56 also contributes to the human hematopoietic system.

Extensive studies on perfusion method plus intra-bone marrow-bone marrow transplantation using cynomolgus monkeys.

The collection of bone marrow cells (BMCs) using a perfusion method has been advantageous not only because of the low contamination of BMCs with T cells from the peripheral blood but also the enrichment of stromal cells, which support hemopoiesis. Before the application of this new method to humans, its safety needed to be confirmed using cynomolgus monkeys. We therefore performed the perfusion method on more than 100 cynomolgus monkeys using the long bones (such as the humerus and femur) and also the iliac bones (for human application); in the more than 150 trials to date, there have been no accidental deaths. Furthermore, the technical safety of a new method for the intra-bone marrow (IBM) injection of BMCs (termed IBM-bone marrow transplantation) has also been confirmed using 30 monkeys. Disclosure of potential conflicts of interest is found at the end of this article.

The characteristics of hematopoietic stem cells from autoimmune-prone mice and the role of neural cell adhesion molecules in abnormal proliferation of these cells in MRL/lpr mice.

BACKGROUND AND OBJECTIVES: Using various animal models for autoimmune diseases, we have previously shown that such diseases are stem cell disorders.1 In order to understand how autoimmune diseases develop, we investigated the distinct qualitative differences between hematopoietic stem cells (HSC) from normal and autoimmune-prone mice. DESIGN AND METHODS: We studied the major histocompatibility complex (MHC) restriction between HSC and stromal cells in vitro and in vivo. We also examined the ability of HSC to adhere to a stromal cell line and, using flow cytometry, analyzed the expression of various adhesion molecules in HSC before and after the onset of autoimmune disease. In addition, the effect of antibodies to anti-adhesion molecules on the proliferation of HSC was investigated. RESULTS: The abnormal HSC of MRL/lpr mice showed no MHC restriction (or preference) with stromal cells either in vitro or in vivo, although there was MHC restriction between normal HSC and stromal cells, as we previously reported.2,3 The abnormal HSC of MRL/lpr mice exhibited enhanced adhesion to stromal cells in vitro and expressed a higher amount of adhesion molecules such as neural cell adhesion molecule (NCAM). Interestingly, the proliferation of HSC in MRL/lpr mice was significantly suppressed by anti-NCAM monoclonaal antibodies. INTERPRETATION AND CONCLUSIONS: Abnormal HSC of MRL/lpr mice are more resilient than normal HSC. Furthermore, among various adhesion molecules, only NCAM shows increased expression on HSC of MRL/lpr mice after the onset of autoimmune diseases, and these molecules contribute to the enhanced proliferation capacity of abnormal HSC in MRL/lpr mice. The present findings suggest that there are intrinsic qualitative differences between HSC from normal and autoimmune-prone MRL/lpr mice.

Analyses of very early hemopoietic regeneration after bone marrow transplantation: comparison of intravenous and intrabone marrow routes.

In bone marrow transplantation (BMT), bone marrow cells (BMCs) have traditionally been injected intravenously. However, remarkable advantages of BMT via the intra-bone-marrow (IBM) route (IBM-BMT) over the intravenous route (IV-BMT) have been recently documented by several laboratories. To clarify the mechanisms underlying these advantages, we analyzed the kinetics of hemopoietic regeneration after IBM-BMT or IV-BMT in normal strains of mice. At the site of the direct injection of BMCs, significantly higher numbers of donor-derived cells in total and of c-kit(+) cells were observed at 2 through 6 days after IBM-BMT. In parallel, significantly higher numbers of colony-forming units in spleen were obtained from the site of BMC injection. During this early period, higher accumulations of both hemopoietic cells and stromal cells were observed at the site of BMC injection by the IBM-BMT route. The production of chemotactic factors, which can promote the migration of a BM stromal cell line, was observed in BMCs obtained from irradiated mice as early as 4 hours after irradiation, and the production lasted for at least 4 days. In contrast, sera collected from the irradiated mice showed no chemotactic activity, indicating that donor BM stromal cells that entered systemic circulation cannot home effectively into recipient bone cavity. These results strongly suggest that the concomitant regeneration of microenvironmental and hemopoietic compartments in the marrow (direct interaction between them at the site of injection) contributes to the advantages of IBM-BMT over IV-BMT. Disclosure of potential conflicts of interest is found at the end of this article.

Human cord blood cells can differentiate into retinal nerve cells.

Retinal degeneration and dystrophy are the major causes of blindness in the developed world. It has been reported that human cord blood cells (HCBCs) can differentiate into neuron-like cells in vitro. We have recently demonstrated that bone marrow cells (BMCs) of both mice and rats can differentiate into retinal nerve cells (RNCs). In the present study, we show the differentiation capacity of HCBCs into RNCs in vivo. We transplanted lineage-negative HCBCs into the subretinal space of severe combined immunodeficiency (SCID) mice. Two weeks after the transplantation, some of the transplanted cells expressed human nestin, human MAP2, human neuron specific enolase (NSE), beta-III tubulin and also rhodopsin. These results indicate that HCBCs can differentiate into RNCs and suggest that our new strategy could be used for the regeneration of retinal nerve cells in degenerative or dystrophic diseases.

Cigarette smoke extract enhances oxytocin-induced rhythmic contractions of rat and human preterm myometrium.

Although smoking during pregnancy is a major risk factor for preterm delivery, the underlying mechanism by which smoking stimulates uterine contractions is still poorly understood. In the present study, we tried to clarify the effects of smoking on myometrial contractility induced by oxytocin (OT) using cigarette smoke extract (CSE). Myometrial strips, which were taken from the rat on day 16 of pregnancy, and from human preterm and term delivery groups, were incubated overnight with several doses of CSE at 37 degrees C under non-hormonal conditions. The uterine contractile sensitivity and activity (force and frequency) upon exposure to OT were investigated. Furthermore, the expression levels of oxytocin receptor (OTR) mRNA in the myometrial strips were investigated by real-time PCR. Contractile sensitivity to OT in the rat CSE (10(-7) pieces/ml) group was found to be significantly higher than in the control group (P < 0.05). Contractile activity did not differ between the CSE and control groups. The expression levels of rat OTR mRNA in the CSE (10(-7) pieces/ml) group were significantly higher than in the control group (P < 0.01). Similarly, in preterm myometrial strips, the expression levels of human OTR mRNA in the CSE (10(-7) pieces/ml) group were significantly higher than in the control group (P < 0.05). These findings suggest that CSE directly increases the contractile sensitivity of preterm myometrium in response to OT by upregulating the expression of OTR mRNA and thereby increases the risk of preterm delivery in women, who smoke during pregnancy.

Primary relapse of acute lymphoblastic leukemia in a cervical smear: a case report.

Uterine cervix and corpus are rarely the initial site of relapse in leukemia or lymphoma. We report herein a case of uterine cervical relapse with B-cell acute lymphoblastic leukemia (ALL). The patient, a 60-yr-old woman, had a history of ALL that had been in remission for 2 yr after chemotherapy. She presented with a chief complaint of genital bleeding. In a routine cervico-vaginal Papanicolau smear, abundant atypical lymphoid cells with round-to-oval nuclei, scant cytoplasm, and high nuclear to cytoplasmic ratios was observed. The nuclei of these cells had fine and dark chromatin and thickened nuclear membranes, with one or several nucleoli being visible. Biopsy under colposcope was performed, and a diagnosis of relapse of ALL was confirmed. The ongoing genital bleeding presented a problem with clinical management of the patient. It was decided to proceed with hysterectomy to end that problem and thereafter proceed with therapy directed against the leukemia. Our results suggest that in patients with known extrauterine cancer, the presence of malignancy in uterine cellular samples provides information regarding the extent of the neoplasm.

Treatment of senile osteoporosis in SAMP6 mice by intra-bone marrow injection of allogeneic bone marrow cells.

A substrain of the senescence-accelerated mouse, SAMP6 (senescence-accelerated mouse prone 6), spontaneously develops osteoporosis early in life. Therefore, this strain is a useful animal model for developing new strategies for the treatment of osteoporosis in humans. We succeeded in treating osteoporosis in SAMP6 mice after the onset of this disease, using a newly developed method of bone marrow transplantation (BMT): Allogeneic bone marrow cells obtained from normal mouse strains were directly injected into the bone marrow cavity of irradiated SAMP6 mice (intra-bone marrow BMT [IBM-BMT]). After the treatment with IBM-BMT, hematolymphoid cells were completely reconstituted by donor-derived cells, and bone marrow stromal cells were also found to be of donor origin. The treated SAMP6 mice showed histologically-normal trabecular bone. In addition, bone mineral density and urinary deoxypiridinoline, a hallmark of bone destruction, were normalized. When the message levels of cytokines (tumor necrosis factor alpha, interleukin-6 [IL-6], IL-11, and receptor activator of nuclear factor-kappa B ligand [RANKL]) were examined, IL-11, RANKL (from bone marrow stromal cells), and IL-6 (from osteoclasts), which regulate bone remodeling, were restored to levels similar to those in normal B6 mice. These findings indicate that not only the hemopoietic system but also the bone marrow microenvironment were normalized after IBM-BMT, resulting in an amelioration of the imbalance between bone absorption and formation.