Appropriateness of surgical antimicrobial prophylaxis in Japanese university hospitals.

BACKGROUND: Surgical antimicrobial prophylaxis (SAP) is one of the major purposes of antimicrobial use. AIM: To determine the adherence to the Japanese SAP guidelines in Japanese university hospitals. METHODS: This was a retrospective cohort study including 15 general hospitals and one dental university hospital. Up to three cases of 18 designated surgeries were evaluated regarding adherence to Japanese SAP guidelines: selection of antibiotics, timing of administration, re-dosing intervals, and duration of SAP. When all items were appropriate, surgery was defined as 'appropriate'. FINDINGS: In total, 688 cases (22-45 cases per surgery) were included. The overall appropriateness was 46.8% (322/688), and the appropriateness of each surgery ranged from 8.0% (2/25, cardiac implantable electronic device implantation) to 92.1% (35/38, distal gastrectomy). The appropriateness of each item was as follows: pre/intraoperative selections, 78.5% (540/688); timing of administrations, 96.0% (630/656); re-dosing intervals, 91.6% (601/656); postoperative selection, 78.9% (543/688); and duration of SAP, 61.4% (423/688). The overall appropriateness of hospitals ranged from 17.6% (9/51) to 73.3% (33/45). The common reasons for inappropriateness were the longer duration (38.5%, 265/688) and choice of antibiotics with a non-optimal antimicrobial spectrum before/during, and after surgery (19.0%, 131/688 and 16.9%, 116/688, respectively), compared to the guideline. CONCLUSIONS: Adherence to the guidelines differed greatly between the surgeries and hospitals. Large-scale multi-centre surveillance of SAP in Japanese hospitals is necessary to identify inappropriate surgeries, factors related to the appropriateness, and incidences of surgical site infections.

Five-year point prevalence survey of healthcare-associated infections and antimicrobial use in a Japanese university hospital.

BACKGROUND: Periodic point prevalence surveys (PPSs) provide a method for assessing changes in healthcare-associated infections (HAIs) and antimicrobial use over time. Following the introduction of an antimicrobial stewardship programme at Nagoya University Hospital (Aichi, Japan) a five-year PPS study was performed to highlight any epidemiological changes. METHODS: One-day PPSs were performed annually in July at Nagoya University Hospital. Data on patient characteristics, medical devices, active HAIs and antimicrobial use were collected using a standard data-collection form. RESULTS: A total of 4339 patients were included. Over the five-year study period the median patient age was 62 years, median duration of hospital admission was nine days, 9% of patients had an HAI and 35.2% received at least one antimicrobial. Overall there were 406 HAIs (95% confidence interval, 369-447) with surgical site infection, pneumonia and febrile neutropenia occurring most frequently. Enterobacterales were the most common pathogens (N = 78, 28.6%) and 32.1% were third-generation cephalosporin-resistant. Meropenem was the most frequently prescribed antimicrobial for HAIs. Surgical antimicrobial prophylaxis changed drastically, with shorter durations and a marked reduction in oral cephalosporin use. However, antimicrobials for medical prophylaxis gradually increased. CONCLUSIONS: This five-year PPS study shows consistent data for patient background, HAIs and causative pathogens and highlights changes in antimicrobial use during the era of the National Action Plan on Antimicrobial Resistance. To describe the epidemiology of Japanese hospitals by PPS, multicentre PPSs including in community hospitals should be performed annually.

The first multi-centre point-prevalence survey in four Japanese university hospitals.

BACKGROUND: The Japanese government adopted a national action plan on antimicrobial resistance, which aims to reduce drug-resistant pathogens and antimicrobial use. A point-prevalence survey (PPS) is a useful surveillance method to gain information about hospital epidemiology; however, no multi-centre PPS has previously been performed in Japan. AIM: To investigate general information about hospital epidemiology, healthcare-associated infections (HCAIs), and antimicrobial use in multiple Japanese university hospitals. METHODS: In July 2016, a multi-centre PPS was conducted using a standardized protocol at four university hospitals in Japan. FINDINGS: A total of 3199 patients were included. Median age and duration of hospital stay were 64 years and 10 days, respectively. A total of 246 (7.7%; 95% confidence interval (CI): 6.8-8.7) patients had 256 active HCAIs, and 933 (29.2%; 95% CI: 27.6-30.8) patients received 1318 antimicrobials. Pneumonia and gastrointestinal system infection were the most common HCAIs (N = 42, 16.4%), and Enterobacteriaceae (N = 49, 30.8%) were the predominant causative organisms. Carbapenems (N = 52, 17.8%), anti-MRSA medications, and cephems with antipseudomonal activity were the most frequently prescribed antimicrobials for HCAIs. As surgical prophylaxis, 46 of 278 antimicrobials (16.5%) were administered orally. Proportions of HCAI and antimicrobial use in each hospital ranged from 4.8% to 9.5% and 19.3%-35.0%, respectively. CONCLUSION: This multi-centre PPS recorded detailed HCAI data and distinct antimicrobial use in Japanese university hospitals. Further surveillance is necessary to reduce HCAIs and formulate feasible plans to achieve the national action plan on antimicrobial resistance.

Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology.

Diagnosis and treatment of bone metastasis requires various types of measures, specialists and caregivers. To provide better diagnosis and treatment, a multidisciplinary team approach is required. The members of this multidisciplinary team include doctors of primary cancers, radiologists, pathologists, orthopaedists, radiotherapists, clinical oncologists, palliative caregivers, rehabilitation doctors, dentists, nurses, pharmacists, physical therapists, occupational therapists, medical social workers, etc. Medical evidence was extracted from published articles describing meta-analyses or randomised controlled trials concerning patients with bone metastases mainly from 2003 to 2013, and a guideline was developed according to the Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Multidisciplinary team meetings are helpful in diagnosis and treatment. Clinical benefits such as physical or psychological palliation obtained using the multidisciplinary team approaches are apparent. We established a guideline describing each specialty field, to improve understanding of the different fields among the specialists, who can further provide appropriate treatment, and to improve patients' outcomes.

Objective tumor response to denosumab in patients with giant cell tumor of bone: a multicenter phase II trial.

BACKGROUND: Giant cell tumor of bone (GCTB) is a rare primary bone tumor, characterized by osteoclast-like giant cells that express receptor activator of nuclear factor-kappa B (RANK), and stromal cells that express RANK ligand (RANKL), a key mediator of osteoclast activation. A RANKL-specific inhibitor, denosumab, was predicted to reduce osteolysis and control disease progression in patients with GCTB. PATIENTS AND METHODS: Seventeen patients with GCTB were enrolled. Patients were treated with denosumab at 120 mg every 4 weeks, with a loading dose of 120 mg on days 8 and 15. To evaluate efficacy, objective tumor response was evaluated prospectively by an independent imaging facility on the basis of prespecified criteria. RESULTS: The proportion of patients with an objective tumor response was 88% based on best response using any tumor response criteria. The proportion of patients with an objective tumor response using individual response criteria was 35% based on the modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 82% based on the modified European Organization for Research and Treatment of Cancer (EORTC) criteria, and 71% based on inverse Choi criteria. The median time of study treatment was 13.1 months. CONCLUSION: The findings demonstrate that denosumab has robust clinical efficacy in the treatment of GCTB.

TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state.

Chronic inflammation is frequently associated with tumorigenesis in elderly people. By contrast, young people without chronic inflammation often develop tumors considered independent of chronic inflammation but driven instead by mutations. Thus, whether inflammation has a significant role in tumor progression in tumors driven by mutations remains largely unknown. Here we show that TNFα is required for the tumorigenesis of osteosarcoma, the most common tumor in children and adolescents. We show that transplantation of AX osteosarcoma cells, which harbor mutations driving c-Myc overexpression and Ink4a-deficiency, in wild-type mice promotes lethal tumorigenesis accompanied by ectopic bone formation and multiple metastases, phenotypes seen in osteosarcoma patients. Such tumorigenesis was completely abrogated in TNFα-deficient mice. AX cells have the capacity to undergo osteoblastic differentiation; however, that activity was significantly inhibited by TNFα treatment, suggesting that TNFα maintains AX cells in an undifferentiated state. TNFα inhibition of AX cell osteoblastic differentiation occurred through ERK activation, and a pharmacological TNFα inhibitor effectively inhibited both AX cell tumorigenesis and increased osteoblastic gene expression and increased survival of tumor-bearing mice. Lethal tumorigenesis of AX cells was also abrogated in IL-1α/IL-1ß doubly deficient mice. We found that both TNFα and IL-1 maintained AX cells in an undifferentiated state via ERK activation. Thus, inflammatory cytokines are required to promote tumorigenesis even in mutation-induced tumors, and TNFα/IL-1 and ERK may represent therapeutic targets for osteosarcoma.

Primary primitive neuroectodermal tumor of the conus medullaris in an elderly patient: a case report and review of the literature.

Primary spinal primitive neuroectodermal tumors (PNETs) are very rare conditions. Most of these tumors occur in children and young adults. A 63-year-old man with a primary spinal PNET in the conus medullaris from the L1 to L2 level is presented in this report. The optimal treatment of primary spinal PNETs is yet unknown. Surgical resection, radiation therapy, and chemotherapy have been advocated for the treatment of spinal PNET based on PNETs at other sites. However, the outcome is very poor. There are a few reports of cases with long-term survival and no recurrence. In these patients, en bloc resections were performed.

Non-D Rh antibodies appearing after apheresis platelet transfusion: stimulation by red cells or microparticles?

BACKGROUND: Apheresis platelets (APs) have gained favour over whole blood-derived platelets on the presumption that they are less likely to provoke alloimmunization to red-blood-cell antigens. CASE REPORTS: Non-D Rh antibodies appeared in three patients after apheresis platelet transfusion. Anti-C and anti-E arose in two female patients with previous antigen exposure. Both anti-c and anti-E arose in a male recipient with no prior transfusion history. MATERIALS AND METHODS: Fifty APs were analysed for residual RBCs and RBC-derived microparticles, using samples obtained from a local blood centre. Cells and microparticles were quantified with a flow cytometry gating scheme, using PE-labelled anti-CD235a (glycophorin A) and FITC-labelled anti-CD41a (platelet gp IIb/IIIa) to distinguish lineage. RESULTS: Apheresis platelets were found to contain a mean of 7·5×10(6) (95% C.I. [6·3-8·5×10(6) ]) RBCs on one manufacturer's device and 5·2×10(6) (95% C.I. [4·0-6·3×10(6) ]) RBCs on another's. RBC-derived microparticles averaged 210·7×10(6) (95% C.I. [166·2-254·2×10(6) ]) on one manufacturer's device and 232·3×10(6) (95% C.I. [194·3-272·9×10(6) ]) on another's. These counts all correspond to volumes of <1 µl. CONCLUSION: Despite RBC contamination of APs below commonly accepted thresholds for Rh immunogenicity, AP transfusion can provoke non-D Rh antibody formation. RBC-derived microparticles, smaller but more numerous than RBCs, are volumetrically comparable and may be a hitherto underappreciated antibody stimulus. Further microparticle research will guide considerations of extended phenotypic matching of platelet components.

c-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis.

The development of cancer is due to the growth and proliferation of transformed normal cells. Recent evidence suggests that the nature of oncogenic stress and the state of the cell of origin critically affect both tumorigenic activity and tumor histological type. However, this mechanistic relationship in mesenchymal tumors is currently largely unexplored. To clarify these issues, we established a mouse osteosarcoma (OS) model through overexpression of c-MYC in bone marrow stromal cells (BMSCs) derived from Ink4a/Arf (-/-) mice. Single-cell cloning revealed that c-MYC-expressing BMSCs are composed of two distinctly different clones: highly tumorigenic cells, similar to bipotent-committed osteochondral progenitor cells, and low-tumorigenic tripotent cells, similar to mesenchymal stem cells (MSCs). It is noteworthy that both bipotent and tripotent cells were capable of generating histologically similar, lethal OS, suggesting that both committed progenitor cells and MSCs can become OS cells of origin. Shifting mesenchymal differentiation by depleting PPARγ in tripotent MSC-like cells and overexpressing PPARγ in bipotent cells affected cell proliferation and tumorigenic activity. Our findings indicate that differentiation potential has a key role in OS tumorigenic activity, and that the suppression of adipogenic ability is a critical factor for the development of OS.

Curettage and allograft reconstruction for giant cell tumours.

PURPOSE: To evaluate treatment outcomes in patients with giant cell tumours after curettage and allograft reconstruction and to identify the risk factors for poor oncological and functional outcome. METHODS: 29 patients with giant cell tumours of bone who underwent curettage and allograft reconstruction were retrospectively reviewed. The adjuvants used were heat treatment by electrocautery and hot water. Types of allograft used, time to bone union, complications, functional outcomes, and risk factors for poor function were analysed. RESULTS: The mean time to bone union was 2.8 (range, 1-5) months. In 7 patients the tumours recurred (6 within 2 years); the 5-year recurrence-free survival rate was 77%. Three recurrences were classified as grade III and 4 as grade II; recurrence and the Campanacci grade showed a trend towards association (p=0.06). Tumour in the distal femur was a risk factor for postoperative fracture (p=0.02). Functional outcomes were excellent in 20 patients, good in 6, fair in 2, and a failure in one. The risk factors for poor function were recurrence (p=0.002) and joint instability (p=0.008) but not the Campanacci grade (p=0.10) or postoperative fracture (p=0.76). Lung metastasis, infection, and non-union were not encountered. CONCLUSION: Despite a relatively high recurrence rate (24%), 26 (90%) of the 29 patients had excellent/good functional outcomes. We recommend the use of adjuvants and allografts for the management of giant cell tumours.

Clinical significance of additional wide resection for unplanned resection of high grade soft tissue sarcoma.

PURPOSE: Unplanned resection of musculoskeletal sarcoma involves tumor excision without any suspicion of malignancy or regard for the necessity of defining adequate margins. For orthopaedic oncologists, many opportunities arise for management of unplanned resections initially performed by non-specialist surgeons. The puropose of this study is to assess the clinical outcomes and the problems of the patients with unplanned resection of high-grade soft tissue sarcoma. METHODS: 77 consecutive patients were retrospectively reviewed. Oncological outcomes together with validity and problems of additional treatments were analyzed. RESULTS: Five-year local recurrence-free survival, metastasis-free survival, event-free survival and total survival were 71.55%, 73.2%, 57.5% and 85.9%, respectively. Among adjuvant therapy including additional wide resection, radiotherapy and systemic chemotherapy, only additional wide resection significantly improved oncological outcomes. CONCLUSION: Additional wide resection appears to be effective in the treatment of high-grade soft tissue sarcomas following primary resection with compromised margins of resection.

Epithelioid sarcoma arising on the forearm of a 6-year-old boy: case report and review of the literature.

Epithelioid sarcoma is a rare malignant tumor that occurs mainly in young adults and most frequently involves the distal portion of the upper extremities. The tumor is particularly rare in children and more frequently involves the head and neck; only one case involving the forearm has been reported in a child under 10 years of age, and he was treated with amputation. We report the case of a 6-year-old boy with an epithelioid sarcoma of the forearm whose initial management had been inappropriate. The patient was ultimately treated with limb sparing surgery. Two years later, no local recurrence was evident but pleural metastases were detected.

Bilateral multiple malignant transformation of Ollier's disease.

We treated a 26-year-old man with a 19-year history of Ollier's disease. Secondary chondrosarcomas developed metachronously at four separate locations: both femora, left proximal tibia and fibular head. All four lesions were surgically excised, and each specimen was histologically identified as grade 1 or 2 chondrosarcoma. Clinical follow-up for 20 years beginning at the time of first tumor surgery has shown no evidence of local recurrence or metastasis. This is the first report of multiple bilateral metachronous malignant transformation of multiple chondromatoses in a patient with Ollier's disease.

Thallium-201 single-photon emission computed tomography in the detection of retroperitoneal schwannoma.

We describe a patient with retroperitoneal schwannoma whose tumour was detectable by 201Tl single-photon emission computed tomography (SPECT). Physiologic uptake in the alimentary tract did not hamper the interpretation on SPECT images. Uptake by the tumour extending along the spinal nerve root was well recognised in axial and coronal images. Our results suggest that 201Tl SPECT may be useful in the detection of retroperitoneal schwannomas.

Nonviral genetic transfer of Fas ligand induced significant growth suppression and apoptotic tumor cell death in prostate cancer in vivo.

To accomplish efficient nonviral gene therapy against prostate cancer (PC), Epstein-Barr virus (EBV)-based plasmid vectors containing EBNA1 gene and oriP were employed and combined with a cationic polymer or cationic lipid. When EBV-plasmid/poly-amidoamine dendrimer complex was injected into PC-3-derived tumors established in severe combined immunodeficiency mice, a considerable expression of marker gene was obtained in the tumors, and the expression level was more than eight-fold higher than that achieved by conventional plasmid vector/dendrimer. Since most PC cells express the apoptotic signal molecule Fas (Apo-1/CD95) on their surface, Fas ligand (FasL) gene was transferred into PC cells to kill the tumor cells. In vitro transfection with pGEG.FasL (an EBV-plasmid with the FasL gene) significantly reduced the viability of PC cells, which subsequently underwent apoptosis. Intratumoral injections of pGEG.FasL into PC induced significant growth suppression of the xenograft tumors, in which typical characteristics of apoptosis were demonstrated by TUNEL staining and electron microscopic observations. When pGEG.FasL transfer was accompanied by systemic administrations of cisplatin, the tumors were inhibited even more remarkably, leading to prolonged survival of the animals. FasL gene transfection by means of EBV-based plasmid/cationic macromolecule complexes may provide a practical therapeutic strategy against PC.

Multiple early gastric cancer associated with sarcoid-like reaction in the regional lymph nodes.

A 68-year-old man was admitted to our hospital because of epigastric pain. An upper gastrointestinal contrast study and endoscopy revealed a II c type tumor in the posterior wall of the pyloric antrum. and computed tomography showed lymph node enlargement along the left gastric artery. Operation was performed after a presumptive diagnosis of gastric cancer with lymph node involvement. During the laparotomy, more extensive lymphadenopathy was found than was detected preoperatively, and tumor metastasis was suspected because of its firmness. Distal partial gastrectomy with D, and more extensive lymph node dissection were performed. Subsequently, the histology of permanent sections revealed not tumor metastasis but a sarcoid-like reaction in the lymph nodes. The patient recovered uneventfully: however, he was killed in an accident 38 months after the surgery. A postmortem examination was not performed, but there had been no clinical signs of either recurrence of gastric cancer or sarcoidosis.

Evidence that HAX-1 is an interleukin-1 alpha N-terminal binding protein.

During studies aimed at understanding the function of the N-terminal peptide of interleukin-1 alpha (IL-1 NTP, amino acids 1-112), which is liberated from the remainder of IL-1 alpha during intracellular processing, we identified by yeast two-hybrid analysis a putative interacting protein previously designated as HAX-1. In vitro binding studies and transient transfection experiments confirmed that HAX-1 can associate with the IL-1 NTP. HAX-1 was first identified as a protein that associates with HS1, a target of non-receptor protein tyrosine kinases within haematopoietic cells. Recent data have also revealed interactions between HAX-1 and three disparate proteins, polycystin-2 (derived from the PKD2 gene), a protein linked to polycystic kidney disease, cortactin, and Epstein-Barr virus nuclear antigen leader protein (EBNA-LP). Sequence analysis of different HAX-1 binding domains revealed a putative consensus binding motif that is present in various intracellular proteins. Overlapping peptides comprising the IL-1 NTP were synthesized, and binding experiments revealed that discrete peptides were capable of interacting with HAX-1. HAX-1 may serve to retain the IL-1 NTP in the cytoplasm, and complex formation between the IL-1 NTP and HAX-1 may play a role in motility and/or adhesion of cells.

Damaged DNA-binding protein DDB stimulates the excision of cyclobutane pyrimidine dimers in vitro in concert with XPA and replication protein A.

Human cells contain a protein that binds to UV-irradiated DNA with high affinity. This protein, damaged DNA-binding protein (DDB), is a heterodimer of two polypeptides, p127 and p48. Recent in vivo studies suggested that DDB is involved in global genome repair of cyclobutane pyrimidine dimers (CPDs), but the mechanism remains unclear. Here, we show that in vitro DDB directly stimulates the excision of CPDs but not (6-4)photoproducts. The excision activity of cell-free extracts from Chinese hamster AA8 cell line that lacks DDB activity was increased 3-4-fold by recombinant DDB heterodimer but not p127 subunit alone. Moreover, the addition of XPA or XPA + replication protein A (RPA), which themselves enhanced excision, also enhanced the excision in the presence of DDB. DDB was found to elevate the binding of XPA to damaged DNA and to make a complex with damaged DNA and XPA or XPA + RPA as judged by both electrophoretic mobility shift assays and DNase I protection assays. These results suggest that DDB assists in the recognition of CPDs by core NER factors, possibly through the efficient recruitment of XPA or XPA.RPA, and thus stimulates the excision reaction of CPDs.

Perinatal development of the rat kidney: proliferative activity and epidermal growth factor.

The immunolocalization of proliferating cell nuclear antigen (PCNA), epidermal growth factor (EGF) and its receptor (EGFR) was examined in the perinatal rat kidney. As the index of proliferative activity, PCNA-positive cell ratios in glomeruli and proximal tubules were determined. The PCNA-positive ratios in both glomeruli and proximal tubules decreased significantly during the perinatal period and tended to decrease as the glomerular developmental stage proceeded as well. PCNA-positive cells were seen predominantly in the nephrogenic zone of the kidney throughout the period examined. They were noted in the collecting ducts of the nephrogenic zone and were rarely seen in those of the central zone of the kidney. On the other hand, PCNA-positive cells were noted in the straight portion of the proximal tubules and were rarely seen in the convoluted one. EGF-positive cells were seen in the proximal tubules, distal tubules and collecting ducts, though EGF-positive cells in the proximal tubules decreased after birth. EGFR-positive cells were seen along the entire length of the proximal tubules and collecting ducts as well as in immature glomeruli, not in mature ones. These results indicate that marked cell proliferation occurs in the collecting ducts in the peripheral area and in the proximal tubules in the central area of the kidney, that the proliferative activity decreases with age during the perinatal days and that EGF plays an important role in the proliferation of glomerular cells, and in both proliferation and maturation of the cells in the proximal tubules and collecting ducts.

In vitro chemosensitivity of human soft tissue sarcoma.

Chemotherapy is essential in the treatment of small round cell sarcomas. However, as yet there is no progress concerning the efficacy of chemotherapy in the treatment of other types of soft tissue tumors (STS). The Histoculture Drug Response Assay (HDRA) is an in vitro chemosensitivity test that has a high correlation with clinical response, the usefulness of which has been reported in various kinds of solid tumors. However, there has never been a report on its use in STS until now. In this study, in order to investigate the variation in chemosensitivity in STS, fresh biopsy or surgical samples of STS were tested using the HDRA method. Drug sensitivity testing by HDRA showed that two drugs, ADM and THP, had a significantly higher inhibitory rate than CDDP, IFOS, or VP-16 in the thirty-three soft tissue sarcomas tested. Depending on the morphological type, spindle cell sarcomas were sensitive to THP, which showed significantly higher inhibition rates than CDDP, IFOS, or VP-16. Small round cell sarcomas were relatively sensitive to all of the drugs tested. However the drug sensitivity of pleomorphic cell sarcoma was low except for ADM and THP, while its sensitivity to THP was higher than about 70%. However, there are numerous other soft tissue sarcomas that do not belong to these categories; drug sensitivity testing in each of them and the devising of individualized treatment strategies seems necessary to improve the therapeutic outcome.