Impact of Flagging/Risk Stratification System on Complications in Hospitalist Hip Fracture Co-management: Retrospective Cohort Study.

Purpose: Hip fractures are associated with high morbidity and mortality, the rates of which can be improved by comprehensive care. To improve hospitalist co-management of hip fractures, we designed and implemented hip fracture template (HFT), a flagging and risk stratification algorithm system. It includes consideration of perioperative management and preventative measures against hip fractures. We examined its effect on morbidity in patients with hip fractures and the factors associated with complications. Methods: We conducted a retrospective cohort study of patients who underwent surgery for hip fracture. The primary outcome was the perioperative complication rate, comparing patients managed with and without HFT. Multivariate analysis was adjusted for age, gender, and any significant variables shown in univariate analysis. Results: HFT was used in 121 patients and not used in 147 patients. In univariate analysis, patients were less likely to have complications if HFT was used (19.0% vs. 29.9%, P = 0.047), but there was no difference in length of stay (17 days vs. 17 days, P = 0.27) or in-hospital-mortality (0.8% vs. 0.7%, P = 1.00) between the groups. In adjusted analysis, patients managed by HFT had lower likelihood of complications (OR 0.55, 95% CI 0.31-0.98). Among patients managed by HFT, those with revised cardiac risk index (RCRI) ≥ 1 were more likely to have complications in both univariate (42.1% vs. 14.7%, P = 0.01) and adjusted analysis (OR 3.37, 95% CI 1.03-10.84). Conclusion: Patients with hip fractures managed with HFT were less likely to have complications, especially those with RCRI ≥ 1, suggesting benefits of using HFT.

Revision surgery in a middle-aged patient with pertrochanteric fracture nonunion due to wedge effect caused by cephalomedullary nail: A case report.

Trochanteric femur fractures have traditionally been treated surgically with compression hip screws or cephalomedullary nails. With the increasing use of cephalomedullary nails, potential complications from this technique have surfaced. One of them is the potential for varus malreduction of trochanteric femur fractures, known as the "wedge effect", which is the distraction of fracture fragments generated during reamer and nail passage resulting in varus malalignment at the neck-shaft angle. Although trochanteric nonunion in the non-elderly is exceedingly rare, we experienced one such case after nailing due to the wedge effect that was subsequently successfully treated with a compression hip screw without bone grafting. Therefore, in the case of stable pertrochanteric fractures (AO/OTA 31A1) in younger patients, compression hip screw surgery may be the better choice of initial surgery to avoid later nonunion.

Multicenter study on atypical femoral fractures in patients with bone metastases taking bone- modifying agents.

Bone-modifying agents (BMAs), with bone-resorptive inhibitory effects, such as zoledronic acid and denosumab, are widely used at higher doses for bone-related events caused by bone metastasis of malignant tumors. These drugs have been suggested to be associated with atypical femoral fractures (AFFs), and the relationship between BMAs and AFFs has attracted attention. To investigate the clinical features including bone union time of AFFs in patients administered BMA for bone metastasis, we conducted a retrospective multicenter study. Thirty AFFs from 19 patients were enrolled in this study. Thirteen patients had bilateral AFFs, and nineteen AFFs had prodromal symptoms. Eighteen AFFs underwent surgery after complete fracture, three failed to achieve bone union and required nonunion surgery, and 11 AFFs that achieved bone union had an average period until bone union of 16.2 months, which was much longer than that previously reported for ordinary AFFs. Seven patients discontinued the BMAs, but not due to AFFs. Stopping BMAs in patients with bone metastasis would make it difficult to secure their performance of activities of daily living, and AFF with BMA administration might require a longer time for union. Therefore, it would be important to prevent incomplete AFF from becoming complete AFF via prophylactic internal fixation.

High-throughput and simultaneous analysis of eight central-acting muscle relaxants in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry in the positive and negative ionization modes.

In this report, a high-throughput and sensitive method for analysis of eight central-acting muscle relaxants in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in the positive and negative ionization modes using tolbutamide as internal standard is presented. After pretreatment of a plasma sample by solid-phase extraction with an Oasis HLB cartridge, muscle relaxants were analyzed by UPLC with Acquity UPLC BEH C(18) column and Acquity TQD tandem quadrupole mass spectrometer equipped with an electrospray ionization interface. The calibration curves for muscle relaxants spiked into human plasma equally showed good linearities in the nanogram per milliliter order range. The detection limits (signal-to-noise ratio = 3) was as low as 0.1-2 ng/mL. The method gave satisfactory recovery rates, accuracy, and precision for quality control samples spiked with muscle relaxants. To further validate the present method, 250 mg of chlorphenesin carbamate was orally administered to a healthy male volunteer, and the concentrations of chlorphenesin carbamate in plasma were measured 0.5, 1, 2, 4, 6, and 8 h after dosing; their concentrations in human plasma were between 0.62 and 2.44 µg/mL. To our knowledge, this is the first report describing simultaneous analysis of over more than two central-acting muscle relaxants by liquid chromatography-tandem mass spectrometry. This has been realized by the capability of our instrument for simultaneous multiple reaction monitoring of the target compounds in both positive and negative ionization modes. Therefore, the present method seems very useful in forensic and clinical toxicology and pharmacokinetic studies.

Spinal Subarachnoid Hematoma After Cerebrospinal Fluid Drainage in Thoracoabdominal Aortic Aneurysm Repair: Case Report and Literature Review.

BACKGROUND: Cerebrospinal fluid (CSF) drainage reduces the risk of paraplegia in thoracoabdominal aortic aneurysm (TAAA) repair. Intracranial hemorrhage after TAAA repair has been reported as a rare complication of CSF drainage; however, spinal subarachnoid hematoma has never been reported. Here, we present a case of lumbosacral subarachnoid hematoma after CSF drainage in TAAA repair. CASE DESCRIPTION: The patient was a 76-year-old man who was hospitalized for TAAA repair. Just before the operation, a CSF drainage catheter was inserted into the L4/5 vertebral interspace. Continuous CSF drainage was performed during the operation. The CSF drain was clamped just after the operation, and the drainage catheters were removed at 24 hours after the operation. On postoperative day 1, the patient experienced pain and paralysis in both lower limbs that worsened over time. Magnetic resonance imaging of the brain and spinal cord was indicative of a spinal subarachnoid hematoma. Removal of hematoma with thoracolumbar and lumbosacral laminectomy was performed, and immediately after the surgery, the pain and paralysis in both lower limbs improved. Six months after the removal of the hematoma, the paralysis in both lower limbs completely resolved and the patient achieved the preinjury activity level. CONCLUSIONS: We present a rare case of lumbosacral subarachnoid hematoma after CSF drainage in TAAA repair. We should consider spinal subarachnoid hematoma when paralysis in the lower limbs occurs after CSF drainage.

Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors.

FGFR signaling is deregulated in many human cancers, and FGFR is considered a valid target in FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3, 4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 with IC50 values of 1.4 to 3.7 nmol/L. Futibatinib covalently bound the FGFR kinase domain, inhibiting FGFR phosphorylation and, in turn, downstream signaling in FGFR-deregulated tumor cell lines. Futibatinib exhibited potent, selective growth inhibition of several tumor cell lines (gastric, lung, multiple myeloma, bladder, endometrial, and breast) harboring various FGFR genomic aberrations. Oral administration of futibatinib led to significant dose-dependent tumor reduction in various FGFR-driven human tumor xenograft models, and tumor reduction was associated with sustained FGFR inhibition, which was proportional to the administered dose. The frequency of appearance of drug-resistant clones was lower with futibatinib than a reversible ATP-competitive FGFR inhibitor, and futibatinib inhibited several drug-resistant FGFR2 mutants, including the FGFR2 V565I/L gatekeeper mutants, with greater potency than any reversible FGFR inhibitors tested (IC50, 1.3-50.6 nmol/L). These results indicate that futibatinib is a novel orally available, potent, selective, and irreversible inhibitor of FGFR1-4 with a broad spectrum of antitumor activity in cell lines and xenograft models. These findings provide a strong rationale for testing futibatinib in patients with tumors oncogenically driven by FGFR genomic aberrations, with phase I to III trials ongoing. SIGNIFICANCE: Preclinical characterization of futibatinib, an irreversible FGFR1-4 inhibitor, demonstrates selective and potent antitumor activity against FGFR-deregulated cancer cell lines and xenograft models, supporting clinical evaluation in patients with FGFR-driven tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/22/4986/F1.large.jpg.

A palmar fracture-dislocation of the proximal interphalangeal joint of the middle finger caused by bowling: a case report.

During bowling, a twenty year old man could not pull out his middle finger from the ball in release and injured his finger. X-ray revealed a palmar fracture- dislocation of the PIP joint. We manipulated the PIP joint, but a gap remained at the fracture site on the X-ray after reduction. Surgical treatment was performed with a screw. Postoperatively, the middle finger was fixed with a splint for two weeks, and then active range of motion exercises were started. One year after the operation, the fracture had healed with a congruous joint surface, and the patient had full range of motion in the middle finger with no difficulties in activities of daily living. The etiology of a palmar fracture-dislocation of the PIP joint is still controversial, but we suggested the mechanism of the fracture-dislocation was caused by a shearing force to the middle phalangeal base from a dorsal direction. The main cause of the current injury was the poor fit between the middle finger and the hole of the bowling ball. Bowling is a popular and safe sport, but we should be aware of unexpected hand injuries related to bowling which may occur, especially in players at a recreational level. Key pointsWe presented a palmar fracture-dislocation of the PIP joint in a middle finger that occured while bowling.We discussed the mechanism and suggested the main cause of the injury was the poor fit between the middle finger and the hole of the bowling ball.We advised that while bowling is recognized as a safe sport, due to its popularity we should be aware of unexpected hand injuries which may occur, especially in players at a recreational level.

Trapezoid Fracture Associated with Scaphoid Fracture in a Football Goalkeeper.

INTRODUCTION: Trapezoid fractures are uncommon in sports. We presented a rare case of a trapezoid fracture associated with a scaphoid fracture caused by punching a ball in a football goalkeeper. CASE PRESENTATION: A 19-year-old male who played as a football goalkeeper visited our hospital with complaints of sustained pain from the right wrist to the hand after punching a ball. Scaphoid fracture was diagnosed on plain radiographs, whereas trapezoid fracture was overlooked. Computed tomography revealed a displaced trapezoid fracture associated with a scaphoid fracture. Both fractures were successfully treated by open reduction and internal fixation using cannulated screws. Almost complete bone union was achieved at 5 months after surgery. The patient returned to play as a football goalkeeper. CONCLUSION: The simultaneous occurrence of trapezoid and scaphoid fractures has never been reported. Trapezoid fractures are rare and can be overlooked on plain radiographs, as what happened in the present case, because the trapezoid is small and overlaps with other carpal bones on plain radiographs. If there is sustained pain in the wrist and hand after punching, combined trapezoid and scaphoid fractures should be considered as the possible injury.

High Potency VEGFRs/MET/FMS Triple Blockade by TAS-115 Concomitantly Suppresses Tumor Progression and Bone Destruction in Tumor-Induced Bone Disease Model with Lung Carcinoma Cells.

Approximately 25-40% of patients with lung cancer show bone metastasis. Bone modifying agents reduce skeletal-related events (SREs), but they do not significantly improve overall survival. Therefore, novel therapeutic approaches are urgently required. In this study, we investigated the anti-tumor effect of TAS-115, a VEGFRs and HGF receptor (MET)-targeted kinase inhibitor, in a tumor-induced bone disease model. A549-Luc-BM1 cells, an osteo-tropic clone of luciferase-transfected A549 human lung adenocarcinoma cells (A549-Luc), produced aggressive bone destruction associated with tumor progression after intra-tibial (IT) implantation into mice. TAS-115 significantly reduced IT tumor growth and bone destruction. Histopathological analysis showed a decrease in tumor vessels after TAS-115 treatment, which might be mediated through VEGFRs inhibition. Furthermore, the number of osteoclasts surrounding the tumor was decreased after TAS-115 treatment. In vitro studies demonstrated that TAS-115 inhibited HGF-, VEGF-, and macrophage-colony stimulating factor (M-CSF)-induced signaling pathways in osteoclasts. Moreover, TAS-115 inhibited Feline McDonough Sarcoma oncogene (FMS) kinase, as well as M-CSF and receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation. Thus, VEGFRs/MET/FMS-triple inhibition in osteoclasts might contribute to the potent efficacy of TAS-115. The fact that concomitant dosing of sunitinib (VEGFRs/FMS inhibition) with crizotinib (MET inhibition) exerted comparable inhibitory efficacy for bone destruction to TAS-115 also supports this notion. In conclusion, TAS-115 inhibited tumor growth via VEGFR-kinase blockade, and also suppressed bone destruction possibly through VEGFRs/MET/FMS-kinase inhibition, which resulted in potent efficacy of TAS-115 in an A549-Luc-BM1 bone disease model. Thus, TAS-115 shows promise as a novel therapy for lung cancer patients with bone metastasis.

TAS-116, a highly selective inhibitor of heat shock protein 90α and ß, demonstrates potent antitumor activity and minimal ocular toxicity in preclinical models.

The molecular chaperone HSP90 plays a crucial role in cancer cell growth and survival by stabilizing cancer-related proteins. A number of HSP90 inhibitors have been developed clinically for cancer therapy; however, potential off-target and/or HSP90-related toxicities have proved problematic. The 4-(1H-pyrazolo[3,4-b]pyridine-1-yl)benzamide TAS-116 is a selective inhibitor of cytosolic HSP90α and ß that does not inhibit HSP90 paralogs such as endoplasmic reticulum GRP94 or mitochondrial TRAP1. Oral administration of TAS-116 led to tumor shrinkage in human tumor xenograft mouse models accompanied by depletion of multiple HSP90 clients, demonstrating that the inhibition of HSP90α and ß alone was sufficient to exert antitumor activity in certain tumor models. One of the most notable HSP90-related adverse events universally observed to differing degrees in the clinical setting is visual disturbance. A two-week administration of the isoxazole resorcinol NVP-AUY922, an HSP90 inhibitor, caused marked degeneration and disarrangement of the outer nuclear layer of the retina and induced photoreceptor cell death in rats. In contrast, TAS-116 did not produce detectable photoreceptor injury in rats, probably due to its lower distribution in retinal tissue. Importantly, in a rat model, the antitumor activity of TAS-116 was accompanied by a higher distribution of the compound in subcutaneously xenografted NCI-H1975 non-small cell lung carcinoma tumors than in retina. Moreover, TAS-116 showed activity against orthotopically transplanted NCI-H1975 lung tumors. Together, these data suggest that TAS-116 has a potential to maximize antitumor activity while minimizing adverse effects such as visual disturbances that are observed with other compounds of this class.

Serial CT and MRI findings in a patient with isolated angiitis of the central nervous system associated with cerebral amyloid angiopathy.

We report serial CT and MRI findings in a biopsy-proven case of cerebral amyloid angiopathy (CAA) with isolated angiitis of the central nervous system (CNS). A 69-year-old man had developed dizziness, dementia, and generalized seizure during the preceding 4 years. An initial examination by brain CT and MRI showed bilateral symmetrical periventricular lesions closely resembling those of Binswanger's disease. Subsequently, the lesions expanded slowly, involving a large area of the right cerebral hemisphere with an obvious mass effect. Since a primary brain tumor was suspected, a brain biopsy was performed, and histopathological examination revealed amyloid beta protein CAA within the meningocortical vessels associated with perivascular monocytic cuffing, indicating the presence of isolated angiitis of the CNS. Multinucleated giant cells containing intracytoplasmic beta protein amyloid around a heavily amyloid-laden cortical vessel were also observed. This is the first case report to show sequential radiographical studies of the leukoencephalopathy associated with CAA and isolated angiitis of the CNS.

[Carotid plaque assessment using inversion recovery T1 weighted-3 dimensions variable refocus flip angle turbo spin echo sampling perfection with application optimized contrast using different angle evolutions black blood imaging].

Vulnerable plaque can be attributed to induction of ischemic symptoms and magnetic resonance imaging of carotid artery is valuable to detect the plaque. Magnetization prepared rapid acquisition with gradient echo (MPRAGE) method could detect hemorrhagic vulnerable plaque as high intensity signal; however, blood flow is not sufficiently masked by this method. The contrast for plaque in T1 weighted image (T1WI) could not be obtained sufficiently with black blood image (BBI) by sampling perfection with application optimized contrast using different angle evolutions (SPACE) method as turbo spin echo (TSE). In addition, an appearance of artifact by slow flow is a problem. Considering these controversial situations in plaque imaging, we examined the modified BBI inversion recovery (IR)-SPACE in which IR was added for SPACE method so that the contrast for plaque in T1WI was optimized. We investigated the application of this method in plaque imaging. As a result of phantom imaging, the contrast for plaque in T1WI was definitely obtained by choosing an appropriate inversion time (TI) for the corresponding repetition time. In clinical cases, blood flow was sufficiently masked by IR-SPACE method and the plaque imaging was clearly obtained in clinical cases to the same extent as MPRAGE method. Since BBI with IR-SPACE method was derived from both IR pulse and flow void effect, this method could obtain the blood flow masking effect definitely. The present study suggested that SPACE method might be applicable to estimate properties of carotid artery plaque.

Sensitive analysis of blonanserin, a novel antipsychotic agent, in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry.

A rapid and sensitive method for analysis of blonanserin in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry is presented. After pretreatment of a plasma sample by solid-phase extraction, blonanserin was analyzed by the system with a C(18) column. This method gave satisfactory recovery rates, reproducibility, and good linearity of calibration curve in the range of 0.01-10.0 ng/mL for quality control samples spiked with blonanserin. The detection limit was as low as 1 pg/mL. This method seems very useful in forensic and clinical toxicology and pharmacokinetic studies.