Delineation of the internal iliac vein using MRI with true FISP sequence in patients with locally recurrent rectal cancer: A pilot study using CT/MRI fusion.

PURPOSE: This study assessed the feasibility of using three-dimensional (3D) models of intrapelvic vascular patterns constructed using computed tomography (CT) and magnetic resonance imaging (MRI) fusion data for preoperative planning in patients with locally recurrent rectal cancer. METHODS: Eleven patients scheduled for pelvic exenteration were included. The 3D fusion data of the intrapelvic vessels constructed using CT and MRI with true fast imaging with steady-state precession sequence (True FISP) were evaluated preoperatively. Contrast ratios (CR) between the piriformis muscle and the intrapelvic vessels were calculated to identify a valid modality for 3D modeling and creating CT/MRI fusion-reconstructed volume-rendered images. RESULTS: The CR values of the internal and external iliac arteries were significantly higher on CT images than MR images (CT vs. MRI; 0.63 vs. 0.45, p < 0.01). However, the CR value of the internal iliac vein was significantly higher on MR than CT images (CT vs. MRI; 0.23 vs. 0.55, p < 0.01). CONCLUSIONS: MRI with True FISP yielded high signal-to-noise ratios and aided in delineating the internal iliac vein around the piriformis muscle. More precise 3D models can be constructed using this technique in the future to aid in the resection of locally recurrent rectal cancer.

Miliary tuberculosis-associated hemophagocytic lymphohistiocytosis with a high level of soluble interleukin-2 receptor successfully treated with concomitant recombinant thrombomodulin: A case report.

Hemophagocytic lymphohistiocytosis (HLH) is a fatal disease characterized by a highly inflammatory state due to the abnormal activation of T lymphocytes and macrophages. Miliary tuberculosis (MTB) is a rare cause of HLH and its clinical appearances occasionally resembles that of intravascular lymphoma (IVL). A 76-year-old woman presented with persistent fever and fatigue. Abnormal laboratory findings showing thrombocytopenia (13,000/µL), hypofibrinogenemia (101 mg/dL), hyperferritinemia (2,312 ng/mL), and markedly elevated soluble interleukin-2 receptor (sIL-2R) level (32,200 U/mL), in addition, hemophagocytosis in the bone marrow (BM) smear, were suggestive of IVL-associated HLH. The pathology of the BM biopsy specimen showed granuloma with non-caseous necrosis, and culture tests using sputum, gastric fluid, urine, and peripheral and bone marrow blood revealed the presence of Mycobacterium tuberculosis, leading to the final diagnosis of MTB-associated HLH. Anti-TB medications and corticosteroids were administered, but thrombocytopenia, hypofibrinogenemia, and hyperferritinemia persisted. Concomitant use of recombinant thrombomodulin (rTM) enabled regression of clinical status. In this case, BM biopsy served as the diagnosis of MTB-associated HLH, although IVL-associated HLH is initially suspected by an extremely high level of sIL-2R. Furthermore, this case report informs that using rTM could improve the outcomes of MTB-associated HLH.

Possibility for Visualizing the Muscle Microstructure by q-Space Imaging Technique.

In the human body, skeletal muscle microstructures have been evaluated only by biopsy. Noninvasive examination of the microstructure of muscles would be useful for research and clinical practice in sports and musculoskeletal areas. The study is aimed at determining if q-space imaging (QSI) can reveal the microstructure of muscles in humans. Forty-three Japanese subjects (controls, distance runners, powerlifting athletes, and teenage runners) were included in this cross-sectional study. Magnetic resonance imaging of the lower leg was performed. On each leg muscle, full width at half maximum (FWHM) which indicated the muscle cell diameters and pennation angle (PA) were measured and compared. FWHM showed significant positive correlations with PA, which is related to muscle strength. In addition, FWHM was higher for powerlifting, control, distance running, and teenager, in that order, suggesting that it may be directing the diameter of each muscle cell. Type 1 and type 2 fibers are enlarged by growth, so the fact that the FWHM of the control group was larger than that of the teenagers in this study may indicate that the muscle fibers were enlarged by growth. Also, FWHM has the possibility to increase with increased muscle fibers caused by training. We showed that QSI had the possibility to depict noninvasively the microstructure like muscle fiber type and subtle changes caused by growth and sports characteristics, which previously could only be assessed by biopsy.

Synovial fluid presepsin as a novel biomarker for the rapid differential diagnosis of native joint septic arthritis from crystal arthritis.

OBJECTIVE: To investigate whether presepsin can be used as a novel biomarker to differentiate between native joint septic arthritis (NJSA) and crystal arthritis (CA). METHODS: This study included 75 patients diagnosed with either NJSA (n = 21) or CA (n = 54). Presepsin in synovial fluid and blood, C-reactive protein, and procalcitonin were measured and compared between the NJSA and CA groups. Receiver operating characteristic (ROC) curve analyses were performed to differentiate between the two groups. RESULTS: Synovial fluid and blood presepsin were significantly higher in the NJSA group than in the CA group (p < 0.0001 and p < 0.01, respectively). The area under the ROC curve for synovial fluid presepsin in the NJSA group compared with the CA group was 0.93 (sensitivity 85.7%, specificity 85.2%, positive predictive value 69.2%, negative predictive value 93.9%, positive likelihood ratio 5.79, negative likelihood ratio 0.17). Among the tests, synovial fluid presepsin was the most accurate. CONCLUSIONS: Measurement of synovial fluid presepsin is reliable for the early diagnosis of NJSA, and synovial fluid presepsin could be used as a novel biomarker for differentiating between NJSA and CA.

A randomized, double-blind, placebo-controlled, phase 3 study of tivantinib in Japanese patients with MET-high hepatocellular carcinoma.

A previous randomized phase 2 study of hepatocellular carcinoma revealed that the c-Met inhibitor tivantinib as second-line treatment significantly prolonged progression-free survival in a subpopulation whose tumor samples highly expressed c-Met (MET-high). Accordingly, this phase 3 study was conducted to evaluate the efficacy of tivantinib as a second-line treatment for Japanese patients with MET-high hepatocellular carcinoma. This randomized, double-blind, placebo-controlled study was conducted at 60 centers in Japan. Hepatocellular carcinoma patients with one prior sorafenib treatment and those with MET-high tumor samples were eligible for inclusion. Registered patients were randomly assigned to either the tivantinib or placebo group at a 2:1 ratio and were treated with twice-a-day oral tivantinib (120 mg bid) or placebo until the discontinuation criteria were met. The primary endpoint was progression-free survival while the secondary endpoints included overall survival and safety. Between January 2014 and June 2016, 386 patients provided consent, and 195 patients were randomized to the tivantinib (n = 134) or placebo (n = 61) group. Median progression-free survival was 2.8 (95% confidence interval: 2.7-2.9) and 2.3 (1.5-2.8) mo in the tivantinib and placebo groups, respectively (hazard ratio = 0.74, 95% confidence interval: 0.52-1.04, P = .082). Median overall survival was 10.3 (95% confidence interval: 8.1-11.6) and 8.5 (6.2-11.4) mo in the tivantinib and placebo group, respectively (hazard ratio = 0.82, 95% confidence interval: 0.58-1.15). The most common tivantinib-related grade ≥3 adverse events were neutropenia (31.6%), leukocytopenia (24.8%), and anemia (12.0%). This study did not confirm the significant efficacy of tivantinib as a second-line treatment for Japanese patients with MET-high hepatocellular carcinoma. (NCT02029157).

Evaluation of various confirmatory tests for the diagnosis of aldosterone-producing adenoma.

INTRODUCTION: Adrenal venous sampling is useful for discriminating unilateral and bilateral hypersecretion in patients with primary aldosteronism, but it is relatively invasive. To determine the site of hypersecretion more non-invasively, we evaluated predictors of unilateral hypersecretion. MATERIALS AND METHODS: We evaluated the baseline characteristics and the results of confirmatory tests of 123 patients with primary aldosteronism who underwent adrenal venous sampling. RESULTS: Unilateral hypersecretion was identified in 22.0%. The plasma aldosterone concentration and aldosterone-renin ratio were significantly higher and serum potassium concentration and plasma renin activity were significantly lower in patients with unilateral hypersecretion. Plasma aldosterone concentrations after captopril challenge test, saline infusion test and rapid adrenocorticotropic hormone stimulation test were significantly higher among patients with unilateral hypersecretion. The plasma aldosterone concentration reduction ratio in saline infusion test and plasma aldosterone concentration elevation ratio during rapid adrenocorticotropic hormone stimulation test were significantly higher in patients with unilateral hypersecretion. However, areas under the curve for these parameters were not superior to the values after confirmatory tests. CONCLUSIONS: The plasma aldosterone concentration values after captopril challenge test, saline infusion test and rapid adrenocorticotropic hormone stimulation test were useful for identifying patients with unilateral hypersecretion. However, value changes or ratios during confirmatory tests are less useful for this aim.

Quantitative analysis of intervertebral disc degeneration using Q-space imaging in a rat model.

The degree of intervertebral disc (IVD) degeneration is qualitatively evaluated on T2-weighted imaging (T2WI). However, it is difficult to assess subtle changes in IVD degeneration using T2WI. Q-space imaging (QSI) is a quantitative diffusion-weighted imaging modality used to detect subtle changes in microenvironments. This study aimed to evaluate whether QSI can detect the inhibitory effects of the antioxidant N-acetylcysteine (NAC) in IVD degeneration. We classified female Wistar rats into control, puncture, and NAC groups (n = 5 per group). In the puncture and NAC groups, IVDs were punctured using a needle. The antioxidant NAC, which suppresses the progression of IVD degeneration, was orally administered in the NAC group 1 week prior to puncture. The progression and inhibitory effect of NAC in IVD degeneration were assessed using magnetic resonance imaging (MRI): IVD height, T2 mapping, apparent diffusion coefficient (ADC), and QSI. MRI was performed using a 7-Tesla system with a conventional probe (20 IVDs in each group). QSI parameters that were assessed included Kurtosis, the probability at zero displacement (ZDP), and full width at half maximum (FWHM). IVD degeneration by puncture was confirmed by histology, IVD height, T2 mapping, ADC, and all QSI parameters (P < .001); however, the inhibitory effect of NAC was confirmed only by QSI parameters (Kurtosis and ZDP: both P < .001; FWHM: P < .01). Kurtosis had the largest effect size (Kurtosis: 1.13, ZDP: 1.06, and FWHM: 1.02) when puncture and NAC groups were compared. QSI has a higher sensitivity than conventional quantitative methods for detecting the progressive change and inhibitory effect of NAC in IVD degeneration.

[Recurrent cerebral embolism due to the disseminated carcinomatosis of bone marrow with early gastric cancer].

A 67-year-old woman who had undergone laparoscopic proximal gastrectomy for early gastric cancer 10 months previously was admitted to our hospital due to dysarthria. Brain MRI demonstrated acute multiple small infarcts in the right middle cerebral artery (MCA) and the right posterior inferior cerebellar artery (PICA) territory, and she was diagnosed as embolic stroke. Anticoagulant therapy did not prevent further ischemic stroke. No embolic sources were detected by MR angiography, carotid duplex sonography, transthoracic and transesophageal echocardiography, and Holter electrocardiography. We also performed upper gastrointestinal endoscopy and contrast-enhanced CT of the thoracoabdominal area, but there was no evidence of local recurrence or lymph node metastases of gastric cancer. As the ALP and D-dimer levels were gradually increasing, we performed PET/CT, which revealed fluorodeoxyglucose (FDG) uptake in the vertebra bone, and disseminated carcinomatosis of bone marrow with early gastric cancer was diagnosed after bone marrow biopsy on Day 41. After undergoing chemotherapy, she had no further stroke and died on Day 207.

Changes in the global spine alignment in the sitting position in an automobile.

BACKGROUND CONTEXT: Studies of the changes in spine alignment in the sitting position have been limited to specific spine segments. Because there have been few studies of global spinopelvic alignment in the sitting position, it is important to assess the changes associated with this position for such settings as developing future design of seats and achieving appropriate restoration of spine alignment. PURPOSE: This study aimed to measure changes in global spine alignment when people are sitting in car seats and to analyze the characteristics of those changes. STUDY DESIGN: This was a prospective, collaborative study of the radiological evaluation of changes in global spine alignment. PATIENT SAMPLE: The study included 113 asymptomatic adult participants (56 men and 57 women) without a history of spine disease or lower limb surgery, and with no current lower back or leg pain. OUTCOME MEASURES: Radiographic findings were assessed by measurement of various angles: cervical lordosis (CL), thoracic kyphosis (TK), thoracolumbar kyphosis (TLK), lumbar lordosis (LL), sacral slope (SS), pelvic tilt (PT), pelvic incidence (PI), C7 sagittal vertical axis (C7-SVA), T1 spinopelvic inclination (T1SPI), and T1 pelvic angle (TPA). METHODS: Radiographs were obtained in the standing and sitting positions. The objective variables analyzed statistically were spine alignments (CL, TK, TLK, LL, C7-SVA, T1SPI, TPA, SS, PT, and PI) measured in the standing position, body alignments (CL, TK, TLK, LL, C7-SVA, T1SPI, TPA, SS, and PT) measured in the sitting position, and stand-to-sit changes (∆CL, ∆TK, ∆TLK, ∆LL, ∆C7-SVA, ∆T1SPI, ∆TPA, ∆SS, and ∆PT). Explanatory variables were sex, age, body height, and body mass index. RESULTS: Changing posture from standing to sitting decreased CL by an average of 5.3°, slightly decreased TK by an average of 1.3°, increased TLK by an average of 6.8°, decreased LL by an average of 35°, decreased SS by an average of 49.2°, increased PT by an average of 49.2°, shifted C7-SVA backward by an average of 106.7 mm, decreased T1SPI by an average of 18.8°, and increased TPA by an average of 21.1°. Statistical analysis revealed that ΔLL was significantly decreased in elderly participants. After the stand-to-sit change, ΔTLK and ∆TPA were significantly increased in taller participants and ΔT1SPI was significantly decreased in taller participants. CONCLUSIONS: Among other changes, most notably LL is decreased and the pelvic tilt is increased when a person is sitting in a car seat. However, these changes in spine alignment differ with age and height. These findings may be useful for the development of future design of seats and for achieving appropriate surgical restoration of spine alignment.

Laser Resonance Frequency Analysis: A Novel Measurement Approach to Evaluate Acetabular Cup Stability During Surgery.

Artificial joint acetabular cup stability is essential for successful total hip arthroplasty. However, a quantitative evaluation approach for clinical use is lacking. We developed a resonance frequency analysis (RFA) system involving a laser system that is fully contactless. This study aimed to investigate the usefulness of laser RFA for evaluating acetabular cup stability. First, the finite element method was performed to determine the vibration mode for analysis. Second, the acetabular cup was press-fitted into a reamed polyurethane cavity that replicated the human acetabular roof. The implanted acetabular cup was vibrated with pulse laser irradiation and the induced vibration was detected with a laser Doppler vibrometer. The time domain signal from the vibrometer was analyzed by fast Fourier transform to obtain the vibration frequency spectrum. After laser RFA, the pull-down force of the acetabular cup was measured as conventional implant fixation strength. The frequency of the first highest amplitude between 2 kHz and 6 kHz was considered as the resonance peak frequency, and its relationship with the pull-down force was assessed. The peak frequency could predict the pull-down force (R2 = 0.859, p < 0.000). Our findings suggest that laser RFA might be useful to measure acetabular cup stability during surgery.

Clinical outcomes and prognostic factors for cavernous hemangiomas of the spinal cord: a retrospective cohort study

OBJECTIVE: Intramedullary cavernous hemangioma (CH) is a rare vascular lesion that is mainly characterized by the sudden onset of hemorrhage in young, asymptomatic patients, who then experience serious neurological deterioration. Despite the severity of this condition, the therapeutic approach and timing of intervention for CH remain matters of debate. The aim of this study was to evaluate the clinical characteristics of CH patients before and after surgery and to identify prognostic indicators that affect neurological function in these patients. METHODS: This single-center retrospective study included 66 patients who were treated for intramedullary CH. Among them, 57 underwent surgery and 9 patients received conservative treatment. The authors collected demographic, symptomology, imaging, neurological, and surgical data. Univariate and multivariate logistic regression analyses were performed to identify the prognostic indicators for neurological function. RESULTS: When comparing patients with stable and unstable gait prior to surgery, patients with unstable gait had a higher frequency of hemorrhagic episodes (52.4% vs 19.4%, p = 0.010), as assessed by the modified McCormick Scale. The lesion was significantly smaller in patients who underwent conservative treatment compared with surgery (2.5 ± 1.5 mm vs 5.9 ± 4.1 mm, respectively; p = 0.024). Overall, the patients experienced significant neurological recovery after surgery, but a worse preoperative neurological status was identified as an indicator affecting surgical outcomes by multivariate analysis (OR 10.77, 95% CI 2.88­40.36, p < 0.001). In addition, a larger lesion size was significantly associated with poor functional recovery in patients who had an unstable gait prior to surgery (8.6 ± 4.5 mm vs 3.5 ± 1.6 mm, p = 0.011). CONCLUSIONS: Once a hemorrhage occurs, surgical intervention should be considered to avoid recurrence of the bleeding and further neurological injury. In contrast, if the patients with larger lesion presented with worse preoperative functional status, surgical intervention could have a risk for aggravating the functional deficiencies by damaging the thinning cord parenchyma. Conservative treatment may be selected if the lesion is small, but regular neurological examination by MRI is needed for assessment of a change in lesion size and for detection of functional deterioration. ABBREVIATIONS: AIS = ASIA Impairment Scale; ASIA = American Spinal Injury Association; CH = cavernous hemangioma; EBL = estimated blood loss; JOA = Japanese Orthopaedic Association; mMS = modified McCormick Scale.

Early diagnosis of septic arthritis using synovial fluid presepsin: A preliminary study.

Therapeutic outcomes for septic arthritis vary greatly depending on the span of time between disease-onset and surgery. The most important factor is making an early and definitive diagnosis; however, some cases may be difficult to diagnose. We investigated presepsin, a biomarker of sepsis, to determine whether or not presepsin in synovial fluid would be useful for the diagnosis of septic arthritis. We selected 18 patients with septic arthritis including periprosthetic joint infections (SA group) and 28 patients with osteoarthritis (OA group). We measured the concentrations of synovial fluid presepsin, blood presepsin and procalcitonin (PCT) in the two groups. We compared the sensitivities and specificities of synovial fluid presepsin, blood presepsin and PCT. Synovial fluid and blood presepsin and blood PCT were all significantly higher in the SA group. Synovial fluid presepsin exhibited both 100% sensitivity and 100% specificity in the SA group, which were higher rates than those for blood presepsin and PCT. We found that synovial fluid presepsin is markedly elevated in case of septic arthritis, and therefore, it has potential as a new biomarker of septic arthritis.

Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole.

BACKGROUND: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. RESULTS: Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level. CONCLUSIONS: The proposed phase II study of the RP2D for the triple-drug combination did not progress because of anticipated difficulty in patient enrollment and further clinical development of KW-2450 was terminated.

A study on the use of the Osstell apparatus to evaluate pedicle screw stability: An in-vitro study using micro-CT.

Pull-out force and insertion torque have not been generally used as intraoperative measures for the evaluation of pedicle screw stability because of their invasiveness. On the other hand, resonance frequency analysis is a non-invasive and repeatable technique that has been clinically used in dentistry to evaluate implant stability e.g. by the Osstell apparatus. In this study, the characteristics of the implant stability quotient (ISQ) value obtained by the Osstell apparatus in the field of spinal surgery were investigated. Biomechanical test materials simulating human bone were used to provide a comparative platform for evaluating each fixation strength measure, including pull-out force, insertion torque, and the ISQ value. To perform pull-out force measurement and to repeat pedicle screw insertion and removal, loosening was artificially created, and its effect was investigated. The grade of loosening was quantified on a micro-CT image after pedicle screw removal. In the comparison of the 3 fixation strength measures, the correlations of the ISQ value with the pull-out force (R2 = 0.339 p <0.0001) and the insertion torque (R2 = 0.337 p <0.0001) were lower than the correlation between pull-out force and insertion torque (R2 = 0.918 p <0.0001). On a micro-CT study, the material volume of the internal threads disappeared after destruction of its integrity due to repeated pedicle screw insertion and removal. Material integrity destruction of the internal threads decreased only the pull-out force and the insertion torque, but it did not affect the ISQ value. The ISQ value only decreased when the material volume of the internal threads disappeared, probably because the ISQ value reflects the resistance against a force in the perpendicular direction of the screw, unlike the conventional measures of fixation strength, such as pull-out force and insertion torque, which reflect axial load.

Preclinical and first-in-human phase I studies of KW-2450, an oral tyrosine kinase inhibitor with insulin-like growth factor receptor-1/insulin receptor selectivity.

Numerous solid tumors overexpress or have excessively activated insulin-like growth factor receptor-1 (IGF-1R). We summarize preclinical studies and the first-in-human study of KW-2450, an oral tyrosine kinase inhibitor with IGF-1R and insulin receptor (IR) inhibitory activity. Preclinical activity of KW-2450 was evaluated in various in vitro and in vivo models. It was then evaluated in a phase I clinical trial in 13 patients with advanced solid tumors (NCT00921336). In vitro, KW-2450 inhibited human IGF-1R and IR kinases (IC50 7.39 and 5.64 nmol/L, respectively) and the growth of various human malignant cell lines. KW-2450 40 mg/kg showed modest growth inhibitory activity and inhibited IGF-1-induced signal transduction in the murine HT-29/GFP colon carcinoma xenograft model. The maximum tolerated dose of KW-2450 was 37.5 mg once daily continuously; dose-limiting toxicity occurred in two of six patients at 50 mg/day (both grade 3 hyperglycemia) and in one of seven patients at 37.5 mg/day (grade 3 rash). Four of 10 evaluable patients showed stable disease. Single-agent KW-2450 was associated with modest antitumor activity in heavily pretreated patients with solid tumors and is being further investigated in combination therapy with lapatinib/letrozole in patients with human epidermal growth factor receptor 2-postive metastatic breast cancer.

Phase 1/2 study of KRN330, a fully human anti-A33 monoclonal antibody, plus irinotecan as second-line treatment for patients with metastatic colorectal cancer.

KRN330 is a recombinant, fully-human monoclonal antibody directed against A33, a surface differentiation antigen that is uniformly expressed in 95 % of colorectal cancers. A previous Phase 1 study of single-agent KRN330 identified a maximum tolerated dose (MTD) of 3 mg/kg q2w and preliminary evidence of clinical activity among patients with advanced and metastatic colorectal cancer (mCRC). This Phase 1/2 trial sought to assess the safety and activity of second-line KRN330 plus irinotecan in patients with mCRC. Patients with mCRC who showed disease progression after FOLFOX/CapOx received intravenous doses of KRN330 (0.5 or 1.0 mg/kg qw or q2w) plus irinotecan (180 mg/m(2)) in a standard 3 + 3 dose escalation. The MTD of KRN330 with irinotecan in 19 patients was 0.5 mg/kg qw in the Phase 1 study with gastrointestinal effects and neutropenia being the predominant dose-limiting toxicities. In the Phase 2 study, the most frequent treatment-related Grade ≥3 toxicities in 44 patients were fatigue (15.9 %), neutropenia (13.6 %), leukopenia (6.8 %), diarrhea (4.5 %), and dehydration (4.5 %). Objective response rate (ORR) was 4.5 % and disease control rate was 45.5 % for the intent-to-treat population. Median progression-free survival was 87 days (95 % CI, 43-136 days). The prespecified ORR of KRN330 plus irinotecan was not met. Further investigation of KRN330 plus other agents may be warranted.

Late development of malignant fibrous histiocytoma at the site of a giant cell tumour 38 years after initial surgery.

The authors report on a patient who developed a malignant fibrous histiocytoma at the site of a benign giant cell tumour, which had been treated by curettage 38 years previously. This latency period is, to their knowledge, the longest yet reported. This female patient was initially treated for a benign giant cell tumour of the proximal tibia when she was 33 years old; she underwent curettage and Kiel bone grafting. She had not received radiation therapy. Twenty eight years later, she underwent a second operation due to recurrence of a tumour. No specific histological diagnosis was possible: histology suggested a benign tumour, however compatible with a low-grade malignant potential but not associated with giant cell tumour. The patient underwent a third operation, with extensive curettage and total knee arthroplasty 38 years after the initial surgery, because of progressive knee pain. Postoperative histopathology study showed high-grade malignant fibrous histiocytoma. Finally, she underwent above-knee amputation because of uncontrollable progression of the tumour. The use of xenogenic bone graft, bone cement and associated bone necrosis potentially contributed to the development of a malignant tumour adjacent to the primary giant cell tumour.

A novel ENG mutation causing impaired co-translational processing of endoglin associated with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited autosomal dominant vascular dysplasia caused by mutations in mainly the endoglin gene (ENG) or activin-like kinase receptor 1 (ALK1) gene (ACVRL1). We investigated the molecular basis of HHT in a Japanese patient, and identified a novel missense mutation in ENG (c.38T>A, p.Leu13Gln) located in the signal peptide's hydrophobic core, but not in ACVRL1. In experiments in COS-1 cells, the Leu13Gln (L13Q) mutant endoglin appeared to be expressed as a precursor form, probably due to impaired protein processing. Flow cytometry analyses of the COS-1 cells transiently expressing recombinant endoglins revealed that the wild-type endoglin was detected on the cell surface, but the L13Q mutant was not. We also analyzed expression patterns of the recombinant endoglins by immunofluorescent staining, and found that the wild-type co-localized with the endoplasmic reticulum (ER), but the L13Q mutant did not. These results implied that the L13Q mutant endoglin fails to insert into the ER, probably due to destruction of the hydrophobic core structure in the signal peptide to be recognized by signal recognition particles. Thus, the Leu13 in the signal peptide of endoglin might be essential for correct protein processing through the ER and cell-surface expression. Taken together, the novel c.38T>A mutation in ENG would impair co-translational processing of the endoglin, and could be responsible for HHT in this patient.