A Fully Functional Drug-Eluting Joint Implant.

Despite advances in orthopedic materials, the development of drug-eluting bone and joint implants that can sustain the delivery of the drug and maintain the necessary mechanical strength in order to withstand loading has remained elusive. Here, we demonstrate that modifying the eccentricity of drug clusters and the percolation threshold in ultrahigh molecular weight polyethylene (UHMWPE) results in maximized drug elution and in the retention of mechanical strength. The optimized UHMWPE eluted antibiotic at a higher concentration for longer than the clinical gold standard antibiotic-eluting bone cement while retaining the mechanical and wear properties of clinically used UHMWPE joint prostheses. Treatment of lapine knees infected with Staphylococcus aureus with the antibiotic-eluting UHMWPE led to complete bacterial eradication and to the absence of detectable systemic effects. We argue that the antibiotic-eluting UHMWPE joint implant is a promising candidate for clinical trials.

Endoscopic submucosal dissection or transanal endoscopic microsurgery for nonpolypoid rectal high grade dysplasia and submucosa-invading rectal cancer.

BACKGROUND AND STUDY AIMS: Transanal endoscopic microsurgery (TEM) has been shown to be highly effective for early rectal cancer, and endoscopic submucosal dissection (ESD) has been introduced to treat noninvasive colorectal neoplasia. The aim of this study was to compare the outcomes of ESD and TEM for superficial early rectal cancer. PATIENTS AND METHODS: We retrospectively analyzed 63 patients with nonpolypoid rectal high grade dysplasia or submucosa-invading cancer who were treated with ESD or TEM, and compared clinical outcomes and safety between the treatment groups. RESULTS: 30 patients underwent ESD and 33 underwent TEM. For ESD compared with TEM, en bloc resection rates were 96.7% vs. 100% (P = 0.476) and R0 resection rates were 96.7 % vs. 97.0 % (P = 1.000). There were no cases of local recurrence or distant metastasis in either group. Antibiotics were required in 11 patients (36.7%) in the ESD group and 33 (100%) in the TEM group (P < 0.001). There was no difference in net procedure time although ESD was associated with shorter total procedure time and hospital stay than TEM, with mean (standard deviation [SD]) 84.0 (51.2) vs. 116.4 (58.5) min (P = 0.0023), and 3.6 (1.2) vs. 6.6 (3.5) days (P < 0.001), respectively. There were no significant differences in complications between the two groups. CONCLUSIONS: Both ESD and TEM are effective and oncologically safe for treating nonpolypoid rectal high grade dysplasia and submucosa-invading cancers. ESD has the additional advantages of minimal invasiveness and avoidance of anesthesia. Therefore, ESD could be recommended as a treatment option for superficial early rectal cancers.

Enhancement patterns of hepatocellular carcinomas on multiphasicmultidetector row CT: comparison with pathological differentiation.

OBJECTIVE: The objective of this study was to determine the incidence of typical and atypical enhancement patterns of hepatocellular carcinomas (HCCs) on multiphasic multidetector row CT (MDCT) and to correlate the enhancement patterns and morphological image findings of HCC with the degree of tumour differentiation. METHODS: MDCT images of 217 patients with 243 surgically proven HCCs were evaluated through consensus reading by two radiologists. Our MDCT protocol was composed of precontrast, arterial, portal and delayed phases. The reviewers analysed the CT images for degree of attenuation; relative timing of washout; presence of dysmorphic intratumoral vessels, aneurysms and necrosis; tumour size; tumour margin; presence of pseudocapsule; intratumoral heterogeneity; and determined enhancement pattern. The imaging features were correlated with tumour differentiation using Fisher's exact test or the χ(2) test. RESULTS: Among 243 HCCs, 137 (56.4%) showed the typical enhancement pattern of HCC, which is arterial enhancement and washout on portal or equilibrium phase images. In the arterial phase, 190 of 243 (78.2%) HCCs showed hypervascularity, with approximately three quarters of poorly differentiated (PD) (34 of 45, 75.6%) and moderately differentiated (MD) HCCs (92 of 123, 74.8%) showing washout during the portal or delayed phases, vs only 50% of well-differentiated (WD) HCCs (11 of 22; p<0.048). The presence of intratumoral vessels and aneurysms, tumour necrosis, attenuation of precontrast, the relative timing of washout, intratumoral attenuation heterogeneity, tumour margin and tumour size were correlated with the pathological differentiation of HCCs (p<0.05). CONCLUSION: A typical enhancement of HCCs on MDCT was not unusual (43.6%) and WD and PD HCCs account for most of the atypical enhancement patterns. Early washout favoured MD and PD HCCs rather than WD HCCs, whereas in our study the presence of intratumoral aneurysm was a highly specific finding for PD HCC.

Characteristics of DNase activities in excretory/secretory products of infective larvae of Haemonchus contortus.

While multiple DNase activities occur in the excretory/secretory products (ESPs) of the adult Haemonchus contortus, the DNase activities in ESPs of the infective larvae (L3) have not been studied. Thus, the DNase activities in ESPs of H. contortus L3 were investigated and compared to those of adults for developmental stage-specific analysis. The DNase activities had relative molecular masses (M rs) of 34 and 36 kDa upon zymographic analysis at pH 5.0 and 7.0 when the larvae were incubated for over 48 h. The 34 and 36 kDa DNases of L3 ESPs were also detected in adult ESPs with similar characteristics. However, the 37 and 38.5 kDa DNases of the adult ESPs were not detected in the L3 ESPs. Since the 37 and 38.5 kDa DNase activities were mainly detected in adult ESPs, these activities appear to be specific to the adult stage whereas the other ESP DNase activities appear to be expressed during multiple stages of the parasite's life cycle. While the difference in DNase activities of L3 and adults remains obscure, the role of DNase in larval development should be further clarified and the identification of stage-specific developmental markers will lead to the discovery of specific factors that stimulate larval development.

Adaptive aberration correction of GRIN lenses for confocal endomicroscopy.

Graded-index (GRIN) lenses serve as a key component for miniature endoscopes because of their small diameters and ease of assembly. However, the nonaplanatic nature of GRIN lenses causes inherent spatial aberrations that lower image resolution and sharpness. Here we present the diagnosis of the aberrations in GRIN probes and the use of adaptive optics to compensate for the wavefront errors in the endoscope. Two different operation schemes based on preset and in situ measurements are demonstrated, both resulting in a substantial reduction of the wavefront error from 0.42 to <0.1 µm.

In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring.

BACKGROUND: In patients with advanced ovarian cancer (OvCa), microscopic residual tumour nodules that remain after surgical debulking frequently escape detection by current treatment assessment methods and lead to disease recurrence. The aim of this study was to evaluate the use of high-resolution fibre-optic fluorescence imaging of the clinically approved photodynamic therapy (PDT) agent benzoporphyin-derivative monoacid ring A (BPD-MA) for detection of microscopic OvCa and for monitoring treatment response. METHODS: Our fluorescence microendoscope consists of a flexible imaging fibre coupled to a custom epi-fluorescence system optimised for imaging BPD-MA, which, after a single administration, serves as both an imaging agent and a light-activated therapeutic agent. After characterisation in an in vitro OvCa 3D model, we used the flexible imaging fibre to minimally invasively image the peritoneal cavity of a disseminated OvCa murine model using BPD-MA administered intraperitoneally (i.p.). To evaluate longitudinal changes in response to treatment, we compared sets of images obtained before and after PDT with those from untreated mice imaged at the same time points. RESULTS: By comparison with histopathology, we report an 86% sensitivity for tumour detection in vivo using the microendoscope. Using a custom routine to batch process-image data in the monitoring study, treated mice exhibited an average decrease of 58.8% in tumour volumes compared with an increase of 59.3% in untreated controls (P<0.05). CONCLUSIONS: Our findings indicate the potential of this approach as a reporter of treatment outcome that could aid in the rational design of strategies to mitigate recurrent OvCa.

In vitro chemosensitivity based on depth of invasion in advanced colorectal cancer using ATP-based chemotherapy response assay (ATP-CRA).

BACKGROUND: Tumors are composed of subpopulations of cells with heterogeneous characteristics that allow for tumor progression and development of treatment resistance. The purpose of this study was to determine if there is heterogeneity in the in vitro chemosensitivity in different invasive sections of a single tumor. MATERIALS AND METHODS: Chemosensitivity in advanced colorectal cancer specimens was examined using an ATP-based chemotherapy response assay. Four chemotherapeutic agents (5-fluorouracil (5-FU), oxaliplatin, irinotecan, and mitomycin) were used for chemosensitivity studies. Tumor tissues were obtained from the superficial (mucosa/submucosa) and deep parts (muscle/subserosa/serosa), respectively. Twenty patients who had results for both the superficial and deep parts were evaluated. RESULTS: The chemosensitivity study showed variable cell death rates in both parts of the tumor. Regression analysis showed some correlations with 5-FU and irinotecan, but not with oxaliplatin or mitomycin. With the exception of three patients in whom no drug was recommended, at least one chemotherapeutic drug showed some consistency between the superficial and deep parts of the tumor. Mitomycin was the most frequently active agent for the superficial part. In the deep part, oxaliplatin and mitomycin were the most active agents. CONCLUSIONS: There may be heterogeneity in the responses to anti-chemotherapeutic agents in advanced colorectal cancer, according to the depth of invasion. Therefore, in clinical situations, chemosensitivity test specimens should be mixed with various parts of the whole tumor in order to obtain representative chemosensitivity and chemoresistance profiles.

The clinical outcome and prognostic factors after multi-visceral resection for advanced colon cancer.

AIM: The value of multi-visceral resection (MVR) for treating primary advanced colon cancer infiltrating into the neighboring organs had been debated because of the high mortality. METHODS: We reviewed 1288 patients who underwent curative resection for pT3-4 colon cancer without distant metastasis from 1994 to 2004. RESULTS: Eighty four patients (6.5%) with colon cancer infiltrating into the neighboring organs (cT4) underwent MVR. The accuracy of the intra-operative decision for true invasion (pT4) was 35.7%. Major surgical morbidity occurred in 11 patients of the standard resection group (0.9%) and in 2 patients of the MVR group (2.3%) (p = 0.206). Most of the recurrence was distant metastasis (20 patients, 23.8%). Local recurrence was occurred in five patients (6.0%). The prognostic factors for recurrence and survival were pathologic tumor invasion (p = 0.033 and p = 0.016, respectively) and lymph node metastasis (p = 0.010 and p < 0.001, respectively). CONCLUSION: Multi-visceral resection was a safe and curative procedure as compared with standard resection for patients with advanced colon cancer. The cause of a poor prognosis in MVR was not local recurrence but distant metastasis. Pathologic tumor invasion and lymph node metastasis were the potential prognostic factors.

Double primary malignancy in colorectal cancer patients--MSI is the useful marker for predicting double primary tumors.

BACKGROUND AND AIMS: The incidence of double primary malignancies (DPM) is known to be higher in colorectal cancer patients than the general population. And, the role of microsatellite instability (MSI) in DPM has been previously studied. We evaluated the clinical features and association between MSI and colorectal cancer patients with DPM. MATERIALS AND METHODS: From September 1994 to May 2004, we reviewed 2,301 colorectal cancer patients with regard to secondary primary malignancies. A subgroup analysis was performed for MSI after January 2003. RESULTS: One hundred forty-five patients (6.3%) had a DPM identified. In DPM group, 57 patients had a synchronous DPM (39.3%), and 88 patients had a metachronous malignancy (60.7%). Male gender (p<0.001) and colon cancer (p<0.001) were the factors related with the development of the DPM. Most of the second malignancies occurred within 3 years after the primary operation. The common second malignancies were stomach (58 patients, 40%) and lung (21 patients, 14.5%). In the subgroup analysis, there was a higher frequency of DPM in the MSI group when compared to the microsatellite stable group (p=0.021). CONCLUSIONS: The careful pre- and postoperative evaluation should be paid for detecting DPM as well as for detecting recurrence in colorectal cancer patients. The results of this study suggest that MSI might be a useful marker for the detection of DPM in colorectal cancer patients.

Local recurrence after curative resection in patients with colon and rectal cancers.

BACKGROUND AND AIMS: There are a range of rates and a number of prognostic factors associated with the local recurrence of colorectal cancer after curative resection. The aim of this study was to identify the potential prognostic factors of local recurrence in patients with colon and rectal cancers. MATERIALS AND METHODS: A retrospective review of 1,838 patients who underwent curative resection of non-metastatic colorectal cancer was conducted. The patients were treated between 1994 and 2004, and had a minimum follow-up of 3 years. RESULTS: There were 994 patients with colon cancer and 844 patients with rectal cancer. The median duration of follow-up was 60.9 +/- 24.5 months. With respect to colon cancer, the local recurrence rate was 6.1% (61 patients). With respect to rectal cancer, 95 patients had a local recurrence (11.3%), the rate of which was statistically greater than the local recurrence rate for colon cancer (p < 0.001). The overall recurrence rate was 16.4% (301 patients), and the local recurrence rate, with or without systemic metastases, was 8.5% (156 patients). Local recurrences occurred within 2 and 3 years in 59.9% and 82.4% of the patients, respectively. In patients with colon and rectal cancer, the pathologic T stage (p = 0.044 and p = 0.034, respectively), pathologic N stage (p = 0.001 and p < 0.001, respectively), and lymphovascular invasion (p = 0.013 and p = 0.004, respectively) were adverse risk factors for local recurrence. The level of the anastomosis from the anal verge was an additional prognostic factor (p = 0.007) in patients with rectal cancer. CONCLUSION: Compulsive follow-up care of patients with colon and rectal cancers is needed for 3 years after curative resection, especially in patients who have adverse risk factors for local recurrence.

Single-detector polarization-sensitive optical frequency domain imaging using high-speed intra A-line polarization modulation.

We demonstrate a novel high-speed polarization-sensitive optical frequency domain imaging system employing high-speed polarization modulation. Rapid and continuous polarization modulation of light prior to illumination of the sample is accomplished by shifting the frequency of one polarization eigenstate by an amount equal to one quarter of the digitization sampling frequency. This approach enables polarization-sensitive imaging with a single detection channel and overcomes artifacts that may arise from temporal variations of the birefringence in fiber-optic imaging probes and spatial variation of birefringence in the sample.

High-speed polarization sensitive optical frequency domain imaging with frequency multiplexing.

Polarization sensitive optical coherence tomography (PS-OCT) provides a cross-sectional image of birefringence in biological samples that is complementary in many applications to the standard reflectance-based image. Recent ex vivo studies have demonstrated that birefringence mapping enables the characterization of collagen and smooth muscle concentration and distribution in vascular tissues. Instruments capable of applying these measurements percutaneously in vivo may provide new insights into coronary atherosclerosis and acute myocardial infarction. We have developed a polarization sensitive optical frequency domain imaging (PS-OFDI) system that enables high-speed intravascular birefringence imaging through a fiber-optic catheter. The novel design of this system utilizes frequency multiplexing to simultaneously measure reflectance of two incident polarization states, overcoming concerns regarding temporal variations of the catheter fiber birefringence and spatial variations in the birefringence of the sample. We demonstrate circular cross-sectional birefringence imaging of a human coronary artery ex vivo through a flexible fiber-optic catheter with an A-line rate of 62 kHz and a ranging depth of 6.2 mm.

Decision for salvage treatment after transanal endoscopic microsurgery.

BACKGROUND: Transanal endoscopic microsurgery (TEM) has emerged as an alternative to classic radical operation for early rectal cancer. Early rectal cancer can be treated by adequate local excision such as TEM. If there are adverse risk factors, especially poor cellular differentiation, close resection margin, or positive lymphovascular invasion or incomplete excision, a radical resection is indicated. This study aimed to clarify the factors related to recurrence for patients required to undergo a salvage operation after TEM. METHODS: This retrospective study analyzed 167 patients who underwent TEM for rectal cancer between 1994 and 2004. Of these patients, 36 with poor differentiation, mucinous carcinoma, proper muscle invasion, lymphovascular invasion, and positive resection margin were included in the analysis. RESULTS: Of the 36 patients, 12 underwent a salvage operation, and the remaining 24 did not because of poor physical condition or refusal of radical surgery. There were a total of 6 (16.7%) recurrences. One (8.3%) of the 12 patients who underwent salvage surgery had systemic recurrence. Five (20.8%) of the 24 patients who did not receive surgery had recurrence (3 local recurrences, 2 distant recurrences). Analysis of the subgroups showed that 2 (28.6%) of 7 patients with lymphovascular invasion had recurrence, and that 1 patient (100%) had a T3 lesion. Three (17.6%) of 17 patients had T2 lesions. CONCLUSIONS: For high-risk patients, TEM followed by radical surgery is the most beneficial in preventing local recurrence. Radical salvage surgery is strongly recommended if pathologic results after TEM show T3 lesion or lymphovascular invasion.

Prognostic significance of beta-catenin in colorectal cancer with liver metastasis.

AIMS: A decreased expression of beta-catenin has been known to be associated with tumour metastasis. The prognostic value of beta-catenin expression in colorectal cancer (CRC) patients with liver metastasis was evaluated. MATERIALS AND METHODS: Seventy patients who underwent curative resection for CRC with liver metastasis were included. Tissue samples from normal colon mucosa, primary CRC and metastatic liver lesions were prepared in tissue microarrays, and were stained by immunohistochemistry with beta-catenin antibody. The beta-catenin expression of primary CRC tissues and metastatic liver tissues was analysed. RESULTS: A high expression of beta-catenin (score > 6) was observed in 42.0% and 21.9% of primary colorectal tissues and metastatic liver tissues, respectively. The beta-catenin expression in metastatic liver tissues was significantly lower than in primary CRC tissues (P = 0.022). The patients were classified into two groups according to the difference in the beta-catenin expression score between the primary CRC and the liver metastasis. Group A was defined as patients showing a remarkably decreased expression of beta-catenin in their metastatic liver tissue and group B was defined as patients showing a maintained or increased beta-catenin expression in their metastatic liver tissue in comparison with their primary CRC. The overall survival and disease-free survival rates were better in group B than in group A, and this was statistically significant (P = 0.02, P = 0.002). CONCLUSION: The decreased expression of beta-catenin in a metastatic liver lesion may be a poor prognostic marker in CRC with liver metastasis and further investigation is necessary.

Numerical study of wavelength-swept semiconductor ring lasers: the role of refractive-index nonlinearities in semiconductor optical amplifiers and implications for biomedical imaging applications.

Recent results have demonstrated unprecedented wavelength-tuning speed and repetition rate performance of semiconductor ring lasers incorporating scanning filters. However, several unique operational characteristics of these lasers have not been adequately explained, and the lack of an accurate model has hindered optimization. We numerically investigated the characteristics of these sources, using a semiconductor optical amplifier (SOA) traveling-wave Langevin model, and found good agreement with experimental measurements. In particular, we explored the role of the SOA refractive-index nonlinearities in determining the intracavity frequency-shift-broadening and the emitted power dependence on scan speed and direction. Our model predicts both continuous-wave and pulse operation and shows a universal relationship between the output power of lasers that have different cavity lengths and the filter peak frequency shift per round trip, therefore revealing the advantage of short cavities for high-speed biomedical imaging.

Evaluation of a modified antimycobacterial susceptibility test using Middlebrook 7H10 agar containing 2,3-diphenyl-5-thienyl-(2)-tetrazolium chloride.

A rapid and accurate antimycobacterial susceptibility test is essential for effective treatment of tuberculosis. The aim of this study was to evaluate a modified method applying 2,3-diphenyl-5-thienyl-(2)-tetrazolium chloride (STC) to the Clinical and Laboratory Standards Institute (CLSI) guideline for susceptibility testing of Mycobacterium tuberculosis. A total of 132 clinical isolates of M. tuberculosis, forty-eight isolates showing resistance to one or more of the first-line antituberculosis drugs, and eighty-four fully susceptible isolates were collected from hospitals of a nationwide distribution from June to September 2004. The modified procedure was conducted basically according to the agar-proportion method described in the CLSI Guideline both with STC 50 mug/mL. The amount of growth in each well was recorded and graded at 2nd and 3rd weeks after inoculation. After 3 weeks of incubation, the diagnostic sensitivity and specificity for the detection of drug-resistant strains of STC-containing agar proportion methods were 100%, except ethambutol-low level resistance, of which the diagnostic sensitivity was 93.4%. After two weeks of incubation in STC-containing agar proportion methods, one hundred of the 107 strain-drug combinations have shown drug resistance, indicating the sensitivity of 93.5%. Especially, all 41 isoniazid-resistant strains and 19 of 21 rifampin-resistant strains (90.5%) could be detected after two weeks of incubation. A modification of the agar proportion method using STC resulted in a reliable and more easily interpretable data, and detected most of resistant strains a week earlier than conventional method.

Elimination of depth degeneracy in optical frequency-domain imaging through polarization-based optical demodulation.

A novel optical frequency-domain imaging system is demonstrated that employs a passive optical demodulation circuit and a chirped digital acquisition clock derived from a voltage-controlled oscillator. The demodulation circuit allows the separation of signals from positive and negative depths to better than 50 dB, thereby eliminating depth degeneracy and doubling the imaging depth range. Our system design is compatible with dual-balanced and polarization-diverse detection, important techniques in the practical biomedical application of optical frequency-domain imaging.

Optical coherence tomography using rapidly swept lasers.

Optical coherence tomography (OCT) has proven to be a useful diagnostic tool in several medical areas. An emerging second-generation OCT technology, termed optical frequency domain imaging, is expected to increase the clinical applications of OCT significantly.

Ultra-high speed and ultra-high resolution spectral-domain optical coherence tomography and optical Doppler tomography in ophthalmology.

We present ultra-high resolution optical coherence tomography (OCT) structural intensity and optical Doppler tomography (ODT) flow velocity images of the human retina in vivo. The ultra-high speed OCT system is based on Spectral Domain or Fourier Domain technology, which provides a sensitivity advantage over conventional OCT of more than 2 orders of magnitude. This sensitivity improvement allows video rate OCT and ODT cross sectional imaging of retinal structures. Images will be presented with axial resolutions of 6 and 3.5 microns. We observed small features in the inner and outer plexiform layers, which are believed to be small blood vessels. Flow velocity images will be presented showing pulsatile flow in retinal arteries and veins.

Ultrahigh-resolution full-field optical coherence microscopy using InGaAs camera.

Full-field optical coherence microscopy (FFOCM) is an interferometric technique for obtaining wide-field microscopic images deep within scattering biological samples. FFOCM has primarily been implemented in the 0.8 mum wavelength range with silicon-based cameras, which may limit penetration when imaging human tissue. In this paper, we demonstrate FFOCM at the wavelength range of 0.9 - 1.4 mum, where optical penetration into tissue is presumably greater owing to decreased scattering. Our FFOCM system, comprising a broadband spatially incoherent light source, a Linnik interferometer, and an InGaAs area scan camera, provided a detection sensitivity of 86 dB for a 2 sec imaging time and an axial resolution of 1.9 mum in water. Images of phantoms, tissue samples, and Xenopus Laevis embryos were obtained using InGaAs and silicon camera FFOCM systems, demonstrating enhanced imaging penetration at longer wavelengths.