Preoperative predictors of health-related quality of life changes (EQ-5D and EQ VAS) after total hip and knee replacement: a systematic review.

BACKGROUND: Patient-reported outcomes are of ever-increasing importance in medical decision-making. The EQ-5D is one of the generic instruments measuring health-related quality of life (HRQoL) in arthroplasty. This review aimed to identify possible predictors of HRQoL changes for patients undergoing total knee replacements (TKR) or total hip replacements (THR). METHODS: A systematic literature review according to the PRISMA guidelines was conducted, searching several databases. Preoperative to postoperative HRQoL changes were evaluated in patients undergoing THR or TKR, using the EQ-5D visual analog scale (VAS) or the preference-based EQ-5D Index were evaluated. Articles were considered with prospectively or retrospectively collected data, as well as registry data, each with statistical analyses of patient-related factors. RESULTS: Eight hundred eighty-two articles were found, of which 21 studies met the inclusion criteria. Predictors were distinguished in alterable and non-alterable ones. The EQ-5D Index indicated a tendency towards beneficial improvements for patients with a high body mass index (BMI) (> 40) and no significant results for the VAS. Additionally, one study found that patient education and preoperative physiotherapy appeared to enhance HRQoL. Some evidence indicated that male gender was negatively associated with changes in the VAS and the EQ-5D Index, but one study reported the opposite. Changes in VAS and EQ-5D Index were lower for older patients, whereas a higher educational level seemed to be advantageous. A high Charnley class led to deteriorating changes in VAS, although a high Kellgren Lawrence classification was positively associated with the EQ-5D Index, in a limited number of studies. For all results, clinical relevance was calculated differently and mainly reported as uncertain or small. CONCLUSIONS: The literature on this topic was weak and offers only limited guidance. Results for alterable predictors, such as the BMI, indicated valuable improvements for highly obese patients. Further, high-quality research is required to support medical decision-making. LEVEL OF EVIDENCE: Level IV, according to the OCEBM Levels of Evidence Working Group.

In vitro study on the mechanisms of action of electrolytic electroporation (E2).

Electrolytic Electroporation (E2) is the combination of reversible electroporation and electrolysis. It has been proposed as a novel treatment option to ablate tissue percutaneously. The present in vitro study in cells in suspension was performed to investigate the underlying mechanisms of action of E2. Different types of experiments were performed to isolate the effects of the electrolysis and the electroporation components of the treatment. Additionally, thermal simulations were performed to determine whether significant temperature increase contributes to the effect. The results indicate that E2's cell killing efficacy is due to a combinational effect of electrolysis and reversible electroporation that takes place within the first two minutes after E2 application. The results further show that cell death after E2 treatment is significantly delayed. These observations suggest that cell death is induced in permeabilized cells due to the uptake of electrolysis species. Thermal simulations revealed a significant but innocuous temperature increase.

Toward a clinical real time tissue ablation technology: combining electroporation and electrolysis (E2).

BACKGROUND: Percutaneous image-guided tissue ablation (IGA) plays a growing role in the clinical management of solid malignancies. Electroporation is used for IGA in several modalities: irreversible electroporation (IRE), and reversible electroporation with chemotoxic drugs, called electrochemotherapy (ECT). It was shown that the combination of electrolysis and electroporation-E2-affords tissue ablation with greater efficiency, that is, lower voltages, lower energy and shorter procedure times than IRE and without the need for chemotoxic additives as in ECT. METHODS: A new E2 waveform was designed that delivers optimal doses of electroporation and electrolysis in a single waveform. A series of experiments were performed in the liver of pigs to evaluate E2 in the context of clinical applications. The goal was to find initial parameter boundaries in terms of electrical field, pulse duration and charge as well as tissue behavior to enable real time tissue ablation of clinically relevant volumes. RESULTS: Histological results show that a single several hundred millisecond long E2 waveform can ablate large volume of tissue at relatively low voltages while preserving the integrity of large blood vessels and lumen structures in the ablation zone without the use of chemotoxic drugs or paralyzing drugs during anesthesia. This could translate clinically into much shorter treatment times and ease of use compared to other techniques that are currently applied.

The combination of electroporation and electrolysis (E2) employing different electrode arrays for ablation of large tissue volumes.

BACKGROUND: The combination of electroporation with electrolysis (E2) has previously been introduced as a novel tissue ablation technique. E2 allows the utilization of a wide parameter range and may therefore be a suitable technology for development of tissue-specific application protocols. Previous studies have implied that it is possible to achieve big lesions in liver in a very short time. The goal of this study was to test a variety of electrode configurations for the E2 application to ablate large tissue volumes. MATERIALS AND METHODS: 27 lesions were performed in healthy porcine liver of five female pigs. Four, two and bipolar electrode-arrays were used to deliver various E2 treatment protocols. Liver was harvested approx. 20h after treatment and examined with H&E and Masson's trichrome staining, and via TUNEL staining for selective specimen. RESULTS: All animals survived the treatments without complications. With four electrodes, a lesion of up to 35x35x35mm volume can be achieved in less than 30s. The prototype bipolar electrode created lesions of 50x18x18mm volume in less than 10s. Parameters for two-electrode ablations with large exposures encompassing large veins were found to be good in terms of vessel preservation, but not optimal to reliably close the gap between the electrodes. CONCLUSION: This study demonstrates the ability to produce large lesions in liver within seconds at lower limits of the E2 parameter space at different electrode configurations. The applicability of E2 for single electrode ablations was demonstrated with bipolar electrodes. Parameters for large 4-electrode ablation volumes were found suitable, while parameters for two electrodes still need optimization. However, since the parameter space of E2 is large, it is possible that for all electrode geometries optimal waveforms and application protocols for specific tissues will emerge with continuing research.

Prostate cancer infiltrating the bladder sphincter successfully treated with Electrochemotherapy: a case report.

We demonstrate feasibility and safety of Electrochemotherapy for treatment of a prostate cancer (PCa) with infiltration of the urethral sphincter. The patient remained continent and potent, toxicity was low, and 6 months of follow-up showed no cancer activity. We conclude that Electrochemotherapy should be further evaluated as treatment strategy for locally advanced PCa.

Treatment of lymph node metastases from gastric cancer with a combination of Irreversible Electroporation and Electrochemotherapy: a case report.

The combination of Irreversible Electroporation and Electrochemotherapy (IRECT) was well tolerated, safe, and had antitumor activity in this case study of a patient with lymph node metastases from gastric cancer. We therefore recommend the consideration of further clinical studies to investigate the treatment of cancerous tissue with IRECT.

Cryoelectrolysis; an acute case study in the pig liver.

We report results from an acute, single case study in the pig liver on the effects of a tissue ablation protocol (we named cryoelectrolysis) in which 10 min of cryosurgery, with a commercial cryosurgical probe, are delivered after 10 min of electrolysis generated by a current of about 60 mA. The histological appearance of tissue treated with cryoelectrolysis is compared with the appearance of tissue treated with 10 min of cryosurgery alone and with 10 min of electrolysis alone. Histology done after 3 h survival shows that the mixed rim of live and dead cells found around the ablated lesion in both cryosurgery and electrolytic ablation is replaced by a sharp margin between life and dead cells in cryoelectrolysis. The appearance of the dead cells in each, cryoelectrolysis, cryosurgery and electrolytic ablation is different. Obviously, this is an acute study and the results are only relevant to the conditions of this study. There is no doubt that additional acute and chronic studies are needed to strengthen and expand the findings of this study.

Single exponential decay waveform; a synergistic combination of electroporation and electrolysis (E2) for tissue ablation.

BACKGROUND: Electrolytic ablation and electroporation based ablation are minimally invasive, non-thermal surgical technologies that employ electrical currents and electric fields to ablate undesirable cells in a volume of tissue. In this study, we explore the attributes of a new tissue ablation technology that simultaneously delivers a synergistic combination of electroporation and electrolysis (E2). METHOD: A new device that delivers a controlled dose of electroporation field and electrolysis currents in the form of a single exponential decay waveform (EDW) was applied to the pig liver, and the effect of various parameters on the extent of tissue ablation was examined with histology. RESULTS: Histological analysis shows that E2 delivered as EDW can produce tissue ablation in volumes of clinical significance, using electrical and temporal parameters which, if used in electroporation or electrolysis separately, cannot ablate the tissue. DISCUSSION: The E2 combination has advantages over the three basic technologies of non-thermal ablation: electrolytic ablation, electrochemical ablation (reversible electroporation with injection of drugs) and irreversible electroporation. E2 ablates clinically relevant volumes of tissue in a shorter period of time than electrolysis and electroporation, without the need to inject drugs as in reversible electroporation or use paralyzing anesthesia as in irreversible electroporation.

Synergistic Combination of Electrolysis and Electroporation for Tissue Ablation.

Electrolysis, electrochemotherapy with reversible electroporation, nanosecond pulsed electric fields and irreversible electroporation are valuable non-thermal electricity based tissue ablation technologies. This paper reports results from the first large animal study of a new non-thermal tissue ablation technology that employs "Synergistic electrolysis and electroporation" (SEE). The goal of this pre-clinical study is to expand on earlier studies with small animals and use the pig liver to establish SEE treatment parameters of clinical utility. We examined two SEE methods. One of the methods employs multiple electrochemotherapy-type reversible electroporation magnitude pulses, designed in such a way that the charge delivered during the electroporation pulses generates the electrolytic products. The second SEE method combines the delivery of a small number of electrochemotherapy magnitude electroporation pulses with a low voltage electrolysis generating DC current in three different ways. We show that both methods can produce lesion with dimensions of clinical utility, without the need to inject drugs as in electrochemotherapy, faster than with conventional electrolysis and with lower electric fields than irreversible electroporation and nanosecond pulsed ablation.

A Vivens Ex Vivo Study on the Synergistic Effect of Electrolysis and Freezing on the Cell Nucleus.

Freezing-cryosurgery, and electrolysis-electrochemical therapy (EChT), are two important minimally invasive surgery tissue ablation technologies. Despite major advantages they also have some disadvantages. Cryosurgery cannot induce cell death at high subzero freezing temperatures and requires multiple freeze thaw cycles, while EChT requires high concentrations of electrolytic products-which makes it a lengthy procedure. Based on the observation that freezing increases the concentration of solutes (including products of electrolysis) in the frozen region and permeabilizes the cell membrane to these products, this study examines the hypothesis that there could be a synergistic effect between freezing and electrolysis in their use together for tissue ablation. Using an animal model we refer to as vivens ex vivo, which may be of value in reducing the use of animals for experiments, combined with a Hematoxylin stain of the nucleus, we show that there are clinically relevant protocols in which the cell nucleus appears intact when electrolysis and freezing are used separately but is affected by certain combinations of electrolysis and freezing.

Electrical breakdown in tissue electroporation.

Electroporation, the permeabilization of the cell membrane by brief, high electric fields, has become an important technology in medicine for diverse application ranging from gene transfection to tissue ablation. There is ample anecdotal evidence that the clinical application of electroporation is often associated with loud sounds and extremely high currents that exceed the devices design limit after which the devices cease to function. The goal of this paper is to elucidate and quantify the biophysical and biochemical basis for this phenomenon. Using an experimental design that includes clinical data, a tissue phantom, sound, optical, ultrasound and MRI measurements, we show that the phenomenon is caused by electrical breakdown across ionized electrolysis produced gases near the electrodes. The breakdown occurs primarily near the cathode. Electrical breakdown during electroporation is a biophysical phenomenon of substantial importance to the outcome of clinical applications. It was ignored, until now.

Addition of shear-wave elastography during second-look MR imaging-directed breast US: effect on lesion detection and biopsy targeting.

PURPOSE: To determine if adding shear-wave elastography (SWE) to second-look ultrasonography (US) after breast dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging helps find or target lesions seen on DCE MR images for US-guided biopsy. MATERIALS AND METHODS: This HIPAA-compliant prospective study was approved by the institutional review board, and written informed consent was obtained from patients. From May 2011 to July 2012, 73 women with 96 Breast Imaging Reporting and Data System (BI-RADS) category 4 or 5 lesions after DCE MR imaging prospectively consented to undergo SWE during second-look US. If a lesion was not confidently seen with B-mode US, SWE during real-time scanning was performed to determine if SWE helped find or target lesions for US biopsy. A qualitative SWE six-point color scale was used to record the maximum elasticity in and around lesions. All lesions underwent US or DCE MR imaging-guided core biopsy. RESULTS: Median participant age was 52 years (range, 21-81 years). In 72 patients who underwent DCE MR imaging, 96 BI-RADS category 4 or 5 lesions were detected in 81 breasts. There were 29 (30%) malignancies (one malignancy was of nonbreast origin), 14 (15%) high-risk lesions, and 53 (55%) benign lesions. US revealed 22 cancers, and seven cancers were detected only with MR imaging. Real-time SWE helped find one lesion and target four lesions that were incompletely assessed with gray-scale US. These five lesions that were localized or targeted for biopsy were invasive cancers, representing 23% of the 22 malignancies detected with US. CONCLUSION: Real-time SWE added to second-look US after DCE MR imaging increased the detection rate of cancers and helped target cancers for US-guided biopsy.

Application of Raman spectroscopy to identify microcalcifications and underlying breast lesions at stereotactic core needle biopsy.

Microcalcifications are a feature of diagnostic significance on a mammogram and a target for stereotactic breast needle biopsy. Here, we report development of a Raman spectroscopy technique to simultaneously identify microcalcification status and diagnose the underlying breast lesion, in real-time, during stereotactic core needle biopsy procedures. Raman spectra were obtained ex vivo from 146 tissue sites from fresh stereotactic breast needle biopsy tissue cores from 33 patients, including 50 normal tissue sites, 77 lesions with microcalcifications, and 19 lesions without microcalcifications, using a compact clinical system. The Raman spectra were modeled on the basis of the breast tissue components, and a support vector machine framework was used to develop a single-step diagnostic algorithm to distinguish normal tissue, fibrocystic change (FCC), fibroadenoma, and breast cancer, in the absence and presence of microcalcifications. This algorithm was subjected to leave-one-site-out cross-validation, yielding a positive predictive value, negative predictive value, sensitivity, and specificity of 100%, 95.6%, 62.5%, and 100% for diagnosis of breast cancer (with or without microcalcifications) and an overall accuracy of 82.2% for classification into specific categories of normal tissue, FCC, fibroadenoma, or breast cancer (with and without microcalcifications). Notably, the majority of breast cancers diagnosed are ductal carcinoma in situ (DCIS), the most common lesion associated with microcalcifications, which could not be diagnosed using previous Raman algorithm(s). Our study shows the potential of Raman spectroscopy to concomitantly detect microcalcifications and diagnose associated lesions, including DCIS, and thus provide real-time feedback to radiologists during such biopsy procedures, reducing nondiagnostic and false-negative biopsies.

Diagnostic power of diffuse reflectance spectroscopy for targeted detection of breast lesions with microcalcifications.

Microcalcifications geographically target the location of abnormalities within the breast and are of critical importance in breast cancer diagnosis. However, despite stereotactic guidance, core needle biopsy fails to retrieve microcalcifications in up to 15% of patients. Here, we introduce an approach based on diffuse reflectance spectroscopy for detection of microcalcifications that focuses on variations in optical absorption stemming from the calcified clusters and the associated cross-linking molecules. In this study, diffuse reflectance spectra are acquired ex vivo from 203 sites in fresh biopsy tissue cores from 23 patients undergoing stereotactic breast needle biopsies. By correlating the spectra with the corresponding radiographic and histologic assessment, we have developed a support vector machine-derived decision algorithm, which shows high diagnostic power (positive predictive value and negative predictive value of 97% and 88%, respectively) for diagnosis of lesions with microcalcifications. We further show that these results are robust and not due to any spurious correlations. We attribute our findings to the presence of proteins (such as elastin), and desmosine and isodesmosine cross-linkers in the microcalcifications. It is important to note that the performance of the diffuse reflectance decision algorithm is comparable to one derived from the corresponding Raman spectra, and the considerably higher intensity of the reflectance signal enables the detection of the targeted lesions in a fraction of the spectral acquisition time. Our findings create a unique landscape for spectroscopic validation of breast core needle biopsy for detection of microcalcifications that can substantially improve the likelihood of an adequate, diagnostic biopsy in the first attempt.

Development and comparative assessment of Raman spectroscopic classification algorithms for lesion discrimination in stereotactic breast biopsies with microcalcifications.

Microcalcifications are an early mammographic sign of breast cancer and a target for stereotactic breast needle biopsy. Here, we develop and compare different approaches for developing Raman classification algorithms to diagnose invasive and in situ breast cancer, fibrocystic change and fibroadenoma that can be associated with microcalcifications. In this study, Raman spectra were acquired from tissue cores obtained from fresh breast biopsies and analyzed using a constituent-based breast model. Diagnostic algorithms based on the breast model fit coefficients were devised using logistic regression, C4.5 decision tree classification, k-nearest neighbor (k -NN) and support vector machine (SVM) analysis, and subjected to leave-one-out cross validation. The best performing algorithm was based on SVM analysis (with radial basis function), which yielded a positive predictive value of 100% and negative predictive value of 96% for cancer diagnosis. Importantly, these results demonstrate that Raman spectroscopy provides adequate diagnostic information for lesion discrimination even in the presence of microcalcifications, which to the best of our knowledge has not been previously reported.

Precision of Raman spectroscopy measurements in detection of microcalcifications in breast needle biopsies.

Microcalcifications are an early mammographic sign of breast cancer and a target for stereotactic breast needle biopsy. We developed Raman spectroscopy decision algorithms to detect breast microcalcifications, based on fit coefficients (FC) derived by modeling tissue Raman spectra as a linear combination of the Raman spectra of 9 chemical and morphologic components of breast tissue. However, little or no information is available on the precision of such measurements and its effect on the ability of Raman spectroscopy to make predictions for breast microcalcification detection. Here we report the precision, that is, the closeness of agreement between replicate Raman spectral measurements--and the model FC derived from them--obtained ex vivo from fresh breast biopsies from patients undergoing stereotactic breast needle biopsy, using a compact clinical Raman system. The coefficients of variation of the model FC averaged 0.03 for normal breast tissue sites, 0.12 for breast lesions without, and 0.22 for breast lesions with microcalcifications. Imprecision in the FC resulted in diagnostic discordance among replicates only for line-sitters, that is, tissue sites with FC values near the decision line or plane. The source of this imprecision and their implications for the use of Raman spectroscopy for guidance of stereotactic breast biopsies for microcalcifications are also discussed. In summary, we conclude that the precision of Raman spectroscopy measurements in breast tissue obtained using our compact clinical system is more than adequate to make accurate and repeatable predictions of microcalcifications in breast tissue using decision algorithms based on model FC. This provides strong evidence of the potential of Raman spectroscopy guidance of stereotactic breast needle biopsies for microcalcifications.

Segregation of radiographic calcifications in stereotactic core biopsies of breast: is it necessary?

Stereotactic-needle core biopsy (SNCB) is increasingly being used for the evaluation of mammographic calcifications. Radiography of SNCB specimens is essential to confirm the presence of calcifications within the biopsy material. To aid and direct the pathologist, it has been recommended that SNCBs be separated into those with and without radiographic calcifications and separately embedded. However, the utility of this separation to the pathologist has not been established. We reviewed 80 consecutive 11 gauge vacuum-assisted SNCB procedures performed for mammographic calcifications. The core biopsies were separated by the radiologist into those with and without radiographic calcifications ("calcs" and "no calcs"). Twenty-nine of 80 (36%) of the "calcs" cores were atypical or malignant, while 23 of 80 (29%) of the "no calcs" cores were atypical or malignant (chi(2) = 0.63, p = NS). The same diagnosis was rendered in the "calcs" and "no calcs" specimens in 61/80 cases (76%). Two cases of ductal carcinoma in situ, four cases of atypical ductal hyperplasia and 13 cases of fibroadenoma were diagnosed in the "calcs" cores only. However, in all cases where the pathologic lesion was seen in the "calcs" core only, the pathologic lesion was present on initial H&E levels and would have been diagnosed even in the absence of core segregation. Deeper sections were deemed necessary in seven of the 80 cases. No change in diagnosis was made on the basis of these deeper sections, even in the cases where histologic calcifications appeared on deeper sections. Separate embedding of SNCBs into those with and without radiographic calcifications does not appear to be of great utility to the pathologist. Equal attention should be given to all cores in the setting of SNCBs for mammographic calcifications.