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Fluorescence-guided-surgery offers intraoperative visualization of neoplastic tissue. Delta-aminolevulinic acid (5-ALA), which targets enzymatic abnormality in neoplastic cells, is the only approved agent for fluorescence-guided neurosurgery. More recently, we described Second Window Indocyanine Green (SWIG) which targets neoplastic tissue through enhanced vascular permeability. We hypothesized that SWIG would demonstrate similar clinical utility in identification of high-grade gliomas compared with 5-ALA.Female C57/BL6 and nude/athymic mice underwent intracranial implantation of 300,000 GL261 and U87 cells, respectively. Tumor-bearing mice were euthanized after administration of 5-ALA (200 mg/kg intraperitoneal) and SWIG (5 mg/kg intravenous). Brain sections were imaged for protoporphyrin-IX and ICG fluorescence. Fluorescence and HE images were registered using semi-automatic scripts for analysis. Human subjects with HGG were administered SWIG (2.5 mg/kg intravenous) and 5-ALA (20 mg/kg oral). Intraoperatively, tumors were imaged for ICG and protoporphyrin-IX fluorescence.In non-necrotic tumors, 5-ALA and SWIG demonstrated 90.2 % and 89.2 % tumor accuracy (p value = 0.52) in U87 tumors and 88.1 % and 87.7 % accuracy (p value = 0.83) in GL261 tumors. The most distinct difference between 5-ALA and SWIG distribution was seen in areas of tumor-associated necrosis, which often showed weak/no protoporphyrin-IX fluorescence, but strong SWIG fluorescence. In twenty biopsy specimens from four subjects with HGG, SWIG demonstrated 100 % accuracy, while 5-ALA demonstrated 75-85 % accuracy; there was 90 % concordance between SWIG and 5-ALA fluorescence.Our results provide the first direct comparison of the diagnostic utility of SWIG vs 5-ALA in both rodent and human HGG. Given the broader clinical utility of SWIG compared with 5-ALA, our data supports the use of SWIG in tumor surgery to improve the extent of safe resections.NCT02710240 (US National Library of Medicine Registry; https://www.clinicaltrials.gov/ct2/show/NCT02710240?id=NCT02710240draw=2rank=1 ).

Introduction: Today, magnetic resonance imaging (MRI) is the standard method for monitoring patients with brain tumors. The ability of conventional MRI in differentiating neoplastic tissue from nonspecific, treatment-related changes after surgery, radio-, chemo- or immunotherapy, however, remains limited. Therefore, advanced MRI sequences and positron emission tomography (PET) are increasingly being considered to improve decision-making. Areas covered: PET using radiolabeled amino acids has evolved into an important diagnostic tool to overcome some of the shortcomings of conventional MRI. In view of the rapidly developing novel treatment strategies, a reliable statement on the response to therapy is becoming increasingly important. This article gives an overview of the current results of PET with radiolabelled amino acids in therapy monitoring of standard therapy as well as various innovative approaches in the treatment of patients with cerebral gliomas. Expert opinion: Amino acid PET has proven to be helpful in therapy monitoring of gliomas, the costs are low in relation to the costs of therapy and the clinical benefit, and a widespread clinical use is highly desirable.

Excision of all visible neoplastic tissue is the goal of EMR of colorectal laterally spreading tumors. Flat and fibrotic tissue can resist snaring. Ablation of visible polyps is associated with high recurrence rates. Avulsion is a technique to continue resection when snaring fails.We retrospectively analyzed colonic EMRs of 564 consecutive referred polyps between 2015 and 2017. Hot avulsion was used when snaring was unsuccessful. Polyps treated with and without avulsion were compared.Hot avulsion was used in 20.9% (n = 112) of all resected lesions. The recurrence rates on follow-up colonoscopy were 17.52% in the avulsion group versus 16.02% in the non-avulsion group (P = .76). Hot avulsion was associated with a trend toward higher rates of delayed hemorrhage (5.35% vs 2.58%; P = .15) and post-coagulation syndrome (1.8% vs 0.47%; P = .15), but polyps treated with any avulsion were larger than those in which no avulsion was used (P .001). There were an insufficient number of adverse events to perform a multivariable analysis to test the effects of avulsion, size, and location on the risk of overall adverse events.Unlike previous reports of using argon plasma coagulation to treat visible polyps during EMR, hot avulsion of visible/fibrotic neoplasia was associated with similar EMR efficacy compared with cases that did not require hot avulsion. The safety profile of hot avulsion appears acceptable.

The presence of inflammatory immune cells in human tumors raises a fundamental question in oncology: How do cancer cells avoid the destruction by immune attack? In principle, tumor development can be controlled by cytotoxic innate and adaptive immune cells; however, as the tumor develops from neoplastic tissue to clinically detectable tumors, cancer cells evolve different mechanisms that mimic peripheral immune tolerance in order to avoid tumoricidal attack. Here, we provide an update of recent accomplishments, unifying concepts, and future challenges to study tumor-associated immune cells, with an emphasis on metastatic carcinomas.

Tumor recurrence in pituitary adenomas is as high as 20% after surgery. Conventional neuronavigation and white light visualization are not sufficiently accurate in detecting residual neoplastic tissue. Fluorescence-guided surgery offers accurate, real-time visualization of neoplastic tissue. The authors' group has explored the use of near-infrared imaging, which is superior to visible-light fluorescence in both signal contrast and tissue penetration, in transsphenoidal endoscopic surgeries for pituitary adenomas using 2 techniques: second window indocyanine green, in which indocyanine green passively accumulates in the tumor, and OTL38, which actively targets folate receptors on adenoma cells. This work establishes the foundation of intraoperative near-infrared imaging for fluorescence-guided neurosurgery.

Following brain cancer treatment, the capacity of anatomical MRI to differentiate neoplastic tissue from treatment-related changes (e.g., pseudoprogression) is limited. This study compared apparent diffusion coefficients (ADC) obtained by diffusion-weighted MRI (DWI) with static and dynamic parameters of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation of treatment-related changes from tumour progression. Forty-eight pretreated high-grade glioma patients with anatomical MRI findings suspicious for progression (median time elapsed since last treatment was 16 weeks) were investigated using DWI and dynamic FET PET. Maximum and mean tumour-to-brain ratios (TBRmax, TBRmean) as well as dynamic parameters (time-to-peak and slope values) of FET uptake were calculated. For mean ADC calculation, regions-of-interest analyses were performed on ADC maps calculated from DWI coregistered with the contrast-enhanced MR image. Diagnoses were confirmed neuropathologically (21%) or clinicoradiologically. Diagnostic performance was evaluated using receiver-operating-characteristic analyses or Fisher’s exact test for a combinational approach. Ten of 48 patients had treatment-related changes (21%). The diagnostic performance of FET PET was significantly higher (threshold for both TBRmax and TBRmean, 1.95; accuracy, 83%; AUC, 0.89 ± 0.05; P

The tumour-associated, cell membrane-bound isoforms IX and XII of human carbonic anhydrase (CA, EC 4.2.1.1) are overexpressed in cancer cells contributing to the hypoxic tumour pH/metabolism regulating machinery and as thus, can serve as markers of malignant neoplastic tissue. Inhibitors of CAs can be employed both for the treatment of hypoxic tumours and in the design of radiotracers for positron emission tomography and imaging of such cancers. The present review provides a comprehensive summary of the progress achieved to-date in the field of developing PET-tracers based on monoclonal antibodies, biomolecules, and small-molecule ligands of CA IX and XII.

Functional magnetic resonance imaging (fMRI) allows the non-invasive assessment of human brain activity in vivo. In glioma patients, fMRI is frequently used to determine the individual functional anatomy of the motor and language network in a presurgical setting to optimize surgical procedures and prevent extensive damage to functionally eloquent areas. Novel developments based on resting-state fMRI may help to improve presurgical planning for patients which are unable to perform structured tasks and might extend presurgical mapping to include additional functional networks. Recent advances indicate a promising potential for future applications of fMRI in glioma patients which might help to identify neoplastic tissue or predict the long-term functional outcome of individual patients.

Background and study aims: Early neoplasia in Barrett’s esophagus is difficult to detect and often overlooked during Barrett’s surveillance. An automatic detection system could be beneficial, by assisting endoscopists with detection of early neoplastic lesions. The aim of this study was to assess the feasibility of a computer system to detect early neoplasia in Barrett’s esophagus.Patients and methods: Based on 100 images from 44 patients with Barrett’s esophagus, a computer algorithm, which employed specific texture, color filters, and machine learning, was developed for the detection of early neoplastic lesions in Barrett’s esophagus. The evaluation by one endoscopist, who extensively imaged and endoscopically removed all early neoplastic lesions and was not blinded to the histological outcome, was considered the gold standard. For external validation, four international experts in Barrett’s neoplasia, who were blinded to the pathology results, reviewed all images.Results: The system identified early neoplastic lesions on a per-image analysis with a sensitivity and specificity of 0.83. At the patient level, the system achieved a sensitivity and specificity of 0.86 and 0.87, respectively. A trade-off between the two performance metrics could be made by varying the percentage of training samples that showed neoplastic tissue.Conclusion: The automated computer algorithm developed in this study was able to identify early neoplastic lesions with reasonable accuracy, suggesting that automated detection of early neoplasia in Barrett’s esophagus is feasible. Further research is required to improve the accuracy of the system and prepare it for real-time operation, before it can be applied in clinical practice.

Nuclear polarity is characterized by intracytoplasmic nuclear positioning and alignment in the tissue. The mechanisms responsible for maintaining nuclear polarity in normal cells and its disturbance in neoplastic cells are not understood. We studied microtubule-organizing center (MTOC) positioning-mediated nuclear polarity in various normal and neoplastic human tissues, as well as in cultured cells. To visualize the MTOC in cells, gamma-tubulin and pericentrin were immunohistochemically stained by fluorescence and non-fluorescence methods. Position of MTOC in normal and neoplastic tissue was assessed by spatial relationship with nucleus and apico-basal axis. We found MTOC positioning to be related to morphogenesis in various normal and neoplastic human tissues, as well as in cultured cells. MTOC positions were different between two-dimensional cultured isolated cells and three-dimensional cultured gland-formed cells. The MTOC position was specific depending on the cell type in the tissue structure. In particular, glandular and urothelial epithelium had a strong relationship with preservation of nuclear polarity and MTOC positioning. Carcinoma cells showed an irregular position or absence of the MTOC depending on poorer differentiation and higher grade of carcinomas. In conclusion, the position of the MTOC affects regulation of nuclear polarity and morphogenesis of normal and pathological tissue structure.

Chondrosarcomas constitute a heterogeneous group of primary bone cancers characterized by hyaline cartilaginous neoplastic tissue. They are the second most common primary bone malignancy. The vast majority of chondrosarcomas are conventional chondrosarcomas, and most conventional chondrosarcomas are low- to intermediate-grade tumors (grade 1 or 2) which have indolent clinical behavior and low metastatic potential. Recurrence augurs a poor prognosis, as conventional chondrosarcomas are both radiation and chemotherapy resistant. Recent discoveries in the biology, genetics, and epigenetics of conventional chondrosarcomas have significantly advanced our understanding of the pathobiology of these tumors and offer insight into potential therapeutic targets.

Initial diagnostics and follow-up of gliomas is usually based on contrast-enhanced MRI. However, the capacity of standard MRI to differentiate neoplastic tissue from posttherapeutic effects such as pseudoprogression is limited. Advanced neuroimaging methods may provide relevant additional information, which allow for a more accurate diagnosis especially in clinically equivocal situations. This review article focuses predominantly on PET using radiolabeled amino acids and advanced MRI techniques such as perfusion-weighted imaging (PWI) and summarizes the efforts of these methods regarding the identification of pseudoprogression after glioma therapy. Areas covered: The current literature on pseudoprogression in the field of brain tumors, with a focus on gliomas is summarized. A literature search was performed using the terms 'pseudoprogression', 'temozolomide', 'glioblastoma', 'PET', 'PWI', 'radiochemotherapy', and derivations thereof. Expert commentary: The present literature provides strong evidence that PWI MRI and amino acid PET can be of great value by providing valuable additional diagnostic information in order to overcome the diagnostic challenge of pseudoprogression. Despite various obstacles such as the still limited availability of amino acid PET and the lack of standardization of PWI, the diagnostic improvement probably results in relevant benefits for brain tumor patients and justifies a more widespread use of these diagnostic tools.

Metabolic imaging has come to occupy a prominent place in the diagnosis and management of microbial infection. Molecular probes available for infection imaging have undergone a rapid evolution starting with nonspecific agents that accumulate similarly in infection, sterile inflammation, and neoplastic tissue and then extending to more targeted probes that seek to identify specific microbial species. This focus review describes the metabolic and molecular imaging techniques currently available for clinical use in infection imaging and those that have demonstrated promising results in preclinical studies with the potential for clinical applications.

Photodynamic diagnostic technique with blue light cystoscopy (BLC) takes advantage of the preferential uptake and accumulation of protoporphyrins in neoplastic tissue which emit a red fluorescence when illuminated with blue light (360–450 nm wavelengths). This allows enhanced visualization of small papillary tumors and flat carcinoma in situ lesions that might have been missed on white light cystoscopy (WLC). There is compelling evidence that the ability of BLC to detect these additional tumors translates into improved recurrence rates compared to WLC. However, the impact of BLC with regard to progression rates and in patients who are managed with intravesical therapy is not yet known. Further work is required to optimize the integration of BLC into clinical practice, but the future for BLC appears promising.

We provide an overview of the available information on the distribution of chemotherapeutics in human tumors, highlighting the progress made to assess the heterogeneity of drug concentrations in relation to the complex neoplastic tissue using novel analytical methods, e.g., mass spectrometry imaging. The increase in interstitial fluid pressure due to abnormal vascularization and stiffness of tumor stroma explains the variable and heterogeneous drug concentrations. Therapeutic strategies to enhance tumor drug distribution, thus possibly increasing efficacy, are discussed. Clinical Pharmacology & Therapeutics (2014); 96 2, 224–238. doi:10.1038/clpt.2014.105

The aim of this study was to evaluate the correlation of the expression of Fas and Fas-L proteins in gastric carcinoma cells on the occurrence of metastases to regional lymph nodes.The study included 89 patients treated surgically for gastric carcinoma. The evaluated clinicomorphological parameters were verified based on both histopathological material collected at surgery and intraoperative image. Fas and Fas-L expression was evaluated immunohistochemically in the neoplastic tissue of the removed gastric tumors.A statistically significant positive correlation between Fas expression in gastric carcinoma cells and the number of regional lymph nodes affected by metastases was observed (p0.05). No such correlation was noticed with respect to Fas-L. A statistically significant correlation between the depth of neoplastic infiltration of the stomach wall (T feature) and the number of affected lymph nodes was observed (p0.05). No statistically significant correlations in the other examined clinicomorphological features and the number of metastatic lymph nodes was observed.A positive Fas expression correlates with more frequent occurrence of metastases to regional lymph nodes. Determination of this protein expression in cancer cells prior to surgery may be helpful for planning the surgical procedure, especially with respect to the extent of lymph node excision.

Objective: To describe and discuss the design, building and usefulness of tissue microarray (TMA) blocks for the study of salivary gland tumors (SGTs). Study Design: Two hundred thirty-eight formalin-fixed, paraffin-embedded SGTs were arranged in blocks of TMA using a manual tissue arrayer. Three representative cores of 1.0, 2.0 or 3.0mm were taken from each original block and their characteristics were analyzed and described. Results: It was created 12 TMA blocks that presented highly representative neoplastic cylinders. However, those neoplasias rich in cystic spaces such as mucoepidermoid carcinoma and Warthin tumor presented more difficulties to be sampled, as the neoplastic tissue available was scarce. Tissue damage and loss during TMA construction was estimated as 3.7%. Conclusion: Representative areas of SGTs, with relatively small loss of tissue, can be obtained with the construction of TMA blocks for molecular studies. However, tumors rich in cystic spaces present more difficulties to be adequately sampled. Key words:Tissue microarray, tma, salivary gland tumors, immunohistochemistry.

Malignant gliomas are locally invasive tumors that offer a poor prognosis. Evidence shows that complete resection of the tumor at the time of surgery confers a significant improvement in overall survival. In recent years, 5- aminolevulinic acid (ALA)-induced fluorescence has been used by neurosurgeons to good effect in increasing the rate of complete resection. Despite the considerable interest in the use of 5-ALA in fluorescence-guided neurosurgery, the mechanisms behind the accumulation of Protoporphyrin IX (PpIX) in neoplastic tissue are unclear. In this review, we summarize the evidence in the literature on the mechanisms underlying the selective production of PpIX with a specific focus on gliomas.

Angiogenesis is a prerequisite for tumor growth and metastatic progression. The discovery of the first specific angiogenic cytokine, VEGF, in 1989 paved the way for the clinical approval of the first antiangiogenic tumor drug 15 years later. This brief commentary highlights and puts into historical perspective the 1985 G.H.A. Clowes Memorial Award Lecture delivered by Dr. Judah Folkman. Thirty years later, this award lecture is a lively testimony of the visionary mind of Dr. Folkman, whose legacy continues to inspire contemporary angiogenesis research. Cancer Res; 76(10); 2854–6. ©2016 AACR. See related article by Folkman J, Cancer Res 1986;46:467–73.

Objective To assess the use of an ultra–high-resolution (UHR) optical coherence tomography (OCT) as an adjuvant diagnostic tool in distinguishing ocular surface squamous neoplasia (OSSN) and pterygia. Design Prospective case series. Participants Thirty-four eyes of 34 patients with conjunctival lesions clinically suspicious for OSSN or pterygia. Methods All patients were photographed and then imaged with a custom-built UHR OCT device. Subsequently, each patient underwent excisional or incisional biopsy with histopathologic diagnosis. Main Outcome Measures Comparison of preoperative UHR OCT images and the corresponding histopathologic specimen; comparison of epithelial thickness between the 2 groups as measured by UHR OCT. Results Preoperative UHR OCT images of OSSN demonstrated similarities to the histopathologic specimens. Both optical and pathologic specimens showed a thickened layer of epithelium, often with an abrupt transition from normal to neoplastic tissue. Likewise, preoperative UHR OCT images of patients with pterygia were well correlated with the histopathologic specimens. As opposed to OSSN, both UHR OCT and pathologic images of pterygia demonstrated a normal thin epithelium, with underlying thickening of the subepithelial mucosal layers. Differences in the measured epithelial thickness on UHR OCT between OSSN and pterygia were statistically significant, with an average epithelial thickness of 346 μm (standard deviation [SD], 167) in OSSN patients and 101 μm (SD, 22) in pterygium patients ( P Conclusions Ultra–high-resolution OCT may show promise as a noninvasive diagnostic tool to evaluate ocular surface lesions. In addition to a statistically significant difference in epithelial thickness, a significant degree of morphologic correlation with the histopathologic results demonstrates its potential in evaluating ocular surface squamous neoplasia and pterygia. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Neuroendocrine differentiation is often found in gastric carcinomas, but the relevance of these cells in gastric carcinogenesis is debated. We applied immunolabeling at the electron microscopic level to study the ultrastructure of neuroendocrine cells in gastric carcinomas to ensure correct cellular classification of dedifferentiated cells. The immunogold labeling at electron microscopic level was compared with an established sensitive immunohistochemical method using light microscopy. Thirteen human gastric adenocarcinomas of the diffuse type were examined for neuroendocrine differentiation by chromogranin A (CgA) labeling at both the light and electron microscopic level. The ultrastructure of CgA-positive cells was compared with CgA-positive cells from controls. Nine of 13 tumors showed CgA-positive cells both at the light and electron microscopic level. The CgA-positive cells displayed altered ultrastructural features compared with controls. Some of the CgA-positive tumor cells had granules typical for enterochromaffin-like cells. Immunoelectron microscopy seems to provide both significant immunolabeling and sufficient ultrastructure to enhance classification of cells in neoplastic tissue.

Introduction: Fluorescence-guided resection (FGR) of brain tumors is an intuitive, practical and emerging technology for visually delineating neoplastic tissue exposed intraoperatively. Image guidance is the standard technique for producing 3-dimensional spatially coregistered information for surgical decision making. Both technologies together are synergistic: the former detects surface fluorescence as a biomarker of the current surgical margin while the latter shows coregistered volumetric neuroanatomy but can be degraded by intraoperative brain shift. We present the implementation of deformation modeling for brain shift compensation in protoporphyrin IX FGR, integrating these two sources of information for maximum surgical benefit. Methods: Two patients underwent FGR coregistered with conventional image guidance. Histopathological analysis, intraoperative fluorescence and image space coordinates were recorded for biopsy specimens acquired during surgery. A biomechanical brain deformation model driven by intraoperative ultrasound data was used to generate updated MR images. Results: Combined use of fluorescence signatures and updated MR image information showed substantially improved accuracy compared to fluorescence or the original (i.e., nonupdated) MR images, detecting only true positives and true negatives, and no instances of false positives or false negatives. Conclusion: Implementation of brain deformation modeling in FGR shows promise for increasing the accuracy of neurosurgical guidance in the delineation and resection of brain tumors.

The quantitative levels of seven of the acute-phase reactant proteins were measured in the plasma of a sample of fifty-four adults all diagnosed as suffering from tuberose sclerosis and compared to that derived from a group of control subjects resident in a hospital for the mentally subnormal. Abnormal levels were found in one or more of the proteins in all but thirteen cases, with no fewer than twenty-six subject (forty-eight per cent) showing results outside the 2SD limits in three or more of the parameters investigated. Only in the alpha1-antitrypsin and fibrinogen were the means not significantly different from the control means but even in these two proteins ten and seven cases respectively individually exceeded the normal mean by more than 2SD. It is suggested that these observations can be explained as the normal response to the presence of neoplastic tissue, and the routine investigation of these and other biochemical components known to respond to the presence of neoplastic tissue may be of help in genetic counselling.

Nanotechnology is increasingly applied to the field of medicine, particularly for the treatment of cancer. In this regard, gold nanoparticles can mediate hyperthermia induction and kill tumor cells upon laser irradiation, thereby functioning as a 'thermal scalpel'. Recent developments in gold nanoparticle design have resulted in their absorption of energy in the near-infrared wavelength spectrum, which is best suited to tissue penetration and, thus, clinical application. Furthermore, to ensure accumulation of nanoparticles in neoplastic tissue, targeting ligands are being incorporated into the thermal scalpel schema. Examples of targeting ligands include antibodies and targeted gene therapy vectors. Therapeutic efficacy has been established in cell culture models for several developed thermal scalpel systems and a small number have demonstrated a therapeutic effect in animal models of cancer. Future considerations include analysis of the biodistribution and therapeutic efficacy of thermal scalpels using stringent models of cancer. Furthermore, the immunogenicity and toxicity of thermal scalpels must be established before clinical translation can be achieved.

Background: Elastography is a relatively new technology that can generate images reflective of tissue stiffness (elasticity). Neoplastic tissue is usually stiffer than normal structures. Objectives: The aim of this study was to evaluate the feasibility and utility of elastography when combined with convex-probe endobronchial ultrasound (CP-EBUS) for predicting and localizing metastatic lymph nodes during endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA). Methods: Consecutive results of endobronchial elastography of lymph nodes performed using EBUS- TBNA were prospectively collected and retrospectively analyzed. Elastography images were acquired as JPEG images and also recorded as video clips. Stiff area ratios [(stiff areas as blue pixels) / (lymph node areas as region of interest pixels)] for each lymph node determined by elastography were collated with the results of pathological diagnosis. We also performed elastography of surgically resected lymph nodes and compared image findings with pathological sections. Results: We evaluated 49 lymph nodes in 21 patients by CP-EBUS. There were 16 metastatic nodes (10 lung cancer metastases and 6 metastases from extrathoracic malignancies). Mean stiff area ratios were significantly greater for metastatic lymph nodes (0.478) than for benign nodes (0.216; p = 0.0002). Using a cutoff value of 0.311 for stiff area ratios, the sensitivity and specificity for predicting metastatic disease were 0.81 and 0.85, respectively. The stiff area was histologically compatible with metastatic distribution in surgically resected lymph nodes. Conclusions: Endobronchial elastography is feasible for lymph nodes when combined with CP-EBUS. Stiff area ratios are useful for predicting metastatic lymph nodes, which may be an efficient guide for TBNA.

Due to its capability to induce accumulation of protoporphyrin IX (PpIX) selectively in a multitude of different pathologies, 5-aminolevulinic acid (ALA) and its derivatives have attracted enormous attention in the field of photodynamic therapy (PDT) in the past two decades. The photochemical and photophysical properties of PpIX have been used for the fluorescence photodetection and photodynamic treatment of neoplasms in several medical indications in which conversion of ALA into PpIX seems to take place preferentially. Recently, this has led to the approval of this therapy for the treatment of actinic keratosis and basal cell carcinoma. When applied topically or systemically, ALA bypasses the negative feedback control that haem exerts on the enzyme ALA synthase (ALAS), which catalyses the natural production of this delta-amino acid, thereby temporarily boosting the generation of PpIX, the direct precursor of haem. Despite considerable interest in this treatment methodology, only little is known concerning the reasons for the selective accumulation of PpIX in neoplastic tissue upon ALA administration. Following an introduction into the biochemical as well as the chemical principles of haem synthesis, the present review tries to summarise experimental evidences of the mechanisms underlying preferential production of PpIX in neoplastic tissues. Thereby, morphological, environmental, enzymatic, as well as cell-specific factors will be discussed.

For over thirty years it has been evident that there is altered glycosyltransferase activity in neoplastic tissue when compared to healthy tissue. It has also long been speculated that disruption of the neoplastic expression of sialic acid on cellular glycoconjugates, is a valid target in anti-metastatic therapeutic development. Over the years attempts have been made to synthesize inhibitors of sialyltransferases in a effort to assist in the validation or dissolution of these enzymes as potential therapeutic targets.

Electrical impedance spectroscopy is a technique that has been investigated as a potential method for the diagnosis of epithelial carcinomas. Finite element modelling can provide an insight into the patterns of current flow in normal and pathological epithelium and hence aid in the process of probe design optimization. In order to develop a finite element model of the structure of normal and precancerous cervical squamous epithelium, it was first necessary to obtain the mean values and ranges of a number of morphological tissue parameters. The most important parameters in discriminating normal from neoplastic tissue were identified as being cell size and shape distribution, nuclear-to-cytoplasmic volume ratio and volume of extracellular space. A survey of the literature revealed an absence of reliable quantitative data for these parameters. We therefore present the results of our own basic image analysis on normal and pathological tissue sections, which we hope will be of use to other workers wishing to model cervical squamous epithelium, or other similar tissue structures.

Sir d We read the recent article by Schmid-Tannwald et al., 1 published in the Journal with a great interest. In this article, the authors discussed the role of quantitative and qualitative assessment of diffusion-weighted (DW) images and apparent diffusion coefficient (ADC) maps in infected and non-infected collections in the liver. As we have a special interest in DW imaging in the characterization of liver lesions, 2e6 we would like to contribute regarding the efficacy of DW imaging and ADC measurement in the evaluation of the hepatic abscess and noninfected fluid collection. As the authors mentioned in the article, ADC values of each lesion were measured by drawing a circular region of interest (ROI), encompassing the entire lesion, on the image in which the lesion was largest. We think that ADC measurement must be performed several times with using small ROIs in different regions and the lowest ADC value must be take into consideration. 2e6 In our clinical practice, we noticed that ROIs encompassing the entire lesion can lead to misinterpretation of the ADC value of the lesion, particularly in those with different components such as necrotic, cystic, infected, or neoplastic tissue. Those areas with high ADC values can increase the mean ADC value of the lesion and can lead to misinterpretation. Another issue is the visual assessment of the DW images and ADC maps, which provides easy and confident evaluation of the solidecystic and simpleecomplicated focal liver lesions. Particularly, in hepatic abscess, central diffusion restriction and peripherally relative increased diffusion in DW images and ADC maps are unique findings and these features can be easily evaluated by visual assessment without time-consuming ADC measurements. Visual assessment is also useful for overcoming the reproducibility problems associated with DW imaging in the liver due different magnetic resonance imaging (MRI) machines, sequence parameters, and differences in ADC values in different parts of the liver.2,4e6

The role of aminolevulinic acid hydrochloride (ALA) in photodynamic therapy (PDT) of in situ neoplasias and tumours of epithelial tumours is steadily increasing and it has been shown to be the drug with most clinical use in PDT. In dermatology, topical PDT with ALA is already postulated to be the treatment of choice for actinic keratoses and superficial basal cell carcinomas. In gastroenterology, pulmonology, uro- and nephrology, neurology and gynaecology ALA has an important role as a photosensitiser not only in the diagnosis of neoplastic tissue but as therapy; first experiences have been made with PDT in these organs. Besides the therapeutic efficacy of this technique, the fluorescence of ALA-induced porphyrins can be effectively used to detect and delineate epithelial and endothelial neoplasms. In dermatology, other indications for ALA-treatment are non-tumoural applications, especially psoriasis, viral-induced diseases, or acne vulgaris. ALA is an effective compound in the diagnosis or therapy of various epithelial and endothelial neoplastic lesions.

The combination of light and chemicals to treat skin diseases is widely practiced in dermatology. Within this broad use of light and drugs, in recent years the concept of photodynamic therapy (PDT) has emerged. PDT is a promising modality for the management of various tumors and nonmalignant diseases, based on the combination of a photosensitizer that is selectively localized in the target tissue and illumination of the lesion with visible light, resulting in photodamage and subsequent cell death. Moreover, the fluorescence of photosensitizing compounds is also utilized as a helpful diagnostic tool for the detection of neoplastic tissue. Intensive basic and clinical research culminated in the worldwide approval of PDT for bladder, esophageal, and lung cancer. The expanding use of this relatively new therapeutic modality in dermatology at many centers around the world has revealed its efficacy for the treatment of cutaneous precancer and cancer, as well as selected benign skin disorders. The following article summarizes the main principles of PDT considering the most recent developments and provides a comprehensive synopsis of the present status of the use of PDT in dermatology. (J Am Acad Dermatol 2000;42:389-413.) Learning Objective: At the conclusion of this learning activity, participants should be able to describe the basic concepts of PDT, including fundamental knowledge of the most relevant photosensitizers, the light sources, the mechanisms involved in PDT-mediated cell destruction, as well as the indications and limitations of photodynamic treatment of skin diseases.

Two cases of treated plasma cell lesions of bone are reported for which contrast-enhanced MRI had suggested necrosis, based on lack of enhancement after gadolinium injection, and in which pathologic examinations revealed the presence of extensive viable neoplastic tissue. These cases highlight the need for cautious interpretation of contrast-enhanced MRI signs of response to treatment and inactivity of lesions in the setting of plasma cell neoplasms.

As the modern era of cryosurgery began in the mid 1960s, the basic features of cryosurgical technique were established as rapid freezing, slow thawing, and repetition of the freeze-thaw cycle. Since then, new applications of cryosurgery have caused numerous investigations on the mechanism of injury in cryosurgery with the intent to better define appropriate or optimal temperature-time dosimetry of the freeze-thaw cycles. A diversity of opinion has become evident on some aspects of technique, but the basic tenets of cryosurgery remain unchanged. All the parts of the freeze-thaw cycle can cause tissue injury. The cooling rate should be as fast as possible, but it is not as critical as other factors. The coldest tissue temperature is the prime factor in cell death and this should be -50 degreesC in neoplastic tissue. The optimal duration of freezing is not known, but prolonged freezing increases tissue destruction. The thawing rate is a prime destructive factor and it should be as slow as possible. Repetition of the freeze-thaw cycle is well known to be an important factor in effective therapy. A prime need in cryosurgical research is related to the periphery of the cryosurgical lesion where some cells die and others live. Adjunctive therapy should influence the fate of cells in this region and increase the efficacy of cryosurgical techniques.

Laser-induced thermotherapy (LITT) is a hyperthermic procedure recently employed to treat cancer in several organs. The amount of coagulated tissue depends on the temperature distribution around the applicator, which plays a crucial role for an optimal outcome: the removal of the whole neoplastic tissue, whilst preventing damage to the surrounding healthy tissue. Although feedback concerning tissue temperature could be useful to drive the physician in the adjustment of laser settings and treatment duration, LITT is usually performed without real-time monitoring of tissue temperature. During recent decades, many thermometric techniques have been developed to be used during thermal therapies. This paper provides an overview of techniques and sensors employed for temperature measurement during tissue hyperthermia, focusing on LITT, and an investigation of their performances in this application. The paper focuses on the most promising and widespread temperature monitoring techniques, splitting them into two groups: the former includes invasive techniques based on the use of thermocouples and fibre-optic sensors; the second analyses non-invasive methods, i.e. magnetic resonance imaging-, computerised tomography- and ultrasound-based thermometry. Background information on measuring principle, medical applications, advantages and weaknesses of each method are provided and discussed.

AIM: To assess whether the use of porcine models is useful for learning endoscopic submucosal dissection (ESD), thus contributing to its subsequent application in human patients. METHODS: This study/learning process was carried out in 3 phases: Phase I: Ex vivo animal; Phase II: In vivo animal; Phase III: Humans. One endoscopist performed 30 gastric ESDs in porcine models, and later 5 gastric ESDs in 5 patients. The ESD was done following the method practiced at the National Cancer Center in Tokyo, Japan. Technical aspects, size, time and speed of ESD, as well as complications were registered. In patients, their clinical, endoscopic and histologic evolution was additionally added. RESULTS: Thirty en bloc ESDs were carried out in animal models. The mean ± SD size of the pieces was of 28.4 ± 1.2 mm, and the time of ESD was 41.7 ± 2.4 min. The time of ESD in the first 15 procedures was 43.0 ± 3.0 min whereas in the next 15 procedures, the time was 40.3 ± 3.9 min, P = 0.588. The speed in the first 15 ESDs was 1.25 ± 0.11 cm2/min vs 2.12 ± 0.36 cm2/min in the remaining 15, P = 0.028. There were no complications. In patients, 5 lesions were resected en bloc. The size of the pieces was 25.2 ± 5.1 mm and the time was 85.0 ± 25.6 min. Endoscopic and histological controls did not show evidence of residual neoplastic tissue. CONCLUSION: A sequential ESD training program of a unique endoscopist, based on the practice in porcine models, contributed to learning ESD for its subsequent application in humans, yielding good results in efficacy and safety.

Due to the profile of released mediators (such as cytokines, chemokines, growth factors, etc.), neoplastic cells modulate the activity of immune system, directly affecting its components both locally and peripherally. This is reflected by the limited antineoplastic activity of the immune system (immunosuppressive effect), induction of tolerance to neoplastic antigens, and the promotion of processes associated with the proliferation of neoplastic tissue. Most of these responses are macrophages dependent, since these cells show proangiogenic properties, attenuate the adaptive response (anergization of naïve T lymphocytes, induction of Treg cell formation, polarization of immune response towards Th2, etc.), and support invasion and metastases formation. Tumor-associated macrophages (TAMs), a predominant component of leukocytic infiltrate, “cooperate” with the neoplastic tissue, leading to the intensified proliferation and the immune escape of the latter. This paper characterizes the function of macrophages in the development of neoplastic disease.

Positron emission tomography (PET) is a non-invasive imaging technique. The ability of PET to visualize biochemistry and physiology in vivo distinguishes this technique from other imaging modalities and renders it of particular interest for oncological studies. PET studies can of en differentiate between normal and neoplastic tissue, as well as identify early signs of malignant degeneration through biochemical or physiological changes. Over the past several years, PET studies have been useful in the early diagnosis and the selection of treatment, as well as in following the progression or regression of malignant disease processes. Of particular significance, PET findings can be quantified by using mathematical modeling and computerized data analysis, which makes it possible to produce quantitative images of human pathophysiology in vivo .

Serum levels and tissue expression of beta subunit of human chorionic gonadotropin were determined in 25 patients with bladder carcinoma. Elevated gonadotropin levels in serum were observed in 5 (20%) patients and immunoreactive cells were found in 5 (20%) tumours. The correlation was poor between serum level and immunohistochemical gonadotropin status. Only one patient showed both elevated serum level and immunohistochemical gonadotropin expression. Our observations suggest that elevated serum levels of gonadotropin may be an indicator of poor prognosis. However, immunohistochemical expression of gonadotropin did not seem to have a similar impact on prognosis in this series.

Aminolevulinic acid (ALA) is a heme precursor that may have potential applications for photodynamic detection and photodynamic therapy-based treatment of solid tumors in a variety of malignancies. ALA may have a role in other applications in surgical oncology based on its ability to discriminate neoplastic tissue from adjacent normal tissue. In this review, we provide a comprehensive summary of the published studies of ALA in noncutaneous solid malignancies.

Pattern recognition has been used in this paper to analyze trace element levels in patients diagnosed with nasal-pharynx cancer (NPC) and in healthy control subjects. Trace elements such as Zn, Cu, Fe, Mn, and Mg have been tested in samples of hair and whole blood. Through Mahalanobis Distance Decision analysis, we have achieved good classification effects in whole blood samples: Efficiency for distinguishing patients in 96% and that of healthy controls is 90%. Classification hair samples is inferior to whole blood: Decision accuracy for patients is 58% and healthy controls is 90%. These results are also shown in a nonlinear mapping figure. At the same time, we have also determined 5 trace element levels in 16 other cancer patients' nonneoplastic and cancerous tissue, with no significant difference between them: Decision accuracy of cancerous tissue is 63%, and in nonneoplastic tissue is 50%, hence, we cannot identify them. It can be inferred that there is no idiosyncratic change of trace elements in cancer patients' neoplastic tissue, the change of a cancerous person may occur in the whole body.

Cell loss is a biological phenomenon that occurs in normal and neoplastic tissue and is an important kinetic factor which contributes to the dynamic state of tumor growth. This relevant phenomenon which was introduced by tumor biologists in the early 1970s while studying tumor growth kinetics has been largely neglected in cancer therapy, although with adequate research it may hold potential for future strategies in cancer treatment. Cell loss occurs through various mechanisms which include exfoliation, metastasis, differentiation and cell death. Methods used for measuring cell loss will be examined and the importance of cell loss in tumor growth will be discussed.

There is little data on the prevalence of residual neoplastic tissue or the rate of endoscopically detected recurrence in patients with prior surgical or endoscopic resection of advanced neoplasia.To compare standard white light with NBI for both the detection, as well as the differentiation, of residual or recurrent neoplastic tissue during real-time endoscopy.A prospective study of 46 consecutive patients undergoing surveillance colonoscopy or upper endoscopy was conducted. Prior resection sites were examined first with white light and then with NBI. Main outcome measurements included the number of distinct lesions identified with white light, the number of additional lesions identified with NBI, and the overall accuracy of endoscopic diagnosis using white light alone or with NBI.Sixty discrete lesions were identified, 43 with white light alone, and an additional 17 with NBI. NBI identified more lesions per patient than white light alone (mean 1.33 vs. 0.96, p0.05) and there was a trend towards increased detection of neoplastic lesions. Recurrent/residual neoplasia was present in 14 patients (30%) and there was a trend towards increased detection with the addition of NBI. About 63% of lesions identified with white light appeared more extensive when examined with NBI. The diagnostic accuracy in predicting histology was equivalent for NBI and white light (87 vs. 88%), though there was a trend towards higher sensitivity for neoplastic lesions with NBI (88 vs. 69%, p = 0.16).A substantial number of patients undergoing surveillance endoscopy had residual or recurrent neoplastic tissue identified at the prior resection site. As NBI detected additional neoplastic lesions as well as demonstrated that lesions detected with white light were more extensive, adjunctive use of NBI for examining post-endoscopy resection sites should be studied in future, larger studies.

The capacity to rapidly and efficiently elucidate a reliable set of disease specific biomarkers is paramount to enable a future of personalized medicine. High throughput screening methods applied to human clinical samples for the discovery of diagnostic, prognostic, and therapeutic targets address this need. Although the ability to analyze either thousands of markers from one sample or one marker from thousands of samples is the current state of high throughput screening, it would be ideal to have the ability to analyze thousands of markers from thousands of samples to expedite the early discovery phase of biomarkers and their validation. This review summarizes the current state of high throughput screening of tissue specimens and discusses its applications. In addition, the rationale, difficulties, strategies, and development of new technologies to address the need for improved high throughput capabilities are discussed.

Cancer is a tissue that requires a genetic program, possibly involving hundreds of genes, as indicated by studies of differential gene expression performed with microarrays in various types of cancer. Cancer is thus a biological process of considerable precision as described by Schrodinger's equation, and it is not simply the random expression of hundreds of genes, but rather a program that gives neoplastic tissue characteristics that are independent of the originating tissue: invasion capacity and destruction of neighbouring tissues, metastasis, and capacity to progressively disengage from the genetic program of the original tissue. This program is common to all types of cancer, and does not appear to be related to the genetic program of any known differentiated tissue. In other words, cancer's genetic program appears to be universal in all tissues, since cancer behaves similarly in all tissues; though depending on the tissue in which it originates it will show certain specific characteristics, reflecting the extent to which the neoplastic cells are able to escape from the characteristics of the original tissue.

Increasingly in the field of medicine, new therapeutic modalities, both surgical and non-surgical, are being introduced. Some of these may significantly alter the pathological appearance of normal and neoplastic tissue and result in problems for the pathologist. In this review, iatrogenic pathology within the female genital tract is described, especially concentrating on the recent literature. Pathological artefacts within the female genital tract are also reviewed. Topics covered include mechanical displacement of normal and neoplastic elements into vascular or tissue spaces and thermal artefacts. Recently described pathological findings in neoplastic and non-neoplastic tissue secondary to hormonal, chemotherapeutic and other medications are discussed. Changes associated with non-surgical management of uterine leiomyomas are also described. It behoves the pathologist to be aware of these iatrogenic lesions and artefacts in order to prevent diagnostic errors.

It has been shown that neoplastic tissue cause alterations in its microenvironment through several mechanisms. Recent evidence from Patocs et al suggests that one of the mechanisms through which it causes these changes is by genetic modification of the surrounding microenvironment.

Angiogenesis is essential for normal and neoplastic tissue growth. In a recent issue of Nature, Komuro and colleagues (Sano et al., 2007) describe how p53 expression in hypertrophying heart muscle impairs HIF-1-mediated neovascularization and contributes to functional decompensation of pressure-overload cardiac hypertrophy.

Oncolytic viruses are being developed as anticancer drugs. They propagate selectively in tumor tissue and destroy it without causing excessive damage to normal non-cancerous tissues. When used as drugs, they must meet stringent criteria for safety and efficacy and be amenable to pharmacological study in human subjects. Specificity for neoplastic tissue is the key to safety, and this goal can be achieved through a variety of ingenious virus-engineering strategies. Antiviral immunity remains a significant barrier to the clinical efficacy of oncolytic viruses but this is being addressed by using novel immune-evasive delivery strategies and immunosuppressive drugs. Noninvasive pharmacokinetic monitoring is facilitated by engineering marker genes into the viral genome. Clinical data on the pharmacokinetics of oncolytic viruses will be the key to accelerating their development and approval as effective anticancer drugs. This review introduces concepts relevant to the use of viruses as anticancer drugs, emphasizing targeting mechanisms as well as safety and efficacy issues that are currently limiting their clinical success.

The epidermal growth factor receptor (EGFr) is considered a major target for treatment of colorectal cancer (CRC). We found a mean EGFr content significantly lower but more activated in colonic neoplastic tissue than in paired normal mucosa. Phosphorylated (pY1068) EGFr detection in CRC may be a better tool than EGFr detection to select patients for targeted therapies.

Ongoing technological developments in endoscopy have led to an ever improving evaluation and management of digestive diseases. The recent development of a new range of high-power magnification, or zoom, endoscopes has boosted interest in this technique, which has become increasingly available to the modern gastroenterologist. Magnification is often used in conjunction with chromoendoscopy in order to improve the detection and diagnosis of neoplastic tissue. Currently, the main clinical indications are the diagnosis of Barrett oesophagus, the colonoscopic surveillance of colonic polyps and the assessment of disease severity or the presence of dysplasia in inflammatory bowel disease. In this article we present an overview of the clinical implementations of magnification endoscopy in current and future gastroenterological practice.