[Colorectal cancer: role of imaging in screening]. / Kolorektales Karzinom: Rolle bildgebender Verfahren in der Vorsorge.

CLINICAL PROBLEM: Colorectal cancer (CRC) is a major cause of cancer-related morbidity and mortality. Most colorectal cancers derive from benign precursor lesions, so-called adenomatous polyps, over a long period of time. Colorectal cancer screening is based on the detection of precancerous polyps and early stage CRC in asymptomatic individuals to reduce CRC incidence and mortality. The protective effect of screening programs can be improved by increasing the screening rates. PRACTICAL RECOMMENDATIONS: Apart from the established examinations, CT colonography (CTC) has been proposed as an optional test for colorectal cancer screening. The detection rates of CTC for large polyps and cancer are similar to the ones of colonoscopy and superior to stool-based tests. CTC is therefore the radiological test of choice for the detection of colorectal neoplasia. It has replaced double contrast barium enema for almost all indications. As a minimally invasive procedure, CTC has a high safety profile and good patient acceptance. The evaluation of extracolonic organs in addition to the colon can increase examination efficacy. The option to choose CTC as a CRC screening test has the potential to increase the overall screening rates.

Learning from clinical phenotypes: Low-dose biophotonics therapies in oral diseases.

This narrative review on the use of biophotonics therapies for management of oral diseases is written as a tribute to Prof. Crispian Scully. His seminal contributions to the field are highlighted by the detailed, comprehensive description of clinical presentations of oral diseases. This has enabled a more thorough, fundamental understanding of many of these pathologies by research from his group as well as inspired mechanistic investigations in many groups globally. In the same vein, a major emphasis of this narrative review is to focus on the evidence from human case reports rather than in vitro or in vivo animal studies that showcases the growing and broad impact of biophotonics therapies. The similarities and differences between two distinct forms of low-dose biophotonics treatments namely photodynamic therapy and photobiomodulation therapy are discussed. As evident in this review, a majority of these reports provide promising evidence for their clinical efficacy. However, a lack of adequate technical details, precise biological rationale, and limited outcome measures limits the current utility of these treatments. Future investigations should attempt to address these shortcomings and develop better designed, rigorous, controlled studies to fully harness the tremendous potential of low-dose biophotonics therapies.

[Imaging of gastrointestinal inflammation : Characteristic patterns and signs]. / Bildgebung gastrointestinaler Entzündungen : Charakteristische Muster und Zeichen.

CLINICAL PROBLEM: Pathological conditions of the gastrointestinal tract can result from various disorders, including inflammatory, infectious, neoplastic, and ischemic diseases. RADIOLOGICAL STANDARD PROCEDURES: Cross-sectional imaging techniques have largely replaced many of the conventional fluoroscopic examinations, such as small bowel follow-through and double-contrast barium enema. The former allow for time-efficient, accurate, and minimally invasive diagnostics. Therefore, they have become important diagnostic tools for the evaluation of inflammatory diseases of the gastrointestinal tract. The distension of the intestinal lumen with orally administered neutral contrast media improves not only the evaluation of the intraluminal aspect, but also of the cross-sectional appearance. Furthermore, with cross-sectional imaging techniques, the additional assessment of the extraintestinal structures and organs is also possible. METHODICAL INNOVATIONS AND ASSESSMENT: With the ongoing development of scanner and software technology, pathologic conditions of the gastrointestinal wall can be characterized in more detail by both computed tomography and magnetic resonance imaging. A structured approach, based on the analysis of typical radiological signs and patterns, combined with the evaluation of extraintestinal findings may help to assign the observed imaging findings to specific disease groups. RECOMMENDATIONS: This article summarizes common signs and typical patterns frequently seen in inflammatory conditions of the gastrointestinal tract. A systematic approach for structured analysis of specific and nonspecific imaging features and common pitfalls may aid in the interpretation and help to narrow the spectrum of potential differential diagnoses.

[CT colonography as routine method]. / CT-Kolonographie in der täglichen Praxis.

CLINICAL/METHODICAL ISSUE: Colorectal cancer is a major public health challenge in Austria and Germany. As the participation in dedicated colonoscopy screening programs is rather low, the question of alternative methods is raised again and computed tomography (CT) colonography seems to be a gentle alternative with a very high patient acceptance. STANDARD RADIOLOGICAL METHODS: In recent years CT colonography (CTC) has been established besides conventional colonoscopy as a radiological method for the investigation of the entire colon. From axial two-dimensional images three-dimensional images can be generated, allowing a virtual flight through the colon which is why this technique is also known as virtual colonoscopy. METHODICAL INNOVATIONS: The technique of CTC has been improved continuously during recent years. On the one hand the steady decrease in the layer thickness (currently ≤ 1 mm) has improved the resolution of volume data sets and on the other hand there has been significant progress in postprocessing. PERFORMANCE: Numerous studies have recently shown that the significance of CTC in the detection of advanced adenomas is similar to conventional colonoscopy. ACHIEVEMENTS: Meanwhile CT colonography is now a routine investigation method established in both symptomatic and asymptomatic patients (screening). PRACTICAL RECOMMENDATIONS: Study data now clearly show that CTC, as an alternative to conventional colonoscopy, is a powerful method for investigation of colorectal cancer. To achieve good results adequate preparation including fecal tagging, standardized technical procedures during the investigation and expertise in both 2D and 3D reading are essential.

[CT colonography: patient preparation and examination technique]. / CT-Kolonographie: Patientenvorbereitung und Untersuchungstechnik.

An examination technique adapted to comply with the demands of CT colonography is not only a basic requirement for a high-quality examination and correct ascertainment of the findings; it is also essential for far-reaching applications of this method of examination. The technique of CT colonography is based on good patient preparation with the aid of fecal tagging, adequate distension of the colon with CO(2) and acquisition of data with the patient both prone and supine in a thin-slice technique using a low-dose protocol. The different technical aspects of CT colonography are explained in this paper.

[Indications for and results of CT colonography: from screening to the symptomatic patient]. / Indikationen und Ergebnisse der CT-Kolonographie: von der Vorsorge bis zum symptomatischen Patienten.

CT colonography (CTC) is also referred to as virtual colonoscopy and is being used with increasing frequency in radiological practice. While there are still no generally accepted, clear-cut indications for its use in mass colorectal cancer screening, there is evidence that this investigation is useful in patients in whom colonoscopy has not been successful or who have known stenotic lesions in the colon. Recent results of significant comparative studies of CTC and conventional colonoscopy will have some influence on the future place of CTC in screening for cancer of the bowel; they show the great potential of CT-aided bowel examination.

[CT colonography: pathologic findings and pitfalls]. / CT-Kolonographie: Pathologische Befunde und Pitfalls.

Thin-section multidetector-row computed tomographic (MDCT) colonography is a powerful tool for detection and classification of colonic lesions. It is based on a helical thin-section (0.75-2 mm) CT dataset of the cleansed and air-distended colon. 2D and 3D projections are prepared and used for image interpretation. Evaluation of CT colonography datasets requires correct perception and interpretation of colonic lesions and filling defects. Various criteria are needed for correct interpretation of filling defects and differentiation between genuine lesions and artifacts. Such defects are characterized by their morphology, their structure, the absorption of contrast medium and their mobility. Knowledge of the morphologic and attenuation characteristics of common colonic lesions and of artifacts is essential for the correct interpretation of a filling defect. This review article summarizes the main imaging features of polyps, diverticula, lipomas, and carcinomas and also of common pseudolesions of the colon.

The use of photodynamic therapy using 630nm laser light and porfimer sodium for the treatment of oral squamous cell carcinoma.

PDT has been demonstrated in clinical studies to be an efficacious method for the treatment of dysplastic, microinvasive and early forms of cancer. The advantage of PDT for early carcinomas of the oral cavity is the ability to preserve normal tissues while effectively treating cancers up to 1cm in depth. The case presented here successfully demonstrates the ability to use PDT to treat maxillary gingival squamous cell carcinoma thereby sparing the use of surgery or radiation therapy at this point in the management of the disease.

Modification of photodynamic therapy-induced hypoxia by fluosol-DA (20%) and carbogen breathing in mice.

The administration of a perfluorochemical emulsion and carbogen (95% O2, 5% CO2) breathing before photodynamic therapy (PDT) was studied to determine how increased levels of tumor oxygenation may affect PDT-induced tumor destruction. C3H/HeJ mice bearing the RIF tumor were given injections of 5 to 10 mg/kg of dihematoporphyrin ethers 24 h prior to treatment. Animals were given injections of 12 ml/kg of Fluosol-DA (20%) followed by carbogen breathing or 12 ml/kg of saline and air breathing (controls) 1 h before tumors were exposed to 135 J/cm2 of 630-nm light treatment. Changes in the hypoxic fraction of tumors, the time course for decreases in tumor cell clonogenicity, and tumor response were measured immediately and at various times after treatment. The administration of Fluosol-DA (20%) and carbogen breathing was found to delay the onset of PDT-induced hypoxia through the first hour posttreatment. Progressive tumor hypoxia was observed after 4 h posttreatment. The time period in which tumors remained well oxygenated coincided with observations of increased tumor cell survival. Decreases in tumor cell clonogenicity were observed only after tumor cells became hypoxic. These findings were consistent with the 24-h delay in complete tumor response in animals given Fluosol-DA (20%) and carbogen breathing before PDT. There were only minor variations in long-term tumor response and cure observed between the two groups tested. A second series of experiments was done to assess any treatment advantage of the adjuvant use of Fluosol-DA (20%) and carbogen breathing with PDT at high tumor photosensitizer levels. At an injected dose of 50 mg/kg of dihematoporphyrin ethers, no such advantage was observed. The administration of Fluosol-DA (20%) and carbogen breathing did not reduce the extent of PDT-induced microvascular damage, maintain high levels of tumor oxygenation through light treatment, or modify the extent of tumor cell kill following treatment.

Lack of reciprocity in drug and light dose dependence of photodynamic therapy of pancreatic adenocarcinoma in vitro.

Two human pancreatic cell lines, MIA PaCa 2 and Capan 2, were treated by photodynamic therapy in vitro with Photophrin (0.01-25 micrograms/ml; 24 h) and then light (1-50 J/cm2; lambda = 630 nm). The following model was fit to 6 datasets with weighted nonlinear regression: [sequence: see text] The symbols are: E, cell growth; Econ, control growth in the absence of the combination; B, background signal; m, slope parameter; gamma, interaction parameter; D, concentration of Photofrin; L, light dose; F, fraction of Photofrin not photobleached by the light dose; k, k1, k2, bleaching parameters; A, distribution parameter for biexponential bleaching equation. Simple reciprocity of photosensitizer concentration and light dose was not found; compensation for photobleaching was critical. MIA PaCa2 required the monoexponential bleaching factor, whereas Capan 2 required the biexponential bleaching factor. The greater photosensitivity of MIA PaCa2 over Capan 2 can be best explained not by differences in the interaction parameter but rather by differences in the photobleaching pattern and rate. It may be possible to further enhance the selectivity of photodynamic therapy if differences in photobleaching between different cell types can be exploited by adequate dosimetry.

Tumor destruction and kinetics of tumor cell death in two experimental mouse tumors following photodynamic therapy.

The effect of photodynamic therapy (PDT) on tumor growth as well as on tumor cell survival in vitro and in vivo was studied in the EMT-6 and RIF experimental mouse tumor systems. In vitro, RIF cells were more sensitive towards PDT than were EMT-6 cells when incubated with porphyrin (25 micrograms/ml, dihematoporphyrin ether) and subsequently given graded doses of light. In vivo, both tumor types responded to PDT (EMT-6, dihematoporphyrin ether, 7.5 mg/kg; RIF, dihematoporphyrin ether, 10 mg/kg; both followed 24 hr later by 135 J of light at 630 nm/sq cm) with severe vascular disruption and subsequent disappearance of tumor bulk. However, whereas the cure rate for EMT-6 tumors was 90%, it was 0% for RIF tumors. Raising the light dose to 200 J/sq cm resulted in 100% cures for EMT-6 tumors accompanied by damage to the surrounding tissues and 13% cures for RIF tumors. Tumor cell clonogenicity following PDT in vivo was assessed using the in vitro colony formation assay. In both tumors, it was found to be nearly unaffected by PDT if the tumor tissue was excised and explanted immediately following completion of treatment. This indicates that the effect of PDT on tumor cells directly was not sufficient to decrease tumor clonogenicity even at doses which led to total macroscopic tumor destruction. Where the tumors remained in situ following PDT and explantation was delayed for varying lengths of time (1 to 24 hr), tumor cell death occurred rapidly and progressively, indicating that tumor cell damage was expressed only if the cells remained exposed to the in situ environment after treatment. The kinetics and extent of tumor cell death were very similar for both tumor types despite their difference in cure rates. The reduction in tumor clonogenicity at 4 hr post-PDT closely matched that of tumor deprived of oxygen for the same period of time, implying that one of the major factors contributing to tumor destruction may be damage of the tumor circulation and the consequences of treatment-induced changes in tumor physiology.

Photofrin photodynamic therapy for treatment of AIDS-related cutaneous Kaposi's sarcoma.

OBJECTIVE: Kaposi's sarcoma, the most common malignancy in AIDS patients, often presents with painful cutaneous lesions that are difficult to treat effectively despite a wide variety of therapeutic approaches. We used photodynamic therapy in an attempt to provide effective palliative treatment for this disease. METHODS: Photodynamic therapy utilizes the activation by light of a photosensitizing drug that preferentially accumulates in tumor tissue such as Kaposi's sarcoma. We enrolled 25 patients who received 1.0 mg/kg of Photofrin 48 h before exposure to 100-400 J/cm2 of 630 nm light. RESULTS: Of the 348 lesions treated, 289 were evaluable: 32.5% had complete clinical response, 63.3% had partial clinical response and 4.2% were clinical failures. There was a strong correlation between response and light dose: 54% of lesions achieved a complete clinical response at optimum light dose (> 250 J/cm2). There was no correlation of response with CD4 cell count nor was there a change in CD4 cell count post-treatment. At 400 J/cm2 full field scabbing and necrosis occurred in 90% of the treated fields. Thus, the maximum tolerated dose was determined to be 300 J/cm2. At light doses of 250 J/cm2 and below the toxicities were limited to erythema and edema in the treatment field. Forty-three biopsies were taken 0.5 h to 4 months post-treatment. These showed little change in the B and T cell infiltrates identified. Kaposi's sarcoma cells disappeared post-treatment in certain lesions. CONCLUSION: Photofrin is effective palliative treatment for HIV-associated Kaposi's sarcoma.

An evaluation of photodynamic therapy in the management of cutaneous metastases of breast cancer.

A series of 37 patients with cutaneous metastases of breast carcinoma were treated with photodynamic therapy (PDT) to the chest wall; decreasing doses of photofrin II and increasing light doses were used in order to test drug/light dose reciprocity and determine the lowest effective dose of photofrin II. 5 patients (13.5%) achieved a complete response, 13 (35.1%) demonstrated partial responses and 19 (51.4%) showed no benefit. The extent and type of recurrent disease were strong determinants of the likelihood of response. Minimal and nodular disease responded well to PDT (5/5 complete responses); partial responses were seen in 11/20 (55%) of patients with disease of moderate extent. No patient with extensive erythema derived any benefit (0/5), and only 2/12 (17%) patients with advanced nodularity showed a partial response. Reduction in photofrin dose to 0.75 mg/kg with reciprocal increases in light dose to 182 J/cm2 did not impair treatment efficacy.

Alterations in receptor-mediated kinases and phosphatases during carcinogenesis.

Increased phosphorylation in cancers can stimulate growth and up-regulate certain receptors. To test whether the functional response of phosphatase receptors is up-regulated during carcinogenesis, we examined the effects of ligands on net phosphorylation in isolated membranes derived from hamster cheek-pouch tissues undergoing malignant transformation. The buccal mucosa of groups of Syrian golden hamsters was exposed thrice weekly to 0.5% dimethylbenzanthracene (DMBA) in acetone for 2-12 weeks to produce premalignant and malignant tissues. Homogenates of these tissues were then incubated with [32P]ATP in the presence of epidermal growth factor (EGF), agonist of somatostatin analogue RC-160, luteinizing-hormone-releasing hormone (LH-RH) [D-Trp6]LH-RH, or combinations of EGF, RC-160, and [D-Trp6]LH-RH. Changes compared to controls in phosphorylation in response to ligands provided estimates of kinase or phosphatase activity. Phosphorylation increased continuously, from the first application of DMBA in a linear fashion, and independently of EGF stimulation. RC-160 and [D-Trp6]LH-RH reduced phosphorylation in vitro. This response occurred in premalignant (weeks 6-10 after DMBA application) as well as malignant tissues (week 12 after DMBA application), but was not significant in normal tissues. The results show a continuous augmentation in phosphatase activity prior to the appearance of cancers, but with a delay in expression following the primary event of increased kinase activity. Significantly less phosphorylation of substrates was induced by both RC-160 and [D-Trp6]LH-RH after in vitro activation by EGF than in the absence of EGF. This suggests that EGF activates latent systems of hormonal receptors. Collectively, these results support the hypothesis that the enhancement of the hormonally stimulated phosphatase in cancers occurs secondarily to the increased kinase activity.

Effect of photodynamic therapy on blood flow in normal and tumor vessels.

The aim of this series of experiments was to determine the dynamic blood flow changes that occur in normal and neoplastic tissues during photodynamic therapy. Mice bearing SMT-F tumors and rats with transplanted chondrosarcomas were injected with graded doses of dihematoporphyrin ether. Studies of changes in single-vessel and whole-tumor blood flow were carried out with 630 nm light activation. A helium neon laser Doppler velocimeter was used to stimulate dihematoporphyrin ether, as well as to measure changes in flow velocity in both single-vessel and whole-tumor models. There was a reduction of flow velocity in all vessels and tumors in animals injected with 1 to 40 mg/kg dihematoporphyrin ether intraperitoneally. The extent of flow reduction was related to drug dose administered. Decreases in blood flow began within 10 seconds of light stimulation and were maximal within 5 minutes. Both normal and tumor vessels responded similarly. We conclude that photodynamic therapy leads to significant microcirculatory changes that may be pertinent to the mechanism of tumor necrosis.

Photodynamic therapy in the management of neoplasms of the perianal skin.

Perianal extramammary Paget's disease, Bowen's disease, and squamous cell carcinoma are three entities that are very rarely reported. Overall, it is generally accepted that wide surgical excision is adequate treatment except under certain circumstances. Consideration has to be given to invasiveness, metastatic potential, multicentricity, and tendency to recur. We describe four patients who, following unsuccessful multiple attempts at achieving microscopically clear margins with surgical excision, were treated at Roswell Park Cancer Institute with photodynamic therapy with a surface illumination method. With a minimum follow-up of 6 months (more than 1 year in three patients), there have been no recurrences to date.

Operation and intracavitary photodynamic therapy for malignant pleural mesothelioma: a phase II study.

From April 1991 to May 1993, 23 patients entered a phase II clinical study of surgical resection and adjuvant intracavitary photodynamic therapy for malignant pleural mesothelioma. Two days preoperatively, patients received an intravenous injection of 2 mg/kg of the photosensitizer Photofrin. Six patients underwent a pleuro-pneumonectomy, and 15 patients a pleurectomy, after which intracavitary photodynamic therapy was administered. A total light energy dose of 20 to 25 J/cm2 was given. In 2 patients the tumor was unresectable due to intrapericardial invasion. Postoperative complications were noted in more than 50 percent of patients; 2 patients died of postoperative complications. Postoperative survival was analyzed according to intraoperative staging proposed by the American Joint Committee for Cancer Staging, published in 1992. The overall estimated median survival is 12 months; that of stage III and IV patients is 7 months. Five patients with stage I and II diseases (who had grossly complete resection by pleurectomy) are alive, disease-free, for 11, 17, 18, 21, and 33 postoperative months. Intraoperative staging is important in carrying out further clinical studies of malignant pleural mesothelioma.

Photodynamic therapy for the treatment of basal cell carcinoma.

BACKGROUND: Photodynamic therapy is an investigational method for the treatment of a variety of solid tumors. The purpose of this study was to determine the optimum factors and illustrate the effectiveness of photodynamic therapy in the treatment of basal cell carcinomas. This was a prospective study in which patients presenting with primary or recurrent basal cell tumors, particularly but not exclusively widespread tumors or large single tumors, were offered the option of photodynamic therapy in their treatment regimen. RESULTS: Patients were administered 1 mg/kg of a photosensitizer (Photofrin II). Light doses (630 nm) ranged from 72 to 288 J/cm2. A total of 37 patients with 151 sites were treated in this study. A complete response rate of 88% was achieved with one application. Morbidity was low; the most significant side effects were moderate pain and edema. CONCLUSIONS: Photodynamic therapy is a modality that offers localized treatment of primary or recurrent nonmelanoma skin cancer. By applying reciprocal doses of photosensitizer and light, the efficacy of photodynamic therapy in the treatment of skin lesions is demonstrated achieving significant light penetration into tissue with a high complete response rate of the lesions and acceptable normal tissue response.