Sensitive imaging of tumors using a nitroreductase-activated fluorescence probe in the NIR-II window.

A nitroreductase (NTR)-activated NIR-II fluorescence probe for tumor imaging is reported. The probe can emit fluorescence in the range of 900-1300 nm, and target hypoxic tumors with NTR overexpression, thus allowing for accurate delineation of tumor margins through deep penetration.

High-Contrast Fluorescence Diagnosis of Cancer Cells/Tissues Based on ß-Lapachone-Triggered ROS Amplification Specific in Cancer Cells.

Discrimination of cancer cells/tissues from normal ones is of critical importance for early diagnosis and treatment of cancers. Herein, we present a new strategy for high-contrast fluorescence diagnosis of cancer cells/tissues based on ß-Lapachone (ß-Lap, an anticancer agent) triggered ROS (reactive oxygen species) amplification specific in cancer cells/tissues. With the strategy, a wide range of cancer cells/tissues, including surgical tissue specimens harvested from patients, were distinguished from normal ones by using a combination of ß-Lap and a Si-rhodamine-based NIR fluorescent ROS probe PSiR3 developed in this work with average tumor-to-normal (T/N) ratios up to 15 in cell level and 24 in tissue level, far exceeding the clinically acceptable threshold of 2.0. What's more, the strategy allowed the fluorescence discrimination of tumor tissues from inflammatory ones based on whether a marked fluorescence enhancement could be induced when treated with PSiR3 and ß-Lap/PSiR3 combination, respectively.

Ratiometric Fluorescence Imaging for the Distribution of Nucleic Acid Content in Living Cells and Human Tissue Sections.

The misregulation of nucleic acids behavior leads to cell dysfunction and induces serious diseases. A ratiometric fluorescence probe is a powerful tool to study the dynamic behavior and function relationships of nucleic acids. However, currently, no such effective probe has been reported for in situ, real-time tracking of nucleic acids in living cells and tissue sections. Herein, the unique probe named QPP-AS was rationally designed for ratiometric fluorescence response to nucleic acids through skillful regulation of the intramolecular charge-transfer capabilities of the electron acceptor and donor. Encouraged by the advantages of the selective nucleic acid response, ideal biocompatibility, and high signal-to-noise ratio, QPP-AS has been applied for in situ, real-time ratiometric fluorescence imaging of nucleic acids in living cells for the first time. Furthermore, we have demonstrated that QPP-AS is capable of visualizing the dynamic behavior of nucleic acids during different cellular processes (e.g., cell division and apoptosis) by ratiometric fluorescence imaging. More significantly, QPP-AS has been successfully used for ratiometric fluorescence imaging of nucleic acids in human tissue sections, which provides not only the cell contour, nuclear morphology, and nuclear-plasma ratio but also the nucleic acid content information and may greatly improve accuracy in clinicopathological diagnosis.

Tumor-targeting multi-shelled hollow nanospheres as drug loading platforms for imaging-guided combinational cancer therapy.

In this work, we developed multi-shelled hollow nanospheres [RGD@am-ZnO@CuO@Au@DOX HNSs] as multifunctional therapeutic agents to achieve effective and targeted Zn2+/Cu2+ therapy, induced drug delivery under low pH/red-light conditions, and enhanced phototherapy under single red-light. The photothermal and photodynamic performance of am-ZnO@CuO@Au HNSs was enhanced relative to that of am-ZnO nanoparticles (NPs) or am-ZnO@CuO HNSs by utilizing the resonance energy transfer process and broad red-light absorption. The pH-sensitive am-ZnO@CuO@Au HNSs were dissolved to Zn2+/Cu2+ in the acidic endosomes/lysosomes of cancer cells, resulting in a cancer cell killing effect. The release performance of doxorubicin (DOX) from RGD@am-ZnO@CuO@Au@DOX HNSs was evaluated under low pH and red-light-irradiated conditions, and targeting of HNSs was confirmed by dual-modal imaging (magnetic resonance/fluorescence) of the tumor area. Moreover, in vivo synergistic therapy using RGD@am-ZnO@CuO@Au@DOX HNSs was further evaluated in mice bearing human pulmonary adenocarcinoma (A549) cells, achieving a remarkable synergistic antitumor effect superior to that obtained by monotherapy. This study validated that RGD@am-ZnO@CuO@Au@DOX HNSs can be a promising candidate for efficient postoperative cancer therapy.

Rational design of some substituted phenyl azanediyl (bis) methylene phosphonic acid derivatives as potential anticancer agents and imaging probes: Computational inputs, chemical synthesis, radiolabeling, biodistribution and gamma scintigraphy.

Bisphosphonates are widely used for treatment of osteoporosis. Recently, they have been reported to be effective anticancer agents. In this work, we designed some substituted phenyl (azanediyl) bis (methylene phosphonic acid) to be tested for their anticancer effect. Both molecular docking and dynamics studies were used to select the top ranked highly scored compounds. The selected hits showed potential in vitro anticancer effect against some cell lines. Biodistribution pattern and gamma scintigraphy were conducted to the most effective derivative (BMBP) after radiolabeling with 99mTc. Results of biodistribution and scintigraphic imaging of 99mTc-BMBP in tumor bearing mice showed a notable tumor affinity, and confirmed the targeting affinity of BMBP to the tumor tissues. As a conclusion, BMBP could act as potential anticancer agent and imaging probe.

Bronchioalveolar carcinoma in an adult alpaca (Vicugna pacos).

BACKGROUND: This report describes a case of a bronchiolar adenocarcinoma in a 6-year old alpaca mare. For the first time in an alpaca, neoplasia was classified by histopathology as a lepidic-predominant bronchiolar adenocarcinoma. CASE PRESENTATION: The mare was referred to the Clinic for Ruminants after a 6-week period of forced breathing and weight loss. The clinical examination included complete blood count, blood chemistry, ultrasound, radiographs and a CT-scan of the thorax. A bilateral pneumothorax and several, structures within the lung parenchyma were diagnosed. Differential diagnosis included neoplasia, tuberculosis and fungal granulomas. The owner requested euthanasia due to the mare's ongoing deterioration. At postmortem examination, the granulomatous changes in the lungs were histopathologically classified as lepidic dominant bronchiolar adenocarcinoma. CONCLUSIONS: Neoplastic diseases are more often seen in South American camelids compared to other farm animal species. The use of a CT scan was helpful in classifying the lung lesions and give a clear prognosis.

Prognostic factors of gingival-alveolar squamous cell carcinoma of the maxilla.

OBJECTIVES: To determine prognostic factors in gingivo-alveolar squamous cell carcinoma of the maxilla (GA-SCC-M), and particularly the prognostic value of both vertical and antero-posterior tumor spread. MATERIAL AND METHODS: Our retrospective study included all naïve-treatment patients treated in our center between 2006 and 2013 for GA-SCC-M. Posterior involvement was considered when the tumor extended behind the mesial side of the first maxillary molar. Spread posterior to the maxillary tuberosity was defined by the spread to at least one of the following structures: pterygomaxillary fissure, pterygoid muscles, and processes. Involvement of the maxillary sinus floor, nasal fossa, and orbital floor was assessed, concerning the vertical spread. RESULTS: A radiological tumor spread to the nasal fossa, maxillary sinus floor, and orbital floor were prognostic factors independently of age, cervical lymph node metastasis and positive margins in multivariate analysis (p < 0.05). Radiological suggested spread tended to be noticeably more predictive of a poor prognosis than histological proven tumoral spread. The prognosis was not significantly different between clinical tumoral spread anteriorly or posteriorly to the first molar (p = 0.46). The prognosis was not worsened, even in case of radiological suggested spread posterior to the maxillary tuberosity (p = 0.09). CONCLUSION: A vertical radiological spread of GA-SCC-M was a prognostic factor but not the extension posteriorly to the maxillary tuberosity. T4b tumors were mostly resectable, proving that a T4b stage was not predictive of unresectability in GA-SCC-M of the maxilla.

Clinical relevance of using autofluorescence bronchoscopy and white light bronchoscopy in different types of airway lesions.

OBJECTIVES: The aim of this study was to evaluate the sensitivity and specificity of autofluorescence bronchoscopy (AFB) according to the macroscopic appearance of airway lesions under white light bronchoscopy (WLB). MATERIALS AND METHODS: The bronchoscopic findings of 708 patients, who were pathologically and clinically diagnosed with airway lesions and underwent both WLB and AFB, were analyzed. RESULTS: We recruited 708 patients for this study, of which 336 (47.5%) had benign lesions; 300 and 254 benign lesions were detected by AFB (specificity, 89.3%) and WLB (specificity, 75.6%), respectively. In 372 (52.5%) patients with bronchiogenic carcinoma, 356 and 235 lesions were identified by AFB (sensitivity, 95.7%) and WLB (sensitivity, 63.2%), respectively. The sensitivity and specificity of AFB for diagnosing lung cancer were higher than those of WLB (P < 0.05). Moreover, AFB showed high sensitivity for detecting lung cancer in cases in which WLB revealed hyperplasia, infiltration, and stenosis (P < 0.05). CONCLUSIONS: AFB combined with WLB could effectively improve the diagnosis of airway lesions.

Bronchioloalveolar cell carcinoma presenting as a "non-resolving consolidation" for two years.

Bronchioloalveolar carcinoma (BAC), a rare form of lung malignancy, is usually seen in non-smokers and women. Three distinct histological forms have been identified viz, mucinous, non-mucinous and mixed or indeterminate. The mucinous variety of BAC may present as a consolidation which is very difficult to differentiate from an infective pneumonia. We present a case of a middle aged female who was evaluated for a "non-resolving consolidation" for a period of two years. She had undergone an inconclusive bronchoscopy and had received several courses of antibiotics including anti-tuberculous therapy without relief. The size of the lesion had remained largely unchanged during this period and there was no significant clinical deterioration in the patient. Transbronchial biopsy done on presentation revealed BAC of the mucinous variety. BAC presenting as a large consolidation without significant change for a period of two years has rarely been documented in the literature.

Radiographic characterization of primary lung tumors in 74 dogs.

Primary pulmonary neoplasia is well recognized in dogs and prognosis depends upon the tumor type. The purpose of this retrospective study was to characterize the radiographic appearance of different primary lung tumors with the goal of establishing imaging criteria to separate the different types. Three-view thoracic radiographs of 74 dogs with histologically confirmed pulmonary anaplastic carcinoma (n = 2), adenocarcinoma (n = 31), bronchioalveolar carcinoma (n = 19), histiocytic sarcoma (n = 21), and squamous cell carcinoma (n = 1) were evaluated. Radiographs were assessed for tumor volume, affected lobe, location within lobe, overall pulmonary pattern, presence of cavitation, mineralization, air bronchograms, lymphadenomegaly, and pleural fluid. Histiocytic sarcomas were significantly larger than other tumor types (271 cm(3); P = 0.009) and most likely to be found in the left cranial (38%; 8/21) and right middle (43%; 9/21) lung lobes, whereas adenocarcinomas were most likely to be found in the left caudal (29%; 9/31) lung lobe. Fifty-seven percent (12/21) of histiocytic sarcomas had an internal air bronchogram. Findings indicate that a large mass in the periphery or affecting the whole lobe of the right middle or left cranial lung lobe with an internal air bronchogram is likely to be an histiocytic sarcoma.

A prediction model for pathologic N2 disease in lung cancer patients with a negative mediastinum by positron emission tomography.

INTRODUCTION: Guidance is limited for invasive staging in patients with lung cancer without mediastinal disease by positron emission tomography (PET). We developed and validated a prediction model for pathologic N2 disease (pN2), using six previously described risk factors: tumor location and size by computed tomography (CT), nodal disease by CT, maximum standardized uptake value of the primary tumor, N1 by PET, and histology. METHODS: A cohort study (2004-2009) was performed in patients with T1/T2 by CT and N0/N1 by PET. Logistic regression analysis was used to develop a prediction model for pN2 among a random development set (n = 625). The model was validated in both the development set, which comprised two thirds of the patients and the validation set (n = 313), which comprised the remaining one third. Model performance was assessed in terms of discrimination and calibration. RESULTS: Among 938 patients, 9.9% had pN2 (9 detected by invasive staging and 84 intraoperatively). In the development set, univariate analyses demonstrated a significant association between pN2 and increasing tumor size (p < 0.001), nodal status by CT (p = 0.007), maximum standardized uptake value of the primary tumor (p = 0.027), and N1 by PET (p < 0.001); however, only N1 by PET was associated with pN2 (p < 0.001) in the multivariate prediction model. The model performed reasonably well in the development (c-statistic, 0.70; 95% confidence interval, 0.63-0.77; goodness of fit p = 0.61) and validation (c-statistic, 0.65; 95% confidence interval, 0.56-0.74; goodness-of-fit p = 0.19) sets. CONCLUSION: A prediction model for pN2 based on six previously described risk factors has reasonable performance characteristics. Observations from this study may guide prospective, multicenter development and validation of a prediction model for pN2.

Imaging of bronchioloalveolar carcinoma in the mice with the αâ ¤ß3 integrin-targeted tracer (99m)Tc-RGD-4CK.

Receptor-based imaging agents have shown improved specificity and sensitivity of cancer diagnosis by targeting the specific features of cancer. Here we reported the (99m)Tc-labeling of a cyclic polypeptide RGD-4CK and the characterization of this agent in vitro and in bronchioloalveolar carcinoma (BAC) xenograft model. The αⅤß3 integrin receptor binding affinity of (99m)Tc-RGD-4CK was determined in BAC. The cancer targeting properties of (99m)Tc-RGD-4CK were determined in NCI-H358 xenografted nude mice. Moreover, the BAC uptake of (99m)Tc-RGD-4CK was blocked with nonradiolabeled RGD-4CK in xenografts. The competitive assay showed that (99m)Tc-RGD-4CK exhibited high specificity to BAC cell line NCI-H358. Biodistribution studies indicated that (99m)Tc-RGD-4CK exhibited high tumor uptake (4.12 ± 1.21% injected dose/g 120 minutes after injection) and prolonged tumor retention (2.08 ± 0.33% injected dose/g 240 minutes after injection) in NCI-H358 xenografted nude mice. Moreover, (99m)Tc-RGD-4CK produced a good tumor-to-lung ratio (2.38) because of low lung activity accumulation 120 minutes postinjection. BAC on the flank of xenografted mice was clearly visualized by single photon emission computed tomography/computed tomography imaging using (99m)Tc-RGD-4CK. In conclusion, this study provides evidence that (99m)Tc-RGD-4CK is a promising agent for noninvasive determination of αⅤß3 integrin status and therapy monitoring in BAC.

Lung flooding enables efficient lung sonography and tumour imaging in human ex vivo and porcine in vivo lung cancer model.

BACKGROUND: Sonography has become the imaging technique of choice for guiding intraoperative interventions in abdominal surgery. Due to artefacts from residual air content, however, videothoracoscopic and open intraoperative ultrasound-guided thermoablation of lung malignancies are impossible. Lung flooding is a new method that allows complete ultrasound imaging of lungs and their tumours. METHODS: Fourteen resected tumourous human lung lobes were examined transpleurally with B-mode ultrasound before (in atelectasis) and after lung flooding with isotonic saline solution. In two swine, the left lung was filled with 15 ml/kg isotonic saline solution through the left side of a double-lumen tube. Lung tumours were simulated by transthoracic ultrasound-guided injection of 5 ml of purified bovine serum albumin in glutaraldehyde, centrally into the left lower lung lobe. The rate of tumour detection, the severity of disability caused by residual gas, and sonomorphology of the lungs and tumours were assessed. RESULTS: The ex vivo tumour detection rate was 100% in flooded human lung lobes and 43% (6/14) in atelectatic lungs. In all cases of atelectasis, sonographic tumour imaging was impaired by residual gas. Tumours and atelectatic tissue were isoechoic. In 28% of flooded lungs, a little residual gas was observed that did not impair sonographic tumour imaging. In contrast to tumours, flooded lung tissue was hyperechoic, homogeneous, and of fine-grained structure. Because of the bronchial wall three-laminar structure, sonographic differentiation of vessels and bronchi was possible. In all cases, malignant tumours in the flooded lung appeared well-demarcated from the lung parenchyma. Adenocarcinoma, squamous, and large cell carcinomas were hypoechoic. Bronchioloalveolar cell carcinoma was slightly hyperechoic. Transpleural sonography identifies endobronchial tumour growth and bronchial wall destruction. With transthoracic sonography, the flooded animal lung can be completely examined in vivo. There is no residual gas, which interferes with ultrasound. Pulmonary vessels and bronchi are clearly differentiated. Simulated lung lesions can easily be detected inside the lung lobe. CONCLUSIONS: Lung flooding enables complete lung sonography and tumour detection. We have developed a novel method that efficiently uses ultrasound for guiding intraoperative interventions in open and endoscopic lung surgery.

Prolonged remission of advanced bronchoalveolar adenocarcinoma in a dog treated with autologous, tumour-derived chaperone-rich cell lysate (CRCL) vaccine.

PURPOSE: This paper presents the treatment of a 12-year-old female spayed Great Dane who presented with vestibular signs (ataxia, nystagmus, hind end collapse). Thoracic radiographs revealed a discrete pulmonary nodule in the right cranial lung lobe. Ultrasound-guided fine needle aspirate detected primary bronchoalveolar adenocarcinoma, verified via computed tomography, with a second smaller nodule discovered in the right cranial lung lobe. MATERIALS AND METHODS: A lateral thoracotomy with right cranial lung lobectomy was performed. Histopathological analysis of the nodules and an excised lymph node identified grade III bronchoalveolar adenocarcinoma with vascular infiltration and lymph node metastasis - a grim diagnosis with a reported median survival time of 6-27 days. A 10-g sample of the tumour was processed into a chaperone-rich cell lysate (CRCL) vaccine, which was administered weekly to the patient. Imiquimod - a Toll-like receptor 7 (TLR7) agonist - was applied topically for the first 12 treatments to stimulate local Langerhans cells. A single injection of bacillus Calmette-Guerin (BCG) was administered for additional immune stimulation at week 30 of treatment. RESULTS: The dog remained stable and in otherwise good health until diffuse relapse occurred 44 weeks after the initial treatment; following gastrointestinal bleeding, the dog was euthanised 50+ weeks post diagnosis. CONCLUSION: To the authors' knowledge, this is the first report of significantly prolonged survival following a diagnosis of grade III/stage III bronchoalveolar adenocarcinoma in a canine patient. This case report suggests that CRCL vaccine combined with topical imiquimod is a safe, effective treatment for canine tumours.

[Diagnostic value of (18)F-FDG PET/CT for solitary nodular-type bronchoalveolar carcinoma].

OBJECTIVE: To assess the value of (18)F-FDG PET/CT in the diagnosis of solitary nodular-type bronchoalveolar carcinoma (BAC). METHODS: The clinical and radiographic data were analyzed retrospectively in 30 patients with pathologically confirmed solitary nodular-type BAC who underwent (18)F-FDG PET/CT examinations between August, 2005 and December, 2006. The morphological and radioactive findings of the lesions were reviewed, and the maximum standard uptake values (SUVmax) were measured. The diagnostic accuracy of PET, PET/CT, and HRCT were analyzed. RESULTS: The (18)F-FDG SUV was markedly lower in BAC than in other well differentiated adenocarcinoma. In 19 of the BAC cases, PET showed a SUVmax of no less than 2.5, demonstrating positive changes. Of the total of 30 cases, 5 had ground glass opacity (GGO) changes, 3 exhibited mixed nodules with GGO changes around the lesions, and 22 cases presented with solid nodules. HRCT showed that BAC located often in the superior lobes of the bilateral lungs, mostly below the pleura in the surrounding lung field; the lesions were patchy or nodular with irregular shapes, showing lobulation in 22 cases, spiculation in 15 cases, pleural indentation in 21 cases, and vacuolar changes in 4 cases. The diagnostic accuracy of PET, PET/CT and HRCT for solitary nodular-type BAC was 36.67%, 93.33%, and 93.33%, respectively. CONCLUSION: The SUVmax of BAC provides only limited value for defining the nature of the lesions, but can serve as a general reference for assessing the disease activity. PET/CT, which allows both functional and imaging assessment, can be a valuable modality to reduce the misdiagnosis rate of BAC.

[Chronic pneumonia?]. / Chronische Pneumonien?

The differential diagnosis of persistent radiologic pulmonary shadow is broad and is illustrated and discussed with the help of four patients histories. The term chronic pneumonia is a misnomer. Particularly, slowly growing types of lung cancer should be considered as a potential etiology. They are potentially curable by surgical resection. Other diseases can be treated as soon as they are specified with appropriate diagnostic methods.

Positron emission tomography in bronchioloalveolar carcinoma of the lung.

OBJECTIVES: This study assessed the maximum standard uptake value of positron emission tomography-computed tomography in patients of pulmonary adenocarcinoma with bronchioloalveolar carcinoma features and whether SUVmax correlates with pathological status, lymph node metastasis, and prognosis. METHODS: We retrospectively reviewed 674 patients diagnosed with non-small-cell lung cancer between January 2002 and June 2009. Patients with clinical stage I-II disease underwent a preoperative PET-CT scan followed by anatomic resection. We reviewed the clinical features of 209 patients with an average follow-up of 87 months. RESULTS: We analyzed clinical variables for 40 patients with BAC features and 169 patients without BAC features. Age, sex, location, and number of dissected lymph nodes, carcinoembryonic antigen level, and lymphovascular invasion had no difference between the two groups. Compared with non-BAC patients, patients with BAC features had a lower SUVmax (2.51 ± 2.02 vs 4.98 ± 4.03, p < 0.001), lower ratio of SUVmax (1.10 ± 0.34 vs 1.22 ± 0.27, p = 0.014), better tumor differentiation (p < 0.001), and smaller tumor size (2.30 ± 1.41 vs 2.97 ± 1.71, p < 0.03). The negative prediction rate was 87.08% for N2 and 80.80% for N1 disease. All patients in the BAC group were alive after the operation. The five-year survival rate of patients without BAC features was 71.2%. CONCLUSIONS: Preoperative SUVmax of PET-CT was more accurate at predicting negative N2 than N1 disease. BAC is associated with markedly better prognosis compared with invasive adenocarcinoma and may be cured with surgical resection Aggressive surgical resection is recommended even for patients with false-negative N2 disease.

Synchronous bronchioloalveolar and squamous cell lung cancer with different 18F-FDG avidity on PET/CT.

We report a case of synchronous multiple primary lung cancer diagnosed by 18F-FDG PET/CT. A 78-year-old man underwent staging FDG PET/CT that demonstrated intense tracer uptake in the primary, and a second lesion with low uptake. Histopathologic evaluation revealed synchronous squamous cell and bronchioloalveolar carcinoma, representing 2 distinct primaries. FDG PET/CT may identify and diagnose synchronous multiple primary lung cancer on the basis of different morphologic and metabolic features of distinct tumor entities. Moreover, pulmonary lesions with low FDG avidity may still represent malignant disease, even in the context of biopsy-proven FDG-avid lung cancer.