Pedram Heidari

Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival

Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.

A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis

5′AMP‐activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth remains to be determined. A small molecule screening was performed and identified MT 63–78, a specific and potent direct AMPK activator. Here, we show that direct activation of AMPK inhibits PCa cell growth in androgen sensitive and castration resistant PCa (CRPC) models, induces mitotic arrest, and apoptosis. In vivo, AMPK activation is sufficient to reduce PCa growth, whereas the allelic loss of its catalytic subunits fosters PCa development. Importantly, despite mTORC1 blockade, the suppression of de novo lipogenesis is the underpinning mechanism responsible for AMPK‐mediated PCa growth inhibition, suggesting AMPK as a therapeutic target especially for lipogenesis‐driven PCas. Finally, we demonstrate that MT 63–78 enhances the growth inhibitory effect of AR signaling inhibitors MDV3100 and abiraterone. This study thus provides a rationale for their combined use in CRPC treatment.

Therapeutic Efficacy and Fate of Bimodal Engineered Stem Cells in Malignant Brain Tumors

Therapeutically engineered stem cells (SC) are emerging as an effective tumor‐targeted approach for different cancer types. However, the assessment of the long‐term fate of therapeutic SC post‐tumor treatment is critical if such promising therapies are to be translated into clinical practice. In this study, we have developed an efficient SC‐based therapeutic strategy that simultaneously allows killing of tumor cells and assessment and eradication of SC after treatment of highly malignant glioblastoma multiforme (GBM). Mesenchymal stem cells (MSC) engineered to co‐express the prodrug converting enzyme, herpes simplex virus thymidine kinase (HSV‐TK) and a potent and secretable variant of tumor necrosis factor apoptosis‐inducing ligand (S‐TRAIL) induced caspase‐mediated GBM cell death and showed selective MSC sensitization to the prodrug ganciclovir (GCV). A significant decrease in tumor growth and a subsequent increase in survival were observed when mice bearing highly aggressive GBM were treated with MSC coexpressing S‐TRAIL and HSV‐TK. Furthermore, the systemic administration of GCV post‐tumor treatment selectively eliminated therapeutic MSC expressing HSV‐TK in vitro and in vivo, which was monitored in real time by positron emission‐computed tomography imaging using 18F‐FHBG, a substrate for HSV‐TK. These findings demonstrate the development and validation of a novel therapeutic strategy that has implications in translating SC‐based therapies in cancer patients. STEM Cells 2013;31:1706–1714

Management of haemophilic pseudotumours with special emphasis on radiotherapy and arterial embolization

Summary.  The haemophilic pseudotumour is an expanding destructive haematoma, which is associated with a considerable amount of morbidity in haemophilic patients. Its prevention is paramount. In fact, this goal can be achieved by primary prophylaxis to avoid muscle haematomas and by adequate and long‐term haematological treatment of muscle haematomas in case they appear. At the moment, surgical excision of pseudotumour is the preferred treatment by many authors. However, there are instances that surgical extraction of the lesion is not feasible. In such situations, radiotherapy and arterial embolization should be considered either alone or as an adjunct to surgery. Conservative management using a combination of radiotherapy and replacement therapy should be considered for treating haemophilic bone pseudotumours, which are located in the skull or in the distal parts of the limbs, especially in conditions where some impediments to surgical excision exist. In fact, the radiation should be delivered to the lesion site in small fragments of 2 Gy or less to a total dosage of 6–23.5 Gy, which is the most recommended radiation dosage, at the moment. Therapeutic arterial embolization of haemophilic pseudotumours should be considered in lesions of large size, especially in pseudotumours of pelvic region, as it may effectively reduce its size and decrease the risk of bleeding complications during surgery. Nevertheless, in view of its temporary effect, embolization may better be performed, as a preparatory procedure, at best about 2 weeks prior to surgery. This time lapse will allow for mass shrinkage but is insufficient for vessel restoration.

Optical Imaging with a Cathepsin B Activated Probe for the Enhanced Detection of Esophageal Adenocarcinoma by Dual Channel Fluorescent Upper GI Endoscopy

Despite significant advances in diagnosis and treatment, the prognosis of esophageal adenocarcinoma remains poor highlighting the importance of early detection. Although white light (WL) upper endoscopy can be used for screening of the esophagus, it has limited sensitivity for early stage disease. Thus, development of new imaging technology to improve the diagnostic capabilities of upper GI endoscopy for early detection of esophageal adenocarcinoma is an important unmet need. The goal of this study was to develop a method for the detection of malignant lesions in the esophagus using WL upper endoscopy combined with near infrared (NIR) imaging with a protease activatable probe (Prosense750) selective for cathepsin B (CTSB). An orthotopic murine model for distal esophageal adenocarcinoma was generated through the implantation of OE-33 and OE-19 human esophageal adenocarcinoma lines in immunocompromised mice. The mice were imaged simultaneously for WL and NIR signal using a custom-built dual channel upper GI endoscope. The presence of tumor was confirmed by histology and target to background ratios (TBR) were compared for both WL and NIR imaging. NIR imaging with ProSense750 significantly improved upon the TBRs of esophageal tumor foci, with a TBR of 3.64±0.14 and 4.50±0.11 for the OE-33 and OE-19 tumors respectively, compared to 0.88±0.04 and 0.81±0.02 TBR for WL imaging. The combination of protease probes with novel imaging devices has the potential to improve esophageal tumor detection by fluorescently highlighting neoplastic regions.

Use of anatomic measurement to guide injection of botulinum toxin for the management of chronic lateral epicondylitis: a randomized controlled trial

Background: When using botulinum toxin for the management of lateral epicondylitis, injection at a fixed distance from an anatomic landmark could result in inadequate paralysis of the intended muscle. We assessed the effectiveness of injection of botulinum toxin using precise anatomic measurement in individual patients. Methods: In this randomized placebo-controlled trial, 48 patients with chronic refractory lateral epicondylitis were randomly assigned to receive a single injection of either botulinum toxin (60 units) or placebo (normal saline). The site of injection was chosen as a distance one-third the length of the forearm from the tip of the lateral epicondyle on the course of the posterior interosseus nerve. The primary outcome measure was intensity of pain at rest, measured with the use of a 100-mm visual analogue scale, at baseline and at 4, 8 and 16 weeks after injection. Results: Compared with the placebo group, the group given botulinum toxin had significant reductions in pain at rest during follow-up (decrease at 4 weeks 14.1 mm, 95% confidence interval [CI] 5.8–22.3; at 8 weeks 11.5 mm, 95% CI 2.0–21.0; at 16 weeks 12.6 mm, 95% CI 7.7–17.8; p = 0.01). As for the secondary outcomes, the intensity of pain during maximum pinch decreased in the botulinum toxin group; there was no difference in pain during maximum grip or in grip strength between the two groups. All but one of the patients in the intervention group experienced weakness in the extension of the third and fourth fingers at week 4 that resolved by week 16. No serious adverse events were reported. Interpretation: The use of precise anatomic measurement to guide injection of botulinum toxin significantly reduced pain at rest in patients with chronic refractory lateral epicondylitis. However, the transient extensor lag makes this method inappropriate for patients whose job requires finger extension. (ClinicalTrials.gov trial register no. NCT00497913.)

Optical Imaging of Periostin Enables Early Endoscopic Detection and Characterization of Esophageal Cancer in Mice

Imaging strategies that detect early stage esophageal squamous cell carcinoma (ESCC) could improve clinical outcomes, when combined with endoscopic approaches. Periostin is an integrin-binding protein that is important in the tumor microenvironment. We created a fluorescent-labeled antibody that recognizes periostin and binds specifically to ESCC xenograft tumors in mice. In L2-cre;p120ctnLoxP/LoxP mice, which develop squamous cell cancers that resemble human ESCC, we visualized the probe in preneoplastic and neoplastic esophageal lesions using near-infrared fluorescent imaging with upper-gastrointestinal endoscopy. Periostin might be a biomarker of the esophageal tumor microenvironment that can be used to detect preneoplastic lesions.

The role of ultrasound in diagnosis of the causes of low back pain: a review of the literature.

Context: Low back pain (LBP) is among the most prevalent musculoskeletal conditions in the developed countries. It is a common problem causing disability and imposing a huge economic burden to individuals and state organizations. Imaging plays an important role in diagnosis of the etiology of LBP. Evidence Acquisition: The electronic databases included: PubMed (1950 to present), Ovid SP Medline (1950 to present) and ISI (1982 to present) and Google Scholar. In every search engine another search was performed using various permutations of the following keywords: ultrasonography, ultrasound imaging, low back pain, back muscles, paraspinal muscles, multifidus, transverse abdominis, muscle size, spinal canal, sacroiliac joint and spondylolisthesis. Results: Magnetic resonance imaging (MRI) is widely used in evaluation of patients with LBP; however, high costs, limited availability and contraindications for its use have restricted MRI utilization. In a quest for a less expensive and readily available tool to investigate LBP, clinicians and researchers found ultrasonography (US) as an alternative. In this review we discuss the US application in diagnosis of some common causes of non-specific chronic LBP. Discussed topics include evaluation of spinal canal diameter, paraspinal and transabdominal muscles, sacroiliac joint laxity, pregnancy related LBP, sacroiliitis, and spondylolisthesis using US in patients with LBP. Conclusions: While the first researches on employing ultrasound in diagnosis of patients with LBP had been focused on spinal canal diameter, recent studies have been mostly performed to evaluate the role of transabdominal and paraspinal muscles on core stability and thereby LBP occurrence. On the other side, Doppler ultrasonography has recently played an important role in objective measurement of joint laxity as a common etiology for LBP. Doppler imaging also in pregnant patients with LBP has been recommended as a safe and sensitive method. As conclusion, according to recent and most prestigious studies, focusing more on transabdominal muscle thickness can be considered as future approach in investigations.

Impact of fluorodeoxyglucose PET on the management of esophageal cancer.

Esophageal cancer is the third most common malignancy of the alimentary tract. The incidence of esophageal cancer has steadily increased over the past three decades. Almost all therapeutic modalities for esophageal cancer are associated with a considerable mortality and morbidity. Consequently, there has been growing concern regarding effective management of esophageal cancer. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) is playing an increasing role in the management of esophageal cancer, offering potential advantages in the accuracy of disease assessment at a number of decision points in the management pathway. This review evaluates the critical role of FDG-PET in (i) diagnosis, (ii) preoperative staging, (iii) monitoring of response to neoadjuvant therapy, (iv) assessment of recurrence and (v) prediction of prognosis of esophageal cancer. We have also compared diagnostic performance of FDG-PET and other current technologies such as computed tomography scan and endoscopic ultrasonography based on available evidence.

Interventional Optical Molecular Imaging Guidance during Percutaneous Biopsy

PURPOSE To investigate indocyanine green (ICG) as a molecular beacon for malignant lesions within the liver and evaluate the ability of a developed handheld imaging system to allow measurement of ICG fluorescence within focal hepatic lesions with high target-to-background ratios in a mouse model. MATERIALS AND METHODS All animal experiments were approved by the institutional animal care committee. A handheld optical molecular imaging device was constructed to pass through the introducer needle of a standard percutaneous biopsy kit. An ex vivo phantom system was constructed to quantify tissue attenuation properties of ICG in liver parenchyma. Subsequently, intrahepatic colorectal cancer metastases were generated in nude mice, and epifluorescence imaging of ICG, as well as histologic analysis of the explanted livers, was performed at 3 weeks after implantation (n = 6). Epifluorescence imaging with the handheld imaging device was then performed on intrahepatic colorectal metastases after the administration of ICG (n = 15) at 3, 6, and 24 hours after injection. Target-to-background ratios were calculated for each time point. Subsequently, a core biopsy of intrahepatic colorectal metastases was performed by using a standard clinical 18-gauge biopsy needle. RESULTS There was avid localization of ICG to the focal lesions at all time points. Similarly, fluorescence within the tumors was greater than that within normal liver, as detected with the handheld imaging system (mean target-to-background ratio ± standard deviation, 3.9 ± 0.2 at 24 hours). A core biopsy of tumor and normal adjacent liver by using a standard biopsy needle demonstrated a sharp margin of fluorescence intensity at the tumor-liver interface. CONCLUSION The custom-designed molecular imaging device, in combination with ICG, readily allowed differentiation between normal and malignant tissue in a murine model of intrahepatic colorectal metastasis.