MR Virtual Biopsy of Solid Renal Masses: An Algorithmic Approach.

Between 1983 and 2002, the incidence of solid renal tumors increased from 7.1 to 10.8 cases per 100,000. This is in large part due to the increase in the volume of ultrasound and cross-sectional imaging, although a majority of solid renal tumors are still found incidentally. Ultrasound and computed tomography (CT) have been the mainstay of renal mass screening and diagnosis but recent advances in magnetic resonance (MR) technology have made this the optimal choice when diagnosing and staging renal tumors. Our purpose in writing this review is to survey the modern MR imaging approach to benign and malignant solid renal tumors, consolidate the various imaging findings into an easy-to-read reference, and provide an imaging-based, algorithmic approach to renal mass characterization for clinicians. MR is at the forefront of renal mass characterization, surpassing ultrasound and CT in its ability to describe multiple tissue parameters and predict tumor biology. Cutting-edge MR protocols and the integration of diagnostic algorithms can improve patient outcomes, allowing the imager to narrow the differential and better guide oncologic and surgical management.

Comparison of magnetic resonance defecography grading with POP-Q staging and Baden-Walker grading in the evaluation of female pelvic organ prolapse.

PURPOSE: The physical examination and pelvic imaging with MRI are often used in the pre-operative evaluation of pelvic organ prolapse. The objective of this study was to compare grading of prolapse on defecography phase of dynamic magnetic resonance imaging (dMRI) with physical examination (PE) grading using both the Pelvic Organ Prolapse Quantification (POP-Q) staging and Baden-Walker (BW) grading systems in the evaluation of pelvic organ prolapse (POP). METHODS: We retrospectively reviewed the charts of 170 patients who underwent dMRI at our institution. BW grading and POP-Q staging were collected for anterior, apical, and posterior compartments, along with absolute dMRI values and overall grading of dMRI. For the overall grading/staging from dMRI, BW, and POP-Q, Spearman rho (ρ) was used to assess the correlation. The correlations between dMRI grading and POP-Q staging were compared to the correlations between dMRI grading and BW grading using Fisher's Z transformation. RESULTS: A total of 54 patients were included. dMRI grading was not significantly correlated with BW grading for anterior, apical, and posterior compartment prolapse (p > 0.15). However, overall dMRI grading demonstrated a significant (p = 0.025) and positive correlation (ρ = 0.305) with the POP-Q staging system. dMRI grading for anterior compartment prolapse also demonstrated a positive correlation (p = 0.001, ρ = 0.436) with the POP-Q staging derived from measurement locations Aa and Ba. The overall dMRI grade is better correlated with POP-Q stage than with BW grade (p = 0.024). CONCLUSION: Overall and anterior compartment grading from dMRI demonstrated a significant and positive correlation with the overall POP-Q staging and anterior compartment POP-Q staging, respectively. The overall dMRI grade is better correlated with POP-Q staging than with BW grading.

The Changing Sensory and Sympathetic Innervation of the Young, Adult and Aging Mouse Femur.

Although bone is continually being remodeled and ultimately declines with aging, little is known whether similar changes occur in the sensory and sympathetic nerve fibers that innervate bone. Here, immunohistochemistry and confocal microscopy were used to examine changes in the sensory and sympathetic nerve fibers that innervate the young (10 days post-partum), adult (3 months) and aging (24 months) C57Bl/6 mouse femur. In all three ages examined, the periosteum was the most densely innervated bone compartment. With aging, the total number of sensory and sympathetic nerve fibers clearly declines as the cambium layer of the periosteum dramatically thins. Yet even in the aging femur, there remains a dense sensory and sympathetic innervation of the periosteum. In cortical bone, sensory and sympathetic nerve fibers are largely confined to vascularized Haversian canals and while there is no significant decline in the density of sensory fibers, there was a 75% reduction in sympathetic nerve fibers in the aging vs. adult cortical bone. In contrast, in the bone marrow the overall density/unit area of both sensory and sympathetic nerve fibers appeared to remain largely unchanged across the lifespan. The preferential preservation of sensory nerve fibers suggests that even as bone itself undergoes a marked decline with age, the nociceptors that detect injury and signal skeletal pain remain relatively intact.

Immunohistochemical localization of nerve growth factor, tropomyosin receptor kinase A, and p75 in the bone and articular cartilage of the mouse femur.

Sequestration of nerve growth factor (NGF) significantly attenuates skeletal pain in both animals and humans. However, relatively little is known about the specific cell types that express NGF or its cognate receptors tropomyosin receptor kinase A (TrkA) and p75 in the intact bone and articular cartilage. In the present study, antibodies raised against NGF, TrkA, and p75 (also known as CD271) were used to explore the expression of these antigens in the non-decalcified young mouse femur. In general, all three antigens displayed a remarkably restricted expression in bone and cartilage with less than 2% of all DAPI+ cells in the femur displaying expression of any one of the three antigens. Robust NGF immunoreactivity was found in mostly CD-31- blood vessel-associated cells, a small subset of CD-31+ endothelial cells, an unidentified group of cells located at the subchondral bone/articular cartilage interface, and a few isolated, single cells in the bone marrow. In contrast, p75 and TrkA were almost exclusively expressed by nerve fibers located nearby NGF+ blood vessels. The only non-neuronal expression of either p75 or TrkA in the femur was the expression of p75 by a subset of cells located in the deep and middle zone of the articular cartilage. Understanding the factors that tightly regulate the basal level of expression in normal bone and how the expression of NGF, TrkA, and p75 change in injury, disease, and aging may provide insights into novel therapies that can reduce skeletal pain and improve skeletal health.

Preventing painful age-related bone fractures: Anti-sclerostin therapy builds cortical bone and increases the proliferation of osteogenic cells in the periosteum of the geriatric mouse femur.

Age-related bone fractures are usually painful and have highly negative effects on a geriatric patient's functional status, quality of life, and survival. Currently, there are few analgesic therapies that fully control bone fracture pain in the elderly without significant unwanted side effects. However, another way of controlling age-related fracture pain would be to preemptively administer an osteo-anabolic agent to geriatric patients with high risk of fracture, so as to build new cortical bone and prevent the fracture from occurring. A major question, however, is whether an osteo-anabolic agent can stimulate the proliferation of osteogenic cells and build significant amounts of new cortical bone in light of the decreased number and responsiveness of osteogenic cells in aging bone. To explore this question, geriatric and young mice, 20 and 4 months old, respectively, received either vehicle or a monoclonal antibody that sequesters sclerostin (anti-sclerostin) for 28 days. From days 21 to 28, animals also received sustained administration of the thymidine analog, bromodeoxyuridine (BrdU), which labels the DNA of dividing cells. Animals were then euthanized at day 28 and the femurs were examined for cortical bone formation, bone mineral density, and newly borne BrdU+ cells in the periosteum which is a tissue that is pivotally involved in the formation of new cortical bone. In both the geriatric and young mice, anti-sclerostin induced a significant increase in the thickness of the cortical bone, bone mineral density, and the proliferation of newly borne BrdU+ cells in the periosteum. These results suggest that even in geriatric animals, anti-sclerostin therapy can build new cortical bone and increase the proliferation of osteogenic cells and thus reduce the likelihood of painful age-related bone fractures.

Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer.

Tumor cells frequently metastasize to bone where they can generate cancer-induced bone pain (CIBP) that can be difficult to fully control using available therapies. Here, we explored whether PLX3397, a high-affinity small molecular antagonist that binds to and inhibits phosphorylation of colony-stimulating factor-1 receptor, the tyrosine-protein kinase c-Kit, and the FMS-like tyrosine kinase 3, can reduce CIBP. These 3 targets all regulate the proliferation and function of a subset of the myeloid cells including macrophages, osteoclasts, and mast cells. Preliminary experiments show that PLX3397 attenuated inflammatory pain after formalin injection into the hind paw of the rat. As there is an inflammatory component in CIBP, involving macrophages and osteoclasts, the effect of PLX3397 was explored in a prostate model of CIBP where skeletal pain, cancer cell proliferation, tumor metastasis, and bone remodeling could be monitored in the same animal. Administration of PLX3397 was initiated on day 14 after prostate cancer cell injection when the tumor was well established, and tumor-induced bone remodeling was first evident. Over the next 6 weeks, sustained administration of PLX3397 attenuated CIBP behaviors by approximately 50% and was equally efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling. Developing a better understanding of potential effects that analgesic therapies have on the tumor itself may allow the development of therapies that not only better control the pain but also positively impact disease progression and overall survival in patients with bone cancer.

NGF blockade at early times during bone cancer development attenuates bone destruction and increases limb use.

Studies in animals and humans show that blockade of nerve growth factor (NGF) attenuates both malignant and nonmalignant skeletal pain. While reduction of pain is important, a largely unanswered question is what other benefits NGF blockade might confer in patients with bone cancer. Using a mouse graft model of bone sarcoma, we demonstrate that early treatment with an NGF antibody reduced tumor-induced bone destruction, delayed time to bone fracture, and increased the use of the tumor-bearing limb. Consistent with animal studies in osteoarthritis and head and neck cancer, early blockade of NGF reduced weight loss in mice with bone sarcoma. In terms of the extent and time course of pain relief, NGF blockade also reduced pain 40% to 70%, depending on the metric assessed. Importantly, this analgesic effect was maintained even in animals with late-stage disease. Our results suggest that NGF blockade immediately upon detection of tumor metastasis to bone may help preserve the integrity and use, delay the time to tumor-induced bone fracture, and maintain body weight.

Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain.

Skeletal injury is a leading cause of chronic pain and long-term disability worldwide. While most acute skeletal pain can be effectively managed with nonsteroidal anti-inflammatory drugs and opiates, chronic skeletal pain is more difficult to control using these same therapy regimens. One possibility as to why chronic skeletal pain is more difficult to manage over time is that there may be nerve sprouting in nonhealed areas of the skeleton that normally receive little (mineralized bone) to no (articular cartilage) innervation. If such ectopic sprouting did occur, it could result in normally nonnoxious loading of the skeleton being perceived as noxious and/or the generation of a neuropathic pain state. To explore this possibility, a mouse model of skeletal pain was generated by inducing a closed fracture of the femur. Examined animals had comminuted fractures and did not fully heal even at 90+days post fracture. In all mice with nonhealed fractures, exuberant sensory and sympathetic nerve sprouting, an increase in the density of nerve fibers, and the formation of neuroma-like structures near the fracture site were observed. Additionally, all of these animals exhibited significant pain behaviors upon palpation of the nonhealed fracture site. In contrast, sprouting of sensory and sympathetic nerve fibers or significant palpation-induced pain behaviors was never observed in naïve animals. Understanding what drives this ectopic nerve sprouting and the role it plays in skeletal pain may allow a better understanding and treatment of this currently difficult-to-control pain state.

Novel factors to improve prediction of nodal positivity in patients with clinical T1/T2 breast cancers.

BACKGROUND: Memorial Sloan Kettering Cancer Center (MSKCC) and MD Anderson Cancer Center (MDACC) have established nomograms to predict sentinel node positivity. We propose the addition of two novel variables-distance of tumor from the nipple and from the skin-can improve their performance. METHODS: Ultrasounds of clinical T1/T2 tumors were reviewed. Distances of the tumor from the skin and from the nipple were measured. MSKCC and MDACC nomogram predictions and the AUC-ROC for each model were calculated. The added utility of the two variables was then examined using multiple logistic regression. RESULTS: Of 401 cancers studied, 79 (19.7 %) were node positive. The mean distance of tumors from the nipple in node-positive patients was 4.9 cm compared with 6.0 cm in node-negative patients (p = 0.0007). The mean distance of tumors from the skin was closer in node-positive cases (0.8 cm) versus node-negative cases (1.0 cm, p = 0.0007). The MSKCC and MDACC nomograms AUC-ROC values were 0.71 (95 % CI 0.64-0.77) and 0.74 (95 % CI 0.68-0.81). When adjusted for the MSKCC predicted probability, addition of both distance from nipple (p = 0.008) and distance from skin (p = 0.02) contributed significantly to prediction of nodal positivity and improved the AUC-ROC to 0.75 (95 % CI 0.70-0.81). Similarly, distance from nipple (p = 0.002), but not distance from skin (p = 0.09), added modestly to the MDACC nomogram performance (AUC 0.77; 95 % CI 0.71-0.83). CONCLUSIONS: Distance of tumor from the nipple and from the skin are important variables associated with nodal positivity. Adding these to established nomograms improves prediction of nodal positivity.