Recent Publications by CFE Educators

Chronic pain is estimated to be the third most prevalent health problem in the world. Although scientists have made great strides in our understanding of the molecular mechanisms through which chronic pain develops, this knowledge has not been translated into new therapies. In this issue of Science Translational Medicine, Wang and colleagues report on the development of a selective antagonist of type 1 adenylate cyclase (AC1), which is induced in subsets of neurons in the central nervous system during the development of neuropathic pain. Blockade of AC1 significantly alleviates the mechanical hypersensitivity that occurs in a mouse model of neuropathic pain without affecting acute pain responsiveness or cognitive and motor function. These features make AC1 a potential therapeutic target for the treatment of neuropathic pain.

We present a novel cell-signaling paradigm in which bone morphogenetic protein 2 (BMP-2) consecutively and interdependently activates the wingless (Wnt)-β-catenin (βC) and Wnt-planar cell polarity (PCP) signaling pathways to facilitate vascular smooth muscle motility while simultaneously suppressing growth. We show that BMP-2, in a phospho-Akt-dependent manner, induces βC transcriptional activity to produce fibronectin, which then activates integrin-linked kinase 1 (ILK-1) via α4-integrins. ILK-1 then induces the Wnt-PCP pathway by binding a proline-rich motif in disheveled (Dvl) and consequently activating RhoA-Rac1-mediated motility. Transfection of a Dvl mutant that binds βC without activating RhoA-Rac1 not only prevents BMP-2-mediated vascular smooth muscle cell motility but promotes proliferation in association with persistent βC activity. Interfering with the Dvl-dependent Wnt-PCP activation in a murine stented aortic graft injury model promotes extensive neointima formation, as shown by optical coherence tomography and histopathology. We speculate that, in response to injury, factors that subvert BMP-2-mediated tandem activation of Wnt-βC and Wnt-PCP pathways contribute to obliterative vascular disease in both the systemic and pulmonary circulations.

OBJECTIVE

To report oncological and functional results in women undergoing radical cystectomy and orthotopic bladder replacement.

MATERIALS AND METHODS

The charts of all women undergoing bladder replacement after radical cystectomy at UCSF through April 2008 were reviewed. Pathologic characteristics, survival (overall and disease-specific), and urinary functional outcomes are reported. Survival was estimated using Kaplan-Meier methods, and Cox proportional hazards regression analyses were performed to determine factors associated with incontinence, retention, and mortality.

RESULTS

Fifty-six women with a mean follow-up of 35 months were analyzed. The cancer recurrence rate was 32%. Kaplan-Meier estimated 5-year recurrence-free, cancer-specific, and overall survival were 54%, 57%, and 47%, respectively. Pathologic lymph node status (HR 14.2, P .001) and age at diagnosis (HR 1.7, P = .04) were the only clinical or pathologic characteristics significantly associated with survival. The overall continence rate (no pads) was 57%. Hypercontinence occurred in 24% of patients.

CONCLUSIONS

With careful patient selection and usage of urethral frozen section, rates of local recurrence are low. Overall rates of incontinence (43%) and hypercontinence (24%) are similar to those previously reported. When pathologically organ-confined, women have an excellent disease-specific survival. Orthotopic bladder replacement is a safe and effective form of urinary diversion after radical cystectomy in women.

BACKGROUND

Standard preoperative imaging for primary hyperparathyroidism usually includes sestamibi scanning (MIBI) and ultrasound (US). In a subset of patients with a positive MIBI and a negative US, we hypothesize that the parathyroid adenomas are more likely to be located posteriorly in the neck, where anatomically they are more difficult to detect by US.

METHODS

We retrospectively reviewed the records of 661 patients treated for primary hyperparathyroidism between 2004 and 2009 at a tertiary referral center. We included patients who for their first operation had a MIBI that localized a single lesion in the neck and an US that found no parathyroid adenoma. We excluded patients with persistent or recurrent hyperparathyroidism, and patients with MIBIs that were negative, that had more than one positive focus, or that had foci outside of the neck. Sixty-six cases were included in the final analysis.

RESULTS

A total of 54 patients (83%) had a single adenoma, 4 (6%) had double adenomas, and 7 (11%) had hyperplasia. Thirty-three patients (51%) had a single upper gland adenoma; 19 of these (58%) were posteriorly located upper gland adenomas (PLUGs). PLUGs occurred more often on the right side than on the left (P = 0.048, Fisher's test). PLUGs were also larger than other single adenomas (mean 1.85 vs. 1.48 cm, P = 0.021, t-test). Seventy-six percent of patients successfully underwent a unilateral or focused exploration. Six patients (9%) had persistent disease, which is double our group's overall average (4-5%).

CONCLUSIONS

Primary hyperparathyroid patients with preoperative positive MIBI and negative US are more likely to have PLUGs.

Pulmonary embolism (PE) is an uncommon and often overlooked cause of ST-segment elevation on the electrocardiogram (ECG). Emergent echocardiography has been cited as a means to rapidly distinguish acute myocardial infarction from PE. However, both of these conditions can present with focal wall motion abnormalities. We report a case of a 51-year-old asymptomatic male who presented to our emergency department with anterior ST-segment elevation and right-heart strain on an ECG. The clinical diagnosis of ST elevation myocardial infarction was in doubt, and an echocardiogram was obtained while the patient was in the emergency department. Although a focal area of hypokinesia was observed on echocardiography, cardiac catherization did not demonstrate any evidence of acute coronary occlusion. A computed tomographic angiogram of the chest was subsequently obtained, which demonstrated evidence of submassive pulmonary emboli. Our case highlights the limited utility of emergent echocardiography in cases of ST-segment elevation.

While several inflammatory cell types participate in cancer development, macrophages specifically play a key role in breast cancer, where they appear to be part of the pathogenesis of high-grade tumors. Tumor-associated macrophages (TAMs) produce factors that promote angiogenesis, remodel tissue and dampen the immune response to tumors. Specific macrophage types contribute to increased metastases in animal models, while human studies show an association between TAMs and tumors with poor prognostic features. Macrophages display a spectrum of phenotypic states, with the tumor microenvironment skewing TAMs towards a 'nonclassical' activation state, known as the M2, or wound healing/regulatory state. These TAMs are found in high-risk breast cancers, making them an important therapeutic target to explore. Improved techniques for identifying TAMs should translate into clinical applications for prognosis and treatment.