CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation

Recruitment of monocytic myeloid-derived suppressor cells (MDSCs) and differentiation of tumor-associated macrophages (TAMs) are the major factors contributing to tumor progression and metastasis. We demonstrated that differentiation of TAMs in tumor site from monocytic precursors was controlled by downregulation of the activity of the transcription factor STAT3. Decreased STAT3 activity was caused by hypoxia and affected all myeloid cells but was not observed in tumor cells. Upregulation of CD45 tyrosine phosphatase activity in MDSCs exposed to hypoxia in tumor site was responsible for downregulation of STAT3. This effect was mediated by the disruption of CD45 protein dimerization regulated by sialic acid. Thus, STAT3 has a unique function in the tumor environment in controlling the differentiation of MDSC into TAM, and its regulatory pathway could be a potential target for therapy

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects

Hepatic resection at a major community-based teaching hospital can result in good outcome.

BACKGROUND: The relationship between volume and outcome has been established in the literature for several complex surgical procedures. Improved outcome has been suggested at high-volume hospitals or with high-volume surgeons. METHODS: The objective of this study was to evaluate the experience of a low-volume hospital with major liver resections. The setting of the study was a community-based teaching hospital with a surgical residency training program. RESULTS: A total of 46 major liver resections were performed between January 1992 and December 2002. Procedures performed were hepatic lobectomies (n = 15; right, n = 11; left, n = 4), trisegmentectomies (n = 5; right, n = 3; left, n = 2), segmentectomies (n = 16; left lateral, n = 12; right posterior, n = 4), and wedge resections (n = 10). Operations were performed by 14 different surgeons; however, 23 operations were performed by 1 surgeon. Sixteen patients (34%) developed 23 complications. The average length of hospital stay was 9.7 days. There were no 30-day postoperative mortalities. Out of 46 patients who underwent major liver resection over the last 10 years, 13 patients are still alive. Overall survival ranged from 3 to 84 months, with a median survival of 30.6 months. The actual 5-year survival was 36% (8 of 22) for all patients operated on \u3e5 years ago, and the actual 2-year survival was 61% (20 of 33). CONCLUSIONS: Major liver resection can be performed safely with low rates of morbidity and operative mortality with careful selection of patients at a low-volume community-based teaching hospital

Ocular pneumoplethysmography in head-injured patients.

Severe head injury is frequently associated with multiple trauma. In the comatose patient, endotracheal intubation and ventilator support are often required, if there is associated dyssynchronous spontaneous effort. The latter is managed with therapeutic (drug) paralysis. An elaborate life-support and monitoring system coupled with controlled paralysis limits the mobility of the patient for diagnostic procedures, and a continuing reevaluation of neurological status is difficult. Under these circumstances the ocular pneumoplethysmograph provides a simple rapid noninvasive assessment of ocular blood flow, and this reflects cerebral blood flow and alterations in brain compliance. Alterations in the therapeutic regimen can be based on these observations

Comparing Predictive Decision Rules in Postoperative CEA Monitoring.

To evaluate the usefulness of serial postoperative carcinoembryonic antigen (CEA) assays, seven previously published decision rules for predicting tumor recurrence were compared retrospectively using CEA values from 214 patients followed 36 to 120 months after surgery for colorectal carcinoma. Decision rules employing cutoff values to predict tumor recurrence were found inadequate for the asymptomatic patient. This attenuation of prognostic usefulness appeared attributable to inadequacies of CEA assays for predicting late recurrences. From these analyses, elevated CEA results without other objective evidence might be insufficient to justify second-look surgery. In addition, late recurring tumors tended not to cause elevated CEA levels