Polyphosphazene polyacids show potential as immunostimulating compounds and materials for microencapsulation. Their synthesis requires multistep chemical transition from a hydrolytically unstable macromolecular precursor, poly(dichlorophosphazene), to a water-soluble polyelectrolyte. Insufficient synthetic control in these reactions can lead to molecular weight variations and formation of macromolecules with "structural defects" resulting in significant variations in polymer performance. Simple and reproducible "one pot-one solvent" method is reported for the preparation of polyphosphazene polyacids-poly[di(carboxylatophenoxy)phosphazene] and its copolymers. Molecular weight characteristics and polymer compositions were studied as a function of reaction parameters. Macromolecular byproducts, incompletely substituted polymers containing hydroxyl groups and partially deprotected polymers containing propyl ester functionalities, were synthesized and characterized. It was demonstrated, that the presence of such groups can affect polymer characteristics, such as hydrolytic degradation profiles, immunostimulating activity, and microsphere forming properties. In vivo studies showed that the immunostimulating activity of polyphosphazene polyacids correlates with the content of acid functionalities in the polymer.

Water-soluble polyphosphazenes emerge as an important class of biologically active macromolecular compounds dictating the need for the development of their well-defined and controlled synthesis. The synthetic pathway leading to biologically active polyphosphazenes involves preparation and chemical transformation of inorganic macromolecular precursorpoly(dichlorophosphazene), PDCP. Synthesis, stabilization, and characterization of this hydrolytically sensitive, reactive intermediate are the focus of the present study. Ring-opening polymerization reaction leading to PDCP has been investigated under strictly controlled conditions by NMR, viscometry, and direct multiangle laser light scattering−GPC methods. A substantial dependence of the molecular weight on degree of conversion and the formation of branched polymer structures have been observed even at early stages of the polymerization process. A new approach has been suggested for the stabilization of PDCP solutions involving the use of diethylene glycol dimethyl ether (diglyme). This stabilization technique allows highly reliable direct analysis of PDCP using chromatographic methods and greatly simplifies PDCP conversion in the organo-substituted polymer.

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An overview of colorectal cancer discussed (Philip Paty) the good outcome after primary management with local control in 90-95 % of colon and 85 % in rectal cancer patients with major progression to metastases and to death related to hematogenous dissemination. The major disease pathways include the APC, aneuploid pathway involving mutations of P53, KRAS, SMAD 4, or the CMP/MSI pathway, mismatched repair defect as characterized by Lynch syndrome, the major hereditary form which may also have KRAS and P53 mutations. The common sporadic colorectal cancers are MS1 high, with many patients having BRAF and KRAS mutations. The sentinel node biopsy in colorectal cancer surgery may provide more definitive staging and perhaps modification of the extent of resection with better outcome as suggested by Dr. Saha. The identification of sentinel lymph nodes outside of the planned bowel resection may increase the resection biologically indicated by the sentinel lymph node location leading to better outcome. In a small study by Dr. Saha, the operation was enhanced in 21 % by extending the length of bowel resection, which increased node recovery to 18.5 nodes versus 12 nodes with the more conventional resection, increasing nodal recovery, and positivity to 60 % with reduction to five year recurrence rate to 9 % versus 27 % with the conventional resection. A new (Swiss) technique for pathologic node examination, the OSNA (the One Step Nucleic Acid diagnostic system), was presented which demonstrated increased detection of micro-metastases in a focused pathology study of 22 patients (Zuber) to 11 out of 15 patients versus the 7 micro-metastases identified by the standard single slide per node, and compared to 14 out of 15 with an intensive multi-slide technique. This suggests value in pursuing OSNA study by other centers with relevant clinical trials to establish its true value. An analysis of liver resection for metastatic colorectal cancer (CRC) emphasized the value of 10-year follow-up (DeAngelica). The 10-year survival of 102 patients among 612 patients was 17 % (Memorial Sloan Kettering data). At the five-year point 99 of 102 survivors were NED and 86 have been free of disease since the resection. The usual five-year figure after hepatic resection reveals that one-third of five-year survivors die from recurrence of distant disease suggesting the value of longer term follow-up in these patients. An additional question reviewed related to the role of neoadjuvant systemic chemotherapy (with response rates in the 50 % range) to produce down staging of the hepatic metastases and allow one to retrieve these patients with possible residual disease. In a series of 116 patients who had hepatic resection of CRC metastases in presence of regional node metastases, post neoadjuvant chemotherapy (normally not candidates for resection) these patients were demonstrated to have a 95 % recurrence at median time of 9 months. This raises a cautionary note to the literature report of five-year survivals in the 20-30 % range for hepatic metastases ...

Colorectal cancer is the second leading cause of cancer related death in the United States. The majority of these deaths are due to metastasis, with the liver easily accounting as the most common site of deposit. While there are multiple steps in the CRC hepatic metastatic cascade, this review attempts to summarize the different processes involved, focusing on the most recent discoveries, as well as the associated effects in relation to prognosis.

Key Clinical MessageCystic neutrophilic granulomatous mastitis (CNGM) is an increasingly recognized entity in the differential diagnosis of granulomatous inflammation involving the breast. We present the first case report of CNGM mimicking carcinoma of the breast with two mixed bacterial species as the causative pathogens (Corynebacterium and Staphylococcus spp.).

In examining the liver’s response to sepsis our lab has found that septic hepatocytes exhibit a higher degree of necrosis when compared to septic thymocytes, which typically die through the canonical apoptotic pathway. Recently, an adaptor protein associated with the Fas/TNF death receptor pathway, Receptor Interacting Protein 1 (RIP1) has been shown to be critical for determining whether a cell’s death is apoptotic or necrotic. We propose to test the central hypothesis that RIP1 activation by death receptor (Fas) during sepsis determines whether the hepatocytes fate is apoptotic vs. necrotic. We approached this problem by delivering RIP1 siRNA in vivo to C57BL/6 mice and observing changes in mortality after septic challenge. Contrary to our hypothesis, RIP1 silenced mice did not survive as long as scrambled sequence injected controls (22.2% vs. 50.0% 14 days post CLP, respectively). When we used a pharmacological/synthetic antagonist of RIP1 kinase, Necrostatin 1 (Nec-1) and examined the mortality of Nec1 treated mice there was no difference from the RIP1 siRNA treated mice (20.0% vs. 22.2% respectively). Further, we carried out a series of comparative histological studies which indicated that septic mice pre-treated with Nec-1 exhibited a preservation of liver glycogen stores (represented by Periodic Acid Schiff [PAS] stain) vs. siRNA treated mice which exhibit lower glycogen stores as well as altered morphology. Furthermore, the histological studies also revealed Nec1 treatment in septic mice increases caspase 3 activity. We speculate that these contradictatory findings are due to the dual signaling responsibilities of RIP1, where the RIP1 kinase domain can induce death through Fas ligation while also initiating pro-survival signaling through NFκB.

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