Canadian guidelines on the management of colorectal peritoneal metastases.

Modern management of colorectal cancer (crc) with peritoneal metastasis (pm) is based on a combination of cytoreductive surgery (crs), systemic chemotherapy, and hyperthermic intraperitoneal chemotherapy (hipec). Although the role of hipec has recently been questioned with respect to results from the prodige 7 trial, the role and benefit of a complete crs were confirmed, as observed with a 41-month gain in median survival in that study, and 15% of patients remaining disease-free at 5 years. Still, crc with pm is associated with a poor prognosis, and good patient selection is essential. Many questions about the optimal management approach for such patients remain, but all patients with pm from crc should be referred to, or discussed with, a pm surgical oncologist, because cure is possible. The objective of the present guideline is to offer a practical approach to the management of pm from crc and to reflect on the new practice standards set by recent publications on the topic.

Surgical management of disappearing colorectal liver metastases.

BACKGROUND: Owing to expanded surgical indications for colorectal liver metastasis (CRLM) and improved systemic therapy, hepatic surgeons are increasingly faced with the problem of disappearing (no longer visible on imaging) liver metastasis (DLM). METHODS: A review of relevant studies was performed. Studies that reported on DLM associated with preoperative chemotherapy for CRLM were identified, and data were synthesized and tabulated. The PubMed database was searched for relevant articles published between January 2000 and December 2012. RESULTS: A complete response on imaging does not necessarily equate with a complete clinical or pathological response. Rather, residual macroscopic disease is found in about 25-45 per cent of patients at the time of operation. Even among patients with a complete pathological response, long-term remission occurs in only 20-50 per cent of those treated with systemic therapy. A durable response of DLM is more common following the use of hepatic artery infusion therapy. CONCLUSION: Liver resection should include all original sites of disease if possible.

Thrombelastography in the surgical patient.

Coagulopathy in surgical patients is an important factor in triggering major perioperative complications, i.e., intra- or postoperative bleeding and thrombo-embolic events associated with an increased mortality and morbidity. Different methods exist to assess the coagulation status of patients before, during and after surgery. Routine coagulation tests have long been considered to be the clinical standard. However, these tests have considerable limitations. Information regarding the kinetics of clot formation, clot strength, interaction of the coagulation components, platelet function and fibrinolysis is not available. Moreover, there is an important delay in obtaining test results. In contrast, thrombelastography and thrombelastometry, which both measure the visco-elastic properties of whole blood, allow the dynamic assessment of a developing clot, from fibrin formation to clot strengthening and clot lysis. Both techniques are increasingly being used in daily clinical practice in order to detect perioperative coagulopathy and to guide predominantly pro-coagulant therapy in different settings. This article provides an overview of both techniques, thrombelastography (TEG) and thrombelastometry (ROTEM), and their field of perioperative application considering of recently published data.

Expression of the ALK tyrosine kinase gene in neuroblastoma.

ALK (anaplastic lymphoma kinase) is a tyrosine kinase receptor, expressed as part of the chimeric NPM-ALK protein, in anaplastic large cell lymphomas (ALCLs) exhibiting the t(2;5)(p23;q35) translocation. As a result of this translocation, the NPM (nucleophosmin) gene is fused to the portion of the ALK gene encoding its intracytoplasmic segment. In normal mouse tissues, mRNA encoding the Alk receptor has been found only in neural cells, suggesting involvement of this receptor in the development of the nervous system. The purpose of the present study was to examine the presence of ALK transcripts and protein in normal human tissues and a variety of cell lines and human tumors. Emphasis was placed on neuroblastomas because other tyrosine kinase receptors are expressed in human neuroblastomas. Fifty-six cell lines, including 29 lines of neural origin, and lymphoid and nonlymphoid tissue specimens, including 24 neuroblastomas, were investigated for ALK expression, using reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry. The results confirmed that mRNA encoding ALK protein was not detectable in any normal or neoplastic hematopoietic tissue tested, except for t(2;5)-positive ALCL. The salient finding was that 13 of the 29 cell lines of neural origin and 22 of 24 neuroblastomas were found to express ALK transcripts and ALK protein. However, no correlation was evident between any known prognostic factors and the level of ALK expression.

Nucleolar localization of the nucleophosmin-anaplastic lymphoma kinase is not required for malignant transformation.

The (2;5)(p23;q35) lymphoma-associated chromosomal translocation creates a novel fusion gene that incorporates parts of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase and nucleophosmin genes. We report here that the product of this fusion gene accumulates within the nucleoli of neoplastic cells, and that previous reports of a predominantly cytoplasmic localization for the protein represent a tissue-processing artifact. However, nucleolar accumulation of nucleophosmin-ALK may not be necessary for its oncogenic action, because an ALK protein expressed in a lymphoma carrying a variant (1;2) chromosomal translocation did not accumulate in nucleoli. Furthermore, an engineered hybrid TPR-ALK protein can transform rodent fibroblasts and produce lymphomas in mice while remaining confined to the cytoplasm. We propose that the transforming action of ALK may not be reliant on its nucleolar localization, a hypothesis that may have implications for studies of other proteins involved in oncogenesis that are relocalized after the creation of fusion genes.

Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis.

The NPM-ALK fusion gene, formed by the t(2;5)(p23;q35) translocation in non-Hodgkin's lymphoma, encodes a 75-kDa hybrid protein that contains the amino-terminal 117 amino acid residues of the nucleolar phosphoprotein nucleophosmin (NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase ALK (anaplastic lymphoma kinase). Here, we demonstrate the transforming ability of NPM-ALK and show that oncogenesis by the chimeric protein requires the activation of its kinase function as a result of oligomerization mediated by the NPM segment. Sedimentation gradient experiments revealed that NPM-ALK forms in vivo multimeric complexes of approximately 200 kDa or greater that also contain normal NPM. Cell fractionation studies of the t(2;5) translocation-containing lymphoma cell line SUP-M2 showed NPM-ALK to be localized within both the cytoplasmic and nuclear compartments. Immunostaining performed with both polyclonal and monoclonal anti-ALK antibodies confirmed the dual location of the oncoprotein and also indicated that NPM-ALK is abundant within both the nucleoplasm and the nucleolus. An intact NPM segment is absolutely required for NPM-ALK-mediated oncogenesis, as indicated by our observation that three different NPM-ALK mutant proteins lacking nonoverlapping portions of the NPM segment were each unable to form complexes, lacked kinase activity in vivo, and failed to transform cells. However, NPM could be functionally replaced in the fusion protein with the portion of the unrelated translocated promoter region (TPR) protein that activates the TPR-MET fusion kinase by mediating dimerization through its leucine zipper motif. This engineered TPR-ALK hybrid protein, which transformed cells almost as efficiently as NPM-ALK, was localized solely within the cytoplasm of cells. These data indicate that the nuclear and nucleolar localization of NPM-ALK, which probably occur because of transport via the shuttling activity of NPM, is not required for oncogenesis. Further, the activation of the truncated ALK protein by a completely heterologous oligomerization domain suggests that the functionally important role of the NPM segment of NPM-ALK in transformation is restricted to the formation of kinase-active oligomers and does not involve the alteration of normal NPM functions.

Effect of tumour promoting agents on protein phosphorylation in human placenta.

1. The effects of okadaic acid (OA) and phorbol-12-myristate-13-acetate (PMA) on protein phosphorylation were studied in human term placentas. 2. When samples treated with tumour promoters were compared with untreated samples, the phosphorylation of a 135 kDa protein was significantly decreased; OA also produced a decrease in phosphorylation of a 24 kDa protein. 3. Both substances produced an alteration in the proportions of bands of masses 170, 65 and 24 kDa, relative to total phosphorylation; PMA treatment also affected the band of mass 135 kDa. 4. Placental cell extracts were also subjected to Western blotting with a protein kinase C (PKC) antibody, reportedly specific for the alpha- and beta-isoforms. 5. Two immunoreactive proteins were detected; an 80 kDa band, presumably corresponding to the alpha- or beta-PKC, and a 64 kDa protein, which could be a degradation production of the 80 kDa protein or it could correspond to another form of the enzyme. The expression of PKC did not change on treatment with PMA.

[Comments on the problem of splitting in anorectic patients]. / Bemerkungen über das Problem der Spaltung bei anorektischen Patientinnen.

The increasing number of hospitalizations of anorectic patients requires the staffs understanding for one of the most difficult problems here: the common strategy. It's failure is interpreted as a counter-transference of the patients inner processes. There are multiple factors of intra- and inter-psychic splitting, which lead to a heightened tendency of social manipulations.