Analysis of the NSQIP experience with hepatectomy indicates that the current mortality and major morbidity rate benchmarks are 2.5% and 19.6%, respectively. Poor outcomes were associated with nutritional status, liver function and the extent of hepatectomy. The NSQIP general surgery morbprob and mortprob values were relatively poor predictors of post-hepatectomy observed morbidity, indicating the need for specialty-specific NSQIP modelling.
When activated, the serine/threonine kinase AKT mediates an antiapoptotic signal implicated in chemoresistance of various cancers. The mechanism(s) of AKT activation are unknown, though overexpression of HER-2/neu has been implicated in breast cancer. Therefore, we determined the incidence of activated AKT in human pancreatic cancer, whether HER-2/neu is involved in AKT activation, and if AKT activation is associated with biologic behaviour. HER-2/neu expression and AKT activation were examined in seven pancreatic cancer cell lines by Western blotting. The in vitro effect of HER-2/neu inhibition on AKT activation was similarly determined. Finally, 78 pancreatic cancer specimens were examined for AKT activation and HER-2/neu overexpression, and correlated with the clinical prognostic variable of histologic grade. HER-2/neu was overexpressed in two of seven cell lines; these two cell lines demonstrated the highest level of AKT activation. Inhibition of HER-2/neu reduced AKT activation in vitro. AKT was activated in 46 out of 78 (59%) of the pancreatic cancers; HER-2/neu overexpression correlated with AKT activation (P ¼ 0.015). Furthermore, AKT activation was correlated with higher histologic tumour grade (P ¼ 0.047). Thus, it is concluded that AKT is frequently activated in pancreatic cancer; this antiapoptotic signal may be mediated by HER-2/neu overexpression. AKT activation is associated with tumour grade, an important prognostic factor.
Activation of the serine/threonine kinase AKT is common in pancreatic cancer; inhibition of which sensitises cells to the apoptotic effect of chemotherapy. Of the various downstream targets of AKT, we examined activation of the NF-kB transcription factor and subsequent transcriptional regulation of BCL-2 gene family in pancreatic cancer cells. Inhibition of either phosphatidylinositol-3 kinase or AKT led to a decreased protein level of the antiapoptotic gene BCL-2 and an increased protein level of the proapoptotic gene BAX. Furthermore, inhibition of AKT decreased the function of NF-kB, which is capable of transcriptional regulation of the BCL-2 gene. Inhibiting this pathway had little effect on the basal level of apoptosis in pancreatic cancer cells, but increased the apoptotic effect of chemotherapy. The antiapoptotic effect of AKT activation in pancreatic cancer cells may involve transcriptional induction of a profile of BCL-2 proteins that confer resistance to apoptosis; alteration of this balance allows sensitisation to the apoptotic effect of chemotherapy.
Diverse signaling pathways variably regulate BCL-2 gene expression in a cell type-specific fashion. Therapy to decrease BCL-2 levels in various human cancers would be more broadly applicable if targeted to transcriptional activation rather than signal transduction cascades. Finally, the apoptotic efficacy of proteasome inhibition with bortezomib paralleled the ability to inhibit NF-kappaB activity and decrease BCL-2 levels.
Poor prognostic features of rectal carcinoids include: large size, deep invasion, LVI, and elevated mitotic rate. The CaRRS score incorporates these features and accurately predicts outcome. Because the CaRRS score is based upon values available on pre-operative biopsy, it can identify patients with very favorable prognosis as well as those with poor prognosis that may benefit from additional staging or surveillance.
Bile duct injury (BDI) after laparoscopic cholecystectomy (LC) remains a significant surgical challenge. Despite claims to the contrary, the incidence of bile duct injury has remained elevated since the introduction of LC. Several issues regarding the surgical management of BDI are controversial, including: (i) identification of the surgeon and centre most capable of managing the injury, (ii) timing of surgical repair, (iii) incidence and significance of associated vascular injury and (iv) identification of patient factors which significantly impact outcome after repair. Variability in timing of referral of BDI to tertiary centres has been noted in the literature. The impact of timing of referral upon post-operative outcomes after definitive surgery has yet to be clearly investigated. We report our experience with 44 patients who required reconstructive surgery after BDI. In contrast to the many studies available in the literature, patients in the current study were classified according to a modern injury classification system. Additionally, we examined the impact of delayed referral to our centre on short- and long-term outcomes after surgical repair of BDI.
Desmoplastic small round blue cell tumors (DSRCTs) originate from a cell with multilineage potential. A molecular hallmark of DSRCT is the EWS-WT1 reciprocal translocation. Ewing sarcoma and DSRCT are treated similarly due to similar oncogene activation pathways, and DSRCT has been represented in very limited numbers in sarcoma studies. Despite aggressive therapy, median survival ranges from 17 to 25 months, and 5-year survival rates remain around 15%, with higher survival reported among those undergoing removal of at least 90% of tumor in the absence of extraperitoneal metastasis. Almost 100% of these tumors contain t(11;22) (p13;q12) translocation, and it is likely that EWS-WT1 functions as a transcription factor possibly through WT1 targets. While there is no standard protocol for this aggressive disease, treatment usually includes the neoadjuvant HD P6 regimen (high-dose cyclophosphamide, doxorubicin, and vincristine (HD-CAV) alternating with ifosfamide and etoposide (IE) chemotherapy combined with aggressively attempted R0 resection). We aimed to review the molecular characteristics of DSRCTs to explore therapeutic opportunities for this extremely rare and aggressive cancer type.
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