Contemporary management and classification of hepatic leiomyosarcoma.

BACKGROUND: Hepatic leiomyosarcomas are rare soft-tissue tumours. The majority of lesions previously considered as leiomyosarcomas have been identified as gastrointestinal stromal tumours (GISTs). Consequently, understanding of the role of liver resection for true leiomyosarcoma is limited, a fact that is exacerbated by the increasing recognition of leiomyosarcoma subtypes. This study presents data on the outcomes of liver resection for leiomyosarcoma and suggests an algorithm for its pathological assessment and treatment. METHODS: Patients were identified from a prospectively collected departmental database. All tumours were negative for c-kit expression. Immunohistochemistry was performed to identify the presence of oestrogen or progesterone receptor (OR/PR) expression or Epstein-Barr virus (EBV) and patients were stratified according to this profile. RESULTS: Eight patients (of whom seven were female) underwent a total of 11 liver resections over a 12-year period. One patient had a primary hepatic leiomyosarcoma. Of those with metastatic leiomyosarcomas, the primary tumours were located in the mesentery, gynaecological organs and retroperitoneum in four, two and one patient, respectively. Both leiomyosarcomas of gynaecological origin stained positive for OR/PR expression. One patient had previously undergone renal transplantation; this leiomyosarcoma was associated with EBV expression. Median survival was 56 months (range: 22-132 months) and eight, six and four patients remained alive at 1, 3 and 5 years, respectively. CONCLUSIONS: Hepatic resection for leiomyosarcoma is associated with encouraging rates of 5-year overall and disease-free survival. The worse outcome that had been expected based on data derived from historical cohorts (partly comprising subjects with GIST) was not observed. An algorithm for pathological classification and treatment is suggested.

Elevated pre-operative neutrophil to lymphocyte ratio predicts disease free survival following pancreatic resection for periampullary carcinomas.

BACKGROUND: The pre-operative neutrophil-to-lymphocyte ratio (NLR), when ≥5 has been associated with reduced survival for patients with various gastrointestinal tract cancers, however, it's prognostic value in patients with periampullary tumour has not been reported to date. OBJECTIVES: To determine the prognostic value of pre-operative NLR in terms of survival and recurrence of resected periampullary carcinomas. METHODS: This was a retrospective cohort study of consecutive patients undergoing pancreatoduodenectomy (PD) for periampullary carcinoma (pancreatic, ampullary, cholangiocarcinoma) identified from a departmental database. The effect of NLR upon survival and recurrence was explored. RESULTS: Overall median survival amongst 228 patients was 24 months (inter-quartile range [IQR]: 12-43). The median survival for those whose NLR was <5 was not significantly greater than those patients whose NLR was ≥5 (24 months [IQR: 14-42] versus 13 months [IQR: 8-48], respectively; p = 0.234). However, for those that developed recurrence, survival was greater in those with an NLR <5 at (20 months [IQR: 12-27] versus 11 months [IQR: 7-22], respectively; p = 0.038). This effect was most marked in those patients with cholangiocarcinoma (p = 0.019) whilst a trend to worse survival was seen in those with pancreatic adenocarcinoma. No effect was seen in patients with ampullary carcinoma (p = 0.516). CONCLUSIONS: This study provides further evidence that pre-operative NLR offers important prognostic information regarding disease-free survival. This effect, however, is dependent upon the tumour type amongst patients undergoing PD.

Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury.

Renal ischemia reperfusion (IR) injury leads to significant patient morbidity and mortality, and its amelioration is an urgent unmet clinical need. Succinate accumulates during ischemia and its oxidation by the mitochondrial enzyme succinate dehydrogenase (SDH) drives the ROS production that underlies IR injury. Consequently, compounds that inhibit SDH may have therapeutic potential against renal IR injury. Among these, the competitive SDH inhibitor malonate, administered as a cell-permeable malonate ester prodrug, has shown promise in models of cardiac IR injury, but the efficacy of malonate ester prodrugs against renal IR injury have not been investigated. Here we show that succinate accumulates during ischemia in mouse, pig and human models of renal IR injury, and that its rapid oxidation by SDH upon reperfusion drives IR injury. We then show that the malonate ester prodrug, dimethyl malonate (DMM), can ameliorate renal IR injury when administered at reperfusion but not prior to ischemia in the mouse. Finally, we show that another malonate ester prodrug, diacetoxymethyl malonate (MAM), is more potent than DMM because of its faster esterase hydrolysis. Our data show that the mitochondrial mechanisms of renal IR injury are conserved in the mouse, pig and human and that inhibition of SDH by 'tuned' malonate ester prodrugs, such as MAM, is a promising therapeutic strategy in the treatment of clinical renal IR injury.