A comparison between patients with gastrointestinal stromal tumours diagnosed with isolated liver metastases and liver metastases plus sarcomatosis.

OBJECTIVES: This study was conducted to compare overall survival (OS) in patients presenting with isolated hepatic metastases with that of patients with synchronous metastatic disease to the liver and sarcomatosis on a background of gastrointestinal stromal tumours (GISTs). METHODS: Patients presenting with metastatic GISTs during 1999-2009 were identified. Survival outcomes were compared between groups. RESULTS: Of the 193 patients with GISTs, 43 patients presented with isolated hepatic metastases and 16 presented with synchronous metastases to the liver and sarcomatosis. Thirteen patients with metastases to the liver and sarcomatosis underwent surgery, and 34 patients with metastatic disease solely to the liver underwent hepatic resection. The proportion of patients treated with preoperative tyrosine kinase inhibitor (TKI) therapy was similar in both groups. Similar OS was observed in both groups (isolated liver metastases group: 40.5 months; liver metastases and sarcomatosis group: 28.7 months; P = 0.620). CONCLUSIONS: Overall survival in patients with GIST and metastatic disease to the liver and sarcomatosis is similar to that in patients with isolated metastatic liver disease. Although patients with a greater disease burden might be expected to show worse survival, these data do not reflect this assumption.

Quantitative measures of visceral adiposity and body mass index in predicting rectal cancer outcomes after neoadjuvant chemoradiation.

BACKGROUND: The association between body mass index as a measure of obesity and rectal cancer outcomes has been inconsistent. Radiologic measures of visceral adiposity using CT scans have not been well characterized among rectal cancer patients. The objective of this study was to examine quantitative radiologic measures of visceral obesity compared with body mass index in predicting patient outcomes among patients undergoing neoadjuvant chemoradiation and resection for locally advanced rectal cancers. STUDY DESIGN: We identified 99 rectal adenocarcinoma patients treated with neoadjuvant chemoradiation and surgical resection. Visceral and subcutaneous fat areas, as well as perinephric fat thickness (PNF), were recorded and categorized as obese (body mass index ≥30, visceral fat area to subcutaneous fat area ratio [V/S] ≥0.4, or median PNF). The Kaplan-Meier method, log-rank test, and Cox proportional hazards models evaluated overall and disease-free survival differences by adiposity. RESULTS: Viscerally obese rectal cancer patients (V/S >0.4 or PNF) were more likely to be older, male, and have pre-existing obesity-related conditions (eg, diabetes, hypertension, and/or hypercholesterolemia). Elevated V/S or PNF was associated with shorter disease-free survival (p = 0.02) or overall survival time (p = 0.047), respectively. Among patients with well to moderately differentiated tumors, visceral obesity was associated with poorer disease-free survival (V/S >0.4: adjusted hazard ratio = 5.0; 95% CI, 1.2-22.0). CONCLUSIONS: Visceral fat area to subcutaneous fat area ratio and PNF were strongly associated with key preoperative metabolic comorbidities, and body mass index was not. Findings suggests that elevated visceral adiposity was associated with an increased risk of recurrence, which was most evident among patients with well to moderately differentiated tumors and those with incomplete response to neoadjuvant chemoradiation treatment. Quantitative measures of visceral adiposity warrant large-scale prospective evaluation.

The role of radical amputations for extremity tumors: a single institution experience and review of the literature.

BACKGROUND: Major amputations are indicated for advanced tumors when limb-preservation techniques have been exhausted. Radical surgery can result in significant palliation and possible cure. METHODS: We identified 40 patients who underwent forequarter (FQ) or hindquarter (HQ) amputations between May 2000 and January 2011. Patient demographics, tumor-related factors, and outcomes were reviewed. RESULTS: There were 30 FQ and 10 HQ amputations. The most common diagnoses were sarcoma (55%) and squamous cell carcinoma (25%). Patients presented with primary tumors (35%), regional recurrence (57.5%), or unresectable limb metastatic disease (7.5%). Presenting symptoms included fungating wounds (35%), intractable pain (78%), and limb dysfunction (65%). Operations were performed with curative intent (10%), curative/palliative intent (70%), or palliation alone (20%). Wound complications occurred in 35%. Pain was improved in 78% of patients following surgery. Despite a 91% negative margin rate, 79% of patients recurred either locally or distantly. Median overall survival was 10.9, 13.2, and 3.4 months in the curative, curative/palliative, and palliative groups, respectively. CONCLUSIONS: In the absence of conservative options, major amputations are indicated for the management of advanced tumors. These operations can be performed safely, resulting in effective palliation of debilitating symptoms. While recurrence rates remain high, some patients can achieve prolonged survival.

The role of Akt activation in the response to chemotherapy in pancreatic cancer.

UNLABELLED: The PI3K/Akt signaling pathway is constitutively activated in some pancreatic cancers; when activated, it inhibits chemotherapy-mediated apoptosis. We examined whether Akt activity correlates with apoptotic resistance to chemotherapy in pancreatic cancer. MATERIALS AND METHODS: A panel of human pancreatic cancer cells was evaluated for basal Akt activity as well as response to three chemotherapies. Chemotherapy-induced cell death was evaluated following either up- or down-regulation of Akt activity. Evaluation of phosphorylation of p21Cip/Waf1, a downstream target of Akt, was also evaluated. RESULTS: There was a broad distribution among pancreatic cancer cell lines by Akt activity, as well as sensitivity to the three chemotherapeutic agents with no apparent correlation. Phosphorylation of p21Cip/Waf1, but not change in total levels, correlated with the chemosensitizing effect of Akt inhibition to paclitaxel. CONCLUSIONS: Basal Akt activity does not appear to be a useful predictor for selection of pancreatic cancers in targeting Akt to broadly induce chemosensitivity.

Surgical management of neurofibromatosis.

Neurofibromatoses are a complex set of genetic diseases with a wide spectrum of clinical manifestations. Life-threatening complications may develop as the result of tumor progression. Surgical intervention is the only effective means of treatment for progressive pain, disfigurement, functional compromise, and malignancy. In the future, molecular advances should allow for the development of targeted therapies to treat patients who have neurofibromatosis in addition to those who have sporadic tumors. Tumor profiling should allow us to guide therapies and predict responses.

Preoperative evaluation of pancreatic adenocarcinoma.

The preoperative evaluation of resectability for pancreatic cancer fails to identify up to 25% of patients who are unfortunately found to be unresectable at surgical exploration. Inoperative findings in this circumstance is usually due to either small volume metastatic disease or regional tumor invasion. While advances in computed tomography (CT) technology has increased accuracy of local tumor extent, occult metastatic disease remains a common problem. Although 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been demonstrated to be useful in the staging of many malignancies (e.g. esophageal cancer, recurrent colorectal cancer, lung cancer), it has not been found to significantly increase the accuracy of determining resectability preoperatively in pancreatic cancer, especially with regard to detection of small volume metastatic disease. There are a variety of pancreatic cancer-specific antigens which are being developed as a method for targeted molecular imaging; we provide preliminary data targeting the integrin alpha(v)beta(6) to demonstrate the potential feasibility of this approach. Further developments may allow the accurate determination of patients with resectable pancreatic cancer, and more importantly, those with unresectable disease that may forego unnecessary surgery, the associated morbidity, and the subsequent delay of appropriate therapy.

Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase.

Eukaryotic cells can synthesize the non-essential amino acid arginine from aspartate and citrulline using the enzyme argininosuccinate synthetase (ASS). It has been observed that ASS is underexpressed in various types of cancers ASS, for which arginine become auxotrophic. Arginine deiminase (ADI) is a prokaryotic enzyme that metabolizes arginine to citrulline and has been found to inhibit melanoma and hepatoma cancer cells deficient of ASS. We tested the hypothesis that pancreatic cancers have low ASS expression and therefore arginine deprivation by ADI will inhibit cell growth. ASS expression was examined in 47 malignant and 20 non-neoplastic pancreatic tissues as well as a panel of human pancreatic cancer cell lines. Arginine deprivation was achieved by treatment with a recombinant form of ADI formulated with polyethylene glycol (PEG-ADI). Effects on caspase activation, cell growth and cell death were examined. Furthermore, the effect of PEG-ADI on the in vivo growth of pancreatic xenografts was examined. Eighty-seven percent of the tumors lacked ASS expression; 5 of 7 cell lines similarly lacked ASS expression. PEG-ADI specifically inhibited growth of those cell lines lacking ASS. PEG-ADI treatment induced caspase activation and induction of apoptosis. PEG-ADI was well tolerated in mice despite complete elimination of plasma arginine; tumor growth was inhibited by approximately 50%. Reduced expression of ASS occurs in pancreatic cancer and predicts sensitivity to arginine deprivation achieved by PEG-ADI treatment. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of pancreatic cancer, a malignancy in which new therapy is desperately needed.